エナンチオ選択的反応に用いる新規ハイブリッド型
スクアラミドアミノアルコール有機分子触媒の開発
メタデータ

言語: English
出版者:
公開日: 2018-06-06
キーワード (Ja):
キーワード (En):作成者: MADHU, Chennapuram
メールアドレス:所属:

URL

https://doi.org/10.15118/00009640

THE DEVELOPMENT OF NEW HYBRID TYPESQUARAMIDE FUSED AMINO ALCOHOLORGANOCATALYSTS
FOR ENANTIOSELECTIVE REACTIONS
ThesisSubmitted in partial fulfillment of the requirements
for the degree of
DOCTOR OF PHILOSOPHY
byMr. Madhu Chennapuram
Supervisor
Professor Hiroto Nakano

DEPARTMENT OF APPLIED SCIENCESGRADUATE SCHOOL OF ENGINEERINGMURORAN INSTITUTE OF TECHNOLOGYMURORAN, JAPAN2017

Madhu Chennapuram

博士論文申請者：工学専攻先端環境創生工学コース：（マデュー チェンアプラム）
博 士 論 文 題 目 ： The Development of New Hybrid Type Sqauaramide Fused
Amino Alcohol Organocatalysts for Enantioselective Reactions

論文内容要旨医薬品を含む多くの生物活性化合物は光学活性物質であり, その鏡像異性体は異なる生体内活性を示すことが多いため, 有効な一方の鏡像異性体を高選択的に合成するための不斉合成反応の開発が重要である. ごく少量の不斉分子によって触媒化される触媒的不斉合成反応の開発は省エネルギーや環境調和の観点から有機合成化学領域の最も重要な研究課題の一つであり, 金属を含有しない有機分子触媒は空気中で安定であり取り扱いやすく安価であるという利点なども有するため, 次世代の環境調和型触媒として現在活発に研究開発が行なわれている.
著者は, 新規多点認識型有機分子触媒としてアミノアルコールとスクアラミドが融合した
ハイブリッド型触媒（SFAA 触媒）を設計し, それを, エナンチオ選択的 (1) イサチン類とニトロアルケン類との不斉ニトロアルドール反応，(2) 3-ヒドロキシ-2-ピリドン類とマレイミド
類との塩基触媒不斉ディールス・アルダー (DA) 付加環化反応, さらに (3) インダノン類と
1,3-ジカルボニル類とのドミノマイケル付加環化反応にそれぞれ適用し，その有機分子触媒としての機能性を検討した.
(1) SFAA 有機分子触媒 A を合成し, 触媒 A を用いるイサチン類とニトロアルカン類との不斉ニトロアルドール反応を検討した．その結果, 触媒 A が不斉触媒活性を示し, 本反応によって優れた化学収率と良好な光学収率で光学活性オキシインドール誘導体を与えることを見出した. 得られるオキシインドール誘導体は，抗癌作用を持つドナキサリジン誘導体などの有用な合成中間体である．
(2) SFAA 有機分子触媒 A を用いる 3-ヒドロキシ-2-ピリドン類とマレイミド類との不斉ディールス・アルダー反応を検討した．その結果，触媒 A が不斉触媒活性を示し, 本反応によってほぼ完全な化学収率と優れた光学収率で光学活性イソキヌクリジン誘導体が得られることを見出した。得られるイソキヌクリジン誘導体は，タミフルなどの抗ウイルス活性化合物の有用な合成中間体である．
(3) SFAA 有機分子触媒 A を用いるインダノン類と 1,3-ジカルボニル類との不斉ドミノマイ
ケル付加環化反応を検討した．その結果，触媒 A が不斉触媒活性を示し, 本反応によってほぼ完全な化学収率と優れた光学収率で光学活性スピロ-2-アミノピラン類が得られることを見出した。得られるスピロ-2-アミノピラン誘導体は，寄生原虫病であるリーシュマニア症に有効な化合物を合成するための有用な合成中間体である．
本研究において著者は, その分子中に「基質との 3 点の水素結合部位と１点の塩基性部位を併せ持つ多点認識機能を持つアミノアルコール-スクアラミドハイブリッド型触媒 (SFAA触媒)」を開発することに成功し, それらが創薬に有効な不斉ニトロアルドール反応，不斉ディールス・アルダー付加環化反応および不斉ドミノマイケル付加環化反応においてそれぞれ良好な不斉触媒活性を示すことを明らかにした. また，本反応によって得られる化合物は
様々な医薬品をはじめとする生物活性化合物の合成中間体として有用であることから，本研究の成果は, 新薬創製の合成開発研究に大きく貢献できると期待される.

Madhu Chennapuram（マデュー チェンアプラム）

博士論文申請者：工学専攻先端環境創生工学コース：

博士論文題目：The Development of New Hybrid Type Sqauaramide Fused Amino Alcohol
Organocatalysts for Enantioselective Reactions

Research summary
Many biologically active compounds, including pharmaceuticals, are optically active. Often, only one of
the enantiomers is required because the enantiomers display different in vivo activities. In pharmaceuticals
in particular, differences in the absolute configuration can affect not only the pharmacological activity but
also the toxicity. Catalytic asymmetric synthesis, in which a low amount of a chiral molecular catalyst
theoretically enables infinite production of an optically active compounds, is among the most importantcurrent challenges in organic synthetic chemistry; it is also important in terms of energy saving andenvironmental friendliness. Environmental effects now have to be considered in chemical syntheses, andenvironmentally benign organic syntheses have been receiving attention. The chiral catalysts used in
catalytic asymmetric syntheses can be divided into two categories: organometallic catalysts and metal-freechiral organocatalysts. Particularly, organocatalysts are stable in air, easy to handle, and inexpensive, sothey are being focused on as next-generation, environmentally friendly catalysts.
On these backgrounds, author aimed to develop the new hybrid type squaramide fused amino alcohol(SFAA) organocatalysts. This SFAA organocatalyst was successfully prepared from commercially available
amino esters by using simple organic transformations and the catalytic activity were demonstrated in theenantioselective (1) nitroaldol, (2) Diels-Alder and (3) domino Michael addition cyclization reactions.
(1) The enantioselective nitroaldol reaction was established with various isatins and nitromethanes using
SFAA organocatalysts. This protocol provides chiral 3-substituted 3-hydroxyoxindoles in excellent
chemical yields and high enantioselectivities. The obtained 3-substituted 3-hydroxyoxindoles are important
synthetic precursors for many biological active and natural compounds such as donaxaridine (anti-cancerdrug).
(2) The enantioselective Diels-Alder reaction was established with 3-hydroxy-2-pyridones and maleimides
using SFAA organocatalysts. This protocol provides the chiral 4-hydroxyisoquinnuclidines in both excellent
chemical yields and enantioselectivities. The obtained chiral 4-hydroxyisoquinnuclidines are synthetic
intermediates for many biological active compounds such as oseltamivir phosphate (anti-influenza drug).
(3) The enantioselective domino Michael addition cyclization reaction was established with 3-dicyano-2indanones and 1,3-cyclic carbonyl compounds using SFAA organocatalysts. This protocol provides thechiral spiro-conjugated 2-aminopyrans in both excellent chemical yields and enantioselectivities. The
obtained chiral spiro-conjugated 2-aminopyrans are significant synthetic intermediates for many biologicalcompounds such as 2-amino-tetrahydrochromene (anti-leishmaniasis).
In this study, author revealed that the new explored new hybrid type squaramide fused amino alcohol(SFAA) organocatalyst having both three hydro-bonding sites and a basic site in the compound with asubstrate shows satisfactory catalytic activity in the enantioselective (1) nitroaldol, (2) Diels-Alder and (3)domino Michael addition cyclization reactions. It is expected that this result might be able to greatly
contribute the development of new drug and its related compounds.

Contents
Chapter 1
Introduction

1

1.2 Catalysis

2

1.3 Chirality

3

1.4 Asymmetric synthesis and its importance3

1.5 Advantages of organocatalysis

4

1.6 Covalent modes of activation

5

1.7 Non-covalent modes of activation

6

1.8 b-Amino alcohol organocatalysts in asymmetric synthesis

8

1.9 Recent progress in squaramide organocatalysis

9

1.10 Structural judgment of thioureas between squaramides

11

1.11 General preparation method for squaramide organocatalysts

11

1.11 Binding modes of squaramido motif with different substrates

12

1.12 Author strategy

13

Chapter 2
New Hybrid Type Squaramide Fused Amino Alcohol Organocatalysts For Enantioselective
Nitro-Aldol Reaction of Nitromethnae with Isatins17

2.1 Introduction

18

2.2 Mechanism

19

2.3 Stereochemical course of the nitro-aldol reaction

19

2.4 Limitation of the nitro-aldol reaction

20

2.5 The enantioselective nitro-aldol reaction of isatins with nitroalkanes

21

2.6 Author strategy

26

2.7 Results and discussions

27

2.7.1 Synthesis of usual type squaramide fused amino alcohol organocatalysts

28

2.7.2 Synthesis of new hybrid type squaramide fused amino alcohol organocatalysts

29

2.7.3 The nitro-aldol reaction of isatin with nitromethane using catalysts 21a-d

31

2.7.4 Nitro-aldol reaction using catalysts 29a-e

32

2.7.5 Optimization of nitro-aldol reaction conditions using catalyst 29c

33

2.7.6 Substrate scope for enantioselective nitro-aldol reaction using catalyst 29c

35

2.7.7 Mechanistic investigation of nitromethane and isatin with squaramido unit

36

2.8 Summary

39

Chapter 3
New Hybrid Type Squaramide Fused Amino Alcohol Organocatalysts For Enantioselective
Diels-Alder Reaction of 3-Hydroxy-2-Pyridones with Maleimides

41

3.1 Introduction

42

3.1.1 Mechanism of Diels-Alder reaction

43

3.1.2 Regioselectivity of Diels-Alder reaction

44

3.1.3 Stereoselectivity in Diels-Alder reaction

45

3.1.4 The diene45

3.1.5 The dienophile

46

3.1.7 Intramolecular hetero Diels-Alder (IMHDA) reaction

48

3.1.8 Intermolecular aza-Diels-Alder reaction

49

3.1.9 Oxo-Diels-Alder reaction50

3.1.10 Thio-Diels-Alder reaction

51

3.1.11 Amino alcohol catalyzed enantioselective Diels-Alder reaction

51

3.2 Base catalyzed Diels-Alder reactions

52

3.3 Previous reports on enantioselective Diels-Alder reaction of 3-hydroxy-2-pyridone withelectron withdrawing dienophiles

54

3.4 Author strategy

57

3.4.1 Results and discussions

58

3.4.2 Enantioselective Diels-Alder reaction using catalyst 29a-e

60

3.4.3 Optimization of DA reaction conditions using catalysts 29a61

3.4.4 Substrate scope for enantioselective DA reaction using catalyst 29a63

3.4.5 Enantioselective DA reaction of substituted pyridones using catalyst 29a

64

3.4.6 Plausible reaction course of the 3-hydroxy-2-pyridones 96a with maleimide 97a using
catalysts 29a66

3.4.7 Plausible reaction course of the 4-bromo-3-hydroxy-2-pyridones 99a with maleimide 97a
using catalysts 29a67

3.5 Summary69

Chapter 4
The New Hybrid Type Squaramide Fused Amino Alcohol Organocatalysts For
Enantioselective Domino Michael Addition Cyclization Reaction70

4.1 Introduction

71

4.1.1 Appearance

71

4.1.2 UV spectroscopy of 2-aminopyrans

71

4.1.3 IR spectroscopy of 2-aminopyrans

72

4.1.4 NMR spectroscopy of 2-aminopyrans

72

4.1.5 Methods of synthesis

73

4.2 Synthesis of spiro-conjugated 2-aminopyrans

74

4.2.1 Synthesis of dispiro-dipyrano-benzoquinones

75

4.2.3 Synthesis of cyclophan 2-aminopyrans

76

4.2.4 Synthesis of spiro-homophthalimidepyrans

76

4.2.5 Synthesis of spiro-benzothiazolepyrans

77

4.3 Chemical properties of 2-aminopyrans

78

4.3.1 Photochemical contraction of pyran ring79

4.3.2 Synthesis of 2,4-disubstitued naphtholpyran

79

4.3.3 Synthesis of tacrine-like analogs from 2-aminopyran

80

4.3.4 Synthetic utility of 2-aminopyrans for dihydrofurans and 2-sufinylimine-chromenes 81
4.4 Previous report on enantioselective synthesis of spiro-conjugated 2-aminopyrans

83

4.5 Author strategy

85

4.5.1 Synthetic utility of chiral spiro-conjugated 2-aminopyrans

85

4.5.2 Results and discussions

86

4.5.3 The enantioselective Michael addition cyclization reaction using catalysts 29a-e

88

4.5.4 Optimization of Michael addition cyclization reaction using catalyst 29a90

4.5.5 Substrate scope for enantioselective domino Michael addition cyclization reaction 91
4.5.6 Plausible reaction course for domino Michael addition cyclization reaction

93

4.6 Summary95

5. Conclusion

96

6. Experimental section

98

7. Acknowledgements

128

8. References

129

Chapter 1
Introduction11.1 Introduction
The enantioselective organocatalysis is most important and well-explored area in syntheticorganic chemistry for synthesizing biological active chiral molecules. Because of its does not
involve any toxic metals or costly enzyme catalysts to carry out the stereoselective organic
reactions. From the last few years, organocatalysis leading explored into one of the mostbreathtaking and precipitously emerging area in synthetic organic chemistry.1,2 The
enantioselective synthesis provides a practical and cost-effective synthesis of chiral molecules, but
designing of simple and efficient synthetic strategies are interesting and often more challenging.
Author PhD objectives were to design and develop the new hybrid type squaramide fusedamino alcohol (SFAA) organocatalysts for asymmetric reactions. The new hybrid type SFAA
oragnocatalysts were developed and used in this thesis mainly concentrated on four sections (i)The development new hybrid type squaramide fused amino alcohol organocatalysts, (ii) Nitroaldol (Henry), (iii) Diels-Alder and (iv) Domino Michael addition cyclization reactions. The brief
discovery and applications of these enantioselective reactions are discussed in the following
sections.
1.2 Catalysis
The catalysis mainly classified in to three major parts, such as metal, enzyme andorganocatalysis. Currently, enantioselective organocatalysis is known as an independent synthetic
research area among enantioselective metallic catalysis and enzymatic catalysis for the synthesisof optically active compounds. Among the metal and enzyme catalysis, the organocatalysis gains
its own importance’s due to non-toxic, availability and easy to synthesis. They are mostly stable
under aerobic conditions, and the organocatalytic reactions do not require very dry conditions tocarry out the reactions.3

2

1.3 Chirality
According to Mislow,4 for chiral molecule the definitions is defined as follows "A molecule
may be chiral if it is non-identical to its mirror images" if it not obeys the above said definition
such compounds are known be achiral, the chirality concept can be also explained by following
way, our right and left hands are mirror images of each other, but cannot be superimposed on eachother when palms are fronting to the same direction. The below depicted generic chiral amino acidis able to exist as mirror images of each other. (Figure 1).

Figure 1. Two enantiomers of a generic amino acids
1.4 Asymmetric synthesis and its importance
Asymmetric synthesis as defined by Morrison and Mosher,5 is a chemical reaction in which
an achiral unit in a group of molecules is converted into a chiral unit, in such course of reaction
unequal amounts of stereoisomers are produced. For example, the (R)-thalidomide shows theactivity towards for morning sickness, while the (S)-thalidomide causes the embryo growth
restriction or death of embryo (Figure 2).

3

H O
O
HN

O

N

H
O

N

NH

O
O

O
O

(R)-Thalidomide(S)-Thalidomide

sedative for morning
sicknesscauses fetal defects

Figure 2. Biological role of thalidomide isomer
Ibuprofen is a nonsteroidal anti-inflammatory drug, in human body its functions as an
antipyretic and analgesic agent. Ibuprofen is commonly used for treatment of acute and chronic
pain, osteoarthritis, rheumatoid arthritis diseases. The pharmacokinetics of ibuprofen differs as thein form of R-(-)-ibuprofen and S-(+)-ibuprofen (Figure 3), in which the (S)-ibuprofen shows antiinflammatory activity while (R)-ibuprofen is found to be non-active.6
CH3

CH3
O

O

OH

OH

(R)-Ibuprofen(S)-Ibuprofen

non-activeside effects

biologically active

Figure 3. The biological role of ibuprofen isomers
1.5 Advantages of organocatalysis
The advantages of organocatalysis gains its own consideration when compared to metaland enzyme catalysis, because the catalysts are usually inexpensive and easy to synthesis andwidely available in a large number, suitable for small-scale to gram-scale reactions, additionallycatalysts are non-toxic and eco-friendly. By these own advantages of organocatalysts many
researchers are focused in development new class of catalysts for enantioselective reactions. For
example, the following organocatalysts are widely and well-studied in the field of syntheticorganic chemistry. (Figure 4).7

4

O
H2N
H3C

N
H
CH3

Ph

O

H
N

OH
CH3

O

Me

O

Me

O
Ph

L-Val-Gly-Ala
tripeptide organocatalysts

OH
Ph

BF4
N
N
N

CH3
CH3

NH2
OH

TADDOL (α,α,α',α',-tetraaryl-2-2disubstituted 1,3-dioxolane-4,5dimethanol

NH2
H3C

F3C
Ph
OH

NOBIN (2-amino-2'hydroxy-1-1'-binaphthyl)

O

N
H

N
H

Triazolium salts

BINOL(1-1'-bi-2-naphthol)N

Chiral diamine
squaramideorganocatalyst
O

OH
OH

CF3

Bn

(S)-Amino-3-methylbutane

F3C

O

N
Bn

N
H

CH3
CH3
CH3
CH3

MacMillan Imidazolidinone
2nd generation organocatalyst

Figure 4. Widely used organocatalysts in asymmetric synthesis
1.6 Covalent modes of activation
In covalent modes of activation iminium and enamine catalysis are well studied inenantioselective synthesis. The iminium catalysis involves the condensation of a secondary aminewith an electrophilic carbonyl containing as substructure, which generates the electrophilic
iminium cation species which are attacked by appropriate nucleophiles to form a chiral product(Scheme 1).8 Regarding to enamine catalysis is one of the very examined exploration study in thearea of enantioselective catalysis. Enamine activation perception is as follows the reversible
condensation of an amine catalyst of electron deficient carbonyl compounds to form an iminium
intermediate that, upon tautomerization to generate the enamine reactive species which is reacts
with an available electrophile.

5

N

N
R

R'
R

iminium species

enamine species

N
H

O
R

R'

catalyst

N
H

O

N
H

R'

R

R

N

N

catalyst
R

R

Nu
E
O
R

Nu
O

* R'
H

* E
R

Scheme 1. Covalent modes of activation
As an example of covalent modes of activation (S)-proline, b-amino alcohols and imidazolidinone
catalysts (Figure 5) are well explored in enantioselective synthesis.9

N
H

O

R

OH

H2N

(S)-Proline

Ph
Ph
OH

β-Amino alcohols

O

Me
N

Ph

N
H

Me
Me

Imidazolidinone

Figure 5. Covalent type organocatalysts
1.7 Non-covalent modes of activation
In non-covalent modes of activation usually hydrogen bond-donor catalysis plays aprimitive role for activation of substrates, which is a well explored research area in enantioselective
catalysis. Among them, non-covalent modes of activation squaramide and thiourea basedorganocatalysts are well studied.10 The squaramide catalyst usually forms a multiple hydrogenbonding’s mode with the substrates (mainly electron deficient conjugated ketones) which allows
an electrophilic site to attack an appropriate nucleophile on it to which subsequently affords thechiral products (Scheme 2).

6

O

O

N
H

N
H
O

R

O
O

N
H

R

R'

O
O

N
H

N
H

O

N
H

catalyst

R'

O

Nu

R
R' * Nu

O
R
R'

Scheme 2. Non-covalent modes of activation
The chiral phosphoric acids, phase transfer catalyst and cinchona based squaramide catalysts arewell explored in field of non-covalent organocatalysts (Figure 6).
CF3

CF3

R

F3C

O

O

N
H

HN

H

O O
P
O OH

N
CF3

F3C

Br
R

N
OMe
N

CF3
Chiral phosphoric acids

Phase transfer catalyst

Figure 6. Non-covalent type organocatalysts

7

Cinchona based squaramide1.8 b-Amino alcohol organocatalysis in asymmetric synthesis
The simple b-amino alcohols and their derivatives can be easily prepared in a single-stepfrom their related compounds such as accessible amino acids. These chiral precursors could beserves as an independent chiral catalyst in enantioselective organocatalysis.11 There are many
benefits of using simple primary b-amino alcohols as new class of organocatalysts, such as easy
to prepare, stability on air/water, and which can be used as both covalent (iminium) and noncovalent (hydrogen bonding donor) interactions.
R
R
H2N

O
OH

R
SOCl2
MeOH

amino acids

O

PhMgBrH2N

O
HClamino acid
ester salts

H2N

stericinfluence

Ph
Ph
OH

Ether, 0° C
basic sitehydrogenbonding site
functionality of β-amino
alcohol organocatalysts

Scheme 3. Preparation method for b-amino alcohols
The b-amino alcohols can be easily prepared from corresponding amino acids ester salts using
simple organic transformation (Scheme 3). The simple primary b-amino alcohols can be easily
derived in to a di amino alcohol, aza-norbornane type amino alcohol and silyl protected amino
alcohol as organocatalysts. By introducing new functional groups on amino alcohol catalyst, there
might be possibility in increasing the enantiomeric phase of catalysts. The primary b-amino
alcohols and their derivatives successfully showed the catalytic activity in important asymmetric
reaction such as Diels-Alder and 1,3-dipolar cycloadditions, Aldol and cross-aldol reactions toafford the valuable chiral biological synthetic intermediates in satisfactory chemical yields andenantioselectively (Scheme 4).12

8

CO2R'NR

CHO
chiralisoquinuclidines
up to 96%, up to 98% ee

N
HO

Ph
Ph
OH

H2N

OH

di amino
alcohol organocatalysts

ON
Hchiral oxindoles

cross-Aldol
reactionPh
PhOH
Diels-Alder H2Nreaction
β-amino alcoholorganocatalyst

TTMSSO
H2N

Ph
Ph
OH

silyl protectedamino alcoholorganocatalyst

β-amino alcohols
in asymmetric synthesis

1,3 dipolar
cycloaddition

up to 95%, up to 92% ee
Ph
Ph
OH

Aldol
reaction

R
N O
R''

R'

CHO
chiral isoxazolidines
up to 83%, up to 97% eeNHaza-norbornane typeamino alcoholorganocatalyst
O

HO
O
N
H
chiral oxindoles
up to 82, up to 64% ee

Scheme 4. The b-amino alcohol organocatalysts for enantioselective reactions
1.9 Recent progress in squaramide organocatalysis
The first example bearing squaramide unit in enantioselective synthesis was described by13
W. Xie and his research is for the enantioselective reduction of pro-chiral ketones which stood bywith borane dimethyl sulfide in the presence of chiral squaramide amino alcohols catalyst (Scheme5), to afforded chiral secondary alcohols in excellent enantioselectivities (99 % ee).
H
N
OH

O

O

O

BH3 Me2S (1.2 equiv)
catalyst (0.2 mol %)

O
R

R'

THF, 0 °C

HO

H

R
R'
35-99% ee

n-Bu

Scheme 5. Bicyclic amino alcohol squaramide organocatalysts for reduction of prochiral ketones

9V. H. Rawal and his research group demonstrated cinchona based squaramide catalyst in
enantioselective Michael reaction with active C-H functions of nitroalkenes, which afforded
anticipated Michael products in both satisfactory chemical yields and enantiomeric excess(Scheme 6).14
O

H

O

O

N

F3C

N
H

HN

H

organocatalyst(0.1 - 2 mol %)

O

R

+

R''

R'''

NO2

R'

CF3

N

cinchona based squaramideorganocatalysis

DCM, rt

O

R'

O

R3
R'''

activated
methylenes

R''
NO2

65-98% yield
77 - 99% ee
1:1 - 50:1 d.r.

nitroalkenes

Scheme 6. Cinchona based squaramide organocatalysts for Michael addition reaction
Furthermore, V. H. Rawal and his research group15 has also reported the enantioselective
Friedel-Craft reaction of indoles with arylsulfonylimines using with cyclohexyl amine derived
squaramide organocatalyst (Scheme 7). The organocatalysts was afforded the indolylsulfonamides, in good excellent chemical yield (up to 96%) and in excellent enantioselectivities(up to 96% ee).
F3C

O

O

organocatalyst(2.5 mol %)

R'

F3C

N
H

N
H
H3C

N
N

cyclohexyl diamine
derived squaramideorganocatalyst

CH3

SO2

N
H

+

THF, 50 °C

Rphenyl sulfonyl
imine

indoles

HN

SO2

R'

R
N
H
75-96% yield
81-96% ee

Scheme 7. Cyclohexyl amine based squaramide catalysts for Friedel-Craft reaction
C. Tang and his research group16 reported the tandem Michael addition and intramolecularcyclization concept with Michael donors and ortho-hydroxynitroolefines to afford the chiral 2aminopyrans using cyclohexyl diphenyldethyleneamine derived squaramide oragnocatalyst. The
catalyst was found to be good H-bonding catalyst for affording the chiral 2-aminopyrans in good
to excellent enantioselctivities (41-95%), using with 10 mol % of oragnocatalyst (Scheme 8).

10

O

CF3

O

Ph
Ph
N

N
H

N
H

CF3

NC

CN

+

O

NH2

82-99% yield
41-95% ee

ortho-hydroxy
nitroolefine

cyclohexyl diphenyl diethylene
amine derived squaramide organocatalyst

CN

CHCl3, 20 °C

OHmalononitrile

NO2

organocatalyst(10 mol %)NO2

Scheme 8. Cyclohexyl diphenyl diethylamine derived squaramide catalyst for Michael addition
1.10 Structural judgement of thioureas between squaramides
The squaramide have the its own structural arrangements and works very effectively whencompared to thiourea and guanidine type of catalysts. The following figure represents the bonddistances and resonance on thioureas and squaramido units (I-IV).17 The two -NH functions bondforming distance is measured practically as 2.13 Å of thiourea (I), the thiourea units exhibits theresonance effect from sulphur atom to -NH functions (II-III). In the case of squaramido unit thetwo -NH functions bond forming distances is 2.71Å (IV), the resonance effect is allowing fromoxygen atoms of cyclobutanedione ring towards -NH functions of squaramido unit (V-VI).
X
N
H

N
H

2.13 Å
X = S, O
I
O
N
H

S

S
N
H

N
H

N
H
II

N
H
III

O
N
H

2.71 Å
IV

O

O

O

O

N
H

N
H

N
H

N
H

V

VI

Figure 7. Structural comparisons between thiourea and squaramide unit
1.11 General preparation method for squaramide organocatalysts
The squarate esters was easily prepared from squaric acid, which is also called as quadratic
acid because of its four carbon atoms approximating to from a square, is an organic compoundwith chemical formula C4H2O4. Squaric acid is also used as reagent for chemical synthesis, used
for instance to make photosensitive squaric dyes and inhibitors of protein tyrosine phosphatases.

11

Recently the squarate esters were gained importance in field of organocatalysts, and its widely
explored as starting materials for synthesizing many squaramide bifunctional organocatalysts. In
addition, the synthesis involves a condensation reaction with dimethyl squarate of amine a, again
respected by a parallel substitution reaction using with a chiral primary amine c affording thebifunctional squaramide units d (Scheme 9).18
O

R-NH2
a

O

O

MeO

OMe

O
N R
H

MeO

dimethyl squarate

O

R'-NH2
c

O

R' N
H

b

N R
H
d

Scheme 9. Common synthesis method for the squaramide organocatalysts
1.12 Binding modes of squaramide motif with different substrates
The squaramide motif is serves as an effective activation function for hydrogen bonding’s
with variety of substrates such as nitro-olefins (VII), conjugated ketones (VIII), pyruvate ketones(IX), oxazolidinone ketones (X) and imino-ester (XI) (Figure 8).19
O

O

O

O

O

O

O

O

O

O

R N

N R'
H

R N

N R'
H

R N

R N
H

N R'
H

R N

H

N R'
H

H

N R'
H

O

O

O

O

N

O

H
O

N

H
O

O

R

R

OR

R

N

RO2C

N

O

OR

R

R
VII

VIII

IX

X

XI

Figure 8. Possible bindings modes of squaramides unit to various hydrogen bonds acceptors

12

1.13 Author strategy
Author aimed to develop new hybrid type squaramide fused amino alochol organocatalysts
by using simple primary b-amino alcohol as chiral precursors, the squaramide organocatalysts are
remarkable four membered ring systems derived from squaric acid. The squaramide unit of thecatalyst part can contribute two proximate and polarized -NH fragments (Figure 9). The
squaramide catalysts function as an effective activation unit for hydrogen-bond donor catalysis
when compared with urea/thiourea and guanidine type catalysts. By these advantages ofsquaramide catalysts author concentrated to the synthesis of usual and new hybrid type squaramide
fused amino alcohol organocatalysts by using amino alcohols.
O

O
R'

N
H

R

N
H

R''
R''

HO

usual typesquaramide fusedamino alcohols

R = R' = alkyl
R'' = H, phenyl

Figure 9. General structure of squaramide organocatalysts
However, recently the usual type squaramide fused amino alcohols are reported in the literature
by Hari C. Bajaj20 and his research group described the synthesis of usual type squaramide fusedamino alcohol organocatalysts using with b-amino alcohol as chiral precursors having isopropyl
and phenyl groups at side chain of the catalyst (Scheme 10). And demonstrated their catalytic
activity in enantioselective allylation reaction of isatins with allyl tributyltin to afford thecorresponding chiral 3-allyl-3-hydroxyindoles in high and enantioselectivities. Moreover, theusual type squaramide fused amino alcohol organocatalysts contains only hydrogen bonding andsteric influences on the molecule.
F3C

O

O
O

R
HN

N
H

F3C

Ph
HO Ph

usual type squaramide
fused amino alcoholorganocatalyst

HO
O

R

+

SnBu3

DCM, −20 °C

NR
isatins(2.5 mol %)allyl tributyltin

O

R
N
R

3-allyl-3-hydroxyoxindoles
up to 95% yield
up to 98% ee

R = i-PrOH, Ph

Scheme 10. Enantioselective allylation of isatins13And its didn’t have any basic site to abstract the proton from pro-nucleophiles to affords highenantioslectivities, additionally, the usual type squaramide fused amino alcohol organocatalysts
are not well studied in the field of enantioselective synthesis. By these drawbacks of usual typesquaramide fused amino alcohol organocatalysts, author aimed to synthesis new hybrid typesquaramide fused amino alcohol organocatalysts by introducing Brønsted basic site on themolecule. After several attempts, author successfully developed the new hybrid type squaramide
fused amino alcohol (SFAA) having multiple activation sites such as two amino and one hydroxygroup as the hydrogen-bonding sites, three steric influences from phenyl groups and side chain of
the SFAA catalysts contains cyclic tertiary amino group that can act as a Brønsted base. And two
amino and one hydroxy group that can form hydrogen bonds with both substrates. By owing theseproperties of SFAA catalysts might be act as trifunctional organocatalysts (Scheme 11).
F3C

O

O
R

R
N
H

F3C

N
H

HO

Ph
Ph

H2N

usual typesquaramide fusedamino alcohols

Ph
Ph
OH

O

O

MeO

N
H

CF3

+

β-amino alcoholorganocatalysts

squaramide mono ester amide

steric influencebasic site
F3C

F3C

O
N
H

O
N
H

N

HO

N
Ph
Ph

H2N

hydrogen bonding site
new hybrid typesquaramide fusedamino alcohols (SFAA)
organocatalysts

Scheme 11. Concept of SFAA catalyst design

14

Ph
Ph
OH

CF3

+

squaramide mono
ester amide

The newly developed hybrid type SFAA organocatalysts having hydrogen bonding, stericinfluences and Brønsted basic sites demonstrated its catalytic activity for enantioselective reactions
such as nitro-aldol reaction, Diels-Alder reaction and domino Michael addition cyclization
reaction to afford the corresponding biologically active synthetic intermediates in highenatioselectivities.
i) Enantioselective nitro-aldol reaction
Author initially tried and explored the catalytic activity of SFAA organocatalysts forenantioselective nitro-aldol reaction of isatins with nitromethane to affords the chiral 3-alkyl-3hydroxyoxindoles in excellent chemical yields (up to 99% yield) and enantioselectivies (up to 95%
ee). The chiral 3-alkyl-3-hydroxyoxindoles are the prominent synthetic intermediates for many
biologically active compounds. Such as the donaxaridine (anticancer), spirobrasinin (antifungal),maremycin B (cytotoxicity), CPC-1 (antibacterial agent) and dioxibrasinin (natural product)(Scheme 12).21
O
O
N
R
isatins

+

R'

NO2

enantioselective
nitro-aldol
reaction

HO
*

SFAA
organocatalyst

R'
* NO2
O

N
R
chiral3-alkyl-3-hydroxyoxindoles
up to 99% yield
up to 95% eenitroalkanes

donaxaridine (anticancer)
spirobrasinin (antifungal)
maremycin B (cytotoxicity)
CPC-1 (antibacterial)
dioxibrasinin (natural product)

Scheme 12. SFAA organocatalyst for enantioselective nitro-aldol reactionii) Enantioselective Diels-Alder reaction
Furthermore, the author has applied the newly prepared SFAA organocatalysts forenantioselective Diels-Alder reaction of 3-hydroxy-2-pyridones with dienophiles to accesses thechiral 4-hydroxyisoquinuclidines in both excellent chemical yield (up to 98%) andenantioselectivities (up to 98%) (Scheme 13).22 The chiral 4-hydroxyisoquinnuclidines are key
synthetic intermediates for bicyclic complex structures and many biological active compounds
such as oseltamivir (antiinfluenza drug), ibogaine (psychoactive drug) and vinblastine andvincristine (anticancer drugs).

