Syntheses and thermal transformations of N-alkyl thiazolidine sulfoxides

Tetrahedron Letters, Vo1.30, Printed in Great Britain

No.4,

1989

pp 425428,

SYNTHESES AND THERMAL TRANSFORMATIONS

0040-4039/89 $3.00 Pergamon Press plc

OF N-ALKYL THIAZOLIDINE

+ .oo

SULFOXIDES

Stephen R. Herchen Polaroid Corporation, Chemical Research, Cambridge, Massachusetts,

02139

Abstract: The title compounds are prepared and their novel thermal chemistry studied for the first time. Aldehydes and thiazolidines can be generated thermally from these compounds. Mechanistic possibilities are discussed. The thiazolidine ring system is an integral pan of a variety of compounds that have found diverse application as medicinally thiazolidines

active agents, flavor enhancing

relates to their argentolytic

instant color film. Thiazolidine expansion

of penicillin

gained notoriety

aminosulfoxide8,

reported

ring is acylated or suffonylated.

of the in vitro ring

thiazolidine

Interestingly,

sulfoxides

are

a natural product that We report

and some initial findings concerning the novel thermal reactivity

reports

describe

unsuccessful

attempts

to synthesize

“N-H” thiazolidine

sulfoxides5

describing these compounds as intrinsically unstable and prone to complex decomposition

We have found that the N-alkyl thiazolidines &f-u forward manner to the corresponding

can be oxidized (1 equiv. MCPBA, CH2Cl2, -lS°C-HT.)

sulfoxides a-29

9-k

R

5

4

5

R5%

R4

Y-k i

_

2

“3

“3

la lb lc

C”3 C”3 C”3

Id 19

C”3 C”3

If

3,5-Dicatbcethoxy benzyl

19

CH3

and CLreactions.

in a straight-

in 60-95% yields (Table 1).7 These sulfoxides were purified by

and are quite stable in the crystalline state.

Rs%

R

interest in

exhibit.

Previous

chromatography

All previously

sulfoxide moiety has been reported and it too possesses an acylated nitrogen4

here the first syntheses of N-alkyl thiazolidine s&oxides these compounds

Polaroids

two decades ago with the discovery

to deacetoxycephalosporins.3

configured such that the nitrogen in the thiatolidine incorporates the thiazolidine

in synthesist

reactivity2 which is the basis of an important imaging mechanism in Spectra@

sulfoxides

sulfoxides

additives and useful intermediates

H S-Ph

N(C”3)2 H(C”3)2

H H

C”3 C”3

2a 2b

S(O)-Ph H H

N(C”3)2 NO2 WH3)2

H H

C”3 C”3 H

2c 2d 2e

H H

“(c”,), “02

z?

H H

21 29

425

CHi

426

When

thiazolidine

sulfoxides

dimethylaminobenzaldehyde (aldehyde/thiazolidine)

(DMAB)

were generally

a-&

were

and thiazolidines -1.91

refluxed &t-k

for 23 and -2-3/l

others we have studied that, in general, N-alkyl thiazolidine dlmethyl groups at C-5 in the thiszolidine Interestingly,

aldehydes

under

for &

and &.g

sulfoxide derivatives

mixtures

of p-

The product ratios

It appears from these compounds and of aromatic aldehydes that bear gem

from thiazolidine

groups at C-4. Thus, DMAB is exclusively produced in high yield when &or derivatives

sulfoxide ring opening to the zwitterions

in dry toluene,

ring produce both aldehyde and thiazolidine products when refluxed in toluene.

are the sole products produced thermally

The nitrobenzaldehyde

nitrogen

were produced in 60-80% yields.*

sulfoxides

bearing gem dimethyl

a are refluxed in dry toluene.

24 and 211 are stable in refluxing toluene

like 5 (Scheme 1) is important for the observed

suggesting

that thiazolidine

reactivity with DMAB-derived

thiazotidine sulfoxides. In contrast to its thermal stability, 2d reacts rapidly with MCPBA under aprotic conditions affording p-nitrobenzaldehyde

in high yield. This reaction could involve the spontaneous

fragmentation

perhaps via the isomeric cyclic sulfinate 8. A similar reaction has been previously cycloreversion

is precedented.

of the unstable sulfone

reported’0

and the heterocyclic

1

I o=s

N-

*&

*=$_

.-

MCPBA ‘, (;

c&Cl2

‘, NO2

N@

s NO2

2fI

Scheme 1 outlines a possible mechanism for the thermal reaction of thiazolidine sulfoxides such as &&that QiV6 rise to thiazolidines j&j&

47 N-

O=S

respectively, and DMAB.

