Stereoespecific syntheses of 2,3-dimethyl-1,4-oxathian S-oxides

Tetrahedron Letters,Vo1.25,No.28,np Printed in Great Britain

STEREOESPECIFIC

) J.L. Garcia Ruano"

J.C. Carretero Quimica

Depto.

Madrid-34

SYNTHESES

Organica.

Facultad

3029-3032,1984

0040-4039/84 $3.00 + .OO 81984 Perqamon Press Ltd.

OF 2,3-DIMETHYL-1,4-OXATHIAN

S-OXIDES

and J.H. Rodriguez

de Ciencias

. Universidad Autonoma de Madrid. Canto Blanco

SPAIN

and --. trans-2,3-dimethyl-1,4-oxathian, their diastereomeric The stereoespecific syntheses of cisS-oxides and their S-dioxide derivatives are reported. The key step in the synthetic pathways is by intramolecular conjugated addition with the cyclization ofa 2-hydroxyalkyl vinylsulphoxide, retention of configuration in the C and S chiral centers.

1,4-Oxathians

have scarcely

been reported

to prepare

cific synthesis

of their 2,3-dialkyl

of diastereomerically The synthesis sequence

been studied

from a conformational

derivatives.

pure S-oxides

viewpoint'.

Several

but they are not that satisfactory

1,4-oxathians2,

In this paper, a new method

for the obtention

of cis- and trans-2,3-dimethyl-1,4-oxathians

of cis-2,3-dimethyl-1,4-oxathian,

z

methods have

for the stereoespe-

is reported.

, was carried out according to the

shown in scheme 1.

Me

PPh3-Xl4 OH

*

Me

Me

or POCl3

‘aOH

OH sflC,

-+

Me

Na 104

OH * Me

_

Me 2

1

so

r--s

*Cl

0

ti Ma

4_(Y+4_ B

Me

7 K2C03

Na104 /

I Me

OH

OH

*

s”2+CI Me

Na104

s\/J

1 was obtained the procedure

or Me

Cje-$a

5a+56 Scheme

following

KOBut

Me

2

The erythro-diol

NaH

SO\// -*

Me

mercaptoethanol

OH

1

by the opening described

of the tm-1,2_dimethyloxirane with 23 . Attempts to cyclize compound 1 with

by Evans

acid catalysis

( BF3 , TsOH , H2S04) were unsuccesful

cases. Similar

unsuccessful results have been obtained by other authors in several attempts to 4 dials . This failure can be expalined because the anchimeric assistance of the

cyclize

related

sulphenylic

sulphur

gives a thiiranium

and complex mixtures

salt intermediate,

3029

with precludes

were obtained

in all

the intramolecular

3030

SN2 attack of thesecond

hydroxyl

group to give the 1,4-oxathian.

of the primary hydroxyl group of ,1, by reflux during 20 hours with PPh3 (1 eq.) 6 compound 2 (yield 90%). The reaction of diol ,l_with POC13 (1 eq.) at O°C 1 a 85:15 mixture (by H-nmr) of compound ,2 and its regioisomer (erythro-2-chloro-3-(2-hy-

Chlorination

in Ccl4 5 , afforded yields

droxyethylthio)

Cyclization

The reaction

butane).

not afford the desired

was then attempted

Oxidation

using the sulphoxides

of 2 with NaI04

mination

sulphoxide

the components

products

These compounds When

with NaH

the mixture

(NaH or KOBut), vinylsulphoxides 1,4-oxathian

a mixture

the above reaction had completely

_5a and ,5@

of se+ga was isolated

were intermediates

2, WCS obtained

occurred

also remains

mixture

,

by oxidation

J2 3 values

without

apparently

fcx and

18 hours,

cyclized

of 4_~+4_8 after 2 hours.

disappeared

mixture

2 with NaI04(1

in DMF containing

of $a +4_fito _6e+a.

of stereomeric

and the only

and characterized.

of vinylsulphide

(yield 80%). These results

in the conversion

by reduction

of sulphoxides

which were isolated

5a "36 was left for 3 days at room temperature,

From the observed cyclization

by stopping

to those obtained

yield.

