Literature Seminar (M2分)

2006.10.21 Shinya Handa (M2)

Nucleophilic Substitution & Addition
Reaction toward Olefin
0 Introduction
Osubstitution

R1

R1XOaddition

O

Nu–

R1O
Nu

X

R1

Nu

OH

Nu–

R1
R2

R2

Nu

How about simple olefin ??

carbonyl or imineolefin

Nu–
R1

X
Nu–

R1

R2

olefin

R1

Nu

R1
R2

Nu

well-know reaction: AdN-E type reaction mechanism
EWG

Nu–
LG

Nu
EWG

LGLG

EWG

Nu

EWG

Nu

Other examples (See below)· Qin-san's lit. seminar (2004.11.20); hydroamination· Fujimori-kun's seminar (2006. 7.19); diamination· Handa's lit. seminar (2006. 7.15); oxidative amination

Contents
0 Introduction ··································· 1
1 Vinyl Substitution Reaction
1.1 Possible Mechanism ················ 2
1.2 SNVπ Substitution ····················· 2
1.2.1 Negative Phenomenon for
SNV1 Substitution
1.2.2 Neighbouring Participation(SNVπ Substitution)

1.3 SNVσ Substitution ······························ 3
1.4 Intramolecular SNVσ Substitution ······· 52 Addition of Enamide to Olefin
2.1 Zinc Aza-Enolate ······························· 7
2.2 N-Aryl Zinc-Enamide ·························· 93 Outlook & Remark ···································· 101/10

1 Vinyl Substitution Reaction
1.1 Possible Mechanism
Chart 1R1R3+R2

R1AdN-E

R2Nu-

X

SNVπNu-R1R2π∗ attack

XBSNVσσ∗ attack

R2Nu

R1R3+ X-

R2CNu
retention

R1NuR2R3+ X-X δ–inversion

R1

SNV1AdN-E substitution & SNVπ substitution

δ–Nu
R3X δ–

R3R1NuR2R3R3R2

D+ X-

Rappoport, Z. Acc. Chem. Res. 1981, 14, 7.
Rappoport, Z. Acc. Chem. Res. 1992, 25, 474.

Chart 2(Z) Cl

R3+ X-

Nu

δ–Nu

R1
R2H

R1AX

Nu-R3HH

CNCN

ClH(E)

R1

R3R2X

Nu nucleofugality

Eelectronnegativity

shorter lifetime of intermediate E
AdN-E

Due to the short lifetime, LG is kicked out
before the rotation.

anti-periplaner

HEtS

SNVπ(Z)HH

CNCNEtSH (E)retention of configuration
enforced concerted mechanism

π Substitution
1.2 SNVπ1.2.1 Negative phenomenon for SNV1 Substitution

co-product

H

Fujita, M. and Okuyama, T. et al. J. Am. Chem. Soc. 2000, 122, 8787.
Fujita, M. and Okuyama, T. et al. J. Org. Chem. 2002, 67, 8130.
Scheme 1

I+Ph
BF4H
69% eeelimination

HROH
60 °C

ORPh-Ichiralitytransfer

8% ee

OR~69% eeconcerted[1,2]-shift

Vinyl cation did not produce.

Neither [1,2]-shift
nor β-elimination
occurred.

HI+PhROracemization

H2/10π Substitution)
1.2.2 Neighbouring Participation (SNVπOkuyama, T. and Ochiai, M. J. Am. Chem. Soc. 1997, 119, 4785.
Scheme 2
RH
ROAc
AcOH
BF4+ R
50 °C
H
I+PhH
H
Chart 3 isotope experiment
SNVσPh

D

H

I+PhA

AcOH
70 °C

I+Ph EPhD

H

B OAc
(E)

Considering anion stability,
in the case of R=Ph
Z isomer should form.
not SNVπ ?

slow reaction

DH

R= C8H17- : exclusively Z form
R= Ph: E/Z = 85/15 lower reactivity

Ph-I

Discrepancy !!

OAc

Ph++Ph
D:1PhH(E)1Neither SNVσ ?

OAc+HOAc

D(Z)CDc.f.)α-D only

SEArtype

MeStBuHF

thiirenium ion

vinylenephenonium ion

DtBu

Luccihini, V. J. Org. Chem. 1982, 47, 590.

σ Substitution
1.3 SNVσ(E)-alkylvinyliodonium salt ; Ochiai, M. et al. J. Am. Chem. Soc. 1991, 113, 7059.

