Synthesis of bicyclo[3.1.0]hexan-2-ones by manganese(III) oxidation in ethanol

PAPER

409

Synthesis of Bicyclo[3.1.0]hexan-2-ones by Manganese(III) Oxidation in

Ethanol

S

ynthesisof Bicyc

e

lo[3.1.0]he

n

xan-2-ones

U

t

singM

a

n(III)

O

xid

r

ation o Asahi,^aHiroshi Nishino*^b

a

Department of Materials and Life Sciences, Graduate School of Science and Technology, Kumamoto University,

Kurokami, Kumamoto 860-8555, Japan

b

Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, Kurokami, Kumamoto 860-8555, Japan

Fax +81(96)3423374; E-mail: nishino@sci.kumamoto-u.ac.jp

Received 18 August 2008; revised 3 October 2008

Dedicated to the memory of the late Professor Jay K. Kochi, Department of Chemistry, University of Houston, USA

clo[3.1.0]hexan-2-ones with no substituent at the C-6 po-

Abstract: N-Propenyl-3-oxobutanamides underwent the manga-

nese(III)-induced oxidative intramolecular cyclization in ethanol to

produce 3-azabicyclo[3.1.0]hexan-2-ones in good yields. A similar

reaction of propenyl 3-oxobutanoates and S-propenyl 3-oxobutane-

sition using the manganese(III)–copper(II) oxidation

system. Although many pharmacologically active bicy-

clo[3.1.0]hexan-2-ones^1ahave no substituent at the C-6

thioates also gave the corresponding 3-oxa- and 3-thiabicy- position, it is important to examine the synthesis of the C-

clo[3.1.0]hexan-2-ones. The reaction details, the structure

determination, and the reaction pathway are described.

6 functionalized analogues using the manganese(III) oxi-

dation system since the substituent effect of the olefin is

essential for the manganese(III) oxidation sequence.⁶

Key words: cyclizations, oxidations, radical reactions, bicy-

clo[3.1.0]hexanones, manganese(III) acetate

Moreover, there have been few reports on the synthesis of

3-thiabicyclo[3.1.0]hexanes⁸even if the compounds

showed antibacterial activities.^1g,hTherefore, we investi-

The 3-aza- and 3-oxabicyclo[3.1.0]hexanes and their de- gated the synthesis of the 3-aza-, 3-oxa-, and 3-thiabicy-

rivatives consisting of a flat and very rigid cyclopropane- clo[3.1.0]hexan-2-ones using N-propenyl-3-oxobutan-

fused g-lactam or g-lactone ring are found in a number of amides, propenyl 3-oxobutanoates, and S-propenyl 3-oxo-

biologically and pharmacologically active compounds.¹butanethioates in order to develop the synthesis of func-

For example, the commercially available procymidone is tionalized cyclopropane-fused g-lactams, g-lactones and

a gray mold disease inhibitor,^1band marasmic acid isolat- g-thiolactones.^6a,7In this paper, we wish to report the suc-

ed from Marasmius conigenus displays a significant anti- cessful results of their synthesis in ethanol as the solvent

microbial activity.^1d,2Therefore, several research groups that has been only less used in the manganese(III)-based

have investigated the synthesis of the 3-aza- and 3-oxabi- oxidation, and also discuss the limitation of the reaction

cyclo[3.1.0]hexanes, and many useful methods have been from the standpoint of the substituents in the olefin.

reported.³The aza- and oxabicyclo[3.1.0]hexanes can

also be easily converted into useful synthetic intermedi-

ates, such as the cis-1,2-cyclopropylamino acids and con-

First of all, the reaction of N-propenyl-N-benzyl-3-oxo-

butanamide 1a (0.5 mmol) with manganese(III) acetate

dihydrate (1.5 mmol) was carried out in glacial acetic acid

(20 mL) at reflux temperature under argon. The butan-

formationally

restricted

cis-1,2-bis(hydroxymeth-

yl)cyclopropanes.^1c

amide 1a was consumed within 30 seconds and underwent

In recent years, we have developed the manganese(III) oxidative intramolecular cyclization to produce the 3-

acetate mediated radical cyclization reaction using simple azabicyclo[3.1.0]hexan-2-one 2a (35%) and pyrrolidin-2-

olefins and 1,3-dicarbonyl compounds, which have been one 3a (48%) (Table 1, entry 1). A comparable result was

effective for the synthesis of highly functionalized hetero- also obtained in the case of the N-methyl-substituted

cyclic compounds.⁴The characteristics of the reaction is 3-oxobutanamide 1b (entry 4). The reaction at 85 °C im-

that the facile ligand exchange of the manganese(III) ace- proved the yield of 2a together with 3a (entry 2). Since the

tate with 1,3-dicarbonyl compounds to generate the man- azabicyclo[3.1.0]hexanone 2a and the pyrrolidinone 3a

ganese(III)-enolate complex in situ, followed by the one- might be formed from the same intermediate, the pyrroli-

electron transfer from an electron-rich C=C bond to the dinone 3a was heated under reflux in acetic acid for con-

complex, produces the corresponding carbon radicals.^4,5version into 2a.^4c,dHowever, the reaction caused only the

The radicals have been utilized for the carbon–carbon decomposition of 3a. It is known that the mild manga-

bond formation in both an inter- and intramolecular fash- nese(III)-based oxidation was carried out in ethanol as the

ion to yield various cyclic compounds.^4,6In connection solvent,⁹which was sometime effective for the cycliza-

with these studies, Bertrand,^7a,bOrena,^7cand Brown^7d–ftion.⁶Therefore, we changed the solvent from acetic acid

reported the synthesis of the 3-aza-, and 3-oxabicy- to ethanol and examined the reaction. Fortunately, the de-

sired azabicyclo[3.1.0]hexanone 2a was obtained as the

sole product (88%) (entry 3).

SYNTHESIS 2009, No. 3, pp 0409–0423

x

.

x

.2

0

9

Advanced online publication: 12.01.2009

DOI: 10.1055/s-0028-1083324; Art ID: F18008SS

The structure of 2a was determined on the basis of the ¹H

NMR, ¹³C NMR, and IR spectra as well as the combustion

410

K. Asahi, H. Nishino

PAPER

Table 1 Oxidation of N-Propenyl-3-oxobutanamides 1a–q with Manganese(III) Acetate Dihydrate^a

O

Me

H

O

R²

O

H

OEt

R⁴

R²

R¹

Mn(OAc)₃

3

4

2

R⁴

R

R²

1

2

R³

N

R¹

N

R³

R⁴

Bn

N

O

R³

N

6

5

Ph

4

R¹

1a–q

2a–q

5

3a,b,k,q: R = OAc

4k,q: R = OEt

6p: R = H

7q: R = OH

Entry

1

R¹

R²

R³

R⁴

1/

Solvent

Temp

Time

Yield (%)^c

Mn(III)^b

(min)

0.5

1

2

3

4–7

1

2

1a

1b

1c

1d

1e

1f

Ph

Bn

Me

OEt

1:3

AcOH

EtOH

AcOH

EtOH

AcOH

EtOH

reflux

85 °C

reflux

r.t.

35

48

88

29

91

98

86

88

92

84

91

46

29

22

70

60

55

23^g

trace

27

–

48

33

–

Bn

1:3

–

3

Bn

1:3.5

1:3

1.5

1

–

4

Me

Et

52

–

5

1:3.5

1:6

1

–

6

1

–

7

Pr

1

–

8

i-Pr

n-Bu

t-Bu

1

–

9

1

–

10

11

12^d

13^e

14

15^f

16^f

17^f

18^f

19^h

20^f

21

22

1g

1h

1i

2

–

PMB

Ph

1.5

–

1j

H

20

–

1k

1l

4-MeC₆H₄

Bn

Et

1:3.5

1:3.7

1:3.5

1

2.5

2

16

–

34 (4k)

4-ClC₆H₄

–

1m

1n

1o

1p

1q

4-FC₆H₄

–

4-FC₆H₄

1.5

2.5

4

–

H

Ph

H

Bn

–

6 (5)

25 (6p)

–

H

–

H

41 h

1

–

Ph

reflux

81

–

16 (7q)

36 (4q)

15

37

^aThe reaction of N-propenyl-3-oxobutanamide 1 (0.5 mmol) was carried out in EtOH or glacial AcOH (20 mL) in the presence of

Mn(OAc)₃·2H₂O. Before the reaction, the mixture was degassed under reduced pressure for 30 min using an ultrasonicator followed by argon

displacement.

^bMolar ratio.

^cIsolated yield based on the amount of the N-propenyl-3-oxobutanamide 1 used.

^dThe butanamide 1i was recovered in 29%.

^eThe butanamide 1j was recovered in 27%.

^fCu(OAc)₂(0.60 mmol) was also added as a co-oxidant.

^gThe product 2o was obtained as a 17:6 diastereoisomeric mixture.

^hThe butanamide 1p was recovered in 14%.

Synthesis 2009, No. 3, 409–423 © Thieme Stuttgart · New York

PAPER

Synthesis of Bicyclo[3.1.0]hexan-2-ones Using Mn(III) Oxidation

411

analysis and high-resolution mass spectrum. The ¹H NMR

spectrum of 2a showed a doublet of doublet at d = 3.43 (1

H, J = 11.0, 6.4 Hz) and a broad doublet at d = 2.99 (1 H,

J = 11.0 Hz) assigned to the H-4 methylene protons, and

a broad doublet at d = 3.33 (1 H, J = 6.4 Hz) due to the H-

5 methine proton, which was deshielded by the anisotro-

pic effect of one of the phenyl groups substituted at C-6.

It is suggested that the dihedral angle between one of the

H-4 protons and H-5 proton must be ca. 90° based on the

O

Mn(OAc)₃

Cu(OAc)₂

Me

O

Me

Bn

N

Me

N

Me

AcOH

reflux

1 min

Bn

1r

8 50%

Scheme 1

We next investigated the deprotection of the nitrogen-pro-

tective group on the azabicyclo[3.1.0]hexanones 2 since

many biologically active azabicyclo[3.1.0]hexanes have

no substituent on the nitrogen atom^1aand the direct prep-

aration of 2j was not effective under the stated reaction

conditions (entry 13). The deprotection of the tertiary bu-

tyl group of 2g was conducted under acidic conditions,¹⁰

for example, 60% aqueous perchloric acid in acetonitrile,

p-toluenesulfonic acid in chloroform, and concentrated

hydrochloric acid in acetone, however, the reaction be-

came complex and none of the desired deprotected com-

pound 2j was detected. The hydrogenolysis of the benzyl

group of 2a was also examined in the presence of palladi-

um-activated carbon and formic acid as a hydrogen do-

nor.¹¹Unfortunately, the reduction of the highly strained

cyclopropane moiety preferentially occurred instead of

the benzyl group, giving the ring-opened pyrrolidinone 6a

(Scheme 2). A similar reduction under a hydrogen atmo-

sphere (50 atm) also gave a similar result. As the reductive

deprotection failed, we next attempted the oxidative

deprotection of the p-methoxybenzyl (PMB) group.¹²The

PMB group of 2h was successfully removed by oxidation

with cerium(IV) ammonium nitrate (CAN) to give the

deprotected azabicyclohexanone 2j in a 67% yield togeth-

er with the oxidation product 2h¢ (22%),^12awhich could be

converted into the desired 2j by the methanolysis in the

presence of potassium carbonate (Scheme 2).^12b

13

observed coupling constant.^7cIn the C NMR spectrum,

two quaternary carbons and a tertiary carbon appeared at

d = 52.5 (C-1), 50.6 (C-6), and 26.7 (C-5), respectively,

assigned to the characteristic peaks of the cyclopropane

ring. All the peaks in the NMR spectrum were also corre-

lated by the H-H COSY and H-C COSY. In addition, the

keto and amide carbonyls appeared at 1697 and 1682

cm^–1in the IR spectrum and d = 200.4 and 168.8 in the ¹³C

NMR spectrum. These spectroscopic data are consistent

with the structure of the 1-acetyl-3-benzyl-6,6-diphenyl-

3-azabicyclo[3.1.0]hexan-2-one (2a), and the elemental

analysis as well as the high-resolution mass spectrum also

agreed with the structure.

A similar reaction of other N-propenyl-3-oxobutanamides

1b–h also gave successful results (entries 5–11). The re-

action of 1i and 1j was not effective because of the steric

hindrance of the N-protecting phenyl group in 1i and the

sensitivity of the secondary amide group in 1j to the oxi-

dant (entries 12 and 13). The bis(4-methylphenyl)-substi-

tuted butanamide 1k predominantly produced the pyr-

rolidinones 3k and 4k (entry 14). The electron-donating

ability of the 4-methylphenyl group probably resulted in

the oxidation of the tertiary radical prior to the cyclization.

