Chiral four-membered cyclic nitrones; asymmetric induction in the (4+2)-cycloaddition reaction of chiral ynamines and nitroalkenes

Tetrahedron Printed in

Letters,Vo1.28,No.50,pp Great Britain

CHIRAL

6397-6400,1987

POUR-MEMBERED

THE

CYCLIC

<4+2)-CYCLOADDITION

0040-4039/87 $3.00 Perqamon Journals

NITRONES; REACTION

ASYMMETRIC OF CHIRAL

+ .OO Ltd.

INDUCTION

YNAMINES

IN

AND

NITROALKENES P.A. Laboratory

van Elburg,

of Organic

G.W.N.

Honig,

Chemistry,

and D.N.

University

Reinhoudt*

of Twente,

Enschede,

The

Netherlands

Abstract. Chiral four-membered cyclic nitrones were synthesized asymmetric (4+2)-cycloaddition of nitroalkenes 1 and chiral ynamines subsequent stereoselective addition of nucleophiles to these nitrones the synthesis of chiral N-hydroxyazetidines. Asymmetric

cycloadditions

the formation Previously

reported

of nitroalkenes

the stereochemistry

ester

increasingly

useful 1 in one reaction.

of more than one bond we have

cycloaddition which

become

the stereoselective 1 and ynamines

at C-2

3. Uponringcontraction

synthesis

2. ’

In this

is determined

only

in controlling

the absolute

of four-membered

reaction

two chiral

by the stereochemistry

two enantiomeric

nitrones

4 (2R,3R)

by the 2. The enabled

stereochemistry

cyclic carbon

during

nitrones

centers

by

at C-3 in the intermediate and 5 (2S,3S)

the

are formed

of

nitron

are formed

in equal

amounts. We anticipated in the

that a chiral

cycloaddition

enantiomeric

with

N,N-dialkylamino group in the ynamines 2 might cause asymmetric induction -resulting in a preferential formation of one of the prochiral nitroalkenes,

nitrones

4 or 5.

use in the asymmetric

synthesis

In this

paper

we describe

of four-membered

the first

cyclic Scheme

a

nitrones

synthesis

of chiral

ynamines

and their

and 1-hydroxyazetidines.

1

(2 R,3R)

R’ = C,H,

(2$3s)

b R’=CH, c The analogy m/e

R’=H racemic with

137.120

pyrrolidine

ynamine

standard

analogy

was

CM+,

calcd

for

(2b)

was

prepared

(chloroethynyllbenzene In

2a

procedures

with

C9H15N:

in a yield the

synthesized from (+)-2-methylpyrrolidine 3 and was obtained in 61% yield [bp 50-52

the

Similarly, HCl-salt

of 16% in analogy

synthesis

(S)-(-)-2-(methoxymethyl)pyrrolidine

1.53); bp 60-62 'C (0.02 mm);

137.120)].

from

of

compound

and mass

of

the

1-ethoxy-1-butyne

spectrum, 6397

m/e

1-ethoxy-1-butyne mass

in

spectrum,

racemic 2,5-dimethyl-l-(phenylethynyl)trans-(+)-2,5-dimethylpyrrolidine4

with the synthesis 2a.

and

OC (5 mm);

chiral

of ynamine ynamine

in 52% yield

2a (Chart 2c

was

and 1). obtained

from

[ [ a lDz5 -4'.1 (benzene, c:

167.131 CM+, calcd for C10H17NO:

167.131)1.

6398

Reaction

of

afforded

the

lithium

the ynamine

spectrum, without

m/e 215.132 racemization

salt

of

(S)-(-)-Z-(methoxymethyl)pyrrolidine [[ c1 I,,25 -74.3

2d in 62% yield calcd

(M+,

in optical

for

yields

C14H17NO:

(benzene,

with

c: 1.75);

215.13111.

