March, 1945
4-METHYLTHIAZOLE
ANALOGS
395
TABLE I PYRIDINE DERIVATIVES -B. 2-Substituent B-Dimethylaminoethylamino8-Diet hylaminoethylaminoy-Aminopropylamino-
p.,M. p., OC., "C. Mm. or 105 4 1.5320 112-134 4 128 2 1.5750
y-(2-Pyridy1amino)-propylamino-
220-225
1
r-Aminohexylami no-
1 3 3 1
7-Diethylaminopropylaminor-Di-n-hutylaminopropylamino7-Piperidinopropylamino-
147-148 162 205-220 185-198 105-107 144-150 135
y-Morpholinopropylamina
164-156
2
55-58
r-Morpholinopropylamino-5-bromo-
182-185 139-144
1 1
76-77 1.5455
186-192 185-200
1 2
. ....
165-168 138-142 148-152 170-171 140-142
2.5 3 2 2
~-(2-Pyridylamino)-hexylamino-
b MorpholinobutylaminoDi-( y-pipddinopropy1)amino-
p- Diethylaminophenylaminop- Methoxyphenylaminoa-Methyl- r-morpholinopropylarnino=-Methyl- y-piperidinopropylamino8- Piperidinobutylamino7- (8-Morpholinoethylamino)-propylamina
y-(B-Diethylaminoethoxy)-propylamino-
0.8 2 0.5
Derivative M. p., OC. 78.5" 223-224g 51' 170-1718 20.7' 204.568.Zd 205.0' 1 1 3 . 6 1 1 4 . 0 33.8* 218' 9.7d 28' 166166' 66.5' 149-149.7 31' 222' 16' 1.5309 40b 163.5-164' 1.5087 26' 149-150' 1.5505 48' 168.5-169'
1.5337
.......
84
1
45-47
. . .. . 1.5351 1.5525* 1.5185
Yield,
%
48' 74 = 350 51.6' 28b 92.5' 48' 40' 42" 40b
%-
Formula CpHiaNvPHCl CirHaNv2HCl CkHiaNr3p.o.'
-Analyses, Calcd. C1,29.79 C1,26.65 N , 20.03
Found 29.78 26.62 20.28
CiaH~aNt
N, 24.50
24.35
CirHisNa.3p. a.'
N , 19.17
19.37
CiaHx~Nc
N , 20.71
20.66
CirHxiNa CisHaNa4p.a.' CiaHxiNvZHCI
N , 20.26 20.03 N, 17.28 17.11 N , 14.37 14.28 CL24.26 24.19 N, 18.98 18.82
220'
CixHisNaO
170-171' 191-192'
CitHnNaOBr N, 13.99 14.10 CnHxiNaO.3 p. a,' N, 18.21 18.33
167.5-168' 231gdec. 165-166' 165-166' 4Sb 145-146.5' 63.5d 14s-149' 30' 178' 68.5' 111-112'
CxiHasNc3p.a.' CiaHoNv2HCl CirHixNsO CiaHiiNaO CicHnNa.2HCl CicHxrN1.2HCl Ci4HaNcO.3HCI CicHisNaO
N, 17.91
N, 13.36 N , 13.97
N, 17.85 N, 13.71
N, 13.71 N, 14.98 N. 16.71
18.11 13.21 13.76 17.84 13.55 13.78 14.90 16.68
Method I. *Method 11. Equal molar amounts of reactants were used. Method 11. One molar excess of aliphatic diamine used. d Synthesized according to Method 11. Two molar excess of aliphatic diamine used. a HyThis material solidified Picrate derivative. 9 Yield based on the amount of aliphatic diamine used. drochloride. The abbreviation p. a. is used for picric acid, CsHzNaO,. on standing to a white, low melting solid. a
niixture was then warmed with 20 g. of powdered sodium hydroxide in pyridine, the mixture filtered, and the filtrate distilled throueh a Claisen flask. After the uvridine and hexamethylenidiamine had distilled over, 38.4g. (66.5%) of 2-((--aminohexylamino)-pyridine (b. p. 162-165 a t 3 mm.) and 6.8 g. (16%) of 1,6-di-(2-pyridylamino)-hexane (b. D. 195-200 a t 3 mm.) were collected. Both products solidified on cooling, t h e first to a low melting solid and the second, on crystallization from methanol, gave clusters of needles melting a t 149-149.7". Both gave crystalline picrates, the first melting a t 165-166' and the second at
222'. The laotter compound gave a hydrochloride which melted at 216 ; Sharp6 reported 216-218".
