29 cyclopropanation

Myers

Chem 115

Cyclopropanation

Reviews:

• Bonding Orbitals in Cyclopropane (Walsh Model):

Roy, M.-N.; Lindsay, V. N. G.; Charette, A. B. Stereoselective Synthesis: Reactions of Carbon–
Carbon Double Bonds (Science of Synthesis); de Vries, J. G., Ed.; Thieme: Stuttgart, 2011, Vol 1.;
731–817.
Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977–1050.
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861–2903.
Li, A-H.; Dai, L. X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341–2372.
eS (")

• Applications of Cyclopropanes in Synthesis

eA (")

Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051–3060.
Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151–1196.
Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603–1624.

!

• Cyclopropane Biosynthesis

Thibodeaux, C. J.; Chang, W.-c.; Liu, H.-w. Chem. Rev. 2012, 112, 1681–1709.

de Meijere, A. Angew. Chem. Int. Ed. 1979, 18, 809–886.
General Strategies for Cyclopropanation:
Introduction

• via carbenoids

"MCH2X"
H
H

HH

H

H
H

H

H
H

H
H

• via carbenes generated by decomposition of diazo compounds

RCHN2
R

• Cyclopropanes are stable but highly strained compounds (ring strain ~29 kcal/mol).
• C–C bond angles = 60º (vs 109.5º for normal Csp3–Csp3 bonds).
• Substituents on cyclopropanes are eclipsed. H–C–H angle is ~120º. As a result, the C–H bonds
have higher s character compared to normal sp3 bonds.

• via Michael addition and ring closure

RCH–LG
EWG

EWG

LG

EWG
R

• Because of their inherent strain, the reactivity of cyclopropanes is more closely analogous to that of
alkenes than that of alkanes.

R

RCH2
EWG

LG

EWG

LG

EWG

R

Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977–1050.
James Mousseau, Fan Liu

1


Myers

Chem 115

Cyclopropanation

• Diastereoselective cyclopropanation is possible in the presence of directing groups:

Simmons-Smith Reaction –– Zinc Reagents in Cyclopropanation
• Original Report:

OH

OH
CH2I2, Zn(Cu)

H

CH2I2, Zn(Cu)

(±)

Et2O, 35 ºC
48%

Et2O, 35 ºC
63%

(±)

OCH3

H

CH3O

H

CH2I2, Zn(Cu)

H

Et2O, 35 ºC
~60%

(±)

(±)

H

H
Dauben, W. G.; Berezin, G. H. J. Am. Chem. Soc. 1963, 85, 468–472.

Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323–5324.

• Interestingly, excess carbenoid can reverse the directing effect of alcohols.

• Reaction Overview:

Zn
R1

"ZnCH2I"

R1
H

R2

OZnR'

OZnR'
H

OBn

OBn

OZnR'
H

I
CH2

H

R1

H
R2

R2

Butterfly transition state

OBn

H

Zinc Reagent

dr

yield

Zn(CH2I)2 (1 equiv)

>25:1

>95%

EtZnCH2I (9 equiv)

1:>25

>95%

Charette, A. B.; Marcoux, J. F. Synlett, 1995, 1197–1207.
• The reaction is proposed to proceed through a "butterfly" transition state.

• Directed cyclopropanation is also possible in acyclic systems:

Simmons, H. E. Org. React. 1973, 20, 1–133.
OH

OH

OH

• Zinc cyclopropanating reagents can be generated in various ways. Both Zn metal and ZnEt2 can be
used.

Et2Zn, CH2I2

CH3

CH3

CH3

CH2Cl2, –10 °C
97%

H

H
130

• Many zinc reagents for cyclopropanation have been developed:

:

1

Charette, A. B.; Lebel, H. J. Org. Chem. 1995, 60, 2966–1967.
• Diastereoselectrive cyclopropanation has been used in tandem asymmetric organozinc additions:

I
Simmons
and Smith

O

I

I

I Zn

Zn

Zn
I

H3C

Denmark

Furukawa

F3C

Zn
I
Shi

O
EtO P
EtO

Zn

1. HBEt2, PhCH3, 23 ºC
2. Et2Zn, i-PrCHO

I

Charette

Ph

General applicability

Highly reactive
carbenoid for
unreactive alkenes

Highly stable carbenoid

H3C

Ph

CH3
O

N
OH
H3C

OH

(4 mol%)

