Regio- and stereocontrol in the intramolecular nitrile oxide cycloaddition to 2-furylthiol- and 2-furylmethanethiol derivatives.

Tetdcdron Vol. 47. No. 23, pp. 3869-3886.1991 Rmted in Great Edin

AND

REGIO-

oo4o4020/91 $3.00+.00 0 1991 Pergamon Press p

STEREWONTROL

IN

ME

2-FURYLTHIOL-

Rita Annunziata, Centro C.N.R.

INTRMOLECULAR

AND E-FURYLWTHANETHIOL

Mauro Cinquini,

and Dipartimento

Organica

and Giulia

Via Marzolo

CYCLOADDITION

TO

DERIVATIVES.

Laura Raimondi

e Industriale

19, 20133 Milano,

and Dipartimenco

OXIDE

Franc0 Cozzi,

di Chimica

Via Golgi

Centro C.N.R.

NITRILE

dell'tlniversita,

Italy

Licini

di Chimica

Organica

1, 35131 Padova,

dell'llniversita,

Italy.

(Received in UK 22 January 1991)

Abstract.

A series of 2-fury1 and 2-furylmethyl substituted length were prepared and showed to undergo

chain

nitrosulphides with a proper a totally regiocontrolled

intramolecular furan-nitrile oxide cycloaddition to give cis-fused products in high yield. Insertion of a stereocenter on the cycloaddends did not allow satisfactory Enantiomerically enriched control of the absolute stereochemistry of the reaction. products of the

(e.e.<95%1

sulphide

The proteiform into organic result tne

molecules

of

especially

reports

variety

is to use furan

role

enhance

were

either

regio-

and

deal

withstanding dipolarophile, furan-nitrile

7-10

as a reagent

oxide

entry to C-4 oxygen

goal.'

can

help

intramolecular

the

cycloaddition.8

stereoselective

synthesis

stereoselective

nitrone

and nitrile

of

problems

of

to

bonus

in the

important

oxide cycloadditions,

reactivity

limited to

number furan,

particularly most

building

this

can play

intermolecularly

react

offered

8,ll

to

processes

poor

very

is indeed

a very

sugars.

a

its insertion

approach

intramolecular

cycloadditions

11

oxidation

heterocycle

dipolar

reaction

3869

this

only

tendency

amino

popular

since

line

makes

However,

synthetic This

involving

by furan

the most

overcome 2

isoxazolines,

of various

offered

this

1,3

scarce

obvious

substituted

to

control.

stereochemical

extremely

One

In

process

sulphoxides.

in cycloaddltions,

27r component.

as they

and

resolution

opportunities

an attractive

with

its

by a kinetic

to the corresponding

of synthetic

47r or

appealing,

3-6

obtained

cycloadducts

by

seem and of not as the

straightforward block for

the

In the course of our studies on 12

we became

interested

in

R. ANNUNZIATA et al.

designing

a

precursors

furan-nitrile

of acyclic

products.

jn this field,

we decided

dipolaropnile,

with

isoxazolines

into

2-Furylthiol The

Lithiation

a functionalized

to

17

1, that was treated

the

followed

(58-62%

the

unreacted

in

alkylation in

57%

compounds

alcohols

recovery 8-10

in

respectively,

only

reagent

nicrile was

assigned

on

hand 19

we

comparison

assignment.

dipole

COnVetXing

This

and tne

manuscript

to

Scheme

P-fury1

alcohols of

overall

the

(94-100%

iodides

yield),

under

nitrous

recycled,

An alternative

nitroethylene

esters

While

and

of

the

could

of compound

Compound

generaced

oui

in DMF

the former

synthesis

(40% yield).

PTC

could be carried

or with sodium nirrice

the

1.

thiolate

2-5, in 68-77%

This reaction

of

in

to the nitro derivatives

intramolecular

of the nitro compounds

were refluxed

examined

basis

unchanged. to which high

any intramolecular

Two stereocenters

to give

purification

in

6

10 was

also

situ

from

the

by flash

products Tricyclic

-1 field

H

20

be detected,

and

13

C

NMR 3-6

11

cycloadduct

lends additional

of defined

relative

and

spectroscopic

systems.

of

while

indicated

for related

6

and

(that also allowed

In the reaction

structure

Only compound

11 and 12 in 79

chromatography

could

Dilute

for 24h in the presence

crlethylamine.

derivatives

fused

CIS-

cycloaddition.

isoxazolines

nitrosulphide).

self-addition

of

and catalytic

cycloaddition

with the data reported

did not afford

experience

and on the regio- and

lithium

their

after

oxide

products the

the

(48-56% yleldj amounts

1

gave

synthesis

upon reduction.

10% of the starting

recovered

regioisomeric

to

The latter were

adding

intramolecular

of about

and 11

reported

IS

Conversion

1-iodo-3-nitropropane

by

18

to give compound

exchange.

of 3 mol equiv of p-chlorophenylisocyanate

75% yield,

sulphur

yield),

variable

also obtained.

solutions

and 7 underwent

tether

to

13

6-10

(0.02M) benzene

cases

yield

2-acetoxynitroethane. With

(80-83%

of 1 with

series

reduction

and iodine-nitro

both

iodides were

prepared

involving

tosylates

afford the corresponding entailed

with

ether with silver nitrite

yield);

previous

lead

reaction.

one pot procedure.

steps

(86-913 yield),

in diethyl

the

could

connecting

a y -aminoalcohol.

this

in situ withw-bromoesters

in four

either

of

by reaction

6-9 was

of

in the chain

of two series of cycloaddends

cycloaddends

in a convenient

preparation

or

that

and other's14

cleaving

of their cycloaddition

yield from furan,

conditions

atom

15

fl -ketol

13

16

route

achieved

a sulphur

on the synthesis

series.

of furan

cycloaddition

On the basis of ours

to insert

implications

synthetic

intramolecular

the goal of simultaneously

reports our results stereochemical

oxide

12

cycloaddends most were

of

the

single

in Scheme

1 was

evidences,

The fact that nicrosulphide

and 10

support to ihe structural

stereochemistry

are formed

in the syn-

3871 Nitrile oxide cycloaddition

Scheme 1

0/ \

I\ (x

ati

0

0

SLi 2, 4.