15

enantioselective
Diels-Alderreaction

OH
R'
N
R

+

O

dienophilesRNO

oseltamivir (antiinfluenza)
ibogaine (psychoactive)
R'

SFAA
organocatalyst

vinblastine and vincristine(anticancer)HOchiral4-hydroxyisoquinnuclidines

3-hydroxy-2pyridones

bicyclic complex compounds

up to 98% yield
up to 98% ee

Scheme 13. SFAA organocatalysts for enantioselective Diels-Alder reactioniii) Enantioselective domino Michael addition cyclization reaction
Moreover, author also successfully applied the SFAA organocatalysts for enantioselective
domino Michael addition cyclization reaction of 3-dicyano-2-indanones with cyclic 1,3-dicarbonylcompounds for affording the chiral spiro-conjugated 2-aminopyrans in both excellent chemicalyield (up to 97% yield) and enantioselectivities (up to 95% ee). The domino Michael addition
cyclization reaction of electron withdrawing indanones with active methylene’s accesses the chiralquaternary streogenic 2-aminopyrans. The chiral spiro-conjugated 2-aminopyrans are the vitalsynthetic intermediates for many biologically active derivatives, such as tacrine derived 2aminopyrans(antialzheimers),

spiro-pyranopyrazoles(antioxidants),

pyranopyranones(anticoagulant) and 2-aminotetrahydrocromenes (antileishmaniasis) (Scheme 14). The detailed
discovery of SFAA organocatalysts preparations and its application for enantioselective reactions
will be discussed in following sections.

NN

enantioslective
domino Michael
addition cyclization

O
+

O
N
R
N-substituted 3-dicyano2-indanones

O

H2N
NC

*

SFAA
organocatalyst

tacrine analogs (antialzheimers)

O

N
R

OO

spiro-pyranopyrazoles (antioxidants)
pyranopyranones (anticoagulant)
2-aminotetrahydrochromenes(antileishmaniasis)chiralspiro-conjugated 2aminopyranscyclic 1,3-dicarbonylcompounds

up to 97% yield
up to 95% ee

Scheme 14. SFAA organocatalysts for enantioselective domino Michael addition cyclization
reaction

16

Chapter 2
The New Hybrid Type Squaramide Fused Amino Alcohol
Organocatalysts For Enantioselective Nitro-Aldol Reaction of
Nitromethane with Isatins17

2.1 Introduction
The nitro-aldol reaction is also referred as (Henry reaction) which is a well-studied reaction
in synthetic organic chemistry. The nitro-aldol reaction was discovered by Belgian chemist LouisHenry during the year of 1895. The nitro-aldol reaction is the usually takes place between
nitroalkane and an electron deficient (ketone/aldehyde) in the presence of catalytic amount of basic
additives to afford the b-nitro alcohol. The obtained b-nitroalcohols can be easily converted into
other functional derivatives such as, nitroalkenes, a-nitro ketones and b-amino alcohols (Scheme
15).23
R'

O2N

R''
R
nitroalkene
dehydration

R

NO2

nitroalkane

O

+
R'

base
R''

ketone/aldehyde

solvent

NO2
R'
R''
OH
β-nitro alcoholR

reduction

NH2
R'
R''
OH
β-amino alcoholR

Scheme 15. General representation of nitro-aldol reaction18

NO2
oxidation
if R' = H

R

R''

O
α-nitro ketone

2.2 Mechanism
The nitro-aldol reaction mechanism leads with deprotonation of nitro-alkane in thepresence of base which forms carbanion at a-position. The active species of carbanion reacts withelectron deficient (ketone/aldehyde) to form the diastereomeric b-nitro alkoxide. The protonationof the alkoxide from the reaction medium forms the b-nitro alcohol as desired product. In nitroaldol course of reaction all the steps are reversible (Scheme 16).24
O
R

N
R'

O

O
:B

H

N

R

O

O

R'

R

N

O
R'

R''
O
R'''
O
R
R''

N

O

O

B-H
R
R''

R'
OH
R'''

N

O

R'
O
R'''

Scheme 16. Mechanism of nitro-aldol reaction
2.3 Stereochemical course of the nitro-aldol reaction
In a stereochemical course of the nitro-aldol reaction usually produces the unequal amountof the isomers. In many enantioselective nitro-aldol reactions syn or anti-isomer can be observedin the course of the reaction. The steric influences of the substrates usually determine thestereochemical outcome of the products in nitro-aldol reaction (Scheme 17).25

R'

OH

O2N

R

anti-isomer

O N O
R
H
R'
H
O

O N O
H
R
R'
H
O

R'

OH

O2N

R

syn-isomer

Scheme 17. The anti/syn stereochemical approach of nitro-aldol reaction

19When it’s come to the one chiral center bearing of nitro-aldol products the stereochemistry
assigned as (R) or (S) its depends on the R groups on the substrates of ketone/aldehyde andnitroalkane. The stereochemistry of resultant nitro-aldol products also obeys the enantiomeric faceapproach of the corresponding nitromethane to electrophilic ketones (Scheme 18).
HO

H

NO2

R

R(R) R'(R)-enantiomer

O
H

NO2

HO

R'

R (S) R'NO2(S)-enantiomer

Scheme 18. (S) or (R) enantiomers of the nitro-aldol reaction
2.4 Limitations of the nitro-aldol reaction
The main drawback of the nitro-aldol reaction is producing the potential side products inthe course of the reaction. In the following reaction the nitromethane reacts with ketone in thepresence of basic medium to form the nitro-aldol adduct. The nitro-aldol adduct has the tendency
to undergo retro nitro-aldol reaction to afford retro nitro-aldol product (nitro-alkene) in thepresence of protic solvent medium. (Scheme 19).
O
R

R'

ketone+CH3NO2basesolvent

NO2
HO
R

R'

-H2O
+OH-

nitro-aldol
adductnitromethane

Scheme 19. General representation of the retro nitro-aldol reaction

20

R'

NO2

R
retro nitro-aldol
product

2.5 The enantioselective nitro-aldol reaction of isatins with nitroalkanes
The enantioselective nitro-aldol reaction of isatins with nitroalkanes affords syntheticallyvaluable chiral 3-alkyl-3-hydroxyoxindoles.26 The 3-substituted 3-hydroxyoxindoles are the core
structural unit in a large array of fascinating natural products with broad spectrum of intriguing
biological activities (Scheme 20). The resulting heterocycles are important synthetic precursors
for many biologically active natural products such as CPC-1 (antibacterial activity), maremycin B(cytotoxicity against K562 human leukemia cell lines), spirobrassinin (anti- fungal, antitumor, andoviposition stimulation activity),

donaxaridine (anticancer activity), and dioxibrassinin(important natural product).
H
N

HO
O
N
H
donaxaridine(anticancer)

H3CS
enantioselective
nitro-aldol
reaction

O
O

+ R'

NO2

N
R
Isatins

HO
*

R'

S

* NO2
O

N
R
chiral3-alkyl-3-hydroxyoxindoles

organocatalyst
nitroalkanes

N

O
N
H
spirobrassinin(antifungal)
O
HO

S
HO

N
H
O

SMe

NMe
N H
Me

N
H

NH

HN
O
N
O
H
maremycin B(cytotoxicity)

SMe

CPC-1
(antibacterial)

dioxibrassinin(natural product)

Scheme 20. General representation of the nitro-aldol reaction of isatins with nitroalkanes usingorganocatalyst

21

W. Wang and his research group27 reported enantioselective nitro-aldol reaction of isatins
1 with nitroalkanes 2 using cupreine 3 as organocatalyst to afford the nitro-aldol adducts inexcellent yields (up to 98%) and with good to excellent enantioselectivities (up to 99%) under themild reaction conditions (Scheme 21). And this strategy relying on non-covalent bond-mediatedcatalysis which is a different approach from other organocatalytic of nitro-aldol reaction. In thismethodology, they also demonstrated the synthetic utility of 3-susbstituted 3-hydroxyoxindoles 4
to afford (S)-(-)-spirobrassinin 5. The (S)-(-)-spirobrassinin is a natural product isolated from
Pseudomonas cichorii (Japanese radishes) in 1987. The compound displays various biologicalproperties including plant defense, antifungal and antitumor activities.

OH
OH

O

X
N

+

R'CH2NO2

DMA, -15 °C

N
R

N
H
cupreine3

cupreine 3(10 mol %)PhCO2H

O

R'
HO
N
R

1.5-16 h

1

2

NO2
O

X
4

up to 98% yield
up to 99% ee

H3CS
N

S
4

O
N
H
5
(S)-(-)-spirobrassinin

Scheme 21. The enantioselective nitro-aldol reaction using cupreine alkaloid
X. -W. Wang and his research group28 reported the enantioselective nitro-aldol reaction of
isatins with nitroalkanes using with bifunctional cinchona alkaloid derivatives as organocatalysts.
In the course of enantioselective nitro-aldol reaction they prepared a series of cinchona alkaloid
derivatives 8a-f, among them 8f has showed the excellent catalytic activity in enantioselective
nitro-aldol reaction of isatins 6 with nitromethane 7 to afford 3-hydroxy-3-(nitromethyl)indolin-2ones 9 in both excellent yields (up to 98%) and enantioselectivities (up to 95%) (Scheme 22).

22

O
O

R'

+

catalyst 8f(10 mol %)CH3NO2NO2O

R'

THF, -15 °C
4-5 days

N
R
6

HO
N
R

7

9
up to 98% yield
up to 95% ee
CF3

H

N

HO

H

N

HO

H

O

S

H

N
H

F3C

H

H

O
N
8a

N
8b

H
H

O
N
8d

H

N

HO
H

HO

N

8c

H

N

BnO

N
8e

N

HN

N

O
H

HO
N
8f

Scheme 22. The enantioselective nitro-aldol reaction of isatins with nitromethane using cinchona
alkaloids
Pravin R. Likhar and his research group29 reported the enantioselective nitro-aldol reactionof isatins 10 with nitromethane 7 in the presence of bis-cinchona based (DHQD)2PHAL 11
alkaloid as organocatalyst. They prepared a series of bifunctional cinchona alkaloid catalysts
possessing pthalazine as a cross linker in between two cinchona alkaloids. They successfully
demonstrated the prepared catalysts catalytic activity in enantioselective nitro-aldol reaction toafford the 3-hydroxyoxindoles 12 in both good to excellent chemical yields (up to 98%) andenantioselectivities (up to 97%) (Scheme 23).

23

catalyst 11(4 mol %)

O
R'

O

+

CH3NO2

NR

HO

THF, -10 °C
11h

N
R
12

7

10

NO2
O

R'

R = H, Me, Bn

up to 98% yield
up to 97% ee

R' = Br, Cl
Et

Et

N

O
H

H

MeO
N

N N

N

O

H

H

OMe
N

11 (DHQD)2PHAL

Scheme 23. The enantioselective nitro-aldol reaction using cinchona based (DHQD)2PHAL
Wang and his research group30 has reported the organocatalytic enantioselective nitro-aldol
reaction of isatins 13 with nitromethane 7 using cinchona alkaloid catalysts 14a-d, among themcatalyst 14d have showed the excellent catalytic activity for affording the 3-hydroxyoxindoles 15
in excellent yield (up to 96%) and high enantioselectivites (up to 92%). And this method
effectively useful for the synthesis of (R)-(+)-dioxibrasinin 16, the dioxibrasinin belongs tophytoalexins class, with possessing potent antimicrobial activity (Scheme 24).

24

O
O

+

CH3NO2N
H
13

HO

catalyst 14d(10 mol %)

O
N
H
15
up to 96% yield
up to 92% ee

THF, 5 °C

7

S
HO

SCH3

N
H
O

15

N
H 16
(R)-(+)-dioxibrassinin
OH

OH
OH

OH
N

N
H

H

N
14a

OH

Ar
HN

14b
CF3
S

F3C

HN

OH
O

N
N

H

N
H

Ar = 3,5-(CF3)2C6H3
14c

14d

Scheme 24. The enantioselective nitro-aldol reaction using cinchona alkaloids

25

NO2

2.6 Author strategy
As part of author research work aim to develop the simple primary b-amino alcohols as a
new class of organocatalysts in enantioselective synthesis. Author successfully prepared the new
hybrid type squaramide fused amino alcohol (SFAA) organocatalysts using with simple primaryb-amino alcohol as chiral precursors. The SFAA catalysts posses with distinctive properties suchas ease to synthesis, stability upon exposure to air, potential towards steric site modifications, andcapability act as trifunctional (enamine activation, non-covalent activation and basic site) catalyst.
The SFAA catalysts can be a more hydrogen bonding possibilities compared to those withurea/thiourea and guanidine catalyst providing more superior rate of enhancements andstereoselective controls in enantioselective reactions. An advantage of chiral SFAA asorganocatalysts is the simple and modular preparation, which offers a facile route to a wide rangeof trifunctional organocatalysts. By this point of view, author synthesized the new hybrid type
SFAA organocatalysts which contains a cyclic tertiary amino group that can act as a Brønsted
base, sterically bulky groups, and two amino and one hydroxy group that can form hydrogen bonds
with both substrates (Scheme 25). The SFAA catalysts X and Y can be easily prepared by thecondensation reaction of a squaramide and the corresponding amino alcohol.

N

Ph
Ph
OH

H2N

O

MeO

N
H
squaramide+

amino alcohols

steric influence
F3C

O

F3C

R
F3C

CF3

steric influencebasic site
O

N
H

CF3

O

N
H

HO

Ph
Ph

F3C

X
hydrogen bonding site

O

O

N
H

N
H
Y

N

HO

Ph
Ph

hydrogen bonding site
new hybrid typesquaramide fusedamino alcohols

R: alkyl or phenyl
squaramide fusedamino alcohols

Scheme 25. Properties of squaramide fused amino alcohol organocatalysts X and Y26

2.7 Results and discussions
The newly developed SFAA organocatalysts posses with multiple hydrogen bonding sites
and steric influence sites within one molecule, it might have shown strong stereochemical
influence in the enantioselective nitro-aldol reaction of isatins with nitromethane. As shown in theplausible transition state Z, where isatin and nitromethane can be conformationally fixed by fourhydrogen-bonding interaction, that is between the two amino groups of the squaramide and thetwo carbonyl groups of the isatins. Between the cyclic ammonium site of squaramide and oxygen
atom of the nitro enolate moiety, and between the cyclic ammonium site and the hydrogen atomof the hydroxy group in the ammonium alcohol intermediate (Scheme 26). Then, the reaction may
proceed stereoselectively to afford the nitro-aldol product with high enantioselectivity.
O
R'

O
N
R
isatins+

F3C

CH3NO2OO
N

nitromethane

F3C

N
H

N
H

Ph
HO Ph

squaramide fused amino alcoholorganocatalysts
CF3
O
O

F3C

N
H

O

H N

O
R N

N

H
O

N
O H

NO2

HO
R'

O
N
R

O

chiral 3-hydroxyoxindoles
R'
plausible trasition state Z

Scheme 26. Conceptualization of enantioselective nitro-aldol reaction using SFAA
oraganocatalysts

27

2.7.1 Synthesis of usual type squaramide fused amino alcohol organocatalysts
Initially, according previous literature procedures,20 author prepared usual type ofsquarmide fused amino alcohol organocatalysts by employing coupling reaction of squarate
monoester amide with corresponding b-amino alcohol which were easily prepared from Grignard
reaction of commercially available amino esters salts. First, author synthesized a series of aminoacids ester salts 18 from corresponding amino acids 17 by reaction with thionyl chloride at 0 °C rt conditions, the amino acids salts were obtained with excellent yields up to 99% (Scheme 27).
R

O

SOCl2
MeOH

R

H2N

OH

0 °C-rt
16 h
99%

H2N

17
R = Me, Ph, Bn, i-Pr

O
OMe
HCl
18

Scheme 27. Synthesis of amino acid salts from amino acids
The obtained amino acids salts were reacted with PhMgBr in argon atmosphere to using dry ether
at 0 °C temperature to afford the b-amino alcohols organocatalysts 19a-d in moderate yields up to
48-59% (Scheme 28). Furthermore, the obtained b-amino alcohol organocatalysts 19a-d werefused with squaramide mono ester amide 20 in dry MeOH solvent at room temperature to furnish
the usual type squaramide fused amino alcohol organocatalyst 21a-d in moderate to good yields
59-70% (Scheme 29)
R
H2N

O
OMe
HCl
18

PhMgBrR

Et2O, 0 oC
15 h
48-59%

H2N

Ph
Ph
OH

19a-d

Scheme 28. Synthesis of b-amino alcohol organocatalysts from amino acid salts

28

CF3
R
H2N

Ph
Ph
OH

F3C

O

O

O

O
R

MeOH

+
F3C

N
H
20

19a-d

F3C

O

24-48 hrt59-70%

OMe

O

N
H

F3C

N
H

HO

Ph
Ph

21a-d

F3C

O

O

N
H

N
H

Me
N
H

F3C

N
H

HO

Ph
Ph

F3C

21a : 70%

F3C

O

HO

21b : 65%

F3C

O

O

O
Ph

Ph
N
H

F3C

Ph
Ph

N
H

HO

Ph
Ph

F3C

21c : 64%

N
H

N
H

HO

Ph
Ph

21d : 59%

Scheme 29. Synthesis of usual type squaramide fused amino alcohol organocatalysts
2.7.2 Synthesis of new hybrid type squaramide fused amino alcohol organocatalysts
Furthermore, by employing previous literature procedures11 author prepared new typehybrid squaramide fused amino alcohol organocatalysts from using L-Serine amino acid 22 asstarting material. The serine was reacted with thionyl chloride in MeOH at 0 °C to afford the serine
methyl ester hydrochloride salt 23 with 99% yield. The obtained salt 23 were reacted with PhMgBr
to afford the serine b-amino alcohol 24 with 54% yield (Scheme 30). Moreover, the amino groupof obtained serine amino alcohol 24 was protected with (Boc)2O to afford compound 25 with 91%
yield.
HO
H2N

O
OH

L-Serine
22

SOCl2
MeOH
0 °C-rt
99%

HO

O

H2N

OMe
HCl
23

Scheme 30. Synthesis of serine b-amino alcohol

29

PhMgBrEt2O
0 °C-rt
15 h
54%

Ph
Ph
OH

HO
H2N
24

Next, the primary hydroxy group of compound 25 protected with MsCl in the presence of Et3N toafford 26 with 81% yield. Furthermore, the compound 26 reacted with cyclic amines (pyrrolidine,piperdine, azapane, morpholine and thiomorpholine) in neat reaction conditions to afford thecompounds 27a-e in 55-65% chemical yields respectively. The Boc group on nitrogen function ofcompounds 27a-e was de-protected using with excess amount of TFA in dichloromethane assolvent at 0 °C to afford the desired amino alcohols 28a-e with 85-95% yields. The obtained
diamine alcohol 28a-e were fused with squramide mono ester amide 20 using MeOH in sealed
tube at 120 °C for 12h to afford the targeted new hybrid type squaramide fused amino alcoholorganocatalysts 29a-e in moderate to good yields (up to 81%) (Scheme 31).
NH

X n

24

(Boc)2O
Et3N

HO

DCM, 0 °C-rt
5 h, 91%

BocHN

Ph
Ph
OH

MsCl, Et3N
DCM, 0 °C-rt
4 h, 81%

25

F3C
F3C
27a-e

TFA, DCM

R

0 °C, 5 h
85-95%

H2N

F3C

Ph
Ph
OH

O

O

N
H

N
H

29a: 56%
F3C

O

N
H

Ph
Ph
HO

O

N
H

F3C

O

N
N
Ph
H
H
Ph
HO
29a-e

F3C

O

O

N
H

N
H

O

Ph
HO Ph

O

O
N

Ph
Ph
HO

O

O

27a-e

R

F3C

N
H

S

MsCl

N
H

Ph
Ph
29e: 81% HO(Boc)2ON
H

Ph
Ph
29d: 78% HO

F3C

N

F3C

OMe

29b: 52%

29c: 62%
F3C

N
H
20

F3C

O

N
H

O

BocHN

N

N

F3C

O

R

neat, 80 °C
12 h
55-65%

26

F3C

N

F3C

BocHN

sealed tube
MeOH, 120 °C
52-81%

28a-e(X = CH2, O, S)(n = 0, 1, 2)

Ph
Ph
OH

MsO

O
H3C S Cl
O

=

O

=
O

O
O

O

Scheme 31. Synthesis of new hybrid type squaramide fused amino alcohol organocatalysts

30

Ph
Ph
OH

The newly synthesized hybride type squaramide fused amino alcohol organocatalysts werecharacterized with 1H-NMR, 13C-NMR, HRMS, and IR spectroscopy. Next, author examined thecatalytic activity of prepared catalysts 29a-e for enantioselective nitro-aldol reaction of isatins 30ac with nitromethane 7.
2.7.3 The nitro-aldol reaction of isatin with nitromethane using catalysts 21a-d
Author desire to examine the catalytic activity of catalysts 21a-d for enantioselective nitroaldol reaction (Table 1), initially, author carried out the reaction of simple isatin 30a withnitromethane 7 using catalyst 21a in THF at 0 °C without using of any basic additives. However,
the expected aldol product 31a was not observed even after 48h and the starting compound 30
recovered completely (entry 1). Then author hypothesized that addition of a basic additive might
initiate the reaction. To implement this hypothesis, the basic additives such as TEA, DIPEA andDMAP were used in the course of reaction to abstract the proton from nitromethane (entries 2-4).
Table 1. Enantioselective nitro-aldol reaction using catalysts 21a-d
OHO

catalysts
21a-d (10 mol %)CH3NO2

O
N
R
30a-c

O

DMAP, solvent
0 oC, 48 hNR

7entrya catalysts
21a-d

NO2

31a-c

R

base

solvent 31a-c yield [%]b ee [%]c

1d
2

a
a

H
H

--TEA

THF
THF

--a

--12

--8

3

a

H

DIPEA

THF

a

25

11

4

a

H

DMAP

THF

a

83

38

5

b

H

DMAP

THF

a

82

32

6

c

H

DMAP

THF

a

83

31

7

d

H

DMAP

THF

a

82

32

8

a

Me

DMAP

THF

b

62

23

9

a

Bn

DMAP

THF

c

75

11

10

a

H

DMAP

DCM

a

92

rac

11

a

H

DMAP

CHCl3

a

85

rac

aThe reaction were carried out with 30a-c (0.13 mmol), 7 (0.67 mmol) in above

mentioned solvents (2.0 mL). bIsolated yields. cEnantiomeric excess wasdetermined on chiral HPLC using Chiralpak AD-H column. dWithout using any base31

By using these basic additives, the reaction was proceeded smoothly and afforded aldol product31a, but the better results was observed by using DMAP as additive (entry 4, 83%, 38% ee). Then,different SFAA catalysts 21b-d were tested and each catalyst showed considerable catalytic
activity and furnished the product 31a in good yields (up to 83%), although the enantioselectivities
was not satisfactory obtained (entries 5-7, up to 32% ee). Among the examined catalysts, 21a wasfound to be the best one to afford aldol product 31a in good chemical yield, although thesatisfactory enantioselectivity was not afforded. Furthermore, different substituted isatins were
examined using catalyst 21a under the same reaction conditions. The reactions of N-methylated
isatin 30b and N-benzylated isatin 30c respectively, afforded the corresponding aldol products 31b
and 31c in moderate chemical yields with poor enantioselectivities (entries 8, 9). The nitro-aldol
reaction was performed in different polar and non-polar solvents. The reaction proceeded
efficiently in DCM and CHCl3 respectively, the aldol product 31a were obtained in good chemicalyield, although in racemic (entries 10, 11). These results shown that catalysts 21a-d were
inefficient to afford the aldol products with satisfactory enantioselectivities and it revealed that abasic additive is necessary to proceed the reaction. By observed results in (Table 1) author assumed
that the introduction of basic site into the core structure of SFAA catalyst could improve theenantioselectivity of the nitro-aldol reaction.
2.7.4 Nitro-aldol reaction using catalysts 29a-e
Next, author examined the catalytic activity of catalysts 29a-e using the best solvent i.e.
THF (Table 2). As the first attempt, catalyst 29a bearing pyrrolidine ring system as a basic site
was tested in the nitro-aldol reaction of simple isatin 30a with nitromethane 7 at 0 °C. As expected,
aldol product 31a was obtained in excellent chemical yield (99%) with moderate enantioselectivity(64% ee) (entry 1). Furthermore, author examined the catalytic activity of other SFAA catalysts
29b-e for this reaction. Catalyst 29b bearing piperidine ring system afforded 31a with excellent
chemical yield (92%) but with low enantioselectivity (39%) (entry 2). The best enantioselectivity(81% ee) with good chemical yield (92%) was obtained by using catalyst 29c bearing azepane ringsystem (entry 3). On the other hand, other two catalysts bearing morpholine and thiomorpholine
ring systems 29d-e, afforded the nitro-aldol product 31a in only trace amounts (entries 4, 5).

32

Table 2. The enantioselective nitro-aldol reaction using catalysts 29a-e
O
CH3NO2

O
N
H
30a

HO

catalysts 29a-e(10 mol %)NO2O

THF, 60 h

N
H
31a

7
entryacatalysts
29a-e

1

a

0

99

64

2

b

0

92

39

3

c

0

92

81

4

d

0

trace

---

5

e

0

trace

---

6

d

RT

85

61

7

e

RT

98

59

temp. (°C) yield [%]b ee [%]caThe reaction were carried out with 30a (0.13 mmol),

7 (0.67 mmol) in dry THF (2.0 mL). bIsolated yields.
cEnantiomeric excess was determined by chiral
HPLC on chiralpak AD-H column

Fortunately, performing these reactions at room temperature successfully afforded the desired
aldol product 31a in good chemical yields with moderate enantioselectivities (29d: 85%, 61% ee;
29e: 98%, 59% ee) (entries 6, 7), but these results were not better than those obtained with catalyst
29c. From these observed results, the catalyst 29a is superior in the nitro-aldol reaction of isatin
30a with nitromethane 7. Furthermore, author investigated optimization reaction condition forenantioselective nitro-aldol reaction using catalyst 29c with isatin 30a and nitromethane 7.
2.7.5 Optimization of nitro-aldol reaction conditions using catalyst 29c
Author next inspected the effect of solvent, molar ratio of catalyst, and reaction temperature(entries 1-20, Table 3). Changing the molar ratio of catalyst 29c to 5 mol% and 20 mol% also
provided the aldol product 31a in good chemical yields and enantioselectivity (5 mol%: 82%, 74% ee, 20 mol%: 93%, 64% ee), respectively (entries 1, 2). Author also optimized the nitro-aldol
reaction at lower temperature (-20 oC), in these reaction condition author observed decreases inboth the chemical yield (70%) and enantiomeric excess (78%) (entry 3).

33

Table 3. Optimization of reaction conditions using catalyst 29c
HO
30a

NO2

catalyst 29c

7O

solvent, temp.