The latter reaction involves two steps, eli9 conjugated addition of alkoxide to the vinyl-

, and nucleophilic

were the vinylsulphoxides

, did

'-$ and 4,~ as intermediates.

of the initial mixture

were identical

conditions

in quantitative

(1.5 eq.) in DMF7 at 40°C during

S-oxides ge+ga8.

group. This was demonstrated

At this point, reaction

1,4-oxathian

of HCl to give 5_a +?a

2 was produced

(1 eq.) gave the diastereomeric

4_B (yield 95%), which by reaction to the corresponding

of ,2 with several bases under different but the vinylsulphide

1,4-oxathian,

es.).

strong bases

indicated

that the

The cis-2,3-dimethyl-

of cyclic sulphoxides

in both se and ,6a (1.7-1.9 Hz), It could be deduced

with PPh3. that the

on C-3. In addition, the configuration of the sulphur 10 in this process . In order to confirm this assumption, which

epimerization

unaltered

would allow us to assign the relative

configuration

of the chiral centers

in acyclic

hydroxy-

, these compounds were separated by column chromatography on silica gel = 4.51, (eluent CHC13:MeOH 25:3 ) and cyclized independently (scheme 2). Compound 4,01( 6 CH-0 6cH_S=2.81 , 6 CH3_co=1.43 and 6 CH _cs=1.25 ppm) yielded only sulphoxide se, whereas 4JB(6CH_0

sulphoxides

$c( and 4_B

=4.36, 6CH_s=2.75,

3 6CH _co _ gCH _Cs=1.33

ment of the sulphinylis

oxygen c&

ppm) yielded

:a. As the axial or equatorial

easily be established

from the chemical

shifts

arrange-

of the H2ax

and H axial protons in the oxathian ring, which must be greatly deshielded in the sulphoxide 11 6ax (see table l), the configurational assignment of acyclic sulphoxides could be established 6a (see scheme 2).

+a+$@

----4;

,

,/

?a{f;gtE} --

NaH Me

\\ \

NaH

Scheme 2

-

hs 02 ti Me

‘; M:

3031

Table 1. Significant

lH-nmr parameters Compound

0

k

sax

J-kd

Me1

2.3

shifts,6

(ppm) I .-

_:e=

22s

6RX

3

4.01

3.79

2.54

1.15

1.39

1.30

1.32

6"

1.6

3.70

3.62

3.12

Ga

1.9

4.55

4.43

2.62

1.20

1.24

9

2.0

4.30

3.99

2.82

1.27

1.42

1:

9.0

3.34

3.69

2.70

1.22

1.10

1_3e

9.7

3.40

3.69

2.53

1.31

1.41

12"

9.7

4.09

4.40

2.34

1.26

1.30

16

9.8

3.74

4.06

2.88

1.30

1.31

of the trans-2,3-dimethyl-1,4-oxathian

1,O was quantitatively

mercaptoethanol.

The observed

a mixture

obtained

1,4 was carried

from the bromohydrin

out in similar way. The

of &-butene

by reaction

with 2-

regioselectivity

than 97% (the minor regioisomer yielded

Chemical

"3

The synthesis a-diol

and derivatives

J2,3

7

“&lx “2ax -

of 1,4-oxathians

in the chlorination of l,O with POC13 was higher 1 was not detected by H-nmr ). The oxidation of l&J with NaI04

of 1_2a and 126 (97%) which were separated

by chromatography.

The cyclization

6CH _Cs =1.29 ppm) with NaHjDMF at 40°C afforded 3 3 only 1,4-oxathian lze, whereas 128 (6,,_,=4.26, 6CH_s=2.80, 6CH _Co=1.3% and 6CH _Cs=1.13 ppm), 3 in identical conditions, yielded a mixture (1:l) of 1_3e and Qa. Slmllar results3were obtained of 1_2a (6CH_0=4.39,

6CH_S=2.80, 6CH

at 20°C. Epimerization

_Co=l.38

of sulphoxide

1_3e in HCl l2 yielded

Me HO

Me

a mixture

Na104

HO

’*OH

of 1_3a and ze

HO so,-

Me

Na104

Cl

Me

I

1_3e

_:

1_3e + 13a

HO+fo_,<';;;;;; PPh3

_?

