May 5, 1958
220 1
CYCLOALKENO [d]THIAZOLIN-2-ONES
form solutions of these two dimorphic products were identical, Anal. Calcd. for C21HZ1KO4: C, 71.78; H, 6.02; N, 3.99. Found: C, 71.79; H, 5.90; N, 3.96 (S). 4-Carbethoxy-4-benzy1-1,5-diphenyl-Z ,3-pyrrolidinedione (Va).-An ethereal solution of 28.1 g. of crude ethyl eth~xalyldihydrocinnamate~~ and 15.0 g. (0.083 mole) of benzylideneaniline was treated as in the preceding experiments and thus afforded 10.1 g. (29.5%) of Va, m.p. 188.0-188.5", after recrystallization from absolute ethanol. Anal. Calcd. for C26HZJSOa:C, 75.53; H , 5.61; S, 3.39. Found: C, 75.53; H , 5.39 (G); S,3 32 (S).
Anal. Calcd. for CllH1003: C , 69.46; H , 5.30. Found: C, 69.42; H, 5.19 (G).
When run on a larger scale this procedure yielded less tractable material, as did decreasing the relative quantities of methanol. N o extensive attempts were made to improve it, however. Thermal Decomposition of 1,4,5-Triphenyl-2,3-pyrrolidinedione.-This substance was placed in a 50-1111. -$ flask connected to a gas buret, as for a Dumas nitrogen determination.8 The air vias displaced by carbon dioxide, and the flask was heated with a flame in such a manner that the gas evolution was moderate and constant. \Yhen gas 4-Substituted-l,5-diphenyl-2,3-pyrrolidinediones(4-Sub- evolution ceased, the apparatus was swept out with carbon stituted-l,5-diphenyl-3-hydroxy-A3-2-pyrrolinones)(111-VI). dioxide, all gases being collected over 50% potassium hydroxide solution. The residual gas from 1.0 g. of solid was -Two methods of preparation were used: A. Borsche's procedure" in which the appropriate a-ketoacid was warmed 65.4 ml. (739.4 mm., 25.5') (85%) and was identified by with benzylideneaniline in ethanol for a few minutes on the mass spectrometric analysis as carbon monoxide.26 The steam-bath. B . Refluxing the corresponding 4-carbeth- residue in the flask was purified by recrystallization from oxy-4-substituted intermediate (IIIa-Va) in methanol con- acetonitrile to give a product, m.p. 333-334"; Borschell had reported 338" (see text). An authentic sample of 2,3taining one equivalent of potassium hydroxide for six hours. melted a t the same temperaSubsequent acidification of the cooled solution afforded the diphenyl-4-hydroxyq~inoline'~ desired product, either as an immediate precipitate or upon ture and showed no depression in melting point upon admixture with the product of this reaction. The infrared evaporation under an air jet. Acetates were prepared by means of acetic anhydride and spectra were identical. An acetate was prepared by means of acetic anhydride sodium acetate," usually being precipitated by dilution with and sodium acetate. After recrystallization from ethanolwater. water it melted a t 149.5-150.5'. The "anils" (phenylamino derivatives) Rere prepared by refluxing the compounds with two equivalents of aniline Anal. Calcd. for C23H17XOz: C, 81.39; H, 5.05; E, for 2-10 min. After cooling the mixtures were diluted with 4.13. Found: C, 81.46; H, 4.97 (G); ru', 4.13 (S). absolute ethanol, whereupon the derivatives crystallized. Pertinent data are assembled in Table I. Thermal Decomposition of 4-Benzyl-l,5-diphenyl-2,3p-Benzylidene-a-ketobutyric Acid.-A procedure de- pyrro1idinedione.--A 0.5-g. sample was treated as in the scribed for another substancez5was adapted for this prepnrapreceding experiment. Less extensive decomposition was tion. By adding 4.6 g. (0.083 mole) of potassium hydroxachieved, but carbon monoxide was again shown to be ide in 10 ml. of absolute methanol to 5.6 g. (0.055 mole) evolved. The decomposition product was purified by reof a-ketobutyric acid (cf. footnote b , Table I for alternative crystallization from acetone-water, m.p. 262.0-262.5". preparations for this substance) and 5.83 g. (0.055 mole) of The infrared spectrum of this sample is almost identical benzaldehyde dissolved in 10 nil. of absolute methanol, with that of 2,4-diphenyl-4-hydroxyquinoline. there was obtained 6.9 g. (13%) of the potassium salt of the acid. When a saturated aqueous solution of this salt was A n d . Calcd. for CZZHI~NO:C, 84.86; H, 5.50; P;, acidified with 1.6 S hydrochloric acid, an oil separated. 4.50. Found: C, 85.02; H, 5.86; S , 4.52 (S). I t was taken up in ether, dried over magnesium sulfate and Conlpounds I11 and IV did not decompose when subjected recovered as a solid upon filtration and evaporation. Reto similar treatment. crystallization from benzene-petroleumo ether (90-100') afforded pure material, m.p. 107.5-108.5 . (24) W. Wislicenus and 51 JIunzesheimer, B e y , 31, 554 (1898) (25) E D Strecher and H F Ryder, THISJ O U R N A L , 74, 4392 1952).
