92(1973)RECUEIL 879

NEW REACTIVE INTERMEDIATES FROM CARBONSULmTR BOND CLEAVAGE IN HETEROCYCLIC COMPOUNDS

BY

S. HOFF, A. P. BLOK and Miss E. ZWANENBURG (Koninklijke/Shell-Laboratorium, Amsterdam (Shell Research B.V.))

The sulfur-carbon bond cleavage with alkali metals in liquid ammonia has been investigated in several heterocycles. Special attention has been paid to substituted 1,4-thiazin-3-ones VIII in which the carbon-sulfur bond is cleft selectively with formation of the dianion X. The protonation, alkylation and acylation of the alkenethiolates X and XI have been studied. Routes to the synthesis of 2,3- dihydroaH-1,4-thiazine XIX and tetrahydro-l,4-thiazepine M have been developed.

1. Introduction

The reductive cleavage of sulfur-carbon bonds in organic molecules with alkali metals in liquid ammonia has long been recognized as a useful means of chemical synthesis. Amino acids containing thiol groups are readily prepared by the reduction of benzyl thio derivatives'. Cyclic dithioacetals can be cleft with sodium in liquid ammonia to the corresponding dithiols'. More recently Brandsma and Schuy13 de- scribed the synthesis of 1-alkenyl and 1-alkynylthiolates by the carbon- sulfur bond cleavage of the corresponding unsaturated thioethers.

We have focused our attention on the application of this reaction to heterocyclic compounds. Our main objective is the synthesis of reactive ionic species, which may be used as starting material for the preparation of new heterocyclic compounds. We ascertained that under certain conditions sulfur-containing heterocycles may be cleft quantitatively to stable dianions with alkali metals in liquid ammonia.

N. 0. Kappel and W. C. Fernelius, J. Org. Chern. 5, 40 (1940). L. A. Stocken, J. Chern. Soc. 1947, 593. L. Brandsma and P. J . W. Schuyl, Rec. Trav. Chim. 88, 513 (1969).

880 S. Hoff et al.

2. Results and discussion

2.1. Preliminary remarks

Treatment of a sulfurcontaining heterocycle with ammoniated electrons - obtained by dissolving alkali metals in liquid ammonia - may lead to the fission of the carbon-sulfur bond. The occurrence of this fission depends on the structure of starting material and is furthermore af- fected by (a) the solubility of the sulfur-containing compound in liquid ammonia,

(b) the reactivity of some heterocycles towards liquid ammonia, (c) the aromaticity of the starting material. As to the last factor, addition of electrons to the aromatic system may occur, finally giving hydrogenated products. In many cases this hydro- genation is faster than or comparable with the rate of the cleavage reaction4.

In the reaction of sodium with benzothiazole, which has also been studied to some extent by Knowles and Watt’, we observed the same sequence (see Scheme 1, path A): first loss of aromaticity by hydro-

which is normally small at molecular weights exceeding 150,

[ Q$2] I

Scheme 1

N=C@ rn@ m

+ NH4Cl I-ecN

Y. L. Gol’dfarb and E. P. Zakharov, J. Org. Chem. USSR 6, 1765 (1970). C. M. Knowles and G. W. Watt, J. Org. Chem. 7,60 (1942).

Carbon-sulfur bond cleavage in heterocyclic compounds 92 (1973) RECUEIL 881

genation of the carbon-nitrogen double bond giving the intermediate benzothiazoline I, followed by cleavage of the carbon-sulfur bond, yielding 2-N-methylaminothiophenol I1 after protonation with am- monium chloride. Upon cleavage of the carbon-sulfur bond, initially a dianion is formed with the negative charges on the originally linked carbon and sulfur atoms. This dianion may undergo a variety of reac- tions depending on the relative basicities, inter- or intramolecular proton transfer to the carbon atom originally bearing the negative charge can take place, which leads to a more stable rearranged dianion. Another possibility is the protonation of the dianion by the solvent, yielding a monoanion and an amide anion.

A further phenomenon in these reactions is the fragmentation of the initially formed or rearranged dianions, which is illustrated by the following example. Path B in Scheme 1 shows a second reaction of benzothiazole. Simultaneously with the hydrogenation (path A) the carbon-sulfur bond in benzothiazole is cleft, yielding the dianion 111. This dianion eliminates HCN in a rather slow reaction, finally yielding thiophenol after protonation with ammonium chloride.