The alkenes 1l–n bearing the electron-withdrawing group

on the R¹and R²aryl groups also afforded the azabicy-

clo[3.1.0]hexanones 2l–n in low yields. However, the

yield was improved by the addition of copper(II) acetate

as a co-oxidant during the reaction (entries 15–17).^6a,7The

azabicyclo[3.1.0]hexanone 2o was obtained in a poor

yield as a 17:6 diastereoisomeric mixture along with tet-

rahydrofuro[3,4-c]pyrrol-4-one 5 (entry 18). The oxida-

tion of butanamide 1p having no substituent at the olefin

terminal produced the corresponding 4-methylpyrrolidi-

none 6p (entry 19).^7g,hUse the manganese(III)–copper(II)

system at room temperature led to the formation of the

corresponding azabicyclo[3.1.0]hexanone 2p having no

substituent at the C-6 position, but in a low yield (entry

20). The oxidation of the ester 1q was significantly affect-

ed by the solvent. When the reaction was carried out in

acetic acid, the corresponding azabicyclo[3.1.0]hexanone

was not produced, but the pyrrolidinones 3q and 7q were

obtained (entry 21). However, a similar reaction in eth-

anol afforded the desired azabicyclo[3.1.0]hexanone 2q

(entry 22). The reaction of 1r in ethanol became messy

and an intractable mixture was obtained. However, the

isopropenylpyrrolidinone 8 was isolated by the manga-

nese(III)–copper(II)-mediated oxidation in acetic acid

(Scheme 1).⁶

O

10% Pd/C, HCOOH

Me

Ph

2a

Bn

N

MeOH, argon

r.t., 15 h

Ph

6a quant

O

Me

Ph

O

CAN

2h

2j

67%

+

N

Ph

MeCN–H₂O

(6% rec.) 0 °C, 30 min

2h'

22%

MeO

K₂CO₃, 18-crown-6

MeOH, r.t., 6 h

96%

Scheme 2

Although the synthesis of 3-oxabicyclo[3.1.0]hexanones

using the manganese(III)–copper(II)-based oxidation of

Synthesis 2009, No. 3, 409–423 © Thieme Stuttgart · New York

412

K. Asahi, H. Nishino

PAPER

propenyl 3-oxobutanoates is known,^7a,b,d–fwe also report- et al. reported the reaction of 9e,^7awe repeated the same

ed the manganese(III) oxidation of 3,3-diphenylprop-2- reaction of 9e from the standpoint of the reaction mecha-

enyl 3-oxobutanoate (9a) in acetic acid, mainly affording nism. Unfortunately, we could not reproduce the yield of

a decomposition product together with a trace amount of 10e (entry 10) even though a previous study achieved a

3,7-dioxabicyclo[3.3.0]oct-8-en-2-one.¹³Since we have 57% yield of 10e. Under our reaction conditions, the reac-

established the convenient route to the azabicy- tion of 9e barely afforded 10e in 28% yield (entry 12).

clo[3.1.0]hexanones 2 from N-propenyl-3-oxobutanamides

A similar reaction of the S-propenyl 3-oxobutanethioates

1 (vide supra), we reconsidered the reaction of 3-oxobu-

11a–d in ethanol gave the desired 3-thiabicy-

tanoate 9a as an analogue of 1. The reaction of 9a was car-

clo[3.1.0]hexan-2-ones 12a–d in moderate yields except

ried out under the conditions established in the reaction of

for the reaction of 11b (Table 3, entries 1–4). The butane-

thioate 11b having an electron-rich aryl group is probably

liable and easily oxidized under the stated conditions, pro-

ducing dihydrothieno[3,4-c]furanone 13b, tetrahydro-

thieno[3,4-c]furanone 14b, and dihydrothiophenone 16b

(entry 2). For comparison with the reaction in ethanol, the

reaction of 11a–d was conducted in acetic acid. As a re-

sult, dihydrothieno[3,4-c]furanones 13a–d and dihy-

1 to successfully give the desired 3-oxabicyclo[3.1.0]hex-

an-2-one 10a (48%) albeit with the recovery of 9a (24%)

(Table 2, entry 1). In order to improve the yield, we exam-

ined several reaction conditions, for example, the reaction

in acetic acid, isopropyl alcohol, or benzene; using man-

ganese(III) picolinate in dimethylformamide instead of

manganese(III) acetate; or adding potassium acetate as a

buffer.⁶Although all attempts failed, using 6 equivalents

drothiophenones 15a–d were mainly obtained (entries 5–

8). The structure of the products 12–16 was well charac-

terized by spectroscopic methods and elemental analyses

of manganese(III) acetate led to the complete consump-

tion of 9a and a maximum yield of 10a (64%) (entry 4).

Other 3-oxobutanoates 9b–d also displayed a similar be-

except for 14b, 14c, 15a, 15b, and 15d, which was de-

havior to produce the corresponding 3-oxabicy-

duced by comparison of the spectroscopic data with those

clo[3.1.0]hexanones 10b–d (entries 6–8). Since Bertrand

of 14a,d and 15c.

Table 2 Oxidation of Propenyl 3-Oxobutanoates 9a–e with Manganese(III) Acetate Dihydrate^a

O

R

O

Mn(OAc)₃

EtOH

Me

R

O

Me

O

R

9a–e

10a–e

Entry

1

9

R

Molar ratio^b

Time (min)

Recovery (%)^c

Yield (%)^d

9a

9b

9c

9d

9e

Ph

1:3.5

1:4.7

1:6

15

30

45

50

45

70

30

15

25

24

27

14

0

48

44

54

64

53

51

62

64

8

2^e

3

4

5

1:7

0

6

4-MeC₆H₄

1:8

0

7

4-ClC₆H₄

1:6

0

8

4-FC₆H₄

1:6

0

9^f

H

1:4

0

10^g

11

12^h

1:4

5

18

9

1:3.5

1:3

19

40

28

^aThe oxidation of 9 (0.5 mmol) with Mn(OAc)₃·2H₂O was carried out in EtOH (20 mL) at reflux temperature. Before the reaction, the mixture

was degassed under reduced pressure for 30 min using an ultrasonicator followed by argon displacement.

^bOxobutanoate 9/Mn(OAc)₃·2H₂O.

^cRecovery of 9.

^dIsolated yield based on the amount of 9 used.

^eCu(OAc)₂(0.60 mmol) as a co-oxidant was also added.

^fThe oxidation of 9e (1 mmol) was carried out in AcOH (20 mL) at 75 °C.

^gThe oxidation of 9e (4 mmol) was conducted in AcOH (10 mL) at 75 °C in the presence of Cu(OAc)₂(4 mmol) and KOAc (16 mmol) in air.

^hCu(OAc)₂(1.5 mmol) and KOAc (2.5 mmol) were added as buffers.

Synthesis 2009, No. 3, 409–423 © Thieme Stuttgart · New York

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Synthesis of Bicyclo[3.1.0]hexan-2-ones Using Mn(III) Oxidation

413

Table 3 Oxidation of S-Propenyl 3-Oxobutanethioates 11a–d with Manganese(III) Acetate Dihydrate^a

O

Me

R¹

O

Me

O

H

R¹

O

OEt

Me

R¹

Mn(OAc)₃

Me

R²

R¹

S

O

S

R¹

S

Me

S

R¹

13a–d

11a–d

12a–d

R¹

14a–d

15a–d: R²= OAc

16b: R²= OEt

Entry

11

R¹

Molar ratio^b

Solvent

Time (min) Yield (%)^c

12

13

8

14

16

23

16

17

–

15,16

1

2

3

4

5

6

7

8

11a

11b

11c

11d

11a

11b

11c

11d

Ph

1:4.5

1:6.5

1:5.5

1:3.5

1:4.5

EtOH

AcOH

10

30

15

20

58

trace

51

37

–

4-MeC₆H₄

4-ClC₆H₄

4-FC₆H₄

Ph

21

8

14 (16b)

–

12

33

28

35

21

–

0.5

30 (15a)

19 (15b)

22 (15c)

30 (15d)

4-MeC₆H₄

4-ClC₆H₄

4-FC₆H₄

1

–

1.5

6

–

10

4

–

^aThe oxidation of 11 (0.5 mmol) with Mn(OAc)₃·2H₂O was carried out in EtOH (30 mL) or AcOH (20 mL) at reflux temperature. Before start-

ing the reaction, the mixture was degassed under reduced pressure for 30 min using an ultrasonicator followed by argon displacement.

^b3-Oxobutanethioate 11/ Mn(OAc)₃·2H₂O.

^cIsolated yield based on the amount of 11 used.

The plausible pathway for the formation of the bicy- When the reaction was carried out in the presence of cop-

clo[3.1.0]hexan-2-ones 2, 10, and 12 could be explained per(II) acetate as a co-oxidant, the yield of the bicy-

by the previously proposed mechanism (Scheme 3).^6a,d,7bclo[3.1.0]hexanones was improved.¹⁴This also supported

The formation of the manganese(III)–enolate complex A the path B rather than the path A. Bertrand et al. also sug-

is the key step in the oxidation. The complex A undergoes gested a similar reaction pathway using the manga-

the oxidative 5-exo-trig cyclization to give the exomethyl nese(III)–copper(II) combination.^7bMoreover, Yang et al.

radicals B followed again by enolization with manga- demonstrated the bicyclo[3.1.0]hexan-2-one II via the

nese(III) at the 1,3-dicarbonyl moiety, affording radicals ionic process using the isopropyl bromide I, which was

C. It was suggested that two possible and reasonable synthetically equivalent of the tertiary carbocation D albe-

routes to the final bicyclo[3.1.0]hexan-2-ones 2, 10, and it under basic conditions (Scheme 4).^3d

12 from the radicals C would be present. When the in-

tramolecular cyclization accompanied by the one-electron

transfer oxidation would occur, the final products 2, 10,

When the reaction was carried out in acetic acid, the pyr-

rolidinones 3, dihydrothienofuranones 13, and dihy-

drothiophenones 15 were preferentially formed rather

and 12 would be produced (path A), while the tertiary car-

than the corresponding bicyclohexanones 2 and 12. It is

bon radicals C (R = aryl group) would undergo the man-

suggested that the tertiary carbon radicals C should be

ganese(III) oxidation to produce the same products during

easily oxidized via the electron-transfer oxidation process

the ionic cyclization process (path B). Since the tertiary

by metal oxidants since the reflux temperature of acetic

carbon radicals C (R = aryl group), except for the primary

and secondary radicals produced from 1o, 1p, and 9e, are

easily oxidized by manganese(III), the path B should be

favored. However, the result of the reaction using prop-2-

enyl 3-oxobutanoate (9e) supported path A since the oxi-

dation actually afforded the corresponding bicy-

clo[3.1.0]hexanone 10e even in the absence of copper(II)

acetate (Table 2, entries 9 and 11). In general, it is known

that the terminal methyl radicals B (R = H and X = O)

generated by the oxidative cyclization of the enolate com-

plex between 9e and manganese(III) cannot be oxidized to

form the corresponding primary cation D without the as-

sistance of copper(II) acetate.^6aTherefore, the ionic cy-

clization in path B must be ruled out in the case of 9e.

acid is higher than that of ethanol.^6dThe 3,4-trans stereo-

chemistry of the pyrrolidinones 3 and dihydrothiophe-

nones 15 is not essential because the thermodynamically

more stable 3,4-trans configuration is favored via the

keto–enol tautomerism (lower panel in Scheme 3). Actu-

ally, the NOESY experiment and the coupling constant

between H-3 and H-4 in the ¹H NMR experiment support-

ed the trans configuration. In addition, the 3,4-trans-pyr-

rolidinone 3a is ca. 17 kJ/mol more stable than 3,4-cis

based on the PM3 calculation.¹⁵Furthermore, the pyrroli-

dinone 6p was recently determined to have the 3,4-trans

configuration.¹⁶

Synthesis 2009, No. 3, 409–423 © Thieme Stuttgart · New York

414

K. Asahi, H. Nishino

PAPER

III

was achieved, the yield of 2o and 2p bearing a mono and

no substituent at the C-6 position, respectively, was poor.

Furthermore, the N-3-methylbut-2-enyl-3-oxobutan-

amide 1r did not afford any bicyclo[3.1.0]hexan-2-ones.

For the plausible pathway for the formation of the bicyc-

lo[3.1.0]hexan-2-ones 2, 10, and 12, the oxidative radical

cyclopropanation in the absence of copper(II) acetate as a

co-oxidant is proposed.

Mn

O

Mn(III)

1, 9, 11

Me

– Mn(II)

EtOH

reflux

X

Me

enolization

5-exo-trig

cyclization

R

B

A

Mn(III) enolization

The NMR spectra were recorded using a JNM AL300 FT NMR

spectrometer at 300 MHz for ¹H and at 75 MHz for ¹³C, with TMS

as the internal standard. The chemical shifts are reported in d values

(ppm). The IR spectra of neat samples were measured by the ATR

method using a Shimadzu 8400 FT IR spectrophotometer and MIR-

acle A, and expressed in cm^–1. The EI MS spectra were recorded on

a Shimadzu QP-5050A GC–MS instrument with an ionizing volt-

age of 70 eV. The high-resolution mass spectra were measured at

the Institute for Materials Chemistry and Engineering, Kyushu Uni-

versity, Fukuoka, Japan. The elemental analyses were performed at

the Instrumental Analysis Center, Kumamoto University,

Kumamoto, Japan. Mn(OAc)₂·4H₂O was purchased from Wako

Pure Chemical Ind., Ltd. Mn(OAc)₃·2H₂O was prepared according

to the method described in the literature.^4,5N-(3,3-Diarylprop-2-

enyl)-3-oxobutanamides 1a–g and 1i–n were prepared by the reac-

tion of the diketene with the corresponding 3,3-diarylprop-2-eny-

lamines obtained by the reaction of the 1,1-diaryl-3-bromoprop-1-

enes with amines.^17,18The 3-oxobutanamides 1o,p,r were also pre-

pared by a similar method. N-(4-Methoxybenzyl)-N-(3,3-diphenyl-

prop-2-enyl)-3-oxobutanamide (1h) was prepared by the reaction of

4-methoxybenzaldehyde with 3,3-diphenylprop-2-en-1-amine fol-

lowed by reduction with NaBH₄in absolute MeOH.¹⁹The 3-oxo-

butanamides 1o,p were synthesized by the reaction of the diketene

with N-benzyl-(3-phenylprop-2-enyl)amine and allylbenzyl-

amine,²⁰respectively. Ethyl N-benzyl-N-(3,3-diphenylprop-2-

enyl)malonate (1q) was prepared by the condensation of N-benzyl-

3,3-diphenylprop-2-enylamine with ethyl hydrogen malonate. The

propenyl 3-oxobutanoates 9a–d were prepared by the reaction of

the diketene with the corresponding propenols which were obtained

by the reduction of the 3,3-diarylpropenoates.¹⁸3-Oxobutanoate 9e

was prepared according to the literature.²¹The S-propenyl 3-oxo-

butanethioates 11a–d were prepared by the reaction of the diketene

with the corresponding propenethiols, which were obtained by the

reduction of the 3,3-diarylpropenoates¹⁸followed by bromination

with PBr₃, thioestrification with KSAc,²²and further reduction with

LiAlH₄.