summary Twenty basically-substituted 2-aminoPYridiIle derivatives have been synthesized from 2-bromopyridine and an ami&&ylamine or from 2. minopyridine and an aminoalel halide. STATE COLLEGE, PA. RECEIVEDNOVEMBER 4, 1944
[CONTRIBUTION FROM THE GATESAND CRELLIN LABORATORIES OF CHEMISTRY, CALIFORNIA
INSTITUTE OF
No.9941
TECHNOLOGY,
Thiamin Analogs. 11. 4-Methylthiazole Analogs's2 BY EDWINR. BUCHMAN AND EDWIN M. RICHARDSON in which R = -CH,CHzOH. The present paper reports the synthesis and antineuritic properties of the seven vitamin analogs CH8 R (a) R = - H (Ia) to (Ig). These analogs were preN=C-NHn. HBr I I (b) = -CzHs -CH=CH2 pared by condensing the appropriate I / c=c (c) 1 (d) = -CHOHCHr CH8-C C-CH-N/ thiazole with a bromopyrimidine de-\cH--s (e) It I1 = -CHZCH~CH~OH rivative, following the procedure used N---CH = -CH*OH -cH2CHoHC''s Br (f) by Williams and Clinea in their synI (g) thesis of the vitamin. Compound (Ia) has previously been reported on by Bergel and ( I ) Paper X X I I io the R. K. Williams series. ( 2 ) The data relating to analogs ( I a ) - ( l f ) were presented before who obtained it by another method, the the Organic Di\,ision of the American Chemical Society a t the Dallas (a) Williains and Cline, THISJ O I I K N A L , 68, 1304 (19;3(;); Cline, The thiamin (vitamin B1) molecule may be represented by formula (I)
meeting, April 1938. Analog (IP) prepared hy Dr. Herbert ?,argent is incliided in lhr nresrnt paper.
Williams and Finkelatein, ibrd., 6 9 , 1032 (1937). (4) Herpel atid T o d d , J , ( ' h r n i . So,.., 1504 ( 1 ! 0 7 ) .
EDWIPU' H. HIXXMAN
396
AND
preparation of (1e)j and of ( 1 ~ has ) ~ been disclosed6" in a number of patents, and in addition physiological data"" 011 ( , I c ) ~ and on (IgI7 have been published. 4-Methylthiazole was obtained by a iuethod given in the literature8; for the preparation of 4-1nethyl-.l-hydroxyniethylthiazole, see the following paper.!' The synthesis of the remaining thiazole interiiietliatcs was carried out as indicated ( i n the acconipanying chart; wherever the synthetic route was Iiot entirely iree of a.mhiguities the constitution i d the final product was iiidependently confirnietl (see Experirnentd) ,
N(CH43 Th-CHZCH2Br ---+ 1VI AgOH T1i-CHzCH2X(CH3)rBr---+ Th-CII=-CH2 heat YII V I I1 HCSSH2 CH~COCHCICOCHP--------+ IX (iso-C3H~0)3AI Th-COCH36a Th-CHOHCH3" x SI HCSSHQ CHrCOCHBr(CH2)aOHl 3 & Th-CH2CHzC1I2OII1' XI1 XI11 SaOCEI CHiCOCHzCOOCH, CHSCH-CHZ
?'h-CH?CH20H11
HBr
___f
-
1 1 0 ) 'fh- - =
1
H C g C, K
-- C I i s
EDWINill. RICHARDSON CHSCOCI-ICO I
Vol. 67
CH3COCClCO S02C12
>o -*
~H~CHCH~ XI1
I>-
CHzCHCH3
xv
Dilute HC1
HCSNH2 CHICOCHCICHZCHOHCHI------+ XVI Th-CHZCHOHCHa' XVI I
Xr. W. L. Sainpson of the Merck Institute for 'Therapeutic Research has tested the thiamin analogs for antineuritic activity by the rat curative method. l 6 None of the substances exhibited vitamin R i potency in doses up to 500 y. Thus e~7eria sinall change in the nature of the thiazole'ittached group K results in complete inactivity." Experimental' The Synthesis of Thiazoles19 from Crude Thioforme been made of this method amide.20-Extensive u ~ has ! 1.5) 'This coinpourid I > incnttont.il i i t the patent literature, English Patent 4.56.735 IC. A , , 31, 2 2 3 2 ( l 0 3 7 ) , Chem. Z m l r . , 108, I, 2810 I:J:371]; its preparation has not hcen described. ' lli) 'l'he negatile reiiiltsxre in agreement with previousreports 0x1 it,.