2.2. Model compounds

With the results of the aforesaid and other experiments* we have been able to select compounds in which quantitative carbon-sulfur bond cleavage can be predicted. In selecting these compounds we paid particular attention to the resulting ionic species which should be a useful starting material for the synthesis of novel heterocycles. An eligible group of compounds are the substituted 2,3-dihydro-4H-1,4- thiazin-3-ones VIII, which can easily be prepared by known methods6. The ring opening of these 1,Cthiazines is effected with two equivalents of lithium or sodium in liquid ammonia in a very fast reaction. The initially formed dianion IX (see Scheme 2) rearranges to the more stable dianion X. Addition of one equivalent of ammonium chloride to the solution of X in liquid ammonia produces the 2-acetamidoalkene- thiolate XI.

* A detailed report on the scope of the carbon-sulfur bond cleavage in heterocyclic

'' H. Sokol and J. J . Riiier, J . Am. Chem. SOC. 70, 3517 (1948). compounds will be presented at a later date.

C. de Stevens, A . Hulamandark and L. Dorfman, ibid. 80, 5198 (1958). C. R . Johnson and C. B. Thunawulla, J. Het. Chem. 6, 247 (1969).

882 S. Hoflet 01.

0 0 I I

N H&l Me=Lior Na

x XI

H ~ O + (R=cH,, RLH) I &H3

(a) R = C H 3 , R' = H

(b) R = C+H5, R' = H CH3 k) R

Id) R R' (CH=CH)2

= CH3 , R' = CH3

xu

Scheme 2

After the evaporation of the ammonia the sodium salts of both mono- anion and dianion can be isolated in quantitative yield. These salts are surprisingly stable and can be stored for several months without noticeable decomposition. The PMR spectra of the sodium salts Xa and XIa in deuterated methanol show a quartet at 6 = 5.7 ppm, J = 1.2 Hz. These data indicate that the configuration of the double bond remains unchanged during the reaction sequence. Additional

. proof for the geometry of the double bond is given by the formation of 2,4-dimethylthiazole XI1 upon cyclization of XI(a) with aqueous HCl. The retention of geometry will be discussed in more detail in the fol- lowing section.

2.3. Alkylation, acylation and isomerization The alkenethiolate XIa can be alkylated in high yields with a variety of alkylating agents (see Table I) in liquid ammonia or in methanol, the latter solvent being used for reactive agents such as chloroacetone and cr$-unsaturated esters. The only product isolated from these reactions is the thermodynamically less stable Z-isomer of Xlll (see Scheme 3).

Carbon-sulfur bond cleavane in heterocyclic compounds 92 (1973) RECUEIL 883

X

I CI Br

CI Br Br CI

CI

CI

CI

-

Table I

Method of

preparation

6 7 6

10 6 I 7 9

8

8

8

Physical constants and spectral data of the reaction Xa or XI + RX - CH,CNHC(CH,)=CHSR XI11

It 0

R

CH3 CH,COCH, CH,CH(OCH,),

CH,CH=CH, CH,CH,Cl CH,CH2CH,CIa CH,COONa'

COCH,

COCH,CI'

COCHzCH,CI'

CHZCHZCOOCH,

Configura- tion of

crude reaction product

Z Z Z Z Z Z z Z

E + Z

E + Z

E + Z

b.p.', "Clrnm Hg

131/19 12210.4

13510.1 08-1 lO/O.OOS

8510.02 - - - -

-

-

Yield, o/ /o

__ 90 71 81 41 90 61 92 93

72

90

88

-

6,,= : PPm

5.20 5.12 5.19 5.20 5.12 5.08 5.10 5.71'

6.92 (E: 5.62 (Z: 6.96 (E)

7.04 (E)

5.79 (z;

5.78 (21

' Crude reaction products, purity >90% according to the PMR spectra.

' Crystallized from methylcyclohexane. Crystallized from toluene.

Melting point of pure E-isomer, crystallized from toluene. The allylic coupling constant in the alkylated and acylated Z-isomers is 1.2 Hz, and 0.8 in the acylated E-isomers.

' DzO as solvent. * The distillation has to be carried out as quickly as possible in order to avoid polymerization and

2-E isomerization.

Isomerization of XIII Z into XIII E can be achieved with a strong base such as potassium tert-butoxide in dimethyl sulfoxide (DMSO). In all cases the base-catalysed isomerization finally leads to an equilibrium mixture with an E/Z ratio of approximately 4 (see Table 11). The struc- tural assignment of the isomers is based upon spectral and chemical evidence. The vinylic hydrogen in the E-isomer is deshielded by the acetamido group and appears at lower field than the corresponding hydrogen in the 2-isomer. The allylic coupling constant in the 2-isomer (Jcisoid = 1.2 Hz) is expected to be larger than that in the E-isomer (Jtransoid = 0.9 Hz). Chemical evidence for the structures has been obtained by the reaction of XI11 with POCI, in pyridine. In the case of the Z-isomers (R = CH, or CH,COCH,) 2,4-dimethylthiazole was

884 S. Hoflet al.

18/22

80120

Table I1

Z-E isomerization of alkylated XI11

6S3 5.31

i::!

