Synthesis of chiral sulfonylmethyl isocyanides, and comparison of their propensities in asymmetric induction reactions with acetophenones1

Tefrohe&on Vol 43, No. 21, pp. 5073 to 5088. 1987 Pnnkd in GreatBntain.

oo4o-4ozo/l37 s3.00+ .I0 Q 1987 Pergamon JournalsLtd.

SYNTHESISOF CHIRAL SULFONYLMETHYL ISOCYANIDES, AND COMPARISON OF THEIR PROPENSITIES IN ASYMMgi’RICINDUCTIONREACTIONSWITH AC’ZTOPHENONES’

Frans J.A. Pieter

Hundscheld.

H.F.M. Rouwette

Department of Organic Nijenborgh

16.

9747

Vishnu K. Tandon,

and Albert

Chemistry,

M. van Leusen+*

Groningen

AC Croningen,

University,

The Netherlands

(Received in UK 2 April 1987)

Swaary. Seven chiral analogues of tosylmethyl isocyanide (TosMIC) were synthesized in order to investigate and compare their ability to achieve asymmetric induction in base mediated reactions with acetophenone and trlfluoroacetophenone. Acid hydrolysis of the intermediate E-oxazolines (10 and 11) gave optically active a-hydroxy aldehydes (12 and 13). Asymmetric pertinent modify

induction

approaches

the highly

is

plays

successPu1,

analogues.

In this

asynrmetric

induction,

a vital

the use of

role

a chiral

non-chlral

synthon

paper the propensity as determined

by the conversion

aldehydes

(12 and 13, Scheme 1).

Furthermore,

(2,

1).

d, Chart

tosylmethyl

is described

analogues

4, 5b. c,

in the synthesis of 2 or chlron.3

synthon,

chiral

isocyanlde

oP seven chiral

is described

One of the most

investigating (TosMIC,

analogues

of acetophenones

the synthesis

molecules.

We are

chiral

of TosMIC towards

to chiral of

ways to

1J4 into a-hydroxy

five

new chiral

TosMIC

Chart 1

&

C”,--@S02CH2N=C

1 ITorMIC~

Q..so2c”2N~c ~o_~02c A

S02CH2N=C

2

5s

R

3

R = OCH,

SC

4 l

:

OCH

,C”l 0

o-

‘CH20CH) S02CH2N=C

Chiral

analogues

TosHIC by a chlral * Dedicated

Sb

‘C2Hg

of TosHIC can be designed

entity

to Professor

+H2N=C

l ,C”3 = OCH

as in compounds 2-5:5

0. 5d

=

h

in two ways:

10s

(11 by replacing

(21 by modifying

Hans Wynberg on the occasion 5073

of

his

6

:

0

the SO2 group

sixty-fifth

the p-tolyl into

birthday.

group of

a chiral

F. J.

5074 6

functionality as in compound 6.

To avoid

A. HUNDXHEID

et al.

resolution of enantiomers, the synthesis of most of the

chlral TosMIC analogues was based on commercially available and cheap optically pure starting materials: (-)-menthol, (+)-lo-camphorsulfonic acid, and the lactic and qalic acids. Only the synthesis of optically active S-phenyl-E-tosylsulfonlmidoylmethyl resolution step.

isocyanide (6)

requires a

6

Previously, reaction of TosMIC with ketones was shown to produce Z-oxazollnes, from which racemic a-hydroxy aldehydes are obtained by acid hydrolysis, according to Scheme 1 with p-tolyl for R*.7

When applied to the unsywetric

ketones, acetophenone and a,a,a-trlfluoroacetophenone,

reaction leads to 2-oxazolines (10 and 11)

this

with two asymmetric carbon atoms: C(4) and C(5). Of

these two, C(5) is retained as the only chiral center in the hydrolysis product a-hydroxy aldehyde (12, 13). Replacement of TosMIC by the chiral analogues 3-6 in the base mediated cycloaddltlons of Scheme 1 leads to the diastereomerlc 2-oxazolines 10 and 11.

The diastereomeric excess (d.e.) of 10 which is a measure of asymmetric induction, can be determined readily by 'H and 19F NMR. By

and 11, acid

hydrolysis a-hydroxy aldehydes 12 and 13 are formed in enantiomerlc excess (e.e.1 which

appears to be the same as the d.e. of the precursor oxazolines 10 and 11, respectively, when 1 optically pure isocyanides are used. Thus, H and 19F NHR can be used to determlne the degree of asymmetric induction in the formation of the (intermediate) 2-oxazolines 10 and 11. As will be shown, this is true even when chiral derivatives of methyl isocyanide are used in racemlc form. Pulte recently, Ito, Sawamura and Hayashia have used a different approach to obtain optically active E-oxazolines. Under influence of a chiral ferrocenylphosphine-gold

(I) catalyst, methyl

isocyanoacetate reacted with aldehydes in a highly enantio- and diastereoselective reaction to 5alkyl-2-oxazollne-4-carboxylates,

TAB,,~

React,c,ns

1.

or

which were converted to E-hydroxy-a-amino acids.

hxyanlde~

Chlral

Hydroxy-2-pheny1propanal

3-5

with

12 According

to DLlsterwmrlc

Acetophenone

to

Scheme

Oxazollnes Entry

I~ocyanide

1

3

2

4

e.e.

(I)

93d 100

CondItlo”.9b

“Cl

PK. benzene('5) PTC,benzene (:5)

Yield

(I)

10a

60

lob

7LI

1.1

eq.

BuLl,

lliF

c-18)

1oc

76

racem.

2.2

eq.

BuLl,

THFe(-78)

100

52

I

PK.

benzene

(15)

1oc

98

I

PK.

benzene

(15)

1Od

83

c-78)

10d

57

THFe(-78)

50

3

5b

4

5b

5 6 7 9 10 11

5b 5c 5c 5c 5E 5d 56

12

54

n

1.1

13

M

n

HeHgI.

14

M

47

8

(temp.

n I

n I

1.1

eq.

BuLl.

2.2

eq.

BuLl.

MF

1Od

54

(!5)

10d

9”

?IC,benzene

(15)

100

‘00

PK.

(15)

10s

66

10s

39

100

75

100

70

TC.

1.1

to1uene

to1uene eg.

eq.

EULl. Et20/NF EULl.

a. sttYJctures or groupA' are depIcted

MF

(-78)

c-78) MF

in ChaPt

(-78)

In 1Od - o-(l-methoxy-2-PPOPOXy)phenyl,

PeSpeCtlVBly: 41

5 ~1

b. ; e.

PTZ “ith Same results

ulth

X BTEAC and 50% Na3H:

c.

10 and Hydrolysl.,

a-Hydmxy

1oa ‘H N%f

4.96 5.22 5.76 5.76 5.76 5.75 5.75 5.75 5.75 5.76 5.76 5.76 5.75 5.76

d.e.

to

(R)-Z-

6 C(U)-H.

and

(S)

Yield

aldehyde

(I)

[alED

12

O.P.

(I)

5.12

18

53

-110.8

16

5.45

33

47

-80.2

31

5.97

110

50

-37.7

15

5.97

15

5.87

110

5.95

17

5.95

33

5.95

17

5.95

20

5.79 5.79

20

5.79

40

5.79

19

5.79

38

1 for reagents3-5: R' in 1Oa

100 - o-see-butoxyphenyl. kleP(O)Cl*

Oxazollnes

1

In 10s

doublets;

- neomnthyl.

"3 In lob

-46.1

-

2-menthoxyethyl.

18 in

- o-(3-tetrahydroluranoxy)phenyl, d.

Determined

on nementhylthlol

ulth

Et20.

REACTIOlOF CAIRAL DERIVATIVESOF SULFOHYLf4ETHYL ISXYANIDES WITH ACEX'OPA~SOIIES: RESULTS AND DISCUSSIOI Results of reactions of chiral sulfonylmethyl isocyanldes 3, 4, Sb, 5a and 5d with acetophenone, according to Scheme 1. are collected In Table

I.

Similar

results

of

3, 5d and 6 with

5075

Synthesis of chiral sulfonylmethyl isocyanidcs c,a,a-trifluoroacetophenone obtained

ulth

By way

are compiled

in Table

example,

of

we will

first

(PTC) conditions to

as a viscous

011,

to give

by comparison

(12,

experimental or (crude)

diastereotopic Scheme

C(4)-H

doublets

(long

or entry

II,

lnductlon

entries

2 (Table

I).

(801)

was

20 and 21). Enantlomerically

under phase transfer

without

being

The optical

Scheme 1).

precursor

The d-e.

Table

reacted

accuracy:

catalysis

as the d.e.

by acid

(0.p.)

or rather

lob was determined

range coupling

purified,

purity

The e.e.,

with data of Hukaiyama et al.’

lob.

asymmetric

(6,

trans-4-(2-menthoxyethylsulionyl)-5-methyl-5-phenyl-2-

found Por 12 was the same: wlthln oxazoline

(4)

which was converted,

(RI-(-)-2-hydroxy-2-phenylpropanal

determined

the reaction

isocyanide

with acetophenone

(lob)

The highest

isccyanide

discuss

pure (-)-(2-menthoxyethylsulionyl)methyl oxazoline

II.

S-phenyl-I-tosylsulionimidoylmethyl

oi

the o.p.,

or 33% observed

by integration

with C(2)-H,

oi

J - 2 Hz) at

hydrolysis

12 was lo

311

or

for

the

the two

6 5.22

and 5.45.

la

R*SOZCH2N=C

H

3-5

“@

base l

-

-

i,

C,H,CR

7

R*SO,

8

RfSOz

I-

R*S02

H

-I

9

“‘\<,‘.“” 'gHS

1

10 R’ = CHJ 11

R’zCF,

a For compound 6 R*SP2 1s to be replaced

e.e.

12 R’= CHJ 13 R’= CFJ

by PhS*(O)NTos.

The proposed

mechanism oi Scheme 1 elucidates

or a-hydroxy

aldehyde

which eventually

1s carried

to the thermodynamically diastereomers

only,

the correlation

12. Asyrmnetric lnductlon on to 12. By ring

iavoured

determines

closure 11

to 8 and base lob

trans-oxazoline.

which are represented

between d.e.

ol oxazoline

the ccniiguratlon induced

10 and

in 7,

epimerization

is formed as a mixture

by R*S02-(R)C(4)-(R)C(5)

at C(5)

at C(4)

of two

(A) and R*S02-(s)C(4)-(S)C(5)

(B) .