–78 ! –10 ºC

CH3
CH3

ZnEt2, CH2I2
CH2Cl2, 23 ºC

OH
CH3

Ph
H

CH3

75%, 99% ee
dr >20:1

Kim, H. Y.; Lurain, A. E.; Garcia-Garcia, P.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2005,
127, 13138–13139.
James Mousseau, Fan Liu

2


Myers

Chem 115

Cyclopropanation

• Asymmetric Simmons-Smith Reaction Using Chiral Auxiliaries

• Stoichiometric Promoter for Asymmetric Simmons-Smith Cyclopropanation

• Allylic alcohols:

• A chiral dioxaborolane auxiliary prepared from tetramethyltartramide and butylboronic acid has
been shown to be effective in the asymmetric cyclopropanation of allylic alcohols.
• A hydrogen peroxide work-up is employed to remove boron side-products.

OBn
O

BnO
BnO

Et2Zn, CH2I2

Ph

O

OBn

OH

O

BnO
BnO

toluene, –35 ! 0 ºC

A (1.1 equiv)

Ph

O

OH

OH

98%, dr >50:1

via

OBn
O

BnO
BnO

O

Me

O Zn
EtZn
C
H2I

BnO

BnO

+

>98%, 93% ee

then 30% aq H2O2

OBn

Ph

HO

OH

0 ! 23 ºC

1. Tf2O, C5H5N
2. DMF, H2O, C5H5N
160 ºC, 90%

Me

Et

H

Zn(CH2I)2, DME, CH2Cl2

O

O

via H C
3

O

O

N(CH3)2

(H3C)2N

CHO
O
B
n-Bu

O

O
Charette, A. B.; Côté, B.; Marcoux, J.-F. J. Am. Chem. Soc. 1991, 113, 8166–8167.

B

H
A

O
O

Zn

Ph H

O

N(CH3)2
N(CH3)2

I

• Allylic amines:
Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc. 1998, 120, 11943–11952.
Ph

OH

H3C

N
CH3

Et2Zn, CH2I2
Ph

CH2Cl2, 0 °C

Ph

OH

H3C

N
CH3

95%, dr = 98:2

• Allylic alcohols are cyclopropanated selectively:
Ph
CH3

OH

• ",#-Unsaturated carbonyls:

H

H3C
O

2.

H3C

CO2i-Pr

O

OH
i-PrO2C

O

CO2i-Pr

CO2i-Pr
OH

H
O

H

H3C

then 30% aq H2O2

OH

80%, 95% ee

Nicolaou, K. C.; Sasmal, P. K.; Rassais, G.; Reddy, M. V.; Altmann, K. H.; Wartmann, M.; O'Brate,
A.; Giannakakou, P. Angew. Chem. Int. Ed. 2003, 42, 3515–3520.
• The cyclopropanation of allenic alcohols affords spiropentane derivatives:

hexanes, –20 °C

Et

H3C

H3C

Et2Zn, CH2I2

C5H5NH•OTs, C6H6
80 ºC, 79%

pTSA, THF

CH3

Zn(CH2I)2, DME, CH2Cl2

H3C

Aggarwal, V. K.; Fang, G. Y.; Meek, G. Org. Lett. 2003, 5, 4417–4420.

1. (EtO)3CH, NH4NO3 (cat.)
EtOH, 23 ºC

ent-A (1.1 equiv)

CH3

H3C

H2O, 65 ºC
yield not provided

O
O

OH
C

CO2i-Pr
CO2i-Pr

Et

H

A (1.1 equiv)
Zn(CH2I)2, DME, CH2Cl2
–10 ! 23 ºC
then 10% aq NaOH

OH
MO
Et
Et

Et
H

H

Et
70%, 97% ee

90%, dr = 97:3
Mash, E. A.; Nelson, K. A. J. Am. Chem. Soc. 1985, 107, 8256–8258.
Mori, A.; Arai, I.; Yamamoto, H. Tetrahedron 1986, 42, 6447–6458.