Ochiai, M. J. Organomet. Chem. 2000, 611, 494. (Review)

Table 1R

BF4-1R

conditions

X+2

I+PhR = n-C8H171a

R = Ph(CH2)21b

R = Ph1cR(Z) exclusivelyalkyne only

· In the case of X= Cl, Br, I, SN2 substitution occurred and the productvia vinylenephenonium ion ??
was given with inversion of configuration.
see above· With TBAF, only terminal alkyne produced.
· Styrene derivative gave E/Z mixture due to the vinylene phenonium ion intermediate.
Scheme 3a
C8H17GBF4-

DCH2Cl2
rt, 10 h

I+PhTBAF
TBAC

Scheme 4RC8H17Scheme 3b
C8H17 BF4-X+H

H(D)yield—62%H:D—
4:96

R

H(D)
D

yield
86%
37%

H:D
100:0
0:100

I

I+Ph

CH2Cl2
rt, 10 hTBAF
TBAC

C8H17X

(D)H

J

yield
—80%

H:D—
5:95+R

H(D)

yield
93%
18%

H:D
5:95
93:7

Mechanism of alkyne formation
H(b) β-elimination

TBAC

R

H

H (b)

I+Ph(a)(a) α-elimination

TBAF

R

[1,2]-shift

RH

H

3/10

Figure 1

Ph-I

SM A has UV absorption around240 nm. By initial addition of X- ,this absorption disappeared.

Z-olefin

At low concentration
proportion dramaticallychanged.

Xalkyne[X-]olefinR
H

Generation of another spiecies
which quickly forms with X- .

alkyneδ–H

I

δ+PhX δ–relative amount of TBAC

SN2 TSChart 4R

K1[X-]H
I+Ph

H
lessreactive

A

R

H

H

I

quite
fast

X

B

k1[X-]

PhX

H

H

H

H

I

C+ Ph-I

R

K2[X-]

H

H

Ph

X

X

I-

D

Ph

less
X reactive

k3'

k2'

k2[X-]R

R+ HX

R+ Ph-I

k1/k2K1 = 1.4 x 10-3 M (for Cl-)
0.5 x 10-3 M (for Br-)(Z)-Aroyloxyvinyliodonium salt ; Ochiai, M. et al. Terahedron Lett. 2005, 46, 1863.
I+Ph

PhCO2(Z)

BF4-nBu4NX

PhCO2+THF, 65 °C

4Table 2PhCO2X

X+PhCO2

5no alkyne
was observed.

I

6strong dependency on[X-] conc.
similarity with E iodonium
isomerretention

inversion
Chart 5

PhCO2
X

X-

PhCO2

BF4-

I+Ph

less
reactive+ Ph-I
X-

SN2

I

E

IX
Ph

PhCO2H
Ph

I

F

GX
PhCO2

PhCO2

I+ Ph-XPh

δ–X
PhCO2X
PhCO2

PhCO2X+ Ph-Ic.f.) Classically, it seemed that SN2 substitution could not occur.
However, recent computational studies suggested that
TS A required lower activation energy than TS B.
ref) Schelegel, H. et al. J. Am Chem. Soc. 2001, 123, 5787.
Lucchini, V. et al. J. Am Chem. Soc. 1995, 117, 2297.
Pross, A. et al. J. Am Chem. Soc. 1994, 116, 5961.
etc.

R

δ–IX
H

R'I

X

σ∗
XTS A

<X

R
R'X

X-Hπ∗
TS B

4/10すこし疑問に思ったことを考えてみる。Now, I will raise a few questions.
Phenonium ion intermediate generated? How is the possibility of ligand coupling ?
Scheme 5PhPh

H

AcOH
70 °C

BF4I+PhH

MeH

HIO
H OPhHPhIOAcPhPhHHI

Ph versus

HHPhIXElectron deicityof I decrease.

OAc
Electron deicityof I increase.

higher reactivity

lower reactivity

XOH

H

OAc

Ph

In the case of AcO- , this spiecies
is lower reactivity ??