N
H

60 h
entrya catalyst 29c(mol %)

31asolvent

temp (°C)

yield [%]bee [%]c

1

5

THF

0

82

74

2

20

THF

0

93

64

3

10

THF

-20

70

78

4

10

toluene

0

89

rac

5

10

benzene

0

98

rac

6

10

m-xylene

0

95

rac

7

10

DCM

0

86

2

8

10

diisopropylether

0

93

2

9

10

CPME

0

86

rac

10

10

1,4-Dioxane

rt

94

55

11

10

Et2O

0

93

21

12

10

THP

0

trace

---

13

10

TFE

0

94

rac

14

10

ACN

0

91

53

15

10

DMA

0

43

74

16

10

DMF

0

57

64

17

10

DMSO

rt

trace

---

18

10

MeOH

0

92

rac

19

10

water

rt

92

rac

20

10

neat

0

96

rac

aThe reaction were carried out with 30a (0.13 mmol), 7 (0.67 mmol) in above mentioned

dry solvents (2.0 mL). bIsolated yields. cEnantiomeric excess was determined byusing chiral HPLC on chiralpak AD-H column

34

The use of non-polar aromatic solvents also afforded 31a with excellent chemical yields (89-95%),
but completely in racemic form (entries 4-6). Furthermore, the reaction in chlorinated and different
ethereal solvents afforded 31a in good to excellent chemical yields (86-94%) (except THP, inwhich case only trace amount of 31a was formed), but very poor to moderate enantioselectivities
were observed (entries 7-12). Moreover, the effect of polar solvents such as TFE, ACN, DMA,
DMF, DMSO and MeOH were also investigated. Unfortunately, satisfactory chemical yields andenantioselectivities were not obtained (entries 13-18). The reaction was also conducted in waterand in neat conditions (nitromethane used as solvent and reactant). Although the product 31a was
obtained in fairly good chemical yields, good enantioinduction was not observed (entries 19 and20). From these results, after screening of catalysts, catalyst loadings, additives, solvents andreaction temperatures, author decided to set the conditions as (catalyst 29c (10 mol %), in THF at
0 °C for 60 h) as optimal conditions for this reaction and started to explore the substrate scope forenantioselective nitro-aldol reaction.
2.7.6 Substrate scope for enantioselective nitro-aldol reaction using catalyst 29c
CH3NO27
catalyst 29c(10 mol %)

O
R2
O

HO

O

THF, 0 oC
60 h

N
R1
30b-k

NO2

HO

R2

N
R1
31b-k

HO

NO2

HO

NO2

O

HO

NO2

NO2

O

O

O

N
Me

N
Bn

N

N
Boc

31b: 97%, 26% ee

31c: 95%, 67% ee

31d: 98%, 41% ee

31e: 82%, 95% ee

HO

HO

Me

NO2 O N
2
O

N
H
31f: 96%, 35% ee
Br

HO

NO2

O
N
H
31j: 92%, 52% ee

NO2 F
O

HO

NO2

O
N
H
31h: 96%, 64% eeNH
31g: trace
I

HO

Cl

HO

O
N
H
31i: 89%, 55% ee

NO2

O
N
H
31k: 97%, 62% ee

Scheme 32. Substrate scope of nitro-aldol reaction using SFAA catalyst 29c

35

NO2

In a substrate scope of nitro-aldol reaction, a variety of isatins 30b-k with nitromethane 7 wereafforded the nitro-aldol products 31b-k in good to excellent chemical yields and moderate to goodenantioselectivities (Scheme 32). The reactions of N-alkylated isatins such as N-methyl-isatin 30b,
N-benzyl-isatin 30c and N-allyl-isatin 30d with nitromethane 7 afforded the desired aldol products
31b-d, respectively, in excellent chemical yields (95-98%) but with low to moderateenantioselectivities (26-67% ee). On the other hand, the nitro-aldol reaction using N-Boc isatin
30e afforded the product 31e in good chemical yield (82%) with excellent enantioselectivity (95%ee). 5-Methyl-isatin 30f provided the aldol product 31f in excellent chemical yield (96%) with low
enantioselectivity (35% ee). Moreover, only trace amount of the aldol product 31g was obtained
from the reaction of 5-NO2-isatin 30g with 7, although the exact reason was not clear. The use of
halogenated isatins 30h-k provided the corresponding nitro aldol products 31h-k with fairly good
to excellent chemical yields (89-97%), but with moderate enantioselectivities (52-64% ee).
2.7.7 Mechanistic investigation of nitromethane and isatin with squaramido unit
Finally, the enantioselective reaction mechanistic pathway of this reaction using author
developed squaramide-fused amino alcohol catalyst 29c was considered based on both the highenantiopurity (81% ee) of the chiral aldol product (S)-31a which was obtained from the reactionof isatin 30a with nitromethane 7 and the calculation analysis (1: natural bonding orbital (NBO)
analysis of the hydrogen bonding of simple squaramide I with isatin 30a or nitromethane 7, 2: thehydrogen bonding distance calculations of complexes A or B, 3: electron density of isatin 30a)
(Figure 10). Thus, (1) NBO analysis was performed subsequently on the optimized structures toquantify the donor-acceptor. The stabilization energies (E (2)) of intermolecular interactions of allcomplexes (complexes A and B) were performed by using second order perturbation theory. As
the calculation result, the stability of A (E(2) / kcal·mol-1 = 1.56) was increased as compared withthat of B (E(2) / kcal·mol-1 = 0.25). This result might be consistent with the stability of thecomplexes. Furthermore, (2) the hydrogen bonding distance of complex A was also shorter thanthat of complex B. In addition, (3) the place of the highest electron density (Mulliken charge
distribution) was on oxygen of amide in isatin 30a.

36

H
N H

O
1

H
N

O

H
N H

O

O
N

N
H

O

H

O

O
I

30a

I

N
H

H

O
7

Complex A

Complex B

E(2) / kcal·mol-1 = 1.56

E(2) / kcal·mol-1 = 0.25

23Complex 2

Complex 1 Complex A

Complex B

Mulliken Charge Distribution of 30a

Figure 10. (1) The calculated second order perturbation energies (E (2) / kcal, Eamol-1) of thesecond donor (H-bond donor of squaramides) and acceptor (oxygenatoms of isatin 30a and nitrate7) interaction for the complexes A and B, (2) the calculated hydrogen bond distances of thecomplexes A and B, (3) The electron density map and Mulliken charge distribution of isatin 30a

37

O
O

CH3NO2

+

N
H
30a

7

F3C

O

O
N

N
H

F3C

N
H

Ph
Ph
HO

29c
CF3

CF3
O

O

O
F3C

N

N

H

H

H

O
HN

O
F3C

N
O
H

O

N

O

HN

O

O

N
O

TS-I
disfavoured

TS-IIfavoured
81% ee

O

O
N O

HO

N

HO

O

O

N
H

N
H

(R)-31a'(S)-31amajor isomerminor isomer

Scheme 33. Plausible reaction course for nitro-aldol reaction

38

N
O

O

H N

O

H

H

N

O

H

From the mechanistic investigation of isatin 30a and nitromethane 7 with squaramido unit I(Figure 12). A model for the enantioselective nitro-aldol reaction a mechanistic pathway is
proposed. First, the active methylene proton of nitromethane is abstracted by basic tertiary aminogroup on azepane ring in catalyst 29c to form nitro enolate, which might also induce the stronghydrogen bonding interaction between the hydrogen atom of the ammonium moiety on azepane
ring in catalyst and oxygen atom of nitro enolate. Next, isatin 30a might fixed with catalyst 29c
through two hydrogen bonds between two carbonyl oxygen atom on isatin 30a and two primaryamino groups on squaramide site in catalyst. When isatin 30a makes the hydrogen bonding tocatalyst, one carbonyl oxygen atom of amide on isatin 30a might binds with the hydrogen atom ofamino group with 3,5-bis(trifluoromethyl)phenyl group as an electron-withdrawing group on
squaramide site in catalyst and other carbonyl oxygen atom on isatin 30a might binds with thehydrogen atom of another amino group on squaramide in catalyst. In addition, the side chain
containing ammonium alcohol moiety on catalyst might be fixed by the hydrogen bonding
interaction between hydrogen atom on the hydroxyl group and ammonium moiety on azepane ringon the side chain. Among the possible two transition states TS-I and TS-II, TS-II has less stericinteraction than that of TS-I, which has strong steric repulsion between four membered squaramide
skeleton and di-phenyl groups on catalyst. Hence the reaction might proceed via the transition state
TS-II, in which nitroenolate coordinated to ammonium moiety on azepane ring could attack on
the isatin from the upper side leading to the formation of (S)-31a as major enantiomer, whereas
minor isomer (R)-31a' might be obtained via the unfavorable transition state TS-I (Scheme 33).
2.8 Summary
In summary, author prepared new hybrid type SFAA catalysts 29a-e from commercial
available amino esters via simple organic transformations and demonstrated their catalytic
efficiency in the enantioselective nitro-aldol reaction of various isatins 30a-k and nitromethane 7.
This protocol provides the chiral 3-substituted 3-hydroxyoxindoles 31a-k in excellent chemicalyields (up to 99%) and excellent enantioselectivities (up to 95% ee). Especially, catalyst 29c
bearing azepane ring system as basic site showed best catalytic activity for this reaction. The
obtained 3-alkylsubstituted 3-hydroxyoxindoles could be important intermediates for the synthesisof many significant biologically active scaffolds. The feasible mechanistic path of this reaction
using newly prepared catalyst 29c was also explained by calculated the second order perturbation

39

energies of second donor [H-bond donor of squaramide] and acceptor (oxygen atoms of isatin 30a
and nitromethane 7) and hydrogen bond distances between catalyst 29c and isatin 30a, andnitromethane 7.12

40

Chapter 3
The New Hybrid Type Squaramide Fused Amino Alcohol
Organocatalysts For Enantioselective Diels-Alder Reaction of 3Hydroxy-2-Pyridones with Maleimides

413.1 Introduction
The Diels-Alder reaction is a classical organic reaction using with conjugated diene anddienophile to form a cyclohexene system, it’s also refered as a [4+2] cycloaddition reaction. The
DA reaction discovered by Otto Diels and Kurt Alder in 1928 (Scheme 34). For their tremendous
contribution presented Nobel prize in chemistry in the year of 1950. The Diels-Alder reaction is
also reliable practical method for constructing the complex bicyclic compounds in syntheticorganic chemistry.

∆
diene + dienophile

cyclohexene

Scheme 34. General representation of Diels-Alder reaction
The [4+2] cycloaddition reaction usually employs with a diene with electron deficient dienophile,in which the diene and dienophile involves an electrocyclic reaction the where diene contributes
4π-electrons while the dienophile contributes 2π-electrons to afford the cyclohexene framework.
In the case of an alkynyl dienophile, the initial adduct can still react as a dienophile if not too
sterically hindered (Scheme 35).31
Y

diene

Y

∆

+
alkenecyclohexene

Y

diene

Y

∆

+

alkyne1,4-cyclohexene

Scheme 35. Diels-Alder reaction using different dienophiles423.1.1 Mechanism of Diels-Alder reaction
The mechanism of Diels-Alder reaction obeys concerted pericyclic reaction pathway. The
reaction follows in a single concerted pathway, during the course of reaction no intermediates areformed. In the mechanism of Diels-Alder reaction the electron rich diene reacts with electron
withdrawing dienophile. Usually it follows [4πS+2πS] cycloaddition, representative that itproceeds through the suprafacial-suprafacial interactions of a 4π-electron system of the diene with
a 2π-electron system of dienophile, an interaction that is thermally allowed called as [4n+2]
cycloaddition (Figure 11).
normal demand

inverse demand
EWG

EDG

+

+

EDG

Diene

EWG

Dienophile

Diene

LUMO

Dienophile

HOMO

LUMO
HOMO

Figure 11. Pictorial representations of frontier molecular orbitals of Diels-Alder reactions
In a normal electron-demand DA reaction predominately occurs between electron rich dienes andelectron deficient dienophiles, while in the case of inverse electron demand DA reaction iscontrolled by electron withdrawing dienes with electron rich dienophiles to afford the DA
adducts.32

43

3.1.2 Regioselectivity of Diels-Alder reaction
The frontier molecular orbital (FMO) analysis is used to explain the regioselectivity
outlines in Diels-Alder reactions. The diene and dienophile resonance effects can be taken inconsideration to assume the regioselectivity of the DA reaction. The figure depicted below shows
the partial moment of resonance charges in a diene creates more electron density towards electron
donating group. In the case of dienophile, the partial resonance charges moment is towards electron
withdrawing group, by these phenomena of resonance effects in diene and dienophiles it’s easy to
predict the regioselectivities of DA reaction (Figure 12).
EDG

EDG
EDG

EDG

EWG

EWG

EDG = Electron Donating GroupEWG = Electron Withdrawing Group-O−, -NR2, -NHR, -NH2, -OR, -OH-COR, -COOR, -CONH2

Figure 12. Diene, dienophile charge distribution
In a normal-demand DA reaction, the diene is bearing with an electron donating group at C1
position takes its major HOMO amount at C4, although the dienophile has the largest LUMO
factor at C2 combination of these factors affords the “ortho” product A. The diene containing at
C2 position as in case of B underneath has the more HOMO factor at C1, which allows the “para”
adduct. Parallel approach for the equivalent inverse-demand DA reaction takes place which gives
rice to related adduct depicted as C and D (Scheme 36).
EDG

EDG
+

EWG

EDG
+

EWG

EDG

EWG

EWG
B

A
EWG

EWG
+

EDG

EWG
+

EDG

EWG

EDG

EDG
C

D

Scheme 36. Regioselectivity in Diels-Alder reaction

44

3.1.3 Stereoselectivity in Diels-Alder reaction
The Diels-Alder (DA) reaction are concerted cycloaddition reactions i.e. thestereochemistry of the reactants which involves in DA reaction as retains in their corresponding
products. For example, the DA reaction of cyclopentadiene with dimethyl fumarate affords two
different products, the endo and exo, might conceivably be formed depending on the manner inwhich the diene and dienophile are disposed in the transition state. According to the endo addition
rule, in diene addition reaction two components arrange themselves in parallel planes. The afforded
bicyclic products as two isomers endo (74% yield) along with exo (26% yield) isomers is depicted
in following reaction. In a similar manner the DA reaction of trans-1,4-butadiene with maleic
anhydride produces two unequal amounts of trans and cis isomers in the course of DA reaction.
In this reaction the stereochemistry of the butadiene retains in the trans DA adduct as major
product (Scheme 37).33
CO2Me

Me

Me
H

O
+

CO2Me
CO2Me

+

CO2Me
CO2Me
endo
74%

CO2Me
dimethyl
fumarate

cyclopentadieneHH[4+2] cycloaddition

+

O

H
H
exo
26%

Me
H O

O

[4+2] cycloaddition

O

Me

O

H
Me

1,4-butadienemaleicanhydride

trans

+

O

O
H
Me

O

cis

Scheme 37. General representation of stereoselectivity in Diels-Alder reaction
3.1.4 The diene
The well explored dienes in DA reaction consists 1-methoxy-3-trimethylsiloxy-1,3butadiene moiety, it’s also referred as Danishefskys diene E, it has precise synthetic value forproviding unsaturated 1,2-cyclohexenone systems. Additionally, the Brassard developed 1,3alkoxy-1-trimethylsiloxy-1,3-butadienes

F,

and

Rawal

explored

1-dialkylamino-3-

trimethylsiloxy-1,3-butadienes G are well-studied in the course of DA reactions. And these45

unsaturated systems (dienes) with appropriate dienophiles provides synthetically valuable
complex motifs in the synthetic organic chemistry (Figure 13).34
TMSO

TMSO

RO

CH3

OR
OMe

TMSO
NR2

OTMS

Danishefsky's
diene E

Brassard diene F

Rawal diene G=

Si CH3CH3

R = alkyl

Figure 13. Most investigated dienes in Diels-Alder reaction
Most of the unstable o-quinodimethanes dienes usually generated by in-situ in the course of the
DA reaction at elevated reaction temperature. For generating o-quinodimethanes reactive species
pyrolysis method usually employed. For example, the benzocyclobutenes, benzosulfones, 1,4elimination of ortho- benzylic silanes, and sulfonyls, produces the unstable o-quinodimethanes
diene reactive species at high reaction temperatures and which can easily participate in the DA
reactions. Additionally, the reduction of a,a'-ortho benzylic dibromides results in the formationof unstable dienes (Scheme 38).

∆

Me

∆
-SO2

SiMe3
NMe3

50 °C
F−

Me

Br
Zn/Ag

Me

SO2

Br

Me

Scheme 38. In-situ generation unstable O-quinodimethanes dienes
3.1.5 The dienophile
The dienophiles posses with electron withdrawing groups on it, many different kinds of
dienophiles can take part in DA reactions.35 Usually they may be the derivatives of acetylene or
ethylene functional moiety containing simple acrylates, chromium bonded acrylates, cyclic

46ketones, vinyl sulfones, allenes, thioketones, nitroso-benzene and electron withdrawing
carboxylates.
O

O

O

CN

NO2

SO2Tf

O

Cr(CO)5

SO2Ph

SO2Ar

H

Ph

O
N

Ph

S
P

MeO2C

N
N

CO2Me

O

CO2Me
•

PhO2S

O
N

CO2Me

O

O

OMe

OMe

O

O
MeO2C

S
CO2Me

O
N
N

N Ph
CO2Me
O

Figure 14. Different types of dienophiles that undergo Diels-Alder reaction

47

Ts

O
N
S

S

O

3.1.7 Intramolecular hetero Diels-Alder (IMHDA) reaction
The intramolecular hetero-Diels-Alder (IMHDA) reaction is useful synthetic protocol insynthetic organic chemistry, it is an adaptable protocol for the synthesis of novel polycyclic
systems. By using this protocol, it is easy to construct the natural products and biologically active
compounds. Recently, Corey and Nicolaou36 has applied the IMHDA protocol to synthesis
macrocyclic dilactone family alkaloid such as, (+)-carpine and (+)-azimine, these natural products
are constructed using, the acylnitroso-DA (IMHDA) protocol (Scheme 39). The synthesis beganwith optically active (S)-1,2,4-butanetriol 32 as starting material. After the successive synthesis of
the compound 33 from 32 its reacted with NaIO4 to afford the compound 34 which was underwent
IMHDA reaction to afford the DA-adducts 35 and 36 as diastereomers. Among them the major
diastereomer 35 was applied for the total synthesis of (+)-azimine 37 and (+)-carpine 38.
OBn
OBn
OH

NHOH
OH

HO

H2O-DMF(50:1)
0 °C, 69%

O

OMOM

32

NaIO4

33
H
IMHDA

intra molecular
hetero Diels-Alder reactions

O

OBn
H

H
+

N
O

34

OBn
H

MOMO
35

36

(6.4:1)
H
N

H
N

MOMO

N
O

N
O

O

MOMO

O

Me

Me
O
O

O

O
O

O
O

Me

N
H

(+)-azimine 37

MeN
H(+)-carpine 38

Scheme 39. Importance of hetero Diels-Alder reaction in (+)-azimine and (+)-carpine synthesis

48

3.1.8 Intermolecular aza-Diels-Alder reaction
The catalytic enantioselective intramolecular aza-Diels-Alder reaction is remains mostadorable protocol for synthesizing many natural products. The aza-Diels-Alder reaction transforms
imines and dienes into a biologically active tetrahydropyridines. The significance of the aza-DielsAlder reaction is for the construction of a six-membered ring containing nitrogen functional.
Recently, Jacobson and his research group37 reported the total synthesis of (+)-Reserpine byemploying an aza Diels-Alder reaction strategy.
O
Me
PMBO

OMe

40
N

AcOH
toluene23 °C
aza-Diels-Alderreaction

39

N H
O
Ts
OHC
43

DCM

N

p-TsOH, toluene
piperidine>19:1 dr, 86%

N
MeO

N H
HO
Ts
OHC
44

MeO

N H
H
Ts
MeO2C

OMe

Ph

Me
N
O

t-Bu S
N
H

N
H

organocatalyst 41(+)-reserpine 45

Scheme 40. Importance of aza-Diels-Alder reaction in (+)-reserpine synthesis
49

OMe

OPMB

Ph
OMe

OPMB

H

H
OTMB

OMe

H

N
MeO

OPMB

N H
O
Ts
OTBS
42

MeO

HF/Py, Pyridine
THF, 0 °C to 23 °C
Dess-Martin Periodinane

H

N

organocatalyst 41

N
Ts

MeO

TBSO

NH2

A highly diastereoselective catalyst-controlled aza-Diels-Alder reaction between imine 39 and αsubstituted enone 40 were observed in the presence of chiral amino organocatalyst 41 providing
the desired DA-adduct 42. The obtained DA-adduct can undergo oxidation in the presence of DessMartin periodinane to afford the aldehyde 43. Further, the compound 43 was cyclized in thepresence of piperidine and p-TsOH in toluene to afford compound 44 with 86% yield. Additional
manipulation of compound 44 involving aldehyde oxidation/esterification, elimination/reductionof alcohol, de-protection of PMB ether and tosyl amine, and installation of the trimethoxybenzoyl(TMB) ester which led to the formation of targeted (+)-reserpine 45 (Scheme 40).
3.1.9 Oxo-Diels-Alder reaction
The oxo-Diels-Alder reaction usually employs of methyl pentadiene with formaldehyde toafford the dihydropyran ring systems. The oxo-Diels-Alder reaction was first reported in 1949
using a methyl pentadiene with formaldehyde (Scheme 41).38b
Me

Me
O
+

∆
H

Me
methylpentadiene

O

H
Me

formaldehyde

dihydropyran

Scheme 41. Oxo-Diels-Alder reaction
M. S. Sigman and his research group38a reported the enantioselective oxo-Diels-Alderreaction using oxazoline 48 based hydrogen bond catalyst. They developed the new elegance ofsegmental oxazoline catalysts that trigger aldehydes 47 via hydrogen bond formation. The
activated aldehydes can participate in highly enantioselective oxo-Diels-Alder reaction with diene
46 (Scheme 42).

50

Ph
O
Ph
Ph
N

OH

O
48

O

CH3COCl
Toluene−78 °C, 48h

R
TBSO
46

HN S

O
catalyst (20 mol %)

O

+

N

O

47

R

O
49

R = alky, aryl.

up to 80% yield
up to 92% ee

Scheme 42. Importance of oxo-Diels-Alder reaction for chiral dihydro-pyrans3.1.10 Thio-Diels-Alder reaction
Recently K. A. Jørgensen and his research group39 reported a enantioenriched sulfur-based
heterocycles by TMS prolinol organocatalyst 52. The catalytic enantioselective Diels-Alderreaction of dienal 50 with dithioester 51 affords the corresponding chiral dihydrothiopyrans 53 inboth good chemical yields (up to 89%) and enantioselectivities (up to 92% ee) (Scheme 43).

N
H

CHO
Bn

O

CHO

52
(5 mol %)

S
+

Ph
Ph
OTMS

SEt

PhCO2H (20 mol%)OS

4 °C, 72 h

CO2Bn
SEt

50

51

53

dienaldithioester

dihydrothiopyrans
up to 89% yield
up to 92% ee

Scheme 43. The oxo-Diels-Alder reaction to synthesis of chiral dihydrothiopyrans3.1.11 Amino alcohol catalyzed enantioselective Diels-Alder reaction
Recently from author research group11f reported the enantioselective Diels-Alder reactionof 1,2-dihydropyridines 54 with acrolein 55 using a simple primary β-amino alcohol catalyst 56
which afforded the, chiral isoquinuclidines 57 in both excellent chemical yields (up to 96%) andenantiomeric excess (up to 98% ee). In addition, the obtained chiral isoquinuclidines are51

successfully converted in to TBS protected chiral piperidines 58 which upon de-protection in thepresence of TBAF afforded the optically aactive chiral piperidine 59 having four continuous
stereogenic-centers (Scheme 44).

H2N

R4

Ph
Ph
OH
CF3CO2H56
β-amino alcoholorganocatalyst

R5

R3

R6

R2

β-amino alcoholorganocatalyst 56(10 mol%)

R7
+

N
CO2R1

ACN-H20
0 °C, 24-36 h

O

54

R2
R1O2C
3
N R
R7
R4
R5

R6

CHO

55

57

1,2-dihydropyridines

acrolein

R1 = Ph or Bn

R7 = H, CO2Me or CN

chiral isoquinuclidines
up to 96% yield
up to 98% ee

R2-6 = H, Me, Ph or allyl

CO2Mechiralisoquinuclidines

HO
N
CO2Bn
58

CO2Me
TBAF

OTBS
OH

HO

OH
OH

N
CO2Bn
59
optical active piperidines

Scheme 44. b-Amino alcohol organocatalyst catalyzed enantioselective Diels-Alder reaction
3.2 Base catalyzed Diels-Alder reactions
Y. Yamamoto and his research group40 reported the enantioselective base catalyzed DielsAlder reaction of anthrone 60 with 2-tert-butyl-phenylmaleimide 61 using pyrrolidine derivative as
basic organocatalysts 62. They obtained the corresponding DA-adduct 63 in excellent chemical yield(up to 97%) and with good enantioselectivities (up to 87%) (Scheme 45).
N

HO

N
O

O
+

HO
catalyst (10 mol %)Nanthrone

O
N
O

CHCl3, rt

O tBu
60

tBu

62

HO

61
2-tert-butyl
phenyl maleimide

63
up to 97% yield
up to 87% ee

Scheme 45. The base catalyzed Diels-Alder reaction of anthrone with 2-tert-butyl-phenyl maleimide52

H. Okamura and his research group41 reported the enantioselective base catalyzed DielsAlder reaction of 3-hydroxy-2-pyrone 64 with optically active acrylate 65 using with catalyst 66, toafford DA-adduct 67 with >95% de. They also demonstrated the synthetic utility of obtained DAadduct for synthesizing (-)-theobroxide 68 (Scheme 46).

HO

O

N
66

O

O

H N

O

O

OH

catalyst (20 mol %)
O

+

OH

N

O

O

i-PrOH:H2O = 95:5

O
O

N

O

Ph

OH

64

65

Ph
67

3-hydroxy-2-pyrone

optically active
acrylatequant. >95% de

68(−)−theobroxide

Scheme 46. The base catalyzed Diels-Alder reaction of 3-hydroxy-2-pyrone with acrylate
D. W. C Macmillan and his research group42 reported the enantioselective Diels-Alderreaction using secondary amine imidazolidinone basic catalyst 71 of tryptamine 69 with enal 70 via
iminium pathway. Which afforded the structurally complex DA-adduct 72 in moderate yields (up to70%) and in excellent enantioselectivities (up to 95%). The obtained DA-adduct 72 was successfully
applied in the total synthesis (-)-vincorine 73 natural product using Diels-Alder/amine cyclizationcascade reaction strategy (Scheme 47).
Me

O
N
Ph
NHBoc

O

+

N
H

Me
Me
HBF4

Me
N

71
catalyst (20 mol %)

MeO2C

O

N
Me
70

tryptamine

enal

N

Me
H

N

CHO

MeCN, −10 °C
H

69

Me

BoC
N

O

CO2Me

CO2Me

72
up to 70 yield
up to 95% ee

Scheme 47. The base catalyzed Diels-Alder reaction of tryptamine with enal

53

H
H

O

73
(-)-vincorine

W. Yang and his research group43 reported the enantioselective Diels-Alder reaction ofenal 74 with diene 75 using catalyst 76 to afford the DA-adduct 77 in good chemical yield (up to88%) and in excellent enantioselectivities (up to 98%). And also, they demonstrated the synthetic
utility of obtained DA-adduct 77 for the total synthesis of (+)-propindilactone G 78 (Scheme 48).
Ph
N
H

Ph
OTES
76

catalyst (10 mol %)

O

OTIPS
+

EtO2C

OTIPS

74

75

77

diene

up to 98% ee
up to 88% yield

Me

O

Me

Me

H
OH

H

Me
H
Me

O

enal

O HO

H
O

TFA (20 mol %)PhMe, −10 °C, 7h

EtO2C

O

O

O
78

propindilactone G

Scheme 48. The base catalyzed Diels-Alder reaction of enal with diene
3.3 Previous reports on enantioselective Diels-Alder reaction of 3-hydroxy-2-pyridones withelectron withdrawing dienophiles.
H. Okamura and his research group41a reported base catalyzed Diels-Alder reaction of 3hydroxy-2-pyridones 79 with dienophiles 80 using triethyamine as base, to afford 4hydroxyisoquinuclidines 81 and 82 with 76% yield (Scheme 49).

Z

X
O

OH

+
R

Et3N
DCM, rt60 h, 76%

Ts
N

O

+
X
R

HO

79

80

81

Z = O, N-Ts

X = EWG
CO2Me, COMe

endo

O

Ts
N
R
X

HO
82
24:1

exo

Scheme 49. The base catalyzed Diels-Alder reaction of 3-hydroxy-2-pyridones with dienophiles
C.-H Tan and his research group reported44 the enantioselective Diels-Alder reaction using
3-hydroxy-2-pyriodones 83a-c with maleimides 84 using a simple new type bifunctional aminoindanol catalysts 85a-d, among the optimized catalysts, the catalyst 85a have showed the best
catalytic activity for afford the chiral 4-hydroxyisoquinuclidines in both excellent chemical yields(up to 97% yield) and enantioselectivities (up to 96% ee) (Scheme 50).

54

N

O

SO2Ar
+

O

N R

OH

O

85a (10 mol %)DCM, 20 h−50 °C

O

N

SO2Ar

HO
O

O
N R

83a-c

84

86

83a: Ar = 2,4,6-Me3C6H5 (Mes)
83b: Ar = 3,5-Me2C6H3
83c: Ar = 2,3,4,5-6-Me5C6

R = alkyl, arylchiral 4-hydroxy
isoquinuclidines
up to 97% yield
up to 96% ee

OH

OH

OH

OH
N

N

N

N

85a

85b

85c

85d

Scheme 50. Enantioselective Diels-Alder reactions of 3-hydroxy-2-pyridones with maleimides
using amino-indanol organocatalysts

55

Recently from author research group reported the simple primary b-amino alcohol45
catalyzed Diels-Alder reaction of 3-hydroxy-2-pyridones 87 as dienes with N-substituted
maleimides 88 as dienophiles to afford the highly substituted optically active isoquinuclidines 90
as a single diastereomers in excellent enantioselectivities (up to 98%) with excellent chemicalyields (up to 95%). In this study, a range of simple b-amino alcohols 89a-i were synthesized fromthe corresponding inexpensive amino acids and their catalytic activity was examined for thisreaction. Among them, catalyst 89a was found to be best catalyst for affording the chiral 4hydroxyisoquinuclidines (Scheme 51).
N

O

SO2Ar
O

+

89a (10 mol %)

N R

OH

DCM, 6 h87

88

Ar = Ts, Mes

R = aryl, alkyl

H2N
89a

HN
89e

H
OH

Ph
Ph
OH

N
89f

O
90

Ph
Ph
H

H2N

O
N R

Ph
Ph
OH

N
89g

H2N

Ph
Ph
O

HN

O
89d

89c

89b
Ph
Ph
OH

SO2Ar

up to 95% yield
up to 98%

H
H2N

N

HO

rt

O

Ph
Ph
OH

O

Ph
Ph
OTMS
89h

Ph
Ph
NH2

H2N
89i

Scheme 51. b-amino alcohol oraganocatalyzed Diels-Alder reaction of 3-hydroxy-2-pyridone withmaleimides

563.4 Author strategy
Author aimed to develop the simple primary b-amino alcohol X and their derivatives as a
new class of organocatalysts, since they are easy to synthesize, stable on exposure to air, an
inexpensive alternative to the other primary amino organocatalysts such as a chiral diamines andcinchona derived primary amines (Figure 15). Most recently, author successfully developed the
new hybrid type squaramide fused aminoalcohol (SFAA) Y and revealed the utility as theorganocatalyst in the enantioselective nitro-aldol reaction of nitroalkanes with isatins to afford
chiral 3-alkyl-3-hydroxyoxindoles, which is useful intermediate for biologically active
compounds. The Diels-Alder (DA) reaction using 3-hydroxy-2-pyridones 91 as dienes in thepresence of dienophiles using SFAA organocatalysts provides synthetically valuablemultifunctional chiral 4-hydroxy-isoquinuclidines 92.
Brønsted
basic site
F3C
R
H2N

*

Ph
Ph
OH

F3C

β-amino alcohool
organocatalyst
X

O
N
H

O

R
N
R
N *
Ph
H
Ph
HO

hydrogenbonding sites
stericinfluencesquaramide fused amino alcoholorganocatalysts
Y

Figure 15. Functionality of squaramide fused amino alcohol (SFAA) organocatalysts
The obtained isoquinuclidines can be easily access to the many biological active compounds suchas oseltamivir (Tamiflu) 93 to prevent both influenza A and B virus. Furthermore, DA adduct also
plays key precursors for the synthesis of ibogaine 94 which is a naturally occurring psychoactive
compound and anticancer drug. And also, isoquinuclidines are the primitive intermediates forsynthesis of vinblastine 95a and vincristine 95b natural products, these natural products play keyrole in chemotherapy medication (Scheme 52).