In entry pairs

1,

an enantiomeric This

(+)-(necmenthylsulionyl)methyl

oP enantiomerically pair

obviously the e.e.

oi

methyl

isocyanide

for

(5b,

have thus confirmed

or 501 e.e., e.e.

experimentally

(A’) the d.e.

entry that,

according

of

when they are only

chiral

of

12

(and In

e.e. 13).

TosMIC analogues

and even when they are racemic

entry

13) will 14

or optically

Slmllarly.

3) gave trans-10c

induction.

181,

or 10a.

Therefore, (entries

Of

the d.e. (as

course,

the induction

in entries in

the

12 in We

or the oxazolines

to investigate

resolved

19-21).

is formed.

by ‘H NHR, but it

or 12 with some acetophenone.

is possible

partially 4-13.

(B*)

two

A and B,

(S)-(-)-(o-sec-butoxyphenylsulPonyl)in 401 d.e., which wght to give

to expectations, it

which gives

to the main pair

as determined

to 15s by contamlnatlon

is a measure of asymmetric

was used,

In addition

and (R*)‘SO,-(R)C(S)-(R)C(5) (181)

as observed.

was lowered

3 of 90% e.e.

or trans-10a.

(R*)‘SO,-(S)C(S)-(S)C(5)

12 irom 18 to 161,

The observed

isocyanide

dlastereomers

is of no consequence

lowers 202 e.e.

related

latter

1. 3, 14. case

10 power

17 and the

e.e.

be zero.

(as

well

active

as

entry

22

of

Table

II)

56 (and 6) lrom the e.e.

a reverse or the final

analysis product

was used to determine a-hydroxy

aldehyde

the 12 (and

5076

F. J. A. HUNDSCHEID ef al. The data of Table

conditions, for

the reaction

entries

I were collected

on the d.e. of

1 and 2,

10. me chemical

(*)-lo-(camphorsulfonyl)methyl

group,

induction

with lsocyanlde

in 5 and 5 with the oxygen

(I.e.

chelation”

R*S02&N-C, or hydrogen increase

introduction

of a second

6-14). of

Appllcatlon

ether

a magnesium derivative abandoned for

methylene

group,

II.

Reaction

(entry

Isocyanlde

of

e.e.

(0

13) resulted

entry

11, ether

to the active

and Chlral

AnaloBa

only

were group.

181.

d.e. Is of

with

the reacting

(lsocyanldes

0 and 9) 51,

1-3,

improvement

center

(entries 16 or use

reagents,

10. This

6 with a chlral

of

It

entries

4 and 8) to form dilithlo

of SOS (Table

3, 5d and 6

functions

by intramolecular

oxygen

against

in lower

induction

the

methylene

the rigidity

50 and 56) gave no further

fsocyanlde

of

approach

was

next to the reacting

II).

o,a,a-Trlfluoroacetophenone

to Oxarollnes

11

1 Condltlo”sa

(I)

with partlcipatlon 13

of one ether

BuLl (entries

which gave an asymmetric 01 TosnIC

closure

power by increasing

(isocyanldes

sulfonimfdoylmethyl

According to Scheme

EntPy

oxygen

except as In

with acetophenone.

10 (33 and 40%. respectively,

two equivalents

therefore

t.ble

of

satisfactory,

Under PTC conditions,

5 with respect

induction

in R*, and in reaction

R*S02CHMN-Cor R*S02CH2N-C) of Scheme 1 , elther

in d.e.

of

ring

3 was low (181,

in position

changes

10 were quite

(2).

reaction

bonding. l5 Whereas introduction

gave a small

of of

isocyanlde

than intermolecular

was hoped to thus improve the asymmetric species

yields

2 underwent intramolecular

rather

asymmetric

introduced

to probe the influence

oxazolines

lsocyanide

camphor carbonyl Since

of

Ylddb0)

!H Nd

c1s/trans

d.e.

19F

(I)

N!‘Rd

c1s/trans

d.c.

(I)

15

1

A

11a

100

5.53

5.38

47:53

-

-79.4

-71.5

47:53

-

16

1

S

110

96

5.53

5.38

34:66

-

-79.4

-71.5

35:65

-

17

3

A

llb

96

5.53

5.49

47:53

16

-80.5

-80.3

46:54

18

5.35

5.33

-71.9

-71.7

5.53

5.49

-80.5

-So.3

35:65

18

-7; .9

-71.7 38: 62

45

6~94

60

5:95

80

4:96

80

18

90

3

90

5

lib

90

34:66

18

5.35 5.33 19

M

20

47

6

21

PBCBII.

6

22

1 for ~eagcnts

CH2C12.

for

C(4)-!I

(see

91

OV.

with

of reaction

5.25

6.33

4O:bO

e

5.25

4.33

41

60

e

5.25

SO

e

80

THF. 20'C: b. Structure3

8.

ln llb - nementhyl, c.

6 C(4)-H;

given

lsocyanlde

in Table

the more reactive

aondltlons

lla

yield

was obtained

Table

II).

Similar

same high chemical Oxazoline

not reported

as a mixture results yields

-79.1

-71.6

-71.4

-79.3

-79.1

-71.6

-71.4

-79.3

-79.1

-71.6

-71.4

of group R* ape deplcted

In Chart and “we

6 CF3:

I,

(6)

failed

8.

In

6 was decomposed.

to react

However,

the haloform

reaction.

‘H NWR only

two doublets

llb

of

llb

47:5317

(118,

the d.e.

in 17% e.e. acid

to

with

(15,

Scheme 1,

R*

first

(entry

Washer’s

a&d”,

in

low as with acetophenone

correlation

with

Scheme 2).1g120

The

16).18

lsocyanlde

(3)

(entries

(~)-(*)-2-hydroxy-2-phenyl-3,3,3-trlfluoroprop~al

Co-(3-tetrahydrofuranoxy)phenylsulfonyl~methyl

with

p-tolyl)

-

in CH2Cl (OOC. 4-5 h). Oxazollne f both by H and “F NMR (entry 15,

B In THF at room temperature

as shown by chemical

lld

needed a different

were tested

(*I-(neomenthylsulfonyl)methyl

(18%) was equally

Under

of oxazollne

This substrate

as determined

with Trlton

were obtained

was hydrolyzed

previously)

with racemic

of cls/trans

were obtalnsd

with acetophenone.

high yields

Such conditions

was used with I-ethylplperldlne

however,

(trifluoromethyl)phenylaaetlc obtained

-79.3

d.

a,a,a-trifluoroacetophenone.

to prevent

when Tl(OEt)4

and trifluoroacetophenone. and 18).

-75.0 -73.4

In 110 - o-(3-tetrehydrofuranoxy)phenyl,

TosHIC, which gave 5-phenyl-4-tosyl-5-trifluoromethyl-2-oxazollne quantitative

-75.5 -73.7

text).

conditions

were obtained set

6.33

Pespectlvely:

S-Phenyl-z-tosylsulfonlmldoylmethyl the reaction

6.26 6.04

B - Trlton

lla - p-tolyl.

In lld - S-phenyl-N-tosylsulfonlmldoyl,

observed

92

lld

3. 56 and 6: A* in

6.33 6.11

100

lid

S

H-Ethylplplrldlne. 1,

98

IId

B

34

a. A - Tl(OEt)4.

11c

A

PaceIn.

6

r&O2

A

17

(13,

(A)-(*I-2-methoxy-2-

A comparable

lsocyanlde

(54,

result entry

was 19):

98%

5077

Synthesis of chiral sulfonylmcthyl isocyanidcs yield

of oxazoline

lle,

ulth

(41%) not higher

a d.e.

than with acetophenone

(cf.

entries

12 and

14). Scheme 2

cF’xCozH

L+

By far lsocyanide

Et20;

yield

the highest

asynnnetric

hydrolysis

o.p.

The cis/trans

of

the oxazolines or racemic

of 801.

a d.e.

case

lld

11 did

mutually

consistent

C(4)-H,

for or,

(Table

(5d)

its

a chlral

chirality

center

needs to be considered.

enriched

of

partially

of enantiomerlcally

is determined

for

resolved

related by two e

CF3. These results

of

are

closely

toe,

spaced

the d.e.

of

these

which initially

results

as in 6 is more made towards

difference

(and their

C is

converted

10e was not affected

showed only

and 5.79.

a

After

two ‘H NMR

treatment

with K2C03

of 0.2 ppm (compare entries

by assuming

(C)

at C(4)

1Oe is slow remains

methylene

are presently

6.

at 6 5.76

with a normal shift

explain

efforts

[o-(3-Tetrahydrofuranoxy)phenylsulionyl]methyl

(A) and cis-R*SO,-(~)C(S)-(~)C(5)

the epimerlzatlon

singlets

two pairs

next to the reactive

oxazoline

of which by a slow eplmerlzatlon Of course,

plus the d.e.

in R*. Consequently,

enantiomerically

We tentatively

enantiomer).

Instead,

of enantlomerlcally

case of

quantitative

6. In the latter

II).

show that

4 h at 20°C two doublets

(lj)C(4)-(R)C(S)

by two pairs

in nearly resolved

exclusively.

above),

In this

conditions

of 271 o.p. It follows that 6 was 341 19 F NHR. In contrast to oxazollnes 1’0,

by

gave two pairs

(as described

gave with acetophenone

9) were obtained.

13 (301 yield)

to trans-diastereomers

(J - 2 Hz) for C(4)-H quite

in MeOH for

of reaction

as with partially

as determined

the cis-isomers.

method to obtain

One peculiarity

with the sulfonimldoylmethyl

With both sets

of R*S02) MS obtained

6 as well

was 95:5.

alternatively,

than the remote

more efficient

lld

the trans-isomers

The above results

lsocyanide

20-22).

and trifluoroacetophenone

for

for

formed,

of

diastereoisomers

doublets

with racemlc

not eplmerlze

isocyanides

eff lclent2’

(80%) was obtalned

(entries

gave hydroxy aldehyde

ratlo

diastereoisomers

doublets

induction

(Scheme 1, with PhS*(O)NTos lnstead

lld

and with

related

b CH31; ’ NaC102.

6 and trifluoroacetophenone

oxazollne

15

lb

13

aNaH,

OCH,

C6”S

3

that

initially

respective

enantiomers)

to RrS02-(s)C(4)-(s)C(5)

by this

l-

only trans-R*S02-

slow epimerization

were (B)

(and

step.

Why

to be explained.

