[2+2] Cycloadditions of Ketenes

An Evans Group Afternoon Seminar

Jake Janey
October 8, 1999

Leading References:
Tidwell, T. T. Ketenes, John Wiley and Sons, 1995.
Ghosez, L.; Marchand-Brynaert, J. Comprehensive Organic Synthesis , Vol. 5, Pergamon, 1991, p. 85-122.
Patai, S. Chemistry of Ketenes, Allenes, and Related Compounds , John Wiley and Sons, 1980.
Staudinger, H. Die Ketenes , Verlag Enke, 1912.

A Brief History
O
Ph

Zn

Ph

Ph2C=C=O

Cl

Wanted to make:

Cl

Ph2C

Cl

Staudinger, H. Chem. Ber. 1905, 38, 1735-1739.

O
hot Pt wire
O

CH 2=C=O

H
Wilsmore, N. T. M. J. Chem. Soc. 1907, 91, 1938-1941.

O
n-Pr3N

Ph
Ph

Cl
H

Wedekind, E. Chem. Ber. 1901 , 34, 2070-2077.

Wedekind, E. Liebigs Ann. Chem. 1901 , 323, 246-257.

Ph2C-C=O
Ketene proposed
but not isolated

n-Pr3NHCl

Summary of Ketene Cycloadditions

R

R'
O

R'

or

O
O

R'

R'

R'

R'
O
Carbonyl

Alkene
O
C

1,3-Dipole
O

X
Y

Imine

R'

R
R'

R = -CH=CH 2

R'
Y

O
X

O
R

R'

R'

Ketene Preparation

From Carboxylic Acid and Their Derivatives:

O

R3N

C O

Staudinger Reaction (very general)

R'

R'
X = Cl, Ts, AcO, DCC, etc...

(CH 3CO)2O

_
RCH 2CO2Ar

H2C C O

O
OH

_
OAr

O
O

C O
H

O
Ph
Ph Br

Br

AcOH

-ArO

_H O
2

Zn
_ ZnBr

Ph2C C O
2

R
C O

Ketene Preparation
Other Methods :
O
550 C

H2C C O

R1

O
R

R1

h
or

R3

R2

R2

O
R'

h
or

C O

O
H

Wolff Rearrangement (variable yields)

R'

N2

-CH 2CH2

C O

Ketene Frontier Orbitals

R
LUMO

or

(* of C=O)

+
C

R'

R'

HOMO

( of C=C)

R'

Ketenes are ambiphilic

HOMO is orthogonal to the plane of the LUMO

or

R'

Silyl Ketene Stability

Hyperconjugation:

+
R3Si

R3Si
C O

_
O

Brady, W. T.; Cheng, T. C. J. Org. Chem. 1977, 42, 732-4.

-> d Donation to Si:

_
R3Si

R3Si

C O

C O

H+

Runge, W. Prog. Phys. Org. Chem. 1981, 13, 315-484.

Si > Donation:

R3Si

C O
H

OH

Fast

R3Si
H

_ O

O
R3Si

OH

OH

H2O
Slow
H

Fast

R3Si
H
H

O
C O
+

Gong, L.; McAllister, M. A.; Tidwell, T. T. J. Am. Chem. Soc. 1991, 113, 6021-8.

R3Si

OH

Dimerization
O
H2C C O

Valuable synthetic intermediate

Clemens, R. J. Chem. Rev. 1986, 86, 241-318.

440 C

Wilsmore, N. T. M. J. Chem. Soc. 1907, 91, 1938-1941.

In General:

R
R'
R'

R
R'

R
R

R
R

R'

C+
O

vs.

HO

O
H

_O

R
R
R
C+
O

Catalyzed Dimerization
Favors -lactones:
O

ZnCl 2

C
R

_
ZnCl 2

_
RCH=C=O

C+
R

Cl2ZnO
-ZnCl 2

O
C+

O
O

Base catalyzed isomerization:

R

_
R

C O

Et 3N
O

O
R

O_
R

RCH=C=O

O
R
RCH 2

R
O

OH

HO

[2+2]

10

Dimerization Mechanism

H
H

+
C

1.726
H

2.673
C

H
G = 32 kcal/mol

+
C

1.613

2.532
C

G = 36 kcal/mol

Seidl, E. T.; Schaeffer, H. F. J. Am. Chem. Soc. 1991, 113, 5195-5200.

