~’HAIiRIACOLOGICALLYACTIVE 6-CHLOROIlIIDAZO [2,1-b]THIAZOLES
Soveniber 1969
1031
Heterocyclic Systems with a Bridgehead Nitrogen. 1I.l 6-Chloroimidazo[2,1-b]thiazole and Some of Its 5-Substituted Derivatives2 JoH?:P. PAOLINI A N D LOUISJ. LEXDVAY The AYalronal Drug Cotnpany, Krsearch Laborutorzrs, Divzsion of Richardson-Mciit 11 Inc., Philndc lphra, I’tnnsylvanra
irll44
Receaved ,4pral 11, 1969 The reactiou of 3-carboxymethyl-2-iminothiazolirle and POCh gives 6-c.hloloimidazo[2,ll-b]t hiazole. This syst,em undergoes electrophilic sitbstitution at the 3 position, as shown hy means of nmr analysis. Home of thew compounds demonstrat,edanttiinflammatoryand antihypertensive activi ty.
The formation of a n imidazo [2,l-b]thiazole from a preformed thiazole usually is accomplished by treatment of a 2-aminothiazo lederivative with a n a-halo ketone. Such reactions give 6-alkyl and 6-aryl deriva t i v e ~ . ~ We - ~ wish to report a new procedure for the synthesis of chloro-substituted imidazo [2,1-b]thiaxoles commencing with a thiazole nucleus, The reaction of 3-carboxymethyl-2-iminothiazoline ( l a ) 6 and Poc13 gives directly 6-chloroimidazo[2,l-b]thiazole (2a). The 6-chloro-3-methyl and 6-chloro-2,3-dihydro derivatives (2b, 4) were prepared from the corresponding carboxymethylimino compounds ( l b , 3) using this procedure. P
Z
R
R 1
2
H b, CHI a.
\CH,COOH 3
4
The susceptibility of this a-excessive system to electrophilic attack permitted the preparation of a variety of ;-substituted 6-chloroimidazo [2,1-b]thiazoles (Table 11). S m r data (Table I) were consistent with electrophilic attack a t the 5 position. This is in agreement with some chemical studies of Pyl, et u L . , ~ as well as nmr studies of Pentimalli, et on alkyl- and arylimidazo[2,l-b]thiazoles. A series of Xannich bases (5-10) TWY prepared by treating 2a with CH20 and a secondary amine in the presence of AcOH. The acidic nature of the medium was critical, as no reaction occurred in the absence of acid, while in the presence of HC1 only a bismethylene compound (11) was obtained. Heating one of the ;Lminoalkylated derivatives (the dimethylaminomethyl compound) with HCl also gave 11. This seems to indicate that the Alannich base is the product of kinetic (1) Part I of this series: J. P. Paolini, J. O w . Chem., 58, 888 (1968). (2) Prpaented in part at the 3rd Middle Atlantic Regional Meeting of the American Chemical Society, Philadelphia, Pa., Feb 1-2, 1968. (3) For a review see W. L. Mosby. “Heterocyclic Systems with Bridge-
head Kitrogen Atoms,” A. Weissberger, Ed., Interscience Publishers, Inc., Sew York, N . Y . , 1961, p 157. (4) T. Pyl, R. Giebelmann, and H. Beyer, Ann., 645, 145 (1961). (5) I . Iwai and T. Hiroaka, Chem. Pharm. Bull. (Tokyo). l a , 813 (19641, used the bromoacetone as well as its anhydride propargyl bromide. (6) J. Druey, H e l p . Chim. A c t a , S4, 226 (1941). ( i ) L. Pentimalli, A. Cogo, and h. AI. Guerra, Gazz. Chim. Itul., 9 1 , 488 (196i).
-6
7
KO.