CAIRAL DERIVATIVESOF METHYLISOCYARYDE:SYRIAESIS AND DISCUSSIOR (+)-(10-Caaphorsulfonyl)~thyl (+)-lo-camphorsulfonlc advantage

of

2 in just carbonyl

4 steps.

isocyanlde attempts

16 1s that

group of 2 is of

to crystallize;

acid

the -S03H function

However, 2, albeit limited

there of

stability

(2)

was prepared

yield

are also

two important appears however, by replacing

into

the desired

disadvantages to interfere

at room temperature,

both disadvantages

by straightforward

chemistry

of 281 (Scheme 3 and Experimental

can be transformed

low reactivity,

the compound can be stored,

to circumvent

success .7c

isocyanide

16 in an overall

probably

associated

because

An

-S02CH2N-C group of

intramolecularly

at -4OOC. Unfortunately,

from

Section).

with 2: (1) 7c.13

the viscous

the

; (2)

011 failed

many different

the C-O group of 2 have not met with

F. J. A. Hmwscmm

5078

ef al.

Scheme 3

S02R

SOZCH2N=C 2

16 R=OH 17

R=CI

16 R=H 19

a sOCl2;

R = CHINHCHO

b Na SO ’ ‘X20, 2 3;

(+)-(N~nWlylsulfonyl)wthyl overall to

yield

isocyanide

from (-)-menthol

39% mainly

NH2CHO; d pOC13, Et3N.

as a stable

(3)

obtained in 6 steps and 261 5 compound. The overall yield was increased

was previously

crystalline

by replacing

Et N by lPr2NH ln the final 12 lmproved method of Ugl et al.

dehydratation

step,

following

the recently

OR 0L

a CH2-CHOEt, Hg(OAcj2;

20

R=H

21

R = CH=CH*

22

R = CH$H$H

23

R q CH$H,SCH,NHCHO

21

R = CHZCH2S01C~2~,~~~~

(-)-(2-Menthoxyethylsulfonyl)wthyl yield

from (-)-menthol

thiolacetic

acid

(20)

could

viscous

011 of

-51.6O

(c 2.0,

to Scheme 4. It was necessary

22, which was converted

Oxidation

be readily

stability,

15 Hz) in ‘H NMR (Table

of

after

Experimental reactivity

lsocyanide

the pilot

synthesis

of non-chlral

(5b).

5a was carried

The model compound 5a is a stable

in reactions

with p-nltrobenzaldehyde

by the results

displacement.

29b by a Mannlch reaction

Sulfinlc

solid,

Attempts

to prepare

out first tiich

5b was synthesized

optically

acid

(581 yield).

Apparently,

28b (66% yield followed

of

the menthol (-)-menthol

led

5c and 5d were

(Scheme 6, and

showed typical in 5 steps

pure set-butanol (Scheme 5). > 981) with potassium o-bromophenolate

CR)-(+I-set-butanol 26 (0.~. as determined by ‘H NHR and Eu(dcmj3.

this

(J -

TosMIC

and with acetophenone.

with 5a, isocyanide

and with

50% e.e.

during

[a];;8

AB quartet

III).

both with racemic

26b of with

resolved

Reaction of o-bromophenolate with the tosylate 24 and 2-menthenes only. Instead. the chlral lsooyanldes 5b.

Section).

Stimulated yield,

l-

with z-

to 13C NMR) with

(according

group shows a well

50 were unsuccessPu1.

to a mixture prepared,

reaction

purlfled

24,

pure state

a-methylene

(S)-(-)-(o-ss-Butoxyphenylsulfonyl)cllethyl derivative

and 125 overall

at which stage a contamination of 23 gave 4 as a colourless with pentane. Dehydration

in epimerically

CHC13). The diastereotoplc

in 6 steps

to use carefully

to 23 by an exchange

(mCPBA) gave sulfone

removed by extraction

limited

(4) was prepared

ieooyanide

according

to prepare

(tosylmethyl)formamide.5 menthol

mCPBA: e FOC13, Et3N.

b CH3C(0)SH, NaOH; ’ t-BuOK, TosCH2NHCHO;d 2 equiv.

Reaction

of

the tosylate

gave 27b in 51% yield,

some 50% racemization

from 27b by Grlgnard

by dehydratation23

and 131 overall

occurred

and SOP) gave formamide

with POC13 and Et3N (671 yield)

5079

Synthesis of chiral sulfonylmethyl isocyanidcs

to

in

lsocpanide

give

2Tb.

Partial

5b with

501

racemlzatlon

no further

Thus,

e.e.

in atep

a towards

took

racwlzatlon

27b was only slightly

place

after

diminished,

the formation

to 455,

of

by use of CsF

acetonltrlle.

Table III.

Some Characterlstlc

Data of Chiral Methyl Isocyanlde

DerIvativea 2-6

1 H Nm

‘3c NHFI

mpa

Uw-C

(OC)

(cm-’

2

011

2180

3 8

67.7-68.4

2180

4.27 and U.58 (15)

165.8. 59.8

Oil

2180

a.55 and 4.83 (15)

165.6, 60.2

5a

93-94

2180

b.65b

164.6, 59.0

5b

011

2180

4.86 and 4.93 (15)

164.1, 58.9

5c

Oil

2150

5.15 and 5.25 (15)

Isocyanide

107.4-108.2

6

93.96 (decomp) 2165

a. Sollds

apa stable

C(o)H2 (t)

4.47 and 5.21 (15)

2150

54

6N_C (a).

AB9. (.I. HZ)

1

(Chart 1)

4.87 and 4.94 (15)

165.3, 59.3

5.11

shelf’ compounds. the oils

but can be atored for long at -4OT:

are of limited

stability

b. In ‘fi NMR of non-chlral

at loom temperature.

aulfonylmethyl

iaooyanlde 5a,

C(o)H2 gave a doublet with J - 2 Hz.

Scheme 5 OH

0.

a +

TorOR

Br

-

0 R

SO,R’

Br

26

26 R’= H

27

29

b

R = -:HMeEf

c

f7=

d

R = 3-tetrahydrofuranyl

le

R’= CH*NHCHO

5 R’= CHpN=C

-FH(hia)CH20C~,

R = menthyl)

a KOHor CsF; b Hg or BuLl, SO2; ’ CH20, NH2CHO; d PQCl

(~)-[o-(1-Methoxy-2-propoxy)phenylsulfonyl~ethy1 5b from the tosylate sluggishly

via

of

yield,

as an 011 of

lsocyanide

(k)-l-methoxy-2-propanol

the Crignard

BuLi was used instead

‘R

of Hg. limlted

of 27~ in only 28 After

steps

stabllity

(26~).~~

5% yield,

the yield

5b,

Et3N.

was prepared

The preparation

however, as for

c and d,

(5~)

3’

of

analogously

28~ (step

was improved to 79% when

5c was obtained

in 291 overall

at room temperature.

Scheme 6 -1.b.c.d -

27

a

R=Me

d

R = 3-tetrahydrofuranyl

a BuLl.

30

R’= SH

31

R’= SCH*NHCHO

32

R’= S02CH2NHCH0

5

Sa: b TosCH2NHCH0, t-BuOK;

R’= SO$H2N=C

’

2 equlv.

to

b) proceeded

uCPBA; d POC13,

!It3N

or

I-Pr2NH.

F. J. A. HUNDSCHJXDef al.

5080

(R)-(-)-Co-(3-Tetrah~droiuFanoxy)~enyls~f~yll~~yl overall

yield

according

hydroxytetrahydrofuran. was subsequently 4).

temperature. 481,

3o Thiol

converted

In contrast

OP 5d could

as deduced Prom the o.p.

5d is

a crystalline

not be determined

of a-hydroxy

aldehyde

(-)-S-Phenyl-K-tosylsulPonimldoyl)msthyl the overall

yield

isocyanide.32 (Table

II,

with

as for

solid

chiral I,

(6).

Optically 22).

active using

6 was obtained

partially

with an e.e.

resolved

in 351

reagents,

entry

of

but was Pound to be

14).

distilled

of 341,

4 (Scheme

at room

Racemic 6 was reported

of 601 was improved to 801 by the use of freshly

entry

the synthesis

which is stable

shirt

12 (Table

lsocyanide

was prepared

29 and (S)-(+)-3-

Prom 27d with BuLi and sulfur 31 and

in 731 yield

the same type of reactions

isocyanide

(56)

(*I-3-hydroxytetrahydrofuran

30d was obtained

to 5d using

to 5b and 5c.

The e.e.

isocyanido

to Scheme 6 from both

previously;6

trimethylsilylmethyl

as deduced Prom the o.p.

S-phenyl-I-tosylsulPonlmidoyl

of

13

Pluoride.6

EXPWIM5fTAL SEZTION General. Hitachi

All

experiments

Perkin-Elmer

Varian XL-100 or 200~MHz Nicolet multiplicity

of

out under N2. ’ H NMRspectra

were carried

R-24B or 200~MHz Nicolet

out in our Analytical

‘J C_H values

only

241 polarimeter

according

ac1d33 mixture

using

as a viscous

oil:

‘H NMR (cDc~~) 2).

23.2

7.81

IR (neat) (9,

1).

the procedure

the reaction

mixture

account.

Elemental

Optical

3),

1.05

(s,

1):

for

the synthesis

microanalyses

31,

(5,

were carried

by a Hannich condensation

of

lo-

1690 and 1530 (NHCHO), 1325 and 1130 cm-’

1.2-2.7

for

0.5

(2).

(m, 71, 2.87

and 3.48

Formamide 19 (27.3

h at -5OC, poured

g (60%) of 2 as a light-brown 4.47

and 5.21

viscous

(s,

(AB 9, J -

31,

mol) was dehydrated

the addition

oil:

of

with CHC13.

and cold (neutral

water, A1203,

2180 (N-C),

1.2-2.7

(m, 7).

Cali

15 Hz, 2); MS, m/e 255 (M');

with

PDC13 was complete,

and extracted

IR (neat)

1.08 (9, 3),

4.73

CHC13).

g, 0.10

in ice-water

19

(S02)’

(AB 9. J - 15 Hz, 21,

+53O (c 2.50,

of TosHIC.~~ After

(SOP) ; ‘H NMR (CDC13) 6 0.93

(AB q , J - 15 HZ, 2),

was

with CHCl The CHC13 extracts were 3’ and concentrated8to give 16.4 g (601) of

(MgS04),

MS, m/e 273 CM+); Cal;?a

isocyanide

was stirred

15.3

1340 and 1140 cm-’

activity

Hamminga.

The combined CHCl extracts were washed with a cold 51 aqueous NaHCO solution 3 3 dried (MgS04) and concentrated. The resulting oil was rapidly chromatographed CHC13) to provide

Me4Sl.