R

CH3

CH2COCH3

CH*CH(OCH,),

CH2CHZCOOCH3

CH,CH=CH,

80120

15/25

Reaction time'

z::: 6.53 5.35

Z E Z E Z E Z E Z

10

5

150

2

I 6°C =

16/24' I 6.25 5.20

' After this reaction time the E/Z ratio did not change. Based upon PMR spectroscopy. This proved to be an equilibrium mixture. The allylic coupling constant in the E-isomers is 0.9 Hz.

isolated in 70%. The E-isomers gave only the corresponding imidoyl chlorides XIV which did not cyclize (see Scheme 3).

0 0 II II

AMLATION cH3,cccH3 ~ w 3 1 ( NHCCHj OR B A S

ACYLATION' - H RS H

X m Z XIIIE

PY RI DI NE CI

\& CH3 R:

Scheme 3

Carbon-suljirr bond cleavage in heterocyclic compounds 92 (1973) RECUEIL 885

Acylation of XIa with acyl halides (see Table I) can be carried out in good yields in aprotic solvents such as dimethoxyethane. In contrast with the alkylated product XIII, the isomerization of the initially formed acylated isomer XI11 2 into the thermodynamically more stable E- isomers proceeds of its own accord under the reaction conditions. In this case the isomerization is presumably catalysed by the weakly basic alkenethiolate XI(a). The suggested mechanism is depicted in Scheme 4. Abstraction of a proton from XI11 Z by base gives the anion XV, which is capable of delocalizing its negative charge as is shown in the mesomeric structure XVI. After rotation and protonation the E-isomer is formed.

CH 0 0 l 3 II

XH3 cHTN!cH3 ‘S = CR

A@ cH3xN-ccH3

XPII xmn

Scheme 4

An addition-elimination mechanism can be ruled out, because the N-methyl compound XVII, which can be prepared from the dianion X and an excess methyl iodide in liquid ammonia, does not isomerize under the relevant reaction conditions. , The faster isomerization rate observed for acylated XI11 relative to that of the alkylated analogue may be explained by the fact that in the first case the proton can be-abstracted by a weak base since the resulting carbanion is more stabilized by delocalkation of the negative charge (see structure XVIII).

2.4. Application of the monoanion XI h the synthesis of dihydro-4H-

The monoanion XIa can be chloroalkylated in high yields with l-bromo- 2-chloroethane and 1 -bromo-3-chloropropane (Table I). Treatment of

I,4-thiazine and tetrahydro-I ,I-thiazepine

886 S. Hoflet al.

these compounds with sodium hydride in boiling toluene gave intra- molecular cyclization to N-acetyl-5-methy1-2,3-dihydro-4H-l ,4-thiazine XIX and N-acetyl-3-methyl-4,5,6,7-tetrahydro-l,4-thiazepine XX in yields of‘ 24 and 41 %, respectively (see Scheme 5) .

The rather low yields of these cyclization reactions are due to the simultaneous elimination of HCI from the alkyl side chain giving the corresponding vinyl (n = 2) and ally1 (n = 3) sulfides. The acylated

products XI11 (R=CCH,Cl or CCH,CH,CI) did not cyclize because of their unfavourable E configuration.

0 0 It I1

cp c=o

0 I1

cYHccH3 H S(CH2)”CL

XIX

Experimental part

Temperatures were uncorrected. PMR spectra were recorded on a Varian A 60D spectro- meter in deuterochloroform with tetramethylsilane as internal standard, unless otherwise stated. The chemical shifts (6) are given in ppm and the coupling constants (J) in Hz. The IR spectra were recorded on a Perkin Elmer 457 spectrometer. The microanalyses of purified compounds were in agreement with the proposed structures, the mass spectra showed the parent peaks and the fragmentations were in line with the structures. The liquid ammonia was condensed from the cylinder and used without further purification. Reactions involving liquid ammonia were performed at its boiling point.

1. The following general procedure was adopted for the reaction of benzothiazole with sodium in liquid ammonia:

To a solution of 0.02 mol of sulfurcontaining heterocyclic compound in 150 ml 01 liquid ammonia we added 0.04 gat* of sodium in small pieces. After the sodium had been

* If both the carbon-sulfur bond cleavage and the hydrogenation take place more than two equivalents of alkali metal will be consumed.

