[ COXTRIBUTION FROM T H E
ORGANIC CHEMICALS D I V I S I O N ,
YI 1 R O R E S E A R C H
I I E P A R T M F Y I', \rOVSANTO CIIEMICAI. COMPANY]
Thiazolethiols and their Derivatives BY JOHN J. D'XMICO R~cr.:rvenJ 1 . i . ~25, 1952
5-Carbomethoxy-4-methyl-2-thiazolethiol, 5-carbethory-4-methyl-2-thiazolethiol and Z-mercapto-4-methyl-5-thiazolyl methyl ketone have been prepared. The corresponding disulfides, zinc salts and sulfenamides were also synthesized. Ail unexpected reaction encouutered wits the decarboxylatioii of 2-inercapto-4-methyl-5-thiazolecarbosylic acid i o givr 2j~utylinrrcapto)-l-tiiethylthiazolewhen treated with butyl alcohol under acidic coiiditioiis. CH ' ,C--:C€f Thiazolethiols and their derivatives containing I 1 t C'O. t HzO substituents, other than hydrocarbon radicals, ill N S the 5-position have been prepared only in a limited \C/ number of examples. 5-Carbethoxy-4-methyl-2-thiS(CH?)aCH? a ~ o l e t h i o l l(11) ~ * ~has been prepared by the reaction 1'111 of ethyl a-chloroacetoacetate with ammonium dithiocarbamate. Saponification of I1 gave ?-mer- This same product VI11 was obtained by the recapto-4-methyl-5-thiazolecarboxylicacidla (IV). action of n-butyl bromide with sodiutn salt of 4-4mmonium dithiocarbamate reacted with inethyl-2-thiazolethiol.
methyl a-chloroacetoacetate and 3-chloro-2,4-penThe thiazvlethiols I, I1 and 111 reacted with 30yo tanedione to fomi 5-carbomethoxy-4-methyl-2-thia-aqueous solution of ammonium persulfate to form zolethiol (I) and 2-mercapto-4-methyl-5-thiazolyl 2,2'-dithiobis- (5-carbomethoxy -4-methylthiazole) methyl ketone (III), respectively. Saponifica- (V), 2,2'-dithiobis-(6-carbethoxy-4-methylthiaz~le) tion of I gave IV. Reaction of I V with n-butyl (VI) and 2,2'-dithiobis-(5-acetyl-4-methylthiazole) alcohol did not yield the expected product, S-carbo- (VII),respectively. The zinc salts of the thiazolethiols IX, X and butoxy-4-methyl-2-thiazolethiol,but instead 2(butylmercapto)-4-methylthiazole(VIII) was ob- XI were prepared by the reaction of an aqueous solution of the sodium salts of I, I1 and I11 with tained. The reaction may be represented as zinc chloride solution. CH,C=CCOOH The thiazolesulfenamides XII, X I I I , XIV, XV, + CHa(CH2)qOH H+ 1 1 XVI, XVII, XVIII, XIX, XX, XXI and XXII -+ s s were prepared by the oxidative condensation of a \C/ piimary or secondary amine with I, 11, 111 and IV. SH The thiazolesulfenamides are in general rather IT' unstable compounds which decompose upon standing to the disulfide and ammonium thiazolyl (1) (a) A Miolati, Gone. c h i m 1 l n l . , 2 3 1 ,575 ( 1 8 9 3 ) . 11,) T. C . I.evi, triercaptide. The stability of the thiazolesulfenibid. 61, 719 (1931).
T I I I A Z O L E T H I O L S AND T H E I R
DERIVATIVES
103
TABLE I THIAZOLETHIOLS CHaC====CCOR
L A \C/ SH
Yield, % crude
R
hT0,
M.p., Obtained
ec.
Reported
Empirical formula
Calcd.