Charette, A. B.; Jolicoeur, E.; Bydlinkski, G. A. S. Org. Lett. 2001, 3, 3293–3295
James Mousseau, Fan Liu

3


Myers

Chem 115

Cyclopropanation

• The dioxaborolane promoter can be used to prepare 1,2,3-trisubstituted cyclopropanes.

• Unfunctionalized alkenes can undergo asymmetric Simmons–Smith cyclopropanation in presence of
a valine/proline dipeptide.

• In the example shown, the intermediate borinate was used directly for Suzuki coupling:

• Selectivity is higher for trisubstituted alkenes than for disubstituted alkenes.
O

O

(H3C)2N
Ph

OH

1. Et2Zn
CH2Cl2, 0 ºC

Ph

OZnEt

2. A (1.2 equiv)

N(CH3)2
O

Ph

O

B

C (1.25 equiv)

Ph

O
n-Bu

ZnEt

H
Ph

H

O

n-Bu
B

B-Zn Exchange

O

4. Pd(PPh3)4
(5 mol%)

CH2Cl2, –78 ! –40 ºC

Ph

H3C

N
CH3
C

absolute stereochemistry
not reported

Long, J.; Yuan, Y.; Shi, Y. J. Am. Chem. Soc. 2003, 125, 13632–13633.
• Catalytic Enantioselective Simmons-Smith Cyclopropanation Reactions
• Chiral bis-sulfonamides have been used to direct asymmetric Simmons–Smith reactions of allylic
alcohols:

Ph

PhI, KOH
THF, 65 ºC

0 ºC, CH2Cl2
83%, 90% ee

CO2CH3

O

B
n-Bu
O
ZnEt

Ph

Et2Zn, CH2I2

BocHN

3. EtZnI•OEt2, CHI3

N(CH3)2
O

H

O

(H3C)2N
ZnI

O

Ph

OH

D (10 mol %)

59%, 92% ee, >20:1 dr

OH

Et2Zn, ZnI2, Zn(CH2I)2

NHSO2CH3

OH

CH2Cl2, 0 ºC
92%, 89% ee

Zimmer, L. E.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 15624–15626.

NHSO2CH3
D

• Homoallylic ethers can be cyclopropanated using a zinc phosphate, prepared in situ from a chiral
phosphoric acid:

OBn

B

B (1.2 equiv)
Et2Zn, CH2I2

OBn

CH2Cl2, 0 ºC

85%, 93% ee

Denmark, S. E.; O'Connor, S. P. J. Org. Chem. 1997, 62, 584–594.
• "Taddolates" can also be used:

E

via
Ar

Ar =

E (25 mol %)

Ar

O
O
P
O
OH

O
O
P
O
OZnCH2I

Ar

Ar

OH

Zn(CH2I)2, 4Å MS
CH2Cl2, 0 ºC
85%, 92% ee

OH

Et

Et

O

O
Ph

Ph
Ph

O

i-PrO

Ti

O

Ph

Oi-Pr

Charette, A. B.; Molinaro, C.; Brochu, C. J. Am. Chem. Soc. 2001, 123, 12168–12175.
Lacasse, M.-C.; Poulard, C. Charette, A. B. J. Am. Chem. Soc. 2005, 127, 12440–12441.

James Mousseau, Fan Liu

4


Myers

Chem 115

Cyclopropanation

• A bifunctional Al-complex is an effective cyclopropanation catalyst and is believed to bind both the
Zn and the allylic alcohol:
ligand (10 mol%)
Et2AlCl (10 mol%)

TBDPSO

OH

H3C

TBDPSO

I

TMS

CH3

CO2Et

1. LiTMP, HMPA
THF, toluene, –95 ºC
2.

ligand

TMS

CO2Et

O

O
NH

via

Te+

OH

Et2Zn, CH2I2
CH2Cl2, 23 ºC
99%, 90% ee

• Telluronium ylides can also be used:

81%, 97% ee

N

OH HO
Ph Ph

O
Zn N Al N
O
O Cl
ZnEt

Liao, W.-W.; Li, K. Tang, Y. J. Am. Chem. Soc. 2003, 125, 13030–13031.

