3 7 9

//g/J

Ala. /896

SYNTHESIS OF KETENE THIOACETALS AND THEIR MONOSULFOXIDE

DERIVATIVES AND THE THERMAL REARRANGEMENTS OF

DIALLYLIC KETENE THIOACETALS

DISSERTATION

Presented to the Graduate Council of the

North Texas State University in Partial

Fulfillment of the Requirements

For the Degree of

DOCTOR OF PHILOSOPHY

BY

Riza Kaya, B.S.

Denton, Texas

August, 198 2

Kaya, Riza, Synthesis of Ketene Thioacetals and Their

Monosulfoxide Derivatives and the Thermal Rearrangements

of Diallylic Ketene Thioacetals. Doctor of Philosophy

(Chemistry), August, 1982, 148 pp., bibliography, 194

titles.

Ketene dimethyl thioacetal monosulfoxide was prepared

in 68% overall yield in two steps starting from methylmag-

nesium chloride. The yield of dithioacetic acid was

improved significantly by employing tetrahydrofuran as

solvent and using elevated temperatures.

A one-pot synthesis of ketene thioacetals from alkyl

halides was developed and several ketene thioacetals were

prepared by this method.

Direct oxidation of ketene thioacetals using m-chloro-

peroxybenzoic acid provided a general route to ketene

thioacetal monosulfoxides. In cases where E and Z isomeric

ketene thioacetal monosulfoxides were possible, the E/Z

isomeric ratio increased as the substituents on the ketene

double bond was increased in size.

Diallylic ketene thioacetals were shown to undergo a

thio-Claisen rearrangement with rearrangement of the

allylic moiety and the ease of the rearrangements was found

to depend on the number of methyl substituents on both the

ketene and the allylic double bonds. The effect of methyl

substituents on allylic carbon-carbon double bond was found

to be greater than the effect of methyl substituents on

ketene double bonds toward increasing the rate of rearrange-

ment. Upon heating, crotyl derivatives were found to undergo

further rearrangements to give thermodynamically more stable

products.

©1983

RIZA KAYA

All Rights Reserved

TABLE OF CONTENTS

Page

LIST OF TABLES v

CHAPTER

I. GENERAL INTRODUCTION 1

II. AN IMPROVED SYNTHESIS OF KETENE DIMETHYL THIOACETAL MONOSULFOXIDE 35

III. ONE-POT SYNTHESIS OF KETENE THIOACETALS FROM ALKYL HAL IDES 6 8

IV. OXIDATION OF KETENE THIOACETALS OF THEIR MONOSULFOXIDES 90

V. THERMAL REARRANGEMENTS OF DIALLYLIC KETENE THIOACETALS 106

BIBLIOGRAPHY 1 3 7

IV

LIST OF TABLES

Table Page

I. Umpolung of the Reactivity of Carbonyl Compounds 2

II. Ketene Thioacetals . . . . . 78

III. Yields and Isomeric Composition of Ketene Thioacetal Monosulfoxides from the m-Chloroperbenzoic Acid Oxidation of Ketene Thioacetals 9 5

v

CHAPTER I

GENERAL INTRODUCTION

In synthetic organic chemistry, it is frequently desir-*

able to be able to change the charge affinity of a carbon

atom in the carbon chain of a carbonyl compound. Especially

in the last decade, the modern concept of "umpolung," or 1 2

charge affinity inversion, ' has resulted in the extensive

development of methodology that features this operation.

Charge affinity inversion is often accomplished through the

intermediacy of so called "masked reagents," and as a result

of this strategy the synthetic utility of the readily acces-3

sible carbonyl function has been enormously extended.

The meanings of umpolung and charge affinity become more

evident if the carbon fragments in the first row of Table I

are considered. These carbonyl fragments have the same type

of reactivity at C-l, C-3, C-5, . . ., C-(2n+l), in their

carbon chains, with these alternate carbon atoms reacting

with nucleophiles (Nu) while the other carbon atoms, C-2,

C-4, . . ., C-(2n) react with electrophiles (E). As a nota-

tion for this affinity pattern, Nl, N3, N5, . . ., and E2,

E4, E6 . . ., designations have been proposed.1,4

*The particular tendency of a carbon atoms to acquire a positive or negative charge.

Carbon fragments with umpolung reactivities are shown

in the second row of Table I. Note the two sets of frag-

ments differ only in the sign of the charge of members with

the same number of carbons.

TABLE I

UMPOLUNG OF THE REACTIVITY OF CARBONYL COMPOUNDS

Normal

Reactivity

N1 o E 2 0 N3 o

Michael Addition

0

E1 0 N2 0 E3 0 N4 0

Reactivity e ' <

with Umpolung

Since species which have umpolung reactivity such as

acyl anions (El) and enolate cations (N2) are not generally

available for synthetic purposes different types of masked

reagents have been developed which provide an umpolung of

normal reactivity.1,5 Sulfur containing compounds consti-

tute a large number of these reagents and various aspects of

_ 6 their chemistry have been reviewed.

Ketene thioacetals, 1, and their monosulfoxides, 2̂ are

widely used masked reagents which serve as enolate cation

equivalents (N2 reactivity) which are not generally

0

v / S ~ R V / " _ R

C — c C = c

/ \ / \ R2 S-R R2 S — R

i. -2-

available. These species react with nucleophiles (Nu) through

the sp2 hybridized C-2 carbon to give anions 3̂ and 4_ which are

stabilized by the adjacent sulfur atoms as shown below.

\ /S-R \ e/s"R

Nu® + C — C > Nu— C — C :

/ V . J \

3 R2 S-R R2 S - R

0 0 I I

R. S - R Ri e / s - R

e ^ 7 X /' Nu: + CZIC > Nu- C — C

/ \ / \ R2 S - R R2 S - R

Stabilization of a—carbanions by sulfur atoms has been

known for many years.^ Even though sulfur and oxygen are in

the same sub-group in the periodic table, oxygen destabilizes , . 8-11

an a—carbanion, whereas sulfur stabilizes an a carbanion.

This difference in stabilization of a-carbanions was first

*7 shown by Gilman and Webb from the metalation of anisole and

thioanisole. Metalation of anisole with n—butyllithium

2

occurred by abstraction of an sp —bonded ring proton at a

position ortho to the substituent, whereas, under the same 3

conditions, thioanisole exchanged an sp -bonded proton for

lithium on the methyl group (structures 5_ and 6_ below) .

S — CH2—Li

Although a-carbanion stabilization by sulfur has been shown

for about 40 years, the question of how a sulfur atom sta-

bilizes an a-carbanion is still subject to theoretical con-

troversy. An often used explanation is that the stabilization

exists because of the overlap between the 2p-orbital of the

carbanion and the energetically rather low lying empty

12 — 20

d—orbitals of the sulfur atom as shown at the top of

page 5.

On the basis of molecular orbital calculations some

authors think the orbital overlap is not important for

21-23

stabilization of ct-carbanions and in fact some authors

say there is no such bonding at all.^'^ Streitwieser and

Ewing, on the basis of acidity measurements and ab initio

SCF calculations, have suggested that the principal mechanism

of stabilization of carbanions by adjacent sulfur is by

polarization,^ which they symbolize as shown below.

V . 0 C — S

/

Later Bordwell, et. al., argued against this suggestion

on the basis of pK measurements, and even though they did

not reject it, they thought more than polarizability was

involved in this stabilization and felt some contribution

. , 11,28 by 2p-3d orbital overlap was involved.

Thus far, it has been difficult to prove what the

actual factors are for this stabilization, but for practi-

cal purposes, whatever the reasons, this stabilization

makes ketene thioacetals and their monosulfoxides quite

valuable synthetic intermediates.

The anions, 3̂ and £, formed by nucleophilic additions,

may be protonated or alkylated and the resulting thio—

\ / S " R \ / S " R \ / S _ R \ / S _ R

N u - C — C H N u - G — C R 3 N U — C G H NU C C R3

R/ V R R / V R R/ V R R / V R

0 0 _7_ _S_ _9_ 10

acetals, 7_ and 8_, and thioacetal monosulfoxides, 9_ and 10_,

can be hydrolyzed to the corresponding aldehydes or ketones,

as shown below in the case of product 1_.

\ /S-R Ri\ // X .. HYD. v „ r r N u - C - C — H > N U - C — C

R2// — R r2 ̂

This hydrolysis step is a crucial one, as indicated by

Grobel and Seebach,6 because the position of the equilibrium

in these hydrolysis reactions lies far to the left. Because

of this, irreversible removal of thiol is necessary to drive

29 n the equilibrium to the right. This is usually accomplished

\ /S~R \ _ C + HJD ^ C—0 + 2 RSH

^ ^ S - R /

by formation of a transition metal thiolate, using metals

such as titanium, copper, silver, cadmium, and mercury.

Of these metals mercury is used the most"^ ^ but other

metals"^-^ have the advantage of being less toxic than

mercury. The equilibrium can also be driven to the right

by allowing the low molecular weight volatile thiols such

\ /S R X c + 2HgX 2 +1^0 > C = 0 + 2 X H g S R + 2 H X

/ ^S-R /

as methanethiol and ethanethiol to be swept away with a

stream of gas such as air or nitrogen.^ ^ Transacetali-

zation of the thiol products to a highly reactive carbonyl

derivative has also been used44 to liberate the carbonyl « 4 5 - 4 8

product as the example below illustrates. Oxidative

and alkylative49-52 hydrolysis of thioacetals are also

H 0 0 C \

+ c = o H ® / H20

H /

HOOCv s

+ H S

commonly used techniques for preparing the corresponding

carbonyl compounds as shown in the reactions below.

R - S

R - S

\ / C

/ \

CO]

R - S

R - S I! 0

\ /

C

/ \

H .©

- R S O H

R S \ /

C

\ - R S H , - H ®

/ o = c

\

\ / S - R \ / S ~ R

+ R ( X > c

/ \ S - R / V S - R

R - 5 H +

\ C — 0

/

R 1

/ S - R \ / h 2 o

> r — > u®

- R - S - R / " H

The yields of the hydrolysis products from thioacetals

and their monosulfoxides are usually above 80%. There are

53

numerous additional examples of hydrolyses of more simple

S,S-acetals which have utilized one of the techniques

discussed above to give carbonyl compounds. In light of

these examples the hydrolysis step should not be viewed as

a potential difficulty. Thus, by using a standard reaction

sequence which is summarized on the following page , ketene

thioacetals and their monosulfoxides can be "used as enolate

Cation equivalents.