57

OH
R'

dienophiles

NOR
3-hydroxy-2pyridone
91

Diels-AlderreactionOR
N
biologically active
compounds
R'

HO

SFAA
organocatalystchiral4-hydroxyisoquinuclidines
92

N
N
H
MeOOC
MeO

O
O

OEt

HN
O

NH2

H3PO4

93
oseltamivir (Tamiflu)(antiinfluenza drug)

N

MeO

N
H
94
ibogaine(psychoactive drug)

N

HO

OH
N
H
R

OAc

95a : vinblastine, R = Me
95b : vincristine, R = CHO(anticancer drug)

Scheme 52. Synthetic utilities of 4-hydroxyisoquinuclidines
3.4.1 Results and discussions
To further expand the efficiency of SFAA as an organocatalyst, author tried the DA
reaction of 3-hydroxy-2-pyridones with dienophiles using chiral SFAA organocatalyst. As aconcept of the expression of enantioselectivity in this reaction using SFAA catalyst, the reaction
might be proceeding through a transition state A, in which the anionic oxygen at 3-position on thepyridones might be fixed by the hydrogen bonding interactions with the ammonium site on catalyst(Scheme 53). Furthermore, the amide oxygen atom of pyridones might be fixed by the hydrogenbonding interactions with two amino hydrogen atoms of the squaramide part on the catalyst, thendienophiles might attack stereoselectively from the less steric interaction site of the fixed dienes
to furnish the chiral isoquinuclidines. The hybrid type squaramide fused amino alcohol (SFAA)
having both Brønsted basic site and hydrogen bonding site in the molecule showed high catalytic
activity as an organocatalyst in the enantioselective Diels-Alder reaction (DA) of 3-hydroxy-2pyridones with maleimides to afford the chiral endo-4-hydroxy-2-azabicyclo[2.2.2]octanes (4hydroxy-isoquinuclidines) with excellent chemical yields and enantioselectivities (up to 95%, up
to 98% ee). Particularly, the use of 4-brominated 2-pyridones afforded the corresponding chiral4-hydroxyisoquinuclidines in both excellent chemical yield and enantioselectivity (95%, 98% ee)
having an opposite absolute stereochemistry in comparison with the chiral endo-DA adduct fromthe reactions using common 3-hydroxy-2-pyridones. The obtained DA adducts could be used as58

synthetic precursors for the synthesis of several natural products that have a broad spectrum offascinating biologically activities.
3-hydroxy-2pyridones

F3C

+
F3C

O
R
R
O

O
N
H

O

R
N
R
N
Ph
*
H
HO Ph

F3C

steric influence
O

O

N
H

F3C

O

SFAA organocatalyst
hydrogenbonding

dienophiles

R

N

O

OH
Ph
Ph Brønsted
N
basic site
*
H
H N R
O

R R

R
ionic hydrogen
O bondingtransition state A

Scheme 53. Concept of SFAA orgaanocatlysts for Diels-Alder reaction

59

O

HO

R
N

O

O
RR

chiral4-hydroxyisoquinuclidines

3.4.2 Enantioselective Diels-Alder reaction using catalysts 29a-e
First, author examined the catalytic ability of SFAA catalysts 29a-e in the DA reactions ofcommon 3-hydroxy-1-tosyl-2-pyridone 96a and N-phenylmaleimide 97a in DCM as a solvent at
0°C (entries 1-5, Table 4). All reactions using catalysts 29a-e, which were easily prepared byauthor previous reported method, afforded the endo-DA adduct [1R,4R]-98a as a major isomer.
Table 4. Enantioselective DA reaction using catalysts 29a-e
F3C

O

+

R

29a: R=

29c: R=

29e: R=

N
Ts

N
N
Ph
H
H
catalysts HO Ph
29a-e

F3C

29b: R=N

29d: R=

N

N

O

OH

O

N Ph

O

O
97a

96a

N

catalyst 29a-e(10 mol%)O

DCM, temp.
24 h

HO

O

S

O

yield
[%]b

ee
[%]c

87
95

64
21

1

a

2

b

0
0

3
4

c
d

0
0

89
49

28
14

5

e

0

43

5

6

a

-20

67

28

-80

57

23

7

N

O
Ph

endo-[1R,4R]-98a

entrya catalyst temp.
29a-e (°C)

N

Ts
N

a

aThe reactions were carried out with 96a (0.07mmol), 97a (0.08 mmol) in DCM (1.0 mL).
bIsolated yields. cEnantiomeric excess wasdetermined on chiral HPLC using Chiralpak AS-H
column.

The catalyst 29a having a basic pyrrolidine ring at side chain showed a good catalytic activity andafforded the DA adduct 98a with good chemical yield and moderate enantioselectivity (87%, 64%ee, entry 1). However, both catalysts, 29b having piperidine ring and 29c having azepane ring, atside chain gave 98a with low enantioselectivities, although chemical yields were fairly good(entries 2,3). Furthermore, catalyst 29d having morpholine ring or catalyst 29e having
thiomorpholine ring at side chain did not show satisfactory catalytic activities in this reaction
conditions (entries 4,5). In addition, the reaction using superior catalyst 29a also tried at low
temperatures (-20°C and -80°C). Although expecting enantioselectivity were not afford anymore,chemical yields were moderate (entries 6,7). From the above results, author revealed that catalyst
29a having five membered pyrrolidine ring system as a Brønsted basic site at side chain is better

60

for obtaining satisfactory results for chemical yield and enantioselectivity.
3.4.3 Optimization of DA reaction conditions using catalyst 29a
In order to optimize the reaction conditions using the superior catalyst 29a, author next
examined the effect of the molar ratio of catalyst 29a, the effect of solvent and reaction time (Table5). The decrease of catalytic loading of 29a to 5 mol% resulted in a slight decrease in the chemicalyield (50%) and a substantial decrease the enantioselectivity (42% ee) (entry 1). The increase of
catalytic loading of 29a to 20 mol% resulted in a slight increase in the chemical yield (90%), but
enantioselectivity was decreased to 32% ee (entry 2) than that of the reaction containing 10 mol%of 29a (entry 1, Table 5), although the reason is not clear. To further improve the enantioselectivity,
author also examined the solvent effects on this reaction. Commonly used aprotic nonpolar(CHCl3, ClCH2CH2Cl, MTBE, Et2O, THF, 1,4-dioxane, toluene, PhCl, xylene) and polar protic(MeOH) solvents were screened, respectively (entries 3-12). The endo-[1R,4R]-98a were obtainedin all solvents with moderate to good chemical yields (62-92%), but enantioselectivity were poor
to low (2-42% ee, entries 3-12). Unfortunately, no improvements in enantioselectivity wereobserved in these solvents in comparison with the use of CH2Cl2 (entry 1, Table 5). Under the best
reaction conditions (DCM, 29a: 10 mol%, 0°C), the reaction time was extended to 48 h and 96 h,
respectively, led to an increase in the chemical yields, although the satisfactory enantioselectivities
were not observed in both reaction times (entries 13,14). From these results, author clarified thatthe use of 10 mol% of catalyst, 0°C of the reaction temperature, and 24 h of reaction time is thebest reaction conditions.

61

Table 5. Optimization of DA reaction using catalyst 29a

O

OH

+
N
Ts

O

N Ph
O
97a

96a

catalyst 29a(10 mol%)Osolvent, 0 °C
time

HO

Ts
N

N
O

O
Ph

endo-[1R,4R]-98a

entryacatalyst(mol %)

time (h)solventyield [%]bee [%]c

1

5

24

DCM

50

42

2

20

24

DCM

90

32

3

10

24

CHCl3

85

7

4

10

24

DCE

82

28

5

10

24

MTBE

82

−9

6

10

24

Et2O

72

7

7

10

24

THF

70

37

8d

10

24

1,4-dioxane

62

10

9

10

24

toluene

78

23

10

10

24

PhCl

92

37

11

10

24

xylene

87

42

12

10

24

MeOH

85

−2

13

10

48

DCM

92

33

14

10

96

DCM

98

38

aThe reactions were carried out with 96a (0.07 mmol), 97a (0.08 mmol) inabove mentioned solvents (1.0 mL). bIsolated yields. cEnantiomeric excess
was determined on chiral HPLC using Chiralpak AS-H column. dThe reaction
was conducted at room temperature.

62

3.4.4 Substrate scope for enantioselective DA reaction using catalyst 29a
Under the optimized reaction conditions, wide ranges of the DA reaction with 2-pyridones
96a,b and maleimides 97b-k were investigated using superior catalyst 29a to afford thecorresponding endo-DA adducts 98b-k and the results are shown in Table 6. First, the reaction of
2-pyridone 96a with several maleimides 97a-i using catalyst 29a (10 mol%) were examined under
optimized reaction condition (DCM, 0°C, 24 h), respectively. The use of N-methylmaleimide 97b
afforded the corresponding DA adduct 98b in an excellent chemical yield (96%), although theenantioselectivity was low (22% ee) (entry 1). The use of N-ethylmaleimide 97c also afforded 98c
in a fairly good chemical yield (90%) and the enantioselectivity also slightly increased to 25% ee(entry 2). Moreover, the reaction of 96a with maleimides 97d-i having electron-donating orelectron-withdrawing groups at 4-position on phenyl group.
Table 6. Substrate scope for DA reaction of pyridones using catalyst 29a

O

OH

+
N
R

O

N R'

DCM, 0 °C
24 h

O

96a,b
entrya dienecatalyst 29a(10 mol%)

97b-k
R

96

R
N

O

HO

O

N
O

R'

98b-k
endo only

dienophileR'

DA adduct
98

yield [%]bee [%]c

97

1

a

Ts

b

Me

b

96

22

2

a

Ts

c

Et

c

90

25

3

a

Ts

d

4-MePh

d

90

20

4

a

Ts

e

4-NO2Ph

e

ndd

nd

5

a

Ts

f

4-FPh

f

89

36

6

a

Ts

g

4-ClPh

g

85

34

7

a

Ts

h

4-BrPh

h

92

42

8

a

Ts

i

4-IodoPh

i

78

37

9

b

SO2Mes

j

Ph

j

92

22

10

b

SO2Mesk

4-BrPhk

95

39

aThe reactions were carried out with 96a,b (0.07 mmol), 97b-k (0.08 mmol) in DCM(1.0 mL). bIsolated yields. cEnantiomeric excess was determined on chiral HPLC
using Chiralpak AS-H column. dNot determined

63

Additionally, N-(4-methylphenyl)maleimide 97d did not afford the corresponding DA adduct 98d
in a satisfactorily enantioselectivity (20% ee), although the chemical yield was fairly good (90%)(entry 3). The reaction with N-(4-nitrophenyl)maleimide 97e having a strong electron-withdrawing
nitro group at 4-position on phenyl group was not proceed to obtained the endo-98e, why thereason is not clear (entry 4). Furthermore, the use of maleimides 97f-i having halogeno group at
4-position on phenyl group afforded the corresponding DA adducts 98f-i in good chemical yields(78-92% ee), but satisfactory enantioselectivities were not obtained (34-42% ee) (entries 5-8) inthe optimized reaction conditions. Author also examined the DA reaction of more steric hindered
3-hydroxy-1-(2,4,6-trimethylphenylsulfonyl)-2-pyridone 96b with maleimides 97j,k respectively.
However, contrary to expectation, the desired endo-DA adducts 98j,k did not obtained withsatisfactorily enantioselectivity (98j: 22% ee, 98k: 39% ee) (entries 9, 10), but, the chemical yields
were sufficient (98j: 92%, 98k: 95%) similar to most of used maleimide dienophiles 97a-d,f-i.
3.4.5 Enantioselective DA reaction of substituted pyridones using catalyst 29a
Author next evaluated the asymmetric DA reactions of 4-halogenated or bulky alkylated
3-hydroxy-2-pyridones 99a-d with maleimides 100a-f using catalyst 29a (10 mol%) at the
optimized reaction conditions (DCM, 0°C, 24 h) (Table 7).
Table 7. Substrate scope for DA reaction of substituted pyridones using catalyst 29a
X

O

OH
+
N
O
R
99a-d

entrya diene

DCM, 0 °C
24 hO
100a-f

R

X

99

O

catalyst 29a(10 mol %)

N R'

R
N

X HO

N

O
R'

O

101a-fendo only

dienophile

R'

100

DA
adduct

yield
[%]b

ee
[%]c

101

1d

a

Ts

Br

a

Ph

a

95

98

2

a

Ts

Br

b

4-BrPh

b

89

75

3

a

Ts

Br

c

Me

c

90

65

4

b SO2Mes

Br

d

Ph

d

92

64

5

c

Ts

Allyl

e

Ph

e

93

74

6

d

Ts

Propyl

f

Ph

f

90

50

aThe reactions were carried out with 99a-d (0.07 mmol), 100a-f (0.08 mmol) in DCM(1.0 mL). bIsolated yields. cEnantiomeric excess was determined on chiral HPLC
using Chiralpak AS-H and chiralcel OD-H columns. dThe aboslute configuration of
101a was determined by X-ray.

64

First, author tried the reaction using 2-pyridones 99a-d having halogeno group at 4-position on
pyridone ring. The enantioselective were observed to increase in all reactions with corresponding
endo-DA adducts 101a-f moderate to excellent enantioselectivities (64-98% ee) and in excellent
chemical yields (89-95%, entries 1-6). In particular, a dramatic increase in enantioselectivity (98%ee, entry 1) was observed in the reaction of 4-brominated-2-pyridone 99a with 100a to afford theDA adduct (1R,4S)-101a, which has the opposite absolute configuration in comparison with DA
adduct (1R,4R)-101a obtained from the reaction of 99a with 100a (entry 1, Table 7). The absolutestereochemistry of [1R,4S]-101a was determined by X-ray analysis (Figure 16). And also, an
improvement of enantioselectivity was conformed in the reactions using 2-pyridones having allyl
and propyl functional groups at 4-position on pyridone ring (entries 5, 6). Although the reactions
afforded the corresponding DA adducts 101e,f with high chemical yields, the enantioselectivity
were moderate to good (101e: 93%, 74% ee, 101f: 90%, 50% ee) (entries 5, 6). From these results,
it might be indicated that the steric influence of substituent group at 4-position on pyridone ringmight participate to fix the direction of diene in the transition state for increasing ofenantioselectivity.

H3C

O S

O

N
O

Ph

N
O

O

OH Br

[1R,4S]-101a

Figure 16. Absolute stereochemistry of DA-adduct 101a by X-ray analysis

65

3.4.6 Plausible reaction course of the 3-hydroxy-2-pyridone 96a with N-phenyl maleimide
97a using catalyst 29a.
O

-0.6370.427

HO-0.563

OH
N
Ts

O

96a
catalyst 29a

Mulliken Charge Distribution

OH
O
O
F3C

N

N
H

N
H

O

O

H

O

F3C

Ts N
I-A

OH

OH
O

O
O
F3C

N

F3C

O

N
Ph
97a

O

N
H

H

O

O

H

N

F3C
O
F3C

Ph

N
O

O

O

O

OH

HO

98a'

O
N Ph

under side
attack
Ts-2: favoured

Ts-1: unfavoured
Ts
N

N
H

Ts N

O
upper side
attack

O

H
O

N Ph

Ts N

N

N
H

Ts
N

64% ee
O

N
O

O

Ph

[1R, 4R]-98a
major isomer

Scheme 54. Plausible reaction course of pyridone 96a with N-phenyl maleimide 97a using catalyst
29a66Based on the both observed enantiopurities (98a: 64% ee, entry 1, Table 4; 101a: 98% ee, entry 1,
Table 7) of chiral DA adducts 98a or 101a that were obtained from the reactions of 96a with 97aor 99a with 100a, and site of the highest electron density (Mulliken charge distribution) in 96a and99a the following enantioselective reaction mechanism were proposed (Schemes 54 and 55). First,
the reaction with 96a might proceed through the more stable transition state Ts-2 than Ts-1 toafford [1R,4R]-98a. Thus, 3-hydroxy-2-pyridone 96a might be fixed with catalyst 29a through thehydrogen bonding interactions of both between the amide oxygen atom of 96a and the two primaryamino hydrogen atoms on the squaramide part of 29a and between the hydrogen atom of theammonium moiety on the pyrrolidine ring of 29a and the anionic oxygen atom at 3-position of 96a(intermediate: I-A). Then, when dienophile 97a attacks on pyridone moiety, the reaction mightproceed through the upper face of anionic pyridone coordinated to catalyst in the transition state(Ts-2) that has less steric interactions between the diamino alcohol part on catalyst 29a and 96athan that of Ts-1 that has more steric interactions (Scheme 54).
3.4.7 Plausible reaction course of the reaction of 4-bromoro-3-hydroxy-2-pyridone 99a with
with maleimide 100a using catalyst 29a.
On the other hand, the reaction of 99a with 100a affording [1R,4S]-101a might proceed
through Ts-4 than Ts-3 (Scheme 55), based on three facts (a)-(c): (a) the reaction proceeded witha high enantioselectivity (98% ee), (b) the obtained DA adduct 101a has an opposite absolutestereochemistry in comparison with the DA adduct 98a obtained from the reactions using 96a and97a, and (c) the site of the highest electron density (Mulliken charge distribution) of 99a was on
the oxygen atom of the amide moiety. Thus, the hydroxyl proton is abstracted from 99a by thebasic tertiary amino group of the pyrrolidine ring of 29a to form intermediates B or C, which might
be fixed by two places of hydrogen bonding interactions both between the hydrogen atom of theammonium moiety of the pyrrolidine ring of 29a and the anionic oxygen atom at 3-position of 99a
and between two primary amino hydrogen on the squaramide part of 29a and the amide oxygen
atom of 29a. In the intermediates I-B or I-C, the intermediate I-B might be more advantageousthan I-A that has larger steric interactions between the bromine atom on pyridone and thepyrrolidine ring of catalyst. And then, the reaction with dienophle 100a might proceed through thetransition state Ts-4 that has less steric interactions between the catalyst part and 99a than Ts-3
that has more steric interactions (Scheme 55).

67

.

Br
-

OH

-

O

N
Ts
99a

Mulliken Charge Distribution

catalyst 29a

OH

OH
O

O

O
F3C

N

O

N
H
H

O

O
F3C

Ts N

F3C

N
H
Br steric repulsion
for upper side

N
H

N

H
O
Ts N
I-C

O

N
Ph
97a

O

OH

OH
O

O
N

O
N

CF3

H
Br

F3C

I-B

F3C

N
O

H

N

O
H

O

N
O H
Br

Ts N

N

F3C
O steric repulsion
for under side
N Ph

CF3

N

H
H

O

O H

Ts N

N Ph
O

O
Ts-4: favoured

Ts-3: unfavoured
Ts
N

Ts
N

O
Br

Br O

HO

O
101a'

N

O
Ph

O

98% ee

O
Br
N
OH
Ph O
[1R, 4S]-101amajor isomer

Scheme 55. Plausible reaction course of 4-bromo-3-hydroxy-2-pyridone 99a with N-phenyl
maleimide 97a using catalyst 29a68

3.5 Summary
Author demonstrated that new hybrid type squaramide fused aminoalcohol (SFAA) 29a
containing both Brønsted basic site and hydrogen bonding site in the molecule showed highly
catalytic activity as an organocatalyst in the enantioselective Diels-Alder reaction of 3-hydroxy2-pyridones 96a,b and 99a-d with maleimides 97a-k, 100a-f with excellent chemical yields andenantioselectivities (up to 95%, up to 98% ee).46 Particularly, the reaction of 4-brominated 2pyridone 99a with maleimides 97a afforded the corresponding 4-hydroxyisoquinuclidines 101a in
both excellent chemical yield and enantioselectivity (95%, 98% ee) having an opposite absolutestereochemistry in comparison with the DA adduct 98a from the reactions using common 3hydroxy-2-pyridone 96a.

69

Chapter 4
The New Hybrid Type Squaramide Fused Amino Alcohol
Organocatalysts For Enantioselective Domino Michael Addition
Cyclization Reaction70

4.1. Introduction
The class of 2-amino-pyrans has been known for several decades. The first representative’s
pyranopyrazole A and pyranopyranone B are from the late 1950s to the early 1960s. Spiroconjugated pyranopyrazole A was obtained in studies on pyrazolone dyestuffs, while
pyranopyranone B served as a precursor for the blood anticoagulant warfarin (Figure 17).
Ph

O

N N
H3C O

CH3
CN

Ph
CN

O

N

O

N
NH2
O
Ph
pyranopyrazole A

NH2pyranopyranone B

Figure 17. The first representatives of 2-aminopyrans
The formation of the pyran ring, bearing an amino group in 2-position, tends to be reversible. The
presence of a strong electron-withdrawing substituent in 3-position (e.g., CN, COR, CO2R) seems
to be crucial for the stability of these compounds. Since the middle 1970s there has been rapid
progress in the chemistry of 2-amino-4H-pyrans, studies on their physicochemical properties, aswell as various types of biological activity. In recent years, modern techniques were applied toaminopyran synthesis, such as, catalytic electro generation, microwave and ultra-sonic assistance,
the use of “green” solvents, and solid-phase synthesis. Reviving interest in 2-aminopyrans can be
attributed to the discovery of new types of biological activity compounds.47
4.1.1 Appearance
Most of the 2-amino-pyrans are colorless, pale-yellow, or pale-cream crystals with highmelting points. They are readily soluble in aromatic hydrocarbons, alcohols, acetone, acetonitrile,chloroform, DMF, and DMSO, and nearly insoluble in hexane and water.
4.1.2 UV spectroscopy of 2-aminopyrans
UV spectroscopy is used as a supplementary method for characterization of 2-aminopyrans
and most correspond to π-π* and π-n electron transfers of C=C-O and C=C-N fragments, as wellas to π-π* transfers of aryl substituents. Compound C 13 reveal a single absorption maximum at296-305 nm, more recently at 206, 243, and 297 nm (when X = CN), and 208, 265, and 298 nm(when = COOMe). Signal maxima at 225-230 nm characterize 2-aminopyrans, while the71tetrahydrochromene D shows maxima at 220 and 269 nm (Figure 18).48
R'
NC

H3C

X

R

NH2
O
C
X = CN, CO2Et,
R, R' = Aryl

H3C

CH3
CN
O

NH2

D

Figure 18. Prominent functional groups of 2-aminopyrans in UV spectroscopy
4.1.3 IR spectroscopy of 2-aminopyrans
Stretching vibrations of an -NH2 group 3450-3200 cm-1 are always present in IR spectra of
2-aminopyrans. special analysis of IR and Raman spectra on a series of non-annulated pyrans has
been carried out. One or several bands in the 1650-1590 cm-1 region, attributed to bending
vibrations of -NH2 and stretching vibrations of C=C, are also characterstics for aminopyrans. Morepropably, these bands correspond to the superposition of d (NH2) and v (C=C) vibrations. A generalfeature of 3-cyanopyrans is the presence of a highly intense stretching band of the -CN group(2205-2180 cm-1). The very high intensity and low-frequency shift possibly can be connected witha developed system of electron π-π-conjugation in an enamino nitrile moiety. Notably, starting andintermediate nitriles used in the synthesis of 2-amino-3-cyanopyrans E show moderate to weak
nitrile group absorption at 2260–2220 cm-1 nitrile band is very characteristic (Figure 19).
C

N

H
N
H
2-amino-3-cyanopyran E
O

Figure 19. Characteristic vibrations of amine and nitrile functional groups in IR spectroscopy
4.1.4 NMR spectroscopy of 2-aminopyrans
NMR spectroscopy is the main method for characterization of 2-amino-4H-pyrans. Most
1

H NMR data were obtained using DMSO-d6 and CDCl3. The spectra always contain a signal forNH2 protons (br. s, 2H), but its chemical shift strongly depends on the nature of a 3-substituent
and conditions. The majority of known 2-aminopyrans contain a single alkyl or aryl substituent

72

R1. So 4H reveals its very characteristic signal at 4.10-4.60 ppm. When R1 is an aryl group withstrong electron-withdrawing substituent in o- or m-positions, the 4H proton singlet shifts downfield
to 4.50–5.50 ppm. When R1 is 2-O2NC6H4, a weak intramolecular hydrogen bond forms. A small
series of 6-unsubstituted 2-aminopyrans reveal an H(6) peak in the region 7.15-7.91ppm in
DMSO-d6 (Figure 20).48b
R1
R2

X

R3

NH2

O

R1 = alkyl, aryl.
R2 = aryl, COR, CO2R, CN
R3 = alkyl, aryl
X = CN, CO2R

substituent X

solvent

CN

CDCl3
DMSO-d6chemical shift (ppm)
4.50-4.82
6.50-7.50

CO2R

CDCl3

6.20-6.30

DMSO-d6

6.50-7.50

Figure 20. Prominent 1HNMR signals of 2-aminopyrans4.1.5 Methods of synthesis
The most widely known 2-aminopyrans contain a primary amino group, generalized in(Scheme 56).
O

R''
+

R
R'

O

102
activemethylenecarbonylcompounds

R'''
EWG

Michaeladdition

O

H

R

N

R'
103

R''
*

R'''
EWG

O

N

104

unsaturated
nitrilesintramolecularcyclization

O R''
*

R
R'

R'''
H EWG

O

NH

O R''
R
R'

R'''
*

EWG

O

NH2

2-iminopyran

2-aminopyrans

105

106

Scheme 56. General method of 2-aminopyran synthesis

73

The general synthetic approach involves cyclization of Michael adducts 104 via nucleophilic
addition of an enolic oxygen 102 to a nitrile group 103 and subsequent tautomeric shift of theresultant 2-iminopyran 105 to 2-aminopyran 106.49
4.2 Synthesis of spiro-conjugated 2-aminopyrans
In contrast to acyclic monoketones, which usually do not form aminopyrans, reactions ofcyclic ketones or their cyanomethylene derivatives with methylene-active carbonyl compounds
gives spiro-conjugated 2-aminopyrans. Their syntheses are represented by fewer examples
relatively to 4-arylpyrans, but many them latter draw attention due to their promising biologicalactivities. The first example of reaction of 3-cyanomethyleneindol-2-one 107 with 1,3dicarbonylcompounds 108 results in the formation of a series of spiro-annulated pyrans 109(Scheme 57). The tert-butylacetoacetate also reacts with 3-(dicyanomethylene)-indo-2-one 110 inthe similar manner. Acetone and acetophenone 111 undergo Michael addition toward, but adducts
112 do not cyclize into pyrans due to their relatively low degree of enolization. On reduction of
the latter adduct 113 by sodium borohydride, the -OH group thus formed immediately attacks thenitrile group with cyclization into 5,6-dihydropyrans 114.49c
Z

CN

HN

R
+

O

O

N
H
107
Z = CN, CO2Et

O
R

HN
R1

108
R = COMe, CO2Et, COPh, H

EtOH
20 °C

Z

R1

NH2
O
109
spiro-annulated pyrans

R1 = Me, Ph, CO2Me
N
NC

CN
O

N
H
110

CN O
R
+

O
Me

R

NC

HN

O
EtOH
20 °C

HO
NaBH4

N
H

111

112

R = Me, Ph

Michael adduct

R

NC

THF

O
N
H
113

HN
O
R

CN
NH2
O
114

5,6-dihydropyrans

Scheme 57. Synthesis of spiro-annulated and 5,6-dihydropyrans74

4.2.1 Synthesis of dispiro-dipyrano-benzoquinones
The synthesis of dispiro-dipyrano compounds is an important challenge, weather both ring
contributing to its structure is unique identical, or whether they are carbocyclic or heterocyclicowing the practical implications of tetra-functionalizing the center spiro atoms. spiropyran is typeof organic compounds known for photochromic properties that provides this molecules ability’sfor being used in the field of medical and material sciences. Spiro-pyrans usually possess aphotochromic property’s, photochromic is a property which forms a change of color in a material
by incident radiation. The A. K. El-shafei and his research group50 developed the synthesis of
dispiro-dipyrano-benzoquinones from the starting material of bis-dithiolobenzoquinone 115 which
upon reaction with piperdine in the presence of ethanol at elevated temperatures afford theoxopropylidene-bis-dithilo-benzoquinone compound 116, which upon further condensation withmalononitrile afford the Michael adduct 117, which undergoes the cyclization give the mixture of
products of dispiro-dipyrano-benzoquinone 118 and 119 (Scheme 58). The spiro-pyrans plays a
key role in photochromic, thermochromics, solvatochromic, and electrochromic properties makes
them especially important in field of technological. Nowadays the spiro-pyrans are most used as
molecular logic devise, photochromic and electro optical devices.
O

O

Me

O
Me

S

S

O
S

EtOH, ∆

O

O
115

Me

NH2

O

Me

O

OH

Me
CN

S

O
S

Me
O

S

S

Me

O

Me
N
H

O

N

Z

Z

S

O

S

S

S

S

S

O

N

O

O

Z

NC

S

CN
O

S

S

S
+

CN

S

O
NC

O
S

S

Me

Me
O
116

117

H2N

O

Me

82%
118

HO

O

Me

28%
119

bis-pyrano

bis-dithiolobenzoquinone

Scheme 58. Synthesis of dispiro-dipyrano-benzoquinones
4.2.2 Synthesis of cyclophan 2-aminopyrans
A cyclophane is a hydrocarbon consisting of an aromatic unit and an aliphatic chain that
forms a bridge between two non-adjacent positions of the aromatic ring. More than 50 years after
the first reported synthesis of [2.2]paracyclophane, and its chemistry is still challenging field of75

ongoing research. The investigation of their physical and stereochemical properties were attractive
point of the [2n]cyclophanes in organic chemistry. Undoubtedly, research with future generationof cyclophanes will continue to contribute some of the most fascinating developments in the fieldof supramolecular chemistry. The A. A. Aly and his research group51 were developed the first
synthesis of spiro-pyranoindanoparacyclophanes 123. In which the carbonyl [2.2]paracyclophane
compound was condensed with malononitrile in basic medium to afford the compound 121, thecompound later allowed to reacted with acetonyl acetone or keto-esters 122 to afford the cyclophan
2-aminopyrans 123 with good to moderate chemical yields (Scheme 59).

