Soveniber 1969 ~’HAIiRIACOLOGICALLYACTIVE

6-CHLOROIlIIDAZO [2,1-b]THIAZOLES 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 treat-
ment of a 2-aminothiazo lederivative with a n a-halo
ketone. Such reactions give 6-alkyl and 6-aryl deriv-
a t i v e ~ . ~ We
- ~ wish to report a new procedure for the 7 -6 \-alueb- 7

synthesis of chloro-substituted imidazo [2,1-b]thiaxoles KO. ~u1,stitiients 2- H 3- H 5- H

commencing with a thiazole nucleus, The reaction of 2a 6-C1 6 . XS ~ i d ‘ ’ , ~ 7 . 3 9 ild 7.39S C . ~

3-carboxymethyl-2-iminothiazoline ( l a ) 6 and Poc13 2b 6-Cl-Y-lIe 6.4.; m e . ( 7.27 s

gives directly 6-chloroimidazo[2,l-b]thiazole (2a). The 1s 6-CI-3-CHO 7 15 lid S . 26 kid
6-chloro-3-methyl and 6-chloro-2,3-dihydro derivatives 11 %5,6-C1? 6.97 ud 7 . 3 : nd
(2b, 4) were prepared from the corresponding carboxy- 36 3,6-1Ier 6.69 itd 7 . 1 7 ud
methylimino compounds ( l b , 3) using this procedure. 0 ud = unsymmetrical doublet. * The coitpling constant of
the doublets was 4.5 cps. e s = singlet. This baud was super-
imposed onto the doublet representing the 3 position, thus there
P Z were three peaks in this region. e m = mtiltiplet. f This tight
midtiplet should show up as a quartet a t higher resolution.
R R The splittingis due to the &Ale, which is also split. This mutual
split,t,ing of a ring proton on an aromatit
1 2 group on an adjacent, ring carbon is seen in the spectrum of 2,4-
a. H dimethylthiazole: S. S. Bhacca, L. F. Johndon, and J. N.
Schoolery, “XlIR Spectra Catalog,” Ysrian Associates, Palo
b, CHI
Alto, Calif., 1962.

control and that the bis compound 11 is the product of

thermodynamic control, a t least in HC1.
\CH,COOH Sitration of 2a proceeded smoothly and in good yield
3 4 a t 20” to give the 6-chloro-&nitro derivative (16). Re-
duction of 16 in the presence of AczO gave the expected
The susceptibility of this a-excessive system to elec- S-acetyl derivative (17). The attempted preparation
trophilic attack permitted the preparation of a variety of a primary amine, as the free base or HC1 salt, by hy-
of ;-substituted 6-chloroimidazo [2,1-b]thiazoles (Table drogenation of 16 gave only intractable oils.
11). S m r data (Table I) were consistent with electro- Potassium thiocyanate and Br2 in ,ZcOH were used
philic attack a t the 5 position. This is in agreement to effect. thiocyanation.* Hydrolysis of the thiocy-
with some chemical studies of Pyl, et u L . , ~ as well as nmr anate derivative 12 with H2SOJ gave the thiolcarbamate
studies of Pentimalli, et on alkyl- and arylimidazo- 13.
[2,l-b]thiazoles. The T’ilsmeier-Haack reaction mas used to give the
A series of Xannich bases (5-10) TWY prepared by aldehyde 18. LhH reduction of 18 gave the methylol
treating 2a with CH20 and a secondary amine in the 19. Although this aldehyde (18) readily formed some
presence of AcOH. The acidic nature of the medium of the carbonyl derivatives such as the semicarbazone
was critical, as no reaction occurred in the absence of 21, oxime 23, hydrazone 22, and nitrovinylene 20, it
acid, while in the presence of HC1 only a bismethylene failed to condense with diethyl malonate under standard
compound (11) was obtained. Heating one of the conditionsgand was rather resistant to oxidation to the
;Lminoalkylated derivatives (the dimethylaminomethyl carboxylic acid in the preqence of H202,H2Cr04, or
compound) with HCl also gave 11. This seems to indi- basic K l l n O ~a t room temperature. -ittempted oxi-
cate that the Alannich base is the product of kinetic dations a t higher temperatures resulted in extensive de-
composition. This reluctance toward oxidation and
(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
condensation with diethyl malonate may be associated
the American Chemical Society, Philadelphia, Pa., Feb 1-2, 1968. with the presence of the formyl group a t a position of
(3) For a review see W. L. Mosby. “Heterocyclic Systems with Bridge- such high electron density that the attempted advances
head Kitrogen Atoms,” A. Weissberger, Ed., Interscience Publishers, Inc.,
Sew York, N . Y . , 1961, p 157. of a nucleophile are resisted.
(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, ( 8 ) K. Takatori and H. Sisliida, J . Phorm. Sor. .Japan, 71, 1367 (1951):
used the bromoacetone as well as its anhydride propargyl bromide. Chem. Abstr., 46, 8099 (19321.
(6) J. Druey, H e l p . Chim. A c t a , S4, 226 (1941). (9) C. F . H. .illen and F. \I- Spangler
. in “Organic Syntheses,” Coll.
( i ) L. Pentimalli, A. Cogo, and h. AI. Guerra, Gazz. Chim. Itul., 9 1 , Vol. 111, E. C. Homing, Ed., John Kiley and Sons, Inc., S e w Tork, N. Y.,
488 (196i). 1955, p 317.
Sovember 1969 I'HARJIACOLOGICALLY XCTIVE 6-CHLOROIMIDAZO [?, 1-b ] T H I A Z O L E S 1033