III

Mn

H

O

Mn(III)

path B

X

Me

R = aryl group

electron-transfer

oxidation

R

C

R

D

path A

ionic

cyclization

R = H

radical

cyclization

– Mn(II)

AcOH

O

X

Me

R

3, 13, 15

R

2, 10, 12

OH

O

X

O

3

4

Me

OAc

R

X

OAc

R

3, 13, 15

Scheme 3

In conclusion, we have developed the convenient synthe-

sis for the 3-aza- 2, 3-oxa- 10, and 3-thiabicy-

clo[3.1.0]hexan-2-ones 12 using the oxidation of simple

N-propenyl-3-oxobutanamides 1, propenyl 3-oxobu-

tanoates 9, and S-propenyl 3-oxobutanethioates 11 with

manganese(III) acetate in ethanol. The use of ethanol as a

solvent promoted the production of the desired bicy-

clo[3.1.0]hexan-2-ones. Although the synthesis of the

6,6-diaryl-substituted 3-azabicyclo[3.1.0]hexan-2-ones 2

Oxidation of N-Propenyl-3-oxobutanamides 1, Propenyl 3-Oxo-

butanoates 9, and S-Propenyl 3-Oxobutanethioates 11; General

Procedure

A 1,3-dicarbonyl compound 1, 9, or 11 (0.5 mmol) and a solvent (20

mL) were placed in a 50 mL flask. Before starting the reaction, the

mixture was degassed under reduced pressure for 30 min using an

ultrasonicator and then filled with argon. Mn(OAc)₃·2H₂O was

quickly added and then the mixture was heated under reflux until

the brown color of Mn(III) had disappeared. The molar ratios and

the reaction times are shown in Tables 1– 3. When EtOH was used

as the solvent, the solvent was removed in vacuo, and the residue

was triturated with H₂O followed by extraction with CHCl₃(3 × 10

mL ). When AcOH was used, H₂O (80 mL) was added to the result-

ing solution, and the aqueous solution was extracted with CHCl₃(3

× 5 mL). The combined organic extracts were dried (MgSO₄) and

then concentrated to dryness. The products were separated by a sil-

ica gel TLC (Wakogel B-10) eluting with CHCl₃. The products

were further purified by recrystallization from appropriate solvents.

O

Me

NaH (1.2 equiv)

Me

Br

t-Bu

N

t-Bu

N

THF, 0 °C, 1 h

80%

Me

I

II

Scheme 4

Synthesis 2009, No. 3, 409–423 © Thieme Stuttgart · New York

PAPER

Synthesis of Bicyclo[3.1.0]hexan-2-ones Using Mn(III) Oxidation

415

1-Acetyl-3-benzyl-6,6-diphenyl-3-azabicyclo[3.1.0]hexan-2-one

(2a)

¹³C NMR (CDCl₃): d = 200.6, 168.6 (2 C, C=O), 138.6, 136.8 (2

C_arom), 129.0, 128.9, 128.5, 128.4, 127.5, 127.3 (10 CH_arom), 52.6,

R_f= 0.42 (CHCl₃–MeOH, 98:2); colorless prisms (Et₂O–hexane);

mp 132 °C.

50.0 (2 C, C-1, C-6), 44.6, 44.0 (2 C, C-4, NCH₂CH₂CH₃), 30.4

(COCH₃), 26.5 (C-5), 19.4 (NCH₂CH₂CH₃), 11.1 (NCH₂CH₂CH₃).

IR (KBr): 1697, 1682 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.41–7.08 (13 H_arom, m), 6.62–6.60 (2 H_arom

Anal. Calcd for C₂₂H₂₃NO₂: C, 79.25; H, 6.95; N, 4.20. Found: C,

79.13; H, 7.06; N, 4.24.

,

m), 4.03 (1 H, d, J = 14.7 Hz, PhCH₂), 3.80 (1 H, d, J = 14.7 Hz,

PhCH₂), 3.43 (1 H, dd, J = 11.0, 6.4 Hz, H-4), 3.33 (1 H, br d,

J = 6.4 Hz, H-5), 2.99 (1 H, br d, J = 11.0 Hz, H-4), 2.65 (3 H, s,

COCH₃).

¹³C NMR (CDCl₃): d = 200.4, 168.8 (2 C, C=O), 138.6, 136.7, 135.2

(3 C_arom), 129.0, 128.9, 128.44, 128.42, 128.3, 127.9, 127.5, 127.3,

127.2 (15 CH_arom), 52.5, 50.6 (2 C, C-1, C-6), 46.4 (PhCH₂), 44.2

(C-4), 30.3 (COCH₃), 26.7 (C-5).

1-Acetyl-3-isopropyl-6,6-diphenyl-3-azabicyclo[3.1.0]hexan-2-

one (2e)

R_f= 0.22 (CHCl₃); colorless needles (Et₂O–hexane); mp 165–

166 °C.

IR (KBr): 1697, 1676 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.42–7.11 (10 H_arom, m), 3.89 [1 H, hept,

J = 6.8 Hz, NCH(CH₃)₂], 3.52 (1 H, dd, J = 11.0, 6.4 Hz, H-4), 3.33

(1 H, br d, J = 6.4 Hz, H-5), 3.11 (1 H, br d, J = 11.0 Hz, H-4), 2.62

(3 H, s, COCH₃), 0.93 [6 H, d, J = 6.8 Hz, NCH(CH₃)₂].

FAB HRMS (acetone–NBA): m/z calcd for C₂₆H₂₄NO₂: 382.1807

(M + 1); found: 382.1805.

¹³C NMR (CDCl₃): d = 200.7, 167.8 (2 C, C=O), 138.7, 136.8 (2

Anal. Calcd for C₂₆H₂₃NO₂: C, 81.86; H, 6.08; N, 3.67. Found: C,

81.79; H, 6.08; N, 3.64.

C_arom), 129.1, 128.9, 128.5, 128.4, 127.5, 127.3 (10 CH_arom), 52.9,

49.9 (2 C, C-1, C-6), 42.1 [NCH(CH₃)₂], 39.3 (C-4), 30.4 (COCH₃),

26.1 (C-5), 19.3, 18.0 [2 C, NCH(CH₃)₂].

1-Acetyl-3-methyl-6,6-diphenyl-3-azabicyclo[3.1.0]hexan-2-one

(2b)

Anal. Calcd for C₂₂H₂₃NO₂: C, 79.25; H, 6.95; N, 4.20. Found: C,

79.50; H, 7.07; N, 4.26.

R_f= 0.16 (CHCl₃); colorless prisms (Et₂O–hexane); mp 184–

186 °C.

1-Acetyl-3-butyl-6,6-diphenyl-3-azabicyclo[3.1.0]hexan-2-one

(2f)

R_f= 0.31 (CHCl₃–MeOH, 98:2); colorless prisms (Et₂O–hexane);

mp 120.0–120.5 °C.

IR (KBr): 1682 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.42–7.09 (10 H_arom, m), 3.60 (1 H, dd,

J = 11.0, 6.2 Hz, H-4), 3.32 (1 H, br d, J = 6.2 Hz, H-5), 3.00 (1 H,

br d, J = 11.0 Hz, H-4), 2.60 (3 H, s, COCH₃), 2.19 (3 H, s, NCH₃).

IR (KBr): 1697, 1680 cm^–1(C=O).

¹³C NMR (CDCl₃): d = 200.4, 168.9 (2 C, C=O), 138.4, 136.7 (2

¹H NMR (CDCl₃): d = 7.43–7.13 (10 H_arom, m), 3.56 (1 H, dd,

J = 11.0, 6.2 Hz, H-4), 3.34 (1 H, br d, J = 6.2 Hz, H-5), 3.15 (1 H,

br d, J = 11.0 Hz, H-4), 2.85–2.75 (1 H, m, NCH₂CH₂CH₂CH₃),

2.69–2.64 (1 H, m, NCH₂CH₂CH₂CH₃), 2.61 (3 H, s, COCH₃),

0.93–0.57 (7 H, m, NCH₂CH₂CH₂CH₃).

C_arom), 128.8, 128.7, 128.47, 128.45, 127.4, 127.3 (10 CH_arom), 52.2,

50.1 (2 C, C-1, C-6), 46.6 (C-4), 30.3 (COCH₃), 28.7 (NCH₃), 26.3

(C-5).

Anal. Calcd for C₂₀H₁₉NO₂: C, 78.66; H, 6.27; N, 4.59. Found: C,

78.70; H, 6.39; N, 4.57.

¹³C NMR (CDCl₃): d = 200.5, 168.4 (2 C, C=O), 138.6, 136.7 (2

C_arom), 129.0, 128.8, 128.4, 128.3, 127.4, 127.2 (10 CH_arom), 52.6,

1-Acetyl-3-ethyl-6,6-diphenyl-3-azabicyclo[3.1.0]hexan-2-one

(2c)

R_f= 0.18 (CHCl₃); colorless prisms (Et₂O–hexane); mp 153–

156 °C.

49.9 (2 C, C-1, C-6), 44.5 (C-4), 41.9 (NCH₂CH₂CH₂CH₃), 30.2

(COCH₃), 28.2 (NCH₂CH₂CH₂CH₃), 26.3 (C-5), 19.7

(NCH₂CH₂CH₂CH₃), 13.5 (NCH₂CH₂CH₂CH₃).

Anal. Calcd for C₂₃H₂₅NO₂: C, 79.51; H, 7.25; N, 4.03. Found: C,

79.69; H, 6.96; N, 4.04.

IR (KBr): 1690, 1682 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.44–7.09 (10 H_arom, m), 3.51 (1 H, dd,

J = 11.0, 6.2 Hz, H-4), 3.33 (1 H, br d, J = 6.2 Hz, H-5), 3.15 (1 H,

br d, J = 11.0 Hz, H-4), 3.06–2.94 (1 H, m, NCH₂CH₃), 2.67–2.58

(1 H, m, NCH₂CH₃), 2.61 (3 H, s, COCH₃), 0.26 (3 H, t, J = 7.2 Hz,

NCH₂CH₃).

1-Acetyl-3-tert-butyl-6,6-diphenyl-3-azabicyclo[3.1.0]hexan-2-

one (2g)

R_f= 0.32 (CHCl₃); colorless prisms (Et₂O–hexane); mp 183–

184 °C.

¹³C NMR (CDCl₃): d = 200.5, 168.2 (2 C, C=O), 138.6, 136.7 (2

IR (KBr): 1699, 1659 cm^–1(C=O).

C_arom), 129.0, 128.8, 128.5, 128.4, 127.5, 127.3 (10 CH_arom), 52.5,

¹H NMR (CDCl₃): d = 7.47–7.13 (10 H_arom, m), 3.65 (1 H, dd,

J = 11.0, 6.2 Hz, H-4), 3.31 (1 H, br d, J = 11.0 Hz, H-4), 3.24 (1 H,

br d, J = 6.2 Hz, H-5), 2.58 (3 H, s, COCH₃), 0.90 [9 H, s,

NC(CH₃)₃].

50.0 (2 C, C-1, C-6), 43.7 (C-4), 36.4 (NCH₂CH₃), 30.3 (COCH₃),

26.2 (C-5), 10.9 (NCH₂CH₃).

Anal. Calcd for C₂₁H₂₁NO₂: C, 78.97; H, 6.63; N, 4.39. Found: C,

79.15; H, 6.44; N, 4.31.

¹³C NMR (CDCl₃): d = 201.1, 168.4 (2 C, C=O), 138.8, 136.8 (2

C_arom), 129.4, 128.9, 128.5, 128.4, 127.5, 127.2 (10 CH_arom), 53.84,

1-Acetyl-6,6-diphenyl-3-propyl-3-azabicyclo[3.1.0]hexan-2-one

(2d)

R_f= 0.27 (CHCl₃); colorless prisms (Et₂O–hexane); mp 136–

53.75 (2 C, C-1, C-6), 48.8 [NC(CH₃)₃)], 43.0 (C-4), 30.4 (COCH₃),

26.9 [3 C, NC(CH₃)₃], 25.4 (C-5).

137 °C.

Anal. Calcd for C₂₃H₂₅NO₂: C, 79.51; H, 7.25; N, 4.03. Found: C,

79.45; H, 7.41; N, 3.96.

IR (KBr): 1697, 1678 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.43–7.10 (10 H_arom, m), 3.56 (1 H, dd,

J = 11.0, 6.2 Hz, H-4), 3.34 (1 H, br d, J = 6.2 Hz, H-5), 3.14 (1 H,

br d, J = 11.0 Hz, H-4), 2.77–2.56 (2 H, m, NCH₂CH₂CH₃), 2.62 (3

H, s, COCH₃), 0.84–0.62 (2 H, m, NCH₂CH₂CH₃), 0.55 (3 H, t,

J = 7.2 Hz, NCH₂CH₂CH₃).

1-Acetyl-3-(4-methoxybenzyl)-6,6-diphenyl-3-azabicy-

clo[3.1.0]hexan-2-one (2h)

R_f= 0.18 (CHCl₃); colorless needles (Et₂O–hexane); mp 158.0 °C.

IR (KBr): 1697, 1678 cm^–1(C=O).