C O

O
+

O
anti:syn
5:1

"A one step concerted process has never been proven for any one example."
Hoffmann, H. M. R. Angew. Chem., Int. Ed. Eng. 1985, 607-608.

11

Ketene-Alkene [2+2]
O
C

Fast

O
C

O
+

O
+

B
1:2

H
Me
C O

Me
O_

Me

C
Me + H

Frey, H. M.; Isaacs, N. J. J. Chem Soc. B, 1970 , 830-832.

H
Me

Me
O_

Me

C
H + Me

12

Regiochemistry
R

C
O

_O

Major

t-Bu

C
t-Bu

CN

CN

t-Bu
NC

Exclusive
Hassner, A.; Cory, R.; Sartoris, N. J. J. Am. Chem. Soc. 1976 , 98, 7698-7704.

Diastereoselectivity:

O
O

O
t-Bu

+
t-Bu

CN

NC

Gheorghiu, M. D.; Draghici, C.; Parvulescu, L. Tetrahedron , 1977, 33, 3295-3299.

t-Bu
CN

13

Endo -Exo Selectivity

O
+

Et 3N

O
+

Cl

H
exo

endo
R

endo

exo

89

11

Cl

87

13

Me

76

24

Ph

67

33

Et

64

36

i-Pr

57

43

t-Bu

10

90

Product ratios at equilibrium

1

H NMR Conformation
H7

H5
O

H1

Hyperconjugative interaction between H

Endo position is more sterically crowded

Ghosez, L.; et. al. Helv. Chim. Acta, 1982, 65, 703-720.

,H7 and * of C=O

14

[2+2] Versus [4+2]

O
+

[4+2]

(3,3)

Machiguchi, T.; Yamabe, S.; et. al. J. Am. Chem. Soc. 1999, 121, 4771-4786.

15

Solvent Effects
Me
C O

Me

O
+
X

Me
exo

endo
X

Solvent

endo / exo

Solvent

endo / exo

Cl

hexane

4.3 / 1

Br

hexane

0.71 / 1

Cl

Et 3N

2.2 / 1

Br

Et 3N

0.28 / 1

Cl

CHCl3

1.6 / 1

Br

CH 3CN

0.14 / 1

Cl

CH 3CN

0.59 / 1

Solvent effects implicate a zwitterionic intermediate

Brady, W. T.; Roe, R. Jr.; Hoff, E. F.; Parry, F. H., III, J. Am. Chem. Soc. 1970, 92, 146-148.
Ph
C O

Alkene

exo / endo (Me)

Me
Alkene

exo / endo (Me)

Cp

>20

EtOCH=CH 2

2.3

Dihydropyran

1.7

Cyclohexene

Cyclooctene

Not a highly ordered transition state

Brady, W. T.; Parry, F. H., III; Stockton, J. D. J. Org. Chem. 1971, 36, 1486-1489.

16

Woodward-Hoffmann Analysis
(2s + 2a)

HOMO

LUMO

Or
HOMO
2 s

+ (2s + 2s )

LUMO (* of C=O)

Calculations seem to support this

orbital analysis
HOMO

Stepwise Versus Concerted

H
C
R'

17
R'

R'
H

least hindered
bond rotation

Stepwise

Concerted

Very large polar effects

Ketenes add stereoselectively to Z alkenes

E olefins yield a mixture of cis and trans products

Z olefins are much more reactive than E

Solvent effects observed, but it could merely be a

ground state effect
KIE seen for many reactions support stepwise
mechanism
Calculations (Wang and Houk) show a highly
asynchronus transition state in the gas phase reaction
All stereochemical outcomes can be rationalized
assuming a stepwise mechanism

18

Transformations of Cyclobutanones
O

OH

O
Ph3SnH

Cl

AcONHEt 3

acetone/H 2O

or Zn

Cl

Cl

R
Cl

Cl

Base

CO2H

Brady, W. T. In The Chemistry of Ketenes, Allenes, and Related Compounds ; Patai, S. Ed.; Wiley: New York, 1980, part
1, ch. 8.

O
L-Selectride
O

H
Cl

HO

Cl

1. Zn, AcOH
2. mCPBA, NaHCO 3

CO2Bn
Recent Progress in the Chemical Synthesis of Antibiotics ;
Lukacs, G.; Ohno, M. Eds.; Springer-Verlag: Berlin, 1990.

Lorreia, C. R. D. et. al.