=-Cl-sfL

4-l

=

R

R

427

Sulfenic acid trapping agents did not affect the course of these reactions, indicating that free sulfenic acids are unlikely intermediates.

A key step involves the known sulfoxide to sulfenate rearrangement z. l3 Thiosulfinates

would be expected to generate the thiosulfinate as shown (z to a).14 Metastable

isomerfzations intermediates thiosulfinate

in these isomerfzations.

have been well studied and are known to undergo

sulfenic anhydrides

Equal amounts

(4 to a.6912 Condensation of fi and fi

(R-S-C-S-R’)

of the observed

have been suggested

products

as possible

could arise via fragmentation

of

8, as shown. Note that cyclic sulfinate 9 is analogous to 3 proposed earlier. A product ratio favoring the

akfehyde could arise if DMAB is generated directly from 6. Scheme 2 outlines a similar mechanism for thermal reactions of thiazolidine

suffoxides such as & and 2f that

produce DMAE? as the sole product. With protons adjacent to sulfur, the possiblity for intermediates

X

Thiosulfinates,

and 1;1. Carbinolamine such

thiosuffonates.14*15 the thermolysis supporting

as those

breakdown

proposed

to the observed

(L , & , JJ_), are

capable

of disproportionation

Low yields of these were isolated from the aminoethanethiol

(presumably

the proposition

from the adventitious that thiosulfinates

S-eliminations

exists for both

aldehyde products would be expected to follow. to disulfides

portion of a as minor by-products 01

hydrolysis of jJ before breakdown to j_Q and carbinolamine)

might

be intermediates.

and

We are continuing

thus

to explore these and other

aspects of this chemistry.

eme 2

/Jr

O=S

Y

N-

R

34

Acknowledgements:

=

-

o-s

t-L ,tL f

R 11

=

-If

S-L “u%

-

R 12

I wish to thank Dr. F. Meneghini for his support and guidance during this work as well as Sir D. H.

R. Barton and Dr. M. Filosa for helpful mechanistic discussions. I also thank Mr. Phil Bdggs of Harvard University for the HRMS.

428

References

and

(1) See Meneghini,

Notes:

F.; Luhowy, R. J. Am. Chem. Sot. 1979, 101, 420 and references therein.

(2) (a) Cieciuch, R. F. W.; Luhowy, Ft. R.: Meneghini, F. A.: Rogers, H. G. U. S. Patent 3719489;

(b) Locatell, Jr., L.:

Meneghini, F. A.; Rogers, H. G. U. S. Patent 3719488.

(3) Morin, R. B.; Jackson, B. G.; Mueller, R. A.: Lavagnino, 1969, 91,

E. R.; Scanlon. W. B.; Andrews, S. L. J. Am. Chem. Sot.

1401.

(4) Chaudhuri, R. K.; Sticher, 0.; Wmkler, T. Tetrahedron Leff. 1981, 22, 559.

(5) Nachtergaele,

W. A.; Anteunis, J. 0. Bull. Sot. Chim. Be/g. 1980, 89, 749.

(6) Numata, T.; Oae, S. Mt. J. Sulfur Chem., A 1971, 7, 215.

(7) All newly synthesized

compounds

were characterized

by elemental

analysis except for compound

& which was

characterized by HRMS. All compounds exhibited spectral data (PMR, IR, MS) in agreement with their structures.

(8) This range of yields reflects differences

in the extent of reaction. The only other materials present along with the

DMAB and thiazolidine products were unreacted thiazolidine sulfoxides.

(9) Product ratios were estimated by analysis of PMR integrations on crude product mixtures.

(IO) Just, G.; Chung, B. Y.; Rosebery, G.: Dupre, M. Can. J, Chem. 1976,54,

(11) (a)Jung, F. Chem.

1260,2089.

Commun. 1976, 525. (b) Block, E.; Penn, R. E.; Bazzi, A. A.: Cremer, D. Tefrahedron

Leff.

1981, 22, 29.

(12) Marfcich, T. J.; Harrtngton, C. K. J. Am. Chem. Sot. 1972, 94, 5115.

(13) To test the possibility of 4 reacting with 8 in an oxygen transfer reaction producing Q_directly, a cross-over experiment was conducted in which a 1 :I mixture of &t and 2a were refluxed together in toluene. Via the oxygen transfer mechanism, one would expect some of a to be reduced to the nitro thiazolidine IQ, which in fact did not occur.

(14) Koch, P.; Ciuffarin, E.; Fava, A. J. Am. Chem. Sot. Ig70,92,

5971.

(15) Kite, J. L.; Venier, C. G.; Heasley, L. J. Am. Chem. Sot. 1967, 89, 3557.

(Received

in USA

13 October

1988)