2a 2b 1s
~u1,stitiients
6-C1 6-Cl-Y-lIe
6-CI-3-CHO
2- H
\-alueb3- H
6 . XS ~ i d ‘ ’ , ~ 7 . 3 9 ild 6.4.; m e . ( 7 15 lid
7
5- H
7.39S 7.27 s
C . ~
S . 26 kid %5,6-C1? 6.97 ud 7 . 3 : nd 3,6-1Ier 6.69 itd 7 . 1 7 ud ud = unsymmetrical doublet. * The coitpling constant of the doublets was 4.5 cps. e s = singlet. This baud was superimposed onto the doublet representing the 3 position, thus there were three peaks in this region. e m = mtiltiplet. f This tight midtiplet should show up as a quartet a t higher resolution. The splittingis due to the &Ale, which is also split. This mutual split,t,ing of a ring proton on an aromatit group on an adjacent, ring carbon is seen in the spectrum of 2,4dimethylthiazole: S. S. Bhacca, L. F. Johndon, and J. N. Schoolery, “XlIR Spectra Catalog,” Ysrian Associates, Palo Alto, Calif., 1962.
11 36 0
control and that the bis compound 11 is the product of thermodynamic control, a t least in HC1. Sitration of 2a proceeded smoothly and in good yield a t 20” to give the 6-chloro-&nitro derivative (16). Reduction of 16 in the presence of AczO gave the expected S-acetyl derivative (17). The attempted preparation of a primary amine, as the free base or HC1 salt, by hydrogenation of 16 gave only intractable oils. Potassium thiocyanate and Br2 in ,ZcOH were used to effect. thiocyanation.* Hydrolysis of the thiocyanate derivative 12 with H2SOJ gave the thiolcarbamate 13. The T’ilsmeier-Haack reaction mas used to give the aldehyde 18. LhH reduction of 18 gave the methylol 19. Although this aldehyde (18) readily formed some of the carbonyl derivatives such as the semicarbazone 21, oxime 23, hydrazone 22, and nitrovinylene 20, it failed to condense with diethyl malonate under standard conditionsgand was rather resistant to oxidation to the carboxylic acid in the preqence of H202,H2Cr04, or basic K l l n O ~a t room temperature. -ittempted oxidations a t higher temperatures resulted in extensive decomposition. This reluctance toward oxidation and condensation with diethyl malonate may be associated with the presence of the formyl group a t a position of such high electron density that the attempted advances of a nucleophile are resisted. ( 8 ) K. Takatori and H. Sisliida, J . Phorm. Sor. .Japan, 71, 1367 (1951): Chem. Abstr., 46, 8099 (19321. (9) C. F . H. .illen and F. \ISpangler . in “Organic Syntheses,” Coll. Vol. 111, E. C. Homing, Ed., John Kiley and Sons, Inc., S e w Tork, N. Y., 1955, p 317.
Sovember 1969
I'HARJIACOLOGICALLY
XCTIVE 6-CHLOROIMIDAZO
1033
[?, 1-b ] T H I A Z O L E S
TABLE I1 3-SCBSTI'ITTED
6-CHLOROIMIDAZO[2,1-b]THI.iZOLES
87.3 13.9 27.1 26.7
Alp, oc 84-86 192-193d 181-183d 144-146d
Hexane i-PrOH i-PrOH AIeOH
CjHaCIS& CaHioCINaS HC1 CioHi4ClN3S .HC1 CioHi4CliY;,OzS.HCI
x
70.5
122-124
CiH16
CioHi2CISaS
9
66.5
110-111
CiH16
10
58.3
126-128
PhlIe
11
73.2
242-244
PhlIe
Yield. '%"
K
SO.