• Camphor-derived sulfur ylides can be employed for stereoselective cyclopropanations of Michaelacceptor olefins:

Shitama, H.; Katsuki, T. Angew. Chem. Int. Ed. 2008, 47, 2450–2453.
Cyclopropanation via Michael Addition and Ring Closure –– Asymmetric Cyclopropanation
Through Chiral Ylides
• In an early report, optically enriched oxosulfonium F was prepared in 3 steps, which
stereoselectively cyclopropanates Michael-acceptors:

O
H3C

S

1. p-tolSO2N3, Cu
CH3OH, 65 ºC

O

p-tol 2. H SO
2
4

H3C

O
Ph

H

F, NaH
Ph

H3C

3. Me3OBF4
Na2CO3

S N
p-tol

DMSO, 23 ºC

O BF4–

CH3

H3C
CH3
Br
Ph
S
OH
acetone
H3C
–20 ºC, 92%

CH3

Ph

CH3
S
OH

CO2CH3

CO2Me

t-BuOK

Ph

THF, –78 ºC

Ph

71%

Ph

77%, 99% ee
dr > 99:1

S N(CH3)2
H3C
p-tol
F

O

H

H3C

CH3

Ph

Ph
H

94%, 35% ee

–
O BF4
H S N(CH3)2

Ph
p-tol
H

O

H3C

OH

Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1968, 90, 6852–6854.

H3C
Br

H3C

S
CH3
OH

CH3

Ph

Ph

acetone
–20 ºC, 92%

H3C

S
OH

CH2

COPh

COPh

t-BuOK
Ph

THF, –78 ºC

Ph

Ph
78%, 96% ee
dr > 99:1

Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W,; Li, K.; Tang, Y.; Wu, Y.-D.; Dai, L.-X. J. Am.
Chem. Soc. 2006, 128, 9730–9740.
James Mousseau, Fan Liu

5


Myers

Chem 115

Cyclopropanation

• Catalytic Enantioselective Ylide Cyclopropanations
• Cinchona alkaloids have been employed to generate chiral ammonium ylides, which
stereoselectively cyclopropanates Michael-acceptors:
O
Br +

Et2N

G (20 mol%)
Cs2CO3

O
Ph

• Chiral sulfoxonium intermediates can be generated in situ by trapping of a rhodium carbenoid:

Ph

O
Ph

Et2N

CH3CN, 80 ºC
94%, 97% ee

N

N

Ts

Rh2(OAc)4 (10 mol%)

O
+

O
CO2Et

H Na+

O

NR3
Cs2CO3

O
NR3Br–

Et2N

O

91% ee, dr = 88:12

"

O
Ph

Et2N

O

oC

catalyst J

Rh2(OAc)4
O

N

O

BnEt3N+Cl- (20 mol%)
1,4-dioxane, 40

CO2Et

Ph

J (20 mol%)

N

RhII

Ph

NR3+

Ph

Ph

H

R*
S

S

O
N

H

CH3

O

O
CO2Et

R*

CH3
J

OCH3
O
Cl

H (20 mol%)
Na2CO3, NaBr

O

O

N
H

O

OCH3
N

CH3CN, 80 ºC
79%, 95% ee

H

G: R = H
H: R = CH3

R

Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem. Int.
Ed. 2001, 40, 1433–1436.

• Asymmetric cyclopropanation through a chiral iminium intermediate:
Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. 2004,
43, 4641–4644.
Johansson, C. C. C.; Bremeyer, N.; Ley, S. V.; Owen, D. R.; Smith, S. C.; Gaunt, M. J. Angew.
Chem. Int. Ed. 2006, 45, 6024–6028.

N
H

• Lanthanum complexes were also found to be effective:

O
Li

O
O

OH
OH

1. La(O-i-Pr)3
THF, 0 ºC ! 23 ºC

2. MeLi, THF

*

0 ºC ! 23 ºC

O
H3C S CH
2
H3C

+

Ph

CH3
CH3

THF, toluene
4Å MS, –55 ºC
73%, 94% ee

La
O

H

H3C

CH3 O

S

Ph

H

CHCl3, –10 ºC
85%, 95% ee, dr = 30:1

O
Ph

n-Pr
H

O
H

O
Li

O
I

*

I (10 mol%)
NaI (10 mol%)

O

O

O
O

Li

n-Pr

*

+

CO2H
(20 mol%)

Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240–3241.