1

4x\

S/\/No2

6, 8,

6.

(CH2)n s' d

0

10

n=2; n-4;

7, 9,

3, 5.

n=3

n-5

NO2

n=3 n-5

i

7

11, n=l;

12, n-2

i

h 6.7

n-2; n-4;

-

5332

)

n\/NO2

-

0

13, n=2;

15a,b, 16a,b,

14, n=3

n=l n=2

O, l-

jrerf

NO2

&

Me

%

17

w:

a, n-BuLi;

IN

I

then Ss; b, Br(CHZ),,COOEt; C. LiAlH4; d, TosCl,

OS 18a.b

TEA;

e, KI, Bu@+I-;

f, AgNO2 or NaNO2; g, I(CH2)3NO2; h, AcOCH~CH~NO~;

i, p-ClCsH4NC0,

TEA; h, NaIOq; jr BrCH2CHWe)CHzCl

Me

3872

R.

ANNUWUTA~~al.

thesis of 11 and 12 from 6 and 7. The control introduction 7 was

of a stereocenter

oxidized

with

sodium

12

on the reagent.

metaperiodate

to give

the

corresponding

13 and 14 in 82 and 87% yield,

respectively.

mixture

diastereoisomeric

15a,b

of

for compound not

ratio was evaluated

15a,b

and

dipolarophile

stereoselection alkene.

an allylic was

reportedL'

disappointing

respect

to

stereochemical in

a

66:34

the

nitrile

outcome

and

cycloaddition

prompted

enantiomerically

The

the

commercially

of

available

sodium ethoxide

gave compound

isoxazolines

followed

the

Also

the -cis-fused

above

was

is

yield.

decomposition.

in

some

of

the

(73% yield)

precedents outcome

to isoxazolines

in

position extent

obtained

stereochemical

two

straightforward

way by condensing

in the presence

of piperidine,

Scheme

Alkylation

in

the

of

the

as 11 or 12 in

experimental

on the basis

were of

sulphoxide

racemic

sodium

single

report

stereochemistry was

analogues

to give nitrosulphides

of

of

in DMF

24

intramolecular give

cricyclic by flash

regioisomers,

to which

on

analogy

a virtually

was

resulted 20

of

purlflcation

accomplished

cycloaddition

19 with nirromethane

to

evidences, 23

nitrite

underwent

after

NMR

Addition

in the presence

conditions,

and literature

however,

with

respectively,

2.

of the sodium salt of 19

two cycloaddends

of absolute

chiral

in

exchange

the cycloadduccs

series,

oxidation:

Next,

being

extent

limited

19 to E-acetoxynitroethane

These

described

20 to the corresponding

25

very

has

the

described

by bromide-nitro

in this case control

metaperiodate

result

20 in 85% yield.

assigned

of the 2-furylthiol

system. Also of compound

products

in this case

structure

18a,b

new approaches

22 and 23 in 77 and 76% yield,

chromatography.

usual

required

21 in 44% overall in

this

of controlling

a

connecting

17, prepared

In this case a stereocenter to

was

an E-configurated

of nitrosulphide

dictate

The

to be 75:25

chain

on

a

23

gave nitrosulphide

cycloaddition,

60% yield.

identical

cycloaddition

gave

stereocontrol

the

practically

compound

Also

ratio.

and

of

inside

racemic

of these

and determined

low extent

located

oxide

can

2-furylmethanethiol

with 1,3-dibromopropane

in 63

the

form (see below).

series.

synthesis

1.

moiety

us to investigate

2-Furylmethanethiol

products

oxide

impossibility

enriched

This

promote

of tne cycloaddition,

the

16a,b,

the cycloaddition

in Scheme

diastereoisomeric

literature,22

to

nitrile

was

three steps from 1 as described with

16a,b.

stereocenter

in an intramolecular

Similarly

and

requires

atom of 6 and

chiral,

Cycloaddition

by 'H NMR spectroscopy

and 70:30 for compound

indeed,

unexpected:

dipole

cycloadducts

configuration

To this end, the sulphur

sulphoxides

diastereoisomeric

a

of the absolute

were

and propanal

attempted. in fair only

with

identical Oxidation

yield in

prepared

the

by the

extensive in

a

very

or 2-methylpropanal,

24 and 25 in 78 and 80% yield,

3873

Nitrile oxide cycloaddition

Schm

2

‘-NO, 20

m/

SW

0

19 S-NO2 21

0,

3

20

dl

O,N

FJ 2

5

N

d

21

0.z

0 .-\ S

‘S

22

19

23

d

S

e_

CH$Q

-

Y R 26a.b. b.

24, K=Et 25, Et-Pr-i

278,

R-Et K=Pr-i

Me

28

29

d

\

Reaaents:

a,AcOCH2CK2N02,

EtOUa: b, EtONa, Br(CH2)aBr; c, NaN02, DMF;

d, P-ClC#4NCO, TEA: e, CH3U02, RCHO, Piperidine; f, Br(CH2)~CoOEt, EtONa; 9, LiAlH,; h, t-BuMe2SiC1, Imidatole; j, LDA, KMPA, HaI; k, Bu,N+F-; 1, HsCl, TEA; m, KI, Bu,N+I-.

3874

R. ANNUNZIATA etal.

respectively. compounds

26

their

However,

cycloaddition

26a,b and 27a,b were obtained of two diastereoisomers.

of a cycloaddend

featuring

an allylic

28 was

in three

high

methylated

(72% yield)

yield),

by the usual

66:34 mixture structures isomer basis

The

poor

assigned

steric

on

of

cycloaddition

that

by

for

the

inserting

oxidation

sulphur

atom

of

tnese compounds

by some

(Table 11. The former,

preliminary

derivative

(87%

a 79% yield

of a

predominance

of

the

be

rationalized

on

the

in agreement

sulphoxide

detectable

16a,b was obtained

both cases the predominant of 13 or 14.2g Oxidation respectively)

with

previous

reagents

1. In kinetic

1.0 mol. equiv.

is

25,

and

29

stereochemistry

reagent.