[ C O X T R I B C I ' I O S F R O M THE
ANS ARBOR.MICH.
RESEARCH DEPARTMENT, CIB.4
Investigations in Heterocycles. BY
(26) Very kindly performed by Professor Richard B. Bernstein of this department.
1V.I
PHARMACEUTICAL PRODUCTS, 1 S C . j
Substituted Cycloalkeno [d]thiazolin-2-ones
GEORGE D E ~ T E V E N S ,A L I C E F. HOPKINSON, A f A R G A R E T A. C O N N E L L Y , DOROTHY C. SCHROEDER
PATRICIA O K E AND
RECEIVED NOVEMBER 19, 1957 The condensation of substituted a-halocycloalkanones with ethyl xanthamidate or ethyl N-methylxanthamidate has resulted in the formation of several new thiazolin-2-ones possessing significant analgetic properties when tested in laboratory animals. These compounds, all cycloalkeno[d]thiazolin-2-ones, are substituted in the 4- or 5-position of the alicyclic ring with a tertiary amino moiety either directly or through a methylene group. The chemistry of the intermediary compounds and the final products is discussed.
I n our general program of synthesizing com- pain in experimental animals suggesting analgesia. pounds of the thiazolin-2-one class for testing as analgetics, i t was found that 2,3,5,6-tetrahydro-3i--- N-CHa methyl-4-cyclopentathiazolin-2-one(I) and its six \/\s/c=o I v\S/C=" carbon analog, 2,3,4,5,6,7-hexahydrobenzothiazoI I1 lin-2-one2q3(11) raised noticeably the threshold of Substitutions on the hetero ring nitrogen other than (1) For part 111 of this series: G. deStevens and Angelina Halamandaris, THISJ O U R N A L , 79, 5710 (1967). methyl led to a diminution in activity concurrent (2) G. destevens, H. A. Luts and J. A. Schneider, ibid., 79, 1516 with an alteration of the toxicity factor. It was (1957). thus felt that a more favorable activity-toxicity (3) G. destevens, A. Frutchey, A. Halamandaris and H A. Luts, ratio might be obtained if alterations in structure ibid.. 79, 5263 (1957).
/I
'
(yTH
GEORGE DESTEVENS, A. F. HOPKINSOK, 11.A. CONNELLY, P. OKEAKD D. C. SCHROEDERVol. SO
2202
through substitution were made, not on the hetero minated viscous material. Dissolution of the ketone ring nitrogen, but rather on the alicyclic portion in glacial acetic containing from 20 to 4070 hydrogen of compounds I and 11. A facile approach to this bromide, however, shifted the equilibrium in favor sort of substitution was through the M a n n i ~ h ~of, ~monobromination resulting in 607, yield of dereaction. sired 2-bromo-5-piperidinomethylcyclopentanone The general sequence of reactions leading to the hydrobromide. Much to our surprise this subdesired product is listed in Scheme I. stance was quite stable, no pronounced decomposition occurring when stored a t 0" for a period of two SCHEME I weeks. The condensation of the 2-bromoketone XCsHio with ethyl xanthamidate proceeded a t the reflux I temperature of ethyl alcohol which served as a solCHz I .HBr vent. This result was unexpected in the light of our recent work3 in which a-chlorocyclopentanone condensed with ethyl xanthamidate only under forcing conditions as compared to the mild reaction conditions for the a-chlorocyclohexanoneethyl xanthamidate condensation. The explanation entertained for the difference in reactivity between these a-halogenated ketones was based on the apparent ease of dehydration of the transition state complex for the six-carbon ring intermediate VI as compared to the corresponding five-carbon ring complex VII. Thus, the cis elimination of water in VI1 appears to involve a higher activation IV v energy than the usually facile trans elimination as The over-all yield of V in the above three step exemplified by VI. It seems that in the present synthesis was 4070 of theoretical. Alarge number case, substitution of a piperidino methyl group