OMe

CH2(CN)2O

EtOH, Et3N
∆

120

NC

CN

122

O
R
CN

EtOH, Et3N∆
R = Me, OEt

R
O
O
Me
123
70-75%

121
80%

carbonyl [2,2]paracyclo-phane
derivative

NH2

spiro-pyranoindanoparacyclo-phanes

Scheme 59. Modular synthesis of spiro-pyanoindanoparacyclo-phanes
4.2.3 Synthesis of spiro-homophthalimidepyrans
The H. Otomasu and his research group52 reported the spiro-homophthalimide pyrans(scheme 60). Their preparation started with the oxohomophthalimide 124 with malononitrile in thepresence of basic medium will give the knoevenagel adduct 125 which further reacts with acetylacetones or keto-esters which led to the formation of desired spiro-pyrans 126. In the same way,
the N-heterocyclic oxindole 127 when reacted with 1,3-carbonyl compounds such as acetylacetone
or keto-esters led to formation of carbocyclic spiropyrans 128. The spiro-homophthalimidepyranspossess a structural feature with an -CO-N-(R)-CO and an imide ring these feautures help them tobe biologically active and pharmaceutically useful motifs. The structural diversity and biologicalimportance of nitrogen containing heterocycles have made them attractive targets for synthesis
over many years. Among them the spiro-homophthalimidepyrans in organic chemistry, imide is afunctional group consisting of two carbonyl groups bound to nitrogen. They are hydrophobic andneutral, and can therefore cross biological membranes in vivo. These compounds are structurally76related to acid anhydrides. The spiro-homophthalimidepyrans have received attention due to theirandrogen receptor antagonists, anticonvulsant, antimicrobial, hypoglycemic, anti HIV-1 activities.
O
NC

O
O
N

CN

O

O

CH2(CN)2
N

Me

O
124

Me

R

Me

O
125

R1

N

O
R1

R = Me, Ph, CO2Me
R1 = COMe, CO2Et, H

R

CN
O

NH2

126
O
N

spiro[homopthalimide]pyrans

Me

O
127
O
Me

N

O
CN

O

N
Me

O

NH2

128
substituted
spiro[homopthalimide]pyrans

Scheme 60. Synthesis of spiro-homophthalimidepyrans4.2.4 Synthesis of spiro-benzothiazolepyrans
The spiro-benzothiazole belongs to the family of bicyclic heterocyclic compounds having
benzene nucleus fused with five-membered ring comprising nitrogen and sulfur atoms. spirobenzothiazole is an important scaffold with a wide array of interesting biological activities andtherapeutic functions including antitubercular, antimicrobial, antimalarial, anticonvulsant,anthelmintic, analgesic, antiinflammatory, antidiabetic and antitumor activities. A. K. El-shafei
and his research group53 were reported the spiro-benzothiazolepyrans 132 from diacylated
benzothiazole 129 as a starting material which upon reaction with sodium methoxide in polar
protic solvents afforded the mono acylated benzothiazole compound 130 which upon condensed
with malononitrile to afford the Michael adduct 131 which underwent cyclization to afford the
spiro-benzothiazolepyrans 132 (Scheme 61).

77

H Me
N

O

S

O

CH2(CN)2
EtOH, base, ∆Me
benzothiazole derivative
129

O
S
NH2
NC
spiro-benzothiazolepyran
132

MeOH,
MeONa
H Me
N

Me

H
N

cyclization
CH2(CN)2O

EtOH, base, ∆
S
130

H
N
S
NC
131

Me
OH
N

Scheme 61. Synthesis of spiro-benzothiazolepyrans
4.3 Chemical properties of 2-aminopyrans
The reactivity of 2-amino-4H-pyrans as well as their chemical properties has been poorly
studied because of their weak stability toward many reactants. They undergo ring opening and recyclization in the presence of strong acids and bases, nucleophiles, and so on. But this feature canbe turned to advantage in the synthesis of various heterocycles via re-cyclization. Thus, theenamino moiety in 2-amino-4H-pyran-3-carbonitriles and 2-amino-4H-pyran-3-carboxylic esters
provides access to diverse derivatives, including fused pyrans. The available data on the chemical
properties of 2-aminopyrans are not systematic, and, in certain cases, are contradictory.

78

4.3.1 Photochemical contraction of pyran ring
The Photochemical contraction of pyran ring in 2-aminopyrans 133 leads to the formationof mixtures of cyclobutenes 134, not easily accessible, accompanied with olefins 135 and alkynes
136.
R
G
R2

R

R1
CN

R

R1

hν

G

R1

+

2
NC
OR
H2N

(SET)

NH2

O

CN

+
NC

CONH2

133

134

135

R2
136

pyran

cyclobutenes

olefins

alkynes

R, R1 = H, i-Pr,Ph, Me
R2 = Me, Ph
G = CN, CO2Et
*

*
R
G
R2

R

R1
CN
O

133

NH2

G

hν
singleelectrontransfer
(SET)

R

R2

R

R1

O

CN

G

NH2

R2

133a

CN
O

NH2

133b

CN

R

R1

R1

+

2
NC
OR
H2N

G

R1
+

NC

CONH2
R2

Scheme 62. Photochemical contraction of aminopyrans
A mechanistic scheme involves intramolecular single-electron transfer (SET) from the enamino
moiety toward C-5 of the ring, and subsequent transannular interaction in zwitter-ionic biradical
133a with formation of stabilized zwitter-ion 133b opening of the oxetane ring in leads tocyclobutene 134, while the secondary photolysis of latter gives the olefin 135 and alkyne 136(Scheme 62).54
4.3.2 Synthesis of 2,4-disubstituted naptholpyrans.
Graham N. Wishart and his research group55 reported the synthetic utility of naphthocarbocyclic 2-aminopyrans under following conditions. The naphtho-carbocyclic 2-aminopyrans
137 was reacted with 2,5-dimethoxytetrahydrofuran under elevated temperatures in the presence79

of acetic acid as solvent medium to afford the 2-N-pyrrolo-carbonitriles 138. In the same way
naphtho-carbocyclic 2-aminopyrans were reacted with N,N-carbonyldiimidazole and succinic acidin dimethylformamide solvent at 80-90 °C, to afford the 2-N-succinimido-carbonitriles 139(Scheme 63). They synthesized a series of 2,4-disubstituted naptholpyrans under the acidic
conditions and found their biological activity for antiinflammatory activity.
NO2

CN
NH2

O

O
MeO

OMe

O

O

137
N

AcOH, ∆

HO

N

O DMF

N

N

OH
80-90 °C

O

NO2

NO2

CN

CN
O

N

O

N

O
139
2-N-succinimido-carbonitriles

138
2-N-pyrrolo-carbonitriles

Scheme 63. Synthetic utility of naphthocarbonitrile
4.3.3 Synthesis of tacrine-like analogs from 2-aminopyrans
In

1993

tacrine(9-amino-1,2,3,4-tetrahydroacridine,

THA)

was

the

first

acetylcholinesterase inhibitor (AChEI) approved in the United States for the treatment of
Alzheimers disease (AD). The tacrine and its analogs 142 were prepared using sloid-phase
synthesis, using cyclohexanone 140 and anthranilonitriles 141 under the microwave irradiation(Scheme 64).

80

NC

R

H2N

R1

NH2

O

R

H+

+

MW

R1

N

140

141

142

cyclohexanone

anthranilonitrile

tacrineScheme 64. General methodology for synthesis of tacrine
Macro and his research group56 reported the synthesis of different tacrine derivatives fromfuctionalized 2-amino-3-cyano-4H-pyrans 143 with cyclic ketones 144 undergoes Friedlander
annulation in the presence of aluminum chloride catalyst under reflux conditions to afford the new
acridine-type tacrines 145. The Friedlander annulation is a straight forward method for thesynthesis of aza-heterocyclic compounds. And also, its well-appreciated tool for the generation oflarge libraries of related heterocyclic compounds which are related to pharmacological activities.
O

Ar

R
Me

+
O

O

O
CN

(CH2)nNH21432-amino-4H-pyrans144
cyclic ketones

R = ethyl, propyl.

n = 0, 1, 2

AlCl3

R

DCE, ∆MeAr

NH2(CH2)nON145
tacrine analogs

Scheme 65. Synthetic utility of 2-aminopyrans for tacrine synthesis
And they tested the prepared tacrine analogs showed the ability towards to inhibit theacetylcholinesterease (AChE) butyrylcholinesterease (BChE) and neuronal uptake of serotonin
and noradrenaline. Changes in the size of the carbocyclic ring of tacrine produced modest potency
against cholinesterase enzymes (Scheme 65).
4.3.4 Synthetic utility of 2-aminopyrans for dihydrofurans and 2-sulfinylimine-chromenes
Dihydrofurans and chromenes and their hetero-fused compounds are important molecular
structures in synthetic organic chemistry. Such as, fungicidal agents, potential antioxidants andpharmaceuticals compounds. Further, these compounds are extensively used in photo chromic81

materials and also as precursors to flavylium dyes. Recently A. Krishnaiah and his research group57
reported a one pot four component reaction for dihydrofurans via simple, efficient, catalyst freegreen protocol in water medium. First 2-amino-4H-pyrans 146 were synthesized using
multicomponent reaction strategy, then 2-aminopyrans were treated with N-chlorosuccinimide inwater medium to obtained hexahydrodihydrofuran-carboxamides 147. When 2-aminopyrans weretreated with N-chlorosuccinimide in alcoholic medium furnishes the hexahydrodihydrofurancarboxylates 148.
In another methodology A. Krishnaiah and his research group reported the synthetic utilityof 2-amino-4H-pyrans 146, using multi-component reaction strategy. Initially they weresynthesized 2-aminocromenes using three components in one pot reaction of aldehyde, 1,3dicarbonylcompound and malononitrile to construct the 2-aminopyrans, in the next stage 2aminopyrans were reacted with N-chlorosuccinimide and aryl amine via sequential addition, toafford hexahydrobenzofuran-2-N-phenyl-corbaxamide 149 derivatives. In same way to 2aminopyrans N-chlorosuccinimide and thiophenol in sequential addition to afford the 2-Nsulfinylimines 150 (Scheme 66).

82

O
O

N Cl

R

O
O

H2O, RT

CN
NH2hexahydrobenzofuran
corbaxamides
up to 56-70% yields

O
147

O
N Cl

O

R
CN
O

O
R1-OH, RT
O

O
O

R
CN

NH2
O
146
2-amino-4H-pyrans
R = alkyl, aryl

R1hexahydrobenzofuran
corbaxylates
up to 58-80% yields

148

O
N Cl

O

R
CNH
N

O
toluene, RTO

R1 = Me, Et, Pr, i-Pr, Bu, i-Bu.

O
149

hexahydrobenzofuran-2-N-phenyl
corbaxamide
up to 93% yields

NH2
O
O

N Cl

R

O
O

toluene, RT

CN
Cl
N
S

2-sulfinyl chromenes
up to 90% yields

150
SH

Scheme 66. Synthetic utility of 2-aminochromenes for the construct of dihydrobenzofurans and 2sulfinyl chromenes
4.4 Previous report on enantioselective synthesis of spiro-conjugated 2-aminopyrans
W. C. Yuan and his research group reported58 the enantioselective construction of spiroconjugated

2-aminopyrans(spiro-[4H-3,3'-oxindoles]

throughdominoknoevenagel/Michael/cyclization sequence catalyzed by cupreine (CPN) organocatalyst. In thisstudy, they synthesized a wide range of optically active spiro-conjugated 2-aminopyrans with good
to excellent enantioselectivities (up to 97%) under mild reaction conditions (Scheme 67).

83

H2N

NC
CN

O

+
O

N
R

R''

R'

151
R = Me, Bn, Allyl, MOM

NC

DCM, 0 °C

O
N
O
R
154
up to 99% yield
up to 97% ee

152
R' = Me, Ph
R'' = Me, OEt, OMe

Ar
R

O

O

catalyst 153d
(10 mol %)

R'
R''

HO
NH

OR

OH

S
NH

N

N
N

N

N

N

153c

HO

153a: R = H
153b: R = OMe
Ar = 3,5-CF3-C6H3
Ar
HN

153d: R = H (cupreine) or CPN
153e: R = Bn
153f: R = Ac

R
S

HN
N
153g: R = H
153h: R = OMe
Ar = 3,5-CF3-C6H3

Ph
Ph

S
N
H

N

S
N
H

Ar

153i

N

N
H

N
H

Ar

153j

Scheme 67. Synthesis of optically active spiro-conjugated 2-aminopyrans
They reported the Michael addition reaction of unsaturated isatin nitriles 151 withlinear1,3-diketones 152 using cupreines 153d-f and cinchona-based alkaloids 153a-b asorganocatalysts. Among them, the catalyst 153d have showed the excellent catalytic activity toafford chiral spiro-conjugated-2-aminopyrans 154 in both excellent chemical yields andenantioslectivities. However, this method failure to construct the chiral spiro-conjugated-2aminopyrans using with cyclic 1,3-dicarbonyl compounds.

844.5 Author strategy
Author aimed to develop the new hybrid type sqauaramide fused amino alcohol (SFAA)
organocatalysts for chiral spiro-conjugated 2-aminopyrans from readily available Michael
acceptors and cyclic 1,3-dicarbonyl compounds using domino Michael addition cyclization
reaction as strategy. However, the construction of one unique spirocyclic-oxindole, incorporatinga 2-amino- 4H-pyran-3-carbonitrile ring at the C3 position of oxindole, is still limited in syntheticorganic chemistry (Figure 21).
H2N

O

NC

*
O

O

N
R
chiral spiro-conjugated 2-aminopyransFigure 21. The hybrid structure of chiral spiro-conjugated 2-aminopyrans4.5.1 Synthetic utility of chiral spiro-conjugated 2-aminopyrans
The most fascinating application of spiro-conjugated 2-aminopyrans 157 in organic
synthesis is undoubtedly due to the highly substituted spiro system of the molecules. The reactionsof the amino and nitrile functional groups of spiro-conjugated 2-aminopyrans, mostly by
nucleophilic additions or spiro-annulation, transform them into a 2-oxindole derivatives. The
oxindoles skeletons system can be easily derived into a wide range of biologically active
compounds, such as rhynchophylline (calcium channel blocker), elacomine (hemiterpene spiroalkaloid) and spirotryprostatin A (anti-mitotic agent). And also, the bifunctional -NH2 and -CN ofspiro conjugated-2-aminopyrans shows reactivity towards electrophilic chlorination andbrominating reactions.

85

EWG

CN
O

N
R
155
3-(dicyanomethylene)-indo-2-one
R = alkyl, aryl
EWG = CN, CO2Et, CONH2

SFAA
organocatalysts

O
+
O

H2N

O

NC

*
O

asymmetric Michael-addition
cyclization

biological active
compounds

O

N
R

156

157

cyclic 1,3-dicarbonylcompoundschiralspiro-conjugated-2-aminopyrans

O

H

O

HN

N
N
O

H

O
H
N

O
H
N

160
spirotryprostatin A
anti-mitotic agent

HO

O
O
O

158
rhynchophylline
calcium channel blocker

HN
159
O
elacomine
hemiterpene
spiro-alkaloid

NH

Scheme 68. Synthetic utility of chiral spiro-conjugated 2-aminopyranschiral spiro-conjugated 2-aminopyrans, especially those which are spiro-fused to other cyclic
frameworks have drawn tremendous interest for researchers in the area of synthetic organic
chemistry and medicinal chemistry. In particular, rhynchophylline 158, is an alkaloid found incertain uncaria species (Rubiaceae), rhynchophylline is a non-competitive NMDA antagonist andcalcium channel blocker. And also, the spiro-oxindole moiety’s easily access to the synthesis ofelacomine 159 hemiterpene spiro-alkaloid and spirotryprostatin A 160 which is an indolic alkaloid
from the 2,5-diketopiperazine class of natural products found in the Aspergillus fumigatus fungus(Scheme 68).
4.5.2 Results and discussions
In continuation of author efforts towards expanding the scope of amino alcohols and theirderivatives as organocatalysts, author focused on the synthesis of squaramide fused amino alcohols
and their applications for enantioselective reactions. The SFAA organocatalysts possess themultiple hydrogen-bonding and stereoinduction sites within the same molecule, and evaluatedtheir catalytic activity in the Michael addition cyclization reaction to synthesis chiral spiroconjugated 2-aminiopyrans using 3-methylenedicyano-indo-2-one and cyclic 1,3-dicarbonylcompounds. Additionally, SFAA catalysts contains a cyclic tertiary amino group that can act as a
Brønsted base, sterically bulky groups, and two amino and one hydroxyl group that can formhydrogen bonds with both 3-dicyano-2-indanones and cyclic 1,3-dicarbonyl compound. As shown86

in the plausible transition state X (Scheme 69). Thus, 3-dicyano-2-indanones and cyclic 1,3dicarbonyl compound can be conformationally fixed by hydrogen-bonding interactions, that is,
between the two amino groups of the squaramide and the two nitrile groups of the isatin, between
the cyclic ammonium site of the squaramide and the oxygen atom of the 1,3-dicarbonyl enolate
moiety, and between the cyclic ammonium site and the hydrogen atom of the hydroxyl group in
the ammonium alcohol intermediate.

CF3
EWG

CN

O

F3C

SFAA organocatalysts
ONR
isatinlenedine
malonitrile

O
N
H

+
EWG

O

O
HN
N
H
O O

CN

Ph
Ph

H

1,3-dicarbonylcompounds

O
NO
R
transitionstate X
Michael addition

R
N
OO

H

*
O

intramolecularcyclization
EWG

O

O
*

C N

O

H EWG
NH

2-iminopyran

O

O
*
O

EWG
NH2

chiralspiro-conjugated 2-aminopyran

Scheme 69. Conceptualization of SFAA catalyzed enantioselective Michael addition cyclization
reaction

87

Then, the Michael addition reaction may proceed stereo-selectively to afford the Michael adductinitially, which upon undergoes cyclization to produce the 2-iminopyrans subsequently the 2iminiopyrans tautomerized into spiro-conjugated 2-aminopyrans to affords in a highenantioselectivities.
4.5.3 The enantioselective Michael addition cyclization reaction using catalysts 29a-e
First, author examined the catalytic ability of SFAA catalyst 29a having a pyrrolidine ringat side chain of the catalyst for Michael addition cyclization reaction of 3-dicyano-2-indanone
161a with dimedone 162a in toluene at room temperature (entry 1, Table 8), afforded the spiropyran 163a in trace amount. Next, catalyst 29b is examined in toluene solvent at room temperaturefor 1h, afforded the spiro-pyran 163a in good chemical yield (82%) with poor enantiomeric excess(9% ee) (entry 2). Furthermore, the reaction was conducted at room temperature and 0 °C using
catalyst 29b and 29c respectively afforded the spiro-pyran 163a in good to excellent chemicalyields (catalyst 29c: 90% yield with 7% ee, catalyst 29b: 87% yield with racemic: entries 3,4).
Moreover, reaction screened in THF solvent at 0 °C for 5h, afforded spiro-pyran 163a in excellent
chemical yield (90%) in racemic. Next reaction was examined with N-benzyl-3-dicyano-2indanone 161b with 162a using catalyst 29b in toluene solvent, afforded spiro-pyran 163b inexcellent chemical yield (95%) but the optical yield was not found (entry 6). Next, reaction is
examined in THF solvent, for 24 h, at 0 °C, afforded chiral spiro-pyran in both good chemicalyield (89%) and enantioselectivities (79 % ee) (entry 7). Subsequently the Michael reaction were
optimized with catalysts 29a and 29b in THF solvent at 0 °C respectively, afforded chiral spiropyran 163b in excellent chemical yields (92% and 95%) and good enantioselectivities (79% ee,
75% ee) (entries 8,9). Moreover, the reaction also screened with catalysts 29d and 29e having
morpholine and thiomorpholine rings at side chain of the catalysts, which afforded the chiral spiropyran in excellent chemical yields (96%, 97%) but the enantiomeric excess was poor (entries
10,11). By observing these results, next author examined the optimization reaction conditions for
Michael addition reaction of N-benzyl-3-dicyano-2-indanone 161b with dimedone 162a using
catalyst 29a in THF solvent at 0 °C for 48h.

88

Table 8. The enantioselective Michael addition cyclization reaction using catalysts 29a-e

CF3

O

O

R
N
H

F3C

N
H

29

R

N

N

29a

29b

29c

O

S

=

Ph
HO Ph

N

N
29d

N

N

O

+
O

N
R
161a-bsolvent

O

OO
N
R
163a-bchiralspiro-conjugated 2-aminopyransdimedone

indanones (R)

29e

NC

solvent
time
temp.

162a

3-dicyano2-indanones
161a: H
161b: Bnentrya catalysts
29a-e

H2N

catalysts 29a-e(10 mol %)ONtime (h) temp. (°C)

yield [%]bee [%]c1aH

toluene

24

RT

trace

----

2

b

H

toluene

1

RT

82

9

3

c

H

toluene

1

RT

90

7

4

b

H

toluene

5

0

87

rac

5

b

H

THF

5

0

90

rac

6

b

Bn

toluene

24

RT

95

rac

7

b

Bn

THF

24

0

89

77

8

a

Bn

THF

48

0

92

79

9

c

Bn

THF

48

0

95

75

10

d

Bn

THF

48

0

96

10

11

e

Bn

THF

48

0

97

rac

aThe reactions were carried out with 161a,b (0.1 mmol), 162a (0.1 mmol) in above mentioned solvents(1.0 mL). bIsolated yields. cEnantiomeric excess was determined on chiral HPLC using Chiralpak AD-H
and Chiralcel OD-H columns.

89

4.5.4 The optimization of reaction conditions for asymmetric Michael addition cyclization
reaction using catalyst 29a
Next, author inspected various reaction temperatures, molar ratios and solvents for Michael
addition reaction using catalyst 29a for 48h (entries 1-15, Table 9). Changing the molar ratio of
the catalyst 29a to 20 and 5 mol% also provided the spiro-conjugated 2-aminopyran 163b inexcellent chemical yield with abnormal differences in enantiomeric excess, 20 mol % of thecatalyst loading afforded the spiro-pyran with poor enantiomeric excess (7% ee).
Table 9. Optimization of reaction conditions using with catalyst 29a
N

N

O

O
+
O

N
Bn
161b

H2N

catalyst 29asolvent
48 h
temp.

O

NC
OO
N
Bn
163b

162a

entryacatalyst
29a (mol %)solvent

1

20

THF

0

96

7

2

5

THF

0

95

83

3

2

THF

0

92

81

4

5

THF

-10

92

73

5

5

THF

-50

90

81

6

5

THF

-80

87

77

7

5

Et2O

0

82

67

8

5

DIPE

0

89

43

9

5

1,4-Dioxane

rt

98

5

10

5

DCM

0

96

7

11

5

chloroform

0

91

13

12

5

DCE

0

89

51

13

5

DMF

0

90

rac

14

5

DMA

0

89

rac

15

5

MeOH

0

92

rac

temp. (°C) yield [%]bee [%]caThe reactions were carried out with 161b (0.1 mmol), 162a (0.1 mmol) in above

mentioned solvents (1.0 mL). bIsolated yields. cEnantiomeric excess wasdetermined on chiral HPLC using Chiralpak AD-H column.

90While the 5 mol % catalyst loading afforded 163b with good enantiomeric excess 83% (entries
1,2). Next, the reaction screened with 2 mol % of catalyst 29a afforded the spiro-pyran 163b in
92% chemical yield with 81% enantiomeric excess (entry 3). Furthermore, Michael reaction was
examined at lower temperature such as -10 °C, -50 °C and -80 °C afforded the spiro-pyran 163bin decreasing chemical yields from (92% to 87%) and slight variations in enantioselectivities. At-10 °C afforded the spiro-pyran in 73% ee, at -50 °C afforded the spiro-pyran in 81% ee while -80°C afforded the spiro-pyran with 77% ee (entries 4-6). Next, Michael reaction was optimized in
ethereal solvent such as Et2O, DIPE (diisopropyl ether) and 1,4-dioxane using catalyst 29aafforded spiro-pyran 163b with excellent chemical yields (82-98%) and poor to moderateenantioselectivities (5-67% ee) (entries 7-9). Furthermore, Michael reaction was also screened inchlorinated solvents such as DCM, chloroform and DCE using catalyst 29a afforded the spiropyran 163b in excellent chemical yields (89-96%) with poor to moderate enantioselectivities (751% ee) (entries 10-12). Subsequently the reaction was also optimized in polar solvents such as
DMF, DMA and MeOH afforded the spiro-pyran in excellent chemical yields (89-92%) but the
spiro-pyran 163b was found in racemic (entries 13-15). Form above results, author optimized thereaction conditions (catalyst 5 mol %, at 0 °C, for 48h) for enantioselective domino Michael
addition cyclization reaction.
4.5.5 Substrate scope for the enantioselective domino Michael addition cyclization reaction
The generality of protocol for the enantioselective domino Michael addition cyclization
reaction was fully demonstrated by evaluating the reactions with between N-substituted 3dicayano-2-indanones 161c-j and cyclic 1,3-dicarbonyl compounds 162a,b using optimized
catalyst 29a in THF solvent at 0 °C for 48 h (Scheme 70). First, the author examined the N-(4methoxybenzyl)-3-dicyano-2-indanone 161c as Michael acceptor with dimedone 162a using
catalyst 29a, afforded chiral spiro-pyran 163c in both good chemical yields and enantiomeric
excess (89%, 81% ee). Next the reaction was optimized with N-Boc group containing 3-dicyano2-indanone 161d with 162a afforded the spiro-pyran 163d in good chemical yield with poor
enantioselectivity (5% ee).

91

N

H2N

N

O
+

R'
R'

O
N
R
161c-jR = PMB, Boc, Me,
TBDMS, 2-methyl naphthyl

catalyst 29a(5 mol %)
THF
48 h
0 °C

O

O

NC
N
R

OO

162a,b(3S)-163c-k

162a = R' = Mechiralspiro-conjugated 2-aminopyrans162b = R' = H

H2N

H2N

O

NC

H2N

O

NC

NC
N

OO

O

N

PMB

OO
N
Me

OO
Boc

163c: 89%, 81% ee

163d: 72%, 5% ee(3S)-163e: 92%, 95% ee

H2N

H2N

H2N

O

NC

O

NC
N

OO

H2N

O

NC
N

OO

determination of absolute configurationof 163e using X-ray crystalography

NC
N

OO

N

O

Et

O

OO
TBDMS

O
163f: 87%, 84% ee

CH3163g: 95%, 75% ee

H2N

H2N

O

NC

163h: 90%, 80% ee

163i: 72%, 76% ee

O

NC
N

OO

OO
N
Me
163k: 90%, 76% ee

163j: 81%, 71% ee

Scheme 70. Substrate scope for enantioselective domino Michael addition reaction

92

Furthermore, Michael reaction was screened with N-methyl-3-dicyano-2-indanones 161awith 162a afforded chiral spiro-pyran 163e in both excellent chemical yields (92%) andenantiomeric excess (95%). The absolute configuration of chiral spiro-pyran (3S)-163e were
determined using with X-ray crystallography. Next, The N-ethy-3-dicyano-2-indanone 161f
screened with 162a using catalyst 29a afforded chiral spiro-pyran in both good chemical yield(87%) and enantiomeric excess (84%). Additionally, the Michael reaction was screened with N(monomethoxymethylether)-3-dicyano-2-indanone 161g and N-(acetyl)-3-dicyano-2-indanone
143h with dimedone 162a using catalyst 29a respectively, which afforded the chiral spiro-pyransin excellent chemical yields (90 to 95%) and good to moderate enantioselectivities (75-80% ee).
Furthermore, the enantioselective Michael addition reaction was screened with sterically bulky
protected 2-methylene naphthyl and silyl protected 3-dicyano-2-indanones 161i and 161j with
162a which afforded the chiral spiro-pyrans 163i and 163j respectively in both good chemicalyields (72-81%) and enantioselctivities (71-76% ee). While changing the 1,3-cyclopentadione
162b as Michael donor in reaction with N-methyl-3-dicyano-2-indanone 161e using catalyst 29aafforded the spiro-pyran 163k in excellent chemical yield (90%) and with moderate enantiomeric
excess (76% ee).
4.5.6 Plausible reaction course for domino Michael addition cyclization reaction
Based on the observed enantiopurities of chiral spiro-pyran 163e in 95% ee which affordedin Michael addition reaction with 161e with 162a, a model of mechanistic pathway for dominoMichael addition cyclization reaction is proposed as follows (Scheme 72). First, the active
methylene proton of dimedone is abstracted by basic tertiary amino group on pyrrolidine ring of
catalyst 29a to form enolate, which might also induce the strong hydrogen bonding interaction
between the hydrogen atom of the ammonium moiety on pyrrolidine ring in catalyst and oxygen
atom of enolate. Next, N-(methyl)-3-dicyano-2-indanone 161e might fixed with catalyst 29a
through two hydrogen bonds between two nitriles functionalities of 161e with two primary aminogroups on squaramide unit of catalyst 29a. In the two possible transition states TS-I and TS-II,
the TS-II has less steric interaction than that of TS-I, which has strong steric repulsion between
dimethyl groups from dimedone with amide carbonyl oxygen atom of 161e. Hence theenantioselective Michael addition cyclization reaction might proceed via TS-II, in which thedimedone enolate co-ordinated to ammonium moiety on pyrrolidine ring could attack93

stereoselectively on the electron deficient olefin carbon of 161e from the above side (Si face)which leading to the formation of (3S)-163e as major isomer, whereas the minor isomer (3R)-163e'might be obtained through the unfavoured transition state TS-I (Scheme 71).
NC

CN

O
N
CH3
161e
+

HO
catalyst 29a

O

N
H

N
H

N

C

C

CH3
O

HO
CF3

N
H

N

O

N
H

N
H

CH3

H3C

Ts-II: favoured

Michaeladdition
CH3
CH3

Michaeladdition
CH3
CH3

O

NC

N

O

NC

H
OO
N

Si face
attackN
CH3
X

intramolecularcyclization
CH3
CH3

O

NC H

CF3

H
OO

CH3
X'

HN

CF3

O
N
O
H3C

H3C

Ts-I: unfavouredN

HN

intramolecularcyclization
CH3
CH3

O

NC H

OO
N

OO
N

CH3
Y'

CH3
Y

tautomerization
H2N

N
C

N C

O

N

CH3

O

CF3

O

O
162a

O

N
H

O
H3C
H3C

O

CH3
CH3

O

NC

tautomerization
H2N
NC

OO
N

CH3
CH3

O

OO
N

CH3

CH3

(3R)-163e'minor isomer(3S)-163e: 95% ee
major isomer

Scheme 71. Plausible reaction course for enantioselective domino Michael addition cyclization
reaction using catalyst 29a94

4.6 Summary
In summary, author developed new hybrid type squaramide fused amino alcohol (SFAA)
catalyst 29a showed the significant catalytic activity in enantioselective domino Michael addition
cyclization reaction with various N-substituted-3-dicyano-2-indanones 161a-j and cyclic 1,3dicarbonyl compounds 162a,b. This protocol provides the chiral spiro-conjugated 2-aminopyrans163a-k in both excellent chemical yields (up to 98%) and enantioselectivities (up to 95% ee). The
resulted chiral spiro-conjugated-2-aminopyrans could be crucial intermediates for the synthesis ofmany biologically active significant scaffolds.