OCHa 73.4 179-180" .. CgH7IYO& OCzHj 75.0 151-152" 15O'eb C7Hg?YTO& Ill CH, 74.4 21O-21lb .. CaHiSOSn Rrcrystallizatioii from benzene. * Recrystallization from ethyl alcohol. I I1
N, %
7.40 6.89 8 .O W
Found
Calcd.
7.45 6.92 8.00
33.88 31.54 37.01
s, 70
Found
33.70 31.30 37.30
ti
TABLE 11
R
Xll.
Yield, % crude
y.p., C."
OCHs 94.5 88-89 1'1 OCzHj 98.0 120-121 99.0 92-93 VI1 CHs Recrystallization from ethyl alcohol. \.
Empirical formula
Calcd. Mol. wt. Found
Calcd.N, %Found
CIUHI?S,O,SI 376.5 374.9 C I ~ H I ~ S ~ O ~404.5 SI 403.5 c ~ ~ H ~ ~ N344.5 ~ o ~ s 342.0 ~
7.44 6.93 8.13
7.50 6.81 8.09
Calcd.
s, %
34.06 31.70 37.23
Found
34.30 31.68 37.22
TABLE I11 ZINC SALTS OF THIAZOLETHIOL NO.
R
Yield, % crude
R.I.p., " C .
I>:
OCH, OCzH6 CHs
95.0 99.0 76.0
123-133 104-110 147-155
S XI
Empirical formula
N,%
Calcd.
s % Found
Found
Calcd.
5.96 6.34 CllH12N204S4Zn 5.90 C I ~ H I & \ ' ~ O ~ ~ 5.96 &I C I Z H ~ ~ N ~ O ~ 6.84 S ~ Z ~ 6.61
29.02 27.29 31.29
29.20 27.99 31.27
Zn, % Calcd. Found
14.79 13.91 15.95
14.80 13.91 16.16
dropwise 238 ml. (0.44 mole) of a 30% aqueous solution of ammonium persulfate over a 30-minute period a t 25-30". After stirring for two hours longer, the precipitate was filtered and dried a t 50". The data are summarized in Table 11. Z-(Butylmercapto)-4-methylthiazole (VIII). Procedure A,-A solution containing 69 g. (0.39 mole) of IV, 290 g. (3.9 moles) of n-butyl alcohol and 5 g. of concd. sulfuric acid Experimental was heated a t 115-116' for two days. The water, 6 ml., Alkyl a-Chloroacetoacetate and 3-Chloro-2,4-pentanediwas allowed to distil off as formed. The excess n-butyl one.-Methyl a-chloroacetoacetate, ethyl a-chloroaceto- alcohol was removed by distillation. Vacuum distillation acetate and 3-chloro-2,4-pentanedionewere obtained by re- of the residue through a four-foot Vigreux type column action of methyl acetoacetate, ethyl acetoacetate and 2,4- yielded an amber colored liquid (45 g., 61.6%), b.p. 83pentdlledione with sulfuryl chloride.3)4 84' (1 mm.), ~ W D1.5460. Thiazolethiols I , I1 and 111.-The reaction was carried out A n d . Calcd. for CsHi3NS2: H, 6.99; h',7.48;S, 34.24; in a manner similar to that described by Mathes.6 Alkyl a-chloroacetoacetate or 3-chloro-2,4-pentanedione mol. wt., 187.3. Found: H. 6.98; N, 7.37; S, 34.16; (1 mole) was added to a stirred solution containing 110 g. mol. wt., 188.0. Procedure B.-To a solution containing 163 g. (1.24 (1 mole) of ammonium dithiocarbamate in 990 g. of water. Immediately an exothermic reaction set in and a precipi- moles) of 4-methyl-2-thiazolethio1, 69.5 g. (1.24 moles) of tate formed. The reaction mixture was stirred for eight potassium hydroxide and 800 ml. of ethyl alcohol, 171 g. hours and allowed to stand for an additional eight hours. (1.24 moles) of n-butyl bromide was added dropwise with The precipitate was filtered, washed with water until the agitation. The reaction mixture was heated under reflux washings were neutral to litmus and