10

©, Nu: +

Ri

R.

\ / S - R

C — C

/ ^ S — R

Ri \

R /

© / S-R

-> Nu—C — c:

V _ S-R

\

Nu— C

r /

0 //

\ R,

11

well. In other words, after addition of the nucleophile the

nucleophile's negative charge is transferred to C-l, which

will later be the carbonyl carbon. This negative carbon

then reacts with an electrophile (El reactivity) which is

the reverse reactivity of a normal carbonyl carbon. In this

regard, ketene thioacetals may be viewed as the umpolung of

ketenes since in ketenes the carbonyl carbon is electro-

54 55 philic and the a-carbon is nucleophilic. '

\ c = c = 0

/

What follows in this chapter is an overview of the types

of reactions which ketene thioacetals and their monoxides

undergo. It is hoped from these examples that an apprecia-

tion can be gained for the broad applicability and versa-

tility that ketene thioacetals and their monoxides have as

a class of masked carbonyl compounds of value in synthetic

investigations.

Seebach and co-workers have described the addition of

n-butyllithium to 2-methylene-l,3-dithiane to form n-hexanal

after protonation and hydrolysis.56 The alkylation of the 57

same addition product with n-pentyl iodide has been shown

to give 2,2-di-n-pentyl-l,3-dithiane.

12

n-Bu v

n-Bu

H .©

v

V

n-Bu Li

H-Pentyl I

v

J l-Pentyl S

J2-Pentyl S

HYD.

0 / /

Jl-Pentyl— C

\ H

HYD.

v

n-Pentyl

H-Pentyl

V C—0

/

It has been found that the metal counterions of the

nucleophiles must be lithium for the addition reactions to

13

occur and the ketene thioacetals must not contain any ally-

lie hydrogen(s) . ^ ^ Interestingly, for intramole-

cular nucleophilic additions Grignard reagents can be used

for additions.^

Br

1) Mg, THFj A

2) H®

When ketene thioacetals contain allylic hydrogens

nucleophiles react to abstract a proton and generate allylic

n-Bu Li

CH3I

Base ©//

Br K

14

anions. As the above reactions indicate, alkylation of the

resulting allylic anions take place at the carbon atom

adjacent to the sulfur atoms. This pronounced selectivity

of alkylation alpha to the sulfur atoms imparts another syn-

thetic use to ketene thioacetals as a^-unsaturated acyl

62,63,64 anion synthons.

HYD. - >

Which is equivalent to:

0

J! B r ©

This reaction sequence has been used in a peptide synthesis,

the key features of which are shown below.

1) n-Bu L i

s 211-t-CH^CI >

15

NHCOOCH 3

C O O C 2 H 5

HYD,

NHCOOCH3

COO(^H5

Recently, reactions of allylic anions with carbonyl

compounds have been investigated with reaction being observed

at C-3 rather than C-l of the allylic anions. This observa-

tion has led to a convenient route to y-lactones as shown

66 below.

R3\ C=0

sec- BuLi

v THF R, /

R

lb

R. R? R.

o HgCI; / HgO Ri Acetone,H20 R-

R-

OH

Ra

16

The limitation that nucleophiles do not add to ketene

thioacetals containing allylic hydrogens, and the limita-

tion that the nucleophile1s counterion must be lithium may

be circumvented by employing the monosulfoxides of ketene

t h i o a c e t a l s . ^ ' ^ ^ S o m e examples are given below.

H 3 C 4 C H 2 ^ C H 2

H /

S-CH, \" / C = c

\ S-CHO II 0

0

© ;L DH 2C — ' C 2) H®

CH-j

/

/ CH

0 II S - C H 3

H 3 C-FCH 2 ^CH X S C H 3 H Y D '

\

CH2 — C - C H 3

0

/ H 3 C 4 C H 2 ^ C H

\

0

II c H

0 //

C H 2 - C \ CH:

0

H 3 C - S ^ 7 CH 3

C — c

^ c - s 7

S-CH S-CH;

17

0

- >

H3c-

sS-CHi

CH.

0 ^S-CH3

HYD.

0

->

H

0

sSCH3

*CH3

0 II

H 3C—s

H 3C-S

\

c = /

H

/ 1) HJZO

\ r j ? H

H3C 0-C S-CH 3

s CH3

HYD.

H3CO-C

A recent report, demonstrated that ketene thioacetal

monosulfoxides can be used in the preparation of methyl

aryldithioacetates and aryl thioacetamides through Pummerer-

rearrangements.^

A r \ /

C ~ C

S-CH3

H / \ S-CH,

II J

0

Ac20

100°C

Ar S-CHo \ /

-> C — C

H / \

S-CH2-0-AC

18

cy^OH

H'

// - > A R - C H 2 — C

\ S - C H 3

R 1 XM-

Rn

N - H

-> A r-C H2— C //

\/R' XR2

The vinyl analogs of ketene thioacetals have been found

to be synthetically valuable compounds . ̂ ^ ^ ^ These

compounds show N4 reactivity which is the umpolung of E4

reactivity that a normal a,3-unsaturated carbonyl compound

shows (See Table I). Thus, n-butyllithium adds to C-4 of

2-(vinyl)-methylene-1,3-dithiane and alkylation of the

resulting anion takes place at the carbon atom adjacent to

the sulfur atoms. Hydrolysis of the alkylated product gives

the corresponding a,8-unsaturated ketone.^

1) n-BuLi 2) CH 3 I

-$ CH3

HYD. •> 0 n-Bu

19

In contrast to simple ketene thioacetals, the vinyl

analogs do not undergo allylic hydrogen abstraction or

56 72 "73

nucleophilic addition at C-2 ' ' but rather nucleophilic

addition at C-4 (N4 reactivity)^ has been observed. The

following examples illustrate typical reactions of vinyl

ketene thioacetals.

> HYD.

1) n-BuLi

2) CH3I

•rv-Bu

1) t-BuLi

2) CH3I t-Bu

HYD. 1-Bu

1)n-Bu L i

2) D20

n-Bu

20

In some cases where vinyl analogs of ketene thioacetals

contain allylic hydrogen(s), it is still possible to remove

an allylic hydrogen, if suitable bases, such as lithium

72

diisopropylamide, are used. The resulting anions undergo

alkylation at the carbon atoms bearing both sulfur atoms.

Since hydrolysis of these alkylated products give correspond-

ing carbonyl compounds, these systems serve as a,B,y,S-

unsaturated acyl anion equivalents.

1) LDA

2) CH3I

HYD. 0

Which is equivalent to:

0 + CH3I

While ketene thioacetals do not show a tendency toward

74 [2+2] cycloaddition reactions their vinyl analogs do

undergo Diels-Alder cycloaddition reactions with electro-

i_ • -i • ^ c- 75,76 philic olefins.

21

+

0

a 0

0

Xylene

A

HYD.

0

^> H

H»C > C *

j^COOH

COOH

H +

*Ph

NC

NC

G II C

CN

X N

•>

Ph h

.CN

hCN

CN

CN

In addition to a-carbanion stabilization sulfur atoms

76 — 81

can also stabilize a-carbonium ions. This fact makes

ketene thioacetals reactive toward electrophiles and these

reactions produce sulfur stabilized carbonium ions.

22

_© + n /

c = c

S - R R \

-> E — C ©

R / \ Q — S - R R /

/S-CH3

\s-CH,

Stabilization of an ct-carbonium ion by sulfur atoms is

explained by 2p-3p ir-overlap between the carbon atom and

8 2 adjacent sulfur atoms.

Carbonium ions resulting from the addition of an

electrophile to ketene thioacetals have been trapped with

hydride anions. This trapping provides a convenient equi-

valent to hydrogenation of ketene thioacetals when protons

are used as electrophiles.^ In simple ketene thioacetals

H

CRCOOH

O

2 - / 0 V 1 I R V / N°2

s ^ — '

E t3 Si H - > o N0-

the site of protonation has been shown by nmr studies of the

8 3 resulting cations and deuterium labeling experiments, to

23

occur at C-2 rather than at C-l. This has also been found

to be true in the systems where the R^ and/or R2 groups

have a high potential to stabilize an adjacent positive

8 4 8 S

charge, such as in the ferrocenyl ' derived ketene thio-

acetals. The fact that protonation takes place exclusively

R ^ C

/ - V * R2 "s f J s

R1 = R2 = ph

R^ = Ferrocenyl, R2 = H

Et3SiH Ph 2CD—^

7

CF3COOD 0S

Ph2D

at C-2 rather than at C-l, has been utilized in ring forma-

86,87 tion reactions.

24

H

H ,©

CH2CI2

EtoSi H V

HYD.

V

0

HYD.

CF^COOH cfcHpt HYD.

5

O

0

25

Corey and Beams used this characteristic protonation to

88 protect lactones and esters against nucleophilic attack,

when the existing methods proved inadequate for this purpose,

( Al-Sf C!-^S"~AKCHjlz H O

H .©

-> HYD.

Reaction with other electrophilic reagents have also been

studied.74'87 For example 13. has been found to undergo an

addition-elimination reaction74 sequence as shown below.

- >

E = Br, cl, SCN, 2,4-(N02)2Phs

The same type of reaction has been observed in acylation

89 reactions of ketene thioacetals.

26

R - S

R - S

R = aryl, alkyl

\ (X.CCOkO C = C H 2 -

/ R.T.

R - S

- >

R-S

\ / c = c

/ \

H

COCX,

X = F, CL

Studies with vinyl analogs of ketene thioacetals and

hydrogen triphenyl phosphonium tetrafluoroborate have shown

90 that protonation takes place at C-4 exclusively.

© © Ph 3PH Bff H3C

CHCt3 , 0-25 C

^©

B F f ^ 3

© © Ph3PHBF4

© © PPh BF

Complete hydrolysis of ketene thioacetals unmasks the

carbonyl functionality, but the first isolable products from

27

the acid catalyzed hydrolysis are thiol carboxy deriva-

91 9 2 93 9 4 * tives. ' ' ' This reaction sequence has been employed

P h \ /

S —CH-

c = c hp

R / \

s — C H -

P h

\ /

•> H C — C ©

/ \

S - C H 3

R S - C H 3

Ph

H20

CH3SH R

\ HC-

/

0 //

\ S - C H 3

9 3 for the synthesis of thiocarboxylates. Further, basic

hydrolysis of thiocarboxylates produce the corresponding

92 carboxylic acids. Mercury (II) catalyzed hydrolysis

1) l-LO » Q

2) OH

3) H © R

CC^H

directly provides the corresponding carboxylic acids. 95

H X \ /

C~C

S - C2H5 HgCl2

0 //

H / \ s - C2H5

H2O CH 3 -CH 2 -C

\ OH

28

Reaction of ketene thioacetals in the presence of

N-chloro- or N-bromosuccinimide and alcohol solvents gives

96 a-haloesters.