For reported

and extracted

3400 (NH), 1746 (C-O),

8.35

F NMRspectra.

of Mr. A.F.

was prepared

on a 60-14~2

Prom internal

formaldehyde (0.30 mol) and formamide (1.0 mol), 23 of N-(tosylmethyl)Pormamide, for 1.5-2 h at 90-95OC. After cooling,

(+)-(lO-CamphorsulPonyl)methyl PW13 using

10 cm cells.

downfield

fool),

5% aqueous NaHC03, dried

6 0.90

(t.

(19) g, 0.10

was poured in ice-water

washed with ice-cold

(d,

(18;

to the synthesis

the reaction

were taken into

Department under the supervision

(+I-z-(lD-Camphorsulfonylesthyl)foruulde camphorsullinic

were recorded

in 6 mits 13 C and ”

machines were used for

13C NMRsignals

measured on a Perkin-Elmer

apparatus

1740 (C-O),

3.01

and 3.69

+20.50

0.82,

(C

CHC13). Menthyl vinyl menthol

ether

(20,

46.8

(21)

was prepared

g, 0.30

mol),

g, 0.03

mol) as a colourless

product

was contaminated

removed easily

according

redistilled

011:

41.03

This

by distillation.

vinyl

g; bp B2-83’C

201 of

with ca.

to the procedure

ethyl (-)-menthol

ether

(15 4x4 Hg) [Lit31c (as

contamination

reported

by Chiellini

34 Prom (-)-

(240 8, 3.33 xx111 and Hg(OAcJ2 (9.6

evidenced

bp 100%

(22 mm Hg)].

by CLC) which could

was removed after

formation

The

not be

of sulfone

24 (see

below). 2-Menthoxyethanethiol

(22)

80 mm011 to a stirred

mixture

0.80

was prepared of

11.2

by addition g of

maol),

during

temperature,

after

in a mixture

of HeOH (100 mL) and 100 mL of

in ice,

the solutlon

which the temperature which the crude was acidified

rose

thiolacetlc (to

crude

of carefully

21 (2.

to 32OC. The mixture acid

adduct

20% aqueous

pH 3) with

ice-cold

distilled

thiolacetic

50 xnxol) and benzoyl was stirred

CIR (neat)

1700 cm-‘,

NaOH, and refluxed 6N HCl and water

acid

peroxide

for

for

(6.0

(200 mg.

1 h at room

C-01 was dissolved 1 h. After

cooling

(200 mL) was added.

g,

SO81

Synthesis of chiral sulfonylmethyl isccyanidcs Extraction

with CHC13 gave crude

contaminated

with ca.

(I$+, calcd

20% of menthol)

216.155).

dissolved

22 which was distilled

Alternatively.

in 20 mL of ether

with 6N HCl. Extraction

as a colourless 10.0

and added.

LlAlH4 In 100 mL of ether.

g (ca.

was refluxed

gave,

N-[(2+lenthoxyethylthio)methyl]formamlde qethyl]formamlde, 5 from 4.33 g of crude Sulfide

mmol).23

23 was obtained

of menthol);

IR (neat)

(m. 51,

(d,

4.36

21,

grade,

n-pentane

was prepared

(pr,

1).

85%).

(s.

011 (1.82

19% overall

(m. 2),

8.0

(br,

1).

8.2

(d.

(-)-(2-Menthoxyethylsulfonyl)aet.hyl with POC13 and Et3N using after

the addition

in ice-water. Florlsll)

of

(CDC13) 6 15.9 (9). 20.6

cd). 51.1

calcd

(SOa:

hexane,

ca.

6.6 mmol).

After

once and the temperature The organic acldllled dried

layer

available

was raised

was extracted

to

11, 3.82 cd).

pressure (s,

129.1

mol)

solid

24 as a

3400 (NH),

(m, 181, 2.7-4.25

4.55

0.5

(m. 5).

h at O°C and then poured

which was chromatographed

(CHC13; -1 1340 and 1140 cm

2180 (N-C),

and 4.83

(AB q. J - 15 Hz, 2);

13C

cd), 31.1 cd). 33.9 (t), 39.6 (t), 47.8 (c 2.0, CHC13): MS. m/e 287.157

CM+,

31,

6.56-7.36

cd).

154.7

t-BuOK. After

to yield

extracts

0.75

from benzene-hexane

Anal.

N, 7.11;

give

30a,

which was purified (9).

in at

110.4

were extracts

were

by distillation ‘H NMR (CDC13) 6 3.76

(d).

120.3

stirred

during

0.5 h. The mixture

(30 mL), and extracted dried

(MgSO,),

mixture:

mp 85-86V;

4.55

and 4.65

C, 54.82:

H, 5.58;

h, 1.23

(.?.I, 120.9

cd),

for

of

30a (1.4

g,

g (0.011 mol) of 23 (2.13 g, 0.01

5 h at room

The resulting

31a, mp 83-84V.

IR (Nujol) (two s,

of

(3 x 15 mt) . The combined

and concentrated.

Prom the same solvent

(s), 31,

was stirred

with ether

1.67 g (851)

C9HllN02S:

solution

in 0.5

z-(tosylmethyl)formamide

to give

for

extracts

(4 x 50 mL). The ether

To an ice-cooled,

(1:3)

Calcd

of 27a

was poured in H20 (30 mL).

6.681 g (81%) of 30a;

1 h at room temperacze,

2),

N. 7.10;

011 was

Analytically

pure

3360 (NH), 1660 and 1530 6.0

(br.

S. 16.24.

l),

6.6-7.8

(m, 4).

Found: C, 54.93:

H,

S. 16.18.

l-[(o-Methoxyphenylsulfonyl)methyl1fo~lde 31a (1.97

g of crude

(31a).

(NHCHO): ‘H NHR (CDC13) 6 3.9 1).

with ether

13C NMR (CDC13) 6 55.6

were washed with H20, with brine,

31a was obtained

g,

(10 mL) and Me2S0 (5 ml) was added,

for

poured in ice-water

crystallized

(0.19

3 h. Then the mixture

12 mm Hg) to

(m. 4);

of ether

stirring

sulfur

solution

BuLi (1.6 M solution 6.0 mmol) 31 was added all

(9).

was added at O°C, in portions,

(s.

sublimed

To a stirred

4.1 mL of

with 2N NaOH (2 x 30 mL). The combined aqueous

(bp 115-118T,

in a mixture

temperature,

5.56:

IR (neat)

with

305.166).

from Ega Chemie).

15’Y in ca.

z-[co-Methoxyphenylthlo)wthyl]formamlde

cm-’

g, 86%),

mL) at -78OC was added dropwise

30 min freshly

(MgS04) and concentrated

126.2

8.0

extraction

A12031 provided 20):

for

IR (neat)

(m, 5).

with 20s aqueous H2S14 and were extracted

under reduced

mol)

4 (1.24

(9); Cal;;8 -51.6O

commercially

in Et20 (30

(1.12 g, 6.0 mol)

0.01

was stirred

011 (932 mg. 65%);

cd), 165.6

273.176).

g, 5.0 mmol) was dehydrated of TosHIC. 23 The work-up was as follows:

(q), 21.9 (q), 22.9 (t), 25.5

(t). 60.2 (t), 80.0

201

2.6-4.0

Compound 24 (1.53

the mixture

(m, 181, 2.8-4.3

(ml,

g (30 uxnol) of mCPBA

neutral

calcd

g, 20

287.155).

o-Methoxybenzenethiol

(s.

(4).

(M’.

the synthesls

with CHC13 gave crude

4 as a colourless

(SO21 ; ‘H NHR (CDC13) 6 0.5-2.5 NMR

for

POC13 was complete,

Extraction

to give

isoayanide

(4.26

with ca.

by repeated

‘H NMR (CDC13) 6 0.5-2.5

(S02);

(PH 3-4)

to y-[(neomentyl-

and 5.17

from (-)-menthol,

MS, m/e 305.165

the procedure

(MI, calcd

product

CCH2C12-CHC13 (1:l);

was

g (25 mmol, 83x1 of 22.

analogously

13 -1)

adduct

g (30 mmol) of

g (contaminated

MS, m/e 273.172

calculated

1);

1.14

to i-C(neomenthylthio)-

4.65

oil:

was prepared

crude 23 (ea.

yield,

of

MS, m/e 216.155 acid

to O°C and acidified 5.40

analogously

Menthol was removed from the crude oily

g,

QQ Hg);

(NHCHO 1; ‘H NMR (CDC13) 6 0.5-2.6

1);

(24)

1685 and 1530 (NHCHO), 1325 and 1130 cm-’ 4.3-5.1

work-up,

viscous

br,

g of

(0.2

thiolacetlc

17 plmol) and l-(tosylmethyl)formamide

22 (ca.

8.12

22 (which was Still

to a suspension

2 h, cooled

(23)

(8 x 30 mL). Column chromatography

colourless

for

the usual

3350 (NH), 1680 and 1530 cm-’ 7.35

g of

bp 82-84%

after

as a colourless.

lj-[(2-Menthoxyethylsulfonyl)methyl3loraaaide 5 from 4.09 sulfonyl)methyl]formamide, (technical

oil:

10.0

30 mm011 of the crude

at room temperature,

The mixture

with ether

to give

g, 0.01 mol)

(328).

To an ice-cooled.

in CH2C12 (20 mt) was added in 0.5

h 3.45

stirred

g (0.02

solution

of sulfide

mol) of mCPBA (technical

F. J. A. HUNDSCHEID et al.

5082 grade,

85%).

extracted

The mixture

to give

1.71

IR (Nujol)

(20 mL), dried

g (75%) of 32a.

Analytically

and 4.90

H, 4.80;

N, 6.11:

complete,

the mixture

which crystallized benzene-hexane

lsocyanide

on cooling,

(s),

51.10;

164.6

H. 4.34:

(9).

CR)-(*)-set-Butyl -

0.5

crystals

(q),

59.0

7.90

(s.

H, 4.75:

1).

Anal.

N, 6.22:

of 5a: yield

Calcd for

and finely

ice-water.

852 mg (85%).

112.3

cd),

120.5

cd),

A brown syrup,

Two crystallizations

mp 93-94°C;

CgHgN03S: C, 51.18:

122.1

H, 4.26:

[c1;;g

+5.80°

according (C 5.00,

(9).

131.1

N, 6.63;

Butyl

tosylate

mixture

et al. 36 employing

liquified.

was stirred

extracted

with

2.28

to the procedure

at 90-100°C

for

3 h. The cooled

distilled

1.69

to give (c 2.154,

C6D6 using

(t,

31,

1.30

CHC13). The e.e.

cd),

27b was prepared

H. 5.07;

also

3),

1.45-2.0

was determined

(m. 2),

Br,

according

34.93.