dried a t 50'. The data for three hours and was filtered to remove potassium bromide. The ethvl alcohol was removed bv evaDoration and are summarized in Table I . distillation of the residue yielded an amber cblored liquid 2-Mercapto-4-methyl-5-thiazolecarboxylic Acid (IV).A solution containing 1 mole of either I or 11, 320 g. (2 (106 g., 45.6%), b.p. B-84' (1 mm.), nz6D 1.5464. moles) of 25% aqueous sodium hydroxide solution and 800 Anal. Calcd. for C ~ H L ~ N SN, ? : 7.48; S, 34.24. Found: ml. of water was stirred a t 60-70" for two hours. ' After N,7.51; S, 33.99. cooling to 15", the solution was made acidic with concd. hyZinc Salts of the Thiazoles IX, X and XI.-To a solution drochloric acid, the precipitate was filtered, washed with of 0.40 mole of either I , I1 or I11 in'160 g. (0.40 mole) of water until free of acid, and dried a t 50". The product, a 10% aqueous sodium hydroxide and 800 ml. of water, was light yellow solid, m.p. 200-203", wds obtained in 79-83% with agitation, a solution containing 27.4 g. (0.20 yield. After recrystallization from benzene, it melted a t added, mole) of zinc chloride in 1160 ml. of water. The reaction 211-212" (reported m . p . 211-212°ia). mixture was stirred for one hour, the resulting precipitate Anal. Calcd. for CjHaSOzS..: N, 7.99; S, 36.59. filtered, washed with water until the washings were neutral Found: N , 8.21; S, 36.10. to litmus and dried a t 50'. The data are summarized in Table 111. Disulfides V, VI and VII1.-To an agitated suspension of Thiazolesulfenamides XII, XIII, XIV, XV, XVI, XVII, 0.40 mole of either I , I1 or I11 in 500 ml. of water was added XVIII, XIX, XX, XXI and XXII. Procedure A . XVIII, (2) All melting points were taken upon a Fisher-Johns block and are XIX, XX, XXI, and XXI1.-This reaction was carried out in a uncorrected. manner similar to that described by Coopera except with (3) E. R . Buchman and E. M. Richardson, THIS J O U R N A L , 61, 891 modification as shown below. To a cooled aqueous solution (1439). containing 0.25 mole of 111 or I V , 170 g. of water and 40 g
amide was found to depend upon the nature of the amine from which it was derived. The thiazolesulfenamides prepared from morpholine or cyclohexylamine were found to be more stable under ordinary conditions.
(4) E. R . Buchman and E. M. Richardson, ibid.. 67, 395 (1946). ( 5 ) R . A. Mathes. U. S . Patent 2,186,421.
(6) R H. Cooper, U S Patent 2,339,002,
.
104
S O
R'
XI1
CIHsSO"
XI11 XIV
CGHIINH (CH3)pCHXH ( C2H6)2N (CH3)sCHSH C4H,xOa
SV SVI XVII
SX x iI
CaHiiSH (CPH6)PN (CH3)zCHSH CdHsSO"
XSII
CdHaNO"
XVIII SIX
Morpholinyl
J. D'AMICO
JOHN
Yield, ('L Procedure crude
R 1) B €3
13
H R
c A A A A 13 A
Mole ratio amine t u thiazulr
M.p, oc.
123-124 133- 124" 55-57
38.0 78.5
1O:l 1.1.1
(i5.5
1O:l
49.1 54.5 48.0 66.0 76.0
1O:l
57-5X
1O:l 10:l 10: 1
69.8 -11.0
4:1 1:l 4:1 3 :1
:1M Oil 53-54 53-54 114-115 Oil 5iJ -52 L lfi-117
69.5 8ti.7
.
,
.
t55,(l 10:1 12.3 3:l Recrystallization from ethyl alcohol.