R,. ,S —CH> 11 NCS or NBS R 0 X 7 2) H,0 \ • //

c = c 1 > x — c — c / \ R 30H, C H X N / v

R2 s — c h 3 r/ or3

In light of above discussion the synthetic utility of

. ketene thioacetals and their monosulfoxides is clearly

evident.

The investigations described in this dissertation evolved

from the need for substantial quantities of ketene dimethyl

thioacetal monoxide for use in a unified synthesis of fused

heterocycles. Preparation of the monoxide by the published

route68 proved unsatisfactory and a considerably more con-

venient route was developed. Generalization of the new route

for ketene dimethyl thioacetal monoxide appeared to offer a

new synthesis of ketene thioacetals and their monoxides and

this possibility was investigated as part of this research

effort. Thus, a convenient synthesis of ketene-thioacetals

starting from readily available alkyl halides was developed

as well as a general oxidation procedure for preparing the

corresponding monoxides. In addition, thermal rearrangements

of diallylic ketene thioacetals were studied.

CHAPTER BIBLIOGRAPHY

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31

37. Reece, C.A., et al., Tetrahedron, 24, 4249 (1968).

38. Narasaka, K., Sakashita, T., and Mukaiyama, T., Bull. Chem. Soc. Jpn., 45, 3724 (1972).

39. Mozi, K., Hashimoto, H., Takenaka, Y., and Takigawa, T., Synthesis, 720 (1975).

40. Mukaiyama, T., Kamio, K., and Kobayashi, S., Bull. Chem. Soc. Jpn., 45, 3723 (1972).

41. Bernstein, S., and Dorfman, I., J. Am. Chem. Soc., 68, 1152 (1946).

42. Mukaiyama, T., Fukayama, S., and Kumamaoto, T., Tetra-hedron Lett., 3787 (1968).

43. Shahak, I., and Sasson, Y., Tetrahedron Lett., 4207 (1973).

44. Maxfeldt, H., Unterweger, W.D., and Helmchen, G., Synthesis, 694 (1976).

45. Romanet, R.F., and Schlessonger, R.H., J. Am. Chem. Soc., 96, 3701 (1974) .

46. Nieuwenhuyse, H., and Louw, R., Tetrahedron Lett., 4141 (1971).

47. Walling, C., and Mintz, M.F., J. Org. Chem., 32, 1286 (1967) .

48. Ho, T.L., Ho, H.C., and Wong, C.M., Can. J. Chem., 51,

153, (1973).

49. Wang-Chang, H.L., Tetrahedron Lett., 1989 (1972).

50. Fetizon, M., and Juzion, M., J. Chem. Soc. Chem. Commun., 382 (1972).

51. Trost, B.M., and Preckel, M., J. Am. Chem. Soc., 95, 7862 (1973).

52. Morkezich, R.L., Willy, W.E., McCarry, B.E., and Johnson,

W.S., J. Am. Chem. Soc., 93, 4415 (1973).

53. See for instance reference 6 and the references therein.

54. Brady, W.T., and Dorsey, E.D., J. Org. Chem., 35, 2732 (1970).

32

55. Scarpati, S., Sica, D., and Santacroce, C., Tetrahedron, 20, 2735 (1964).

56. Seebach, D., Burstmghaus, R., Grobel, B.-Th, and Kolb, M., Liebigs Ann. Chem., 830 (1977).

57. Carlson, R.M., and Helquist, P.M., Tetrahedron Lett.,

173 (1969).

58. Seebach, D., and Kolb, M., Liebigs Ann. Chem., 811 (1977).

59. Seebach, D., Synthesis, 17 (1969).

60. Hutchins, R.R., J. Org. Chem., 44, 3599 (1979).

61. Anderson, N.A., Duffy, P.F., Denniston, A.D., and Grotjahn, D.B., Tetrahedron Lett., 4315 (1978).

62. Seebach, D., Kolb, M., and Grobel, B.-T., Tetrahedron Lett., 3171 (1974).

63. Corey, E.J., and Kozikowski, A.P., Tetrahedron Lett., 925 (1975).

64. Murphy, W.S., and Wattonasin, S., Tetrahedron Lett., 1827 (1979).

65. Closs, A., and Huguenin, R., Helv. Chem. Acta, 57, 533 (1974) .

66. Kozikowski, A., and Chen, Y.-Y., J. Org. Chem., 45, 2236 (1980).

67. Herrmann, J.L., Richmn, J.E., Wepplo, P.J., and Schlessinger, R.H., Tetrahedron Lett., 4707 (1973).

68. Herrmann, J.L., Kieozykowski, G.R., Romanet, R.F., Wepplo, P.J., Schlessinger, R.H., Tetrahedron Lett., 4711 (1973).

69. Herrmann, J.L., Kieczykowski, G.R., Romanet, R.F., and Schlessinger, R.H., Tetrahedron Lett., 4715 (1973).

70. Romanet, R.F., Schlessinger, R.H., J. Am. Chem. Soc., 96, 3701 (1974).

71. Ogura, K., Ito, Y., and Tsuchihaski, G.-I., Synthesis, 736 (1980).

33

72. Seebach, D., Kolb, M., and Grobel, B.-T., Angew. Chem. Int. Ed. Engl., 12, 69 (1973).

73. Cages, B. and Julia, S., Tetrahedron Lett., 4065 (1978).

74. Carey, F.A., and Neerguard, J.R., J. Org. Chem., 36, 2731 (1971).

75. Carey, F.A., and Court, A.S., J. Org. Chem., 37, 4474 (1972).

76. Darishefsky, S., McKee, R., and Singh, R.R., J. Org. Chem., 41, 2934 (1976).

77. Brown, H.C., Okamoto, Y., and Irukai, T., J. Am. Chem. Soc., 80, 4964 (1958).

78. Corey, E.J., and Bloc, E., J. Org. Chem., 31, 1663 (1966).

79. Tucker, W.P., and Roof, G.L., Tetrahedron Lett., 2747 (1967).

80. Yoshida, Z.-I., Yoneda, S., Sugimoto, T., and Kikukawa, 0., Tetrahedron Lett., £3, 3999 (1971).

81. Corey, E.J., and Kim, C.U., J. Am. Chem. Soc., 94, 7586 (1972).

82. Block, E., "Reactions of Orguno Sulfur Compounds", Academic Press, Inc. 1978.

83. Carey, F.A., and Court, A.S., J. Org. Chem., 37, 1926 (1972).

84. Hill, E.A., Wiesner, R., J. Am. Chem. Soc., 91, 509 (1969).

85. Feinberg, J., Rosenblum, M., J. Am. Chem. Soc., 91, 4324 (1969).

86. Anderson, N.H., Yamamoto, Y., and Denniston, A.D.,

Tetrahedron Lett., 4547 (1975).

87. Brinkmeyer, R.S., Tetrahedron Lett., 207 (1979).

88. Corey, E.J., and Beames, D.J., J. Am. Chem. Soc., 95, 5829 (1973).

34

89. Hogo, M., Masuda, R., and Komitori, Y. , Tetrahedron Lett.,

1009 (1976).

90. Clar, D.A., and Fuchs, P.L., Synthesis, 628 (1977).

91. Russell, G.A., and Ochrymowycz, L.A., J. Org. Chem., 35, 764 (1970).

92. Marshall, J.A., and Belletire, J.L., Tetrahedron Lett.,

871 (1971).

93. Seebach, D., Burstmghaus, R., Synthesis, 461 (1975).

94. Okuyama, T., and Fueno, T., J. Am. Chem. Soc., 102, 6590 (1980).

95. Volger, H.C., and Arenes, J.F., Rec. Trav. Chem., 76, 847 (1957) .

96. Grobel, B.-T., Burstinghaus, R., and Seebach, D., Synthesis, 121 (1976) .

CHAPTER II

AN IMPROVED SYNTHESIS OF KETENE DIMETHYL

THIOACETAL MONOXULFOXIDE

Introduction

Ketene dimethyl thioacetal monosulfoxide, 1_, was first

prepared by Schlessinger and co-workers in 197 3.̂ " Since then,

it has found varied use as a formylmethyl synthon. Sulfox-

H S — C H 3 \ / c = c _1_

H 7 X S — C H 3 II 0

ide 1, reacts with a variety of enolate anions as a Michael

acceptor in high yields to give, after hydrolysis of the

intermediate adduct, 1,4-dicarbonyl compounds in which the

carbonyl group derived from 1 is an aldehyde. A few

R, 0 . S~ C H3

\ n 11 1 + c — 0 > Ri-C-CH-CH— CH

r 2 — ^ 0 k \~CHi

0

35

36

0 /° uvn I I '

_ > R - C - C H - C H - C I \

r 2 h

specific examples of its reactions with enolate anions are

1 given below.

0 II

H 3 C 0 2 C \ 1 ) N A H H 3 C 0 2 C \ Z S ~ C H 3

CH? > CH-CK-CH 920\° / 2) / \

BJC O f ' H3C 0 2 C X S - C H 3

H3C02C\ 0 H Y D . /

- > C H - C H 2 - C

H X A C 7 X H

0 0 II 11

o 1 J L D A . i-BuO Cv ,S~CH3 / 2) 1

H 3 C - C — Y F P > C H 2 - C H 2 - C H 9 4 %

Vt -BU V S - C H 3

0 0

H Y D . > t-BuO-C-CH2-CH2— C g7o/o

X H

37

0"

0:

1) NaH 2) 1

3) f-F

/

CH

\

0 1! S - C H

3

9 1 %

S-CH,

HYD.

0

CH^C //

\ H

90 %

0

II H3C0-C

V

1) LDA

2) 1

3) I #

0

H3CO- C ->

CH^

0 II S - C H .

/ 3

CH 88 %

V C H 3 __

HYD.