a t of variations of the secondary amine in the initial position 4 of VI1 alters, through steric factors, the stage of the synthesis was made. However, regardless of the nature of the secondary amine or ketone used, each Mannich condensation was carried out in essentially the same manner. The ratio of alicyclic ketone secondary amine hydrochloride: 38% formaldehyde was 5:1:1, respectively, the excess ketone serving as a diluent. The reaction mixture was heated to the boiling point of conformations of hydroxyl and hydrogen atoms in the ketone or until reflux occurred. Usually a vigor- the molecule in such a way as to facilitate dehydraous reflux period followed which after having spent tion. itself, the reaction mixture was worked up. We The synthesis of thiazolin-2-one compounds in have found, as previously reported,6 that an ex- which the secondary amine was directly attached tensive reflux period only serves to decompose the to carbon 4 of the molecule was carried out in a Mannich base different manner (see Scheme 11). i'iCjHio
SCHEME I1 NR* I
G
i,l
Another interesting feature from a theoretical point of view was the replacement of cyclohexanone in our Mannich condensations with cyclopentanone. The LIannich base, using piperidine, was obtained readily as the hydrobr0mide.j However, it is well-known that a-bromocyclopentanone and its derivatives7 are extremely unstable, liberating hydrogen bromide readily to yield a,@-unsaturated ketones and further decomposition products. The bromination step thus appeared to be beset with inherent difficulties. An attempt to brominate 2-piperidinomethylcyclopentanone hydrobromide dissolved in glacial acetic acid only led to what appeared to be decomposable polybro(4) (5) (G) (7)
C. Mannich and R . Braun, B e y . , 53, 1874 (1920). C . Mannich and D. Schaller, Ayck. Pkarm., 276, 575 (1938). C . hfannich and P. Honig, ibid., 265, 598 (1927). R. M. Acheson. J. Ckem. Soc.. 4232 (1956).
SRz I
The reaction of the chloroketone with the secondary amine was carried out by a modification of the Mousserong method. Substitution of the piperidino moiety directly on carbon 5 of a hexahydrobenzothiazolin-2-onerequired the use of 2-cyclohexenone. This behaves similar to ethyl vinyl ketone in condensation with piperidine. The resulting compound, 3-piperidinocyclohexanone (VIII), upon bromination, can give either the 2- or the 6-bromo derivative. Tenta( 8 ) hl. Mousseron, J. Julien and Y . Jolchine, Bull. SOC. chim. France, 757 (1952).
CYCLOALKENO [d]THIAZOLIN-2-ONES
May 3, 1958
2203
TABLE I Y-(CHz)m
I
Yield,
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
?n R 0 H 1 0 CHs 1 o H 1 0 CHa 1 0 H 1 0 CHs 0 1 H 0 1 CHa 0 1 H 0 1 H 1 1 H 1 1 CH3 1 1 H 1 1 CHa 1 1 H 1 1 CHI 1 1 H 1 1 CHa 1 1 H 1 1 H 1 1 H 1 1 CHa 1 1 H 1 1 CHs 1 1 H
26
1
1 CHa
27 28 29 30 31
1 1 1 1 1
1 1 1 2 0
Nu. n 1 1
2 3 4 5 6 7
8
H CHa H H H
Y -N(CHs)z -N(CHa)i - N C ~ H ~ ~ ~ -NCsHia -N(CzHa)zOe -N(C2H4)20 -KCsHiod -NCsHio -S(CzHa)zO -NCsHizf -N(CHI)Z -N(CHa)z -NC4HaQ -NCaHa -NCaHio -KCaHia -N(CZH4)ZO -K(CzHdzO -N(CsHdPCHs -N(C&Hg)3CHa -N(CsH34CHa -N(CaHg)4CH3 -S(CsHiz) -N(CsHIZ) -SCsHa-4,4'-(CsHs)(COOCzHs) -NCsHs-4,4-(CsHs)(COOCzHs) -N(CzH4)zSCHai -X(CzH4)zXCHa -S(CzIi4)zNCH&HzOH -K(CHa)z -N(CsHio)
14.0 206-209 5 . 0 185-187 1 0 . 0 224-226 5 . 0 193-195 12.0 202-204 178-180 11.0 227-229 42.0 251-252 1 3 . 0 205-208 23.0 189-190 3G.0 214-216 30.0 236-238 43.0 238-240 30.0 242-244 60.0 240-242 3 0 . 0 230-232 38.0 211-213 43.0 230-232 34.0 227-229 37.0 242 30.0 248 35.0 255 55.0 235-236 3 3 . 0 220-222 15.0 242-244 25.0
CzaHaiBrXiOaS
6.40h
C~HZ~B~ZNZOS ClaHzsBrzNzOS 37.93 37.66 CiaHzsBrzKzOzS C11HlgBrKzOS 43.00 43.51 CnHlsBrNzOS 45.14 44.96
?.!.p.,
c.