Carbon-sulfur bond cleavage in heterocyclic compounds 92 (1973) RECUEIL 887

dissolved, we added 0.04 rnol of ammonium chloride to protonate the resulting anionic reaction products..We evaporated the ammonia on a water bath and extracted the resul- ting residue several times with chloroform. After washing with a sodium-chloride- saturated water solution and drying over anhydrous sodium sulfate, we evaporated the chloroform and distilled the residue at reduced pressure. The isolated products were compared with authentic samples.

2 . Preparation of the 2.3-dihydro-4H-1,4-thiazin-3-ones VIIl

The thiazines VIII (a), (b) and (c) were synthesized according to the procedure of C. R. Johnsod" and the benzothiazine Vlll (d) according to Unger7.

V l l l (b) (R=C,H,, R '=H). Yield: 502,; m.p. 82.8-83.4"C (crystallized from ethyl alcohol).

VIIl (c) (R=R'=CH,); m.p. 141.8-142.6 "C, lit.hh132-1330C.

3. Preparation of the thiolates X and X I

To a solution of 0.05 rnol of 2,3-dihydro-4H-I,4-thiazin-3-one VIII in 200 ml of liquid ammonia we added 0.1 gat sodium or lithium in small pieces. Subsequently we evaporated the ammonia and a white crystalline material resulted. We removed the last traces of ammonia by evaporation for 2 hours at 80oC and 0.01-0.001 mm Hg. The quantitatively obtained disodium or dilithium salts X must be handled in a nitrogen atmosphere and with exclusion of moisture. Under these conditions they can be stored for several months.

The monoanion XI mixed with one equivalent of sodium or lithium chloride was obtained in loo:/, yield by the addition of 0.05 rnol of ammonium chloride to the solution of the dianion X in liquid ammonia. followed by the isolation procedure as described above.

4. Formation of 2.4-dimethylthiazole from X or X I A solution of 0.04 rnol of the sodium 2-acetamidopropenethiolate X or XI in 100 ml of 6 N HCI was heated for two hours at 6OoC. The reaction mixture was then extracted with ether. After washing and drying, 69 :/, of 2,4-dimethylthiazole was isolated by distillation.

5 . Preparation of 2-N-methylacetamido-I-methylrhiopropene X VII To a solution of 0.03 rnol of the disodium salt Xa in 150 ml of liquid ammonia, prepared as described under 3, we added a fourfold excess of methyl iodide. After the addition most of the ammonia was evaporated and water saturated with sodium chloride was added to the residue. This residue was subsequently extracted with chloroform, washed with a sodium chloride-saturated solution and dried over anhydrous sodium sulfate. Distil- lation gave pure XVII; b.p. 88OC14 mm, yield 96"<,.

P M R : 6,,-, = 5.91 (q), J = 1.2 Hz.

6. A lk ytat ion of 2-acetamidopropenethioiate Xla in liquid ammonia To a stirred solution of 0.03 rnol of sodium 2-acetamidopropenethiolate XI in 150 ml of liquid ammonia, prepared as described in experiment3, we added a twofold excess of alkylating agent. Fifteen minutes (in the case of BrCH,CH(OCH,), 5 hours) after the addition we evaporated the ammonia and worked up the residue as described in experi- ment 5 . See Table I for further data.

0. Unger and G. Graaf, Ber. 30, 608 (1897).

888 S. Hoffet al.

7 . Alkylation of 2-acetamidopropenethiolate XIa in methanol

To a stirred solution of the ammonia-free sodium 2-acetamidopropenethiolate XIa, prepared as described in experiment 3, in 100 ml of anhydrous methanol we added a solution of 0.03 mol of alkylating agent in 20 ml of dry methanol at 0-50C. After the addi- tion, which required 15 minutes, the reaction mixture was warmed to room temperature and stirring continued for one hour. Then most of the methanol was evaporated and a saturated sodiumchloride solution was added to the residue, which was subsequently extracted with chloroform (3 times) and dried over anhydrous sodium sulfate. The alkylated XI11 was obtained after distillation or crystallization. See Table I for further data.

