Tatsuya Nitabaru (M2)
Lit. Seminar 080618

Strained Molecules in Organic Synthesis~ featuring on three-membered rings ~for cyclobutadienes : see Mr. Yamatsugu's Lit. Sem. 061129

0. Introduction

stable up to 200 C
cyclopropane

methylenecyclopropane

1-methylcyclopropene

SE = 27.5 kcal/mol

SE = 40.9 kcal/mol

SE = 51.1 kcal/mol

Heat of Formation
3C + 3H2(gas)
6C + 6H2(gas)cyclopropane + 12.7 kcal/mol
cyclohexane - 29.6 kcal/mol

Strain Energy (SE) : 12.7 - (-29.6/2) = 27.5 kcal/mol(cf. cyclobutane : 26.5 kcal/mol)

The introduction of each trigonal carbon center into a threemembered ring introduces an additional 12 - 14 kcal/mol of ring strain.

s: 18%, p:82%

104H
H
s: 32%, p:68%

orbital of cycloproane

HContents
1. Cyclopropenes
1. Asymmetric Synthesis of Cyclopropenes
2. Mechanism Study of Catalysis
3. Ring Expansion [3 to 5]
2. Methylenecyclopropanes
1. Ring Expansion [3 to 4]
2. [3 + 2] Cycloaddition & Theoretical Study
3. Intramolecular Cycloaddition

MeHMeHHOHHHMeIsocalysterol

1/10

1. Cyclopropenes
1-1. Asymmetric Synthesis of Cyclopropenes
Scheme 1

Rh catalyzed cyclopropenation
YX

N2N2hνbase

YX
Rh2LnRh2
Rh carbenoid

X ∗ YhνRalkyne

heatR

base

about Rh catalyzed C-H activation;
see Mr. Yamaguchi & Tanaka Lit. Sem.
060909 & 070207
Figure 1

Various Retrosysnthesis of Cyclopropenes
Doyle et al. JACS, 1992, 114, 2755
OR'
N2+H

O

diazoacetateRRh2(5R-MEPY)4 (1 mol %)CH2Cl2

1-alkyne

Rh2(5R-MEPY)4HHNO

CO2R'OMeHRcyclopropene

O
14(R)-bezyloxazolidinone
HNO

1234567891011124(S)-isopropyloxazolidinone
HNOOO
25% eesame condition

36% eeIt seems that dipolar influences from Rh2(5R-MEPY)4
ligand's carboxylate substituents are primary determinantsof enatiocontrol in these reacton.
Carbene dimer is major byproduct.
Slow addition & higher aklyne ratio suppress it.
In reactions with methyldiazoacetate, intramolecular C-H
insertion compete with cyclopropanation.
OORhOHON2Hdisubstituted alkynes

Scheme 2MeN2CHCO2Et
O

2/10Rh2(5R-MEPY)4+
TMS

d-menthyly. 39% 16% ee

PhtBu

y. 26% 20% ee

Doyle, Muller and Shapiro, JACS, 1994, 116, 8492
N2CHCOZ+catalyst
R(10 eq)

cyclopropene

Davies, OL, 2004, 6, 1233
123
4
56
78
9
10111213

quarternally carbon center forming

catalyst
ArCO2MeN2>
stability

donor/acceptor typeHCO2MeN2

acceptor typeThe donor/acceptor-type carbenoids are more stabilizedthan
the conventional carbenoids derived from diazoacetate.

substituent on diazoacetate

substituent on alkyne

The reactions proceed without
regard to EWG or EDG .

Too stable to react ...?
Cyclopropenation is favored
over benzylic C-H insertion.
Cyclopropenation precede
cyclopropanation.
This substrate reacts withstyrene and gives 90% ee.
Then the failure may be due tothe instability of the product.

Table 3

Electron rich alkynes react faster than normal alkyne.
Does the reaction mechanism have a close relation toelectron density of alkynes ?

3/10

1-2. Mechanism Study of Catalysis
Electron rich alkynes react faster.
Stabilized cationic species at transition state concern ...?
The author proposed that the alkynes and olefins react by side-on mannar.
For olefins, the reaction proceeds with retention of stereochemistry.
Davies, JACS, 1996, 118, 6897
alkyneolefin

R1

R2H

H

EWG

R2

Side-on model
R1
H

δ+Rh

cis

R1

H

H

R2 trans

R

EWG

R1HH

R

H

δ+Rh

R2

sterically hindered

Corey, JACS, 2004, 126, 8916

Novel Catalyst

Rh2L2(tBuCO2)2

Rh2L4

Rh2L3(OAc)

Tfachiral space

PhNORh>activity

1Figure 22NPhRh
10

the upper rightquadrant is achiralhowever...
Ph+ N2CHCO2Et

cat. (0.5mol%)

HH

Ch2Cl2, rt

PhCO2Ety. 84%

99%ee

cat. 197%ee

cat. 10
cat. 2

cat. 1086% ee 91% ee

The rate determing step is nucleophilic
addition of diazoacetate to Rh2L4.
high face-selectivity for carbenoid
low(only 2:1) π-facial selectivity

80% ee88% eePh

Scheme 3. available for C-H insertion
CO2Me
cat. 1 (1mol%)
CH2Cl2, rt

N2O

Ph

MeO2C HOH
Phy. 51%, ee. 96%

4/10Figure 3or Ph+PhHHCO2Et(~2:1)

94%ee
91%eeTheoretical calculation

Davies, JACS, 2003, 125, 15902
Singleton, JACS, 2005, 127, 6190

tribridged carbenoid
HMeNRh
MeO2C

OH
MeO2C

Rh OCHON

HPr

If 6 reacts...

OO

Me N

HRh2

MeLet A exist...