95

5. Conclusion
Many biological active molecules, including pharmaceuticals, are optically active. In
biological systems of human beings only one form of enantiomers plays key role in treatment ofdiseases. Therefore, synthesis of optically active molecules is often more challenging in the fieldof synthetic organic chemistry. The catalytic asymmetric synthesis is useful for the preparation of
biologically active molecules including a drug. The enantioselective synthesis usingorganocatalysts is recognized as an independent synthetic tool besides asymmetric metal catalysis
and enzyme catalysis, and the catalysts are easy to handle even on large scale and relatively lesstoxic compared to transition metals. In the present thesis, author aimed to develop an efficient new
hybrid type squaramide fused amino alcohol (SFAA) organocatalysts for enantioselective
reactions. The SFAA organocatalysts were prepared by using with simple amino alcohol withmono ester squaramide and the catalysts possess with multiple activation sites in the molecule suchas, three hydrogen bonding sites from two amine functions and one hydroxy function. And also,
contains an Brønsted basic site on the side chain of catalysts from cyclic amines (pyrrolidine,piperidine, azapane, morpholine and thiomorpholine) which can abstract the proton from pronucleophiles. By these properties of SFAA organocatalysts enables the formation of covalent andnon-covalent intermediates with wide-variety of the substrates and allows one enantiomeric facefor enantioselective reactions. The prepared SFAA organocatalysts successfully applied forenantioselective nitro-aldol (chapter 2), Diels-Alder (chapter 3) and domino Michael addition
cyclization reactions (chapter 4).
In chapter 2, author discussed about the detailed application of SFAA organocatalysts forenantioselective nitro-aldol reaction. The usual and new hybrid type SFAA organocatalysts 21a-d
and 29a-e were prepared and examined in enantioselective nitro-aldol reaction of isatins 30a-kwith nitromethane 7. Among the prepared SFAA organocatalysts, the catalysts 29c has showed
the best catalytic activity to afford the chiral 3-alkylated-3-hydroxy-oxindoles 31a-k in excellent
chemical yields and enantioselectivities (up to 99%, up to 95% ee). The obtained chiral 3alkylylated-3-hydroxy-oxindoles 31a-k are prominent synthetic intermediates for many
biologically active compounds such as the donaxaridine (anticancer), spirobrasinin (antifungal),maremycin B (cytotoxicity) and CPC-1 (antibacterial agent).
In chapter 3, author discussed about the detailed application of SFAA organocatalysts forenantioselective Diels-Alder reaction. The new hybrid type SFAA organocatalysts 29a-e showed96catalytic activity for enantioselective Diels-Alder reactions of 3-hydroxy-2-pyridones 96a,b and4-substituted 3-hydroxy-2-pyridones 99a-d with maleimides 97a-k respectively. Among the
optimized SFAA catalysts, the catalysts 29a showed best catalytic activity to afford the chiral 4hydroxyisoquinnuclidines 98a-k and 101a-f in excellent chemical yields and enantioselectivities(up to 95%, up to 98% ee) respectively. Particularly, the reaction of 4-brominated 2-pyridone 99awith maleimides 97a afforded the corresponding 4-hydroxyisoquinnuclidines 101a in both
excellent chemical yield and enantioselectivity (up to 95%, up to 98% ee) having an opposite
absolute stereochemistry in comparison with the DA adduct 98a from the reactions using common
3-hydroxy-2-pyridone 96a. The obtained chiral 4-hydroxyisoquinnuclidines 98a-k and 101a-f areprominent synthetic intermediates for bicyclic complex structures and many biological active
molecules such as oseltamivir (antiinfluenza drug), ibogaine (natural product) and vinblastine andvincristine (anticancer drug).
In chapter 4, author discussed about the detailed application of new hybrid type SFAA
organocatalysts for enantioselective domino Michael addition cyclization reaction. The new
hybrid type SFAA organocatalysts 29a-e has showed catalytic activity for domino Michael
addition cyclization reaction of cyclic 1,3-dicarbonyl compound 162a,b with electron withdrawing
2-indanones 161a-j. Among the optimized SFAA organocatalysts, catalyst 29a has showed thebest catalytic activity to afford chiral spiro-conjugated 2-aminopyrans 163a-k in excellent
chemical yields and enantioselectivities (up to 97%, up to 95% ee). The obtained chiral spiroconjugated 2-aminopyrans 163a-k are the prominent synthetic intermediates for many biologically
active analogs, such as tacrine derived 2-aminopyrans (antialzheimers), spiro-pyranopyrazoles(antioxidants),

pyranopyranones(anticoagulant)and2-aminotetrahydrocromenes(antileishmaniasis).
In conclusion, author developed new hybrid type squaramide fused amino alcohol (SFAA)
organocatalysts. The prepared SFAA organocatalysts successfully applied in enantioselective
nitro-aldol, Diels-Alder and domino Michael addition cyclization reactions which afforded thebiologicalactivechiralsynthetic

intermediatesinexcellentchemicalyieldsandenantioselectivities. It’s expected that these results might be able to contribute greatly in thedevelopment of new synthetic drugs in the field of synthetic organic chemistry.

97

6. Experimental section
General information: All commercial reagents were purchased and used without further
purification. All reactions were carried out under argon in flame-dried glassware with magnetic
stirring. Thin layer chromatography was performed on silica gel 60 F254, and the analytes weredetected by using UV light (254 nm) and iodine vapor. Column chromatography was carried out
on silica gel 60N (40-100 µm). Melting points were measured with a micro melting point
apparatus. 1H NMR (500 MHz) and 13C NMR (125 MHz) spectroscopic data were recorded ineither CDCl3 or (CD3)2SO. The 1H NMR spectral data are reported as follows: chemical shifts (δ)
in ppm from tetramethylsilane (δ = 0.0 ppm) or the residual solvent as an internal standard [forCDCl3: δ = 7.26 ppm; for (CD3)2SO: δ = 2.50 ppm], multiplicity [s (singlet), d (doublet), t (triplet),q (quartet), dd (doublet of doublets), m (multiplet), and br. (broad)], coupling constants in Hertz(Hz), integration, and assignment. The 13C NMR spectroscopic data were measured with complete
proton decoupling. Chemical shifts are reported in ppm from the residual solvent as an internal
standard (for CDCl3: δ = 77.16 ppm). IR spectra were measured with an JASCO 4100 FT-IR
spectrophotometer. 1H (500 MHz) and 13C NMR (125 MHz) spectroscopic data were recorded
using JEOL JNM-ECA500 instrument. Optical rotations were measured with a JASCO DIP-360
digital polarimeter. HRMS data were obtained by EI and FAB using Hitachi RMG-GMG and
JEOL JNX-DX303 sector instruments.
Chapter 2: The New Hybrid Type Squaramide Fused Amino Alcohol Organocatalysts For
Enantioselective Nitro-Aldol Reaction of Nitromethane with Isatins
General procedure for the synthesis of compounds (21a-d): To a stirred solution of compoundsquaramide mono ester amide 20 (149 mg, 1 mmol) in dry MeOH (5 mL) was added thecorresponding amino alcohol 19a-d (1 mmol) at room temperature, and the resulting mixture wasstirred at the same temperature for 12 h. Upon completion of the reaction indicated by TLC, theexcess amount of MeOH was evaporated under reduced pressure to give the crude reaction
mixture, which was purified by flash column chromatography (hexane/EtOAc, 6:4) to afford 21ad as pure compounds in moderate to good yields.

98

(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-1,1-diphenylpropan-2yl)amino)cyclobut-3-ene-1,2-dione (21a): Pale yellow solid (MeOH). 170 mg, 70% yield. m.p.
202-205 °C. [α]D24 = –38 (c = 0.5, MeOH ). IR (neat) = 3223, 2980, 1687, 1417, 1115, 825 cm-1.
F3C

F3C

O
N
H

N
H

21a

= 7.00 Hz, 3H).

1

O

13

H NMR (500 MHz, DMSO-d6): δ 10.40 (s, 1H), 8.03 (s, 2H),

Me

7.99 (d, J = 10.50 Hz, 1H), 7.62 (s, 1H), 7.51 (t, J = 7.00 Hz,

Ph
Ph
HO

3H), 7.40 (t, J = 7.50 Hz, 2H), 7.26-7.20 (m, 3H), 7.09 (t, J =7.50 Hz, 1H), 6.42 (s, 1H), 1.00 (d, J = 7.0 Hz, 3H), 0.83 (d, J

C NMR (125 MHz, DMSO-d6): δ 184.6, 180.0, 170.1, 161.8, 146.2, 145.3,

141.1, 128.3, 127.8, 126.8, 126.4, 125.7, 125.6, 124.2, 122.1, 117.9, 114.6, 81.1, 63.6, 28.7, 22.3,
17.5. EI-MS m/z: 534 (M)+, 556.8 (M + Na)+. HRMS (EI) calcd for C27H20F6N2O3 m/z: 534.1378(M)+ found: 534.1390.
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-3-methyl-1,1-diphenylbutan2-yl)amino)cyclobut-3-ene-1,2-dione (21b): White solid (ether). 150 mg, 65% yield. m.p. 197198 °C. [α]D24 = –647 (c = 0.5, MeOH). IR (neat) = 3215, 2986, 1696, 1497,740 cm-1. 1H NMR
F3C

O(500 MHz, DMSO-d6): δ 8.28 (s, 1H), 8.21 (d, J = 11.00 Hz,

O1H), 8.04 (d, J = 10.50 Hz, 1H), 7.50-7.43 (m, 4H), 7.34-7.23
F3C

N
H

N
H

21b

Ph
Ph
HO

(m, 4H), 7.20-7.11 (m, 1H), 5.76 (s, 1H), 5.68 (s, 1H), 5.125.10 (m, 1H), 4.40 (s, 1H), 4.19 (s, 1H), 0.93 (d, J = 7.00 Hz,3H), 0.75 (t, J = 6.50 Hz, 3H). 13C NMR (125 MHz, DMSO-d6): δ 189.8, 182.4, 177.3, 173.1,
146.8, 130.2, 129.3, 128.8, 128.3, 128.1, 127.9, 127.5, 126.6, 126.0, 125.8, 125.6, 125.5, 125.0,
80.5, 63.7, 28.5, 22.4, 17.7. EI-MS m/z: 562 (M)+. HRMS (EI) calcd for C29H24F6N2O3 m/z:
562.1691 (M)+ found: 562.1705.
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-3-phenyl-1,1-diphenylbutan2-yl)amino)cyclobut-3-ene-1,2-dione (21c): White solid (ether). 150 mg, 62% yield. m.p. 197198 °C. [α]D24 = –47 (c = 0.5, MeOH). IR (neat) = 3215, 2986, 1696, 1497,740 cm-1. 1H NMR
F3C

F3C

O
N
H
21c

(500 MHz, DMSO-d6): δ 10.4 (s, 1H), 8.80-8.78 (d, J = 10 Hz,

O
N
H

Ph

1H), 8.01 (s, 2H), 7.64-7.69 (m, 3H), 7.35-7.38 (m, 2H), 7.08-

Ph
Ph
HO

7.25 (m, 11H), 6.75 (br, 1H), 6.22-6.24 (d, J = 10 Hz, 1H). 13C
NMR (125 MHz, DMSO-d6): δ 184.64, 179.96, 168.35, 162.61,

145.61, 144.15, 140.82, 139.01, 131.36, 131.09, 128.93, 128.08, 127.52, 126.76, 126.62, 126.22,
99126.15, 124.16, 121.99, 118.04, 114.8, 80.44, 63.38. EI-MS m/z: 596 (M)+. HRMS (EI) calcd for
C32H22F6N2O3 m/z: 596.1581 (M)+ found: 596.3181.
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-1,1,3-triphenylpropan-2yl)amino)cyclobut-3-ene-1,2-dione (21d): White solid (MeOH). 100 mg, 59% yield. m.p. 253255 °C. [α]D24 = –25 (c = 0.5, MeOH). IR (neat) = 3265, 2986, 1686, 1446, 855 cm-1. 1H NMR
F3C

O(500 MHz, DMSO-d6): δ 10.15 (s, 1H), 8.05 (d, J = 10.00 Hz,

O
Ph

F3C

N
H
21d

N
H

Ph
Ph
HO

1H), 7.93 (s, 2H), 7.66 (d, J = 7.50 Hz, 2H), 7.60 (s, 1H), 7.54
(d, J = 7.50 Hz, 2H), 7.46 (t, J = 7.50 Hz, 2H), 7.29 (t, J = 7.50
Hz, 1H), 7.19 (t, J = 7.50 Hz, 4H), 7.15-7.05 (m, 4H), 6.62 (s,1H), 5.47-5.41 (m, 1H), 2.83 (d, J = 7.00 Hz, 2H). 13C NMR(125 MHz, DMSO-d6): δ 183.8, 179.6, 169.6, 160.9, 145.4, 145.1, 141.0, 137.9, 131.5, 131.2,
129.3, 128.6, 128.2, 127.9, 127.0, 126.4, 125.5, 124.2, 122.0, 117.6, 79.7, 62.2, 36.8. EI-MS m/z:
610 (M)+, 633 (M + Na)+. HRMS (EI) calcd for C33H24F6N2O3 m/z: 610.1691 (M)+ found:610.1697.
General procedure for the synthesis of compound (26): To a stirred solution of compound 24(1.0 g, 4.1 mmol) in dry DCM (20 mL) was added triethylamine (1.03 g, 10.2 mmol) and stirred
for 5 min followed by addition of (Boc)2O (1.39 g, 6.3 mmol) then stirring was continued for 3 h
at room temperature. After completion of the reaction indicated by TLC, reaction mixture wasquenched with ice cold water and extracted with DCM (3x50 ml), solvent was evaporated under
reduced pressure. The crude reaction mass of compound 25 (1.6 g, 4.6 mmol) was dissolved in dry
DCM (20 mL) was added triethylamine (1.17 g, 11.6 mmol) and methanesulfonyl chloride (0.63
g, 5.5 mmol) at 0 °C and reaction was allowed to stir at room temperature for 5 h. Then reaction
mixture was quenched with ice cold water and extracted with DCM (3x50 ml), solvent wasremoved under vacuum and the residue was purified by flash column chromatography(hexane/ethyl acetate 9:1) to afford the compound 26 in good yield.
(S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3,3-diphenylpropyl-methanesulfonate(26):

White solid (Ether). 1.9 g, 85% yield. m.p. 152-154 oC. [α]D21 = –57.14 (c = 0.7, EtOH). IR (neat):3012, 2966, 2817, 1622, 1456, 1158, 1028 cm-1. 1H NMR (CDCl3, 500 MHz): d 7.51 – 7.44 (m,4H), 7.35 – 7.18 (m, 6H), 5.25 (d, J = 8.5 Hz, 1H), 4.92 – 4.85 (m, 1H), 4.38 – 4.27 (m, 2H), 3.94
100

MsO
BocHN
26

Ph
Ph
OH

(bs, 1H), 2.86 (s, 3H), 1.33 (s, 9H). 13C NMR (CDCl3, 125 MHz) d: 156.1,
144.4, 143.8, 128.8, 128.4, 127.6, 127.3, 125.6, 125.2, 80.4, 80.0, 69.5,
56.0, 37.3, 28.2. FAB-MS m/z: 422 (M+H)+. HRMS (FAB) calcd for
C21H28NO6S m/z: 422.1637 (M+H)+: found: 422.1634.

General procedure for the synthesis compounds (27a-c): The Compound 26 (1.0 mmol) was
charged in 50 mL round bottomed flask and the corresponding cyclic amine (3 mmol) was added
drop-wise at room temperature. After 5 min stirring the temperature was raised to 70° C andallowed to stirred for 12 h. After completion of the reaction, indicated by TLC, the crude reaction
mixture was purified by flash column chromatography using (hexane/EtOAc, 7:3) to afford thecompounds 27a-e in moderate yield.
(S)-tert-butyl-(1-hydroxy-1,1-diphenyl-3-(pyrrolidin-1-yl)propan-2-yl)carbamate (27a):White solid (Ether). 65% yield. m.p. 113-115 oC. [α]D21 = –53.1 (c = 0.32, EtOH). IR (neat): 3096,
2918, 2817, 2834, 1725, 1565,1456, 1165, 1018 cm-1. 1H NMR (CDCl3, 500 MHz): d 7.54 – 7.52(m, 2H), 7.48 – 7.47 (m, 2H), 7.31 – 7.24 (m, 4H), 7.17 – 7.13 (m, 2H),
N
BocHN
27a

Ph
Ph
OH

5.23 (d, J = 5.0 Hz, 1H), 4.63 (d, J = 5.0 Hz, 1H), 2.81 – 2.74 (m, 2H), 2.70
– 2.60 (m, 2H), 2.40 – 2.30 (m, 2H), 1.78 – 1.68 (m, 4H), 1.35 (s, 9H). 13C
NMR (CDCl3, 125 MHz) d: 155.8, 146.8, 145.2, 128.4, 128.2, 126.68,

126.65, 125.3, 125.1, 81.7, 79.4, 56.3, 55.7, 54.3, 28.4, 28.3, 23.7. EI-MS m/z: 396 (M)+. HRMS
(EI) calcd for C24H32N2O3 m/z: 396.2413 (M)+: found: m/z: 396.2417 (M)+.
(S)-tert-butyl(1-hydroxy-1,1-diphenyl-3-(piperidin-1-yl)propan-2-yl)carbamate (27b): White
solid (Ether). 62% yield. m.p. 85-87 oC. [α]D21 = –88.0 (c = 0.25, EtOH). IR (neat): 3086, 2910,
N
BocHN
27b

Ph
Ph
OH

2856, 1721, 1623, 1555, 1467, 1148, 1022 cm-1. 1H NMR (CDCl3, 500
MHz): d 7.59 – 7.51 (m, 2H), 7.50 – 7.44 (m, 2H), 7.30 – 7.20 (m, 4H),
7.18 – 7.12 (m, 2H), 5.30 – 5.22 (m, 1H), 4.70 – 4.62 (, 1H), 2.76 – 2.73(m, 1H), 2.56 – 2.42 (m, 2H), 2.10 – 2.02 (m, 2H), 1.60 – 1.52 (m, 4H),

1.42 – 1.30 (m, 12H). 13C NMR (CDCl3, 125 MHz) d: 155. 8, 147.5, 145.2, 128.4, 128.2, 126.7,
126.6, 125.3, 125.2, 81.4, 79.4, 59.1, 56.3, 54.0, 28.4, 26.3, 23.7. EI-MS m/z: 410 (M)+. HRMS
(EI) calcd for C25H34N2O3 m/z: 410.2569 (M)+: found: m/z: 410.2565 (M)+.

101

(S)-tert-butyl-(3-(azepan-1-yl)-1-hydroxy-1,1-diphenylpropan-2-yl)carbamate (27c): White
solid (Ether). 55% yield. m.p. 67-69 oC. [α]D21 = –80.0 (c = 0.25, EtOH). IR (neat): 3094, 2895,
2812, 1732, 1645, 1532, 1428, 1156, 1019 cm-1. 1H NMR (CDCl3, 500
N
BocHN
27c

Ph
Ph
OH

MHz): d 7.55 (d, J = 5.0 Hz, 2H), 7.48 (d, J = 10.0 Hz, 2H), 7.30 – 7.24
(m, 4H), 7.18 – 7.12 (m, 2H), 5.28 – 5.20 (m, 1H), 4.68 – 4.62 (m, 1H),
3.00 – 2.92 (m, 1H), 2.44 – 2.36 (m, 2H), 1.70 – 1.52 (m, 8H), 1.34 (s,9H). 13C NMR (CDCl3, 125 MHz) d: 155. 7, 146.9, 145.3, 128.4, 128.2, 126.7, 126.6, 125.3, 81.5,
79.4, 59.0, 58.2, 54.0, 28.4, 27.9, 26.6. EI-MS m/z: 424 (M)+. HRMS (EI) calcd for C26H36N2O3
m/z: 424.2726 (M)+: found: m/z: 424.2728 (M)+.
General procedure for the synthesis of compounds (28a-e): The compounds 27a-e (1 mmol)
were dissolved in DCM (10 mL) followed by slow addition of TFA (0.382 mL, 10 mmol) at 0 oC
and stirred for 1 h at room temperature. After completion of reaction, indicated by TLC. The
residue was basified using with saturated aq. NaHCO3 solution and extracted with DCM (3x15mL) and the combined organic layers were washed with brine and dried over Na2SO4. The solvent
was evaporated under reduced pressure to afford compounds 28a-e in good to excellent yield.
(S)-2-amino-1,1-diphenyl-3-(pyrrolidin-1-yl)propan-1-ol (28a): Light yellow solid (Ether).
135 mg, 90% yield. m.p. 113-115 °C. [α]D24 = –74 (c = 1.09, EtOH ). IR (neat) = 2933, 2803, 1556,
1448, 1355 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.64 (d, J = 8.50 Hz, 2H), 7.53 (d, J = 8.50 Hz,
N
H2N
28a

Ph
Ph
OH

2H), 7.33-7.25 (m, 4H), 7.20-7.13 (m, 2H), 3.92 (q, J1 = 3.50, 7.00 Hz,
1H), 2.76 (q, J1 = 7.00, 13.00 Hz, 1H), 2.62-2.60 (m, 2H), 2.42-2.40 (m,2H), 2.28 (dd, J1 = 3.50, 13.00 Hz, 1H), 1.76-1.70 (m, 4H). 13C NMR (125MHz, CDCl3): δ 146.3, 145.8, 128.4, 128.2. 126.6, 126.5, 125.9, 125.6,

79.9, 57.6, 55.1, 55.0, 23.7; FAB-MS m/z: 297 (M+H)+. HRMS (FAB) calcd for C19H25N2O m/z:
297.1967 (M+H)+ found: 297.1963.

102

(S)-2-amino-1,1-diphenyl-3-(piperidin-1-yl)propan-1-ol (28b): Pale yellow solid (Ether). 145
mg, 95% yield. m.p. 125-126 °C. [α]D25 = –66 (c = 1.38, EtOH). IR (neat) = 3432, 2836, 2321,
1561, 1446 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.60 (d, J = 7.50 Hz, 2H), 7.51 (d, J = 7.50 Hz,2H), 7.33-7.24 (m, 4H), 7.20-7.15 (m, 2H), 3.96 (q, J1 = 4.50, 6.50 Hz,
N

Ph
Ph
OH

H2N
28b

1H), 2.62-2.39 (m, 3H), 2.20-2.16 (m, 3H), 1.57-1.50 (m, 4H), 1.38 (s, 2H).
13

C NMR (125 MHz, CDCl3): δ 146.9, 145.2, 128.3, 128.2, 126.6, 126.5,

126.1, 125.8, 79.5, 59.1, 56.3, 54.0, 28.5, 26.3. FAB-MS m/z: 310 (M+H)+.

HRMS (FAB) calcd for C20H27N2O m/z: 311.2123 (M+H)+: found: 311.2126.
(S)-2-amino-3-(azepan-1-yl)-1,1-diphenylpropan-1-ol (28c): Pale yellow solid (Ether). 131 mg,
86% yield. m.p. 145-146 °C. [α]D23 = –40 (c = 2.4, EtOH). IR (neat) = 3504, 2933, 2326, 1615,
1452 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.60 (d, J = 8.50 Hz, 2H), 7.51 (d, J = 8.50 Hz, 2H),
7.33-7.24 (m, 4H), 7.21-7.155 (m, 2H), 3.92 (q, J1= 4.50, 7.50 Hz, 1H),
N
H2N

Ph
Ph
OH

3.71 (s, 3H), 2.69-2.65 (m, 2H), 2.57-2.52 (m, 3H), 2.48 (dd, J1 = 4.50,
13.50 Hz, 1H), 1.63-1.56 (m, 5H). 13C NMR (125 MHz, CDCl3): δ

28c

146.3, 145.5, 128.4, 128.3, 127.3, 126.6, 126.1, 125.7, 79.8, 59.9, 56.8,

54.5, 28.0, 27.1. FAB-MS m/z: 325 (M+H)+. HRMS (FAB) calcd for C21H29N2O m/z: 325.2280(M+H)+: found: 325.2279.
(S)-2-amino-3-morpholino-1,1-diphenylpropan-1-ol (28d): Light yellow solid (Ether). 130 mg,
85% yield. m.p. 110-113 °C. [α]D23 = –66 (c = 1.0, EtOH). IR (neat) = 3386, 3324, 2950, 1599,
1449, 1259 cm-1. 1H NMR (500 MHz, CD3OD): δ 7.29 (d, J = 8.00 Hz, 2H), 7.18 (d, J = 8.00 Hz,2H), 6.98 (t, J = 8.00 Hz, 2H), 3.76 (dd, J1 = 3.00, 9.00 Hz, 1H), 2.20 (s,
O

N
H2N
28d

Ph
Ph
OH

2H), 2.10 (q, J = 9.00, 13.00 Hz, 1H), 1.88 (s, 2H), 1.83 (dd, J = 3.00,
12.50 Hz, 1H). 13C NMR (125 MHz, CD3OD) δ: 147.6, 146.8, 129.5,
129.3, 127.9, 127.8, 127.2, 126.8, 80.7, 68.2, 61.2, 55.4, 54.6. FAB-MS

m/z: 313 (M+H)+. HRMS (FAB) calcd for C19H25N2O2 m/z: 313.1916 (M+H)+: found: 313.1904.

103

(S)-2-amino-1,1-diphenyl-3-thiomorpholinopropan-1-ol (28e): White solid (Ether). 131 mg,
85% yield. m.p. 94-96 °C. [α]D25 = –74 (c = 1.09, EtOH). IR(neat) = 3582, 2952, 2359, 1673, 1491
cm-1. 1H NMR (500 MHz, CD3OD): δ 7.73 (s, 1H), 7.48 (d, J = 7.50 Hz, 2H), 7.39 (d, J = 7.50 Hz,2H), 7.20-7.12 (m, 2H), 3.93 (s, 1H), 2.64 (s, 2H), 2.48 (s, 2H), 2.35 (s,
N

S

Ph
Ph
OH

H2N
28e

2H), 2.30-2.25 (m, 3H), 2.12 (d, J = 13.00 Hz, 1H). 13C NMR (125MHz, CD3OD): δ 147.4, 146.8, 129.5, 129.3, 127.9, 127.8, 127.2, 126.2,
126.9, 80.7, 61.5, 57.2, 54.9, 28.9. EI-MS m/z: 328 (M)+. HRMS (EI)

calcd for C19H24N2OS m/z: 328.1609 (M)+: found: 328.1608.
General procedure for the synthesis of compounds (29a-e): The compound 20 (100 mg, 1mmol) and corresponding amino alcohol 28 (1 mmol) were charged in sealed tube in 20 mL MeOH
solvent were added and the sealed tube was closed tightly without any air gap and the reaction
mixture was stirred for 12 h at 120 °C. After completion of the reaction indicated by TLC, theexcess solvent was evaporated under reduced pressure resulted the crude mass, which was purified
directly by flash column chromatography using (CHCl3/MeOH 9:1) to afford the compounds 29ae in moderate to good yield.
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-1,1-diphenyl-3-(pyrrolidin-1yl)propan-2-yl)amino)cyclobut-3-ene-1,2-dione (29a): Brown solid (Ether). 99 mg, 56% yield.
m.p. 145-146 °C. [α]D25 = –45 (c = 1.0, CHCl3). IR (neat): 3566, 3250, 3198, 2965, 1680, 1596
cm-1. 1H NMR (500 MHz, CD3OD): δ 8.02 (s, 2H), 7.63 (d, J = 8.50 Hz, 2H), 7.55 (t, J = 7.50 Hz,
F3C

O3H), 7.39 (t, J = 8.00 Hz, 2H), 7.26 (t, J = 7. 50 Hz, 1H), 7.21

O
N

F3C

N
H

N
H
29a

Ph
HO Ph

(t, J = 7.50 Hz, 2H), 7.11 (t, J = 7.50 Hz, 1H), 5.45 (d, J =6.50 Hz, 1H), 3.00 (d, J = 8.50 Hz, 1H), 2.77 (s, 2H), 2.60 (d,J = 13.00 Hz, 1H), 2.46 (s, 2H), 1.78 (s, 4H). 13C NMR (125MHz, CD3OD): δ 186.1, 182.0, 171.6, 164.0, 146.5, 146.3, 142.6, 129.7, 129.2, 128.4, 128.1, 127.0,
126.8, 127.0, 126.8, 125.8, 123.7, 119.2, 116.4, 58.9, 56.0, 24.5. EI-MS m/z: 603 (M)+. HRMS
(EI) calcd for C31H27F6N3O3 m/z: 603.1957 (M)+: found: 603.1948.