Me .

-9

Me

“Cl

-

P

_T-)-

Me

Me

that 123a was more stable

1_3a

Scheme 3

?? suggesting

/-l/-s--o 0hMe

12a+12$ _ -

f--s o+Me

with NaH/DMF

(4:1),

Me

Me POC13

*

and

than 1_3e. This mixture

at 40°C for 3 days. This result

indicates

remain unaltered

that the epimerizatlon

despite

treatment

of sulphur

had

3032

taken place on the a-sulphinyl Sulphones with NaTO4.

carbanion

2 and 15 were prepared

The cyclization

intermediate.

by oxidation

of sulphones

*

P

H

KOEd

R2

sulphoxides

,8 and l-5, which in turn were obtained

Me Rl H

of the corresponding

5 and 1,3

by oxidation

of

H Nat04

*

so+2k&I

Me

8: Rl =H, R;!=OH 12: Rl =OH, R2=H

9,: RS=H,Rq= Me 13: R3= Me, R4=H

Cje+fja:R3=H,Rq=Me 1_3e+1_3a: Ra=Me,

Rq=H

Scheme 4 sulphides

2 and 12 with excess NaI04, required

only sulphone 2, whereas

yielded yielding

a mixture

only 2 hours at room temperature.

in the cyclization

any C-alkyl

procedure

is under study. We think that the careful

(&hydroxythiols

and epoxides,

bromohydrins

(or aryl) substituted

and the anomalous

8

on C-3 took place,

(1:5) of 2 and 1, (scheme 4).

The scope of this method as a more general and derivatives

of 1,5 epimerization

Compound

cyclizat:on

or

1,4-oxathian. sulphoxide

of

for the obtention

selection

B-dihaloalkanes) The conformational

12s and sulphone

REFERENCES 1.

of 1,4-oxathians

of starting

will permit analysis

products

the synthesis

of

of these compounds

12 are also being studied.

AND NOTES

See for example, Riddell F.G., "The Conformational Analysis of Heterocyclic Compounds" Academic Press, London (198O),p.116 . 2. Pihlaja K. and Pasanen P. in " The Chemistry of Ethers, Crown Ethers, Hydroxyl Groups and their Sulphur Analogues" Ed. Patai S.(Suplement E), John Wiley & Sons, Chichester(l980) p.844. 3. Rooney R.P. and Evans S.A.; J.Org. Chem., 1980, 45, 180. 4. Black D.K.; J.Chem.Soc. (C), 1966, 1708. R.C. and Evans S.A.; J.Org.Chem., 1982, 4_ 3980. 5. Barry C.N., Baunrucker S.J., Andrew 6. In similar conditions, the reaction of compound L with SOC12 yielded an equimolecular mixture of both regioisomers. 7. Yields are lower in other solvents such as acetonitrile or THF. 8. Subindexes e and a indicate the equatorial or axial arrangement of the sulphinylic oxygen. acting as nucleophile amines ( 9. Intermolecular conjugated additions to vinylsulphoxides, Abbot D.J., Colonna S. and Stirling C.J.M.; Chem. Comm., 1971, 471),sodium methoxide ( Tsuchihashi G., Mitamura S. and Ogura K.; Tetrahedron Lett., 1973, 2469) and stabilized carbanions (Tsuchihashi G., Mitamura S., Inone S. and Ogura K.; Tetrahedron Lett., 1973, 323) have been reported. 1 lO.As estimated by H-nmr, the ratio 4a:48 was essentially the same as the ratio 6e:6a. ll.Foster A.B., Inch T.D., Qadir M.H. and Weber J.M., Chem. Comm., 1968, 1086; Cook M.J., Kemia-Kemi, 1976, 2, 16. The use of this criterium has been possible because all sulphoxides exhibit values of J 5ax 6ax larger than 11 Hz. 12.Mislow

K.; Rec. Chem. Prog.,

(Received

in

UK

8 May

1967, 21, 217.

1984)