Roth

(chloroethynyl)benzene

bp 105-108 OC (0.002

ynamines

2c and 2d were

mm>; mass synthesized

of more than 95%. 5 Chart

1

c---l

c-5 T

CH3

CH,OCH,

1

k3

C2H5

(z) 2_b

?a

When the racemic in a total

eluting

oxide;

fraction

slow eluting the basis

the

3H) (Chart

[5a; Yield:

ynamine

of 43% (ratio

64:36).7

The

shows in the lH-NMR

spectrum

2).

Molecular

that in the nitrone the pyrrolidinyl

isolated

by preparative

TLC a fast

ether

of the pyrrolidinyl

bp 40-60 ‘C)l ether)

substituent

to the racemic

nitrone

stereochemistry

and a

1. Mainly on

in both isomers

4a ( 6 0.87, bd, 3H)

to the isomer

diastereomers

at C-3.

two doublets

models of both with the

group

were

(2’S,5’S,2S,3R)

separated

spectrum

two doublets

cis-substituted

we assigned

fraction

5a ( 60.82, d,

shielded

in the ‘H-NMR

and

to

the

gel;

nitrones

eluent:

fraction

only

one methyl

due to shielding

5d

3H)

4d and 5d, indicate

4d, which is formed isomer

in a

28%; Rf - 0.5)

at 6 0.70 and 0.03 (J = 6.3 Hz,

spectrum

nitrone

[silica

The slow eluting

stereochemistry

to the diastereomeric

stereochemistry

TLC

were isolated

(4d; Yield:

3H).

diastereomeric

(2’R,5’R,2R,3S>//(2’S,5’S,2S,3R)

nitrones

by preparative

The fast eluting

at 8 0.89 and 0.57 (J = 6.3 Hz,

possible

may be strongly

Therefore

la, two diastereomeric

bp 40-60 OC 1:2 (v/v)].

(2’R,5’R,2S,3R)1/(2’S,5’5,2R,3S)

the

group

of

by the phenyl in excess,

the

(2’R,5’R,2R,3S)//

stereochemistry.

of racemic

40% (d. e.

ynamine

> 95% based

doublets

at

Reaction

of ynamine

6 0.68 and

2b with nitroalkene on NMR

-8.08

28% (e.

> 95% based (J = 6.3 Hz,

difference

of the chemical 5d, we assigned

shifts

This

the methyl

The groups

of the methyl

product

3H) for the methyl

leg also afforded

on NMR spectroscopy). 3H) for

lb* gave only one diastereomeric

spectroscopy).

( J = 6.3 Hz,

2b with nitroalkene

and -0.20

nitrone

groups

with nitroalkene

16%; Rf - 0) shows in the ‘H-NMR

(5d; Yield:

of

separated

were

bp 40-60 OC 1: 1: 1 (V/V) 1 giving

(chloroform/petroleum

stereochemistry

2b was reacted ether

Reaction

were

ether

and the (2’R,2S,3S)11(2’S,2R,3R)

chloroform/petroleum

group

diastereomers

nitrones

mp 180-182 OC (chloroform/diisopropyl

of the methyl

(2’R,2R,3R)//(2’5,2S,35) in excess

The

mp 182-185 ‘C

20%; Rf - 0.2;

absorptions

R3= C,H,

two diastereomeric

la,6

ether/petroleum

41%; Rf - 0.6;

d

2).

When racemic

(Chart

of 66 :34.

R3= C,H,

(Sk-(-, 2

with nitroalkene

chloroform/diethyl

[4a; Yield:

fraction

which is formed

yield

eluent:

of the ‘H-NMR

we assigned

2a was reacted

of 61%,7 and in a ratio

yield

[aluminum

ynamine

c

‘H-NMR

the (2’R,5’R,2R,3S)1/(2S,5’S,2S,3R)

in the

spectrum

in the nitrones

(5e)

IH-NMR

nitrone

of 5f exhibits group.

in a yield

spectrum

of the pyrrolidinyl

only one diastereomeric

of the pyrrolidinyl

groups

shows

groups

nitrone

(5f) in a yield of

two doublets

On the basis

at 6 0.57

of the large

5e and 5f, as was also observed

stereochemistry

two

substituent.

to the nitrones

in

5e and 5f.