We

represent

enriched 28

30

also

by

1 H NMR

out

therefore

and the rigid structure

on

compound

highly

11 and 12

from

the

(76% yield).

In

of the cycloaddition

since the products

(see below):

(31a.b

this prevented

of the mCPBA oxidation. sulphide

oxidation,

to secure

selective.

(0.5 mol.

of (+I-diethyl

23

process.

acid, gave

while

ratio

products

convenient

Indeed, a number

(70% yield),

in lower yield

that is known

conditions

form.

a

stereodifferentiating

carried

enantioselective

reagent,

resolution

could

was the major

Among

oxidation

the

in 85:15 diastereoisomeric

of the diastereoselectivity

mCPBA

24,

11. 12, 22, and 23.

some tendency to decompose

for

17,

oxidation with m-chloroperbenzoic

of 22 and 23 proceeded

of Sharpless's

on

of a highly

a safe determination available

center

14,

the absolute

has been reported,

isomer

isomer obtained

showed

13,

to control

experiments

upon low temperature

15a as a single

of

in enantiomerically

This was confirmed

of Ti(OPr-i14;

converted

alCOhO1

iodo

was

The

can

is

cycloadducts

the possibility

Table

and

of cycloadducts our

suggested

the analW3OUS

compound

approach.

of our isoxazolines

the

the

27

position

a stereogenic

of sulphides

modification

botn

reaction

3Da and 3Db, to which the indicated

reaction

be very difficult

oxidations

and 32a,b,

This

of 29 gave

of NOE experiments.

of enantioselective

latter

the

19, silyl derivatives

yield).

and

Cycloaddition

considerations,

to a different

the

handle for obtaining

sulphoxide

from

and the resulting

(76% yield)

in an equatorial

observed

and enantioselective

reasoned

co investigate

overall

isoxazolines

basis

interaction

that it would

turned our attention

Diastereo-

the

(71%

since

(82 and 76%, respectively),

starting

(91% yield),

(60% yield).

group

stereoselectivity

indicate

We

steps

stereoselective,

12

clearly the

procedure

non

We then decided

29, -via the mesylate

tne methyl

of simple

observations.

yielding

of two diastereoisomeric

were

having

"

stereocenter:

and deprotected

into the nitrosulphide

totally

in good yield

as 50:50 mixture

prepared

was

The

equiv.

tartrate)

good

results

of tBuOOH;

sulphide

we

selected

stereocontrol are

wnen

collected

0.25 mol.

a

in

equiv.

11 gave exclusively

3875

Nitrileoxidecycloaddition

Table

1. Stereoselective

Sulphide

oxidation

of 11, 12, 22, and 23.

Sulphoxide

Oxidant

D1astereoisomer,ca a:b ratio

11

mCPBA

15a.b

12

mCPBA

16a,b

Q D

%

22c

3

85:15

11

TBHP/Ti(OPr-l),/(+)DET

15a,b

397:

3

85

-561.1

12

TBHP/Ti(OPr-i)4/(+)DET

16a,b

297:

3

95

-511.5

lid

TBHP/VO(acac)2

15a,b

397:

3

36

t233.1

12d

TBHP/VO(acac)2

16a,b

>/97: 3

43

t223.3

22

TBHP/Ti(OPr-i)4/(+)DET

31a,b

28

tl85.3

23

TBHP/Ti(OPr-i)4/(+)DET

32a,b

64

-151.6

aAs determined 1 H

297:

[I

E.e.b

NMR

in

pre-established

solution,

397:

b

by 300 MHz 'H NMR spectroscopy.

spectroscopy

conditions

Ei0:20e

c

the

presence

of

3

As determined

for a isomers

(-)-trifluoromethyl-9-anthrylcarbinol

on racemic compound. 'As determined d Sulphide recovered from

0.5-1.0.

TBHP/Ti(OPr-i)4/(t)-DET.

by 300 MHz

for a isomers the

in

in CHC13 with

oxidation

e31b had e.e. 35%.

sulphoxide (-)-15a in 60% yield based on the oxidant. The e.e. was determined as 85% by 1 H NMR spectroscopy in the presence of (-)-trifluoromethyl-9-anthrylcarbinol, in conditions product

pre-established (-I-16a

enantiomerically sulphides

11

(48%

yield

pure

by

and

tBuOOH/VO(acac12 yield,

12,

to

43% e.e.1,

give

being

was

obtained

Compound

obtained

recovered

the

sulphoxides

the

(+I-15a

kinetic

31

(based on the

sulphoxide

a single shown

sake

resolution, 36%

The oxidation

oxidant)

the

by the

(-)-32a

of

were

e.e.1

From compound

pure, as evaluated

isomeric

was

For

(50% yield,

diastereoisomers.

afforded

that

technique.

series was then examined.

a single

of 12

oxidant),

described from

in 48% yield

as 64%.

15a. Oxidation

on

above

28% enantiomerically

23 afforded

was determined

the

based

both as single

of the E-furylmethanethiol of 31a,b

on racemic

and

to

isomeric be

95%

completeness, treated (+I-16a

with (36%

of the cycloadducts 22 a 80:20 mixture

major usual

(52% yield),

isomer,

32

(+I-3la,

1 H NMR technique. the e.e. of which

R. ANNUNZIATA~~ al.

The

stereochemical The

comments. definitely

outcome

of

enantiomeric

higher

than

the

kinetic

excesses

those

resolution

observed

obtained

for

with the

showed

differentiated

more

stereoselective

ligands. The greater

difference

for

in 11 and 12 than in 22 and 23 can account

are the

reasons

any reasonable

understand reports. In

lower enantioselection

this

explanation

result.