* l i d ' a n d i r d ) , s * l:or ( 1 ~ Schultzi ) reported antineuritic 1) j t e n r y with pigeons; thc l i s h ~tlie d ) , greater part oi the experiments described here h a s t,wn re;)eated in this Laboratory by Drs. H. Sargent and h l . J , Schlatter, supplementing observations due t o these investigat o r , . h , v c ! W C I L iuclndw1 in the present paper. I l ! l ) S c e ( d j 1Villst.itter .inti N'irth, H e r . , 42, 1008 (1WiJ); ( 1 ~ ) s ii.ii1, i , l ) Cerecedo and Tolpiu, THIS JOURNAL, 59, l(iti(l (1937), w ) Iii,rhntxn and Ilichardioil, i b l d , , 61,891 (1939); CFj btrvens and ( I : i - & ~ l ) , (g) liuchnlan. Ileinis uiid Sargent, !J41), ( h ) 'Torld, I3erael and Jacob, .I. (.lzrja? f i . t r i n x t o i i : i n i l SloKKridpe, i k i d , 4 4 3 (l9,3!+1. -norkers, I l c l u . C h i m . A d a , 20, 204 ( 1 9 x 7 ' 1 , (1940); 25, 362, 528 (19.42); ( k ) Ochiai and SOL.l a p u r r , 5 9 , 228, 4112 (1939) [C. .I., 94, liil 1 ' 1 4 0 ) I ; Hur.. 73, 28 (1030); i l i I'esina, .I. G c n . C'hevii. ( Y . 5. h I < . ) 9 , X o t (19:i!I) IC, A , , 34, 4 2 1 1( I W U ) ] ; (m)Y; ( i i ) ' ~ ; niimcroiis r,.ct.iit 1 ~ , ~ t r n i . . 1111 the b,iris of c~pel-icnre in this 1,ahorntory the m t t l i o ~ tln a y ilc rccuinrncndcd almwt uithout reserve for the prepa") ,sition, cotuparc however: i !l!llL!j; ( p ) Etlenme)-er 2 ) , t h e relictionY betv.ec.n 2 O K 2, :~-dibrvmoliroyniini ','tL>riel,Iici.. 4 9 , I Ii:, (lilliij. A l t h n u c h the p u r i t y o f t h e . t i n i t l ( u i r d u ~ i d ~ ~ ~ : l iriflucncrs ~ t ~ ~ l l y t h e yichl oi thiazole tlii.: i.Lctur 11 ' ? been in\ e \ i i g n t r d thoroughly,
March, 1945
4-METHYLTHIAZOLE
ANALOGS
397
in this Laboratory. Because of the unstable nature of mm.), 130-132' (745 mm.), and 8 g. of unchanged a-chlorothiofonnamide, it is essential that its reaction with a n a-ethylacetoacetic ester. a-halogen ketone be carried o u t . at the lowest feasible 4-Methyl-5-ethylthiazole (IV) was made from (111) temperature. Most a-chloro ketones react smoothly a t prepared by each of the above methods; the products obroom temperature; in the case of a-bromo ketones and of tained were identical in all respects. Chlorinated (11) especially reactive a-chloro ketones, it was found advisable (26.5 9.) was condensed with 20 g. of thioformamide and to bring the reactants together a t 0" or below and t o pro- 25 cc. of alcohol. Refractionation of the resultine 11 e. of vide for external cooling since the reaction may be strongly crude thiazole gave 8.8g. (29%), b. p. 78-79' (25km.5, b. exothermic. Unless otherwise specified the a-halogen p. 169.5-170' (745 mm.), dz6, 1.042. ketone was mixed a t 0" with 1.5 to 2 times the theoretical Anal. Calcd. for C ~ H Q N S :C. 56.65: H. 7.13:. N.. of crude thioformaniide and a small amount of absolute 11.01. Found: C,56.57;-H,6.82; N, 11.14. . alcohol. The reaction mixture was allowed t o stand for The picrc$e was recrystallized from alcohol, m. p. periods up t o seven days in the ice box (omit in the case of 164.7-165.1 ; the methiodide from methanol-ether, m. p. less reactive halogen ketones), and then for periods up t o 130.5-131.5'. (IV) was also obtained from ThCH?; two weeks a t room temperature (reaction usually com- CHzCl.ll One gram of the latter was heated at 140-150 plete in three to four days). The product was then treated in a sealed tube for eight hours with 10 cc. of 577, aqueous with excess ti N hydrochloric acid and washed with ether hydriodic acid. The resulting solution was then stirred to remove non-basic material. The ether extract rarely a t 0" while 6 g. of zinc dust and 7 cc. additional