6399

Chart 2

a (~‘R,~R,~R)/(~‘S,XS,~S)

R3 = C,H,;

b (2’S,2R,3R)-w

R3=

C,H,,R’=

c

R3

C,H,;

(2’S,2S,3R)-(-)

q

a k’R,2S,3SI/(2’S,2R,3R)

R6 = CH, CH,OCH,

b

(2’s,2s,3s)-(-)

R6 = CH,OCH,

c

(2

(~‘R,s’R,~S,~R)/(~‘S,~‘S,~R,~S)

pure ynamine 2c was reacted

TLC [aluminum oxide;

fast eluting fraction

[4b;

(choroformldiisopropyl c: 0.71);

with nitroalkene

eluent : acetone/petroleum

d

R’ = C,H,

e

$

f

R’=CH,

2: H

la a mixture of two diastereomeric

and a slow eluting fraction

Rf - 0.3; mp 170-173 OC (chloroform/diisopropyl

[5b;

Both diastereomers

were separated

ether bp 40-60 OC 3: 2 (v/v> I, giving a

Yield 33%; [ a lDz5 +47.8 (chloroform,

ether)]

R, 3S)-W

(~‘R,~‘R,~R,~SM(PS,S’S,~S,~R)

nitrones was isolated in a total yield of 51%, 7 and in a ratio of 73:27. by preparative

2

CH3

CH3

When the optically

‘S,

c:

Yield:

0.65);

Rf - 0.4;

mp 177-178 OC

11%; [ a lDz5 -109.1

(chloroform,

ether) I (Chart 2). From molecular models and

from comparison of the NMR data with those of the nitrones 4a and 5a we concluded

that nitrone

is

5b

in a

of 46%,

the (2S,ZR,3R)

stereochemistry

and

nitrone

which

the (2’S,2S,3S)

stereochemistry. the optically were isolated

ynamine 2d was reacted with nitroalkene

chromatography

gave nitrone

(chloroformIdiisopropy1 assigned

4c

ether);

[Yield:

22%; [ a lDz5 -416.7

mass spectrum,

m/e

440.209

(M+,

calcd

c: 0.836); for

of the nitrones

(chloroform,

c:

0.58);

nitrones

by column

mp > 240 OC

m/e 440.209 CM+, calcd for C28H28N2C3: 440.21O)l.

to nitrone 4c, which was formed in a d.e.

[Yield 10%; [ cx lDz5 +304.8 (chloroform, spectrum,

la for 3 h, two diastereomeric

in a ratio of 28 :68 and in a total yield of 52%. 7 Separation

of 41%. the (2’S,ZS,3R)

stereochemistry.

mp > 240 OC (chloroformIdiisopropy1 440.21O)l

CZ8Hz8N203:

was

assigned

We

Nitrone 5c ether);

the

mass

(Z’S,ZR,3S)

stereochemistry. Reaction of racemic nitrone 4a with allylmagnesium gave the allylsubstituted 74.9 (s,

C-4 and C-2);

1-hydroxyazetidine mass spectrum,

of the NMR spectra of corresponding

bromide,

in a mixture of diethyl ether and benzene,

6a in a yield of 20% [13C-NMR 6: 170.0 (s, C=O), 77.1 and

m/e 404.248 CM+, calcd for C26H32N202:

1-hydroxyazetidines

we assigned the (Z1R,2R,3S,4S>//(2*S,2S,3R,4R)

without substituents

stereochemistry

74.9

(s,

C-4 and C-2);

stereochemistry

]D25 - 41.8;

mass spectrum,

as shown in Chart 3. l1

(chloroform, m/e

434.258

c: 1.58);

On the basis in the pyrrolidine ring, 10

to I-hydroxyazetidine

When the optically active nitrone 4b was reacted with allylmagnesium isolated in a yield of 54%. [[a

404.246)1.