Addition of halide: metal halide
Addition of carbanion: organometalOhomoallylalcoholH

directing group introduction

Strategies for improvement of E/Z selectivity
Scheme 6Phβ,γ-unsuturatedcarbonylσ Substitution
1.4 Intramolecular SNVσ
stereospecific aziridine formation; Shipman, M. et al. J. Am. Chem. Soc. 2004, 126, 6868.
Scheme 7aRHNRBr
NaNH2, NH3,–78 °C, 1 h
37-57%

1-(Z)Scheme 7bHNRNRBr

77-93%

1-(E)

2-(E)

N

NaNH2, NH3,–78 °C, 1 h2-(Z)single isomer about double bondinversion of configuration

stereospecific benzofuran formation; Ando, K. and Narasaka, K. et al. Org. Lett. 2004, 6, 2461.
Scheme 8a

MeMe

Scheme 8b

MeMeX
OH

NaH
DMF, rt3-(E)X=Cl: 95%
X=Br; 70%O

Figure 2ahydrogenbondingOH4X

NaH
DMF, 110°C3-(Z)quantative SM recovery

perpendicular
to double bond plane

Figure 2b∆E=+18.5kcal/mol∆G=+17.1kcal/mol∆E=-29.9kcal/mol∆G=-29.4kcal/mol· Through the reaction, O-H(vinyl position) distance was constant.
Hydrogen bonding might work.
· In the case of (Z)-isomer stable TS was the interaction with π* orbital.
even though the relatively higher energy was required.
· With dichrolo-compound, interaction with σ* orbital is impossible
due to the steric and elecronic repulsion by chroline.

O 4MeClOHZ-1b∆E=+28.8kcal/mol∆G=+28.5kcal/mol∆E=+25.5kcal/mol∆G=+25.3kcal/mol
MeCl
ClOH 3a-ts

These stereospecific substitution reaction
suggested SN2 reaction mechanism.

5/10

interaction

Narasaka, K. and Ando, K. et al. Bull. Chem. Soc. Jpn. 2003, 76, 2009.
Figure 3Scheme 9BrOHBr

Ph

Me

Li

nBuLi
tol, rtMePhDLiBr∆E= 0 kcal/mol∆G= 0 kcal/mol

Li

MeOH

OlongBrPh
MeB
lithium halogen
alkylidene carbenoidAHO

LiLiMeO∆E= +6.56 kcal/mol∆G= +5.58 kcal/mol

PhOMePhC

This carbenoid easily isomerizes even at –85°C.
Then computational study was held to clarify
whether SN2 type or not.

BrLiLiO
MePh

Synthesis of indene from dibromoalkene∆E= -37.5 kcal/mol∆G= -38.5 kcal/mol

Br introduction is varsatile.
Table 3Me??

LiLi

Br

E
Intermediate ??
Due to Lithium bridges,aryl anion can interact
with Br σ* ??

SNVσ substitution at sp2 nitrogen; Narasaka, K. et al. Eur. J. Org. Chem. 2005, 4505.(Review)
Scheme 10MeO(CF3CO)2O
chroranilNFMeOMeONMeGOH[O]MeNMeH

OCOCF3Only Z-isomer is reactive.
E/Z isomerization occurred.

MeO

Such a kind of nitrogen introduction on aromatic ring is interesting.

IN

Mefrom anti : 83%
from syn : 81%

Seemingly, such substitution reaction is unfavourable. However...
Figure 4LK
8.8 kcal/mol

not big difference !!
Both pathes are feasible.

JInteraction
might exist.

M
8.0 kcal/molN
Narasaka, K. and Nakamura, E. et al.
Chem. Lett. 1998, 111.

6/10

What factor prompts sp2 nitrogen substitution predominantly ??
1 selection of solvent
polar solvent: Beckmann rearrangement

non-polar solvent: substitution

2 selection of leaving group
trigger to find this phenomenon: nBu4NReO4, TfOH condition
3 electron dencity of aromatic ringinteraction benzene π orbital and leaving group on oxime
4 proper length of the tether
to form 5 or 6 membered ring.
c.f.)

R2

N

R1O2C

OMs
R4

R1O2C

R3

R2
R1O2C
R1O2C

DBU
CH3CN, rt

Beckmann rearr.

R3
N

71-97% y.

substitution

R42 Addition of Enamide to Olefin
2.1 Zinc aza-enolate (employing alkylzinc)
Nakamura, E. et al. Angew. Chem., Int. Ed. 1997, 36, 2491.
Scheme 11 Me2N

Me2N1) tBuLi
2) ZnBr2N

R1ZnX

Me2N

NZnBu
R3R1R2R2E

branchedN

D

R2R3O

ZnBu

R1CE

R1H3O+

Me2N
H

R3N

E

R1

R3F

linear

R2N

Me2N

CH2=CH2R2

Me2N

E+ZnBuB

BuLi

Table 4Me2N

R3N

R1R2B X=Br
C X=BuButyl anion
did not react.