A

for

similar

that,

with

is

sterically

a

at

Less evident

of tetrahydrothiophene

experimental

not

33

well

of the substituent

of the oxidation

behaviour

reactions,

for this observation.

and more

few were

12 and 23. We do not work

common

is necessary

feature

of

to

literature

30,33

conclusion

we

2-furylthiolfashion

for similar

sulphides

a

derivatives

E-furylmethanethiol

11 and 22 with respect to that of thiopyran derivatives

derivatives have

the

in steric bulkiness

sulphur

for the

of

observations

oxidations

requires

P-furyltniol

compounds

series: this is in line with a number of previous that always

experiments

the

showed

that

intramolecular

and 2-furylmethanethiol

derivatives

to give high yield of -cis-fused

number of synthetically stereochemistry locations

on

stereocontrol. established sulphide

chain

An

connecting

alternative

by a kinetic

to sulphoxide

approach

to

oxide

cycloadditions

in a completely

that in principle

Various

reaction dipole

resolution

occur

products,

useful transformations.

of tne cycloaddition the

furan-nitrile

attempts

by inserting

on

reigocontrolled

are amenable

to control

a stereocenter

to a

the absolute in different

and dipolarophile

resulted

in poor

to

fair

enantiomerically

enriched

cycloadducts

was

process

involving

a diastereo-

and enantioselective

oxidation.

Experimental. 1 H and l3 C NMR spectra were recorded

with

on CDC13

are

solutions.

were measured a

Perkin

Chemical

shifts

on a Perkin-Elmer

Elmer

chromatography;

DMF

employing

and

240

instrument.

organic

extracts

CH2C12

anhydrous

from

in ppm

Silica were

gel

dried

from

from

Elemental was

over

pressure.

CaH2;benzene

WP 80 or a Varian

downfield

241 spectrometer.

removal of the solvent under' reduced HMPA,

a Bruker

used

sodium

Et3N

Optical

rotations

were performed

analytical

sulphate

THF and Et20 were sodium;

TMS.

analyses for

XL 300 instrument

and

and filtered

distilled

from

KOH.

from All

with flash

before LiAlH4;

reactions

solvents were run under Argon.

General procedure for the synthesis of esters 2-5. To a stirred

solution

of 2-furyllithium l7 (50 mnol) in THF (250 ml),

mmol) was added portionwise then treated

with

at 0°C. The dark red solution

ethyl w-bromo

alkanoate

(45 mmol).

The

sulphur

(1.6 g, 50

was kept at 0°C for mixture

was

stirred

1.5 h and at room

3877

Nitrileoxidecycloaddition

temperature then

overnight, the

added;

hydroxide,

and the reaction

organic

phase

washed

twice

and then with brine. The products

chromatography

with 90:10 hexanes:diethyl

requires:

C, 53.98;

by addition

with

5%

ether mixture

of water. aqueous

Diethyl

ether was

solution

as pale yellow

of

sodium

oils by flash

as eluant.

in 68% yield.

1 H NMR: a

H, 6.04.

a

were isolated

2 was obtained

Ethyl 3-(P-furylthio)propanoate CgH1203S

quenched

6.31-7.46

Found:

C, 54.06;

(m, 3H); 4.09

H, 6.12.

(q, ZH);

2.93

(t, ZH); 2.56 (t, 2H); 1.21 (t, 3H).

Ethyl

3 was obtained

4-(2-furylthio)butanoate

C10H1403S

requires:

requires:

4 was obtained

requires:

(t, 2H); 2.27 (t, 2H); 1.37-1.71

O"C,

ether

a diethyl

dropwise.

The reaction

(5 ml/mm01

15-30 min. After cooling 15% aqueous

NaOH

The precipitate

quantitative

dissolved

in dry CH2C12

were

reaction

added

mixture

concentrated chromatography

to

ester)

solution

then warmed

H20

and

of

ester

ether (3 ml/g

of LiAlH4)

(1.2 mol equiv)

the

with crude

acid

H, 5.15.

H,

7.57.

(q, 2H); 2.73

After H20

purity

overnight and

products

the that

ether mixture

C14H1604S2

requires:

C, 53.83;

added

NMR).

at

phase

room

was

added for

in this order.

To

in

the

alcohol,

chloride

(1.0 mol

temperature,

as

at

of LiAlH4),

separated,

isolated

dried,

oils

by

the and flash

as eluant. was

3-(2-furylthio)propylester

(1 ml/g

and tosyl

stirring

were

were

1 H

(by

organic

H20

mm011

and refluxed

to give the crude alcohol

Et3N

order.

(20-30

(ca. 100 ml),

(10 ml/mmol),

give

59.18;

of ester) cooled

up to room temperature

high

washed

C,

Found:

(10 ml/mm01

very

with a 70:30 hexanes:diethyl

C, 54.01;

(m, 7H); 4.13

of

ether

in

was

H, 7.00.

(q, 2H); 2.78

(m, 3H); 4.10

6.30-7.46

and the solvent was evaporated

yield

in this

4Aethylphenylsulphonic Found:

was

of LiA1H4),

was filtered

virtually

equiv)

in 76% yield.

in diethyl

at 0°C wet diethyl

(1 ml/g

C, 57.88;

Found:

of the tosylates.

(3 mol equiv)

mixture

6.66.

(m, 6H); 1.21 It, 3H).

General procedure for the synthesis of LiAlH4

H,

(q, 2H); 2.73

(m, 3H); 4.12

6.25-7.43

C, 59.48; H, 7.49. 'H NMR: a

To a suspension

55.93;

(m, 4H); 1.26 (t, 3H).

5 was obtained

6-(P-furylthio)hexanoate

C12H1803S

C,

(m, 3H); 4.04

in 75%*yield.

'H NMR:a

C, 57.87; H, 7.06.

(t, 2H); 2.35 (t, 2H); 1.57-1.95

Ethyl

6.22-7.40

Found:

(m, 2H); 1.15 (t, 3H).

Ethyl 5-(2-furylthio)pentanoate C,,H1603S

'H NMR:a

C, 56.05; H, 6.58.

(t, 2H); 2.35 (t, 2H); 1.80-2.05

in 77% yield.

obtained

H, 5.16.

in

82%

'H NMR:a

yield.