6a.l’

bromide 1-hydroxyazetidine

“C-NMR

CM+, calcd for

6: 170.4 (s. GO),

C27H34N203:

6b was 76.6 and

434.25711

with a

6400

Finally,

when

the

l-hydroxyazetidine 170.5

(s,

C=O),

of

optically

active

80.7 and 76.2

1. Comparison

482.257)

shifts

optically

6c was obtained (s,

nitrone

C-4and

characteristic

active

compound

was

reacted

mass spectrum,

of 6c with those

substituents

and

,OH

secondary

we have

amines

nitroalkenes

will

and be

the

allylmagnesium (chloroform, 482.254

bromide,

the

c: 0.36);

CM+, calcd

structures,

6

:

for C31H34N203:

lo shows

(2’S,2S,3S,4S)

chiral

13C-NMR

similar

chemical

stereochemistry

to

the

6c .

R” k

C6H&j-,$-

In conclusion

m/e

of related

we assigned

Chart c,3%

with

of 31% [[ ci. ]D25 +74.6;

C-2);

of the NMR spectra

the

4c

in a yield

shown the

that

a (2’R,2R,3S,4S)//(2’S,2S,3R,4R)

; R3 = C,H,,

R6= CH,

b

(2’$2R,3S

; R3 = C,H,;

R6= CH,OCH,

c

(2’5,2S,3S,4S)-(+)

, R3 = C,H,,

R6= CH,OCH,

chiral

promising

further

3

ynamines

results

investigated

49-C-)

and

in

are the

readily

available

asymmetric

extended

to

from

the corresponding

(4+2)-cycloaddition

other

(cyclo)addition

chiral

reactions reactions

of

with chiral

ynamines.

This

Acknowledgement. Research

(SON)

with

investigation

financial

was

aid from

supported

the Netherlands

by

the

Netherlands

Organization

Foundation

for Advancement

for

of Pure

Chemical Research

(ZWO).

REFERENCES 1. 2. 3.

4. 5.

6. 7.

8. 9. 10. 11.

AND NOTES

Oppolzer, W. Angew. Chem. (19841, 96, 840. Pennings, M.L.M.; Reinhoudt, D.N. J. Org. Chem. (1982), 47, 1816. a Delavarenne, S.Y.; Viehe, H.G. “Chemistry of Acetylenes” (19691, Dekker, H., ed., New York. E Brandsma, 1,. “Preparative Acetylenic Chemistry” (1971), Elsevier, Amsterdam. c Brandsma, L. ; Verkruijsse, H. D. “Synthesis of Acetylenes, Allenes and Cumulenes” (198n, Elsevier, Amsterdam. Harding, K.E.; Rurks, S.R. J. Org. Chem. (1981), 46, 3920. Hydrolysis of the optically active ynamine5+ave the corresponding amides (from 2~: [c( ID 25 -71.2 (chloroform, c: 0.66); from 2d: [ a 1 -48.8 (chloroform, c: 1.89). The optical rotations corresponded with the rotations of the qmides, prepared independently from the corresponding onticallv active amines and acid chlorides. Robertson, D.N. J. Org. Chem. (1960). 25, 47. The isolation of the nitrones in yields lower than 60% is due to the simultaneous formation of instable (2+2)-cycloadducts. Pennings et al. reported the simultaneous formation of 4-nitrocyclobutenes, as the (2+2)-cycloadducts, in the reaction of vnamines and nitroalkenes (see ref. 2). Hass, H.B.; Susie, A.G.; Heider, R.L. J: Org. Chem. (1950), 15, 8. Worral, D.E. Org. Synth. (1929). 2, 66. Van Elburg, P.A.; Reinhoudt. D.N. ; Harkema. S.; Submitted for publication. a From previous work it is known that Grignard reagents add stereoselectively from the less Findered side of the four-membered ring; van Elburg, P.A.; Reinhoudt, D.N. Submitted for publication. & From X-ray studies and NMR studies of 1-hydroxyazetidines we concluded that the hydroxyl group at the nitrogen atom is preferentially trans to the carhamoyl group at C-2; van Elburg, P.A.; Reinhoudt, D.N.; Harkema, S. Submitted for publication. (Received

in

UK 21

October

1987)