230-232
28.0 230-231 14.0 226-228 5.5 12.0 212-214 208-210
Found C 38.62 41.07 45.05 46.75 41.44 42.86 45.26 46.58 41.07 46.58 41.11 43.15 45.03 46.64 46.84 48.78 42.97 44.56 48.29 48.43 48.20 49.71 48.54 49.80 54.45
Andyses, % Calcd. Found H H 5.07 5.51 5.52 5.82 6.00 6.01 6.35 6.41 5.33 5.46 5.71 5.80 6.01 6.30 6.05 6.31 5.33 5.25 6.35 6.40 5.79 5.84 6.23 6.41 6.05 5.99 6.39 6.35 6.44 6.35 6.67 6.98 5.79 5.71 6.06 6.13 6.69 6.62 6.69 6.59 6.69 6.69 6.97 6.94 6.72 6.65 6.97 7.30 6.07 6.15
Empirical Calcd. formulab C CaHiBBrNzOS 38.86 CioHiTBrNzOS 41.10 CisHisBrNzOS 45.14 CiaHziBrKzOS 46.84 CIIHITBCNZOZS41.12 Ci?HisBrKzOzS 42.99 CizHisBrKzOS 45.28 CiaHziBrNzOS 46.85 CuHiiBrSzOzS 41.10 C I ~ H Z ~ B T S Z O46.85 S 40.96 CloHliBrNzOS 43.00 CizHisBrNzOS CizH1gBrA-20S 45.14 Ci3HziB~Kz0S 46.84 46.84 C13HziBrNzOS CuHraBr?izOS 48.41 CnHiaBrNzOzS 42.98 CisH2iBrNzOzS 44.70 ClaH2aBrXzOS 48.42 ClrHzaBrNzOS 48.42 CIPHZJBCXZOS 48.42 CisHzsBrKzOS 49.86 Ci4HzaBrSzOS 48.42 ClsHzsBrAzOS 49.86 CzzHzgBrNzOaS 54.80
R'
U.v.abs.,c Found A,., N m p t 10.07 9.72 245 5640 9.59 9.25 245 5080 8.77 8.95 245 5320 8.40 8.50 245 4960 8.72 8.69 245 5200 8.36 8.13 245 4830 8.80 8.91 249 4490 9.6Zh 9.54* 249 4319
Calcd.
N
8.40 9.56 9.12 8.77 8.41 8.41 8.07 8.36 8.02 8.09 8.09 8.09 7.75 8.06
8.39 9.30 8.91 8.76 8.45 8.45 7.83 8.25 7.73 7.85 8.05 8.08 7.40 8.31
6.00h
5.65
7.47h 7.10h 5.84 5.68
9.79 9.48 9.15 9.12 8.77
6.23 6.00
5,81 6.28
245 245 246 247 247 247 246 246 246 246 246 247 246 246 247
5110 2870 5110 4970 4970 4650 4930 4660 4450 5220 5120 4750 5230 4590 5610
5.53
245
4780
9.62 9.10 8.95 8.95 8.40
247 4680 247 4310 245 5100 246
5200
These are calculated on the basis of the a-hnloketone-ethyl xanthamidate or ethyl N-methylxanthamidate condensation. * The compounds were isolated as mono- or dihydrobromides. All determinations were made on a Beckman recording spectrophotometer, Model DKl; ethyl alcohol was used as the solvent. Piperidine. e Morpholine. HexamethyleneEthyl-4phenylisonipecotate. i N-Methylpiperazine. imine. Pyrrolidine. Sulfur. 0
tively, we have assigned the bromo group to carbon G on the basis of our experience with this type of reaction in which bromination will always occur on the carbon alpha to the ketone group but furthest removed from the nitrogen.