IR (neat)

4.27

-35.80

Cal;’

mol),

a few crystals

added dropwise

a solution

of

Et20 (10 qL).

The mixture

mixture

was indicated

was hydrolyzed

with

combined Na2C03 extracts 1.98 (t,

H. 5.86;

of Reinhoudt

1.25

(d,

3),

into

E-butyl

ether for

keeplng

IR (Ccl,) 4.3

2550, (q,

The colourless

solid

Calcd

for

Method B. Compound

Thus a mixture

of o-bromo-

CsF (460 mg, ca.

gave a colourless

were placed

oil,

(after

ca.

layer

6.6-7.85

3.05

mixture 0.013

was cooled

2 h).

was

mO1) in

to -50°C of

At room temperature with ether

the

(10 x 25

aqueous Na2CU3(5x20mL).The 011 crystallized (S02H); 8.10

(s,

was prepared

used for

was crystallized

g,

below -15OC. Completion

was extracted

(m, 4), (29b)

magnesium (320

refluxing

27b (50% e.e.;

3 h. The suspension

colourless

g, 5.0 mm011 with CH20 and HCONH2by the procedure

(tosylmethyl)formamide.23

flask

1280 and 1090 cm-l

1),

[.al~

(m, 4);

Anal.

34.52.

10% H2S04 at O°C and extracted

(~)-(-)-~-[(oa~-Butoxyphenylsulionyl)methyl]folramide (1.12

6.5-7.5

dlstlllation

with saturated

with cold The resulting

011 was -1 1590 and 3000 cm ;

570 mg, 2.5 mmol),

the temperature

H2S04. The water

were extracted

(m, 21,

Br,

et al.37

dried

drop in temperature

were acidified

NaOH (10

yellow

55%.

In a flame

with stlrring

101 ice-cooled

mp 48-50°;

pale

and dry Et20 (50 mL). To the stirred

the solution

solutions

1.4-2.0

CHC13), e.e. (28b).

(S)-o-bromophenyl

(MgS04) and concentrated.

g (66%) of 28b; 31,

iodine

by a continuous

mL). The combined ether mL), dried

of

was refluxed

and dry SO2 gas was bubbled reaction

acid

(m, l),

(10 mL) and

10; aqueous

1480,

at 6 1.06 and 1.01.

Found: C, 52.68;

(c 2.0,

(RI-(+I-sec-

to be 50% by ‘H NMR (200 MHz) with Eu(dmcJ3 in

to the procedure

(S)-(-)-o-ss-Butoxybenzeneaulfinic

with

The resulting

mm Hg);

mol)

on a low flame until at 100°C.

was poured in water

and concentrated.

to the

g, 0.01

in 0.5 h. The reactlon

were washed twice

bp 62-64OC (0.05

(d,

with stirring

435 mg, 2.5 nrmol), (RI-(+)-set-butyl tosylate (26b, 3 mmcl) and HeCN (20 mL) after refluxing for 24 h and kugelrohr

mg, 0.013

cd),

CCXI~~

according

25 (1.73

and heated

(25,

392 mg (69%) of 27b:

136.9

(m,

Found: C,

of Cason et al:26

bath preheated

mixture

peaks of the two CH3 doublets

the integrated

CIOH13BrO: C, 52.40;

(MgS04),

g (51%) of 27b:

‘H NMR (CDC13) 6 0.98

2180

6.80-8.0

S, 15.16.

o-Bromophenol

was put in an oil

Et20 (3 x 25 mL). The combined extracts NaCl (10 mL), dried

phenol

modification.

g, 0.01 mol) was added dropwlse

mL), with aqueous

-32.5O

a slight

The whole assembly

(26b,

from

IR (Nujol)

EtOH)].

powdered KOH (0.58 g, 10.35 mmol) were mixed together

the mixture

for

S, 15.08.

EtOH) [Lit.35

of Niederl

Calcd

S, 13.71.

Compound 32a (1.14 g, 5.0 ramol) was dehydrated used for TosMIC. 23 After the addition of POC13 was

(S)-(-)-o-Brcmophenyl -sac-butylether (27b). Method A. Compound 27b was prepared procedure

on cooling

from CH Cl -hexane: mp 125-126V: ? 2 H NMR (CDC13) 6 3.96 (s. (S02)’

(m, 4),

and washed with

(t),

was

NaHC03 ( 10%. 20

crystallized

h at O°C and then poured in ice-water.

tosylate(2Ob) was prepared

+11.3O (c 5.45,

6.50-7.80

oil

'H NMR (CDC13)6 3.98 (s, 31, 4.65 (d, J - 2 Hz, 2),

(S02);

Anal.

N, 6.63:

for

was collected

gave colourless

1335 and 1150 cm-’

(5a).

The solid

then washed wl th aqueous

Found: C, 47.05;

the procedure

was stirred

13C NMR (CDC13) 6 56.1

S, 13.97.

then filtered.

The resulting

pure 32a was obtained

(d of AB q, J - 8 and 15 Hz, 21,

C, 47.16;

with POC13 and Et3N by folloulng

156.9

the filtrate,

(MgSO4) and concentrated.

(o-Hethoxyphenylsulfonyl)met.hyl

(N-C),

5 h at room temperature,

3390 (NH), 1680 and 1530 (NHCHO), 1280 and 1120 cm-l

4.70

CgHllN04S:

4);

for

with CH2C12 (10 mL), combined with

mL), with water

3),

was stirred

with Et20 (7 x 25 on cooling

to give

‘H NHR (CDC13) 6 0.92 1). from sulfinlc

the synthesis

acid

28b

of i-

from CH2C12-hexane to give

800 mg

Synthesis of chiral sulfonylmethyl

(58%)

of 29b:

From the

mp loo-103V.

same solvent

cm -' (S02): ‘H NHR 4.95

(d of

1.1,

CHC13).

6.20;

Analytically

mixture:

AB q, J - 15 Hz,

N, 5.25:

Calcd

S,

6.7-7.9

2),

at

For

C12H17N04S:

then

If? (neat)

18.5

4.55

(q),

155.7

C, 53.13;

(q,

4.86

(t),

(t),

same

e.e.

(*)-(1-Methoxy-2-propyl) Sanno ,38

mol).

g.

631):

(9,

3),

74.7

(d),

calcd

76.5

and

75.2

S.

11.80.

(d),

2),

113.1

Anal.

113.6

(m, 1). 4.85 and

Calm -30.6O Found:

(c

C, 52.96;

H,

115.5

For C

1490,

(d),

the

(d),

(t,

which

3),

(m. 4);

(1.35

was stirred

5b,

6,

5

The

For

0.5

h

was

of a colourlesa

6 1.0

6.6-8.0

29b

of To~MIC.~~

mixture

crude

viscous

1.35

(d,

3),

oil:

1.5-2.0

13C NMR (CDC13) 6 9.4

(q),

cd), 136.8 cd), 122.3 (a),

131.7 253.076

CM', calcd 253.077).

with

Eu(dcm)3

in 79% yield,

This

in C6D61.

according

was prepared

analogously

and KOH (2.8

g,

1595,

6.5-7.7

3000 (m.

121.7

H 10 13Br02’

2).

Formamide synthesis

to

the

procedure

of

From ICN Pharmaceuticals).

mol)

(m. 1),

the

852 mg (675)

28b [determined

(27~)

0.048

For

gave

MS, m/e

was prepared

IR (neat)

(s),

give

120.2

(d),

For

ether g,

4.45

Calcd

benzene

to

(purchased

8.64

SulFonylmethyl used

‘H NMR (CDC13)

(S02);

(26~)

mm Hg): (d,

with

Florlail

of 501 as Found

(25,

3.55

(t),

244.010).

1280 and 1120

(m, 2), 4.20-4.80

POC13 was complete,

(c 1.16. CHC13).

l-methoxy-2-propyl

bp 52O (0.005 3.45

cryatallizations

(NHCHO),

1675

N. 5.16:

(5b).

(AB q, J - 15 Hz,

tosylate

o-bromophenol

of

cm-’

From (t)-lmethoxy-2-propanol

(*)-o-Bromophenyl 0.04

4.93

(a); CCXI;~ -35.3"

had the

H, 6.27:

procedure

Extraction

1150

and

58.9

addition

CHC13 over

1340 and

1),

28.4

the

Et3N by the

Ice-water.

with

(N-C),

(s), 164.1

material

in

rapidly

2180

(m, 2),

After

poured

chromatographed

by two more

(NH),

(9, 1); MS. m/e 271 (t4+):

isocyanlde

pOC13 and

with

was as Follows:

O°C and

3300

11.73.

was dehydrated

work-up

was obtained

(m, 5), 7.96

(S)-(-)-(o-ss-ButoxyphenylsulFonyl)methyl mmol)

material IR (Nujol):

6 1.04 (t. 31, 1.42 (d, 3), 1.55-2.20

(cycle)

Anal.

pure

mp llo-lll°C;

5083

isocyanides

(d).

cm-‘;

4):

to mol)

27b From 26c

as

colourlesa

‘H NMR (CDC13)

(d),

132.8

H, 5.30;

Br,

(4);

(9.76 011

6 1.35

13C NMR (CDC13) 6 16.5

127.8

C, 48.97:

0.05

(d.

(q),

3),

58.7

Found:

solution

of

3.35 (q).

MS, m/e 244.007

32.65.

g,

(6.13

(H+;

C, 49.03;

H. 5.32:

BP. 32.47. (+)-o-(l-Methoxy-P-propoxy)phenylaulFinlc mmol)

In Et20

mmol).

After

was

the

introduced

poured and

extracted

with

and

8.0

saturated

to

1280

(m, 4),

give

cm-’

9.02

glve

2.73

a dense

of

28~ as

was converted

reaction

to

mixture

water,

with

brine,

(neat)

3450

(NH),

(9,

3).

3.60

(d,

g,

9.3

synthesis

of

For

0.5

the

combined

011,

which

yellow

h at

oil

at

-20°C

dried

2),

4.7

overnight,

(MgS04)

1680 and

O°C and

then

organic

layers

1695

(m,

were

acidified

extracts

were

dried

viscous

syrup;

(d.