0 II

HJCO-C

/ c h 2 — c

//

\ 8 5 %

H

Enamines are also good nucleophiles for reaction with

1 as shown with the 1-pyrolidino-l-cyclohexene.^

0

1

£ 9 2 %

SCHQ

c c , | H Y D - V

|| 3 9 5 % 0

0

C - 0 \ H

38

Although, it is not evident from the protonation of the

Michael adduct anions, alkylation of these anions showed

that the initially formed sulfur stabilized anions undergo

proton exchange reactions to give enolate anions. These

proton exchange reactions occur if the enolate anions are

more stable than the sulfur stabilized anions as illustrated

2 by the two examples below. Thus, depending on the type of

0

HC0-C\

e}> HCO-C/

I f 0

Hp op ->

H3C02C

CH

0 II S-CH3

S-CH 3

H3CO2C S-CH H3C O2C

- >

S-CH H3C O2C S-CH,

S-CH-

RX ( Yield ) : CH3I ( 97 % ) , C2H5I ( 8 7 % ) >

CHpCH-CH 2—Br ( 97% ) , HC = C-CH-Br ( 91 % )

0 0

'I " c ru H5C2° 1 H5C20 C \ ^ - x /

S ~ C H 3

39

s - c h 3 s - c h 3 h 5 c 2 o c H c C p C

s - c h 3 s - c h 3 r x

enolate anion, reaction with 1 allows substitution at the

a-carbon atom of a carbonyl group as well as attachment of

a formylmethyl group. If the enolate anion is less stable

than the sulfur stabilized anion, then no proton exchange

reaction will take place and alkylation will occur at the

carbon atom adjacent to the sulfur atoms as the example below

2 illustrates. Since the hydrolysis of these Michael adducts

0 // t-BuO-C-' ©

CH-

R X

0

II © / S - c h 3

-> i-BuO-C-CH^CHj-C?

\

0

0 II

-> i -Bu-0-C-CH 2 -CH 2 - c

» /S-CH,

S-CH, II 3

0

V c H 3

RX( Yield ): CH 3 I ( 91%] CH^CH-CHjBr { S8 % )

give carbonyl groups, this regiospecific alkylation gives

access to ketone functionality, rather than aldehyde

40

functionality, if the originally reacting enolate anion is

less stable than the sulfur stabilized anion. However, 1

has been most often used as a formylmethyl group precursor,

A few examples of its use in organic synthesis are given

W 1 , 3,4,5 below.

SCH 1) LDA

SCH

HYD.

- V 1 C H 2 , ^ R 1)t-BucfK® > SCH-,

SCH: 2) 1 H X S 3 II

0 SCH,

HYD. ->

(CH2)6-CCLR

41

0 o

^ 5

OH

1) Base

2 ) 1

0 II S ch3

^ H 1 5

OH

Results and Discussion

For another research project, ketene dimethyl thio-

acetal monosulfoxide, iL, was needed in substantial amounts,

and its synthesis was attempted according to the reported

procedure"'" for which the reaction sequence is given below.

0 0 \ \ / /

c - c h2o

H / V

9

3A Sieves

CH30H OH

B l | -E t 2 0

CH3SH

H P S \

HC

^ c s /

0 //

\ OCH,

H3CO \ H C

/

0 //

- c

HO

Li AlH/

THF

\ OCH-

HXS 3 \

h3cs /

CH —CH 2 0H NaH

H3C S

— > CH-CH,-0Ac CH3COCI 2

h3cs

42

0 II

H , C S \

m - C P B A . . . . . . . . . K 0 H

q CH2CI2 U H 3 C S

> C H — C H - > 0 A c — > L B e n z e n e

»fs\ C^rCH

H 3 C s /

2 7 7 % O v e r a l l

In this syntehsis, several difficulties were encountered.

Perhaps the primary reason for these difficulties was the

fact that the article which described this synthesis did not

contain an experimental section. In the first step of the

above synthesis a polymeric compound was obtained. Conse— g

quently, the first step was carried out in a different way.

In the second step, until it was realized that boron tri-

fluoride etherate must be used as a solvent rather than using

it only in catalytic amounts, the methylthiohemiacetal was

obtained instead of the thioacetal. Similarly, difficulties

with the other steps led to the decision that the reported

route for this synthesis was unsatisfactory because of cost

in time and reagents. Consequently, an investigation of an

easier synthetic method was undertaken. In view of Ziegler

and Chan's recent synthesis of ketene thioacetals from 7

dithioic acid dianions, the following reaction sequence was

proposed for the synthesis of 1_. There were two limiting

factors in this plan. First, the reported yield of

43

„ D C S , H 3 C M gCl 2 ) H +

2 > CH, // 2 n-BuLi

\ SH

H2CzzC

S Li

SLi

3

2CH3 I S-CHJ

H2C [0]

\ -» H 2 C — c

S-CH-

0 II

/S-CH 3 N

i_ xS -CH3

7,8 dithioacetic acid was quite low, ' 18-20%, and second, the

oxidation of ketene dimethyl thioacetal, 4_, could possibly

give the epoxide 5_, rather than the sulfoxide. Theoreti-

cally, it appeared more reasonable that oxidation of £

would give the sulfoxide to give a conjugated system (a

stabilizing transformation) than to give the epoxide with

its strained 3-membered ring (a destabilizing transformation)

In addition to these potential difficulties, overoxidation

S-CH-

H2C /

V / o

•S-CH,

/

\

0 II S-ch3

S-CH-

0

6

44

°

/S-CH 3 /S~CH 3

1_ H2C — C H C = z C %_

\ - C H . }s-CH. 0 ^ \ \

3

u 0

of the sulfur atoms to give the disulfoxide £ or the

sulfones 1_ and 8̂ were also possible. Even though the over-

oxidation products were not desired, their formation was

not viewed as a problem, since these overoxidation products

were expected to show the same type of reactivity (N2

reactivity) as ketene dimethyl thioacetal monosulfoxide.

Thus, attention was focused on improving the yield of

dithioacetic acid. Various reaction conditions were in-

vestigated and the best results were obtained when the

reaction of methylmagnesium chloride and carbon disulfide

was carried out in tetrahydrofuran rather than in ethyl

ether. Further, since the reaction was found to be sluggish,

it was necessary to carry it out at elevated temperatures,

40-45°C, or long reaction times for the formation of the

Grignard adduct. Thus, the reaction of methylmagnesium

chloride in tetrahydrofuran with carbon disulfide at 40-4 5°C,

for 2 hours followed by protonation of the Grignard adduct

with mineral acid resulted in a substantial increase in

yield, from 18-20% to 55-60%. The reaction of dithioacetic

45

acid with two equivalent of n-butyllithium, in tetrahydro-

furan, at -78°C afforded ketene dimethyl thioacetal in 70%

yield.

Various oxidizing agents were investigated for the oxi-

dation of ketene dimethyl thioacetal, 4_, to its monosul-

9

foxide 1_. Attempts with N-chlorosuccinimide, pyridinium

chlorochromate^ and hydrogen peroxide,^ failed to give the

expected monosulfoxide. However, the oxidation of 4 to 1

could be accomplished by using m-chloroperoxybenzoic acid.

The reaction of with m-chloroperoxybenzoic acid is

exothermic and allowing the reaction to occur above 0°C caused

the formation of some side reaction products. Therefore, it

was crucial to control the addition of m-chloroperoxybenzoic

acid and for this purpose it was added to a dilute methylene

chloride solution of £, in small increments as a solid. Thus,

the oxidation of 4_ with m-chloroperoxybenzoic acid yielded

a virtually pure product, uncontaminated with starting

material 4_, or the possible overoxidation products 6, 1_ and

46

Because of the rather low overall yield of 39% for ketene

dimethylthioacetal via dithioacetic acid, and the relatively

high yield of 70% for ethyl dithioacetate reported by

Meijer, another related route to £, via methyl thioacetate,

was investigated. Methyl dithioacetate, 1_, was prepared in

55% yield by conditions similar to those reported for the

14

preparation of the ethyl ester. The yield of 1_ was some-

what lower than that reported for the ethyl ester and was

due in part to the presence of a higher boiling fraction in

the crude product mixture. This product, purified by frac-

tional distillation, was identified as dimethyl trithiocar-

bonate, 8̂ , both by comparison of its IR spectrum with that of

an authentic sample and by the compatability of its nmr and

mass spectra with the structure of dimethylthiocarbonate. 14

Meijer and co-workers reported £ as a major contaminant in

the preparation of dithioesters from t-butyl, sec-butyl and

cyclohexylmagnesium halides, but, surprisingly, not in the

preparation of ethyl dithioacetate or methyl dithiopropionate

by similar alkylations of Grignard-carbon disulfide adducts.

The possibility that this compound could have been overlooked

in the preparation of ethyl dithioacetate and methyl dithio-

propionate was checked by preparing these compounds and £

was not detected in the crude products. Several mechanistic

possibilities for the formation of £ were considered but its

mode of formation is still unknown. Although Meijer did not

give a mechanistic pathway for the formation of 8_, he

47

postulated that 9̂ was the intermediate for the formation of

this compound. This intermediate seemed unlikely since, if

it were a precursor to 8̂, then alkylation of the Grignard

adduct of methylmagnesium chloride and carbon disulfide with

ethyl iodide would give diethyltrithiocarbonate, 1(), which

neither we nor they observed in the preparation of ethyl

dithioacetate. The following mechanism may explain the

/ / 11 LDA / S ~ C H 3 * 3 ° - c x - T T E f i ^ "

H > c = c x

S-CH, S — CHj - I A

formation of 8_. But this mechanism cannot explain why

H 3C-S X CIMg-S^ H5C2-S\

C —S C—S C —S

H3C-S/ CIMg-S7 H5C2-S

/

8 9 10

S //

S h3C — c //

SM9CI CIMgS—C

CS2 v CS? \ 2CH.I H.CMgCl 1 > HC— C 1 > S - >

3 V /

48

/S /S // // H X — C ^ ® C H 3 — C

X s C H3 5 ~~CH3

c

HX S — C ^ w , 3 \\ Hf-S'

diethyl trithiocarbonate, 1(), was not obtained when the

Grignard adduct was allowed to react with ethyl iodide in

the preparation of ethyl dithioacetate. In the synthesis of

15

some xanthates, !3 has also been found as a side reaction

product, and its formation has been explained by the reaction

of sodium methanethiolate with the previously alkylated

S /

R O — C 2 > R O - C > / Y / CH 3 I _ / / R O C S S

G

X # No® X SCH3

s // R O — C

\ S + CH3S Na

/ RO C

// Hf~s\

R 0 - \ + C H3 S° N a 9 > . C = S

S - C H 3 HJC-S

49

xanthate salt. The same type of mechanism may operate here

too, as shown below. However if this were the case one

S ,S // CH.I // CH-XSSMgCl

H 3C— C 3 > H 3 C - C 2 >

XSMgCI XS-CH3

//S

H.C— C \

S + CH3S MgCl

HP — C

ii \Ns

H C S \ CH3I H £ S \

CH3SMgCl + CS2 > C-S > C = S

ClMgS 7 H f S /

would expect to observe S_ in the preparation of methyl dithio-

propionate. All attempts, such as nonaqueous and inert

atmosphere work-ups, failed to result in the isolation of 11.