Synthesis 2009, No. 3, 409–423 © Thieme Stuttgart · New York

416

K. Asahi, H. Nishino

PAPER

¹H NMR (CDCl₃): d = 7.40–7.09 (10 H_arom, m), 6.64 (2 H_arom, d,

J = 8.4 Hz), 6.54 (2 H_arom, d, J = 8.4 Hz), 3.95 (1 H, d, J = 14.7 Hz,

4-MeOC₆H₄CH₂), 3.75 (1 H, d, J = 14.7 Hz, 4-MeOC₆H₄CH₂), 3.72

(3 H, s, OCH₃), 3.41 (1 H, dd, J = 11.0, 6.2 Hz, H-4), 3.31 (1 H, br

d, J = 6.2 Hz, H-5), 2.96 (1 H, br d, J = 11.0 Hz, H-4), 2.64 (3 H, s,

COCH₃).

¹³C NMR (CDCl₃): d = 200.3, 168.6 (2 C, C=O), 158.6, 138.6, 136.7

(3 C_arom), 129.1, 128.6, 128.8, 128.4, 128.3, 127.4 (11 CH_arom),

127.22 (C_arom), 127.16 (CH_arom), 113.7 (2 CH_arom), 55.0 (OCH₃),

52.5, 50.4 (2 C, C-1, C-6), 45.7 (4-MeOC₆H₄CH₂), 44.0 (C-4), 30.2

(COCH₃), 26.6 (C-5).

1-Acetyl-3-benzyl-6,6-bis(4-chlorophenyl)-3-azabicy-

clo[3.1.0]hexan-2-one (2l)

R_f= 0.42 (CHCl₃–MeOH, 98:2); colorless prisms (Et₂O–hexane);

mp 165–166 °C.

IR (KBr): 1693 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.27–7.07 (11 H_arom, m), 6.66–6.63 (2 H_arom

,

m), 4.13 (1 H, d, J = 14.5 Hz, PhCH₂), 3.86 (1 H, d, J = 14.5 Hz,

PhCH₂), 3.48 (1 H, dd, J = 11.0, 6.4 Hz, H-4), 3.28 (1 H, br d,

J = 6.4 Hz, H-5), 2.99 (1 H, br d, J = 11.0 Hz, H-4), 2.64 (3 H, s,

COCH₃).

¹³C NMR (CDCl₃): d = 199.8, 168.1 (2 C, C=O), 136.7, 134.8,

134.7, 133.7, 133.3 (5 C_arom), 130.1, 129.6, 129.3, 128.7, 128.4,

128.0, 127.4 (13 CH_arom), 52.2, 49.1 (2 C, C-1, C-6), 46.5 (PhCH₂),

43.9 (C-4), 30.3 (COCH₃), 27.0 (C-5).

Anal. Calcd for C₂₇H₂₅NO₃: C, 78.81; H, 6.12; N, 3.40. Found: C,

78.61; H, 6.08; N, 3.33.

1-Acetyl-3,6,6-triphenyl-3-azabicyclo[3.1.0]hexan-2-one (2i)

R_f= 0.47 (CHCl₃–MeOH, 98:2); colorless needles (Et₂O–hexane);

mp 141.0 °C.

Anal. Calcd for C₂₆H₂₁Cl₂NO₂: C, 69.34; H, 4.70; N, 3.11. Found:

C, 69.12; H, 4.72; N, 3.16.

IR (KBr): 1695, 1682 cm^–1(C=O).

1-Acetyl-3-benzyl-6,6-bis(4-fluorophenyl)-3-azabicy-

clo[3.1.0]hexan-2-one (2m)

R_f= 0.38 (CHCl₃–MeOH, 98:2); colorless microcrystals (Et₂O–

¹H NMR (CDCl₃): d = 7.51–6.81 (15 H_arom, m), 4.11 (1 H, dd,

J = 11.0, 6.2 Hz, H-4), 3.54 (1 H, br d, J = 11.0 Hz, H-4), 3.48 (1 H,

br d, J = 6.2 Hz, H-5), 2.65 (3 H, s, COCH₃).

hexane); mp 122.0–122.5 °C.

¹³C NMR (CDCl₃): d = 200.1, 168.2 (2 C, C=O), 138.3, 137.7, 136.5

(3 C_arom), 129.1, 128.9, 128.7, 128.6, 128.5, 127.7, 127.5, 125.7,

121.9 (15 CH_arom), 52.9, 50.4 (2 C, C-1, C-6), 46.7 (C-4), 30.4

(COCH₃), 26.0 (C-5).

IR (KBr): 1701, 1684 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.33–6.68 (13 H_arom, m), 4.01 (1 H, d,

J = 14.6 Hz, PhCH₂), 3.93 (1 H, d, J = 14.6 Hz, PhCH₂), 3.49 (1 H,

dd, J = 11.2, 6.4 Hz, H-4), 3.29 (1 H, br d, J = 6.4 Hz, H-5), 2.99 (1

H, br d, J = 11.2 Hz, H-4), 2.64 (3 H, s, COCH₃).

¹³C NMR (CDCl₃): d = 200.1, 168.4 (2 C, C=O), 163.7, 163.3,

160.4, 160.0, 135.0, 134.32, 134.29, 132.4, 132.4 (5 C_arom), 130.5,

130.4, 130.0, 129.9, 128.5, 128.1, 127.4, 116.3, 116.0, 115.7, 115.4

(13 CH_arom), 52.5, 49.0 (2 C, C-1, C-6), 46.6 (PhCH₂), 44.1 (C-4),

30.4 (COCH₃), 27.1 (C-5).

Anal. Calcd for C₂₅H₂₁NO₂: C, 81.72; H, 5.76; N, 3.81. Found: C,

81.90; H, 5.83; N, 3.79.

1-Acetyl-6,6-diphenyl-3-azabicyclo[3.1.0]hexan-2-one (2j)

R_f= 0.36 (CHCl₃–MeOH, 98:2); colorless prisms (Et₂O–hexane);

mp 94–96 °C.

IR (KBr): 3290 (NH), 1697 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.45–7.12 (10 H_arom, m), 5.30 (1 H, br s, NH),

3.58 (1 H, dd, J = 11.0, 6.2 Hz, H-4), 3.44 (1 H, br d, J = 6.2 Hz, H-

5), 3.18 (1 H, br d, J = 11.0 Hz, H-4), 2.55 (3 H, s, COCH₃).

¹³C NMR (CDCl₃): d = 200.2, 172.1 (2 C, C=O), 138.5, 136.9 (2

C_arom), 129.0, 128.9, 128.6, 128.5, 127.5, 127.4 (10 CH_arom), 51.3,

50.0 (2 C, C-1, C-6), 39.5 (C-4), 30.3, 29.6 (2 C, COCH₃, C-5).

Anal. Calcd for C₂₆H₂₁F₂NO₂: C, 74.81; H, 5.07; N, 3.36. Found: C,

74.89; H, 5.15; N, 3.29.

1-Acetyl-3-ethyl-6,6-bis(4-fluorophenyl)-3-azabicy-

clo[3.1.0]hexan-2-one (2n)

R_f= 0.28 (CHCl₃–MeOH, 98:2,); colorless prisms (Et₂O–hexane);

mp 151.0 °C.

IR (KBr): 1697, 1688 cm^–1(C=O).

FAB HRMS (acetone–NBA): m/z calcd for C₁₉H₁₇NO₂: 292.1338

(M + 1); found: 292.1339.

¹H NMR (CDCl₃): d = 7.41–6.88 (8 H_arom, m), 3.59 (1 H, dd,

J = 11.0, 6.2 Hz, H-4), 3.29 (1 H, br d, J = 6.2 Hz, H-5), 3.13 (1 H,

br d, J = 11.0 Hz, H-4), 3.08–2.96 (1 H, m, NCH₂CH₃), 2.77–2.65

(1 H, m, NCH₂CH₃), 2.61 (3 H, s, COCH₃), 0.38 (3 H, t, J = 7.3 Hz,

NCH₂CH₃).

¹³C NMR (CDCl₃): d = 200.2, 168.0 (2 C, C=O), 163.7, 163.3,

160.5, 160.1, 134.3, 134.2, 132.51, 132.47 (4 C_arom), 130.7, 130.6,

130.1, 130.0, 116.1, 115.8, 115.7, 115.4 (8 CH_arom), 52.6, 48.5 (2 C,

C-1, C-6), 43.7 (C-4), 36.6 (NCH₂CH₃), 30.4 (COCH₃), 26.6 (C-5),

11.1 (NCH₂CH₃).

Anal. Calcd for C₁₉H₁₇NO₂·3/8H₂O: C, 76.52; H, 6.00; N, 4.70.

Found: C, 76.71; H, 6.09; N, 4.47.

1-Acetyl-3-benzyl-6,6-bis(4-methylphenyl)-3-azabicy-

clo[3.1.0]hexan-2-one (2k)

R_f= 0.29 (EtOAc–hexane, 2:8); colorless microcrystals (Et₂O–hex-

ane); mp 180–182 °C.

IR (KBr): 1697, 1684 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.27–6.98 (11 H_arom, m), 6.63–6.60 (2 H_arom

,

Anal. Calcd for C₂₁H₁₉F₂NO₂: C, 70.97; H, 5.39; N, 3.94. Found: C,

71.10; H, 5.24; N, 3.96.

m), 3.99 (1 H, d, J = 14.7 Hz, PhCH₂), 3.93 (1 H, d, J = 14.7 Hz,

PhCH₂), 3.43 (1 H, dd, J = 11.0, 6.2 Hz, H-4), 3.30 (1 H, br d,

J = 6.2 Hz, H-5), 3.01 (1 H, br d, J = 11.0 Hz, H-4), 2.65 (3 H, s,

COCH₃), 2.33 (3 H, s, CH₃), 2.21 (3 H, s, CH₃).

1-Acetyl-3-benzyl-6-phenyl-3-azabicyclo[3.1.0]hexan-2-one

(2o)

Stereoisomer 1

R_f= 0.22 (CHCl₃); colorless oil.

¹³C NMR (CDCl₃): d = 200.7, 169.0 (2 C, C=O), 137.1, 136.9,

135.9, 135.4, 134.0 (5 C_arom), 129.7, 129.2, 128.7, 128.3, 128.1,

128.0, 127.2 (13 CH_arom), 52.7, 50.3 (2 C, C-1, C-6), 46.5 (PhCH₂),

44.2 (C-4), 30.4 (COCH₃), 26.8 (C-5), 21.2, 21.0 (2 C, 2 × CH₃).

IR (KBr): 1686 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.36–7.14 (10 H_arom, m), 4.50 (1 H, d,

J = 14.7 Hz, PhCH₂), 4.39 (1 H, d, J = 14.7 Hz, PhCH₂), 3.51 (1 H,

dd, J = 10.3, 5.9 Hz, H-4), 3.27 (1 H, br d, J = 10.3 Hz, H-4), 3.00

(1 H, dd, J = 5.9, 5.5 Hz, H-5), 2.68 (1 H, d, J = 5.5 Hz, H-6), 2.41

(3 H, s, COCH₃).

Anal. Calcd for C₂₈H₂₇NO₂: C, 82.12; H, 6.65; N, 3.42. Found: C,

82.27; H, 6.71; N, 3.44.

Synthesis 2009, No. 3, 409–423 © Thieme Stuttgart · New York

PAPER

Synthesis of Bicyclo[3.1.0]hexan-2-ones Using Mn(III) Oxidation

417

¹³C NMR (CDCl₃): d = 199.6, 170.2 (2 C, C=O), 136.1, 132.6 (2 C_ar-

_om), 128.8, 128.5, 128.3, 128.2, 127.8, 127.7 (10 CH_arom), 48.1 (C-

1), 46.6 (2 C, C-4, PhCH₂), 40.7 (C-6), 30.1 (COCH₃), 22.2 (C-5).

¹³C NMR (CDCl₃): d = 203.2, 168.7, 168.6 (3 C, C=O), 141.4,

140.4, 135.4 (3 C_arom), 128.7, 128.2, 128.1, 128.0, 127.92, 127.88,

127.6, 127.1, 126.9 (15 CH_arom), 87.9 (AcOC), 58.9 (C-4), 47.7 (C-

2), 46.5 (PhCH₂), 39.7 (C-3), 30.1 (COCH₃), 22.1 (OCOCH₃).

FAB HRMS (acetone–NBA): m/z calcd for C₂₀H₂₀NO₂: 306.1494

(M + 1); found: 306.1460.

FAB HRMS (acetone–NBA): m/z calcd for C₂₈H₂₈NO₄: 442.2018

(M + 1); found: 442.2020.

Stereoisomer 2

R_f= 0.18 (CHCl₃); colorless oil.

4-(Acetoxydiphenylmethyl)-3-acetyl-1-methylpyrrolidin-2-one

(3b)

IR (KBr): 1695, 1684 cm^–1(C=O).

R_f= 0.29 (CHCl₃–MeOH, 98:2); colorless oil.

IR (KBr): 1746, 1717, 1690 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.36–7.06 (8 H_arom, m), 6.57–6.55 (2 H_arom

m), 4.03 (1 H, d, J = 14.7 Hz, PhCH₂), 3.96 (1 H, d, J = 14.7 Hz,

PhCH₂), 3.38–3.33 (2 H, m, H-4, H-6), 2.96 (1 H, br d, J = 11.0 Hz,

H-4), 2.74 (3 H, s, COCH₃), 2.72–2.69 (1 H, m, H-5).

¹³C NMR (75 MHz, CDCl₃): d = 203.5, 169.1 (2 C, C=O), 135.4,

132.1 (2 C_arom), 129.3, 128.9, 128.5, 127.8, 127.7, 127.2 (10

CH_arom), 46.3 (PhCH₂), 45.2 (C-1), 43.3 (C-4), 37.6 (C-6), 29.9 (2

C, COCH₃, C-5).