Bromination of XI1 and condensation of XI11 with ethyl xanthamidate proceed normally. In Table I are presented the analytical data for the compounds prepared.
02e: o+u-
SCHEME I11 N(CHs)z
CzH,OOC\ (CHz)z
4
H
VI11
Thus, i t follows that the final product isolated is assigned formulation IX.
aN-fl-y-H XI
(1951).
=c)
(CH3)2NCH2CHzCf XI
I
(CHz)z
:=O XII
N(CH3)z
I
0: (CHz)z
B'z
vs/c=o
Finally, a series of reactions were carried out (see Scheme 111) in order t o lengthen by one methylene group the carbon chain a t position 4 of the hexahydrobenzothiazoline-2-one. The two steps leading to compound XI1 have been reportedg to give yields in the neighborhood of 15y0 due to the predominant formation of 0alkylated material rather than the desired XI. (9) w. E. Doering and s. J. Rhoads, THISJOURNAL, 73, 3082
NaOR
N ( c ~ ~ ~ ) ~
.HBr
0 I
COOC2H6
XI11
A
N(CH3)z
I
(CHz)z
.HBr
(JT; XIV
Pharmacology.-The procedure employed for testing these compounds for analgetic activity is essentially the Wolff-Hardy method as modified by Gross.2s10 Among the compounds listed in Table I, preparation 15 showed pronounced analgesia in experimental animals. Compound 16, the N-methyl derivative of 15, displayed analgetic (10) F. Gross, Helv. Physioi. Acta, 5, 31 (1947).
2204
GEORGE DESTEVENS, .A. F. HOPKINSOK, 14.9. CONNELLY, P. OKEAISD D. C.SCIIROEDER Vol. SO
properties but with a higher toxicity factor. Compounds 7 and 8 , analogs of 2,3,5,6-tetrahydro-4Hcyclopentathiazolin-2-one2, also displayed analgetic properties. Noticeable decrease in activity was had when the piperidino moiety of compound 15 was exchanged for dimethylamino, pyrrolidino or morpholino, whereas exchange of piperidine for hexamethyleneimine had no adverse effect. I t was of interest to determine what analgetic influence the 4-phenyl-4-carbethoxypiperidinomoiety" would exert when substituted a t position 4 of hexahydrobenzothiazoline-?-one. Thus, compounds 2s and 26 were prepared but were found to CsHj COOC2H5 \/
/i.
--
1
8
1
Essentially the procedure involvcs diswlving the hydrobromide salt of the hlannich base in 20y0-357G hydrogen bromide-acetic acid solution and chilling the solution t o 0". An equivalent amount of bromine is added dropmise. Upon completion of addition, the temperature of the reaction mixture is brought slowly up t o room temperature by stirring for approximately one hour. The pale yellow solution is triturated several times with ethyl ether whereupon a crystalline or an oily viscous a-bromoketone was isolated. Some of these hrornoketories could be recrystallized only with difficulty and a certain amount of decomposition; the viscous oils resisted all dtteinpts to be recrqstallized. Consequently, the bromo derivatives of the blannich bases mere used directly as such for the preparation of the desired thiazolin-2-ones. C. General Preparation of Thiazolin-2-ones.-Thc following procedure is typical: Equal molar equivalents of 2bromo-6-piperidinomethylcyclohexanone and ethyl xanthamidate'6 were added to 200 ml. of ethj 1 alcohol and the solution was refluxed with stirring for 6 hours.17 After chilling overnight, the precipitate was collected and recrystallized from 100 ml. of hot water. Other solvents vhich can be employed for recrJ-stallizing the compounds outlined in Table I are methyl alcohol, ethyl alcohol, n-prop) 1 alcohol and isopropyl alcohol.