104

(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-1,1-diphenyl-3-(piperidin-1yl)propan-2-yl)amino)cyclobut-3-ene-1,2-dione (29b): Brown solid (Ether). 100 mg, 54% yield.
m.p. 125-126° C. [α]D25 = –23.0 (c = 1.0, EtOH). IR (neat): 3554, 3447, 1794, 1733, 1671, 1558
F3C

O

cm-1. 1H NMR (500 MHz, CD3OD): δ 8.02, (s, 2H), 7.64 (d,

O
N

F3C

N
H

N
H
29b

Ph
Ph
HO

J = 7.00 Hz, 2H), 7.56 (d, J = 9.00 Hz, 2H), 7.50 (s, 1H), 7.40
(t, J = 8.00 Hz, 2H), 7.27 (t, J = 7.50 Hz, 2H), 7.11 (t, J =7.50 Hz, 1H), 5.53 (d, J = 7.50 Hz, 1H), 3.17-2.80 (m, 3H),
2.58 (s, 2H), 1.73-1.44 (m, 4H), 1.31-1.25 (m, 2H), 0.88 (t, J= 11.00 Hz, 1H). 13C NMR (125 MHz, CD3OD): δ 186.1, 182.0, 171.6, 164.2, 145.8, 142.4, 129.9,
129.3, 128.6, 128.3, 127.1, 126.8, 125.8, 123.6, 119.2, 116.7, 81.4, 60.9, 59.4, 56.1, 32.9, 26.0,
23.9, 14.6. FAB-MS m/z: 618 (M+H)+. HRMS (FAB) calcd for C32H30F6N3O3 m/z: 618.2191(M+H)+: found: 618.2203.
(S)-3-((3-(Azepan-1-yl)-1-hydroxy-1,1-diphenylpropan-2-yl)amino)-4-((3,5bis(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (29c): Yellow solid (Ether). 117
mg, 62% yield. m.p. 161-162° C. [α]D23 = –23.0 (c = 1.0, EtOH). IR (neat): 3522, 3493, 1793, 1648
cm-1. 1H NMR (500 MHz, CDCl3): δ 7.93 (s, 1H), 7.64-7.52 (m, 4H), 7.46 (d, J = 6.00 Hz, 2H),
F3C

O

7.36 (t, J = 7.50 Hz, 3H), 7.23 (t, J = 6.00 Hz, 2H), 7.17-

O
N

F3C

N
H

N
H
29c

Ph
Ph
HO

7.14 (m, 2H), 7.05 (t, J = 7.00 Hz, 1H), 5.44 (s, 1H), 3.12
(d, J = 14.00 Hz, 1H), 2.94 (s, 1H), 2.60 (s, 2H), 2.41 (s,2H), 1.61-1.35 (m, 8H). 13C NMR (125 MHz, CDCl3): δ
182.4, 181.7, 171.6, 162.4, 143.6, 143.0, 139.7, 129.2,

128.8, 127.7, 127.6, 125.2, 124.9, 124.0, 121.9, 117.7, 116.5, 115.3, 80.3, 59.7, 59.3, 57.8, 54.0,
27.1, 26.8, 23.6, 22.5. FAB-MS m/z: 632 (M+H)+. HRMS (FAB) calcd for C33H32F6N3O3 m/z:
632.2342 (M+H)+: found: 632.2341.
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-3-morpholino-1,1diphenylpropan-2-yl)amino)cyclobut-3-ene-1,2-dione (29d): White solid (Ether). 142 mg, 78%
yield. m.p. 238-240 °C. [α]D25 = –8.00 (c = 1.10, EtOH). IR (neat): 3589, 3423, 1797, 1568, 1541
cm-1. 1H NMR (500 MHz, CD3OD): δ 8.03 (s, 2H), 7.58 (t, J = 7.50 Hz, 4H), 7.53 (s, 1H), 7.37 (t,

105

F3C

O

J = 7.50 Hz, 2H), 7.26-7.21 (m, 3H), 7.11 (t, J = 7.00 Hz,

O
N

F3C

N
H

N
H
29d

O

2H), 5.48 (t, J = 4.50 Hz, 1H), 3.63-3.54 (m, 4H), 2.70 (q,J1 = 9.50 Hz, 13.50 Hz, 3H), 2.54 (d, J = 12.00 Hz, 1H),

Ph
Ph
HO

2.24 (s, 2H). 13C NMR (125 MHz, CD3OD): δ 186.3, 181.8,
171.8, 163.4, 146.6, 146.4, 142.6, 129.7, 129.3, 128.4,

128.0, 126.7, 125.8, 123.7, 119.2, 116.6, 80.8, 68.2, 61.4, 60.0, 55.5. FAB-MS m/z: 620 (M+H)+.
HRMS (FAB) calcd for C31H28F6N3O4 m/z: 620.1984 (M+H)+: found: 620.1984.
(S)-3-((3,5-Bis(trifluoromethyl)phenyl)amino)-4-((1-hydroxy-1,1-diphenyl-3thiomorpholinopropan-2-yl)amino)cyclobut-3-ene-1,2-dione (29e): White solid (Ether). 151
mg, 81% yield. m.p. 234-236 °C. [α]D25 = –11.00 (c = 1.0, EtOH). IR (neat): 3522, 3462, 1800,
1652, 1573 cm-1. 1H NMR (500 MHz, CD3OD): δ 8.03 (s, 2H), 7.58 (t, J = 7.50 Hz, 4H), 7.53 (s,F3CO1H), 7.37 (t, J = 7.50 Hz, 2H), 7.26-7.21 (m, 3H), 7.11 (t,

O
N

F3C

N
H

N
H
29e

S

Ph
HO Ph

J = 7.00 Hz, 1H), 5.46 (m, 1H), 2.91 (t, J = 7.50 Hz, 2H),
2.69-2.49 (m, 8H). 13C NMR (125 MHz, CD3OD) δ: 186.2,
181.8, 171.8, 163.4, 146.7, 146.4, 142.5, 129.7, 126.3,
128.4, 128.0, 126.9, 126.6, 125.8, 123.6, 119.1, 116.6, 80.8,

61.6, 60.3, 57.2, 29.0. FAB-MS m/z: 636 (M+H)+. HRMS (FAB) calcd for C31H28F6N3O3S m/z:
636.1756 (M+H)+: found: 636.1760.
General Procedure for the synthesis of compounds (31b-k): To the stirred solution of isatins
30b-k (20 mg, 1.0 equiv.) and catalyst 29c (0.1 equiv.) in THF (2 mL) was added nitromethane 7(5.0 equiv.) at 0 °C and stirring was continued for appropriate times at same temperature. Aftercompletion of reaction indicated by TLC, the excess solvent was removed under reduced pressure
yields the crude mass, which was purified by flash column chromatography using (Hexane/EtOAC
6:4) solvent system to afford the nitro-aldol products 31b-k. The enantiomeric were determinedby chiral HPLC using ChiralPak AD-H and AS-H columns.

106

(S)-tert-butyl 3-hydroxy-3-(nitromethyl)-2-oxoindoline-1-carboxylate (31e): Yellow solid. 24
mg, 98% yield. m.p. 134-136 °C. [α]D23 = +2.8 (c = 1.0, EtOH). IR (neat): 3995, 1732, 1616, 1540,
1191, 720 cm-1. (1H NMR, 500 MHz, CDCl3): δ 10.19 (s, 1H), 7.77 (t, J = 8.00 Hz, 1H), 7.66 (t, JOHO= 8.00 Hz, 1H), 7.44 (t, J = 9.00 Hz, 1H), 7.25-7.19 (m, 1H), 7.08 (s, 1H),
N O

5.22 (q, J1 = 14.00, 19.00 Hz, 2H), 1.58 (s, 9H). 13C NMR (125 MHz,O

CDCl3): δ 173.5, 148.9, 140.3, 131.2, 127.1, 125.3, 125.0, 115.3, 84.7, 78.5,

N
Boc
31e

72.6, 28.4. EI-MS m/z: 308 (M)+. HRMS (EI) calcd for C9H8N2O4 m/z:
208.0484 (M-Boc)+: found: m/z: 208.0491 (M-Boc)+. The enantiomeric

excess was determined by HPLC; DAICEL chiralpak AD-H column, (solvent system (hexane/2propanol) 85:15; flow rate 1.0 mL/min, detection UV 254 nm; retention time 10.27 min (major)and 17.46 min (minor), ee = 95 %).
(S)-3-hydroxy-5-iodo-3-(nitromethyl)indolin-2-one (31k): Brown solid. 24 mg, 97% yield. m.p.
160-161 °C. [α]D21 = +53.3 (c = 0.3, EtOH). IR (neat): 3991, 1730, 1615, 1543, 1182, 825 cm-1.
1

H NMR (500 MHz, DMSO-d6): δ 10.23 (s, 1H), 7.71 (d, J = 1.50 Hz, 1H), 7.57 (dd, J1 = 1.50,
OI

HO

8.00 Hz, 1H), 6.79 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.02 (q, J1 = 8.00,
N O
O

N
H
31k

39.50 Hz, 2H). 13C NMR (125 MHz, DMSO-d6): δ 175.3, 142.4, 138.6,
133.1, 130.7, 112.5, 84.6, 77.8, 72.4; EI-MS m/z: 333.9 (M)+. HRMS (EI)
calcd for C9H7N2O4I m/z: 333.9450 (M)+: found: 333.9460. The
enantiomeric excess was determined by HPLC; DAICEL chiralpak AD-H

column, (solvent system (hexane/2-propanol) 85:15; flow rate 1.0 mL/min, detection UV 254 nm;
retention time 12.51 min (minor) and 16.89 min (major), ee = 95 %).

107

Theoretical calculations
The gas phase geometry optimization of the molecules leading to energy minima wasachieved using the B3LYP hybrid functional with the 6-31G(d) basis set as implemented in theGaussian 09. For all optimized structures, vibrational normal mode analysis was carried out toensure that the obtained structures were corresponding to minimum energy state.
1) Gaussian 09, Revision D.01,
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G.
Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P.
Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A.
Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V.
N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S.
S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz,J. Cioslowski, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2013.
Table S1. Cartesian coordinates (Angstroms) for 7.
Point Group: C1
Total energy = -414.73904622 hartree
Symbol X
YZ
C-0.69483 0.630929 -0.01183
C
0.694817 0.63089 -0.01182
C
0.773873 -0.85541 -0.00734
C-0.77383 -0.85544 -0.00725
O-1.6942 -1.64271 0.01256
O
1.694236 -1.64269 0.012404
N-1.69573 1.541533 -0.04631
H-2.62735 1.190591 0.136318
H-1.5357 2.507005 0.201903
N
1.695716 1.541776 -0.04665
H
1.535579 2.506321 0.205273
H
2.627053 1.19038 0.136876
Table S2. Cartesian coordinates (Angstroms) for 30a.
Point Group: C1
Total energy = -513.06346656 hartree
Symbol X
Y
Z
C-2.64303 0.801652 -0.00028
C-2.75694 -0.59401 0.000096
108

C
C
C
C
H
H
H
H
C
C
O
O
N
H

-1.6325-0.3823-0.25463-1.37979-3.53775-3.74459-1.74092-1.25983
1.181637
1.909511
1.749486
3.0988020.884436
1.053908-1.43064-0.82532
0.5786
1.397911
1.416287-1.04721-2.51126
2.477471
0.899999-0.49268
1.969806-0.71151-1.42729-2.42376

0.00030.000254-0.00019-0.00049-0.00039
0.000185
0.000471-0.00073
0.000078-0.00011
0.000743-0.00062
0.000258-0.00024

Table S3. Cartesian coordinates (Angstroms) for 30a.
Point Group: C1
Total energy = -245.00932811 hartree
Symbol X
YZ
N
0.173845 -0.00011 -0.01168
O
0.732444 1.092099 0.003192
O
0.730299 -1.09321 0.003236
C-1.32526 0.001028 -0.0026
H-1.66502 0.91265 -0.49085
H-1.66722 -0.90041 -0.50823
H-1.63506 -0.00883 1.045001
Table S4. Cartesian coordinates (Angstroms) for Complex A (7 + 30a).
Point Group: C1
Total energy = -927.82276495 hartree
Symbol
C
C
C
C
O
O
N
H
H
N
H
H

X
3.281111
3.421373
4.901437
4.746214
5.443092
5.782951
2.2613072.482575
1.301782.593896
1.621988
3.023265

Y
0.736693-0.61779-0.52533
0.974288
1.955326-1.32968
1.574223
2.560079
1.331783-1.66162-1.63231-2.57459Z-0.14973
0.149173
0.223862-0.11256-0.28077
0.45252-0.4292-0.46886-0.20956
0.358593
0.070832
0.424907
109

C
C
C
C
C
C
H
H
H
H
C
C
O
O
N
H

-5.2444-5.82171-5.04618-3.66829-3.07351-3.85585-5.87991-6.9037-5.51285-3.38106-1.62244-1.40837-0.72195-0.35625-2.67528-2.85069

1.514967
0.255126-0.89267-0.73806
0.523839
1.656968
2.378689
0.158461-1.86042
2.621244
0.348343-1.18484
1.157301-1.77896-1.71608-2.69971

0.319302
0.116042-0.1033-0.11205
0.091305
0.307380.485546
0.127378-0.2595
0.461951
0.018904-0.24323
0.123021-0.36347-0.30787-0.46435

Table S5. Cartesian coordinates (Angstroms) for Complex B (7 + 30a).
Point Group: C1
Total energy = -659.76437807 hartree
Symbol X
YZ
C-1.27292 -0.69431 -0.04863
C-1.26923 0.69548 0.030308
C-2.75259 0.775621 0.056425
C-2.75692 -0.76842 -0.03533
O-3.55337 -1.68333 -0.07685
O-3.54407 1.693665 0.119141
N-0.33966 -1.66479 -0.15501
H-0.65798 -2.61754 -0.03886
H
0.62964 -1.47574 0.070069
N-0.32937 1.662455 0.112317
H
0.632234 1.468876 -0.14012
H-0.6472.61599 0.000338
N
3.261333 -0.01106 -0.01538
O
2.702388 1.007235 -0.41407
O
2.698955 -1.03687 0.358079
C
4.755328 0.017801 0.057795
H
5.013172 0.471515 1.017662
H
5.114319 -1.00791 0.006076
H
5.116177 0.635958 -0.76241

110

Chapter 3: The New Hybrid Type Squaramide Fused Amino Alcohol Organocatalysts For
Enantioselective Diels-Alder Reaction of 3-Hydroxy-2-Pyridones with Maleimides
General procedure for the synthesis of compounds (98a-k) and (101a-f): To a 4-mL of sample
vial containing catalyst 29a (6 mg, 10 mmol), 3-hydroxy-2-pyridones 96a,b and 99a-d (20 mg,
0.07 mmol) and 1mL of DCM were added. The solution was allowed to stir at 0 °C for an hour,
followed by maleimides 97a-k (14 mg, 0.08 mmol) were added. After stirring for 23 h at same
temperature, the solvent was removed under reduced pressure. The residue was purified by flash
column chromatography (Hexane/EtOAc: 90:10 to 60:40) to afford the DA adducts 98a-k and101a-f. The enantiomeric excess was determined by chiral HPLC using Chiralpak AS-H and
Chiralcel OD-H columns.
(4R)-7-hydroxy-2-phenyl-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7-(epiminomethano)isoindole1,3,8-(2H)-trione (98a): White solid. 28 mg, 96 % yield. m.p. 241-242 °C. [α]D23 = –14 (c = 0.7,
MeOH). IR (neat): cm-1 = 3449, 3065, 1781, 1712, 1449, 1351, 1240, 1159. 1H NMR (500 MHz,CDCl3, ppm): δ 7.89 (d, J = 8.00 Hz, 2H), 7.45 (t, J = 7.00 Hz, 2H), 7.40 (t, J

Ts
N

O

HO

= 7.50 Hz, 1H), 7.35 (d, J = 8.00 Hz, 2H), 7.16 (d, J = 8.00 Hz, 2H), 6. 48 (q,
N

O
98a

O
Ph

J = 6.00, 8.50 Hz, 1H), 6.39 (d, J = 7.50 Hz, 1H), 5.84-5.82 (m, 1H), 4.07 (s,1H), 3.76 (q, J = 4.00, 8.00 Hz, 1H), 3.16 (d, J = 8.50 Hz, 1H), 2.45 (s, 3H).
13

C NMR (125 MHz, CDCl3, ppm): 172.6, 172.1, 169.8, 146.4, 136.8, 134.6,

131.13, 130.14, 129.4, 129.33, 129.32, 128.2, 126.7, 78.0, 52.4, 47.4, 44.1, 21.9. MS (FAB): m/z= 439 [M+H]+, HRMS (FAB): calcd. for C22H18N2O6S m/z 439.0987; found: 439.0966. The
enantiomeric excess was determined by chiral HPLC using CHIRALPAK AS-H cloumn (solvent
system: MeOH; flow rate 0.2 mL/min; temp 25°C; detection UV 254 nm; retention time 21.66 min(major) and 33.31 min (minor), ee = 64%).
(4R)-7-hydroxy-2-methyl-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7-(epiminomethano)isoindole-O

1,3,8-(2H)-trione (98b): White solid. 27 mg, 96 % yield. m.p. 231-232 °C.

Ts
N

HO

[α]D24 = –15 (c = 0.4, MeOH). IR (neat): cm-1 = 3456, 3072, 1778, 1709,
N

O
98b

O
Me

1458, 1360, 1238, 1154, 1112. 1H NMR (500 MHz, CDCl3, ppm): δ 7.85 (d,J = 8.50 Hz, 2H), 7.33 (d, J = 8.00 Hz, 2H), 6.35 (q, J = 5.50, 7.50 Hz, 1H),
6.24 (d, J = 8.00 Hz, 1H), 5.74-5.72 (m, 1H), 4.04 (s, 1H), 3.59 (q, J = 4.50,

8.00 Hz, 1H), 3.02 (d, J = 8.50 Hz, 1H), 2.93 (s, 3H), 2.42 (s, 3H). 13C NMR (125 MHz, CDCl3,111ppm): 173.9, 173.2, 169.9, 146.3, 136.3, 136.7, 134.5, 130.1, 129.1, 128.2, 77.8, 52.2, 47.5, 44.1,
25.4, 21.9. MS (FAB): m/z = 377 [M+H]+, HRMS (FAB): calcd. for C17H16N2O6S m/z 377.0814;
found: 377.0809. The enantiomeric excess was determined by chiral HPLC using CHIRALPAK
AS-H column (solvent system: MeOH; flow rate 0.2 mL/min; temp 25°C; detection UV 254 nm;
retention time 18.99 min (major) and 22.18 min (minor), ee = 22%).
(4R)-7-hydroxy-2-ethyl-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7-(epiminomethano)isoindole1,3,8-(2H)-trione (98c): white solid. 26 mg, 90 % yield. m.p. 134.5 °C. [α]D24 = –18 (c = 0.5,
MeOH). IR (neat) cm-1 = 3458, 3070, 1771, 1700, 1451, 1355, 1218, 1144, 1113. 1H NMR (500O

MHz, CDCl3, ppm): δ 7.87 (d, J = 8.50 Hz, 2H), 7.34 (d, J = 8.00 Hz, 2H), 6.36

TsN(q, J = 5.50, 8.00 Hz, 1H), 6.25 (dd, J = 4.50, 8.00 Hz, 1H), 3.50 (q, J = 7.00,

HO

O

N
O
98c

Et

14.50 Hz, 2H), 2.99 (d, J = 8.00 Hz, 1H), 2.44 (s, 3H), 1.08 (t, J = 7.00 Hz, 3H).
13

C NMR (125 MHz, CDCl3, ppm): 173.4, 172.9, 169.9, 146.3, 136.5, 134.5,

130.1, 129.0, 128.2, 77.8, 52.3, 47.3, 43.9, 34.3, 21.9, 12.9. MS (FAB): m/z =391 [M+H]+, HRMS (FAB): calcd. for C18H18N2O6S m/z 391.0988; found: 391.0966. The
enantiomeric excess was determined by chiral HPLC using CHIRALPAK AS-H column (solvent
system: MeOH; flow rate 0.2 mL/min; temp 25°C; detection UV 254 nm; retention time 21.19 min(major) and 33.5 min (minor), ee = 26%).
(4R)-7-hydroxy-2-(p-tolyl)-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7-(epiminomethano)isoindole1,3,8-(2H)-trione (98d): White solid. 30 mg, 90 % yield. m.p. 236.1 °C. [α]D23 = –20 (c = 0.2,
MeOH). IR (neat): cm-1 = 3485, 2360, 1740, 1696, 1514, 1404, 1369, 1155, 1099. 1H NMR (500
MHz, CDCl3, ppm): δ 7.89 (d, J = 8.50 Hz, 2H), 7.35 (d, J = 8.50 Hz, 2H), 7.25 (t, J = 7.00 Hz,

O2H), 7.03 (d, J = 8.00 Hz, 2H), 6.46 (q, J = 6.00, 8.00 Hz, 1H), 6.38 (d, JTsN= 7.00 Hz, 1H), 5.84-5.81 (m, 1H), 4.17 (s, 1H), 3.75 (q, J = 4.50, 8.50

HON

Hz, 1H), 3.18 (d, J = 8.00 Hz, 1H), 2.44 (s, 3H), 2.36 (s, 3H). 13C NMR

O(125 MHz, CDCl3, ppm): 172.8, 172.4, 169.8, 146.3, 139.4, 136.7, 134.5,

O98d130.1, 130.3, 129.3, 128.4, 128.2, 126.0, 78.0, 52.4, 47.3, 43.9, 21.9, 21.3.
Me

MS (FAB): m/z = 453 [M+H]+, HRMS (FAB): calcd. for C23H20N2O6S

m/z 453.1102; found: 453.1132. The enantiomeric excess was determined by chiral HPLC using
CHIRALPAK AS-H column (solvent system: MeOH; flow rate 0.2 mL/min; temp 25°C; detection
UV 254 nm; retention time 22.2 min (major) and 41.9 min (minor), ee = 25%).
112

(4R)-7-hydroxy-2-(4-fluorophenyl)-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (98e): White solid. 30 mg, 89 % yield. m.p. 202205 °C. [α]D24 = –15 (c = 0.2, MeOH). IR (neat): cm-1 = 3675, 1705, 1653, 1511, 1374, 1224, 1156,
1090. 1H NMR (500 MHz, CDCl3, ppm): δ 7.87 (d, J = 8.00 Hz, 2H), 7.34 (d, J = 8.50 Hz, 2H),O

7.16-7.09 (m, 4H), 6.45 (q, J = 6.00, 8.00 Hz, 1H), 6.37 (dd, J = 1.00, 8.00

TsN

Hz, 1H), 5.82-5.80 (m, 1H), 4.27 (s, 1H), 3.80-3.77 (m, 1H), 3.23 (dd, J =HO

N

1.00, 8.50 Hz, 1H), 2.43 (s, 3H). 13C NMR (125 MHz, CDCl3, ppm): 172.7,

O

172.2, 169.8, 163.4, 161.5, 146.4, 136.7, 134.4, 130.1, 129.3, 128.2, 128.1,

O

126.9, 116.5, 116.3, 78.0, 52.3, 47.3, 43.9, 21.9. MS (FAB): m/z = 457
98e

F[M+H]+, HRMS (FAB): calcd. for C22H17FN2O6S m/z 457.0891; found:457.0868. The enantiomeric excess was determined by chiral HPLC using CHIRALPAK AS-H
column (solvent system: MeOH; flow rate 0.2 mL/min; temp 25°C; detection UV 254 nm;
retention time 20.44 min (major) and 27.61 min (minor), ee = 36%).
(4R)-7-hydroxy-2-(4-chlorophenyl)-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (98f): White solid. 30 mg, 85 % yield. m.p. 225.7°C. [α]D24 = –11 (c = 0.2, MeOH). IR (neat): cm-1 = 3853, 1781, 1730, 1703, 1643, 1617, 1565,

O

1495, 1342, 1089. 1H NMR (500 MHz, CDCl3, ppm): δ 7.89 (d, J = 8.50

TsNHz, 2H), 7.42 (d, J = 9.00 Hz, 2H), 7.36 (d, J = 8.00 Hz, 2H), 7.14 (d, J =HO

N

8.50 Hz, 2H), 6.47 (q, J = 5.50, 8.00 Hz, 1H), 6.38 (q, J = 4.00, 8.00 Hz,

O1H), 3.18 (d, J = 8.50 Hz, 1H), 2.45 (s, 3H).13C NMR (125 MHz, CDCl3,

Oppm): 172.4, 171.8, 169.7, 146.4, 136.8, 135.5, 134.5, 130.1, 129.6, 129.4,
98f

Cl

128.2, 127.4, 78.0, 52.3, 47.4, 44.1, 21.9. MS (FAB): m/z = 473 [M+H]+,

HRMS (FAB): calcd. for C22H17ClN2O6S m/z 473.0516; found: 473.0562. The enantiomeric
excess was determined by chiral HPLC; CHIRALPAK AS-H column (solvent system: MeOH;
flow rate 0.2 mL/min; temp 25°C; detection UV 254 nm; retention time 23.1 min (major) and
34.71 min (minor), ee = 35%).

113

(4R)-7-hydroxy-2-(4-bromophenyl)-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (98g): White solid. 35 mg, 92 % yield. m.p. 217.5°C. [α]D24 = –23 (c = 0.3, MeOH). IR (neat): cm-1 = 3735, 3352, 1711, 1595, 1490, 1364, 1272,

O

1165, 1087. 1H NMR (500 MHz, CDCl3, ppm): δ 7.89 (d, J = 8.50 Hz,

TsN2H), 7.58 (d, J = 8.50 Hz, 2H), 7.36 (d, J = 8.50 Hz, 2H), 7.08 (d, J = 8.0
Hz, 2H), 6.47 (q, J = 6.00, 8.00 Hz, 1H), 6.38 (d, J = 7.50 Hz, 1H), 5.84-

HO

N

O

5.81 (m, 1H), 4.04 (s, 1H), 3.75 (q, J = 4.0, 8.50 Hz, 1H), 3.14 (d, J = 8.50

OHz, 1H), 2.45 (s, 3H). 13C NMR (125 MHz, CDCl3, ppm): 172.2, 171.7,

98g

Br

169.8, 146.4, 136.8, 134.6, 132.6, 130.16, 130.13, 129.4, 128.2, 127.7,
123.2, 78.0, 52.3, 47.4, 44.1, 21.9. MS (FAB): m/z = 517 [M]+, HRMS

(FAB): calcd. for C22H17BrN2O6S m/z 517.0096; found: 517.0095. The enantiomeric excess wasdetermined by chiral HPLC using CHIRALPAK AS-H column (solvent system: MeOH; flow rate
0.2 mL/min; temp 25°C; detection UV 254 nm; retention time 24.5 min (major) and 39.0 min(minor), ee = 49%).
(4R)-7-hydroxy-2-(4-iodophenyl)-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (98h): White solid. 33 mg, 78 % yield. m.p. 202–
205 °C. [α]D24 = –19 (c = 0.1, MeOH). IR (neat): cm-1 = 3744, 3587, 2362, 1710, 1489, 1374, 1167,

O

1088, 993. 1H NMR (500 MHz, CDCl3, ppm): δ 7.89-7.87 (m, 2H), 7.76 (d,

Ts
N

HO

J = 9.00 Hz, 1H), 7.46-7.38 (m, 1H), 7.34 (d, J = 7.50 Hz, 2H), 7.16 (d, J =N

7.50 Hz, 1H), 6.93 (d, J = 8.50 Hz, 1H), 6.49-6.44 (m, 1H), 6.38 (t, J = 7.50

OHz, 1H), 5.84-5.81 (m, 1H), 4.20 (s, 1H), 3.78 (q, J = 4.00, 8.00 Hz, 1H),O

3.21 (d, J = 8.00 Hz, 1H), 2.44 (s, 3H).13C NMR (125 MHz, CDCl3, ppm):
98hI

172.7, 172.3, 171.8, 169.7, 146.4, 138.5, 136.7, 130.7, 130.1, 129.4, 128.2,

127.9, 126.2, 78.0, 52.4, 47.4, 44.0, 21.9. MS (FAB): m/z = 564 [M]+, HRMS (FAB): calcd. for
C22H17IN2O6S m/z 564.9950; found: 564.9958. The enantiomeric excess was determined by chiral
HPLC using CHIRALPAK AS-H column (solvent system: MeOH; flow rate 0.2 mL/min; temp
25°C; detection UV 254 nm; retention time 26.64 min (major) and 46.87 min (minor), ee = 36%).

114

(4R)-7-hydroxy-2-phenyl-9-mesitylsulfonyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (98i): White solid. 29 mg, 92 % yield. m.p. 234.1°C. [α]D24 = 57 (c = 0.4, CH2Cl2). IR (neat): cm-1 = 3213, 2970, 1787, 1517, 1456, 1345, 1125,

O

1109, 1098. 1H NMR (500 MHz, CDCl3, ppm): δ 7.46-7.38 (m, 3H), 7.17 (d, J

Mes
N

HO

= 8.00 Hz, 2H), 6.97 (s, 2H), 6.54 (t, J = 8.00 Hz, 1H), 6.50 (d, J = 5.50 Hz,
O

N
O
98i

Ph

1H), 5.88 (t, J = 4.00 Hz, 1H), 4.10 (s, 1H), 3.90 (q, J = 4.50, 8.50 Hz, 1H),
3.24 (d, J = 8.50 Hz, 1H), 2.59 (s, 6H), 2.30 (s, 3H). 13C NMR (125 MHz,CDCl3, ppm): 172.7, 172.2, 170.6, 144.8, 141.1, 137.3, 132.3, 131.6, 131.1,

129.3, 129.2, 129.0, 126.3, 78.1, 51.5, 47.9, 44.6, 22.7, 21.2. MS (FAB): m/z = 467 [M+H]+,
HRMS (FAB): calcd. for C24H22N2O6S m/z 467.1204; found: 467.1272. The enantiomeric excess
was determined by chiral HPLC using CHIRALPAK AS-H column (solvent system: MeOH; flowrate 0.2 mL/min; temp 25°C; detection UV 254 nm; retention time 23.3 min (major) and 31.8 min(minor), ee = 22%).
(4R)-7-hydroxy-2-(4-bromophenyl)-9-mesitylsulfonyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (98j): White solid. 35 mg, 95 % yield. m.p. 221.5°C. [α]D24 = 90 (c = 0.4, CH2Cl2). IR (neat): cm-1 = 3821, 3742, 3567, 1780, 1700, 1670, 1489,

O

1373, 1188, 1079. 1H NMR (500 MHz, CDCl3, ppm): δ 7.57 (d, J = 8.50

Mes
N

HO

Hz, 2H), 7.09 (d, J = 8.50 Hz, 2H), 6.98 (s, 2H), 6.55 (q, J = 5.50, 8.00
NHz, 1H), 6.49 (d, J = 8.00 Hz, 1H), 5.89-5.87 (m, 1H), 4.11 (s, 1H), 3.91

O(q, J = 4.50, 8.50 Hz, 1H), 3.27 (d, J = 8.50 Hz, 1H), 2.59 (s, 6H), 2,30 (s,O

98j

3H).13C NMR (125 MHz, CDCl3, ppm): 172.3, 171.9, 170.5, 144.9, 141.1,
Br

137.4, 134.4, 132.5, 132.4, 131.5, 130.1, 129.0, 127.7, 127.5, 123.1, 78.1,

51.4, 47.9, 44.7, 22.7, 21.2. MS (FAB): m/z = 545 [M+H]+, HRMS (FAB): calcd. for
C24H21BrN2O6S m/z 545.0401; found: 545.0404. The enantiomeric excess was determined bychiral HPLC using CHIRALPAK AS-H column (solvent system: MeOH; flow rate 0.2 mL/min;
temp 25°C; detection UV 254 nm; retention time 29.83 min (major) and 38.17 min (minor), ee =
38%).

115

(4S)-6-bromo-7-hydroxy-2-phenyl-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (101a): White solid. 28 mg, 95 % yield. m.p.
242.5 °C. [α]D25 = 40 (c = 0.1, MeOH). IR (neat): cm-1 = 3815, 3734, 1716, 1596, 1495, 1394,
TsN
O

1342, 1291, 1205, 1153, 1086. 1H NMR (500 MHz, CDCl3, ppm): δ 7.91
(d, J = 8.00 Hz, 2H), 7.47-7.40 (m, 3H), 7.37 (d, J = 8.50 Hz, 2H), 7.16 (d,OJ = 7.00 Hz, 2H), 6.72 (d, J = 6. 00 Hz, 1H), 5.83 (q, J = 4.50, 7.00 Hz, 1H),
N

Ph

OH
O
101a

Br

4.30 (s, 1H), 3.79-3.75 (m, 1H), 3.30 (d, J = 8.00 Hz, 1H), 2.46 (s, 3H). 13C
NMR (125 MHz, CDCl3, ppm): 172.2, 171.1, 167.6, 146.6, 134.3, 130.9,

130.2, 129.5, 129.4, 129.0, 128.8, 128.3, 126.4, 78.5, 53.3, 47.9, 44.0, 21.9. MS MS (FAB): m/z =517 [M]+, HRMS (FAB): calcd. for C22H17BrN2O6S m/z 517.0061; found: 517.0065. The
enantiomeric excess was determined by chiral HPLC using CHIRALPAK AS-H column (solvent
system: MeOH; flow rate 0.2 mL/min; temp 25°C; detection UV 254 nm; retention time 21.2 min(major) and 24.8 min (minor), ee = 98%).
(4S)-6-bromo-7-hydroxy-2-(4-bromophenyl)-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (101b): White solid. 30 mg, 89 % yield. m.p. 245°C. [α]D23 = 32 (c = 0.2, MeOH). IR (neat): cm-1 = 3769, 2355, 1712, 1595, 1490, 1364, 1272,
1165, 1087. 1H NMR (500 MHz, CDCl3, ppm): δ 7.89 (d, J = 8.50 Hz, 2H), 7.57 (d, J = 9.00 Hz,
O

Br HO

2H), 7.36 (d, J = 8.50 Hz, 2H), 7.04 (d, J = 9.00 Hz, 1H), 6.71 (d, J =Ts
N

6.50 Hz, 1H), 5.82 (q, J = 4.50, 7. 00 Hz, 1H), 4.37 (s, 1H), 3.82 (q, JN= 4.50, 8.00 Hz, 1H), 3.35 (d, J = 7.50 Hz, 1H), 2.45 (s, 3H). 13C NMR

O(125 MHz, CDCl3, ppm): 172.0, 170.9, 167.6, 146.7, 134.2, 132.7,

O130.2, 129.9, 129.0, 128.8, 128.3, 127.9, 123.3, 78,5, 53.2, 47.9, 44.1,
101b

Br

21.9. MS (FAB): m/z = 596 [M]+, HRMS (FAB): calcd. for

C22H16BrN2O6S m/z 596.9130; found: 596.9131. The enantiomeric excess was determined bychiral HPLC using CHIRALPAK AS-H column (solvent system: MeOH; flow rate 0.2 mL/min;
temp 25°C; detection UV 254 nm; retention time 23.55 min (major) and 29.03 min (minor), ee =
74%).