,

¹H NMR (CDCl₃): d = 7.36–7.22 (10 H_arom, m), 4.46 (1 H, ddd,

J = 8.4, 3.3, 2.9 Hz, H-3), 3.78 (1 H, d, J = 3.3 Hz, H-4), 3.63 (1 H,

dd, J = 10.3, 8.4 Hz, H-2), 3.51 (1 H, dd, J = 10.3, 2.9 Hz, H-2),

2.48 (3 H, s, NCH₃), 2.27 (3 H, s, COCH₃), 2.09 (3 H, s, OCOCH₃).

¹³C NMR (CDCl₃): d = 203.0, 168.7, 168.4 (3 C, C=O), 141.5, 140.5

(2 C_arom), 128.2, 128.1, 128.0, 127.9, 127.0, 126.8 (10 CH_arom), 87.8

(AcOC), 59.0 (C-4), 50.1 (C-2), 40.0 (C-3), 29.9, 29.2 (2 C, Ac,

NCH₃), 22.1 (OCOCH₃).

FAB HRMS (acetone–NBA): m/z calcd for C₂₀H₂₀NO₂: 306.1494

(M + 1); found: 306.1425.

FAB HRMS (acetone–NBA): m/z calcd for C₂₂H₂₄NO₄: 366.1705

1-Acetyl-3-benzyl-3-azabicyclo[3.1.0]hexan-2-one (2p)

(M + 1); found: 366.1681.

R_f= 0.13 (CHCl₃); colorless oil.

4-[Acetoxybis(4-methylphenyl)methyl]-3-acetyl-1-benzylpyr-

rolidin-2-one (3k)

R_f= 0.40 (CHCl₃—MeOH, 98:2); colorless oil.

IR (KBr): 1744, 1717, 1688 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.27–6.84 (13 H_arom, m,), 4.43 (1 H, ddd,

J = 8.8, 3.7, 3.7 Hz, H-3), 4.34 (1 H, d, J = 14.7 Hz, PhCH₂), 3.89

(1 H, d, J = 3.7 Hz, H-4), 3.88 (1 H, d, J = 14.7 Hz, PhCH₂), 3.47 (1

H, dd, J = 10.6, 8.8 Hz, H-2), 3.38 (1 H, dd, J = 10.6, 3.7 Hz, H-2),

2.31 (9 H, br s, COCH₃, 2 × CH₃), 2.02 (3 H, s, OCOCH₃).

¹³C NMR (CDCl₃): d = 203.4, 168.8, 168.7 (3 C, C=O), 138.4,

137.62, 137.60, 137.4, 135.4 (5 C_arom), 128.82, 128.77, 128.6,

127.9, 127.5, 127.1, 126.9 (13 CH_arom), 87.9 (AcOC), 59.0 (C-4),

47.7 (C-2), 46.5 (PhCH₂), 39.6 (C-3), 30.1 (COCH₃), 22.1

(OCOCH₃), 21.0 (2 C, 2 × CH₃).

IR (KBr): 1693 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.37–7.18 (5 H_arom, m), 4.48 (1 H, d, J = 14.7

Hz, PhCH₂), 4.31 (1 H, d, J = 14.7 Hz, PhCH₂), 3.42 (1 H, dd,

J = 10.3, 5.9 Hz, H-4), 3.12 (1 H, br d, J = 10.3 Hz, H-4), 2.62 (3 H,

s, COCH₃), 2.38 (1 H, ddd, J = 7.7, 5.9, 5.1 Hz, H-5), 1.92 (1 H, dd,

J = 7.7, 4.0 Hz, H-6), 1.09 (1 H, dd, J = 5.1, 4.0 Hz, H-6).

¹³C NMR (CDCl₃): d = 203.4, 171.0 (2 C, C=O), 136.2 (C_arom),

128.8, 128.1, 127.8 (5 CH_arom), 46.5, 46.4 (2 C, C-4, PhCH₂), 39.0

(C-1), 29.7 (COCH₃), 25.0 (C-5), 24.2 (C-6).

FAB HRMS (acetone–NBA): m/z calcd for C₁₄H₁₆NO₂: 230.1181

(M + 1); found: 230.1157.

Ethyl 3-Benzyl-2-oxo-6,6-diphenyl-3-azabicyclo[3.1.0]hexane-

1-carboxylate (2q)

R_f= 0.44 (CHCl₃–MeOH, 98:2); colorless prisms (CHCl₃–EtOAc–

FAB MS: m/z (%) = 410 (100, M – 59), 367 (16), 195 (37), 91 (42).

hexane); mp 148.0 °C.

IR (KBr): 1728, 1678 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.45–7.08 (13 H_arom, m), 6.64–6.61 (2 H_arom

m), 4.05 (1 H, d, J = 14.7 Hz, PhCH₂), 4.01–3.91 (2 H, m,

OCH₂CH₃), 3.81 (1 H, d, J = 14.7 Hz, PhCH₂), 3.51 (1 H, dd,

J = 11.0, 6.2 Hz, H-4), 3.23 (1 H, br d, J = 6.2 Hz, H-5), 3.01 (1 H,

br d, J = 11.0 Hz, H-4), 0.98 (3 H, t, J = 7.0 Hz, OCH₂CH₃).

¹³C NMR (CDCl₃): d = 167.6, 165.9 (2 C, C=O), 139.7, 136.7, 135.5

(3 C_arom), 129.1, 129.0, 128.51, 128.47, 128.44, 128.0, 127.6, 127.3,

127.2 (15 CH_arom), 61.4 (OCH₂CH₃), 47.5 (C-1), 46.6 (PhCH₂), 45.2

(C-6), 44.2 (C-4), 27.2 (C-5), 13.8 (OCH₂CH₃).

In order to further characterize 3k, the pyrrolidinone 3k (0.05

mmol) was hydrolyzed with aq 10% H₂SO₄(2 mL) in AcOH (4

mL). After stirring the mixture for 2 h at r.t. in air, H₂O (10 mL) was

added and the aqueous phase was extracted with CHCl₃(3 × 5 mL).

The combined CHCl₃extracts were dried (MgSO₄), and then con-

centrated to dryness. The corresponding alcohol 3k¢ was obtained in

95% yield, which was further purified by recrystallization from

Et₂O–hexane.

,

3-Acetyl-1-benzyl-4-[hydroxybis(4-methylphenyl)methyl]pyr-

rolidin-2-one (3k¢)

R_f= 0.31 (CHCl₃–MeOH, 98:2); colorless prisms (Et₂O–hexane);

mp 161–162 °C.

Anal. Calcd for C₂₇H₂₅NO₃: C, 78.81; H, 6.12; N, 3.40. Found: C,

78.56; H, 6.19; N, 3.39.

IR (KBr): 3600–3200 (OH), 1709, 1670 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.34–7.03 (13 H_arom, m), 4.37 (2 H, s,

PhCH₂), 4.07 (1 H, ddd, J = 9.0, 5.3, 4.8 Hz, H-4), 3.80 (1 H, d,

J = 5.3 Hz, H-3), 3.41 (1 H, dd, J = 10.3, 9.0 Hz, H-5), 3.12 (1 H,

dd, J = 10.3, 4.8 Hz, H-5), 2.47 (1 H, s, OH), 2.27 (3 H, s, CH₃),

2.25 (3 H, s, CH₃), 2.07 (3 H, s, COCH₃).

¹³C NMR (75 MHz, CDCl₃): d = 204.5, 169.3 (2 C, C=O), 142.4,

142.2, 137.1, 136.8, 135.8 (5 C_arom), 129.4, 129.1, 128.7, 127.8,

127.6, 125.4, 125.3 (13 CH_arom), 79.2 (HOC), 58.2 (C-3), 47.1 (C-

5), 46.8 (PhCH₂), 41.1 (C-4), 30.6 (COCH₃), 20.9 (2 C, 2 × CH₃).

4-(Acetoxydiphenylmethyl)-3-acetyl-1-benzylpyrrolidin-2-one

(3a)

R_f= 0.33 (CHCl₃–MeOH, 98:2); colorless oil.

IR (KBr): 1746, 1719, 1690 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.32–7.16 (13 H_arom, m), 7.03–7.00 (2 H_arom

,

m), 4.45 (1 H, ddd, J = 8.6, 3.7, 3.5 Hz, H-3), 4.37 (1 H, d, J = 14.9

Hz, PhCH₂), 3.92 (1 H, d, J = 3.7 Hz, H-4), 3.84 (1 H, d, J = 14.9

Hz, PhCH₂), 3.52 (1 H, dd, J = 10.6, 8.6 Hz, H-2), 3.41 (1 H, dd,

J = 10.6, 3.5 Hz, H-2), 2.30 (3 H, s, COCH₃), 2.04 (3 H, s,

OCOCH₃).

Anal. Calcd for C₂₈H₂₉NO₃: C, 78.66; H, 6.84; N, 3.28. Found: C,

78.59; H, 6.86; N, 3.24.

418

K. Asahi, H. Nishino

PAPER

Ethyl 4-(Acetoxydiphenylmethyl)-1-benzyl-2-oxopyrrolidine-3-

carboxylate (3q)

R_f= 0.27 (CHCl₃); colorless oil.

H, dd, J = 10.3, 6.2 Hz, H-6), 3.28–3.17 (2 H, m, H-3a, H-6a), 3.10

(1 H, br d, J = 10.3 Hz, H-6), 1.75 (3 H, s, CH₃), 1.08 (3 H, t, J = 7.0

Hz, OCH₂CH₃).

IR (KBr): 1742, 1697 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.27–7.19 (13 H_arom, m), 7.02–7.00 (2 H_arom

¹³C NMR (CDCl₃): d = 171.3 (C=O), 141.2, 136.1 (2 C_arom), 128.8,

128.5, 128.2, 127.9, 127.8, 126.7 (10 CH_arom), 109.5 (C-3), 87.4 (C-

1), 57.2 (C-3a), 56.5 (OCH₂CH₃), 48.5 (C-6), 46.8 (PhCH₂), 43.5

(C-6a), 19.6 (CH₃), 15.2 (OCH₂CH₃).

,

m), 4.53 (1 H, ddd, J = 8.8, 4.0, 3.7 Hz, H-4), 4.38 (1 H, d, J = 14.7

Hz, PhCH₂), 4.19 (2 H, q, J = 7.0 Hz, OCH₂CH₃), 3.77 (1 H, d,

J = 14.7 Hz, PhCH₂), 3.75 (1 H, d, J = 4.0 Hz, H-3), 3.67 (1 H, dd,

J = 10.6, 8.8 Hz, H-5), 3.31 (1 H, dd, J = 10.6, 3.7 Hz, H-5), 2.04 (3

H, s, OCOCH₃), 1.27 (3 H, t, J = 7.0 Hz, OCH₂CH₃).

¹³C NMR (CDCl₃): d = 170.0, 168.8, 168.7 (3 C, C=O), 141.3,

139.7, 135.3 (3 C_arom), 128.6, 128.2, 128.1, 127.9, 127.7, 127.5,

127.4 (15 CH_arom), 87.3 (AcOC), 61.8 (OCH₂CH₃), 51.2 (C-3), 47.8

(C-5), 46.3 (PhCH₂), 40.6 (C-4), 22.1 (OCOCH₃), 14.0

(OCH₂CH₃).

FAB HRMS (acetone–NBA): m/z calcd for C₂₂H₂₆NO₃: 352.1913

(M + 1); found: 352.1922.

3-Acetyl-1-benzyl-4-methylpyrrolidin-2-one (6p)¹⁶

R_f= 0.11 (CHCl₃); colorless oil.

IR (KBr): 1715, 1684 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.37–7.20 (5 H_arom, m), 4.47 (1 H, d, J = 14.7

Hz, PhCH₂), 4.40 (1 H, d, J = 14.7 Hz, PhCH₂), 3.40 (1 H, dd,

J = 8.8, 7.3 Hz, H-5), 3.24 (1 H, d, J = 7.0 Hz, H-3), 2.89–2.75 (2

H, m, H-4, H-5), 2.45 (3 H, s, COCH₃), 1.06 (3 H, d, J = 7.0 Hz,

CH₃).

FAB HRMS (acetone–NBA): m/z calcd for C₂₉H₂₉NO₅: 472.2124

(M + 1); found: 472.2124.

3-Acetyl-1-benzyl-4-[ethoxybis(4-methylphenyl)methyl]pyrro-

lidin-2-one (4k)

R_f= 0.47 (EtOAc–hexane, 2:8); colorless oil.

IR (KBr): 1719, 1688 cm^–1(C=O).

¹³C NMR (CDCl₃): d = 203.6, 169.6 (2 C, C=O), 135.9 (C_arom),

128.7, 128.0, 127.7 (5 CH_arom), 63.5 (C-3), 52.0 (C-5), 46.8

(PhCH₂), 30.4 (COCH₃), 28.2 (C-4), 18.7 (CH₃).

FAB HRMS (acetone–NBA): m/z calcd for C₁₄H₁₈NO₂: 232.1338

¹H NMR (CDCl₃): d = 7.25–6.95 (13 H_arom, m), 4.20 (1 H, d,

J = 14.8 Hz, PhCH₂), 4.07 (1 H, ddd, J = 9.0, 4.2, 3.8 Hz, H-4), 3.93

(1 H, d, J = 14.8 Hz, PhCH₂), 3.88 (1 H, d, J = 4.2 Hz, H-3), 3.49 (1

H, dd, J = 10.4, 9.0 Hz, H-5), 3.24 (1 H, dd, J = 10.4, 3.8 Hz, H-5),

3.03–2.89 (2 H, m, OCH₂CH₃), 2.38 (3 H, s, COCH₃), 2.33 (6 H, br

s, 2 × CH₃), 1.03 (3 H, t, J = 7.0 Hz, OCH₂CH₃).