of hydricontained any significant amount of unreacted a-halogen odic acid were added over twenty-four hours. The mixketone. However, in order to recover from it small ture was made alkaline and steam distilled; extraction of amounts of thiazole, it was extracted with small portions the distillate with ethcr gave a small amount of base from of aqueous hydrochloric acid and the hydrochloric acid which picrate and methiodide were prepared. These were extracts combined with the main reaction product. This shown (niised m. P . ~ to ~ )be identical with material made latter was made alkaline by the addition of a large excess from (111). of concentrated aqueous alkali (alkali carbonate was used 4-Methyl-5-( p-bromoethy1)-thiazole (VI).-Ten grams i n the case of thiazole esters and other thiazoles altered by of vitamin thiazole11 (V)was cautiously mixed with 100 caustic alkali). Usually the thiazole separated as an oil; cc. of hydrobromic acid (aqueous solution saturated at solid alkali hydroxide or alkali carbonate was added to room temperature), the mixture p@d in a sealed tube saturation and the base extracted with ether. Since most and heated for twelve hours a t 100 . The contents of the thiazoles readily give a precipitatez1 when treated with tube were evaporated on a steam-bath a t reduced pressure ethereal picric acid, in the case of these substances the ex- t o a small volume, cooled and diluted with water. Extraction was continued until a negative test was obtained cess potassium carbonate was added and the liberated base with this reagent. The ether solution was dried over taken up in ether, dried over sodium sulfate and distilled sodium sulfate or caustic alkali (the latter can be used oniy from a bath a t below 110°,z6yield 11.3 g. (78%), b. p . in case of simple alkyl thiazoles; in the case of hydroxy- 87-88' (2 m n ~ . ) . ~ ~ alkyl thiazoles, there is a certain amount of interaction) Anal. Calcd. for CaHsBrNS: C, 34.96; H, 3.91. and distilled. Final purification was effected by fraction- Found: C, 34.82; H, 4.13. ation, usually in VQCUO,or in special cases by conversion to The stable picrate was recrystallized from ethanol-water, a crystalline derivative and regeneration. m. p. 128.3-128.5'. (VI) has only a limited stability; 4-Methylthiazole was prepared8 from chloroacetone in after twelve hours at room temperature it had become 32y0 yield, b. p. (743 mm.) 132.1-132.4", dZ5,1.112, picrate, cloudy and on longer standing was entirely converted to m. p. 184.5°1gr*0 (analysis). a solid polymer.z8 3-Chloropentanone-2 (111)z z (a).-The chlorination of [ p-( 4-M ethylthiazol yl-5) -ethyl ]-trim ethylammonium 43 g. (0.5 mole) of methyl n-propyl ketone (11) (b. p. 101distilled (VI) (11.3 8.) was Bromide (VII).-Freshly 102') diluted with 50 cc. of c. P. benzene was accomplished mixed with 50 cc. of trimethylamine solution (367' in benby adding 63 g. (0.5 mole) of sulfuryl chloride over a zene) and heated in a sealed tube for twelve hours a t 100". twenty-minute period while excluding moisture, stirring The crystalline product was filtered off, washed with ether and keeping the temperature a t 20" by external cooling. and dried, yield 11.0 g. (76%), m. p. 228.0-228.5" from The reaction mixture was fractionated in vacuo, 26.5 g. absolute ethanol. (447; yield) of (111) boiling a t 62-66' (56 mm.) being obA n d . Calcd. for C O H I ~ B ~ N C, ~ S :40.70; H, 6.46; tained. (b) Twenty-five grams of a-chloro-a-ethylacetoacetic N,10 56. Found: C,40.99; H,6.69; N,10.60. The corresponding chloride