3.40

(a,

3.60

to

the

3).

mixture

2),

was

were

IR (neat) (d,

16

Dry SO2 gas

extracts

The combined

(29c).

and

was extracted concentrated

(NHCHO), 1280,

3),

poured

6.6-8.3

to 1320

(m, 6);

combined with (MgSO4)

1070-1120,

4.60

68%):

3.4

(m,

1),

6.7-

28~ (3.15

g,

13.7

cm-’

(S02);

washed

nlth

H20,

CHC13-benzene 2150

(N-C),

1.35 (d, 3), 3.3 (a, 3). 3.5 (d. 21, 4.65

dried

1280 and

after

the

and

(m. 1). 5.25 and 5.15

with

colourlesa

oil;

(d,

3).

IR 3.35

287.083).

procedure

of

1340

storing

SulFonylmethylFormamide

brown

(MgSO,)

synthesis

was washed

of 29c as

(M+, calcd

(5~).

(l:l) over neutral

1145,

separated

the

‘H NMR (CDC13) 6 1.40

MS, m/e 287.084

The resulting

For

The extract

g (87%)

Et N Following 3 was as Follows: After addition

with

IR (neat)

give

acid used

which

CH2C12.

pOC13 and

ice-water.

Sulflnic

procedure

The 011,

with

lsocyanide

with

in

were

was chromatographed g,

2 h).

layers

29~ with CH20 and HCONH2 according 23 The work-up was as Followa:

mmol) was dehydrated ToaMIC. 23 The work-up

(1.7

(ca.

15 ca.

The ether

a colourlesa 3),

g.

The reactlon

The ether

(~)-[o-(l-Methoxy-2-propoxy)phenylaulFonyl]methyl (2.67

10°C

(3.67

in hexane,

1).

of N-(tosylmethyl)Formamide. the

to

(8 x 20 mL).

‘H NMR (CDC13) 6 1.35

27c

H solution

(8 x 10 mL).

(~)-~-[o-(l-Methoxy-2-propoxy)penylsulFonylmethyl~For~mide mmol)

(1.6

precipitate.

ether

(5 x 15 mL). ether

BuLl

was raised

yellow

with

with

g (79%)

To a stirred

10 mL of

temperature

extracted

extracted

(S02): (3,

to

the

Na2C03 solution

H2S04 and were

concentrated

1240

1 h,

2 N H2.W4 and

(28~).

dropwise

was complete,

-4OOC For

10 mL of

acid

-78OC was added

addition

at

into

10% aqueous and

(10 mL) at

used

29~

For

the

POCl

the mixture was stirred 3’ was extracted with benzene:

oil

concentrated A1203 to cm-’

(So2)

to give

give

a yell-

5c as

a pale

; ‘H NHR

(CDC13) 6

(AB q. J - 15 Hz. 2). 6.7-8.1

(m,

5084

F. J. A. HUNMS, m/e 269.071

4);

11.90.

CM+, calcd

Found: C. 52.96:

269.072).

H, 5.80;

tosylate

(S)-(*)-3-Tetrahydrof~anyl

Anal.

N, 4.81;

from (i)-(+)-3-hydroxytetrahydrofuran

35.5oc.

Ld;”

+18.4O

Cm, 1).

7.33

and 7.50

(d),

126.8

13.23.

(d),

Found:

(c 2.40,

129.3

(AB q, 4);

13C NMR (CDC13) 6 20.5 (3).

133.0

H, 5.77;

144.3

3-tetrahydrofuraeyl g,

12.0 mmol),

and KOH (700 mg, 12.5 ~1) (c 1.98,

(m. 1). cd). for

128.0

(d).

ether

(d).

H, 4.52; ”

5.0 mmol) in 731 yield;

6 2.32

(m. 2).

3.95

for

ct.),

was prepared

(1.68

1590 cm-‘;

153.5

hexane

(m, 1).

g, 691):

285.067

66.7

(t),

72.4

with

as colourless

mp 107.4-108.2°C;

Hg),

ct.),

4.86;

N,

132.2

after

-56.40

(m. 2).

cd),

(t),

cd),

4.0

BuLi in 351 yield; lld (13).

acid

(15)

(Table

of

c,

53.99;

shift

Cal:’ 4.85

(s),

114.1

Anal.

Calcd

32.81. to 30a from 27d (1.21 ‘H NHR (CDC13) in 75% yield from 306 and

from CH2C12-

CHC13); IR (Nuj01) 6.60-8.2

-2.2O

Co];’

entry

(c 1 .4,

3250 (NH),

(m, 6);

MS, m/e

of 27%.20 The e.e.

(80%) of lld.

Thls material

Formamide 326 (390 mg. 1.37 22 Pure 56 was of Ugi et al.

(AB q. J - 15 Hz, 2). 5.18

(t), (3).

72.5

N, 5.29:

(6)

(t),

Anal.

79.1

Calcd for S, 11.87.

However,

12 (Table

(d),

the e.e.

1, entry

‘H

cd),

121.2

cd),

of

H,

5d could

not be

was calculated

to be

14).

from partially

resolved

isocyanlde

s-

and 2.1

by conversion

equiv. to

to 2-hydroxy-2-phenyl-3,3_triiluoro-

(~)-(+)-2-methoxy-2-phenyl-3,3,3-trifluoroproplonic

yield of

(SOP):

(m, I), 6.85-8.17

113.9

of 6 was determined

hydrolysis

in 66% yield;

C12H,3N04S: C, 53.93: The e.e.

was prepared

CHC13). The e.e.

to

(2:l)

1235 and 1150 cm-’

+7.2=', c 1.1, CHC13), methyl

22) and subsequent

was converted

2150 (N-C),

reagents.

isocyanide

(5d).

from benzene-hexane

(18%) of

(Calm

to Scheme 2, overall

to an o.p.

15 and the d.e.

H, 4.88;

chlral

fluoride6

II,

66.8 165.3

10e and the 0.p.”

This material

(according

corresponds

112.6

was prepared

(m. 3),

to the procedure

and 4.94

ct.),

(3).

(-)-z-Phenyl-z-tosylaulfonlmidoylDethy1

propanal

cd),

241.994).

Br,

10.0 mol)

(m, 4),

(c 1.52, CHC13);

(c 1.8,

(m, 41, 4.90 lsocyanlde

4.87

59.3

155.0

way be using

(382)

phenyl-t-tosylsulfonlmldoyl oxazoline

3.9

(c 1 .4, CHC13); obtalned

Calm’ -28.8O

(m, 21,

two crystalllzatlons

(m, 4).

4.00

136.7

in a direct

47% from the d.e.

of

78.3

g.

mm Hg).

Two crystallizations

(c 2.0, CHC13); IR (Nujol)

5.24; s, 11.98. Found:

determined

2.42

(m, 2),

analogously

C01,2~ -30.6O

to 31a in 801 yield].

POC13 and iPr2NH’ according

needles

13 C NMR (CDC13) 6 32.3

(s),

S,

to 27b from o-

(0.15

CM+: calcd

(326)

Cal:

oil:

mp 107.5-llO°C;

[a]:' -40.80

NMR (CDC~ ) 6 2.30

123.5

81.2

H, 5.82;

285.067).

mmol) was dehydrated

(m, 4);

(t).

4.97

(m, 5).

(~)-(-)-[o-(3-Tetrahydrofuranox~)pheny~ulfonyl]wthyl obtained

S,

and

(m. 4).

71.7

(27d.

H, 4.59:

was prepared

(0.2 w

(NHCHO); ’ H NMR (CDc13) 6 2.30 (H+; calcd

(t),

Stuart

C, 54.53:

bp 115-117V

Found: C, 49.62:

6.6-7.8

31d Cviscous

crystals:

gave colourless

1640 cm-’

N. 5.20;

mp 34.5-

3.68

analogously

tosylate

MS, m/e 241.993

(30d)

23 analogously

F-(tosylmethyl)formamlde

3).

65.7

‘H NMR (CDC13) 6 21.5

(t),

(3);

Br, 32.92.

bp 105-108°C

(m. 41, 4.92

to 32a from crude

(3.

C11H,404S:

(~)-(-)-~-[o-(3-Tetrahydroiuranox~~~enylaulfony~thyl~fo~lde analogously

of

crystals,

2.37

32.1

Calcd

(27d)

oil

@)-(-j-o-(3-Tetrahydrofuranoxy)benzenethiol g,

(m. 2).

(S)-(+)-3-tetrahydrofuranyl

1485,

133.2

C, 49.38;

C10H1,Br02:

to the procedure

as colourless

(q),

Anal.

13C NMR (CDC13) 6 32.5

(m, 10;

cd),

(3).

as a colourless

CHC13); IR (neat)

6.5-7.7

121.8

H, 5.61;

S, 13.22.

(E)-(-j-o-Bromophenyl

-35.8O

according

3o in 80% yield

MeOH); ‘H NMR (CDC13) 6 1.96

brawphenol

2.16

C12H15N04S: C. 53.52:

was prepared

(d),

C, 54.44:

(25,

Calcd for

S. 11.24.

(266)

Ipson3’

er crl.

16.51);

C-j-6

Cal:’

+19.S0

was calculated

was identical

(c 1.4, CHC13). which

to be 34% from the 0.p.

with racemic

6 by IR.

(271)

of

‘H NHR and mixed

mp. ~ans-4-(2-l(enthoxyethylsulfonyl)-5-#thyl-5-pheny1-2~xazoline Conditions

(entry

(180 mg. 1.5 ml) chloride

2).

To a stirred

in benzene

(TEBACl) and 75 mL of

The alkaline

aqueous layer

solution

of

isocyanlde

(15 mL) was added 18 mg (i.e.

(lob).

extracted

with ether

Procedure:

PTC

4 (430 mg. 1.5 mmol) and acetophenone 5 mol I)

50% aqueous NaOH, and the mixture

was twice

Typical

of benzyltrlethyl~nlum

was stirred

for

3 h at lo-15’C.

(25 mL). The combined organic

layers

were

5085

Synthesis of chiral sulfonylmethyl isocyanides washed with ice-cold yellow 2.06

oil; (s,

dried

(Na2SO4) and concentrated

to yleld

1620 (C-N),

1320,

1260 and 1140 cm-’

‘H NMR (CDC13) 6 0.5-2.5

31, 2.80-4.20

determined

WaB

H20 (10 mt).

IR (neat)

(m, 51,

5.22

from the ratio

and 5.45

(1:2)

(two d, J - 2 Hz, l),

of the integrated

doublets

Trans-4-(oaec-Butorlphenylsulfonyl)-5athyl-5-phenyl-2-oxazollne BuLi/THP (entry 3). To a stirred Bolutlon of iaocyanide THF at -90°C mixture

was added 0.35

was stirred

for

(m, 8),

was slowly

syrup;

2.17

The d.e.

to the reaction raised

(s.