(0.25 mole) of 25% aqueous sodium hydroxide solution, 1 mole of amine was added with agitation at such a rate that the reaction mixture did not exceed a temperature of 27'. The mixture was cooled to 13' and 42 ml. of 25% sulfuric acid added dropwise a t 13-15' in 20 minutes. To this mixture, a t 13-20", was added, drop by drop, with stirring in two hours, 170 ml. (15 g./100 ml.) of aqueous sodium hypochlorite solution. The excess sodium hypochlorite was destroyed by the addition of l g. of sodium sulfite. For XVIII, X X I and X X I I the reaction mixture was cooled to lo', the precipitate was filtered, washed with water until free of chloride and dried a t room temperature. For X I X and X X , the reaction mixture was extracted with 500 ml. of ethyl ether, the ether extract washed with water until the washings were neutral to litmus, dried over sodium sulfate and the ether removed in vucuo. Procedure B. XII, XIII, XIV, XV, XVI, XVII and XXI To an aqueous solution containing 0.12 mole of either I , I1 or 111, 9.6 g. (0.24 mole) of sodium hydroxide in 200 ml. of water and 1.2 moles of the amine, was added, drop by drop, with stirring in 2.5 hours, 30.6 g. of iodine dissolved in 400 ml. of water containing 40 g. of potassium iodide. For all thiazolesulfenamides except XI11 and XVI, the precipitate was filtered, washed with water until free from alkali, ant1 air-dried a t room temperature. For X I I I and XVI, the reaction mixture was extracted with 500 ml, of ethyl ether, the ether extract washed with water until washings were neutral to litmus, dried over sodium sulfate and and ether removed in vucuo. Procedure C . XVII.-To a solution containing 39 g (0.096 mole) of VI and 1200 ml. of heptane a t 50°, 19.2 g. (0.22 mole) of morpholine was added. The reaction mix-
Ilti-117
*s,j-.57
N, % Calcd. Found
10.21 10.21 9.78 11.37 10,7fj
10.00 10.37 9.89 11 . LiO 1 1, 00
, . .
...
9.71 9.71 10.36 11.46 12.16 10.84 10.84 10.76
9.77 9.70 10.39 11.52 11.97 11.08 11.10 10.84
s, %
Calcd.
Found
24.38 ... 22.39 26.03 24.63 24.63 22.23
23.50
... 22.62 25.78 24.49 24.10 22.49
...
...
23.72 26.24 27.81 24.82 24.82 24.63
23.27 26.31 27.72 24.47 24.71 24.75
ture was heated a t 50' for one hour. After cooling to 25', the morpholine salt of 11 was recovered by filtration. The filtrate was successively washed with 2% aqueous sodium hydroxide solution and water until the washings were neutral to litmus and the heptane removed in vucuo at 35-40'. After cooling the residue to lo", a precipitate formed which was filtered, washed with water arid airdried a t room temperature. Procedure D. XI.-To an aqueous slurry containing 50 g. (0.26 mole) of I, 150 g. of water and 24.8 g. (0.29 mole) of morpholine a t 50-52', was added, drop by drop, with stirring in 50 minutes, 160 ml. (14.6 g./100 ml.) of aqueous sodium hypochlorite solution. After cooling to l o o , the 'precipitate was filtered, washed with water until free of chloride and air-dried at room temperature. The product, a white solid, m.p. 100-105', was obtained in 78.5% yield. A f t y recrystallization from ethyl alcohol, it melted a t 123124 . The data for thiazolesulfenamides are summarized in Table IV.
Acknowledgment.-The writer wishes to acknowledge his indebtedness to Messrs. M. W. Harman, R. H. Cooper and R. 0. Zerbe for assistance rendered during the course of this investigation. Grateful acknowledgment is also made for the analyses rendered by Mr. Edward Null and to Monsanto Chemical Company for permission to publish this work. SITRO, W E S VIRGINIA ~