5-Piperidino-2,3,4,5,6,7-hexahydrobenzothiazolin-2-one N-€1 I
be devoid of aiialgetic properties. These few examples serve to demonstrate the different biological effects associated with apparently slight changes in chemical structure. In a forthcoming report from these Laboratories a more detailed account of the chemical structure-biological function of this class of compounds will be presented. Acknowledgment.-The authors are grateful to Dr. E. Schlittler for his interest and encouragement throughout this investigation. Lye would also like to express our gratitude to Dr. J. A. Schneider and his collaborators for the biological testing and to Mr. Louis Dorfman and his associates for the microanalyses and the spectral data. Experimentali2 A . General Procedure for Mannich Condensation.-The procedure employed for the Mannich condensations has been described. A mixture of five parts of alicyclic ketone, one part of secondary amine hydrochloride and one part of 38% formaldehyde solution is heated to approximately loo", whereupon a vigorous reaction occurs. External heat is removed from the flask and the reaction is allowed to proceed of itself. At the end of the reflux period, the solution is chilled immediately t o 5 O , an equal volume of water is added and the solution is made alkaline to pH 9 to 10. This alkaline solution is extracted thoroughly with ether and the ether extract dried over anhydrous K2CO3. ilfter drying and filtering, dry hydrogen bromide gas is passed into the filtrate to obtain the h) drobromide salt of the hlannich base. The free bases and their hydrohalide salts have been described in a review. B. General Procedure for Bromination of Mannich Ketones.-Bromination of the ketones was conducted in 20%3553 hydrogen bromide-acetic acid s ~ l u t i o n . ' ~ - ' ~ (11) 0. Eisleb, U. S. Patent ?,l(i7,3Sl (1939). (12) All melting points in Table I and in this section arc uncorrected. (13) A . H T.and, A. Ziegler ancl J . 12. Sprague, THISJorJnN.41., 69, 125 (1947).
(Cornpound3' in Table I).-Twentv prams (0.21 mole) of cyclohexenone was added slowly with-stirring and external cooling t o 19.5 g. (0.21 mole and lOyoexcess) of piperidine. -1fter standing overnight, the solution was refluxed for one hour. After making the solution strong alkaline, it was extracted with ether and the ether extract dried over Sa2SOI. The drying salt was filtered off and dry hydrogen bromide gas was bubbled through the filtrate. .ifter several triturations of the viscuus residue with dry ether, a tan powder was obtained and recrystallized from a small ainouiit of cthyl alcohol. Crystals' of 3-piperidinocyclohexanone hydrobromide, m.p. 158-1613", were obtained in 45'5 1-ield. Anal. Calcd. for CllH20BrS0: C, 50.4; H. '7.67; X, 5.35. Found: C, 49.70; H, 7.82; N, 5.17. X solution of 8.0 g. (0.036 rriole) of 3-piperidinocyclolicxannne hydrobromide in 10 ml.of glacial acetic acid containing 205% hydrogen bromide was chilled to 5" and treated dropwise with 5.8 g. (0.026 mole) of bromine dissolved in 5 ml. of glacial acetic acid. Crystals began to form when addition Tvas complete whereupon 20 ml. of ether was added and the mixture stirred for one hour. Chilling, filtering and washing the precipitate with dry ether yielded 8.8 g. of 2bromo-5-piperidinocyclohexanonehydrobromide, which was analyzed as such due to its tendcncy to decompose \vhcn attempts were made to recrystallize it. AmZ. Calcd. for C11H1J3r2SO: S,4.11. Found: S , 4.08. The preparation of the desired S-piperidino-2,3,4,5,6,7hexahydrobenzothiazolin-2-one hydrobromide v a s carried out as outlined above. SUMMIT, S . J. (14) C . hlannich and T. Goldarch, Be?., 61, 263 (1928). (15) C. Djerassi, R . A . hlizzoni and C . R . Scholz, J . Ovg. C h e v . , 15, 700 (1950). (16) For t h e preparation of 2,3,4,5,0,7-hexahydro-3-methyl-4piperidinomethylbenzothiazo~in--o-one,the previously described ethyl S-methylxanthamidate (see ref. 3) was used. (17) From an experimental point of view it is appropriate to note
that the extent of reaction was followed by periodically pigetting an aliquot of reaction solution, working it up and submitting the crystalline material t o infrared spectroscopic analysis. T h e presence of 2bromoketone impurity would exhibit an appreciable band a t 1730 cm.-l. When the reaction had gone to completion, the 1730 cm.-' xyas abFent and only the 1660 and 1630 cm.-l bands, characteristic for the 2.8.4,5,G,7-hexahydrobenzothiazolin-2-onemoiety, were predominant.