As anticipated, the reaction of methyl dithioacetate

with one equivalent of lithium diisopropylamide (LDA) in

tetrahydrofuran at -78°C, followed by addition of dimethyl

sulfate, afforded ketene dimethyl thioacetal in good yield.

Thus, ketene dimethyl thioacetal monosulfoxide, 1, was syn-

thesized in three steps via either dithioacetic acid or

methyl dithioacetate in moderate yields. However, it

appeared possible to decrease the number of steps for the

synthesis of ^ to two and also increase the yield of dimethyl

thioacetal, £, if a one-pot synthesis of £ was explored.

50

The reaction of methylmagnesium chloride with carbon di-

sulfide followed by the reaction of the adduct with one

equivalent of lithium diisopropylamide at -78°C and then with

dimethyl sulfate afforded 4 in 80% yield. In this method,

H 3 C M g C l + c s 2

/ S Li

H2C = C \ SMgCl

-> //

H3C— C \

SMgCl

(CH30 )2S02

R.T. ->

LD A

7$°C ->

/SCH3

H 2C=C \ SCH-

the use of a 1:1 ratio of Grignard reagent to carbon disulfide

was found to be necessary. Use of excess carbon disulfide

lowered the yield of £ presumably because of the formation

of methyl 3 , 3-bis (methyltnio) dithiopropenate, 12_, which was

s II

H3C s — c \

/S-CH3

12 c = c

H / \ S-CH-

isolated and characterized (nmr, ir, elemental analysis).

The following mechanism may account for the formation of 12̂

in the presence of excess carbon disulfide.

51

H3CMgC( + CS2

.©

/ H2C — c < -

V

// ->H3C

\

© np-

// c

V

SMgCl

CS^

LDA

S

I I c \ /

CH-

S II c

H f ^ s 9

©

H

\

/

- ©

r

V

S H

•4- H £ —

/

V

(CBjO )2S02 / •> h 2 c = c

SH

+

11 VcH, /f\

^ s //

h 3 c — c Xs-CH-

C / S - C H 3

H f - s ' c = c

H / \

S - C H ,

12

If the above mechanism is correct, then 13 and/or methyl

dithioacetate must form along with 12_. Indeed, by careful

workups, methyl dithioacetate was isolated and identified by

52

comparison with an authentic sample. The mechanism was also

verified in the following manner: the dianion was generated

by using a 1:1 molar ratio of methylmagnesium chloride and

carbon disulfide followed by treatment of the intermediate

adduct with one equivalent of lithium diisopropylamide, and

then the dianion was allowed to react with 0.5 equivalent of

carbon disulfide and the resulting adduct was methylated.

In this way 12̂ was obtained in 73% yield in addition to a

quantity of methyl dithioacetate.

Compound 16, very similar to ketene dimethyl thio-

acetal monosulfoxide, was expected to show similar chemical

properties towards enolate anions as 1 does and have the

potential advantages of commercial availability of the key

starting material, 14, as well as more mild hydrolysis con-

ditions of enolate anion adducts. Several attempts were

H3C-

0 // 2 LDA

\ U

SH

-> h2C= /

—c

OLi (CH 30) 2SQ 2

\ SLi

(CH3O)2SO2

v

CHGC^

0 //

\ S-CH 3

17

/0-CH3

C 15

VS-CH3

[0]

\/

0-CH. /

H2C—C \

16

S-CHQ II 3 0

53

made to obtain 16_ by the method outlined on the previous page,

but in all cases carbon alkylation took place rather than

oxygen alkylation when the dianion was allowed to react with

dimethyl sulfate and 17_ was isolated rather than 15.

As a result of above exploration ketene dimethyl

thioacetal monosulfoxide was prepared in 6 8% overall yield

in only two-steps. This synthesis represents a significant

improvement over the previously reported method both in

terms of preparation time and cost of reagents. In these

explorations the yield of dithioacetic acid was also improved

significantly.^

Experimental

Proton nuclear magnetic resonance (nmr) spectra were

recorded on a Hitachi Perkin-Elmer model R-24B, 60 M Hz

nuclear magnetic resonance spectrometer employing deuter-

ated chloroform as a solvent and tetramethylsilane as an

internal standard. Infrared (ir) spectra were recorded on

a Beckman Model 33 grating infrared spectrometer. Mass

spectra were obtained on a Hitachi Perkin Elmer RMU-6E,

Double Focusing Mass Spectrometer. Elemental analyses were

performed by Midwest Microlab, Ltd., Indianapolis, Indiana.

Methylmagnesium chloride and n-buthyllithium were

purchased from Aldrich Chemical Co. Tetrahydrofuran (THF)

was dried and purified before use by distillation from sodium-

potassium alloy under a nitrogen atmosphere. Carbon

54

disulfide was commercially available in 99+% purity and was

used without further purification. Diisopropylamine was

purified by distillation from calcium oxide and stored over

3-8 molecular sieves. All other reagents were used without

further purification and purchased from commercial sources.

Dithioacetic Acid. Into a dry, 1000 mL round bottom

flask, equipped with a magnetic stirrer, condensor, dropping

funnel and a thermometer was added 0.2 moles of methylmag-

nesium chloride in tetrahydrofuran, and the solution was

diluted with tetrahydrofuran to give a 1 molar solution.

Into this stirred solution 0.22 moles of carbon disulfide

dissolved in an equal volume of dry tetrahydrofuran was

added under nitrogen at a rate sufficient to increase the

temperature of the reaction mixture to 40-45°C and maintain

this temperature during the remainder of the carbon disulfide

addition. After the addition was complete the reaction

mixture was stirred for 2 hours while maintaining the tem-

perature between 40-45°C. The solution was then cooled to

room temperature and 200 mL of ether was added and after

stirring 5 minutes the contents of the flask was poured into

400 mL of cold 10% HC1 solution. After stirring the result-

ing mixture 30 minutes, the layers were separated, and the

aqueous layer was extracted with ether. The ether layer

and extracts were dried over anhydrous magnesium sulfate.

Filtration and removal of the solvent under reduced pressure

55

gave 13.27 g of a dark red liquid. Purification by distilla-

tion gave 10.5 g (57%) of the product bp 50 C/44 mm; ir

(neat),18 2976, 2920, 2481, 1431, 1357, 1216, 1190, 1107, 903,

860 cm-1; nmr, 5=2.79 (s, 3 H), 6.18 (s, 1 H); mass spectrum,

m/e (%), M+2 94 (6.5), M+l 93 (3.2), M+ 92 (46.5), 77 (3.8),

76 (6.5), 61 (22.3), 60 (25.8), 59 (100), 58 (45.5), 57

(14.6).

Methyl Dithioacetate. Methylmagnesium chloride (0.25

mol) in tetrahydrofuran (1 molar solution) was allowed to

react with 0.275 moles of carbon disulfide in the same

manner as in the preparation of dithioacetic acid. After

stirring the reaction mixture for 2 hours at 4 0-45°C, the

reaction mixture was cooled to room temperature and 0.25

moles of dimethyl sulfate was added to the reaction mix-

ture, without allowing the temperature of the reaction

mixture to exceed 40^C. The resulting solution was stirred

2 hours at room temperature and then 300 mL of ether was

added. After stirring the resulting solution 5 minutes, the

contents of the flask was poured into 500 mL of ice water.

The resulting mixture was stirred for 30 minutes and the

layers separated. The aqueous layer was extracted with

ether and the combined organic layers were dried over anhy-

drous magnesium sulfate. Filtration and removal of the

solvent under reduced pressure yielded a dark red liquid.

19 o Fractional distillation of this liquid, bp 60 /55 mm, gave

56

14.2 g (55%) of methyl dithioacetate.^ Ir (neat), 2915,

1418, 1362, 1195, 1098, 863 cm"1; nmr, 6=2.52 (s, 3 H); 2.76

(s, 3 H); mass spectrum, m/e (%), M+2 108 (3.6), M+l 107

(2.8), M+ (45.3), 91 (4.1), 76 (3.1), 61 (5.1), 60 (3.8),

59 (100), 58 (16.3).

Anal. Calcd. for S, 33.93; H, 5.69. Found:

C, 34.20; H, 5.81.

Dimethyl Trithiocarbonate. The second fraction from the

20

fractional distillation of methyl dithioacetate, bp 106-

110°C/27 mm, was found to be dimethyl trithiocarbonate; ir

(neat),21,22 2910, 1410, 1070, 960, 870, 858, 812 cm-1; nmr,23

6=2.68 (s); mass spectrum; m/e (%), M+2 140 (9.0), M+l 139

(3.8), M+ 138 (51.1), 93 (24.8), 92 (11.3), 91 (82.7), 79

(13.5), 78 (11.3), 77 (28.6), 76 (100), 64 (21.1), 59 (55.6),

58 (18.8), 57 (18.1).

Ketene Dimethyl Thioacetal (Via the One-Pot Method).

A solution of 90.0 mL (0.252 mol) of 2.8 molar methyl mag-

nesium chloride in tetrahydrofuran under nitrogen was diluted

with tetrahydrofuran to make a 1 molar solution. Then a

solution made by diluting 19.2 g (0.250 mol) of carbon di-

sulfide with an equal volume of tetrahydrofuran was added

under nitrogen to the mechanically stirred Grignard reagent

at a rate sufficient to increase the temperature of the

reaction mixture to 40-45°G and maintain this temperature

during the remainder of the carbon disulfide addition.