O
Ph

CH3
CH3

Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129,
13410–13411.

David W. Lin, Fan Liu

6


Myers

Chem 115

Cyclopropanation

Asymmetric Cyclopropanation using Metal Carbenes
• Transition metals catalyze the cyclopropanation of electron-rich olefins via carbenoids formed from
electron-deficient diazo compounds.

• Since the initial report, extensive research has been done to develop other C2-symmetric Cu(I) and
Ru(II) oxazoline complexes.
various linker
groups
used here

• The catalytic cycle proceeds via a Fischer-type (electrophilic) metal carbene formed from diazo
precursors:

R1

various
groups
used here

R1

N2
R2

R3

R2

ML*

R2

R1

R3

MLn
N2
R1

R3

t-Bu

transition
state

R2

N

t-Bu
catalyst

• Many alkenes can be used, with styrenes and enol ethers being the most common.

electron-rich
alkene

Fischer-type (electrophilic)
metal carbene

O
N

H
H

H
MLn

O

• The reaction proceeds with retention of the olefin geometry:
O

• This methodology is most effective for three classes of diazo substrates:
R

• Diazo substrates with one electron-withdrawing group

R'

OR''

+

CO2R''
R'

catalyst

N2

R

R = aryl, alkyl, OR

• Diazo substrates with two electron-withdrawing groups
• Diazo substrates with one electron-withdrawing group and one electron-donating group

• Up to three stereocenters can be formed.
• Cu(I) and Ru(II) oxazoline complexes typically give trans-1,2-cyclopropanes selectively:

• Diazo Substrates with One Electron-Withdrawing Group
• The use of C2-symmetric Cu(I) oxazoline complexes for cyclopropanation was first reported by
Evans:
I (1 mol%)
CuOTf (1 mol%)

O

+

Ph

OEt
N2

t-BuO2C
F
Ph

Ph
+

CHCl3, 23 ºC
77%

CO2Et
99% ee

Ph

CO2Et

O

F

97% ee

+
Ph

trans:cis = 81:19

Cu
H

H3C

I (0.12 mol%)
CuOTf (0.1 mol%)

O
+

OEt
N2

CHCl3, 0 ºC
91%, >99% ee

H3C

CO2Et

H3C CH3
O

H3C

O
N

N

t-Bu

3

O CH3

F

F

H

Ph
93% ee
trans-cyclopropane
(major)

t-Bu
Cu

H

N
N

t-Bu
disfavored

t-Bu

CO2t-Bu

favored

56%
dr = 81:19
t-BuO2C
Ph

CH3

N
N

O CH

t-Bu

CuOTf•I
Ot-Bu

N2

t-Bu

O CH

CO2t-Bu
3

O CH3

Ph

H

F
89% ee
cis-cyclopropane
(minor)

I
Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726–728.

Haufe, G.; Rosen, T. C.; Meyer, O. G. J.; Fröhlich, R.; Rissanen, K. J. Fluorine Chem. 2002, 114,
189–198.
David W. Lin, Fan Liu

7


Myers
• Examples of Cu(I)- and Ru(II)-catalyzed enantioselective cyclopropanations:

I (2.5 mol%)
CuOTf (2 mol%)
PhNHNH2 (2 mol%)

O
O

Chem 115

Cyclopropanation

OEt

CO2CH3

N2

• Chiral Ir(III)-salen complexes afford cis-1,2-cyclopropanes with high enantioselectivities:
O

H

EtO2C

CH2Cl2, 0 ! 20 ºC
91% ee (crude)

CO2Me

O

H

Ot-Bu
N2
III (1 mol%)

p-CF3C6H4

THF, –78 ºC
73%, 97% ee
dr = 97:3

after recrystallization:
53%, >99% ee

N
F3C

N
Ir

CO2t-Bu

O

O
X
Ph Ph

O
Bưhm, C.; Reiser, O. Org. Lett. 2001, 3, 1315–1318.
• Intramolecular reactions can also proceed with high enantioselectivities:

CH3

O
O

I (0.12 mol%)
[Cu(MeCN)4]PF6 (1 mol%)

CH3

O
O

CH2Cl2, 23 ºC
82%, 90% ee

N2

Ot-Bu

BzO

H

F3C

Ot-Bu
N2

CH2Cl2, 0 ! 20 ºC
85%, 99% ee
dr = 96:4

CO2t-Bu

IV (1 mol%)
DMAP (50 mol%)
EtO2C

II (0.5 mol%)

III, X = p-Tol

BzO

• Co(II)-porphyrin complexes can cyclopropanate electron-deficient alkenes enantioselectively:

Doyle, M. P.; Peterson, C. S.; Parker Jr., D. L. Angew. Chem. Int. Ed. 1996, 35, 1334–1336..

O

THF, –78 ºC
87%, 94% ee
dr = 96:4

Suematsu, H.; Kanchiku, S.; Uchida, T.; Katsuki, T. J. Am. Chem. Soc. 2008, 130, 10327–10337.

O

O

N2

III (1 mol%)

CO2t-Bu

PhCH3, 23 ºC
92%, 91% ee
dr = 99:1
O

F3C

H3C
EtO2C

CO2t-Bu

O
Ph

H2N

O
N

IV (1 mol%)
DMAP (50 mol%)

Ru

Ph H2O Cl

N
CO Ph

Ph

O

PhCH3, 23 ºC
77%, 97% ee
dr = 99:1

O
NH

N

N

HN

Co

Ot-Bu

CH3

CH3

3,5-di-t-BuPh
O

NH

N2
H3C

H3C

CH3

N

N

HN
O

O
3,5-di-t-BuPh
CO2t-Bu

H2N

H3C

CH3

IV

H3C

CH3

O

II

Ito, J.-i.; Ujiie, S.; Nishiyama, H., Chem.–Eur. J. 2010, 16, 4986–4990.

Chen, Y.; Ruppel, J. V.; Zhang, X. P. J. Am. Chem. Soc. 2007, 129, 12074–12075.
David W. Lin

8


Myers

• At low temperatures, rhodium(III) catalysts are compatible with higher !-alkyl-!-diazoesters, which
otherwise often undergo undesired "-hydride elimination upon metal carbene formation:

O
Ph

Chem 115

Cyclopropanation

n-Bu

EtO

Rh2[(S)-PTTL]4
(0.5 mol%)
hexane, –78

N2

• !-nitro-!-diazo aryl ketones give cis cyclopropanes selectively:

O
EtO2C

oC

93%, 96% ee
dr = 99:1 (trans:cis)

n-Bu

O
O Rh O

Ph

Cl

O2N

Ph3C

O Rh O

N2

N

OCH3

O

Rh2[(S)-TCPTTL]4
(0.1 mol%)
Et2O, –50

t-Bu

Cl

O
O2N

Cl

O

oC

OCH3 Rh O

68%, 94% ee
dr = 96:4

3
Rh2[(S)-PTTL]3TPA

Cl

N

Rh O

O

t-Bu

CF3

4

CF3

Rh2[(S)-TCPTTL]4

Boruta, D. T.; Dmitrenko, O.; Yap, G. P. A.; Fox, J. M. Chem. Sci. 2012, 3, 1589–1593.
• Diazo Substrates with Two Electron-Withdrawing Groups

Lindsay, V. N. G.; Lin, W.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 16383–16385.

• While symmetrical diazomalonates give poor selectivities, unsymmetrical diazomalonates are
excellent substrates:

O

O

N

OCH3
N2

Ph

Rh2[(S)-NTTL]4
(1 mol %)

O
N

DCE, 23 ºC

CO2CH3
Ph

79%, 96% ee
dr > 30:1 (cis:trans)

O
Rh O

H3CO2C

Ph

R
N2

Ph

CH2Cl2, 23 ºC

O
R

NO2

4

H3C CH3
H3CO2C

Ph

in situ generated
carbene precursor

Ph
trans
(favored for
R = OEt, n-Bu)

Charette, A. B.; Wurz, R. P.; Ollevier, T. Helv. Chim. Acta 2002, 85, 4468–4484.