6.29-7.81

(t, 2H); 2.71 it, 2H); 2.43 (s, 3H); 1.87 (m, 2H).

4-Methylphenylsulphonic

acid 4-(2-furylthio)butylester

C, 55.11; H, 5.61. C15H,804S2

requires:

was obtained

C, 55.19; H, 5.56. 'H NMR: a

4.05 (t, 2H); 2.74 (t, 2H); 2.47 (s, 3H); 1.55-1.92

(m, 4H).

in 80% yield.

6.29-7.82

Found:

(m, 7~1;

3878

R. ANNUNZIATAetal.

4+4ethylphenylsulphonic

acid

was

5-(2-furylthio)pentylester

Found: C, 56.30; H, 5.87. C,6H2004S2

requires:

acid 6-(2-furylthio)hexylester

C, 57.70; H, 6.18. C,7H2204S2

requires:

3.98 (t, 2Hl; 2.68 (t, 2Hl; 2.41 (s, 3H); 1.20-1.65 General

procedure

for the synthesis

of the iodides.

To a solution

and K2C03

(1.2 mol equiv)

in benzene

(50 ml)

was

added.

The

two-phase

of the tosylate

(100 ml),

mixture

etner was added, the phases were separated; .

aqueous

solution

gave the crude 80:2D

of sodium thiosulphate, iodides

that were

hexanes:diethyl

(20 mmol),

by

mixture

as eluant.

oils, that were used without

further

purification.

path

The

Bu4N+I-

stirred

cne organic

short

ether

(m, 7H);

(1 mol equiv)

of KI (3 mol equiv)

and then with water.

purified

6.25-7.78

Found:

6-9.

vigorously

Diethyl

: 6.30-7.81

in 83% yield.

'H NflR: a

a solution

was

yield.

(m, 8Hl.

of the nitrosulphides

Synthesis

82%

(m, 6H).

was obtained

C, 57.60; H, 6.26.

in

'H NMR a

H, 5.92.

C, 56.45;

(m, 7H); 3.99 (t, 2H); 2.66 (t, 2H); 2.43 (s, 3H); 1.20-1.77 4-lkthylphenylsulphonic

obtained

at

60°C

in water

overnight.

layer was washed

Evaporation

column

products

with an

of the solvent

chromatography

were

pale

with

yellow

a

mobile

Synthesis of the nitrosulphides.

Method A. To a solution of the iodide (l-3 mm011 in dry

diethyl

(3 mol equiv)

ether

The resulting and

the

(5 ml/mmol), suspension

filtrate

hexanes:diethyl

AgN02

added

portionwise

over

was stirred for 24-48 h at RT, then was filtered

concentrated

ether

was

mixture

and

purified

as eluant.

by

Yields

flash were

through

chromatography

48-56%

a 2h period.

with

in yellow

oily

celire

a

75:25

products.

Method B. The iodide (l-3 mm011 was added to a solution of NaN02 (2 mol equiv) in DMF (2 ml/mmolI,

and

the

mixture

product was extracted

several

by flash chromatography

44.91;

2H); 2.07-2.41

24-48

times with diethyl

6.

Found:

H, 4.85; N, 7.48. 'H NMR:a

h. Water

was

then

added

ether. The crude products

and

the

were purified

C,

44.99; 6.34-7.51

H,

4.79;

N,

(m, 3H); 4.70

7.53.

C7HgN03S

(t, 2H); 2.81 (t,

(m, 2H).

4-(2-FurylthioI-1-nitrobutane C, 47.75;

H, 5.51;

1.43-2.33

(m, 4H).

N, 6.96.

5-(2-FurylthioI-1-nitropentane C, 50.22;

H, 6.09;

1.17-2.07

(m, 6H).

N, 6.51.

6-(2-Furylthiol-1-nitrohexane C, 52.38;

at RT for

as above. Yield were 58-62%.

3-(2-Furylthiol-l-nitropropane requires:C,

stirred

H, 6.59;

N, 6.11.

7. Found: C, 47.85; H, 5.50; N, 7.00. C8H11N03S 'H NMR: a

6.31-7.46

(m, 3H); 4.30

(t, 2HI; 2.81

8. Found: C, 50.15; H, 6.01; N, 6.51. CgH13N03S 'H NMR: a

6.31-7.48

(m, 3H); 4.36

(t, 2H);

2.73

9. Found: C, 52.42; H, 6.61; N, 6.04. C10H15N03S 'H NMR: a

6.31-7.47

(m, 3H); 4.34

It, 2H);

2.71

requires: (t, 2H);

requires: (t, 2Hl;

requires: (t, 2H);

3879

Nihileoxiclccycloa&iition

1.18-2.14

(m, 8H).

2-(2-Furylthio)-l-nitroethane

10. To a solution

O"C,

(0.266

Z-acetoxy-1-nitroethane

stirred

at 0°C for

and the organic

g,

3h; the reaction

phase was

mnol)

The products

ether mixture N, 8.02.

was

was

as eluant,

Found:

C, 41.51;

H, 4.13;

NMR:a

6.36-7.53

(m, 3H); 4.54 (t, 2Hj; 3.24 (t, 2H).

C6H7N03S

3-(2-Furylthio)-2-methyl-1-nitropropane with

alkylation conditions experimental (60% yield, H, 5.51;

synthesis

conditions method

N, 6.96.

of esters

stirred

13 and

at O"C, NaI04

by flash chromatography

(m, 3H); 4.15-4.67

(0.428 g, 2 mm011 Usual

41.44;

requires:

H,

6.41-7.60

4.53;

N, 6.96.

C7HgN04S

(m, 3H); 4.41-4.60

H, 5.12;

6.55-7.69

N,

(10 ml),

stirring

as described

3H); 4.45

2-acetoxy-1-nirroethane

C7HgN03S

the

requires:

experimental

conditions)

and

47.87; H, 5.57; N, 6.87. C8H11N03S

C, 47.75; (m, 2H);

in 87%

of

added

g, 2 mm011

product

in 85%

H, 4.85;

was

N, 7.48.

N, 6.45.