IR (neat) 3).

4.4

(m. 1).

(4OS) was determined

5.76

dried

stirring

and 5.67

from the ratio

(C-N).

1300 and 1120

and 5.12

iaocyanide

cm-l

(3)

(two d. J - 2 Hz. 11, 7.1-7.6

Typical

with MF (5 mL). The

(60 mg, 0.5 wol)

(5 qL) was added. to give

(S02)

of the integrated (lOa,

(k)-5c

and acetophenone.

Yield

2 Hz, l),

6.6-8.1

(m, 10);

801, (d,

(m, 6);

d.e.

yellow

31, 2.0

d.e.

oil; (s,

doublets 1).

601,

1310,

of

471 o.p.

1270 and 1145 cm-l

11, 5.76

and 5.79

(a,

3),

IR (Nujol) 4.04

1150 cm-l

Anal. s,

and acetophenone.

3.3

(lOd,

1620 (C-N).

(m, 5).

4.60

(S02);

Yield

701,

‘H NHR (CDC13) 6 1.95

pale

1320-1260

(m, 1).

5.75

entry

6). From -1 and 1140 cm

and 5.95

(two d. J -

(toe,

yellow

(m, 2).

2.00

(two d, J - 2.1 Hz and J - 1.9 Hz. 11, 6.8-8.2

5a and acetophenone.

for

1620

11, 4.96

171.

Yield

(S02); ‘H NHR (CDC13) 6 2.14

Calcd

(br,

181.

C,7H17N04S: C, 61 .63;

92s; 3).

(9.

(a,

4.22:

N,

IR (neat)

3),

(9,

3.85

10); d.e.

was prepared

qp 170-171OC:

3.82

H, 5.13:

011:

(m,

Trsns-4-~o-Methoxyphenylsulfonyl~-5lethyl-5-phe~l-2-oxazoline from iaocyanide

and 5.87.

From (+)-

aemi-solld;

(m. 181, 2.06

IR (neat)

3),

1Oc

(m, 10).

at 6 5.76

Cls/traM-5-Methyl-5-phe~l-4-~o-~3-tetrah~drofur~oxy~phe~lsulfonylI-2-oxazollne From CR)-(-)-5d

The mixture

‘H NMR (CDC13) 6 0.7-2.0

;

entry

Yield

and acetophenone.

in THF

141 mg (76%) of

Trsns-4-[o-(l~ethoxy-2-propoxy~pbenplsulfo~l]-5rethyl-5-phenyl-2-oxazoline (SO21 ; ‘H NMR (CDC13) 6 1.35

Rocedure:

(two d, J - 1 Hz and 2.1 Hz, 11, 6.6-8.2

(3h)

(33%)

2 h between -50 and -60°C,

NH4Cl solution

‘H NHR KDC13) 6 0.7-2.8

(S02);

for

and 1150 cm-’

(m, 181,

The d.e.

126 mg. 0.5 tmnol) in 5 mL of

(MgS04) and concentrated

1320-1270

lob as a

and 5.45.

of acetophenone

Trans-5-Methpl-4-(n~nthylsulfonyl)-5-phenyl-2-oxazollne (neomenthylaulfonyl)methyl

(m, 6).

at 6 5.22

5b (501 8.e.;

After

mixture.

1625 (C-N),

7.0-8.2

olmol) of BuLi In hexane diluted

to O°C and saturated

with CH2C12 (3 x 15 qL),

was extracted as a yellow

M. 0.56

451 mg (74%) of

(loo).

15 min at -8OOC. Then a solution

(5 mL) was added dropwise the temperature

mL (1.6

(S02);

3).

IR (Nujol)

5.74

(d,

S. 9.66.

entry

14).

1620 (C-N).

(m, 4),

5.05

(m,

382.

analogously

1615 (C-N),

J - 2 HZ, 1).

Found: C, 61 .28:

to

10a

1320-1280

and

6.8-8.0

Cm. lo).

H, 5.08:

N, 4.39;

9.62.

Cis/trans-4-N~nthylsulfonyl-5-phe~l-5-trlfluorolethyl-2-oxazollne 42 Ti(OEt)4/~-ethylpiperidine (entry 17). To a stirred 2.0 mm011 and l-ethylpiperidine isocyanide

3 (0.24

a aolutlon

of a,a.a-trifluoroacetophenone

After mt).

stirring After

Celite

for

raising

as filter

g,

(0.138

1 wol)

1 h at 0%

solution

(0.175

the reaction

g,

mixture

to 20°C,

The filtrate

of

Typical

Procedure:

tltanlumtetraethoxlde

(0.456

1.2 nrmol) in 2 mL of CH2C12 was added a solution

in CH2C12 (2 mL) at O°C. After

the temperature aid).

g,

(lib).

stirring

the mixture

for

g.

of

30 mln at O°C

1.0 mmol) in CH2C12 (2 mL) was added dropwise. was quenched with

the reaultlng

eolld

saturated

Na2S04 solution

waa removed by flltration

was washed with H20 (2 x 5 mL), with brine

(2

(using

(5 mL), dried

(Na2S04) and concentrated to give 400 mg (96%) of llb as a viscous oil; IR (neat) 1620 cm-’ (C-N); 1 H NMR (CDCl ) 6 0.7-2.8 (m, 18). 4.09 (br. 1). 5.33, 5.35, 5.49 and 5.53 (four d. J - 2.1, 1.9, 3 2.1 and 1.9 Hz. respectively), 7.25-7.80 (m, 6); “F NMR (CDC13) 6 -71.74, -71.92, -80.27 and -80.46;

d.e.

ias.

Cls/trans-4-Tosyl-5-phenyl-5-trifluorolethyl-2-oxazoline 16).

To a stlrred

mmcl) in 50 mL of temperature

0.66

solution

THF (previously qL of

which 62 pL of acetic was dissolved concentrated

of TosMIC (1, diatllled

a BOlutiOn of acid

(lla). Typical

0.80

TritOn

g,

Procedure:

fram sodium and benzophenone) B (40s

in MeOH). The mixture

and 0.6 mL of H20 were added.

After

removal

1.45

g (3.93

mmcl, 96%) of

lla: IR (Nujol)

B (entry

(0.71

g,

4.1

was added at raom was stirred

of

in 50 mL of CH2C12 and was washed with H20 (3 x 20 mL). dried to yield

Trlton

4.1 mmol) and trifluoroacetophenone

the solvents,

for

4 h, after the residue

(HgS04) and -1 1630 (C-N) cm ; ‘H NMR (CDC13) 6

F. J. A. HUNDSCHE~D ef al.

5086 2.36

(s,

3),

6 -71.50 entry

5.53

and 5.83

(two d, J - 1.9 Hz and J - 2.1 Hz, 1).

7.1-8.0

(m, 10):

and -79.44.

19).

(m, 2).

From (RI-(-)-5d

3.5-4.31

Hz. 11, 6.7-8.22

and trlfluoroacetophenone.

(m, 4).

4.84

(m, 10);

“F

(m. 1).

6.04,

Yield

6.11,

NMR (CDC13) 6

6.26

-73.41,

98$,

viscous

and 6.31

-73.73,

(four

-75.03

oil;

‘H NMR (CDC13) 6 2.16

d, J - 2.1, and -75.47:

1.9, d.e.

Cls/trans-5-Phenyl-4-(~-phenyl-~-tosylsulfonimidoyl~-5-trlfluorolethyl-2-oxazoline From c-j-6

and trifluoroacetophenone.

5.25

and 6.33

-79.3;

d.e.

Yield

(two d, J - 2.1 Hz. l),

91%. dark viscous

6.98-8.10

(m, 15):

(R)-(-)-2-Hydroxy-2-phenylpropanal

(121.’

added 2 N HCl (3 mL). The mixture (10 qL),

extracted

as a colourless 108-llO°C l),

Typical

Procedure. (lob,

was stirred

overn;ght

with Et20 (3 x 15 mL), dried

liquid,

(0.3

7.4

22).

(br s,

-71.6,

3),

-79.1

and

w

(br s,

IR (neat)

51, 9.4

(s.

at room temperature,

distillation:

3440 (OH). 1720 cm-’

1);

[a]:

-80.2O

The mixture

(150 mL) and extracted

with

mL), with brine oil,

(30 mt),

bp 90-llO°C

Typioal

dried

(0.1

Procedure.

(lib, overnight

1.5 g,

(Na2S04) and mncentrated

to give

with H20

12 was obtained

mm Hg) [Llt.43 (s,

31,

To a solution

bp

4.3

of

3.6 mmol) in MF

at room temperature,

Et20 (3 x 50 mL). The combined extracts

which was converted

trans-4-(2-

then diluted

Aldehyde

‘H NMR (CDCl ) 6 1.60 g3 CHC13), o.p. 31s.

(13).

was stirred

of

(C-0);

(c 1.73,

(~)-(+)-2-Hydroxy-2-phenyl-3.3,3-trifluoropropmal added 2 N HCl (10 qL).

solution

(MgS04) and concentrated.

83 mg (47%) by kugelrohr

Hg)];

To a stirred

500 mg, 1.2 mmol) in THF (15 mL) was

neomenthylsulfonyl-5-phenyl-5-trifluoromethyl-2-oxazoline

yellow

‘H NHR (CDC13) 6 2.40

NHR (CDC13) 6 -71.4,

and 1.9

entry

(ltd.

oil;

“F

2.1 41%.

801.

menthoxyethylsulfonyl)-5-methyl-5-phenyl-2-oxazollne

s,

(CDC13)

"F NM

(br

4-

(30 mL) was

then diluted

with H20

were washed with H20 (3 x 20

0.37

g (511)

of crude

13 as a pale

to 14 as such.

(~)-(+)-2-t4ethoxy-2-phenyl-3.3,3-trlfluoropropanal (14). To a solutionof crude aldehyde13 (0.372 g)

in Et20 (30 mL) was added at room temperature

After

1 h 0.6 g (4.0 nmol) He1 was added,

was poured

in ice-water

(100 mL) and extracted

washed with H20 (2 x 20 mt), was distilled

at reduced

(CDC13) 6 3.5

(s,

(CDC13) 6

54.66

cd),

(d),

131.1

3).

dried

(q),

84.72

193.0

cd);

(96-97OC,

(m. 5), (q,

which the mixture with ether

9.66

2JFc - 37 Hz),

123.16

[a],20 l7.2O (C 1.01,

rapidly (1.06

stirred

solution

of purified

mL, 10 rmnol) in 50 mL of

methoxy aldehyde

extracted

with hexane

(2 x 25 mL). The aqueous

(25 mL), &led

at reduced

pressure

(m, 5).