CH2=CH2 Ph

Me2N

R3

R1

R2A

NN

CH2=CH2PhN

NOMeMe(SAMP)
Me2N

MeMe2N

PhC6H13NPhMeArN

MeLigand exchange (Br->Bu) increased the reactivity toward
unactivated olefin.
(Toward vinyl Grignard reagent, Br spiecies did work well.)Nakamura, E. et al. J. Am. Chem. Soc. 2003, 125, 6362.
OR2
R1N1) MesLi
2) ZnCl23) R3LiO

ZnR3R1

Gethylene
20 atmN

R1

R3Zn
NCH2O H2C

E+ ;H3O+CH2

E

CH2JI

H

chiral auxiliary

Table 5

R2

OR2

proposed TS

R1R2

R3

yieldee

R1R2

R3

yieldeeiPr

MeMe8592tBu

MetBu

7388tBuMe Si2Bu1455

Me3Si

Me8676

iPrMe3SiMe

8194tButBu

MeMe8794

PhtBu

Me3SiMe9195

7/10

OTMS

N= tBu91%
98% eeNH84%
18% ee89%90% eeethylene 20-30 atm
propylene 8 atm

47%
93% ee
Ph82%
96% ee93%96% eeTable 571%
78% eelinear productE/Z ratio affect the ee.
To give E enamide exclusively, Mesityl was used as
the ligand on zinc. -> 81% y. 58% ee· Branched product selectively generated.
1° zinc anion is electronically and sterically favourable.
(with styrene: linear adduct < electronic effect? )· When the reaction between Li enamide and alkyliodide, alkyl group was introduced from β-face.
Transition state is different ?
· Adequate soft charater is suitable for the olefin ?
Toward alkyl halide, Mg enamide is better. (Nakamura, E. et al. J. Am. Chem. Soc. 2005, 127, 14192.)
Toward vinylborane; Nakamura, E. et al. J. Am. Chem. Soc. 2004, 126, 14344.
Me2N

1) tBuLi
2) ZnCl2
3) BuLiN

Me2N ZnBuBuN

Z-majorTable 6BR'2

Me2N
NH(1.0 eq)
99.7% E0 °C, 24 hhexane
then H2OOBR'2BR'2 = BOsyn

should be Z isomer

Busyn
E

BR'2Mesyn

EEsyn

Esyn

total
99.2dranti

ZBR'2anti

E

MeEEsynZ

Me2NNZnBu

successive
Michael addition(diastereoselective)

Due to dimethylamine
α alkyl locates opposite side of N ?
Z-enamide ??

Me2N
Me2N

ZnBu
N

coordination ??

Nrather far ??

RH

ZnBu

BR'2TS

8/10

2.2 N-aryl Zinc-Enamide
Nakamura, E. et al. J. Am. Chem. Soc. 2004, 126, 11820.
ArAr

1) tBuLi
2) ZnCl2
3) BuLi

NR1

NR3

ZnBu

R1R2R2N-substituent effectN+ C6H135 eq.

Me65 °C, 24h
neatthen H3O+

why ??

OEt

C6H13Me

olefinenamideElectron rich aniline was good

Figure 4ZnBu

Et

ER1

R2Ar

R3O

poor diastereoselectivity
syn/anti=7/3~6/4
not affect E/Z enamide

N-substituent effect
ArN

ZnBu

+

Et
Meenamide

4 atm

aromatic

Figure 5

electron richX

O65 °C, 60h
neat
Et
then H3O+

X=Et3N-

X=Me-MeMe

olefinEffect of substituent is not clear.

atmospheric pressure

Table 7

Table 846:56

high yieldThe E/Z geometry of enamide did not affect the syn/anti selective production.
not 6-membered boat form TSo-methylsubstituent on benzene ring gave better reactivity.

linear adduct only
stability of benzyl anion(prior to steric effect)

Zinc enamide had poor reactivity with Michael acceptor.
OO-tBuPolymerization occurred.
70 % recovery of starting imine

9/10

Always more than 2 equivalentof electrophile is needed.

Chart 6

1.0 eq.: consumed by Bu-crosscoupling

Unreacted enamide which interfere the coupling reaction was trapped.

3 Outlook & RemarkAcarbonylationDhydrocyanation

BC

aminationhydroxylation
cleavage

reductionoxidation

10/10