was made from ThCHzester (b. p. (2 mm.) 58-60', obtained in 86% yield by chlorinationz3 of ethyl a-ethylacetoacetate in benzene CHzC1ll; after twenty-four hours of heating a t 100" with solution with sulfuryl chloride) was heated under reflux 36% trimethylamine solution the yield of product was from a bath a t 100' with 80 cc. of glacial acetic acid and 20 60% (unreacted chlorothiazole was recovered). The cc. of concentrated c. P. hydrochloric acidz4; gas was given quaternary chloride is an extremely hygroscopic crystalline solid, easily soluble in water and alcohol. off slowly. After twenty hours of heating, the reaction 4-Methyl-5-vinylthiazole (VIII).-Ten grams of (VII) mixture was cooled, neutralized with alkali and extracted with ether. Fractionation of the ether extract gave 1.6 g. (chloride could also be used) was dissolved in 30 cc. of water, silver oxide from 10 g. of silver nitrate was added of (111), the major portion of which boiled a t 61-62" (56 and the suspension shaken for one hour. After filtering and washiiig with a little water, the filtrate (ca. 70 cc.) was (21) Four exceptions of similar structure have been noted: treated with 6 g. of potassium hydroxide and the resulting ThWOOCHa, ThCOOCzHs, ThCHO and ThCOCHa. The picrates solution refluxed for thirty minutes.2Q The decomposition of these compounds arc quite appreciably soluble in ether and crystdllize from the solution only on strong cooling; TbCOOCHa picrate, m. p. 107.6-107.8' from isopropyl ether. (22) (a) Conrad, A ? Z I &186, . , 211 (1877); (b) Vladesco, Bull. soc. c h i m . , [3] 6, 832 (1891); (c) Korschun, ibid., [4] 3, 595 (1908), the b. p. 63' (95 mm.) reported is in error. (23) Compare (a) Forster and Newman, J. Chcm. SOC.,97, 1365 (1910), the b. p. (0.3 mm.) 64' reported is in error; (b) Macbeth, i b i d . , 123. 1125 (1923). (21) Cf. ref. 22a; under these conditions rr-ethylacetoacetic ester is readily converted t o (11). That a,a.disubstituted acetoacetic, esters ofler greater resistance t o hydrolysis has been recoynized; see for in+t;\nce. Hiufson nnif Haii.ier. T m s J O T I R N A ~ . . 63, 3163 ( 1 U 1 1 )
(25) The picrates of (IV) and of (V) give only a very small m. p. depression when mixed. (26) Higher temperatures resulted in extensive polymerization. (27) Ref. 14 and also German Patent 702,831 (1941) (Andersag and Westphal inventors) issued to I. G. Farhenindustrie, A . G . describe the preparation of this compound by another method, b. p. Y j O ( 3 mm.), picrate m. p. 129'. (28) ThCHzCHsCI, previoualy reported11 to be stable, is in fact much more stable than ( V I ) . On long standing, however, it also polymerizes and some samples have been observed t o pass t o a solid. (29) Aqueous solutions of the quaternary base are unstable; a n attempt t o evaporate such a soltition prior t o ~lwompositionr v < t i l t e d in a milch poorer yield
EDWINR. BUCHMAN AND EDWIN hl. RICHARDSON
398
Vol. 67
took place smoothly; (VIII) separated as a n oil which ( 2 3 excess) of bromine which was added slowly with was isolated by extracting with ether and distilling at re- stlrring over a period of one and one-half hours while the duced pressure, b. p. 76-78" (21 mm.), yield 2.6 g. (557,), a second phase temperature was maintained at 5-10'; dz2d 1.090. appeared when about half the bromine had been added. Anal. Calcd. for CsH7NS: C , 57.56; H, 5.64; N, The crude product (XII) was isolated by extraction with ether, the extracts were dried over sodium sulfate and sol11.19. Found: C, 57.23; H , 5.23; N,10.71. The base on standing a t room temperature was soon con- vent was removed at 30 mm. and temperatures below verted to a thick viscous polymer (cf. styrene). The pic,- 50'; yield 52.2 g. of only slightly colored oil. This material was cooled to -10' and mixed with 25 g. rate was recrystallized from ethanol, m. p. 162.2-162.7 , of thioformamide and !O cc. of methanol which also had not appreciably altered on standing. 