PrA

B

Pr

21.5 kcal/mol higher
than tetrabridged one

Figure 1

HRh2
MeO2C
enyne metathesis

Figure 2+ Rh2L4
H

CO2Me

End-on model

4

Figure 3

Corey et al. JACS, 2005, 127, 14223
H
H3C(H2C)4+CO2Et

N2CHCO2EtPenN
O

Rh2(OAc)2(DPTI)2Rh2(OAc)(DPTI)3Rh2(DPTI)4

They can't synthesize.

5/10

1-3. Ring Expansion [3 to 5]

Ma , JACS, 2003, 125, 12386
Battiste , TL, 1975, 1, 45

2. Methylenecyclopropanes (MCPs)
2-1. Ring Expansion [3 to 4]
Furstner et al, JACS, 2006, 128, 6306

> 97% D-labeled[1,2] rearr.

hydrogen shift

For entry3 and 4, high concentration causes
dimerization.

Alkyl substituted MCPs also undergo ring expansion.

6/10

Shi, JACS, 2006, 128, 7430
R are aromatic substituents. Substrates which have EDG at orthoposition give better yield.
When R are aklyl substituents, reaction doesn't proceed.

2-2. [3 + 2] Cycloaddition & Theoretical Study
Scheme 3. Thermal [3+2] cycloaddition

OCO2Me80 C, MeCN

OOa∆

OOO

BnOt

91%1OBuN

CO2MeOtOO

PhH, reflux
Ar

86% (96:4)

2b
MeCN, reflux
trimethylenemethane(see Mr. Nagawa's Lit. Sem.)

CO2MeOOBu

3N

OBn

91%

E. Nakamura, JACS, 1989, 111, 7285
JOC, 1990, 55, 5553 JOC, 1998, 63, 1694

Metal catalyzed hetero [3+2] cycloaddition
Lautens, JACS, 1996, 118, 9597
from previous studies...
Ni0 : 1. parent MCP undergoes proximal ring opening
2. monosubstituted MCPs undergo proximal anddistal ring opening
3. MCPs which bear dialkyl substituents at cyclopropyl
or vinylic carbon undergo distal ring opening preferentially0
Pd : all types of MCPs undergo distall ring opening regardlessof the substitution pattern

Scheme 4

Noyori, JACS, 1970, 92, 5780 & TL, 1978,48, 4823
Scheme 5
Ni(MeCN)2Ni(COD)2 : proximal attack (A)with phosphine or phosphite : distal attack (B)
Ni(MeCN)2 : distal attack (B)Scheme 6
196a196b7/10

Theoretical Study of Pd Insertion & [3+2] Cycloaddition Mechanisms
Fujimoto et al, Inorg. Chem. 1996, 35, 231
Inorg. Chem. 2000, 39, 1113

Scheme 1

Theoretical works on d10 matal-TMM have revealed thatthey have a zwitterionic charge distribution.
TMS
OAc
Experimental results support this mechanism: TMM-PdL2
stepwisecomplexes demand that olefin has electron-deficient groups.
On the other hand... MCP-Pd complexes react both with electron-rich olefins and electron-poor olefins.
PdL2

Scheme 2PdL2+distal bond insertion
4123

Path 1

Path 2PH3 PdPath 1

Path 2Path 3

η2(with MCP) mechanism
1

Path 4

432

Path 3

Pd PH3proximal bond insertion

20.5
19 26.8

-64.1
-72.8

25

-53.7
-68.1

22(TS)149.2
135.6

2
3

Path 4

PH3 Pd14

Path 5
Path 520 21.9
28.4

8/10

24

21 19.0
26.1

138.2
23(TS)
133.5

Pd catalyzed [3+2] cycloaddition of aldehydes and imines

Y. Yamamoto et al. ACIE, 2001, 40, 7Y. Yamamoto et al. TL, 2001, 42, 6203

Other Pd, Pt sources didn't
catalyze the reaction.
additive:
PPh3, PBu3, P(OPh)3
slow and low yield

Table 2Ph

no reaction
additive:
PPh3, OPtBu3, P(o-tolyl)3
good to high yieldbidentate ligands
trace

solvent:
THF, MeCN, Diox, DMF
good to moderate yield
CH2Cl2no reaction

R1
R

Pd0X

R3

R

Other Reactions

R1

22

R2

Ma, JACS, 2004, 126, 9645

distal bond insertion

R1
R1R3

Pd
R2X PdR3

R1 γRPdβ2R3αX

Figure 1 Proposed mechanism

XX = O, NTs

Shi, Chem. Eur. J., 2006, 12, 510

Scheme 19/10

Y. Yamamoto, JOC, 2004, 69, 3202
Scheme 1rigid

R1 γβR2PdαN

NNNNNAB

y. 52 ~ 61%

34 ~ 49%

R1R1R2NH2N

R1R2Pd0N

R26%
N

NTMS

N

Pd0OAcN

These heteroaromatics can't
make rigid coordination to Pd.
Then reactions don't proceed(at all).

Pd N NNNN

different reaction position

NN

PdN N

no reaction no reaction

N3

complicated mixtureof unidentified products?

A or BN?

2-3. Intramolecular CycloadditionE. Nakamura, Tetrahedron, 1989, 45, 3088

Motherwell, TL, 1989, 30, 7107
retention

Scheme 2

Table 1

bicyclo [4,3,0]

anti-Bredt rule

Lautens, JACS, 1996, 118, 9597

bicyclo [3,3,0]

Table 2

Substitution at R1 and R2 havelittle effect on stereoselectivity.
Table 3

Scheme 3
EE
Pd
H
Table 4OR

Pd
H

1EH
RO
R

PdO

2

3

E
PdO
H
H

R
5

Si subsutituted alkynes also didn't cyclize.

10/10

RO4E