H
CO2Bn

Tetrahedron Lett. 1993, 27-30.

19

Application to Ginkgolide B

MeO

MeO

MeO
O

1. (COCl) 2, PhH
tBu

tBu

2. n-Bu 3N, PhCH 3,

tBu
H

(80%)
C

CO2H

O
O

HO
HO

tBu

O
H

O
Me

OH

Ginkgolide B
Three stereocenters set via an
intramolecular [2+2]

Corey, E. J.; Kang, M. -C.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N.

J. Am. Chem. Soc. 1988, 110, 649.

20

Un-catalyzed [2+2] Mechanism

38 kcal/mol
_

O+

H
H

path A

+
H

H
H

H
path B
O

H
H

HH

32 kcal/mol

Pons, J. -M.; et. al. J. Am. Chem. Soc. 1997, 119, 3333.

BF3 Catalyzed [2+2] Mechanism

21

14 kcal/mol
O+

F 3B O
H

H
H

path A

+
H

H
H

H
path B
O BF 3
+

H
H

24 kcal/mol
Pons, J. -M.; et. al. J. Am. Chem. Soc. 1997, 119, 3333.
Concerted, asynchronus early transition state with a half electron charge on boron as calculated by Gaussian
(MP2/G-31 and HF/G-31) with ZPE corrections and solvent effects.
Cossio, F. P.; et. al. J. Am. Chem. Soc. 1994, 116, 9613.

Chelation Controlled Ketene-Aldehyde [2+2]

BnO

1. MgBr 2Et 2O
-43 C, CH 2Cl 2

O
BnO

2. KF2H 2O
CH 3CN

TMS

98:2 = anti:syn
94% yield

d.e. with TMS group not reported

H

O C

TMS

Ph
O
Br

Mg

H
O

Me

Br

Vemribo, R.; Romo, D. Tetrahedron Lett. 1995, 36, 4159.

see also: Pommier, A.; Pons, J.-M.; Kocienski, P.J.; Wong, L.

Synthesis 1994 , 1294.

22

23

Lewis Acid Catalyzed [2+2]

O
+

TMS

MABR (1eq), CH 2Cl2

-78 C, 2h
R

TMS

MABR =

Br

Al

82% yield
Cis product only
when R=Et

Br

Me

O
R

TMS

O
R

C
O
MABR

Concepcion, A. B.; Maruoka, K.; Yamamoto, H.

Cis

O
MABR
TMS

Tetrahedron , 1995 , 51, 4011.

Trans

24

Catalytic, Enantioselective [2+2]

O

O
+

toluene, 30mol% cat.

TMS

TMS

Ph

-80 C to -30 C

R
H

O
cat. =
R

TMS

Ph

O 2S Ar
N
Al
N

Me

O 2S Ar
Entry

cis:trans

Yield (%)

ee (%)

Bn

100:0

43

40

BnCH 2

100:0

43

44

c-hex

95:5

57

55

Bn

83:17

56

83

BnCH 2

90:10

80

44

c-hex

85:15

32

68

C11H23

94:6

67

47

p-MeOC 6H4CH 2

99:1

77

83

Bn

79:21

82

62

10

BnCH 2

90:10

85

30

11

c-hex

77:23

57

53

12

Bn

75:25

72

82

13

BnCH 2

94:6

82

36

14

c-hex

69:31

43

67

15

C11H23

82:18

67

48

16

p-MeOC 6H4CH 2

70:30

81

75

Dymock, R. W.; Kocienski, P. J.; Pons, J. -M. Chem. Commun. , 1996, 1053

25

in-situ Ketene-Aldehyde [2+2]

2.5-20 mol% Al(SbF 6)

+
X

EtNi-Pr2 , CH2Cl 2, -25 C

1.5 eq.
(X = Cl or Br)

O
R

60-93% yield

Only cis product observed when EtCOCl utilized

Nelson, S. G. et. al. Tetrahedron Lett. 1999, 65, 35-39.