2a
H CHzS (CH3)2 CH?S(CzHs)* CH2K (C2H4OH)z
)
6 7
Cr? s t n solvent
Formulab
29.0 197-200 AIeOH 12 YCN 13.0 143-147 EtOH SCONH, 13 112-113 Cyclohexane 3 2 , .i 14 c1 133-135 Skellysolve 192.3 1.i Br 192-194 86.5 Phlle 16 NO2 131-133 38.8 XHCOCH3 17 C6H14 140-142 EtOH 57.0 CHO lh 22.7-235 dec 46.6 PhAIe 19 CH2OH 29.0 MeOH 197-200 CH=CHN02 20 18.5 DAIF >250 dec CH=NNHCONH? 21 123-126 10.5 CH=NNHz 22 CsH6 23.9 PhlIe 202-203 CH=NOH 23 90.0 174-176 CN 24 CsHs 49.6 i-PrOH 166-16'1 23 CONH, DXF-HZO 40.6 205 dec COOH 26 EtOH-H20 4.0 130-134 CH=NOCHj 27 i-PrOH C H=N 0C Hz C H=CH, 16.9 170-177 2s CH=NOCH*C=CH 14.4 i-PrOH 137-138 29 139-140 CH=NOCH~-~,~,~-(OCH~)~CP,H~ 14.7 EtOH 30 5 These are the yields of analytically pure material. * All compounds were analyzed for C, H, S and are wit,hiii +0.45",unless otherwise indicated. < C1: calcd, 22.36; found, 22.44. HCI salt. e C : calcd, 31.11; found, 31.53. f C: calcd, 29.49; found 30.10. C1: calcd, 17.41;found, 17.39.
TABLEIT, 4 S T I I N F L . i ~ ~ M A T O R ACTIVITY Y
h-".
Level of act.a
2a
A4
4 8
A
9 10
A
A A
NO.
19 22 24 25 27
Level oi acLa
A A C
C
A
R 32 A 1.i B Pheuylbutazone B 1)ecre:ise i n abscess weight: A = 20-3057 (weak), B 14
(1
a0-405;,
c = 40-50~;;.
=
was removed from the effluent liquid and the residue was purified by cryst,allization. 5-Acetarnido-6-chloroimidazo[2,1-b]thiazole (17).-A mixture of 6-chloro-3-nitroimidazo[2,1-b]thiazole (16) (13.6g, 0.067mole), -4~20(25ml), arid 105; Pd-C (1.5g) in AcOH (100ml) was shaken under 3.1 kg of H,, cm* until the theoretical amount of HP was absorbed. The misture was filtered through a Celite pad. The solvent was removed from the filtrate, by evaporation in mcuo, with heat. The residual oil was poured onto ice and the resulting solid was filtered off aiid washed with cold H20 and purified. 6-Chloroimidazo[2,1-b] thiazole-5-thiolcarbamate (13).-To concentrated H2S04 (100 nil), maintained at. loo, was added 6chloro-5-t~hiocyanatoimidazo[2,1-b] thiazole (12) (28 g, 0.13 mole). After the addition was complete, the reaction mixture was stirred for an addit,ional 1 hr, then poured onto ice, the resulting solid was filtered off, washed with HZO, and purified. 6-Chloroimidazo[2,1-b] thiazole-5-carboxaldehyde (18).--POC13 (15.5g, 0.1 mole) was added t o a cooled mixture of D l I F (7.5g, 0.1 mole) in CHCI, (150 ml). Then 6-chloroimidazo[2,1blthiazole (2a) (15.9 g, 0.1 mole) was added cautiously to the DAIF-POCIa complex. After addit ion was complete, the react,ion mixture was heated under reflux for 2 hr. The solvent was removed by evaporation in uucuo and the residue was poured into ice and H20. The resulting solid was filtered off, washed well with HzO, and purified. 6-Chloroimidazo[2,1 -b]thiazole-5-aldoxime (23).--NHzOH. HC1 (3.5g, 0.05 mole) in H20 (26ml) was added to a boiling solution of (i-chloroiinidazo[%,1-b] t,hitt~ole-6-ctLrboxaldehyde ( 1 8 ) (9.3 g, 0.05 mole) in Et,OH (150 ml). The reaction mixture was boiled for 15 min, then cooled, and the solid was filtered off and purified.