¹³C NMR (CDCl₃): d = 204.3, 168.8 (2 C, C=O), 138.5, 138.2,

137.4, 137.2, 135.5 (5 C_arom), 128.7, 128.5, 128.24, 128.16, 127.9,

127.4 (13 CH_arom), 83.8 (EtOC), 58.8 (C-3), 58.6 (OCH₂CH₃), 47.5

(C-5), 46.5 (PhCH₂), 38.6 (C-4), 30.6 (COCH₃), 21.0 (2 C,

2 × CH₃), 15.4 (OCH₂CH₃).

(M + 1); found: 232.1332.

Ethyl 1-Benzyl-4-(hydroxydiphenylmethyl)-2-oxopyrrolidine-

3-carboxylate (7q)

R_f= 0.13 (CHCl₃); colorless microcrystals (CHCl₃–hexane); mp

146.0 °C.

IR (KBr): 3200–3500 (OH), 1732, 1674 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.42–7.13 (15 H, m), 4.46 (1 H, d, J = 15.0

Hz, PhCH₂), 4.33 (1 H, d, J = 15.0 Hz, PhCH₂), 4.04–3.87 (3 H, m,

H-4, OCH₂CH₃), 3.66 (1 H, d, J = 7.0 Hz, H-3), 3.42 (1 H, dd,

J = 10.3, 9.2 Hz, H-5), 3.17 (1 H, dd, J = 10.3, 6.2 Hz, H-5), 2.90 (1

H, br s, OH), 1.09 (3 H, t, J = 7.0 Hz, OCH₂CH₃).

FAB HRMS (acetone–NBA): m/z calcd for C₃₀H₃₄NO₃: 456.2539

(M + 1); found: 456.2503.

¹³C NMR (CDCl₃): d = 170.5, 169.4 (2 C, C=O), 144.8, 144.7, 135.8

(3 C_arom), 128.73, 128.70, 128.3, 127.9, 127.6, 127.4, 127.2, 125.6

(15 CH_arom), 78.7 (COH), 61.5 (OCH₂CH₃), 51.0 (C-3), 47.1, 46.8

(2 C, C-5, PhCH₂), 43.9 (C-4), 14.0 (OCH₂CH₃).

Ethyl 1-Benzyl-4-(ethoxydiphenylmethyl)-2-oxopyrrolidine-3-

carboxylate (4q)

R_f= 0.38 (CHCl₃–MeOH, 98:2); colorless oil.

IR (KBr): 1734, 1695 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.34–7.20 (13 H_arom, m), 7.03–7.00 (2 H_arom

m), 4.32 (1 H, d, J = 15.0 Hz, PhCH₂), 4.21 (2 H, q, J = 7.0 Hz,

OCH₂CH₃), 3.95 (1 H, ddd, J = 8.1, 4.8, 4.0 Hz, H-4), 3.86 (1 H, d,

J = 15.0 Hz, PhCH₂), 3.71 (1 H, d, J = 4.8 Hz, H-3), 3.58 (1 H, dd,

J = 10.6, 8.1 Hz, H-5), 3.24 (1 H, dd, J = 10.6, 4.0 Hz, H-5), 3.12–

3.02 (1 H, m, OCH₂CH₃), 2.99–2.89 (1 H, m, OCH₂CH₃), 1.28 (3

H, t, J = 7.0 Hz, OCH₂CH₃), 1.07 (3 H, t, J = 7.0 Hz, OCH₂CH₃).

¹³C NMR (CDCl₃): d = 170.7, 169.0 (2 C, C=O), 141.0, 140.6, 135.6

(3 C_arom), 128.6, 128.5, 128.4, 128.11, 128.05, 128.0, 127.9, 127.8,

127.5 (15 CH_arom), 84.1 (EtOC), 61.7, 58.7 (2 C, 2 × OCH₂CH₃),

51.3 (C-3), 47.5 (C-5), 46.4 (PhCH₂), 41.3 (C-4), 15.3, 14.2 (2 C,

2 × OCH₂CH₃).

Anal. Calcd for C₂₇H₂₇NO₄·0.5H₂O: C, 74.87; H, 6.38; N, 3.24.

Found: C, 74.91; H, 6.55; N, 3.51.

,

3-Acetyl-1-benzyl-4-isopropenylpyrrolidin-2-one (8)

R_f= 0.36 (CHCl₃); colorless oil.

IR (KBr): 1717, 1686 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.36–7.20 (5 H_arom, m), 4.80–4.71 (2 H, m,

H₂C=C), 4.47 (1 H, d, J = 15.0 Hz, PhCH₂), 4.41 (1 H, d, J = 15.0

Hz, PhCH₂), 3.60 (1 H, d, J = 7.3 Hz, H-3), 3.50–3.39 (2 H, m, H-

4, H-5), 3.04 (1 H, dd, J = 10.6, 2.2 Hz, H-5), 2.47 (3 H, s, COCH₃),

1.64 (3 H, br s, CH₃).

¹³C NMR (CDCl₃): d = 203.2, 169.2 (2 C, C=O), 143.5 (H₂C=C),

135.7 (C_arom), 128.8, 128.1, 127.8 (5 CH_arom), 111.9 (H₂C=C), 60.2

(C-3), 49.2 (C-5), 46.9 (PhCH₂), 39.8 (C-4), 30.6 (COCH₃), 20.2

(CH₃).

FAB HRMS (acetone–NBA): m/z calcd for C₂₉H₃₂NO₄: 458.2331

(M + 1); found: 458.2289.

FAB HRMS (acetone–NBA): m/z calcd for C₁₆H₁₉NO₂: 258.1494

(M + 1); found: 258.1509.

5-Benzyl-3-ethoxy-3-methyl-1-phenyl-1H-tetrahydrofuro[3,4-

c]pyrrol-4(5H)-one (5)

Hydrogenolysis of 2a in the Presence of Palladium-Activated

Carbon; 3-Acetyl-1-benzyl-4-diphenylmethylpyrrolidin-2-one

(6a)

To a solution of 2a (0.2 mmol) in formic acid–MeOH (5:95, 20 mL)

was added 10% Pd/C (100 mg) and the mixture was stirred for 15 h

at r.t. under argon in a dark room. The resulting mixture was filtered

R_f= 0.13 (CHCl₃); colorless oil.

IR (KBr): 1688 cm^–1(C=O).

¹H NMR (300 MHz, CDCl₃): d = 7.38–7.25 (10 H_arom, m), 4.68 (1

H, d, J = 14.7 Hz, PhCH₂), 4.65 (1 H, d, J = 5.9 Hz, H-1), 4.33 (1

H, d, J = 14.7 Hz, PhCH₂), 3.62–3.49 (2 H, m, OCH₂CH₃), 3.40 (1

PAPER

Synthesis of Bicyclo[3.1.0]hexan-2-ones Using Mn(III) Oxidation

419

by a Celite column to remove Pd/C, and the filtrate was concentrat-

ed to dryness. The obtained residue was triturated with H₂O fol-

lowed by extraction with CHCl₃(3 × 5 mL). The combined CHCl₃

extracts were dried (MgSO₄) and concentrated to dryness, giving

the ring-opened pyrrolidinone 6a in a quantitative yield; R_f= 0.24

(CHCl₃); colorless oil.

Anal. Calcd for C₁₉H₁₆O₃: C, 78.06; H, 5.52. Found: C, 78.36; H,

5.68.

1-Acetyl-6,6-bis(4-methylphenyl)-3-oxabicyclo[3.1.0]hexan-2-

one (10b)

R_f= 0.27 (CHCl₃); pale yellow microcrystals (Et₂O–hexane); mp

141–142 °C.

IR (KBr): 1759, 1705 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.30–7.01 (8 H_arom, m), 4.41 (1 H, dd, J = 9.9,

5.5 Hz, H-4), 4.15 (1 H, br d, J = 9.9 Hz, H-4), 3.67 (1 H, br d,

J = 5.5 Hz, H-5), 2.59 (3 H, s, COCH₃), 2.30 (3 H, s, CH₃), 2.23 (3

H, s, CH₃).

IR (KBr): 1717, 1684 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.34–7.11 (15 H_arom, m), 4.40 (1 H, d,

J = 14.7 Hz, PhCH₂), 4.34 (1 H, d, J = 14.7 Hz, PhCH₂), 3.81 (1 H,

dddd, J = 12.1, 8.4, 5.5, 5.1 Hz, H-4), 3.66 (1 H, d, J = 12.1 Hz,

CHPh₂), 3.47 (1 H, d, J = 5.5 Hz, H-3), 3.36 (1 H, dd, J = 9.9, 8.4

Hz, H-5), 2.86 (1 H, dd, J = 9.9, 5.1 Hz, H-5), 1.99 (3 H, s, COCH₃).

¹³C NMR (CDCl₃): d = 204.0, 169.1 (2 C, C=O), 142.3, 141.8, 135.7

(3 C_arom), 128.7, 127.94, 127.89, 127.62, 127.56, 126.9, 126.8 (15

CH_arom), 61.0 (C-3), 56.4 (CHPh₂), 49.9 (C-5), 46.7 (PhCH₂), 37.5

(C-4), 30.6 (COCH₃).

¹³C NMR (CDCl₃): d = 197.9, 171.5 (2 C, C=O), 138.0, 137.6,

134.4, 133.0 (4 C_arom), 130.1, 129.4, 128.6, 128.1 (8 CH_arom), 64.9

(C-4), 51.2, 50.7 (2 C, C-1, C-6), 31.9, 29.8 (2 C, COCH₃, C-5),

21.1, 21.0 (2 C, CH₃).

Anal. Calcd for C₂₁H₂₀O₃: C, 78.73; H, 6.29. Found: C, 78.46; H,

6.25.

Oxidative Deprotection of p-Methoxybenzyl (PMB) Group of

2h Using CAN

The 3-azabicyclo[3.1.0]hexan-2-one 2h (0.3 mmol) was dissolved

in MeCN–H₂O (1:2, 10 mL) and the solution was cooled to 0 °C fol-

lowed by adding cerium(IV) ammonium nitrate (CAN) (1.05 mmol,

3.5 equiv). After stirring 30 min at 0 °C, EtOAc (5 mL) and aq sat.

NaHCO₃(20 mL) were added to the mixture, and the resulting so-

lution was extracted with EtOAc (3 × 5 mL). The combined EtOAc

extracts were (MgSO₄) and concentrated to dryness. The obtained

crude products were separated by TLC (wakogel B-10) by eluting

with CHCl₃or Et₂O–hexane (8:2) to afford 2j (67%) and 2h¢ (22%)

together with recovered 2h (6%). The by-product 2h¢ (0.03 mmol)

was dissolved in MeOH (2 mL) containing 18-crown-6 (3 mg).

K₂CO₃(0.09 mmol) was added to the mixture, and the mixture was

then stirred for 6 h at r.t. in air. The reaction was quenched by sat.

aq NH₄Cl (10 mL) and extracted with CHCl₃(3 × 5 mL). The com-

bined CHCl₃extracts were dried (MgSO₄) and concentrated to dry-

ness. The obtained products were separated by TLC (wakogel B-10)

by eluting with CHCl₃–MeOH (98:2) to give 2j (96%).

1-Acetyl-6,6-bis(4-chlorophenyl)-3-oxabicyclo[3.1.0]hexan-2-

one (10c)

R_f= 0.22 (CHCl₃); pale yellow microcrystals (Et₂O–hexane); mp

184–186 °C.

IR (KBr): 1759, 1701 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.38–7.10 (8 H_arom, m), 4.46 (1 H, dd,

J = 10.3, 5.5 Hz, H-4), 4.11 (1 H, br d, J = 10.3 Hz, H-4), 3.66 (1 H,

br d, J = 5.5 Hz, H-5), 2.59 (3 H, s, COCH₃).

¹³C NMR (CDCl₃): d = 197.2, 170.9 (2 C, C=O), 135.3, 134.6,

134.1, 133.9 (4 C_arom), 130.1, 129.9, 129.6, 129.1 (8 CH_arom), 64.7

(C-4), 50.4, 50.0 (2 C, C-1, C-6), 32.1, 29.8 (2 C, COCH₃, C-5).

Anal. Calcd for C₁₉H₁₄Cl₂O₃: C, 63.18; H, 3.91. Found: C, 62.88; H,

3.97.

1-Acetyl-6,6-bis(4-fluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-

one (10d)

R_f= 0.18 (CHCl₃); colorless microcrystals (Et₂O–hexane); mp 161–

162 °C.

1-Acetyl-3-(4-methoxybenzoyl)-6,6-diphenyl-3-azabicy-

clo[3.1.0]hexan-2-one (2h¢)

R_f= 0.22 (Et₂O–hexane 8:2); colorless prisms (Et₂O–hexane); mp

205–208 °C.

IR (KBr): 1722, 1699, 1670 cm^–1(C=O).

IR (KBr): 1769, 1693 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.41–6.91 (8 H_arom, m), 4.46 (1 H, dd,

J = 10.3, 5.5 Hz, H-4), 4.13 (1 H, br d, J = 10.3 Hz, H-4), 3.67 (1 H,

br d, J = 5.5 Hz, H-5), 2.59 (3 H, s, COCH₃).

¹³C NMR (CDCl₃): d = 197.3, 171.1 (2 C, C=O), 164.1, 163.7,

160.8, 160.4, 132.90, 132.85, 131.6, 131.5 (4 C_arom), 130.5, 130.4,

130.1, 130.0, 116.9, 116.7, 116.0, 115.7 (8 CH_arom), 64.7 (C-4),

50.6, 50.0 (2 C, C-1, C-6), 32.1, 29.8 (2 C, COCH₃, C-5).