26

"Masked Aldol"
O

O
Br

cat. (10 mol%)

i-Pr2NEt

R3N

Bn

i-Pr

N
F3CO 2S

catalyst
[time (h), temp (C)]

% yield

% ee 3
(configuration )

entry

Aldehyde 2 (R)

BnOCH 2

5b (8, -40)

91

92 (R)

PhCH 2CH2

5a (16, -50)

93

92 (S)

PhCH 2CH2

5a (72, -78)

89

95 (S)

CH 2CH(CH2)8

5b (16, -50)

91

91 (S)

Me2CHCH2

5a (24, -50)

80

93 (S)

BnOCH 2CH 2

5b (16, -40)

90

91 (S)

TBDPSOCH 2

5b (16, -40)

74

89 (R)

BnOCH 2

5a (16, -50)

86

93 (R)

Me3C

5a (16, -50)

91

85 (R)

5b (24, -40)

56

54 (R)

C6H11

cat. = 5a: R = Me
5b: R = Cl

R3NHBr

Al
R

[RCHO cat.]

i-Pr

Nelson, S. G.; Peelen, T. J.; Wan, Z. J. Am. Chem. Soc. Web ASAP Oct. 4, 1999.

SO 2CF3

27

Enantioselective Base Catalyzed [2+2]

C O

1-2 mol%
quinidine

Cl 3C-CHO

toluene, -50 C
Cl3C

+N
MeO

H
CCl3

-O
O 2CCH3
H

Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977.

95% yield
98% ee

Transformations of -Lactones
R2

Cl2RC

AlR 3
O

-CO2

O
1

R2

or BF 3

28

HO

Cl2RC

R1

CRCl2
O n

CO2H

Lavallee, C. et. al. Macromolecules , 1984, 17, 2457.

Me2S

R'

R2N

CuCN
O

R'Li (2eq)

R2N

Arnold, L. D.; Drover, J. C. J.; Vederas, J. C. J. Am.

Chem. Soc. 1987, 107, 4649.

R2

O
O

OH

base
R1

or acid

Nu
R

Nu = OH 2, ROH, R 2NH

Zaugg, H. E. Org. React. 1954, 8, 305.

CO2H

29

Staudinger Reaction
O
R1

R3
N

X = Cl, Br
R2

R3N:

O
R3
H

R1
N
_
+
X

R2

R3

R3N:

R3
4 conrotatory

R1
+

R1

N
R2

R2

R1

N
R3

N
X

R2

R1

_
R3

R2

4 conrotatory
_

R3

N
X

R1
R2

R3
X

O
N

R1
+
R2

30

Diastereoselective Staudinger
O
N3

Ph
Cl

Et 3N, CH2Cl 2

N3

Ph

20 C

Ph

N3
+

N
O

Ph

Ph
N

Ph

addition of acid chloride (to imine + Et 3N)

66%

34%

addition of Et 3N (to imine + acid chloride)

33%

67%

Bose, A. K.; Anjaneyula, B.; Bhattacharya, S. K.; Manhas, M. S.

Tetrahedron 1967, 23, 4769.

Xc
Cl

BnN=CHR
Et 3N

N
O

Ph
R

yield (%)

de (%)

Ph

90

94

trans-PhCH=CH-

82

90

80

94

Evans, D.A.; Sjogren, E.B. Tetrahedron Lett. 1985, 3783-6, 3787-90.

Bn

Transformations of -Lactams

31

1. B2H6, THF
2. H 3O+

HN

HO

R'

" R O2C

Rh 2(OAc) 4

R
N

NH

N2

" R O2C

R'

O
O

R'OCHN
R'OCHN
1. H 2NOH, MeOH
N
O

2. CH 2Cl2
Me

NEt2

Recent Progress in the Chemical Synthesis of Antibiotics ; Lukacs, G.; Ohno, M. Eds.; Springer-Verlag: Berlin, 1990 .

Application To -Lactam Antibiotics

O
O
N

Xc
Cl

R
[H]

BnN=CHR
Et 3N

32

H2N

N
O

Ph

R
NH

Bn

H H H
N

PhO

Carbacephalosporin Nucleus
O

O
CO2H

Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1985, 3783-6, 3787-90.

Evans, D. A.; Williams, J. M. Tetrahedron Lett. 1988, 5065-8.

NH 2

Conclusion

Ketenes undergo [2+2] cycloadditions with

alkenes, carbonyls, imines, and other unsaturated
functionalities.
Ketenes are ambiphilic, thus the mechanism of
the cycloaddition is stepwise with the ketene
acting as either the nucleophile, or the eletrophile.
Most cycloadditions are highly stereoselective
and regioselective, although the stereochemical
outcome is not always predictable.
Ketenes cycloadditions provide access to a
variety of useful synthetic intermediates, including
-lactams.

33