NMR:a

Found:

C,

'H NMR:a

(m, 4H). etnoxide at 0°C.

(2 mmol) After

added dropwise.

yield.

C,

(m, 2H).

5.10;

dropwise

were

Found: 'H

as on oil.

sodium

that

and

as eluant.

N, 6.89.

yield

H,

products

in

Found:

1 H NMR:a

C,

in

10 min Work-up

45.01;

6.25-7.37

H, (m,

(t, 2H).

nitropropane

salt of 19 by alkylation

for

(2 mm011

as an oil.

4.46;

(m, 2H); 1.80-2.25

(0.266

C, 44.91;

H,

by

exchange

2.68-2.78

mixture

in 82% yield

a solution

the only

(t, 2H); 3.83 (s, 2H); 3.15

3- C(2+urylnethyl)thio]-lthe sodium

10 gave

ether:methanol

C, 44.23;

was

1

(79% yield,

requires:

crude

'I-!

experimental

of sulphide

(m, 2H); 2.30-2.56

(m, 2H); 3.06-3.34 20. To

the

41.37;

obtained

19 (0.228 g, 2 mmol)

for compound

4.76; N, 7.53.

C,

requires:

-I-nitroethane

compound

at O"C,

14 was

C8HllN04S

(m, 3H); 4.43-4.63

2-[(Furylmethyl)thio] EtOH

6.37.

obtained

(m, 2H); 2.92-3.45

4-(P-FurylsulphinylI-1-nitrobutane 44.40;

gave

with a 98:2 diethyl 13 was

solution

from

in H20 (3 ml) was added dropwise

work-up

3-(2-FurylsulphinylI-1-nitropropane

steps

iodine-nitro

(m, 2H);

NH4Cl

N, 8.09.

for

C8H11N03S

was

chromatography

4.07;

exchange and

at

oil in 57% yield.

yield,

of the iodides),

mixture

of saturated

H,

three

2-5), chlorine-iodine

14. To a stirred

at RT overnight.

in

(70%

6.25-7.41

(10 ml) cooled

purified

prepared

'H NMR: a

of nitrosulphoxides

The

by flash

C, 41.61;

C, 47.83; H, 5.57; N, 7.00.

Synthesis

dropwise.

to give a yellow

B). Found:

(m, 1H); 1.12 (d, 3H).

the mixture

was

(10 ml) cooled

by addition

propane

see the synthesis

2.32-2.52

MeOH

17

in THF

purified

requires:

1-bromo-3-chloro-2-methyl

see the

added

was then quenched

separated.

with a 70:30 hexanes:diethyl

2

of 1 (2 mmol)

21 was

with

obtained

, as an oil, in two steps from

1,3-dibromopropane

bromine-nitro requires:

exchange

C, 47.75;

(73% yield, (61%,

method

H, 5.51; N, 6.96.

see 8).

above Found:

'H NMR:a

for C,

6.15-

3880

R. ANMJNZIATA et al.

-7.39 (m, 3H); 4.48

2H); 3.83 (s, 2H); 2.05-2.80

(t,

-nitrobutane

2-[(Z-Furylmethyl)thio]-1 of 25 in 78% yield.

’ H NMR:a

lH1; 1.40-1.82

(m, 2H), 0.95

6.15-7.32

CgH13N03S

for the synthesis

requires:

(d, 2H); 3.71

imethylethyl)dimethylsilyi]

from the sodium

(83%), reduction

(m, 3H); 4.37

23

as described

C, 50.22;

(s, 2H); 3.05-3.38

H, (m,

(t, 3H).

3-[(2-Furylmethyl)thio]-1-[[(1,1-d steps

(m, 4H).

prepared

Found: C, 50.09; H, 6.01; N, 6.58.

6.09; N, 6.51.

in three

24 was

with LiAlH4

salt

of 19 -via alkylation

(loo%), and standard

oxylpropane with

silylation

ethyl

with

28 was prepared

3-bromopropanoate

TBOMSCl

and imidazole

H 0 SSi requires: C, 58.69; H, 9.15. 'H NMR: 14 26 2 2.46-2.73 (m, 2H); 1.70-1.96 (m, 2H); 0.95 (s,

in DMF (85%). Found: C, 58.78; H, 9.23. C d6.257.33

(m, 3H); 3.61-3.84

9H); 0.05

(m, 4H);

(s, 6H).

3-[[1-(2-Furyl)ethyl]-l-thio]-lsolution

of LDA

(1.7 mm011

mm011 was added dropwise. after 10 min., temperature

yield

was of

flash

starting

of

obtained

product

the

mixture

that were 3H20

These

were

hexanes:

the

mmol),

in benzene

C, 50.22;

mixtures

as

was

by flash

refluxed

to allow

eluants

to

ether see

mixture above),

(method

give

the

91%

mesylates

separation

as

eluant).

from

'H NMR: a

The

to give

the

which

B). Found:

N, 6.51.

to room

chromatography.

enough

by The

29 was

C, 50.36; 6.15-7.32

H, (m,

(m, 2H1; 1.60 (d, 3H). A

mol

24 h under

purified

1.61

(72% by NMR)

conditions into

(3

g,

to warm-up

of product

cycloaddition.

and the residue

stirred equiv), nitrogen.

by flash

cycloadducts.

solution and The

catalytic urea

chromatography

Relevant

NMR

of

was with

data

are

2 and 3.

11, m.p. 76-77"C, was obtained as eluant.

H, 6.09;

(0.46

converted

(87%,

4-chlorophenylisocyanate

(50 ml/mmol)

allowed

(t, 2H); 1.90-2.30

intramolecular

was evaporated

in Tables

diethyl

28

(0.8 ml) was added, followed,

was

not separable

into the iodide

requires:

sulphide

in THF in the standard

alcohols.