TABLE
I1
3-SCBSTI'ITTED 6-CHLOROIMIDAZO[2,1-b]THI.iZOLES

SO. K Yield. '%" Alp, oc Cr? s t n solvent Formulab

2a H 87.3 84-86 Hexane CjHaCIS&
) CHzS (CH3)2 13.9 192-193d i-PrOH CaHioCINaS HC1
6 CH?S(CzHs)* 27.1 181-183d i-PrOH CioHi4ClN3S .HC1
7 CH2K (C2H4OH)z 26.7 144-146d AIeOH 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

12 YCN 29.0 197-200 AIeOH

13 SCONH, 13.0 143-147 EtOH
14 c1 3 2 , .i 112-113 Cyclohexane
1.i Br 92.3 133-135 Skellysolve 1-
16 NO2 86.5 192-194 Phlle
17 XHCOCH3 38.8 131-133 C6H14
lh CHO 57.0 140-142 EtOH
19 CH2OH 46.6 22.7-235 dec PhAIe
20 CH=CHN02 29.0 197-200 MeOH
21 CH=NNHCONH? 18.5 >250 dec DAIF
22 CH=NNHz 10.5 123-126 CsH6
23 CH=NOH 23.9 202-203 PhlIe
24 CN 90.0 174-176 CsHs
23 CONH, 49.6 166-16'1 i-PrOH
26 COOH 40.6 205 dec DXF-HZO
27 CH=NOCHj 4.0 130-134 EtOH-H20
2s C H=N 0C Hz C H=CH, 16.9 170-177 i-PrOH
29 CH=NOCH*C=CH 14.4 137-138 i-PrOH
30 CH=NOCH~-~,~,~-(OCH~)~CP,H~ 14.7 139-140 EtOH
5 These are the yields of analytically pure material. * All compounds were analyzed for C, H, S and are wit,hiii +0.45",unless other-
wise 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.

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 6-
chloro-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 result-
ing solid was filtered off, washed with HZO, and purified.
6-Chloroimidazo[2,1-b] thiazole-5-carboxaldehyde (18).--PO-
TABLEIT- C13 (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[2,1-
, 4 S T I I N F L . i ~ ~ M A T O R ACTIVITY
Y
blthiazole (2a) (15.9 g, 0.1 mole) was added cautiously to the
h-". Level of act.a NO. Level oi acLa DAIF-POCIa complex. After addit ion was complete, the reac-
2a A4 19 A t,ion mixture was heated under reflux for 2 hr. The solvent was
4 A 22 A removed by evaporation in uucuo and the residue was poured into
8 A 24 C ice and H20. The resulting solid was filtered off, washed well
9 A 25 C with HzO, and purified.
6-Chloroimidazo[2,1 -b]thiazole-5-aldoxime (23).--NHzOH. HC1
10 A 27 A (3.5g, 0.05 mole) in H20 (26ml) was added to a boiling solution
14 R 32 A of (i-chloroiinidazo[%,1-b] t,hitt~ole-6-ctLrboxaldehyde ( 1 8 ) (9.3 g,
1.i B Pheuylbutazone B 0.05 mole) in Et,OH (150 ml). The reaction mixture was boiled
(1 1)ecre:ise i n abscess weight: A = 20-3057 (weak), B = for 15 min, then cooled, and the solid was filtered off and puri-
a0-405;, c = 40-50~;;. fied.