4-Methyl-5-acetylthiazole (X).6a--Sulfuryl chloride (62.5 been cooled to -10 . The condensation proceeded smoothly and yielded 23.3 g. of distilled thiazole (48% g. = 0.5 mole) was added slowly a t room temperature with from the dihydropyrane). The base was converted to the stirring over a period of four hours to 50 g. (0.5 mole) of acetylacetone (b. p. 69-70' (99 mni.)) mixed with 50 cc. picrate by addition to the theoretical amount of picric of c . P. benzene. Fractionation of the product yielded acid in ethyl acetate, yield 49.5 g. (Myo),m. p. 105.6106.2' from alcohol, analysis for ClrHuN!OaS. 53 g. (79%)30 of chloroacetylacetone ( I X ) , b . p. 56-59' A careful search failed to disclose any significant amount (28 mm.). Twenty-five grams of (IX) reacted with 17 g. of thio- of isomeric picrate in the mother liquors (in one experiment formamide; 15.3 g. (5555) of product was obtained, the a few crystals of material m. p. 140-141' were obtained major portion of which boiled atO96-97' (9 xnm.) and from mother liquors; the amount did not suffice for purificatioii) ; thus the moriobromination of acetobutyl alcohol crystallized on standing, m. p. 27.5 Anal. Calcd. for CsH7NOS: C, 51.04; €1, 5.00; K, gives essentially one product. The free base was regenerated from the picrate by treating with aqueous hydro9.92. Found: C,51.26; H, 4.95; N, 10.08. (X)has a characteristic odor, picrate,21 m. p. 107.6- chloric acid, removing picric acid with ethyl acetate and liberating from the hydrochloride with alkali as usual, 108.0' from ethyl acetate-ether. yield sS%, b. p. 122-124" (2 mm.), d", 1.150. 4-Methyl-5-(a-h~droxeth~l) -thiazole (XI).ea sJ1-Five Anal. Calcd. for C ~ H I I N O S :C, 53.47; H, 7.05; N, grams of (X) togelher with-8.5 g. of aluminum isopropoxide and 110 cc. of absolute isopropyl alcohol were in- 8.91. Found: C,53.28; H, 7.04; N,8.90. ( X I I I ) (1.4 9.) was treated with 14 cc. of concentrated troduced into a flask equipped with fractionating column nitric acid and the mixture heated for six and one-half and distilled at such a rate (bath temperature 120-140') that the acetone formed during the reaction was removed. hours at 40'. After evaporation in vacuo, the residue After four hours of heating the distillate gave no further was dissolved in water and sulfate ion quantitatively retest for acetone. The material in the flask was treated moved by addition of a n equivalent amount of barium with a small amount of water and solid potassium hydrox- nitrate solution. The resulting solution was again evapide and repeatedly extracted with ether. The combined orated. taken up in a small volume of dilute potassium extracts were dried with sodium sulfate and distilled in hydroxide solution and concentrated hydrochloric acid vacuo yielding 3.9 g. (78%) of product boiling for the most added cautiously. j3-(4-Methylthiazolyl-5)-propionicacid (0.75 g.) precipitated, was washed with water and repart at 103-104" (2 mm.). Anal. Calcd. for CcHoNOS: C, 50.32; H, 6.34; N, crystallized from methanol using Norite, m. p. 179.0179.5'. 9.78. Found: C, 50.85; H , 6 . 