50:50

in five steps from 28. To a

gave a mixture

as an oil in the usual conditions

for

(l-3

benzene

indicated

Compound

a

was converted

procedure

triethylamine

collected

Usual work-up

(t, 2H); 4.00 (q, 1H); 2.45-2.67

nitrosulphide

filtered,

at -78"C, HMPA

3.2 mmol). The reaction

two

(with

6.03; N, 6.58. CgH13N03S

General

at -78"C,

Et20, Et3N, O"C, 30 min, 76%) that were stable

in 60% yield

3H); 4.41

(10 ml) cooled

by Bu4NtFthe

29 was prepared

lh stirring

material,

deprotected

chromatography

methylated

After

Me1 (0.200ml,

a mixture

(CH3S02Cl,

in THF

and stirred overnight.

and unreacted mixture

by

nitropropane

Found:

C, 49.77;

in 79% yield

H, 4.24;

with

N, 8.31.

a 85:15

C7H7N02S

hexanes:diethyl requires:

ether

C, 49.69;

H,

4.17; N, 8.28. Compound

12, nD25 1.5578,

was

obtained

in 75% yield

with

a 80:20

hexanes:diethyl

ether

3881

Nitrile oxide cycloaddition

Table 2. Relevant

'H NMR data of cycloadducts

11, 12. 15, 16, 18, 22, 23, 26, 30a (see

Schemes for numbering).

H-C,

H-C2

H-C3

11

6.61

5.43

5.80

12

6.54

5.26

5.50

Compound

a Typical

15a

6.63

5.67

6.00

15b

6.86

5.56

6.05

16a

6.51

5.56

5.96

16b

6.76

5.46

6.12

18a

6.58

5.36

5.76

18b

6.61

5.37

5.73

22

6.66

5.35

5.65

23

6.58

5.38

5.38

26a

6.63

5.30

5.60

266

6.65

5.33

5.60

3Oa

6.63

5.28

5.43

3ab

6.56

5.25

5.50

31a

6.59

5.44

5.84

31b

6.72

5.42

5.75

32a

6.61

5.38

5.68

J, 92 and J2 93 values were 2.5-3.0 Hz for all cycloadducts.

J, , 3 was

less than

1.0 Hz.

mixture 4.95;

as eluant.

Found:

C, 52.49;

H, 5.00;

N, 7.59. C H NO S requires: 89 2

C, 52.44;

H,

N, 7.64.

Compounds

15a,b

were

obtained

dichloromethane:methanol

mixture

obtained

impure of 15a. Found:

H, 3.81;

N, 7.56.

in as

a

75:25

eluant.

15a

ratio

in

had

m.p.

63%

yield

150-151°C

C, 45.31; H, 3.86; N, 7.66. C7H7N03S

with (dec).

requires:

a 15b

97:3 was

C, 45.40;

R. ANNUNZJATACIal.

were

Compounds 16a.b ether:methanol C, 48.11;

obtained

mixture

in

as eluant.

a

70:30

no-- 1.5561, were obtained

requires:

ether mixture

as eluant.

with

yield

a

94:6

diethyl

16b had m.p. 120-121°C.

Found:

in a 66:34

Found:

C,

ratio

52.47;

in 73% yield H,

5.04;

N,

with

a 80:20

7.58.

C8HgN02S

C, 52.44; H, 4.95, N, 7.64.

Coqmund 22, m.p. 76-77"C, was obtained mixture

60%

C, 48.23; H, 4.55; N, 7.03.

requires:

76

hexanes:diethyl

in

16a had m.p. 128-129°C;

H, 4.46; N, 7.11. C8HgN03S

Conpounds 18a,b,

ratio

as eluant.

Found:

C, 49.78;

in 77% yield

H, 4.23;

w1t.h a 70:30

N, 8.36.

C7H7N02S

hexanes:diethyl requires:

ether

C, 49.69;

H,

4.17; N, 8.28.

Coqmund 23,

m.p.

102-103"C,

ether mixture

as eluant.

was

obtained

in 76% yield

with

a 75:25

Found: C, 52.31; H, 4.86; N, 7.69. C8HgN02S

hexanes:diethyl

requires:

C, 52.44;

H, 4.95; N, 7.64.

Compounds26a,b were obtained in 78% yield as a 50:50 mixture of diastereoisomers 80:20 hexanes:diethyl

ether mixture

as eluant.

appeared

solid.

C, 54.69;

as a waxeous

Found:

The two products H, 5.70;

were

N, 7.17;

with a

not separated

CgH11N02S

and

requires:

C,

54.80; H, 5.62; N, 7.10.

Compounds27a,b were obtained 70:30

hexanes:diethyl

ether

as 50:50 mixture mixture

of diastereoisomers

as eluanc.

Spectral

data

in 80% yield

were

in

Compounds30a,b were obtained as a 66:34 mixture of dlastereoisomers 70:30 hexanes:diethyl

ether

mixture

as a thick oil that

H, 5.68; N, 7.14. CgH11N02S

as eluant.

solidifies requires:

upon

(5 ml) cooled

The reaction aqueous

at -78"C, 80% mCPBA

was warmed-up

solution

and concentrated

of NaHC03

to 0°C

to give the crude

11, sulphoxide

compound

12,

a

agreement

with those reported

85:15

General

procedure for

stirred

solution

the

of freshly (2 ml),

in 79% yield with a

were

not separated

in the freezer.

Found:

and

C, 54.71;

at this

and

of sulphide was

the organic

was

as

added

temperature

a single

obtained

in

for

layer was

that was purified

obtained

16a,b

solution

in

in one portion. 5h. A

saturated

separated,

by flash isomer

(0.05 mmol)

dried,

chromatography.

in 70% yield.

76%

yield.

M.p.'s

22,

23 via

oxidation.

(0.260 ml,

1.5 mmol)

From

were

in

above.

kinetic

resolution

distilled

Ti(OPrij4

added at RT under vigorous

standing

(0.215 g, 0.5 mmol)

product

of

two products

A stirred

added,

15a was

mixture

The

and stirred

was then

From compound

dichloroethane

with

C, 54.80; N, 5.62; N, 7.10.