O

O
N

N

Ph

Ph

82%, 91% ee
dr = 94:6 (trans:cis)

Cu+
SbF6

Ph
–

V

• Alternatively, !-nitro-!-diazo acetates give cis cyclopropanes with cobalt(II)-porphyrin catalysts:

O

O
NO2

NO2

Moreau, B.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 18014–18015.

• For !-nitro-!-diazo carbonyls, the diastereoselectivity is sensitive to the nature of the carbonyl
substituent:

Rh2(OAc)4

V (2 mol%)
Na2CO3
C6H6, 23 ºC

t-Bu

Marcoux, D.; Charette, A. B. Angew. Chem. Int. Ed. 2008, 47, 10155–10158.

NO2

O

H3CO2C
I

O
Rh O

I

NO2

N

Rh2[(S)-NTTL]4

O

• !-nitro-!-diazo esters give trans cyclopropanes selectively. In the example below, the oxidant
iodosobenzene can be used to form the carbene precursor from !-nitro esters in situ:

R

NO2

Ph
cis
(favored for
R = Ph, t-Bu)

NO2
O

O2N

OEt

IV (5 mol%)
DMAP (50 mol%)
hexanes, 0 # 23 ºC
81%, 95% ee
dr = 93:7

O2N

OEt

NO2

N2
Zhu, S.; Perman, J. A.; Zhang, X. P. Angew. Chem. Int. Ed. 2008, 47, 8460–8463.

David W. Lin

9


Myers

Chem 115

Cyclopropanation

• Diazo Substrates with One Electron-Withdrawing Group and One Electron-Donating Group
• Metal carbenes with adjacent electron-donating and electron-withdrawing groups ("push-pull"
systems) are relatively stable and reactive.

• A wide range of electron-withdrawing groups within the diazo substrate are tolerated:
O
H3CO P
H3CO

• Rhodium(II) complexes using chiral ligands derived from proline have often been employed:

Rh2[(S)-PTAD]4
(2 mol%)

Ph
N2

Ph

t-Bu

CO2CH3
N2

Rh2[(S)-TBSP]4
(1 mol%)

Ph
Ph

Ph

83%, 87% ee

Rh O

F3C

CO2CH3

Ph

N

O

Rh O

4

Rh2[(S)-PTAD]4
(1 mol%)

Ph
N2

Ph

Rh2[(S)-TBSP]4
Rh2[(S)-TBSP]4

(1 mol%)

H

O
Rh O

Rh2[(S)-PTAD]4

O S O
Rh O
N

Ph

Ph

Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437–3440.

CO2CH3

pentane, 23 ºC

PhCF3, 23 ºC
94%, >98% ee
dr > 20:1

O
H3CO P
H3CO

CO2CH3

F3C

Ph

H

Ph

2,2-dimethylbutane
50 ºC, 86%
99% ee, dr > 30:1

4

Denton, J. R.; Sukumaran, D.; Davies, H. M. L. Org. Lett. 2007, 9, 2625–2628.

pentane, 23 ºC

N2
OCH3

82%, 88% ee
dr = 98 : 2

H
NC

H3CO

N2
Doyle, M. P.; Zhou, Q.-L.; Charnsangavej, C.; Longoria, M. A.; McKervey, M. A.; GarcÌa, C. F.
Tetrahedron Lett. 1996, 37, 4129–4132.
Davies, H. M. L.; Bruzinski, P. R.; Fall, M. J. Tetrahedron Lett. 1996, 37, 4133–4136.
• Styrenes can also be considered as electron-donating groups on the diazo substrate:

CO2Me
N2

Et

CO2Me

pentane, 23 ºC
65%, >95% ee

Et

Ph

toluene, –78 ºC
86%, 90% ee
dr = 97:3

NC

Ph

H

Ph

Denton, J. R.; Cheng, K.; Davies, H. M. L. Chem. Commun. 2008, 1238–1240.
• N-sulfonyl-1,2,3-triazoles serve as alternatives to diazo compounds as carbene precursors:

H3CO2S N N N
Rh2[(S)-TBSP]4
(1 mol%)

Rh2[(S)-PTAD]4
(2 mol%)

Ph

H
Ph

Ph

1. Rh2[(S)-NTTL]4
(0.5 mol%)
DCE, 65 ºC
2. K2CO3, MeOH

H

[Rh]
H3CO2S

N

O
H

67%, 98% ee
dr > 20:1

O
Rh O

N

Rh O

t-Bu

O

Rh2[(S)-NTTL]4

4

R
H

Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J. J. Am. Chem. Soc. 1996,
118, 6897–6907.

Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin, V. V. J. Am. Chem. Soc. 2009,
131, 18034.
David W. Lin
Grimster, N.; Zhang, L.; Fokin, V. V. J. Am. Chem. Soc. 2010, 132, 2510.

10


Myers

Chem 115

Cyclopropanation

Selected Transformations of Cyclopropanes

Selected Industrial Examples

• Cyclopropanes can undergo direct C-H functionalization enantioselectively by Pd(II) complexes
with chiral amino acid ligands.

• A copper-catalyzed diazo decomposition led to the asymmetric cyclopropanation of 2,5-dimethyl2,4-hexadiene in good yield and high enantioselectivities:

• A special directing group is required on the cyclopropane substrate to coordinate the Pd(II)
complex and direct insertion into the adjacent cis C-H bond.

H3C

• The directing group is readily available and can be hydrolyzed to give the corresponding acid:

H3C

F
OBn O

F
N
H

F

CuCl (0.2 mol%)
Ligand (0.22 mol%)
Ph3CPF6 (0.22 mol%)
EtOAc, 0 ºC, 92%

Ot-Bu
n-Bu
F
OBn O

Ag2CO3, NaHCO3
t-Amyl-OH, 40 ºC
62%, 92% ee

F

CH3
(3.86 g)
O

F
CH3
O
CH3
Ph B
CH3
O
CH3
Pd(OAc)2 (10 mol%)
CN
ligand (20 mol%)

CH3

F
N
H
Ph

CN

O
Cl3C
n-Bu

O
N
H

F
CO2H

N2

Ot-Bu
H3C
H3C H3C

H3C
H3C

F

O

O
N

N

Ot-Bu
H3C

88:12

CH3
71% ee

chrysanthemic acid

t-butyl ester
(a key intermediate
to pyrethroid
insecticides)

H3C CH3

ligand

O

H3C

CH3

96% ee

(1.41 g)

Ligand

F

H3C

O

CH3
CH3

Wasa, Y.; Engle, K. M.; Lin, D. W.; Yoo, E.-J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598–19601.
Itagaki, M.; Masumoto, K.; Suenobu, K.; Yamamoto, Y. Org. Proc. Res. Dev. 2006, 10, 245–250.

• Cyclopropanes can undergo vinylcyclopropane-cyclopentene rearrangements:

• Cinchona alkaloids were applied to the synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic
acid ethyl esters in good yield and modest ee's.
H

TBSO
H3C

N2

O

t-Bu
N
O
Cu
O
N
t-Bu
toluene, 110 ºC, 84%

H
O
TBSO
H3C

O

•

H

O

O

1. Br2, CCl4
Et2O, 0 ºC
2. DBU, DMF
50 ºC, 48%

TBSO
H3C

•
O

•

•
O

Ph

N

OEt

TBSO
H3C

Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, 5574–5576.
Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559–3562.

H

O

O

Br
(16.74 g)

Ph

N

CO2Et

H2O, 0 ºC
Crude yield:
A key intermediate in the
78%, 77% ee
preparation of many
After Chromatography:
hepatitis C inhibitors

55%, >99% ee

Catalyst
Br–
HO

•

Cat (3 mol %)
NaOH, toluene

Br

(11.3 g)

Et2AlCl, CH2Cl2
0 ºC, 80%

+

N

N
CF3
F3C

Belyk, K. M.; Xiang, B.; Bulger, P. G.; Leonard, W. R.; Balsells, J.; Yin, J.; chen, C.-y. Org. Proc.
Res. Dev. 2010, 14, 692–700.
James Mousseau, David W. Lin, Fan Liu

11