¹H NMR (CDCl₃): d = 7.57–7.16 (10 H_arom, m), 7.08 (2 H_arom, d,

J = 8.8 Hz), 6.80 (2 H_arom, d, J = 8.8 Hz), 4.32 (1 H, dd, J = 12.5, 6.2

Hz, H-4), 3.83 (3 H, s, OCH₃), 3.82 (1 H, br d, J = 12.5 Hz, H-4),

3.56 (1 H, br d, J = 6.2 Hz, H-5), 2.55 (3 H, s, COCH₃).

¹³C NMR (CDCl₃): d = 198.6, 169.1, 168.8 (3 C, C=O), 162.7,

138.1, 136.6 (3 C_arom), 130.8, 129.5, 129.0, 128.8, 128.4, 128.3,

127.8 (12 CH_arom), 126.0 (C_arom), 112.9 (2 CH_arom), 55.3 (OCH₃),

53.7, 52.3 (2 C, C-1, C-6), 43.4 (C-4), 30.4 (COCH₃), 27.2 (C-5).

Anal. Calcd for C₁₉H₁₄F₂O₃: C, 69.51; H, 4.30. Found: C, 69.40; H,

4.41.

1-Acetyl-3-oxabicyclo[3.1.0]hexan-2-one (10e)^7a

R_f= 0.15 (Et₂O–hexane, 1:1); colorless oil.

Anal. Calcd for C₂₇H₂₃NO₄·0.5H₂O: C, 75.58; H, 5.50; N, 3.27.

Found: C, 75.64; H, 5.39; N, 3.40.

IR (KBr): 1771, 1697 cm^–1(C=O).

1-Acetyl-6,6-diphenyl-3-oxabicyclo[3.1.0]hexan-2-one (10a)

R_f= 0.16 (Et₂O—hexane, 1:1); colorless microcrystals (Et₂O–hex-

ane); mp 153.0–153.5 °C.

IR (KBr): 1759, 1703 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.44–7.15 (10 H_arom, m), 4.41 (1 H, dd,

J = 9.9, 5.5 Hz, H-4), 4.14 (1 H, br d, J = 9.9 Hz, H-4), 3.70 (1 H,

br d, J = 5.5 Hz, H-5), 2.59 (3 H, s, COCH₃).

¹H NMR (CDCl₃): d = 4.36 (1 H, dd, J = 9.5, 4.7 Hz, H-4), 4.21 (1

H, br d, J = 9.5 Hz, H-4), 2.85–2.79 (1 H, m, H-5), 2.58 (3 H, s,

COCH₃), 2.07 (1 H, dd, J = 8.1, 4.2 Hz, H-6), 1.44 (1 H, dd, J = 5.7,

4.2 Hz, H-6).

¹³C NMR (CDCl₃): d = 200.5, 172.7 (2 C, C=O), 67.1 (C-4), 36.4

(C-1), 29.8 (C-5), 29.2 (COCH₃), 24.1 (C-6).

¹³C NMR (CDCl₃): d = 197.6, 171.3 (2 C, C=O), 137.1, 135.7 (2

1-Acetyl-6,6-diphenyl-3-thiabicyclo[3.1.0]hexan-2-one (12a)

R_f= 0.49 (CHCl₃); colorless microcrystals (Et₂O–hexane); mp

130.0 °C.

C

_arom), 129.3, 128.7, 128.6, 128.3, 128.1, 127.8 (10 CH_arom), 64.7

(C-4), 51.4, 50.5 (2 C, C-1, C-6), 31.8, 29.7 (2 C, COCH₃, C-5).

420

K. Asahi, H. Nishino

PAPER

IR (KBr): 1697 cm^–1(C=O).

¹³C NMR (CDCl₃): d = 189.8 (C=O), 158.4 (C-1), 140.8, 138.1,

137.7, 136.6 (4 C_arom), 129.21, 129.18, 126.4, 125.7 (8 CH_arom),

113.3 (C-6a), 96.0 (C-3), 57.0 (C-3a), 34.3 (C-4), 21.1, 21.0, 13.0

(3 C, 3 × CH₃).

¹H NMR (CDCl₃): d = 7.47–7.12 (10 H_arom, m), 3.76 (1 H, br d,

J = 7.3 Hz, H-5), 3.71 (1 H, dd, J = 10.8, 7.3 Hz, H-4), 3.24 (1 H, br

d, J = 10.8 Hz, H-4), 2.45 (3 H, s, COCH₃).

FAB HRMS (acetone–NBA): m/z calcd for C₂₁H₂₁O₂S: 337.1262

(M + 1); found: 337.1258.

¹³C NMR (CDCl₃): d = 202,2, 198.1 (2 C, C=O), 138.2, 136.3 (2

C

_arom), 129.1, 128.7, 128.6, 128.4, 127.8, 127.6 (10 CH_arom), 61.7

(C-1), 50.7 (C-6), 34.1 (C-5), 30.2 (COCH₃), 28.0 (C-4).

1,1-Bis(4-chlorophenyl)-3-methyl-1,6a-dihydrothieno[3,4-c]fu-

ran-4(1H)-one (13c)

R_f= 0.62 (CHCl₃); colorless oil.

FAB HRMS (acetone–NBA): m/z calcd for C₁₉H₁₇O₂S: 309.0949

(M + 1); found: 309.0945.

IR (KBr): 1655 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.45–7.38 (2 H_arom, m), 7.18–6.96 (6 H_arom

Anal. Calcd for C₁₉H₁₆O₂S: C, 74.00; H, 5.23. Found: C, 74.00; H,

5.25.

,

m), 4.91–4.83 (1 H, m, H-3a), 3.02 (1 H, dd, J = 10.3, 7.3 Hz, H-4),

2.67 (1 H, dd, J = 11.4, 10.3 Hz, H-4), 2.27 (3 H, d, J = 2.2 Hz,

CH₃).

¹³C NMR (CDCl₃): d = 189.2 (C=O), 157.8 (C-1), 141.7, 137.5,

134.5, 134.2 (4 C_arom), 128.9, 127.8, 127.1 (8 CH_arom), 113.3 (C-6a),

94.6 (C-3), 57.0 (C-3a), 34.1 (C-4), 12.9 (CH₃).

1-Acetyl-6,6-bis(4-chlorophenyl)-3-thiabicyclo[3.1.0]hexan-2-

one (12c)

R_f= 0.51 (CHCl₃); pale yellow oil.

IR (KBr): 1697 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.38–7.10 (8 H_arom, m), 3.74 (1 H, dd,

J = 10.3, 7.3 Hz, H-4), 3.70 (1 H, br d, J = 7.3 Hz, H-5), 3.18 (1 H,

br d, J = 10.3 Hz, H-4), 2.44 (3 H, s, COCH₃).

¹³C NMR (CDCl₃): d = 201.6, 197.5 (2 C, C=O), 136.4, 134.5,

134.1, 133.8 (4 C_arom), 130.0, 129.64, 129.57, 129.0 (8 CH_arom), 61.5

(C-1), 49.1 (C-6), 34.3 (C-5), 30.2 (COCH₃), 27.8 (C-4).

FAB HRMS (acetone–NBA): m/z calcd for C₁₉H₁₅Cl₂O₂S:

377.0170 (M + 1); found: 377.0177.

1,1-Bis(4-fluorophenyl)-3-methyl-1,6a-dihydrothieno[3,4-c]fu-

ran-4(1H)-one (13d)

R_f= 0.58 (CHCl₃); colorless oil.

IR (KBr): 1665 cm^–1(C=O).

FAB HRMS (acetone–NBA): m/z calcd for C₁₉H₁₅Cl₂O₂S:

377.0170 (M + 1); found: 377.0200.

¹H NMR (CDCl₃): d = 7.45–7.38 (2 H_arom, m), 7.19–6.93 (6 H_arom

m), 4.91–4.82 (1 H, m, H-3a), 3.02 (1 H, dd, J = 10.3, 7.3 Hz, H-4),

2.67 (1 H, dd, J = 11.4, 10.3 Hz, H-4), 2.27 (3 H, d, J = 2.2 Hz,

CH₃).

¹³C NMR (CDCl₃): d = 189.4 (C=O), 164.1, 163.9, 160.8, 160.6 (2

C_arom), 158.0 (C-1), 139.33, 139.29, 135.11, 135.06 (2 C_arom), 128.4,

128.3, 127.7, 127.5, 115.8, 115.5 (8 CH_arom), 113.3 (C-6a), 94.9 (C-

3), 57.3 (C-3a), 34.1 (C-4), 12.9 (CH₃).

,

1-Acetyl-6,6-bis(4-fluorophenyl)-3-thiabicyclo[3.1.0]hexan-2-

one (12d)

R_f= 0.38 (CHCl₃); pale yellow oil.

IR (KBr): 1697 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.43–6.89 (8 H_arom, m), 3.75 (1 H, dd,

J = 10.3, 7.3 Hz, H-4), 3.71 (1 H, br d, J = 7.3 Hz, H-5), 3.20 (1 H,

br d, J = 10.3 Hz, H-4), 2.44 (3 H, s, COCH₃).

¹³C NMR (CDCl₃): d = 201.9, 197.8 (2 C, C=O), 163.9, 163.5,

160.6, 160.2, 134.0, 133.9, 132.10, 132.06 (4 C_arom), 130.4, 130.3,

130.1, 130.0, 116.6, 116.3, 115.9, 115.6 (8 CH_arom), 61.8 (C-1), 49.1

(C-6), 34.4 (C-5), 30.2 (COCH₃), 27.9 (C-4).

FAB HRMS (acetone–NBA): m/z calcd for C₁₉H₁₅F₂O₂S: 345.0761

(M + 1); found: 345.0750.

3-Ethoxy-3-methyl-1,1-diphenyltetrahydrothieno[3,4-c]furan-

4(1H)-one (14a)

R_f= 0.67 (Et₂O–hexane, 1:1); colorless microcrystals (hexane); mp

145–146 °C.

FAB HRMS (acetone–NBA): m/z calcd for C₁₉H₁₅F₂O₂S: 345.0761

(M + 1); found: 345.0763.

IR (KBr): 1728 cm^–1(C=O.

3-Methyl-1,1-diphenyl-1,6a-dihydrothieno[3,4-c]furan-4(1H)-

one (13a)

R_f= 0.29 (CHCl₃–hexane, 1:1); colorless oil.

IR (KBr): 1661 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.50–7.10 (10 H_arom, m), 4.95–4.87 (1 H, m,

H-3a), 3.02 (1 H, dd, J = 10.5, 7.2 Hz, H-4), 2.68 (1 H, dd, J = 11.2,

10.5 Hz, H-4), 2.28 (3 H, d, J = 2.0 Hz, CH₃).

¹H NMR (CDCl₃): d = 7.43–7.20 (10 H_arom, m), 4.54 (1 H, ddd,

J = 14.7, 12.1, 5.1 Hz, H-3a), 3.50–3.39 (2 H, m, OCH₂CH₃), 3.33

(1 H, dd, J = 10.3, 5.1 Hz, H-4), 3.12 (1 H, d, J = 14.7 Hz, H-6a),

2.89 (1 H, dd, J = 12.1, 10.3 Hz, H-4), 1.74 (3 H, s, CH₃), 0.76 (3 H,

t, J = 7.0 Hz, OCH₂CH₃).

¹³C NMR (CDCl₃): d = 197.2 (C=O), 145.7, 141.6 (2 C_arom), 128.3,

128.2, 127.40, 127.37, 126.4, 126.1 (10 CH_arom), 100.7 (C-1), 84.3

(C-3), 66.2 (C-6a), 56.9 (OCH₂CH₃), 54.9 (C-3a), 32.7 (C-4), 20.8

(CH₃), 14.9 (OCH₂CH₃).

¹³C NMR (CDCl₃): d = 189.7 (C=O), 158.3 (C-1), 143.5, 139.2 (2

C_arom), 128.6, 128.5, 128.3, 127.9, 126.5, 125.7 (10 CH_arom), 113.3

(C-6a), 95.8 (C-3), 57.1 (C-3a), 34.2 (C-4), 12.9 (CH₃).

FAB MS m/z (%) = 309 (82, M – 45), 249 (100), 167 (46), 105 (40).

FAB HRMS (acetone–NBA): m/z calcd for C₁₉H₁₇O₂S: 309.0949

(M + 1); found: 309.0944.

Anal. Calcd for C₂₁H₂₂O₃S: C, 71.16; H, 6.26. Found: C, 71.11; H,

6.25.

1,1-Bis(4-methylphenyl)-3-methyl-1,6a-dihydrothieno[3,4-c]fu-

ran-4(1H)-one (13b)

R_f= 0.49 (CHCl₃–hexane, 8:2); colorless oil.

IR (KBr): 1663 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.72–6.96 (8 H_arom, m), 4.91–4.85 (1 H, m,

H-3a), 3.00 (1 H, dd, J = 10.3, 7.3 Hz, H-4), 2.69 (1 H, dd, J = 11.4,

10.3 Hz, H-4), 2.36 (3 H, s, CH₃), 2.32 (3 H, s, CH₃), 2.27 (3 H, d,

J = 2.2 Hz, CH₃).

3-Ethoxy-1,1-bis(4-methylphenyl)-3-methyltetrahydro-

thieno[3,4-c]furan-4(1H)-one (14b)

R_f= 0.51 (Et₂O–hexane 2:8); colorless oil.