8. Acylation of 2-acetamidopropenethiolate XIa in dimethoxyethane

To a stirred suspension of 0.03 rnol of the ammonia free sodium 2-acetamidopropene- thiolate XIa in 100 ml of dry dimethoxyethane we added 0.03 rnol of the acyl chloride in 20cc of dry dimethoxyethane in 30 minutes at -6OOC. After about five hours at -60°C the reaction mixture was neutral. After warming to room temperature the reaction mixture was worked up as described under experiment 7. The crude product consisted in all cases of a mixture of E and Z-isomers in a ratio of 4. When the reaction was follow- ed by PMR spectroscopy the formation of the Z-isomer was observed first and then isomerization into the E-isomer. For further data see Table I.

9. Preparation of XIII Z (R=CH,COONa)

To a solution of 0.03 rnol of the ammonia-free disodium salt X, see experiment 3, in 100 ml of dry methanol we added 0.03 rnol of monochloroacetic acid in 10 ml of dry methanol in 15 minutes at 0-5"C. Stirring was continued for one hour at room tempera- ture. Then the methanol was evaporated, and a solid residue obtained which consisted of sodium chloride and the sodium salt of the substituted acetic acid derivative (see Table I). Attempts to isolate the free acid failed.

10. Preparation of XIII Z (R=CH,CH,COOCHJ

We added 0.03 rnol of methyl acrylate to a solution of 0.03 mol of the ammonia-free sodium 2-acetamidopropenethiolate XI in 100 ml of dry methanol in 15 minutes at OOC. Then the reaction mixture was stirred for two hours at room temperature neutralized with a 1 N HCl/ether solution. The work-up was as described under experiment 7. For further data see Table I.

11. Base-catalysed E-Z isomerization of alkylated XIII To a solution of the pure 2-isomer of XI11 in DMSO we added 0.1 equivalent of potas- sium tert-butoxide. The course of the reaction at room temperature was followed by PMR spectroscopy. For results see Table 11. In one case R=CH, the E-isomer of XI11 was isolated by neutralizing the basic reaction mixture with a 1 N HCllether solution and working up the crude product in the way described under 7. XI11 E, R=CH,, b.p. 98- 10O0C/0.O03 mm Hg, m.p. 52-53°C (crystallized from toluene).

12. Formation of 2,4-dimethylthiazole from XIII Z (R=CH, or CH,COCH,)

To a solution of 0.02 rnol of XI11 Z (R=CH, or CH,COCH,) in 50 ml of dry pyridine we added 0.01 rnol of POCI, in 10 ml of pyridine with stirring at -10°C. Stirring was continued for two hours at room temperature. Then the reaction mixture was concen- trated, water was added and the product extracted with ether. After washing and drying, distillation yielded 70 "/, of 2,4-dimethylthiazole in both cases.

Carbon-sul/ur bond cleavage in heterocyclic compounds 92 (1973) RECUEIL 889

13. Reaction of XIII E (R=CH,) with POCI, The same procedure as described under 12 was applied to XI11 E (R=CH,). Hydrolytic work-up recovered the starting material. When this reaction was followed by PMR spectroscopy the formation of the imidoyl chloride VIX was derived from the difference in chemical shift of the methyl groups.

14. Preparation of N-acetyl-5-methyl-2.3-dihydro-4H-l.4-thiazine XIX A mixture of 0.02 mol of the chloride XIII, R = CH,CH,CI (prepared according to experiment 7), 0.02 mol of sodium hydride and 300 ml of dry toluene was heated with stirring at 5OoC for four hours. After washing, drying over anhydrous sodium sulfate and evaporation of the solvent, the crude reaction mixture was purified by column chromatography (silica gel-benzene). Analytical samples were obtained either by sublima- tion or crystallization from methylcyclohexane. Yield: 240/,; m.p. 74.1-74.5oC. 1R : FC+: I643 cm- ' vcs: 1603 cm-' PMR : o(: 6 Ha = 2.11 (d) 6 H, = 3.00 (m)

u

15. Preparation of N-acetyl-3-methyl-4,5,6,7-tetrahydro-J,4-thiazepine X X

A mixture of 0.02 mol of the chloride XIII*, R = CHzCH2CH,CI, 0.02 mol of sodium hydride in 500 ml toluene was refluxed for five hours. The product was worked up as described in experiment 14, purified over silica gel with a SO:( benzene-20% dichloro- methane mixture, and crystallized from pentane.

1R : 7c'c=o: 1643 cm-', vc,c: 1608 cm-' PMR: c$ 6 Ha = 2.03 (d) 6 H, s 2.0 (m)

c=o 6 H, = 2.06 (s) 6 H, 2.7 (m)

Yield: 41 :<, m.p. 3636.7oC. N

6 H, z 3.7 (m) 6 H, = 6.07 (q) J = 1.1 Hz

(Received January 2nd, 1973)

* Crude reaction product.