1 7 ; N.9.51. Anal. Calcd. for C,HoNO&S: C, 49.10; H , 5.30; N, (XI) is rt quite viscous oil d*54 1.172, picrate, ni. p. 142.18 18 Found: C,49.04; H, 5.65; N.8.49. 143.1" from alcohol. A portion of the acid was methylated with ethereal diPentanol-4-0ne-2~~ was brominated in aqueous solution azorriethane and the product sublimed in a small still. with one molecular equivalent of bromine and the product extracted with ether. After drying the extract and re- The methyl ester (oily), picrate, m. p. 120-121", on heating moving solvent i?~W U C Z L O the , crude bromide was condensed for fourteen hours in a sealed tube a t 120-130" with satuwith thioformamide to give a small yield of thiazole which rated rncthyl alcoholic ammonia, gave the corresponding was converted t o the picrate, m. p. 117.2-117.7°33 after amide, in. p. 97-98ON from dioxane-ether. a-Aceto-7-valerolactone (XIV)."--To a solution of 69 g. recrystallization from ethanol and from ethyl acetate. A n a l . Calcd. for C12Hl~iYaOaS: C, 38.71; H, 3.25; (3 moles) of sodium in 1000 cc. of absolute methanol, 348 g. ( 3 moles) of methyl acetoacetate was first added, and Pi,15.05. Found: C, 38.91; H , 3.51; N,14.69. This picrate is presumably derived from 4-(&hydroxy- then over a period of seventy-five minutes 173 g. (3 moles) of propylene oxide (b. p. 33.5") slowly with stirring (icepropyl)-thiazole formed from a bromo ketone corisisting bath, anhydrous conditions). The temperature was (cf. broniiriationg of mainly of l-bromopen~anol-.l-on~-Z allowed to rise slowly to room temperature and after standketobutyl alcohol). ing for twelve hours the solvent was removed under water 4-Methyl-5-( 7-hydroxypropyl)-thiazole (XIII) .-5pump vacuum. The whit.e solid residue was dissolved in Methyl-1,2-dihydropyraneJ4(30 g., b. p. 106.3-106.4") was miscti with 150 cc. of water, to which a few drops of ice-water and the solution acidified with sulfuric acid at hydrobromic acid had been added, and stirred a t room 0" and extracted repeatedly with ether. The extracts temperature for one-half hour. A slightly exothermic re- after drying over sodium sulfate were fractionated in action took place and after fifteen minutes the organic vacm, b. p. 120-128" (15 mm.), yield 162.5 g. (38%); phase had disappeared. The resulting acetobutyl al- refractionated material boiled at 125" (15 mm.). Anal. Calcd. for CIH,OOJ: C, 59.14; H, 7.09. Found: cohol solutions was treated (compare ref. 13) with 50.0 g. c, 58.85; H, 7.33. (:lU) These coiiditionr arc apparently superior to those given in the a-Chloro-a-aceto-7-valerolactone (xv).-The above 1iter;iturc 162.5 g. of (XIV)was niised with 150 cc. of c. P. benzene
.
' j c
[,"$I) liediictioii of ( X ) w i t h aluminum amalgam
gave a small crgbtitlline suIj..tince :pinacol) aiid otller o i l y material boiling liichcr than the de5ired alcohol. ( 3 2 ) Clniaeu, B e y . , 25, ? I f , & (18!>2), A ~ J z .S06, , 324 (1899);
amoiaiit of
:I
picrate, m. p. 160.0-160.5°. ,t;iined; i t did not depress the n, p. when mixed with the picrntv r,f like properties obtainedYfrom crude ketobutyl alcohol. !I) l,ipi>, A n n . . 289, 187'(lSilSj. A solution containing acetobatyl alcohol may conveniently i x pr,'p r w l i , v lic,it ill; .-z n i v t h i I -I-c:irbethoxy-1.2-dihydropyranp
(I'erkin, .I. C h e m . S ~ J L61, , , 709 (1887)) with an equal volornr of 0.6 S hydrorliloric arid for une hour a t 1 0 0 O . (36: The preparaiion of this compound (m. p. Y 6 O ) b y another m e t h o d has been reported, r e f . 1 4 : Andersag and Westphal ( t o a'intlrrop