57

After addition was complete the reaction mixture was stirred

for 2 hours, maintaining the temperature between 40-45°C,

and then cooled to room temperature and diluted with tetra-

hydrofuran to make a 0.7 molar solution. The resulting

reaction mixture was cooled to -78°C with a dry-ice acetone

bath and then a 0°C solution of 0.25 mol of lithium diiso-

propylamide in tetrahydrofuran was added dropwise, during

30 minutes, to the cold reaction mixture. The resulting

solution was stirred at -78°C for 1 hour and an additional

20 minutes at room temperature. Then a solution of 63.1 g

(0.5 mole) dimethyl sulfate in an equal volume of tetra-

hydrofuran was added at room temperature. The reaction

mixture was stirred for 2 hours and poured into excess of

5% aqueous sodium bicarbonate solution. The layers were

separated and the aqueous layer was extracted with ether and

the combined organic layers were dried over anhydrous mag-

nesium sulfate. Filtration and removal of the solvents

under reduced pressure gave crude ketene dimethyl thio-

acetal. Distillation under reduced pressure gave 24.0 g

(80%) of pure ketene dimethyl thioacetal; bp 72°C/24 mm; ir

(neat), 1580, 1560, 1445, 1430, 1327, 1108, 983, 802-865

cm-"*"; nmr, 6=2.28 (s, 6 H) , 5.08 (s, 2 H) ; mass spectrum,

m/e (%) M+2 122 (8.4), M+l 121 (7.1), M+ 120 (79.5), 107

(4.0), 106 (2.7), 105 (18.8), 75 (8.7), 74 (13.1), 73 (100),

61 (40.6), 45 (53).

58

Anal. Calcd. for C4HgS2: C, 39.96; H, 6.71. Found:

C, 40.11; H, 6.76.

Lithium Diisopropylamide (LDA). Into a magnetically

stirred 1.5 molar solution of diisopropylamine (0.25 mol) in

tetrahydrofuran was added 0.25 mol of n-butyllithium in

hexane at -10° to 0°C, under nitrogen. After the addition

of n-butyllithium was complete, the reaction mixture was

stirred at -10° to 0°C for 30 minutes and transferred into

the Grignard adduct solutions.

Ketene Dimethyl Thioacetal (Via Dithioacetic Acid).

Into a solution of 0.48 mol of n-butyllithium in hexane/

tetrahydrofuran (0.7 molar solution) was added 0.24 mol

of dithioacetic acid at -78°C, under nitrogen in 10 minutes.

The reaction mixture was stirred at -78°C for 2 hours and

then 0.48 mol of methyl iodide was added. After stirring

the resulting solution at -78°C for 15 minutes, the cooling

bath was removed and the solution was stirred at room tem-

perature for 2 hours. Then the reaction mixture was poured

into 500 mL of hexane and the resulting solution was washed

with 500 mL of 5% potassium bicarbonate. The layers were

separated and the aqueous layer was extracted with hexane.

The combined organic solutions were dried over anhydrous

magnesium sulfate. Filtration and removal of the solvent

under reduced pressure yielded crude ketene dimethyl thio-

acetal. Distillation under reduced pressure gave 20.2 g

59

(70%) of pure (nmr) ketene dimethyl thioacetal.

Ketene Dimethyl Thioacetal (Via Methyl Dithioacetate).

Diisopropylamine, 5.2 g (0.52 mol) was dissolved in 50 mL of

tetrahydrofuran and into this solution was added 0.50 mol of

n-butyllithium in hexane at -10° to 0°C, under nitrogen.

After stirring the resulting solution for 30 minutes, 5.31 g

(0.50 mol) of methyl dithioacetate was added and the result-

ing solution stirred for 2 hours. Then 7.1 g (0.50 mol) of

methyl iodide dissolved in 25 mL of tetrahydrofuran was

added to the reaction mixture and the resulting solution

stirred overnight. The reaction mixture was poured into

250 mL of ice water and after stirring the resulting mixture

for 15 minutes the layers were separated and the aqueous

layer was extracted with ether and the combined organic solu-

tions were dried over anhydrous magnesium sulfate. Filtra-

tion and removal of the solvent under reduced pressure

yielded 5.65 g (94%) of ketene dimethyl thioacetal. Puri-

fication by distillation gave 4.0 g (67%) of material.

Ketene Dimethyl Thioacetal Monosulfoxide (m-Chloro-

peroxybenzoic Acid As Oxidant). Ketene dimethyl thioacetal,

6.01 g (0.05 mol), dissolved in 100 mL of methylene chloride

was cooled to -8°C under a nitrogen atmosphere and then

10.20 g (85%, 0.05 mol) of m-chloroperoxybenzoic acid was

added in portions at such a rate that the temperature of

the reaction mixture did not exceed 0°C. The resulting

60

reaction mixture was stirred at -5 C, for 15 minutes and

then for 1 hour at room temperature. Then the reaction

mixture was poured into 200 mL of 5% aqueous sodium bicar-

bonate solution. The layers were separated and the aqueous

layer was extracted with methylene chloride. The organic

layer and extracts were combined and dried over anhydrous

magnesium sulfate. Filtration and removal of the solvent

under reduced pressure gave 5.8 g (85%) of material in

quite pure form (nmr). Further purification by distilla-

tion gave 4.8 g (71%) of product; bp 145-150°C/27 mm; ir

(neat) 3490, 1593, 1429, 1330, 1070, 970, 893 cm nmr,

6=2.38 (s, 3 H), 2.64 (s, 3 H), 5.51 (d, 1 H, J= 2Hz), 6.01

(d, 1 H, J= 2Hz); mass spectrum, m/

137 (0.8), M+ 136 (5.9), 90 (8.4),

(15.1).

'e (%) , M+2 138 (.5) , M+l

89 (4.8), 73 (100), 58

Attempt to Oxidize Ketene Dimethyl Thioacetal to the

Monosulfoxide with N-Chlorosuccinimide• Ketene dimethyl-

thioacetal, 2.4 g (0.02 mol) was d

anhydrous methanol and 2.73 g (0.0^

mide was added to this solution in

the addition the temperature of the

not allowed to rise above 5°C. Af-tp

N-chlorosuccinimide was complete,

stirred at 0°C for 1 hour and then

hour at room temperature. Then th^

ssolved in 7 mL of

mol) of N-chlorosuccini-

small portions. During

reaction mixture was

er the addition of

the reaction mixture was

stirred an additional 1

methanol was removed

61

under reduced pressure leaving a. solid and a liquid residue.

The liquid was dissolved in ether and separated from the

solid by filtration. After removing the ether under re-

duced pressure a very small amount of yellow liquid remained,

the nuclear magnetic resonance spectrum of which indicated

that it was not the desired compound.

Attempt to Oxidize Ketene Dimethyl Thioacetal to the

Monosulfoxide with Hydrogen Peroxide. Into a solution of

1.2 g (0.01 mol) of ketene dimethyl thioacetal in 15 mL of

acetone was added 0.01 mol of hydrogen peroxide (3.4% in

H20) at -4°C in a period of 15 minutes. The resulting

solution was then stirred at -6°C for 15 minutes and then

stirred for 4 hours at room temperature. The reaction

mixture was extracted with ether and the combined ether

extracts dried over anhydrous magensium sulfate. Removal

of the solvent under reduced pressure gave the starting

material.

Ketene Dimethyl Thioacetal Monosulfoxide (NaIC>4 As

Oxidant). Sodium metaperiodate, 11.9 g (0.0556 mol) was

dissolved in 150 mL of a 1:9 methanol-water mixture and into

this solution was added 6.4 g (0.0532 mol) of ketene di-

methyl thioacetal in 50 mL of methanol at 0 C in a period

of 10 minutes. The reaction mixture was stirred 19 hours

at 0°C and then filtered. The sodium iodate filtercake was

washed with methylene chloride. The resulting two layers

62

were separated and the aqueous layer was extracted with

methylene chloride. The organic layer and extracts were

combined, dried, and removal of the solvent under reduced

pressure gave ketene dimethyl thioacetal monosulfoxide along

with some unidentified compounds as determined by nmr spec-

troscopy. No further purification was attempted.

Attempt to Oxidize Ketene Dimethyl Thioacetal to the

Monosulfoxide with Pyridinium Chlorochromate. Into a solu

tion of 2.4 g (0.02 mol) of ket^

30 mL of methlene chloride was

(0.03 mol) of pyridinium chloro

chloride containing 0.9 g of so4

a period of 15 minutes at -12°C

stirred at this temperature for

an additional 1 hour at room te:

solution was added 50 mL of eth

flask were poured into 250 mL

solution and the layers were se;

was extracted with ether and th

combined and dried over anhydro

tion and removal of the solvent

of

Methyl 3 ,3-Bis(methylthio)

a 1 molar methylmagnesium chlo

furan was added 0.1 mol of carb

equal volume of tetrahydrofuran

ne dimethyl thioacetal in

added a suspension of 6.4 g

chromate in 30 mL of methlene

ium acetate as buffer during

The reaction mixture was

30 minutes and then stirred

smperature. To the resulting

er and the contents of the

cold 5% sodium bicarbonate

(parated. The aqueous layer

e organic and ether extracts

LIS magnesium sulfate. Filtra-

gave the starting material.

dithiopropenate. To 0.1 mol of

ride solution in tetrahydro-

on disulfide dissolved in an

at a rate sufficient to

63

increase the temperature of the reaction mixture to 40-45 C

and maintain this temperature range during the remainder of

the carbon disulfide addition. After the addition was

complete the reaction mixture was stirred for 2 hours main-

taining the temperature between 40-45°C. Then the reaction

mixture was cooled to room temperature and diluted with

tetrahydrofuran to give a 0.5 molar solution. Then a 0.1

mol solution of lithium diisopropylamide in tetrahydrofuran

was added to the previous solution during 30 minutes at -78°C

The resulting solution was stirred at -78°C for 1 hour and

for an additional 30 minutes at room temperature. To this

resulting solution was added 0.05 mol of carbon disulfide

dissolved in equal volume of tetrahydrofuran during,10

minutes. The reaction mixture was stirred at room temper-

ature for 3 hours and then 0.3 mol of dimethyl sulfate was

added at a rate sufficient to increase the temperature of

the reaction mixture to 45°C. The resulting solution was

stirred for 1 hour and poured into 1000 mL of 5% sodium

bicarbonate solution. The layers were separated and the

aqueous layer was extracted with ether. The organic layer

and ether extracts were combined and dried over anhydrous

magnesium sulfate. The solution was filtered and concen-

trated under reduced pressure by removal of the solvent

until about 100 mL of solution remained. Then 25 mL petro-

leum ether was added to this solution and the flask main-

tained at 0°C overnight. A precipitate formed and was

64

filtered and washed with petroleum ether. The solid was

dried in air to give 7.7 g (73%) of product. The filtrate

was placed on a rotary evaporator and the solvent evaporated

to give an oily residue which was subjected to fractional

distillation and at 60°C/55 mm methyl dithioacetate was

collected.