116

(4S)-6-bromo-7-hydroxy-2-methyl-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (101c): White solid. 23 mg, 90 % yield. m.p. 248°C. [α]D24 = 40 (c = 0.5, MeOH). IR (neat): cm-1 = 3723, 2880, 1767, 1627, 1347, 1222, 1095,
1089. 1H NMR (500 MHz, CDCl3, ppm): δ 7.86 (d, J = 8.50 Hz, 2H),

Ts
N

O

Br HO

7.34 (d, J = 8.00 Hz, 2H), 6.60 (d, J = 6.50 Hz, 1H), 5.73 (q, J = 4.50,
N

O
101c

O

6.50 Hz, 1H), 4.25 (s, 1H), 3.60 (q, J = 4.00, 8.00 Hz, 1H), 3.19 (d, J =Me

8.00 Hz, 1H), 2.95 (s, 3H), 2.43 (s, 3H). 13C NMR (125 MHz, CDCl3,ppm): 173.1, 172.1, 167.7, 146.6, 134.2, 130.2, 128.9, 128.6, 128.2, 78.3,

53.1, 47.8, 44.2, 25.5, 21.9. MS (FAB): m/z = 456 [M+H]+, HRMS (FAB): calcd. for
C17H15BrN2O6S m/z 456.9817; found: 456.9893. The enantiomeric excess was determined bychiral HPLC using CHIRALPAK AS-H column (solvent system: IPA:Hexane = 90:10; flow rate
0.5 mL/min; temp 25°C; detection UV 254 nm; retention time 28.0 min (major) and 37.6 min(minor), ee = 62%).
(4S)-6-bromo-7-hydroxy-2-phenyl-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (101d): White solid. 26 mg, 92 % yield. m.p. 245°C. [α]D24 = 32 (c = 0.4, MeOH). IR (neat): cm-1 = 3931, 3869, 3488, 1603,

Ts
N

O

Br HO

O
101d

1505, 1457, 1339, 1281, 1102, 976. 1H NMR (500 MHz, CDCl3, ppm): δNO

7.56 (d, J = 8.50 Hz, 2H), 7.08 (d, J = 8.50 Hz, 2H), 6.97 (s, 2H), 6.54 (q, JPh= 6.00, 8.00 Hz, 1H), 6.49 (d, J = 6.50 Hz, 1H), 5.89-5.86 (m, 1H), 4.10 (s,1H), 3.91 (q, J = 4.00, 8.50 Hz, 1H), 3.26 (d, J = 8.50 Hz, 1H), 2.58 (s, 6H),

2.30 (s, 3H). 13C NMR (125 MHz, CDCl3, ppm): 172.3, 171.9, 170.5, 144.9, 141.1, 137.4, 134.4,
132.5, 132.3, 131.5, 130.1, 129.0, 127.7, 127.4, 123.1, 78.1, 51.4, 47.9, 44.7, 22.7, 21.2. MS(FAB): m/z = 545 [M]+, HRMS (FAB): calcd. for C24H21BrN2O6S m/z 545.0345; found: 545.0357.
The enantiomeric excess was determined by chiral HPLC; CHIRALPAK AS-H column (solvent
system MeOH; flow rate 0.2 mL/min; temp 25°C; detection UV 254 nm; retention time 23.55 min(major) and 29.03 min (minor), ee = 74%).

117

(4S)-6-allyl-7-hydroxy-2-phenyl-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (101e): White solid. 29 mg, 93 % yield. m.p. 224°C. [α]D24 = 23 (c = 0.4, MeOH). IR (neat): cm-1 = 3976, 3748, 1708, 1596, 1497, 1353, 1296,
O

1226, 1188, 1084. 1H NMR (500 MHz, CDCl3, ppm): δ 7.89 (d, J = 8.00

TsNHz, 2H), 7.46-7.38 (m, 3H), 7.35 (d, J = 8.00 Hz, 2H), 7.11 (d, J = 7.50
N

HO

O

O

Hz, 2H), 6.10-6.08 (m, 1H), 5.76 (q, J = 4.00, 6.00 Hz, 1H), 5.63-5.54

Ph(m, 1H), 5.02 (dd, J = 9.00, 10.00 Hz, 1H), 4.88 (dd, J = 15.50, 17.00

101e

Hz, 1H), 4.00 (s, 1H), 3.68 (q, J = 4.00, 8.00 Hz, 1H), 3.13 (d, J = 8.50

Hz, 1H), 2.95-2.81 (m, 2H), 2.46 (s, 3H).13C NMR (125 MHz, CDCl3, ppm): 172.7, 172.1, 170.1,
148.1, 146.3, 134.6, 132.5, 131.1, 130.1, 129.4, 129.3, 128.2, 126.3, 121.9, 118.7, 79.0, 52.2, 47.5,
44.2, 33.5, 21.9. MS (FAB): m/z = 479 [M+H]+, HRMS (FAB): calcd. for C25H22N2O6S m/z
479.1270; found: 479.1272. The enantiomeric excess was determined by chiral HPLC using
CHIRALCEL OD-H column (solvent system: IPA/Hexane = 50/50; flow rate 0.5 mL/min; temp
25°C; detection UV 254 nm; retention time 24.8 min (major) and 50.3 min (minor), ee = 75%).
(4S)-6-propyl-7-hydroxy-2-phenyl-9-tosyl-3a,4,7,7a-tetrahydro-1H-4,7(epiminomethano)isoindole-1,3,8-(2H)-trione (101f): White solid. 28 mg, 90 % yield. m.p.
225.5 °C. [α]D23 = 18 (c = 0.5, CH2Cl2). IR (neat): cm-1 = 3987, 3878, 3427, 2979, 1709, 1567,

O

1478, 1345, 1234, 1125, 1089. 1H NMR (500 MHz, CDCl3, ppm): δ

Ts
N

HO

101f

7.91(d, J = 8.50 Hz, 2H), 7.45 (t, J = 7.00 Hz, 2H), 7.40 (t, J = 7.50 Hz,
N

O

O

Ph

1H), 7.35 (d, J = 8.00 Hz, 2H), 7.11 (d, J = 7.0 Hz, 1H), 6.09-6.07 (m,1H), 5.76 (q, J = 4.50, 6.00 Hz, 1H), 3.99 (s, 1H), 3.70 (q, J = 4.00, 6.00
Hz, 1H), 3.12 (d, J = 8.50 Hz, 1H), 2.44 (s, 3H), 2.23-2.17 (m, 1H),

2.08-2.01 (m, 1H), 1.36-1.211 (m, 2H), 0.74 (t, J = 7.50 Hz, 3H). 13C NMR (125 MHz, CDCl3,ppm): 172.8, 172.3, 170.3, 149.5, 146.2, 134.7, 131.2, 130.0, 129.4, 129.2, 128.2, 126.1, 120.9,
79.2, 52.2, 47.6, 44.2, 31.2, 21.8, 20.1, 13.5. MS (FAB): m/z = 481 [M+H]+, HRMS (FAB): calcd.
for C25H24N2O6S m/z 481.1421; found: 481.1431. The enantiomeric excess was determined bychiral HPLC using CHIRALPAK OD-H column (solvent system: IPA/Hexane: 50/50; flow rate
0.5 mL/min; temp 25°C; detection UV 254 nm; retention time 58.0 min (major) and 51.6 min(minor), ee = 51%).

118

X-ray Crystallography of (101a):
Single crystals suitable for X-ray crystallography were obtained by a diffusion of 2propanol into a dichloromethane solution of 101a. X-ray diffraction data were collected at 150 K
on a Rigaku XtaLAB mini diffractometer with graphite monochromated Mo Kα radiation (λ =0.71070 Å). The structure was solved by direct methods (SHELX 2013)[1] and expanded using
Fourier techniques. The non-hydrogen atoms were refined anisotropically. Hydrogen atoms wererefined using the riding model. The final cycle of full-matrix least-squares refinement [2] on F2 wasbased on 4752 observed reflections and 289 variable parameters and converged (largest parameter
shift was 0.00 times its esd.) with unweighted and weighted agreement factors of:
R1 = S ||Fo| - |Fc|| / S |Fo| = 0.0478
wR2 = [ S (w (Fo2 - Fc2)2 ) / S w(Fo2)2]1/2 = 0.1218
The goodness of fit[3] was 1.06. Unit weights were used. The maximum and minimum
peaks on the final difference Fourier map corresponded to 0.22 and -0.64 e-/Å3, respectively. A
total of 16453 reflections were measured and 4752 were unique (Rint = 0.0480). Crystal data andrefinement statistics are shown in Table S1. Atomic coordinates Biso involving hydrogen atoms
are listed in Table S2. Crystallographic data of 101a has been deposited with Cambridge
Crystallographic Data Center, deposition no. CCDC 1552298.
[1] Sheldrick, G.M. Acta Cryst., 2008, A64, 112-122.
[2] Least Squares function minimized: (SHELXL2013)
Sw(Fo2-Fc2)2 where w = Least Squares weights.
[3] Goodness of fit is defined as:[Sw(Fo2 - Fc2)2/(No - Nv)]1/2
where: No = number of observations
Nv = number of variables
Table S1. Crystal data and structure refinement for (101a):
A. Crystal Data
Empirical Formula
Formula Weight
Crystal Color, Habit
Crystal Dimensions
Crystal System

C22H17BrN2O6S
517.35colorless, block0.400 X 0.400 X 0.350 mm
orthorhombic

119Lattice Type
Lattice Parameters

Primitivea = 8.6469(14) Å
b = 10.2464(16) Åc = 23.712(4) ÅV = 2100.9(6) Å3

Space GroupZ value
Dcalc
F000µ(MoKa)Pca21 (#29)
4
1.636 g/cm3
1048.00
21.056 cm-1
B. Intensity Measurements

Diffractometer
Radiation

XtaLAB mini
MoKa (l = 0.71075 Å)graphite monochromated
50kV, 12mA
-123.0oC
75.0 mm (diameter)
540 exposures-60.0 - 120.0o
32.0 sec./o
30.00o-60.0 - 120.0o
32.0 sec./o
30.00o-60.0 - 120.0o
32.0 sec./o
30.00o-60.0 - 120.0o
32.0 sec./o
30.00-60.0 - 120.0o
32.0 sec./o
30.00o-60.0 - 120.0o
32.0 sec./o
30.00oVoltage, Current
Temperature
Detector Aperture
Data Images
w oscillation Range (c=54.0, f=0.0)
Exposure Rate
Detector Swing Angle
w oscillation Range (c=54.0, f=120.0)
Exposure Rate
Detector Swing Angle
w oscillation Range (c=54.0, f=240.0)
Exposure Rate
Detector Swing Angle
w oscillation Range (c=54.0, f=0.0)
Exposure Rate
Detector Swing Angle
w oscillation Range (c=54.0, f=120.0)
Exposure Rate
Detector Swing Angle
w oscillation Range (c=54.0, f=240.0)
Exposure Rate
Detector Swing Angle

120

Detector Position
Pixel Size
2qmax
16453

50.00 mm0.073 mm55.0oNo. of Reflections Measured

Total:

Unique: 4752 (Rint = 0.0480)
Parsons quotients (Flack x parameter): 1976
Corrections

Lorentz-polarization
Absorption(trans. factors: 0.334 - 0.479)
C. Structure Solution and Refinement

Structure Solution
Refinement
Function Minimized
Least Squares Weights

Charge Flipping (Superflip)
Full-matrix least-squares on F2
S w (Fo2 - Fc2)2
w = 1/ [ s2(Fo2) + (0.0315 . P)2+ 0.0000 . P ]where P = (Max(Fo2,0) + 2Fc2)/3
55.0o

2qmax cutoff
Anomalous Dispersion
No. Observations (All reflections)
No. Variables
Reflection/Parameter Ratio
Residuals: R1 (I>2.00s(I))
Residuals: R (All reflections)
Residuals: wR2 (All reflections)
Goodness of Fit Indicator
Flack parameter (Parsons' quotients = 1976)
Max Shift/Error in Final Cycle
Maximum peak in Final Diff. Map
Minimum peak in Final Diff. Map

All non-hydrogen atoms
4752
289
16.44
0.03440.03750.07791.063
0.015(5)0.001
0.22 e-/Å3-0.64 e-/Å3

Table S2-1. Atomic coordinates and Biso/Beq
atom
Br1
S2
O3
O4
O5
O6
O7

x
0.94209(4)0.29923(12)0.2253(3)0.7312(3)0.7736(3)0.2187(3)0.5685(3)y0.28893(4)0.30199(8)0.4116(2)0.0150(2)0.0524(2)0.1807(3)0.1199(3)z0.96282(2)1.07492(3)1.04920(10)0.88084(10)1.01117(9)1.07844(11)1.09159(9)121Beq
3.349(12)1.637(16)2.23(5)2.30(5)
1.67(4)2.24(5)2.18(5)

O8
N9
N33
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C22
C23
C24
C25
C26
C27
C28
C29
C30
C31
C32

0.3225(3)0.4596(3)0.5338(3)0.3700(4)0.7288(4)0.6192(4)0.6253(4)0.5611(4)0.5610(4)0.6623(4)0.4182(4)0.5455(3)0.4615(4)0.4133(4)0.3419(4)0.4425(4)0.4633(4)0.4561(4)0.3852(5)0.6103(5)0.6833(5)0.4988(5)0.7078(4)0.4896(4)0.4876(5)0.2892(2)0.2798(3)0.1502(3)0.3443(3)0.2713(3)0.0786(3)0.3624(3)0.1786(4)0.1439(3)0.1447(3)0.1970(3)0.0951(3)0.3211(3)0.2209(3)0.2588(4)0.4628(4)0.0696(4)0.4155(4)0.2961(3)0.1289(4)0.2117(4)0.4565(5)0.2032(4)0.0611(4)0.4961(4)0.85400(10)1.03545(11)0.85392(11)1.14157(14)0.97342(13)0.89295(12)0.96085(14)1.04755(14)0.79415(13)0.99622(13)0.94146(13)0.95042(13)0.97519(12)0.87872(14)1.18597(15)1.14940(16)0.76135(15)1.24935(15)1.23979(14)0.67940(14)0.77045(14)1.30860(18)0.71280(17)0.70363(15)1.20411(16)1.85(5)1.48(5)1.28(5)
1.46(5)1.35(6)1.40(6)
1.47(5)
1.46(6)
1.36(5)1.22(5)
1.23(5)
1.16(5)
1.39(5)1.28(5)
1.88(6)2.19(7)
1.81(6)
2.11(7)2.05(7)2.16(7)
1.97(7)3.02(8)2.40(8)2.27(7)2.42(7)

Beq = 8/3 p2(U11(aa*)2 + U22(bb*)2 + U33(cc*)2 + 2U12(aa*bb*)cos g + 2U13(aa*cc*)cos b+ 2U23(bb*cc*)cos a)
Table S2-2. Atomic coordinates and Biso involving hydrogen atoms
atom
H5A
H14
H18
H19
H20
H22
H23
H24
H26
H27
H28
H29A
H29B

x
0.738840.650890.316490.49858
0.38624
0.294170.461140.37883
0.366100.626620.749540.599850.50360y0.004750.444390.16205
0.01061
0.393360.176710.52000
0.02453
0.23918
0.12463
0.26326
0.49973
0.37925z
1.03706
0.944640.95474
0.962800.968121.17950
1.118590.778011.27062
0.63982
0.79338
1.308171.33292
122

Biso
2.009
1.761
1.470
1.390
1.664
2.256
2.625
2.172
2.455
2.591
2.366
3.630
3.630

H29C
H30
H31
H32

0.42052
0.79187
0.424200.54103

0.516960.24868
0.00857
0.57577

1.32311
0.696110.68082
1.21031

3.630
2.876
2.730
2.909

Theoretical calculations1)
The semiempirical molecular-orbital method (PM6) was used to perform theconformational analysis with Gaussian 09 program package. The gas phase geometry optimizationof the molecules leading to energy minima was achieved using the B3LYP hybrid functional withthe 6-31G(d) basis set as implemented in the Gaussian 09. For the optimized structures of thestates, vibrational normal mode analysis was carried out to ensure that the obtained structures werecorresponding to minimum energy state. The Mulliken charge distribution was calculated on
B3LYP level with 6-31G (d) basis sets.
1) Gaussian 09, Revision D.01,
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G.
Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P.
Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A.
Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V.
N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S.
S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz,J. Cioslowski, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2013.

SC1

SC2

123

Figure S1. Scan of total energies of intermediate 99a generated by varying two torsion angles(the dihedral scans showed with u-shaped arrows, as shown in the left structure). The arrow atthe bottom represents the global energy minimum conformer.
Table S1. Cartesian coordinates (Angstroms) for (99a):
Point Group: C1
Total energy = -3863.932410 hartree
Symbol X
YZ
C
1.346895 -1.99268 -0.14018
C
2.542824 -1.42262 -0.43711
C
2.785261 -0.09376 0.012257
C
1.868794 0.621205 0.736319
C
0.565705 0.035603 1.088738
H
1.047491 -2.99105 -0.42482
H
3.29116 -1.96654 -0.99719
O-0.2987 0.585679 1.746126
O2.036101 1.875519 1.201676
H
2.927871 2.176657 0.946108
N
0.408194 -1.2705 0.559344
S-2.00604 -1.99123 -0.21631
C-2.62766 -0.33177 -0.27424
C-2.33525 0.464747 -1.38129
C-3.40723 0.139543 0.785754
C-2.83871 1.763558 -1.41977
H-1.73945 0.068544 -2.19595
C-3.89684 1.437584 0.72454
H-3.62241 -0.49936 1.634939
C-3.61699 2.270749 -0.37135
H-2.62279 2.39192 -2.27971
H-4.50356 1.81564 1.543079
C-4.13049 3.689255 -0.40208
H-3.53032 4.332517 0.25431
H-4.08621 4.111891 -1.4103
H-5.16679 3.747048 -0.05169
Br
4.465589 0.729387 -0.39927
O-1.38222 -2.32206 -1.49394
O-2.94548 -2.87299 0.456449
O-0.73337 -1.94754 0.961139

124

Chapter 4: The New Hybrid Type Squaramide Fused Amino Alcohol Organocatalysts For
Enantioselective Domino Michael Addition Cyclization Reaction
General procedure for the synthesis of compounds (163a-k): To a 4-mL sample vial containing
dimedone 162a (0.1 mmol) and catalyst 29a (5 mol%) added anhydrous THF (1.0 mL). The
reaction mixture allowed to stir at 0° C for 1 h, followed by added 3-dicyano-2-indanones 161a-j(0.1 mmol) at same temperature. The reaction mixture was allowed stirred at the same temperaturefor 48 h. After completion of reaction, indicated by TLC, the residue was purified by using flash
column chromatography (ethyl acetate/hexane, 4:6) to afford the desired products 163a-k inmoderate to excellent chemical yield. The enantiomeric excess was determined by chiral HPLC
using Chiralpak AD-H and Chiralcell OD-H columns.
(3S)-2-amino-1-benzyl-7,7-dimethyl-2,5-doxo-tetrahydrospiro(chromene-4,3-indoline)-3carbonitrile (163b): White solid. 92 mg, 98% yield. m.p. 250-251 °C. [α]D24 = –22 (c = 0.18,
MeOH solvent). IR (neat): cm-1 = 2962, 2189, 1706, 1632, 1492, 1470. 1H NMR (500 MHz,DMSO-d6, ppm): δ 7.55 (d, J = 7.00 Hz, 2H), 7.40-7.30 (m, 5H), 7.18 (t,H2NO

J = 7.50 Hz, 1H), 7.02 (t, J = 8.00 Hz, 1H), 6.74 (d, J = 8.00 Hz, 1H),

NC
O

O

4.96 (q, J = 16.50, 29.50 Hz, 2H), 2.66 (q, J = 17.50, 25.00 Hz, 2H), 2.27

N(d, J = 16.50 Hz, 1H), 2.18 (d, J = 16.50 Hz, 1H), 1.10 (s, 3H), 1.07 (s,

Bn
163b

3H) ppm. 13C NMR (125 MHz, DMSO-d6, ppm): 195.2, 176.8, 164.6,
159.0, 142.6, 136.2, 133.6, 128.48, 128.40, 127.2, 127.1, 123.0, 122.7,

117.5, 110.7, 109.0, 57.2, 50.0, 46.6, 43.4, 32.0, 27.7, 27.12. MS (EI): m/z = 425 [M]+, HRMS
(EI): calcd. for C26H23N3O3 m/z 425.1748; found: 425.1745. The enantiomeric excess wasdetermined by chiral HPLC; CHIRACELL OD-H column (solvent system (80:20) Hexane/IPA;
flow rate 0.5 mL/min; temp 25°C; detection UV 210 nm; retention time 33.38 min (major) and
56.77 min (minor), ee = 83%).
(3S)-2-amino-1-(4-methoxybenzyl)-7,7-dimethyl-2,5-doxo-tetrahydrospiro(chromene-4,3H2N

indoline)-3-carbonitrile (163c): White solid. 70 mg, 89% yield. m.p.

O147-149 °C. [α]D24 = –21 (c = 0.18, MeOH solvent). IR (neat): 2972, 2189,

NC
O

O

N
PMB
163c

1707, 1470, 1370 cm-1 = 1H NMR (500 MHz, DMSO-d6, ppm): δ 7.41 (d,J = 8.50 Hz, 2H), 7.33 (s, 2H), 7.18-7.06 (m, 2H), 6.94 (t, J = 10.00 Hz,
1H), 6.86 (d, J = 5.00 Hz, 2H), 6.69 (d, J = 8.00 Hz, 1H), 4.83 (q, J =125

20.00, 23.50 Hz, 2H), 3.71 (s, 3H), 2.60 (q, J = 17.50, J = 29.00 Hz, 2H), 2.15 (dd, J = 16.00,
28.00 Hz, 2H), 1.04 (s, 3H), 1.00 (s, 3H). 13C NMR (125 MHz, DMSO-d6, ppm): 195.0, 176.6,
164.5, 158.9, 158.4, 142.6, 133.6, 128.9, 128.5, 128.2, 122.9, 122.5, 117.4, 113.7, 110.6, 109.0,
57.2, 55.0, 49.9, 46.5, 42.7, 32.0, 27.6, 27.0. MS (EI): m/z = 455 [M]+, HRMS (EI): calcd. for
C27H25N3O3 m/z 455.1834; found: 455.1838. The enantiomeric excess was determined by chiral
HPLC; CHIRALCELL OD-H column (solvent system (80:20) Hexane: IPA; flow rate 0.5
mL/min; temp 25°C; detection UV 254 nm; retention time 48.74 min (major) and 92.45 min(minor), ee = 81%).
(3S)-2-amino-1-(tertiarybutyloxy)-7,7-dimethyl-2,5-doxo-tetrahydrospiro(chromene-4,3indoline)-3-carbonitrile (163d): White solid. 57 mg, 72% yield. m.p.135-136 °C. [α]D24 = –10 (c= 0.18, MeOH solvent). IR (neat): cm-1 = 3309, 3179, 2189, 1720, 1715, 1610, 1407, 1309. 1H
H2N

NMR (500 MHz, DMSO-d6, ppm): δ 7.87 (d, J = 8.00 Hz, 1H), 7.30 (t, JO= 10.00 Hz, 1H), 7.12 (t, J = 7.50 Hz, 1H), 7.02 (d, J = 6.50 Hz, 1H), 4.99

NC
O

O

N

(s, 2H), 2.56-2.46 (m, 2H), 2.23-2.13 (m, 2H), 1.65 (s, 12H), 1.11 (s, 3H),
1.06 (s, 3H). 13C NMR (125 MHz, DMSO-d6, ppm): 195.0, 175.5, 163.9,

Boc
163d

158.3, 149.1, 139.8, 131.4, 129.4, 125.0, 123.2, 116.3, 115.5, 112.2, 84.6,

50.4, 40.9, 32.4, 28.6, 28.3, 27.9. MS (FAB): m/z = 436 [M]+, HRMS (FAB): calcd. for
C24H26N3O5 m/z 436.1845; found: 436.1863. The enantiomeric excess was determined by chiral
HPLC; CHIRALCELL OD-H column (solvent system (Hexane/IPA) 90:10; flow rate 0.5 mL/min;
temp 25°C; detection UV 254 nm; retention time 47.78 min (major) and 53.24 min (minor), ee =5%).
(3S)-2-amino-1-methyl-7,7-dimethyl-2,5-doxo-tetrahydrospiro(chromene-4,3-indoline)-3carbonitrile (163e): White solid. 86 mg, 92% yield. m.p.195-196 °C. [α]D24 = –23 (c = 0.18,
MeOH solvent). IR (neat): cm-1 = 3308, 3176, 2189, 1720, 1715, 1612, 1432, 1402. 1H NMR (500
H2N

MHz, DMSO-d6, ppm): δ 7.29 (s, 1H), 7.25 (t, J = 8.00 Hz, 1H), 7.04 (d,O

J = 7.50 Hz, 1H), 7.00-6.96 (m, 2H), 3.12 (s, 3H), 2.56 (d, J = 4.00Hz,

NC
O
N
Me
163e

O

2H), 2.11 (q, J = 16.00, 32.50 Hz, 2H), 1.02 (s, 3H), 0.98 (s, 3H). 13C
NMR (125 MHz, DMSO-d6, ppm): 194.9, 176.6, 164.3, 158.9, 143.5,
137.4, 133.5, 128.9, 128.2, 125.3, 122.8, 122.4, 117.2, 110.7, 108.2,

57.0, 49.9, 32.0, 27.5, 27.0, 26.4, 21.1. MS (EI): m/z = 349 [M]+, HRMS (FAB): calcd. for126

C20H19N3O3 m/z 349.3814; found: 349.3820. The enantiomeric excess was determined by chiral
HPLC; CHIRALCELL OD-H column (solvent system (Hexane: IPA) 80:20; flow rate 0.5
mL/min; temp 25°C; detection UV 254 nm; retention time 95.54 min (major) and 48.69 min(minor), ee = 95%).
(3S)-2-amino-1-(methylenenaphthyl)-7,7-dimethyl-2,5-doxo-tetrahydrospiro(chromene-4,3indoline)-3-carbonitrile (163j): White solid. 60 mg, 81% yield. m.p. 188-190 °C. [α]D24 = –11 (c= 0.18, solvent). IR (neat): cm-1 =H2N3395, 3196, 2996, 2189, 1782, 1676, 1610. 1H NMR (500

MHz, DMSO-d6, ppm): δ 8.03 (s, 1H), 7.90-7.87 (m, 2H), 7.79-7.77 (m,O

1H), 7.61 (d, J = 8.50 Hz, 1H), 7.51-7.42 (m, 2H), 7.38 (s, 2H), 7.36 (s,

NC
O

O

1H), 7.10 (t, J = 7.50 Hz, 2H), 6.96 (t, J = 7.50 Hz, 1H), 6.74 (d, J = 8.00
Hz, 1H), 5.08 (dd, J = 16.50, 68.00 Hz, 2H), 2.62 (q, J = 17.50, 28.00 Hz,

N2H), 2.19 (dd, J = 16.00, 41.00 Hz, 2H), 1.06 (s, 3H), 1.02 (s, 3H). 13C
NMR (125 MHz, DMSO-d6, ppm): 195.1, 176.8, 164.6, 159.0, 142.6,
133.7, 133.6, 132.9, 132.2, 128.3, 128.0, 127.6, 127.5, 126.2, 125.8, 125.5,
125.2, 123.0, 122.6, 110.7, 108.9, 57.1, 50.0, 46.7, 43.4, 32.0, 27.6, 27.0.

163j

MS (EI): m/z = 475 [M]+, HRMS (FAB): calcd. for C30H25N3O3 m/z
475.1823; found: 475.1894. The enantiomeric excess was determined by chiral HPLC;CHIRALCELL OD-H column (solvent system 80:20, Hexane: IPA; flow rate 1.0 mL/min; temp
25°C; detection UV 254 nm; retention time 45.82 min (major) and 66.26 min (minor), ee = 71%).
(3S)-2-amino-1-methyl-2,5-doxo-tetrahydrospiro(chromene-4,3-indoline)-3-carbonitrile(163k): White solid. 68 mg, 90% yield. m.p. 267-268 °C. [α]D24 = –20 (c = 0.18, MeOH solvent).
IR (neat): cm-1 = 3302, 2187, 1723, 1671, 1629, 1293. 1H NMR (500 MHz, DMSO-d6, ppm): δ
H2N

7.30-7.22 (m, 3H), 7.08-7.05 (m, 1H), 7.00-6.95 (m, 2H), 3.12 (s, 3H),O

2.70-2.61 (m, 2H), 2.25-2.14 (m, 2H), 1.936-1.88 (m, 2H). 13C NMR (125

NC
O
N
Me
163k

O

MHz, DMSO-d6, ppm): 195.0, 178.8, 159.0, 144.5, 133.5, 128.4, 122.8,
122.5, 117.1, 110.5, 108.1, 57.0, 50.0, 46.5, 32.0, 27.6, 27.0, 26.5. MS (EI):m/z = 321 [M]+, HRMS (EI): calcd. for C18H15N3O3 m/z 321.3312; found:321.1145. The enantiomeric excess was determined by chiral HPLC;CHIRALPAK AD-H column (solvent system 80:20, Hexane: IPA; flow rate 1.0 mL/min; temp
25°C; detection UV 254 nm; retention time 12.81 min (major) and 28.44 min (minor), ee = 76%).
127

7. Acknowledgments
With an immense pleasure, first I would like to express my sincere thanks to my supervisor
Prof. Hiroto Nakano for his invaluable encouragement and guidance in my research career. The
research work presented here would have not been possible without his suggestions and everwillingness to teach. I have greatly benefited from several stimulating and constructive criticism
during my initial learning period. I consider myself luckiest person to be part of his research group.
I sincerely, thank to Prof. Niwayama Satomi and Prof. Koji Uwai for their valuable time andsuggestions in my thesis examination. I also, extend my acknowledgements to all faculty membersin the chemistry department for their kindness and timely help. I am grateful to the President,
Muroran Institute of Technology for giving me an opportunity to use infrastructure, necessary
facilities and granting me necessary funds for attending the scientific programs and conferences. I
would like to thank Eunsang Kwon and Yuko Okuyama for their continuous analytical support tomy research work. I sincerely thanks to Chigusa Seki for her kindness and timely help.
My acknowledgement would be incomplete without expressing my gratitude to my parents. I am
greatly indebted to my parents for their unconditional love and affection. Without theirencouragement, it would be impossible for me to achieve the present stage in my life.

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