General procedure for the mCPBAoxidation. CH2C12

agreement

a

23

those reported.

appeared

with

(+I-diethyl

(0.110

stirring.

of

ml,

0.38

The resulting

11,

12,

tartrate mmol) yellow

in dichloroethane solution

To

in dry

(2 ml)

was stlrred

a

was

at RT for

3883

Nitrile oxide cycloaddition

12, 18, 22, 23, 26. 30 (see Schemes

11,

13C NMR data for cycloadducts

3. Relevant

Table

for numbering).

Compound

C-l

c-2

c-3

C-N

11

149.6

102.1

91.5

110.8

161.0

12

148.9

102.1

90.4

99.6

153.2

l&

149.6

102.1

92.5

110.7

163.9

18b

149.9

101.7

92.5

111.3

164.0

22

149.5

101.5

89.5

106.2

160.3

23

148.9

101.2

86.6

95.3

153.7

26a

149.4

101.2

89.6

106.7

162.4

c-4

26b

149.4

101.5

90.3

107.2

162.3

30aa

150.1

101.9

87.0

98.4

154.4

30ba

148.7

101.7

85.9

99.4

152.8

a In DMSO.

5 min.

and then was cooled down at -20°C.

mnoll was added, followed

after additional

sulphide

(1.5 mnol). The yellow

addition

of H20 (5 ml), warmed-up

filtered

through

then

washed

brine.

celite,

with

chromatography

of

to

diastereoisomeric

to RT,

and the filtrate

10% aqueous

Evaporation

solution

the

give

ratios,

sodium

unreacted

were reported

in the Table

Compound

(+I-31a,

28%,

C7H7N03S

requires:

Compound

(-I-32a,

C8HgN03S

requires:

e.e.

gave

and enantiomeric

rotations

had

64%,

had

TBHP

(0.079 ml,

(3 ml) solution

of

17-20 h, quenched

by

was

stirred

at -20°C for

and

stirred

for lh. The resulting

extracted

with CHC13.

a

yellow

oil

sulphide excesses

The organic

5% aqueous that

and

sodium was

the

were mentioned

0.75

mixture

was

layers

were

hydroxide,

and

purified

by

flash

sulphoxide.

Yields,

in the text,

optical

1.

m.p.

m.p.

C, 48.23; H, 4.55;

at -2O"C,

5 min by a dichloroethane

122-124X.

C, 45.40; H, 3.81; N, 7.56. e.e.

5 min.

metabisulphite,

solvent the

After

C, 45.48;

31b was obtained

152-154°C. N, 7.03.

Found:

Found:

H,

3.90;

N,

7.55.

N,

7.09.

impure of 31a.

C, 48.43;

H,

4.63;

3884

R. ANNUNZIATA~~ al.

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17. N.D. Ly, M. Schlosser,

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1,3-Dipolar

led to tne formation of intramolecular

Cycloaddition

Chemistry;

of nitrile

1,3-dipolar

oxide dimers.

cycloadditions

A. Padwa, Ed.; Wiley

see: A.

Interscience,

1984,

vol. 2, pp. 277-406. 21. A.P. Kozikowski, 22. W. Dehaen, 23. During

Y.Y. Chen, Tetrahedron

A. Hassner,

the preparazion

identical

Tetrahedron

Lett., 2081, 1982.

Letc., 743, 1990; and references

of this manuscript,

to one here described

an intramolecular

(25 to 27a,b)

tnerein.

cycloaddition

was published:

A. Hassner,

reaction W. Dehaen,

J. Org. Chem., 55, 5505, 1990.

24. The alternative

procedure

tAgNO

in diethylether)

gave

much

lower

yields

in this

case. 25. We Could

not establish

intrinsic

cycloaddend

thermal

if decomposition

lability

to undergo

occurs at reagent

of a benzyl-type

a retro-Michael

sulphoxide

reaction

or

or cycloadduct the

in the presence

for this observation. 26. W.E. Parham, F.L. Ramp, J. Am. Chem. Sot., 73, 1293, 1951.

level.

possibility

for

The

the

of base can account

R.

27. The minor

isomer 30b showed a

HC-5 of the isoxazoline. 28. Review: and

J. Drabowicz,

Sulphoxides,

Interscience, 29. This could

Patai,

S.

position;

the

mCP8A

the e.e.

presence

Conference

of the

and

The

Chemistry Stirling,

C.J.M.

of

Sulphones

Eds.;

Wiley

15a and 16a have the

of molecular

models

sulphoxide

the equatorial

than the axial one. Moreover occur

on the

equatorial

lone

oxygen

lone pair

the furan pair,

in

oxygen

closer

in

bonding. 0. De Lucchi,

and (+I-16a, (35.3

of optical

of

base.

For

the oxidation

as evaluated and

Tetrahedron

Lett.,

2575,

1989; and

41.5

for

reaction

basic of

22

W. Bastmann

of Organic

improved

5964, 1989; and references

and

(see text) (+I-16a,

therein.

&he

instability, sodium

very

nicely

respectively)

especially

hydroxide

diastereoisomeric

the minor diastereoisomer

and Bioorganic

and K.B. Sharpless,

17, pp. 31-48; F.A. Davis, R. ThimmaReddy,

some

(5% aqueous

by prefereni,ially decomposing

Hoecnst,

1 H NMR

(+I-15a

31 and 32 showed

instance

in Scereochemlscry

by

rotations.

in the text compound

31a,b to 90:10, Kagan,

to

hydrogen

values

by comparison

32. As mentioned

33. H.B.

isomers

6. Licini, G. Modena,

of (+)-15a

agree with

of

irradiation

therein.

31. The e.e.'s

work-up

Rappoport,

accessible

oxydation

space, -via intermolecular 30. F. Di Furia,

M. Mikolajczyk,

by inspection

can

direct

upon

1988, pp. 233-378.

12 seems more

the

Z.

signal

isomer 30a NOE was 4% (DMSO solution).

P. Kielbasinski,

of sulphide

obtained

10% NOE of the methyl

For the major

suggest that the major

an equatorial

references

ANNUNZ~ATA et al.

ratio

of

31b.

Transformations.

Eds.; VCH, Wheinneim,

M.C. Weismiller,

in

solution)

J. Am. Cnem.

Workshop 1987, vol. Sot.,

111,