For an analytical sample of 3,3-bis(methylthiopropen-

ate), 2 g of material was dissolved in a minimum amount of

chloroform and eluted through a neutral alumina column using

methylene chloride as eluent. The solution was concentrated

on a rotary evaporator and a few drops of petroleum ether

added and the resulting solution cooled. The resulting

crystals were filtered and air-dried; m.p. 84-85°C; ir (as

melt), 2980, 2910, 1472, 1428, 1333, 1292, 1245, 1001, 956,

888, 784, 732, 672, 613 cm"1; nmr, 6= 2.42 (s, 6 H), 2.49

(s, 3 H), 6.70 (s, 1 H); mass spectrum, m/e (%), M+2 212

(0.9), M+l 211 (0.4), M+ 210 (4.4), 197 (19.5), 196 (9.7),

195 (100), 180 (8.0), 163 (9.7), 115 (10.6), 101 (42.5), 100

(8.9) , 91 (70.8), 69 (8.8) .

Anal. Calcd. for C gH 1 0S 4: C, 34.25; H, 4.79; S, 60.96.

Found: C, 34.39; H, 5.00; S, 60.66.

Attempt To Synthesize Ketene Dimethyl 0,S Acetal By The

One-Pot Method. A 125 mL (1 molar, 0.2 mol) portion of

n-butyllithium solution in hexane, was diluted with 175 mL

o of tetrahydrofuran and cooled to -78 C. To this solution

65

was added 7.85 g (97%, 0.1 mol) of thiolacetic acid dissolved

in 50 mL of tetrahydrofuran, in 10 minutes. The reaction

mixture was stirred 1.5 hours at this temperature and then

28.4 g (0.2 mol) of methyliodide was added to the reaction

mixture. The resulting solution was stirred at room tem-

perature for 15 hours and poured into 300 mL of n-hexane and

the resulting solution washed with 300 mL of 5-s sodium bi-

carbonate solution. The layers were separated and the

aqueous layer was extracted with hexane. The organic layer

and hexane extracts were combined and dried over anhydrous

magnesium sulfate. The solvent was removed under reduced

pressure and the resulting crude material was distilled;

bp 36°C/34 mm. It was identified as methyl thio propionate;

bp24 119-120°C/ ir, 2979, 2963, 2938, 1738, 1690, 1464,

1250, 1025, 830; nmr, 5=1.14 (t, 3 H, J= 7Hz), 2.23 (s, 3 H),

2.51 (q, 2 H, J= 7Hz).

CHAPTER BIBLIOGRAPHY

1. Herrmann, J.L., Kieczykowski, G.F., Romanet, R.F., and Wepplo, P.J., and Schlessinger, R.H., Tetrahedron Lett., 4711 (1973).

2. Herrmann, J.L., Kieczykowski, G.R., Romanet, R.F., and Schlessinger, R.H., Tetrahedron Lett., 4715 (1973).

3. Ban, Y., Ohnuma, T., Seki, K., and Oishi, T., Tetra-hedron Lett., 727 (1975).

4. Kieczykowski, G.R., Pogonowski, C.S., Richman, J.E., and Schlessinger, R.H., J. Org. Chem., 42, 175 (1977)

5. Davis, R. and Untch, K.G., J. Org. Chem., 44, 3755 (1979).

6. Bernstein, Z., and Ben-Tshai, D., Tetrahedron, 33, 881 (1977) .

7. Ziegler, F.E., and Chan, C.M., J. Org. Chem., 43, 3065 (1978).

8. Kharash, M.S., and Reinmuth, 0., "Grignard Reactions of Nonmetalic Substances", Prentice-Hall Englewood Cliffs, NJ, 1954, p. 1287.

9. Harville, R., and Reid, S.F., Jr., J. Org. Chem., 33, 3976 (1968).

10. Corey, E.J., and Suggs, J.W., Tetrahedron Lett., 2647 (1975).

11. Reid, E.E., "Organic Chemistry of Bivalent Sulfur", Vol. II. Chemical Publishing Co. Inc., New York, NY, 1960, p. 65.

12. Leonard, N. J. , and Jhonson, J.R., vl • Org. Chem., 27, 282 (1962).

13. Jhonson, J.R., and Kfeiser, J.E., "Organic Synthesis", Coll. Vol. 5, 791 (1973).

66

67

14. Meijer, J., Vermeer, P., and Brandasma, L., Reel. Trav. Chim. Pays-Bas, 92, 601 (1973).

15. Tomita, R., and Nagano, M., Chemical and Pharmaceuti-cal Bulletin, 20, (11, 2302(1972).

16. Kaya, R., and Beller, N.R., J. Org.. Chem., 46_, 196

(1981).

17. Chemical Abstracts, 1, 1693 (1907).

18. Mecke, R. , and Spiesecke, H., Ber., 89^ 1110 (1956).

19 Reid, E. Emmet, "Organic Chemistry of Vibalent Sulfur" Chemical Publishing Co., Inc., New York, 1962 Vol. 4, p. 78 .

20. God t, H.C., Jr., and Wann, R.E., J. Org. Chem., 2_6, 4047 (1961).

21 Krebs, V.B., and Mueller, A., Z_. Anor g. Allg. Chem., 348 (1-2), 107-112 (1966).

22. Sadtler Standard Spectra, IR Spectrum no=20911.

23. Sadtler Standard Spectra, NMR Spectrum no=2883M.

24. Reid, E. Emmet, "Organic Chemistry of Bivalent Sulfur"

Chemical Publishing Co. Inc., New York, 1962, V. 4, p. 66.

CHAPTER III

ONE-POT SYNTHESIS OF KETENE THIOACETALS

FROM ALKYL HALIDES

Introduction

As mentioned in the general introduction ketene thio-

acetals have been used as key intermediates in a wide variety

of organic syntheses. Especially in the last decade, as a

consequence of their wide use, a host of methods have been

developed for their preparation."'" One of the earliest

studies of the formation of ketene thioacetal functionality,

was the preparation of 1,1-bis-(ethylthio)propene. It has

been prepared by a rather abnormal dehydrohalogenation

2 3

reaction of B-chloropropionaldehyde diethyl mercaptal. '

The same ketene thioacetal, has also been prepared by the

/S-Cft e a H3 C x /S" C2 H5

' RO K x ' C I - C H ^ C H ^ C H > C~C

X S - H /

elimination of ethanethiol from 1,1,2-tris-(ethylthio)propane

in the same year.4 The latter method has been used in

68

69

cn3 /S-CjHs H3C s Sh 5 I ' i~BuO KT

HcCoS—CH — CH > C ~ C 2 v -C2H5SH , \

XS-C2H5 H7 S - C ^

following years for the preparation of ketene diethyl thio-

acetal and ketene di-n-butylthioacetal but this method gave

5 6 side products along with the desired ketene thioacetals. '

H5C2S-CH2— CH — = > H 2 C = C

^ S - C ^ ^ " ^ 5

+ C ^ S - C H Z Z C H - S ^ + H 3C- C( SC^H5)3

Later, a Wittig reaction was utilized for the synthesis of

7 8 9 ketene thioacetals from aldehydes. ' ' This reaction failed

S-R 0 Ri S-R / // \ /b

PhoP — C + R.— C > C ~ C 3 l — pk p n

\ \ 3 / \ S-R H H S-R

70

j S 7

+ CKj01jp _ , c ^ 0 , 3 p S > ^J^PIOCH), 0 //

R - C R-

\H )z={ ) + (CH30)3P0

H'

to give ketene thioacetals with ketones. In recent years

the Harner-Wittig reaction has allowed the utilization of

ketones for the preparation of ketene thioacetals.^^

/ S R 0 ,SR 7 II 7

(R0)3P + C I — C H > ( R 0 ) 2 P _ C H

a s r X S R

DBase R̂ SR

2) Rj R2 C=0 X /

C ~ C + ( R 0 L P 0 0 H 3) HT / \ 2

R 27 X S R

Ketene thioacetals have also been synthesized by the Peter-

12—16 son Olefination reaction as summarized below. Corey has

RS RS RS R< \ \ \ /

1)rvBuLi 1)n-BuLi CH2 2}{CH3)̂ Si CI

> CH"Si{CH3)3 2)R,R2C-0 ^ C — C

RS 7 RS7 RS 7 XR 2

71

employed an organoaluminum compound, bis-(dimethylaluminum)-

1,3-propanedithiolate, to utilize esters for the synthesis

17 of ketene thioacetals. Recently, an interesting reagent,

( HjC^Al-S- (CĤ 3 S - AI (CH3)2 + R1R2CH-C02CH3 ->

2,2-dipyridyl disulfide, has been reported by Japanese

researchers for the preparation of ketene thioacetals as

18 shown below. Thioamides have been found to be potential

1) n-BuLi

2) & s -J

->

o

72

intermediates to ketene thioacetals, and several ketene

thioacetals, prepared by utilizing thioamides, have been

reported in recent years.^

t© I R-CI-U— C

\ / C H 3 \ K ^ C H 3 N N

•CH3 N CH3

HS-a

H S — '

A close examination of the above methods reveal that

the sources of sulfur atoms in ketene thioacetals, prepared

by these methods, are thiols. A more readily accessible

reagent for the source of sulfur atoms is carbon disulfide.

Undoubtedly, because of its ready availability, carbon

disulfide has also been used in the synthesis of ketene

thioacetals as a source of both sulfur atoms. Thus, several

20-22 preparations of ketene thioacetals from dithioesters,

23

and from dithioacids, which are prepared by the reaction

of Grignard reagents with carbon disulfide, have been re-

ported. These reaction sequences are summarized on the

next page.

73

// R1 CH — C

\

e /s@ /SR

- > R . C H = C — — — > R1 CH —C

S R. Liq. NH3 1

\ SR* \ SR,

R 1 \ / /

C H — C LiNH-

->

R-/ \ S4CH.4-CI 1 n

Ri

R

\ / ' C = C

-CI \

/ CH.

\ /

s t c H2 )N _,

R A

s — CH2

R

CZIC

/ \ s (ci-y n_-j

R« \ //

R

C H — C Br2, Dioxane \ //

R / \ 20 C

S - C H ,

B r - C

R /

— C

\ S - C H :

R MgCl \ /S^R

T H F -> C = C

R / ^ S - C H 3

//

R

C H - C / \

2 LDA R 1 \ / S L i R 1 \

_ / RX V -> c — c > c —c

SH R / \ SLi R /

SR

SR

74

R| S

^ // D 2 L D A C H — C >

/ ^ 2) X CH2CH2CH2X

R2 S H

Since considerable attention has been paid to a-keto

ketene thioacetals, it is worth briefly mentioning here

about their synthesis. In all reported cases of the syn-

thesis of this class of compounds the source of sulfur

atoms has always been carbon disulfide. Thus, active

methylene compounds react with carbon disulfide in the

presence of a suitable base to give dithioic acid dianions

24 — 27 subsequent alkylation of which afford ketene thioacetals.