11.13

28 Hz), 118.9 (q. +11.80

layer

(c 1.5,

1);

“F

extracts

crude

129.0

cd).

were

product,

421) of

14;

which ‘H NMR

13C NMR

129.2

(9).

129.8

of sodium chlorite

was added dropwlse

8 h

. After

was dissolved with

were combined,

g (0.73

0.190

addition

127.3

to a

cd),

6 N HCl to pH ca.

cd),

g of crude material.

129.9

3, and

washed with H20 (25 mL),

mmol. 732) of 15;

128.6

of 6 N NaOH

in H20 (50 mL) and

cd),

Distillation

'H NMR (CDC13)6 3.5

NHR (CDC13)6 -71.46; 13C NMR (CDC13)6

‘JCF - 291 Hz).

CHC13), o.p.

for

was acidified to give

1 mmHg) gave 0.17 (s,

~1.

A solution

(pH 3.5)

The residue

layers

(Na2S04) and concentrated

(106-108°C,

g of

14 (204 mg, 1.0 mm011 and 2-methyl-2-butene

pressure.

with Et20 (2 x 50 mL). The organic

with brine

(s. 3), 7.0-7.6

(15).20

t-BuOH at 30°C and then stirred

10, t-BuOH was removed at reduced

2 h. The mixture

NMR (CDC13) 6 -70.92;

'JFc 286 Hz).

acid

to pH ca.

then extracted

(q,

0.39

g (1.5

“F

for

The combined

CHC13).

1 .25 rnw~l)‘~ in 1 mL of NaH2P04 buffer

g, 851.

0.32

'JFH - 2 Hz, 1);

(~)-(+)-2-Methoxy-2-pheyl-3,3,3-trlfluoroproplonic (NaC102, 0.14

to give

12 ran Hg) to glve (9,

removed previously).

was refluxed

(3 x 50 mt).

(Na2SD4) and concentrated

pressure

7.0-7.6

96 mg (4.0 mmol) of NaH (oil

after

131.0

55.4 (q), 84.4 (s),

171.7

171.20

Acknowledgment. This investigation was supported Research (SON) with financial aid (to P.H.F.M.R. for the Advancement of Pure Research (ZWO).

by the Netherlands Foundation for Chemical H.) from the Netherlands Organization

and F.J.A.

(9);

Synthesis of chiral sulfonylmethyl &cyanides

5087

References and Notes 1. Chemistry of Sulfonylmethyl Isocyanides 32. For part 30 see J. Moskal and A.M. van Leusen. J. Org. Chem. 51, 4131 (1986). 2. J.D. Moriaon and H.S. Masher in “Asyaxaetric Organic Reactionsw, Prentice Hall, Engeluood ciirf3, N.Y. 1971. The Chlron Approach”, Pergamon Press, New 3. S. Hanesaian in “Total Synthesis of Natural Products. York 1984. Chem. 5. Slll 4. The chemistry of TosMIC has been reviewed: (a) A.M. van Leusen, Lect. Heterocycl. in the Organic Chemistry of Sulfur”. B. (1980); (b) A.M. van Leusen, in “Perspectives Zwanenburg and A.J.H. Klunder. Eds., Elsevier, Amsterdam 1987, p. 119. isocyanide (3) was previously described. It has been used for the 5. f+)-Neomenthylsulfonylmethyl first synthesis of optically active 2-methylcyclobutanone: D. van Leusen, P.H.F.M. Rouwette and A.M. van Leusen, J. Org. Chem. 46, 5159 ( 1981). 6. D. van Leusen and A.M. van Leusen. Reel. Trav. Chim. Pays-Bas 103. 41 (1984). (a) O.H. Oldenziel and A.M. van Leusen, Tetrahedron Lett. 167 (1974); 7. See ref. 4a, and also: (b) 0. Possel. Ph.D. Thesis, Groningen (1978); (c) P.H.F.M. Rouwette, Ph.D. Thesis, Groningen (1979). 8. Y. Ito, M. Sowamura and T. Hayashl, J. Am. Chem. Sot. 108, 6405 (1986). 1253 (1978). 9. T. Mukalyama, Y. Saklto and M. Asami, Chem. Lett. 10. Throughout this paper, e.e. and o.p. are assumed to be equal. H NMRof the 4-tosyl-2-oxazolines indicates that only one isomer la formed, provided that the 11. substituenta at C(5) are sufficiently different in size. Fo~25-~-butyl-5-methyl-4-tosyl-2oxazoline the trans stereochemistry was established by NOE. Ph.D. Thesis, Croningen (1975). 12. O.H. Oldenzlel, assigned the structure 13.13-dimethyl-Zreaction p6~Q~ct,,~fq,F.~e tatively 13. To the intramolecular ldodec-3-ene-6.6-dioxide. Intermolecular reaction oxa-4-aza-6-thiatetracyclo[6.4.1 products, however, were obtained from 2 and p-nltrobenzaldehyde or benzoyl chloride and base: 5-(p-nltrophenyl)oxazole (901) and 4-(lo-camphorsulfonyl)-5-phenyloxazole (7011, respectively. see ref. 7c, p. 22. with success in asymmetric induction. see i.e.: J.D. 14. Chelation has been used previously Morrison in “Asymmetric Synthesisn. Vol. 3, Ch. 3 and 4, Academic Press, New York 1984. in Stereochemistry”, Ch. 6, Butterworths. London, 1954. 15. W. Klyne in “Progress van Nlspen, C. Hensink and A.M. van Leusen, Tetrahedron Lett. 3723 (1980). 16. S.P.J.M. sides of the oxazoline ring. 17. Trans is defined here for R+S(O)(X) and Ph at opposite C. Guantl and E. Narlaano, J. Chem. Sot. Perkin I, 1278 18. L. Colombo, C. Cennarl, C. Scolastico, (1981). oP the hydroxy group prior to oxidation is necessary since a-hydroxy acids are prone 19. Protection to oxldative cleavage, cf. P. Blumbergs, M.P. LaMcntagne and J.L. Stevens, J. Org. Chem. 37, 1248 (1973). 20. J.A. Dale and H.S. Masher, J. Am. Chem. Sot. 95, 512 (1973). Acta 18, 1 (1985) and references cited therein; (b) S.C. Pyne. 21. (a) C.R. Johnson, Aldrichlmica J. Org. Chem. 51, 81 ( 1986). 400 (1985). 22. R. Obrecht, R. Herrmann and I. Ugi, Synthesis, and A.M. van Leuaen, Org. Synth. 57. 102 ( 1977). As was 23. cf. B.E. Hoogenboom, O.H. Oldenzlel shown for example, in the synthesis of 3 the use of @r2NH lnstead of Et3N usually gives higher yields and/or purer products and 1s now recommended. J. Kurz, H. Helnzel and A. Hubele, Llebigs Ann. them. 24. (a) Ii. Huckel, D. Maucher, 0. Fechtlg, 645, 115 (1961); (b) A similar mixture of menthenes was obtained in unsuccessful attempts t45 convert the tosylate of f-)-5-methyl-2-(2-phenyl-1sopropyl)cyclohexanol (from f*)-pulegone) into a 2-thlol, J. Boon, unpublished results. 25. E.J. Corey and H.E. Ensley. J. Am. Chem. See. 97, 6908 (1975). J. Org. Chem. 26. 3645 (1961). 26. J. Cason and J.S. Correia, pure 1.2-propanediol is available from lactic acid: (a) J. Combos, E. 27. Enantlomerically Hasllnger and U. Schmidt, Chem. Ber. 109, 2645 (1976); (b) C. Helchlorre. Chem. Ind. (London) 218 (1976). with minor changes in reaction conditions, cf. P. Beak and C-H. 28. The yield may vary considerably Chen, Tetrahedron Lett. 4979 (1985) and references therein. H. Wynberg and A. Bantjes. Org. Synth. Coil. Vol. IV, 534 (1963). $: V.K. Tandon, A.M. van Lessen and H. Wynberg, J. Org. Chem. 48, 2767 (1983). P.D. Brewer, J. Tagat and P. Helqulst, Tetrahedron Lett. 4145 (1977); (b) 31. (a) C.A. Hergrueter, ibid, Tetrahedron L&t. 4573 (1977). 32. A.C. Brouwer and A.M. van Leusen, Synth. Comm. 865 (1986). (bl S. Smiles and T.P. Hilditch, 33. (a) S. Krishna and H. Slngh, J. Am. Chem. See. 50, 792 (1928); J. Chem. Sot. 519 (1907). E. Chiellinl, Gazz. Chem. Ital. 102, 830 (1972). and V.P. Pittman, J. Chem. Sot. 1072 (1935). $1 J. Kenyon, H. Phllllps J. Am. Chem. See. 53, 1928 (1931). 36. J.B. Niederl and S. Natelson. D.N. Reinhoudt, F. de Jong and H.P.M. Tomassen. Tetrahedron Lett. 2067 (1979). Chem. Abstr. 51, 16431~ (1957). 33:: Y. Sanno, Yakugaku Zasshi 77, 626 (1957); 39. R. Stuart and T. Ipson. J. Org. Chem. 9. 235 (1944). 40. This compound is unstable at room temperature. Attempts to49etermine the e.e. by NMRtechniques (i.e. chiral shift reagents or methylphoaphonic dichloride l were unsuccessful. 41. (a) B.L. Ferlnga, A. Smaardljk, H. Wynberg, B. Strijtveen and R.M. Kellogg, Tetrahedron Lett. 997 (1986); (b) B. Strljtveen, B.L. Ferlnga and R.M. Kellogg, Tetrahedron 43, 123 (1987).

5088

F. J.

A. HUNDSCHEIDet

al.

Experimentally it was Pound to be crucial to use a combination OP both bases. Other bases or base-combinations. which led either to destruction ot the lsocyanide or to decomposition oP trllluoroacetophenone, were e.g. K CO t-BuOK. Tl(OEt) - K CO and Ti(OEt)4-t-BuOK. 43. O.H. Oldenzlel and A.M. van Leusen, 2 T&rahedron Lett. 167 (1973). 44. (a) J.E. Lynch and E.L. Eliel, Tetrahedron Lett. 2855 (1981); (b) ibid, J. Am. Chem. Sot. 106, 2943 (1984); (c) C.A. Kraus and B. Roth, J. Org. Chem. 85, 4625 (1980). 42.