IR (KBr): 1732 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.28–7.01 (8 H_arom, m), 4.50 (1 H, ddd,

J = 14.7, 12.1, 5.1 Hz, H-3a), 3.48–3.42 (2 H, m, OCH₂CH₃), 3.28

(1 H, dd, J = 9.9, 5.1 Hz, H-4), 3.10 (1 H, d, J = 14.7 Hz, H-6a), 2.89

PAPER

Synthesis of Bicyclo[3.1.0]hexan-2-ones Using Mn(III) Oxidation

421

(1 H, dd, J = 12.1, 9.9 Hz, H-4), 2.42 (3 H, s, CH₃), 2.31 (3 H, s,

CH₃), 1.72 (3 H, s, CH₃), 0.80 (3 H, t, J = 7.0 Hz, OCH₂CH₃).

3-Acetyl-4-[acetoxybis(4-methylphenyl)methyl]dihydro-

thiophen-2(3H)-one (15b)

R_f= 0.20 (CHCl₃–hexane, 8:2); colorless oil.

IR (KBr): 1746, 1720, 1686 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.29–7.12 (8 H_arom, m), 4.66 (1 H, ddd,

J = 7.7, 4.8, 4.4 Hz, H-3), 3.91 (1 H, d, J = 4.8 Hz, H-4), 3.58 (1 H,

dd, J = 11.7, 7.7 Hz, H-2), 3.38 (1 H, dd, J = 11.7, 4.4 Hz, H-2),

2.34 (3 H, s, CH₃), 2.33 (3 H, s, COCH₃), 2.29 (3 H, s, CH₃), 2.05

(3 H, s, OCOCH₃).

¹³C NMR (CDCl₃): d = 197.5 (C=O), 142.8, 138.9, 136.9 (4 C_arom),

128.9, 128.8, 126.3, 126.0 (8 CH_arom), 100.6 (C-1), 84.3 (C-3), 66.3

(C-6a), 56.8 (OCH₂CH₃), 54.8 (C-3a), 32.6 (C-4), 21.1, 21.0, 20.8

(3 C, 3 × CH₃), 15.0 (OCH₂CH₃).

FAB MS: m/z (%) = 337 (100, M – 45), 277 (33), 211 (32), 195 (29),

119 (27).

1,1-Bis(4-chlorophenyl)-3-ethoxy-3-methyltetrahydro-

thieno[3,4-c]furan-4(1H)-one (14c)

R_f= 0.73 (Et₂O–hexane, 1:1); colorless oil.

IR (KBr): 1732 cm^–1(C=O).

¹³C NMR (CDCl₃): d = 203.0, 200.6, 168.8 (3 C, C=O), 137.9,

137.8, 137.3, 136.7 (4 C_arom), 128.94, 128.87, 127.5, 127.4 (8

CH_arom), 87.9 (AcOC), 68.4 (C-4), 46.2 (C-3), 32.3 (C-2), 29.l2

(COCH₃), 22.2 (OCOCH₃), 21.03, 21.01 (2 C, 2 × CH₃).

¹H NMR (CDCl₃): d = 7.47–7.02 (8 H_arom, m), 4.48 (1 H, ddd,

J = 14.7, 12.1, 5.2 Hz, H-3a), 3.53–3.35 (2 H, m, OCH₂CH₃), 3.30

(1 H, dd, J = 9.9, 5.2 Hz, H-4), 3.06 (1 H, d, J = 14.7 Hz, H-6a), 2.88

(1 H, dd, J = 12.1, 9.9 Hz, H-4), 1.72 (3 H, s, CH₃), 0.80 (3 H, t,

J = 7.0 Hz, OCH₂CH₃).

FAB MS: m/z (%) = 337 (100, M – 59), 211 (57), 154 (25), 119 (21),

91 (8).

3-Acetyl-4-[acetoxybis(4-chlorophenyl)methyl]dihydro-

thiophen-2(3H)-one (15c)

R_f= 0.33 (CHCl₃); colorless oil.

IR (KBr): 1746, 1722, 1690 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.35–7.14 (8 H_arom), 4.65 (1 H, ddd, J = 8.1,

3.7, 3.3 Hz, H-3), 3.88 (1 H, d, J = 3.7 Hz, H-4), 3.63 (1 H, dd,

J = 12.1, 8.1 Hz, H-2), 3.36 (1 H, dd, J = 12.1, 3.3 Hz, H-2), 2.30 (3

H, s, COCH₃), 2.09 (3 H, s, OCOCH₃).

¹³C NMR (CDCl₃): d = 196.4 (C=O), 143.9, 139.8, 133.64, 133.56

(4 C_arom), 128.6, 128.5, 127.7, 127.5 (8 CH_arom), 101.0 (C-1), 83.4

(C-3), 66.2 (C-6a), 57.1 (OCH₂CH₃), 54.7 (C-3a), 32.4 (C-4), 20.7

(CH₃), 15.0 (OCH₂CH₃).

FAB MS: m/z (%) = 377 (40, M – 45), 307 (30), 289 (18), 154 (100),

136 (77), 89 (12).

¹³C NMR (CDCl₃): d = 202.2, 199.7, 168.6 (3 C, C=O), 138.7, 138.3

(2 C_arom), 134.4 (2 C_arom), 128.7, 128.60, 128.56 (8 CH_arom), 86.9

(AcOC), 68.5 (C-4), 45.2 (C-3), 32.2 (C-2), 28.9 (COCH₃), 22.1

(OCOCH₃).

3-Ethoxy-1,1-bis(4-fluorophenyl)-3-methyltetrahydro-

thieno[3,4-c]furan-4(1H)-one (14d)

R_f= 0.71 (Et₂O–hexane, 1:1); colorless microcrystals (hexane); mp

172–173 °C.

IR (KBr): 1732 cm^–1(C=O).

¹H NMR (CDCl₃) : d = 7.39–6.95 (8 H_arom, m), 4.50 (1 H, ddd,

J = 14.7, 12.5, 5.1 Hz, H-3a), 3.52–3.35 (2 H, m, OCH₂CH₃), 3.29

(1 H, dd, J = 9.9, 5.1 Hz, H-4), 3.08 (1 H, d, J = 14.7 Hz, H-6a), 2.87

(1 H, dd, J = 12.5, 9.9 Hz, H-4), 1.73 (3 H, s, CH₃), 0.78 (3 H, t,

J = 7.0 Hz, OCH₂CH₃).

¹³C NMR (CDCl₃): d = 196.7 (C=O), 163.7, 163.6, 160.4, 160.3,

141.6, 141.5, 137.3, 137.2 (4 C_arom), 128.1, 128.0, 127.9, 127.8,

115.4, 115.3, 115.2, 115.0 (8 CH_arom), 100.9 (C-1), 83.5 (C-3), 66.2

(C-6a), 57.0 (OCH₂CH₃), 54.9 (C-3a), 32.4 (C-4), 20.7 (CH₃), 15.0

(OCH₂CH₃).

FAB MS: m/z (%) = 377 (22, M – 59), 307 (37), 289 (18), 154 (100),

136 (63), 89 (11).

Anal. Calcd for C₂₁H₁₈Cl₂O₄S: C, 57.67; H, 4.15. Found: C, 57.68;

H, 4.18.

3-Acetyl-4-[acetoxybis(4-fluorophenyl)methyl]dihydro-

thiophen-2(3H)-one (15d)

R_f= 0.29 (CHCl₃); colorless oil.

IR (KBr): 1746, 1722, 1688 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.35–6.99 (8 H_arom, m), 4.71 (1 H, ddd,

J = 8.1, 4.0, 3.7 Hz, H-3), 3.89 (1 H, d, J = 4.0 Hz, H-4), 3.65 (1 H,

dd, J = 12.1, 8.1 Hz, H-2), 3.35 (1 H, dd, J = 12.1, 3.7 Hz, H-2),

2.30 (3 H, s, COCH₃), 2.08 (3 H, s, OCOCH₃).

¹³C NMR (CDCl₃): d = 202.4, 199.9, 168.7 (3 C, C=O), 163.9,

160.6, 136.1, 136.0, 135.63, 135.58 (4 C_arom), 129.5, 129.39,

129.36, 129.3, 115.6, 115.5, 115.3, 115.2 (8 CH_arom), 87.0 (AcOC),

68.5 (C-4), 45.4 (C-3), 32.3 (C-2), 29.0 (COCH₃), 22.2 (OCOCH₃).

FAB MS: m/z (%) = 391 (16, M + 1), 345 (98, M – 45), 285 (47),

229 (98), 154 (100), 136 (72).

FAB HRMS (acetone–NBA): m/z calcd for C₂₁H₂₁F₂O₃S: 391.1179

(M + 1); found: 391.1181.

Anal. Calcd for C₂₁H₂₀F₂O₃S: C, 64.60; H, 5.16. Found: C, 64.66;

H, 5.27.

FAB MS: m/z (%) = 345 (100, M – 59), 285 (52), 219 (22), 137 (21),

136 (20).

3-Acetyl-4-(acetoxydiphenylmethyl)dihydrothiophen-2(3H)-

one (15a)

3-Acetyl-4-[ethoxybis(4-methylphenyl)methyl]dihydro-

thiophen-2(3H)-one (16b)

R_f= 0.40 (Et₂O–hexane, 2:8); colorless prisms (hexane); mp 130–

R_f= 0.40 (CHCl₃); colorless oil.

IR (KBr): 1746, 1722, 1686 cm^–1(C=O).

131 °C.

¹H NMR (CDCl₃): d = 7.33–7.25 (10 H_arom, m), 4.69 (1 H, ddd,

J = 7.9, 4.0, 3.9 Hz, H-3), 3.96 (1 H, d, J = 4.0 Hz, H-4), 3.62 (1 H,

dd, J = 11.9, 7.9 Hz, H-2), 3.43 (1 H, dd, J = 11.9, 3.9 Hz, H-2),

2.28 (3 H, s, COCH₃), 2.09 (3 H, s, O COCH₃).

¹³C NMR (CDCl₃): d = 202.8, 200.3, 168.7 (3 C, C=O), 140.5, 140.0

(2 C_arom), 128.3, 128.2, 128.1, 128.0, 127.3, 127.2 (10 CH_arom), 87.9

(AcOC), 68.5 (C-4), 45.8 (C-3), 32.3 (C-2), 29.1 (COCH₃), 22.2 (O

COCH₃).

IR (KBr): 1724, 1688 cm^–1(C=O).

¹H NMR (CDCl₃): d = 7.39–7.07 (8 H_arom, m), 4.32 (1 H, ddd,

J = 8.1, 8.1, 7.3 Hz, H-4), 3.65 (1 H, d, J = 8.1 Hz, H-3), 3.40 (1 H,

dd, J = 11.4, 7.3 Hz, H-5), 3.19 (1 H, dd, J = 11.4, 8.1 Hz, H-5),

3.01–2.91 (1 H, m, OCH₂CH₃), 2.83–2.73 (1 H, m, OCH₂CH₃),

2.382 (3 H, s, CH₃), 2.376 (3 H, s, CH₃), 2.35 (3 H, s, CH₃), 1.01 (3

H, t, J = 7.0 Hz, OCH₂CH₃).

FAB MS: m/z (%) = 309 (95, M – 59), 249 (100), 167 (38), 105 (26).

¹³C NMR (CDCl₃): d = 203.7, 202.0 (2 C, C=O), 138.2, 137.7,

135.9, 135.7 (4 C_arom), 129.2, 128.9, 128.7 (8 CH_arom), 84.8 (EtOC),

422

K. Asahi, H. Nishino

PAPER

67.3 (C-3), 59.1 (OCH₂CH₃), 48.4 (C-4), 31.6 (C-5), 29.7 (COCH₃),

21.1 (2 C, 2 × CH₃), 14.9 (OCH₂CH₃).

Kurosawa, K. Heterocycles 1998, 48, 465. (k) Chowdhury,

F. A.; Nishino, H.; Kurosawa, K. Tetrahedron Lett. 1998,

39, 7931. (l) Chowdhury, F. A.; Nishino, H.; Kurosawa, K.

Heterocycles 1999, 51, 575. (m) Kumabe, R.; Nishino, H.;

Yasutake, M.; Nguyen, V.-H.; Kurosawa, K. Tetrahedron

Lett. 2001, 42, 69. (n) Qian, C.-Y.; Nishino, H.; Kurosawa,

K. J. Org. Chem. 1993, 58, 4448. (o) Rahman, M. T.;

Nishino, H.; Qian, C.-Y. Tetrahedron Lett. 2003, 44, 5225.

(p) Rahman, M. T.; Nishino, H. Org. Lett. 2003, 5, 2887.

(q) Rahman, M. T.; Nishino, H. Tetrahedron 2003, 59,

8383. (r) Kumabe, R.; Nishino, H. Tetrahedron Lett. 2004,

45, 703. (s) Kumabe, R.; Nishino, H. Heterocycl. Commun.

2005, 10, 135. (t) Fujino, R.; Nishino, H. Synthesis 2005,

731.

FAB MS: m/z (%) = 337 (68, M – 45), 239 (100), 119 (30), 91 (9).

Anal. Calcd for C₂₃H₂₆O₃S: C, 72.22; H, 6.85. Found: C, 72.08; H,

6.63.

Acknowledgment

This research was supported by Grants-in-Aid for Scientific

Research (C), No. 15550039 and No.19550046, from Japan Society

for the Promotion of Science. We gratefully acknowledge Professor

Teruo Shinmyozu, Institute for Materials Chemistry and Enginee-

ring, Kyushu University, Japan, for the measurement of the high-

resolution FAB mass spectra.

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PAPER

Synthesis of Bicyclo[3.1.0]hexan-2-ones Using Mn(III) Oxidation

423

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Synthesis of bicyclo[3.1.0]hexan-2-ones by manganese(III) oxidation in ethanol

DOI: 10.1055/s-0028-1083324

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