0 °, Pi II II II

R - C R-C R-C S

\ Base \ Q CS 2 ^ 0

CH 2 • > CH > H C — C

Y 7 Y / Y / \ 0

0 8 R - C S 0 R — C s - R

Base ^ / 2 R^X ^ ^ 1

C ~ C 3 > c = c

Y 7 V / \ - R 2

Y = Ac, CN» Ph

7 5

Depending on the acidity of the a-hydrogens of the active

methylene compounds, different type of bases such as sodium

and potassium alkoxides have been used. For the reaction of

acetophenone with carbon disulfide sodium hydride has been

used, and for cyclohexanone, the lithium salt of 4-methyl-2,

6-di-t-butylphenol has been utilized for the synthesis of 28 — 30

the corresponding a-ketoketene thioacetals. The main

advantage of the latter base is that it reacts only very

slowly with carbon disulfide. However, chromotagraphic

methods need to be used to separate the phenol from the

ketene thioacetal products.Finally, a recent paper

0

+ 2 C S 2

2 C H 3 I • »

0 SCH-,

^ S C H :

described the use of tetraethylammonium hydrogensulfide and

1,1-dichloroalkenes for the preparation of ketene thio-

acetals.^*^

76

©®

\ / ' ® e Ri\ / s NEt' \ / U (Et/NHS ) X 7

C=C V - e » C = C / v — 2 Et.N CI / \e©

r/ CI _2 *s r/ s NEt4

RX

R, SR R. S

\ / \ // C~C and/or H— C—C

r / \ r r / X s R

Results and Discussion

As seen firom the general review of the preparation of

ketene thioacetals in the introductory portion of this

chapter, there are mainly two sources of sulfur atoms for

ketene thioacetals, thiols and carbon disulfide. In com-

paring these two sources, carbon disulfide is the more

readily available and economical. The methods which use

carbon disulfide as a source of sulfur utilize either di—

thioesters or dithioacids. The preferred route in the

preparation of ketene dimethyl thioacetal (Chapter 11) by

the one—pot method compared to its preparation from dithio-

acetic acid or methyl dithioacetate raised the following

question. Is this one—pot method a general one for the

77

synthesis of ketene thioacetals or is it useful only for this

specific compound? Because of the importance of this class

of compounds the scope and limitations of this one-pot

method were chosen for investigation. Consequently, a

number of ketene thioacetals were prepared by this procedure.

The procedure involved the sequential transformation of an

alkyl halide to the corresponding Grignard reagent, dithioic

acid anion, dithioic dianion, and finally to a ketene thio-

acetal, as formulated below. Yields of the prepared ketene

\ \ \ M g \ C S 2

C H - X > C H M g C l > / /

R 2 F*2

R , S R i S L i X ^ L D A X /

C H — C > C — C

R 2/ M g X R 2 ^ S M g C l

2 R X

R 1 \ / S " R

^ c = c

R / ^ S - R

thioacetals varied considerably depending on the particular

starting material and were calculated from the amount of

78

alkyl halide if the Grignard reagent was prepared or from

the amount of Grignard reagent when commercial (titrated)

material was used. The results are summarized in Table II.

Satisfactory yields were obtained with simple alkyl halides

and poor yields were obtained from cyclohexylmagnesium

chloride and benzylmagnesium chloride. The poor yields from

Table II

KETENE THIOACETALS

Alkyl Halide

Ketene

S,S-Acetal

Alkylating

Agent Yield %

H3CCI h 2 c = c ( s c h 3 ) 2 ( c h 3 o ) 2 so 2 8 0

H3CCI H2C=C(SC2H5)2 (C^HsOIJSO^ 7 2

H3CCI H2C=C(SCH2Ph)2 PhCH^Cl 8 0

H5C2Br H f

x c z c ( s c h 3 ) 2 h '

( c h 3 o ) 2 s o 2 7 0

n-H7C3Cl

h 5 c ,

CZC(SCHJ, / j 2

H

(CH-JO^S 0 2 6 0

i-H7C3Cl

H f \ CZC(SCHJ 9

H f (CH3O 0 2 6 5

TABLE II Continued

79

Alkyl Halide

Ketene

S,S-Acetal

Alkylating

Agent Yield %

n-CAH9Cl xczrc(scH3)2

H

( C H 3 0 ) 2 S 0 2 70

Qci < Q l = C ( S C H 3 ) 2 (CH30^5°2 5 - 1 0

PhCH2Cl

Ph \ / C = C ( S C H 3 ) 2

H

( C H 3 0 ) 2 S 0 2 9

H 2 C ~ C H - C H 2 C I

HfZCH

c~c(SCH3)2

H

(CH3o ]̂ SO2 —

these Grignard reagents were not unexpected in view of the

32 reported low yields of methyl cyclohexyldithioate and

33

methyl phenyldithioacetate obtained from the corresponding

Grignard reagents and carbon disulfide. In light of the

above reports it seems these Grignard reagents do not

react with carbon disulfide as expected. This explains the 34

formation of methyl N,N-disopropyldithiocarbamate which

was the major product of these reactions. Presumably, the

80

s i c h 3 i 2 c ^ ich 3i 2ch n -\ \ ? Ef? » N - C

/ ^ ^ © s> (CH3)2CH (CH 3) 2CH SLi

(CH30)2S02

(CH 3) 2CH S

-> N — C

/ \ (CH^CH s-ch 3

carbamate forms by the reaction of lithium disopropylamide,

which is used as the base in these reactions, with unreacted

carbon disulfide, as shown above. Similarly, the one-pot

procedure failed altogether in the case of allylmagnesium

bromide. In this case, the major isolable product was also

N,N-disopropyldithiocarbamate indicating that the reaction

between allylmagnesium bromide and carbon disulfide is poor,

in the sense that the expected Grignard adduct does not form

in respectable amount.

Although this one-pot procedure differs from the pro-

cedures which utilize dithioic acids and dithioates only in

utilizing the anions of such acids and esters as nonisolable

intermediates, it decreases the preparation time of the

ketene thioacetal products considerably and better overall

81

yields are obtained. As far as the Grignard reagent addition

to carbon disulfide this one-pot method should be the method

of choice compared to the methods which utilize dithioic

acids and esters for the synthesis of ketene thioacetals.

Experimental

The same instruments, as in Chapter II were used to

record the proton nuclear magnetic resonance, and infrared

spectra. Mass spectra were recorded on a Finnigan GC/MS

32 00 with a 6100 Data System. Elemental analysis were per-

formed by Midwest Microlab, Ltd., Indianapolis, Indiana.

Methylmagnesium chloride, ethylmagnesium bromide and n-butyl-

lithium were purchased from Aldrich Chemical Co. and used

without further purification. The same purification and

drying procedures were used for tetrahydrofuran, carbon

disulfide, diisopropylamine and for other reagents as indi-

cated in the experimental part of Chapter II.

Ketene Dithioacetals (Ketene S,S-acetals); General Pro-

cedure. Into a mechanically stirred 1 molar solution of the

Grignard reagent (0.25 mol) in tetrahydrofuran or tetrahydro-

furan/ether under nitrogen is added a solution of carbon

disulfide (19.0 g, 0.25 mol) dissolved in an equal volume

of tetrahydrofuran at a rate sufficient to increase the

temperature of the reaction mixture to 4 0-45 C and maintain

this temperature during the remainder of the addition. After

82

the addition is complete, the mixture is stirred for 2 hours

at 40-45°C, diluted with tetrahydrofuran to give a 0.7 molar

concentration of the Grignard-carbondisulfide adduct, and

then cooled to -78°C with a dry ice/aceton bath. Then,

lithium diisopropylamide (0.25 mol) in tetrahydrofuran is

added during 45-60 minutes and the reaction mixture stirred

for 45 minutes after the addition is complete. The mixture

is allowed to warm to room temperature, stirred an additional

20 minutes, and a solution of the alkylating reagent (2 equi-

valents) in an equal volume of tetrahydrofuran is added at

a rate sufficient to increase the temperature of the reaction

mixture to 40^C and maintain this temperature during the

remainder of the addition. After the addition is complete,

the reaction mixture is allowed to cool to room temperature,

stirred for 2 hours, and poured into excess 5% aqueous

sodium hydrogencarbonate solution. The aqueous layer is

extracted with ether (3 x 250 mL) and the organic layer and

ether extracts combined. The resulting organic solution is

dried over magensium sulfate and distilled of solvent on a

rotary evaporator to give a residue of crude ketene dithio—

acetal which is purified by distillation under reduced

pressure.

Ketene diethyl thioacetal. The reaction between methyl-

magnesium chloride (in tetrahydrofuran) and carbon disulfide

was carried out by the general procedure described above,

83

and alkylation of the dianion with diethyl sulfate gave

ketene diethyl thioacetal in 72% yield; bp20 95-100 C/26

mm; ir (neat), 3007, 2962, 2896, 1550-1600, 1468, 1392,

1284, 1120, 1069, 985, 870, 808, 772 cm"1; nmr (CDC13),

5=1.25 (t, 6 H, J= 7Hz), 2.72 (q, 4 H, J= 7Hz), 5.23

(s, 2 H); mass spectrum, m/e (%) , M+2 150 (1.3), M+l 149

(0.3), M+ 148 (7.9), 120 (40.8), 119 (16.5), 92 (26.3), 87

(11.8), 75 (27.0), 59 (100), 58 (47.4).

Ketene Dibenzyl Thioacetal. Methylmagnesium chloride

(in tetrahydrofuran) and carbon disulfide were allowed to

react in the same manner as in the general procedure.

After formation of the dianion benzyl chloride was added

and the resulting reaction mixture was stirred for 2 hours

at 4 0°C and then overnight at room temperature to give

ketene dibenzyl thioacetal in 80% yield (nmr). The com-

pound decomposed on attempted distillation under reduced

pressure. Ir (neat), 3095, 3065, 2950, 1622, 1601, 1520,

1477, 1435, 1259, 1120, 1095, 1050, 881, 792, 725 cm"1;

nmr (CDC13), 6=3.85 (s, 4 H), 5.18 (s, 2 H), 7.07 (s, 10 H)

1,1-Bis(methylthio)propene. Ethylmagnesium bromide

(in ether 3.2 m