Substituted imidazo2,1-bthiazoles from 2-aminothiazoles and alpha;-bromo ketones: efficient preparation and proof of structure

摘要

J. CHEM. SOC. PERKIN TRANS. I 1989 Substituted Imidazo[2,1 -b]thiazoles from 2-Aminothiazoles and a-Bromo Ketones: Efficient Preparation and Proof of Structure G. Denis Meakins," Sally R. R. Musk, Colin A. Robertson, and Lee S. Woodhouse Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford, OX I 30Y The salts formed from m-aminothiazoles and a-bromo ketones (RCOCH,Br) have been basified, and the products converted into amides. Examination of the amides established that they are 2-acylimino-2,3-dihydrothiazoles rather than 2-acylaminothiazoles. Thus the a-bromo ketones attack the endo-N of the 2-aminothiazolesr and the imidazo[2,1 -b]thiazoles obtained by cyclising the salts have the substituent (R) of the bromo ketone at position 6. Efficient procedures have been developed for preparing a range of imidazo[2,1 -b]thiazoles.Related reactions of 2-aminothiazoles, with an a-bromo aldehyde and with ethyl bromoacetate, have been studied. Four papers'-4 contain the main previous work on imidazo- [2,1-b]thiazoles (7). In the original preparation 2-amino-4-methylthiazole was heated at 100 "C with phenacyl bromide; the product obtained (in unspecified yield) on basification was formulated as 3-methyl-6-phenylimidazo[2,l-b]triazole [structure (7Ba) in Scheme 11. Subsequent preparation^,^^^ from various 2-aminothiazoles and a-bromo ketones, were represented as proceeding in similar fashion, i.e., with the substituent (R3)of the a-bromo ketone occupying position 6 of the imidazothiazole nucleus.No evidence was adduced for the correctness of the proposed formulae which, as shown in Scheme 1, involve the assumption of initial attack at the endo-N of the aminothiazoles. Although certain electrophiles (notably alkyl halides) are known to react at this site of the ambient nucleophiles, others (such as acid chlorides and anhyrides) give products formed by substitution at the e~0-N.~cr-Bromo ketones are intermediate in their electrophilic reactivity; to assume for these a particular course of reaction is therefore unsatisfactory. In the present work it was planned to establish the structures of the known products, and to develop efficient procedures for preparing a wider range of imidazothiazoles required for subsequent studies of their substitution reactions.[Only the well-known 2-aminothiazoles (1; R' = R2 = H or Me) and (1; R' = Me or Et, R2 = H) had been used as starting materials Distinction between the alternative structures for the imid- azothiazoles, corresponding to reactions at different centres of the 2-aminothiazoles, is made more clearly by examining the intermediates in the synthesis rather than the final products. As discussed later, some of the intermediates [structures (4) or (9)] obtained by basifying the initial salts can be isolated. The amides formed by acylating these could be 2-acylimino-2,3- dihydrothiazoles [(5) and (S)] or 2-acylaminothiazoles [(lo) and (ll)], systems which, as discussed earlier,6 have character- istically different i.r.C=O bands. From the results in Scheme 2 it emerges that the trifluoroacetyl and 2-thenoyl derivatives obtained here have structures (5) and (8) respectively, and hence that the imidazothiazoles are correctly represented by structure (7).The salts (3) were obtained in high yield from a range of a-bromo ketones and 2-aminothiazoles. Chloroacetone is much less effective than bromoacetone, and this may explain why a less convenient route (starting from prop-2-ynyl bromide) was used in the earlier preparations of the 6-methyl products (7Af) and (7Bf). The imines (4), formed by basifying the salts (3), differ widely in the ease with which they cyclise to the imidazo- thiazoles (7). Those (4; R = Me) derived from bromoacetone cyclise spontaneously and cannot be isolated; those with R3 = (substituted) phenyl cyclise on heating in ethanol, but for those with R3 = 2-thienyl cyclisation requires a higher temperature. This trend accords with the expected order of electrophilicity, viz., acetyl benzoyl 2-thenoyl.Preparation of the imidazothiazoles is effected more con- veniently by reversing the order of the steps, i.e., cyclisation of the salts (3) followed by basification. [One salt (3Ee), in which R3 = 2-thienyl, remained unchanged under the general conditions, and the corresponding imidazothiazole (7Ee) was obtained only from the imine (4Ee).] Attempted purification of the p-nitrophenyl salt (3Ad), the least soluble of its type, by crystallisation from dimethylformamide gave the imidazo- thiazole (7Ad) directly in an overall yield of 68% from 2-aminothiazole. Mesomeric interaction between N-4 and the p-nitrophenyl group in the product may be expected to reduce its basicity and thus facilitate the loss of hydrogen bromide from the cyclised salt.Related work on 2-aminothiazoles is shown in Scheme 3. The course of the reaction between 2-bromo-2-phenylethanal (15) (prepared here by an improved procedure) and 2-aminothiazole is extremely sensitive to the nature of the solvent; tetra-hydrofuran is the best for the present purpose. Even at 20 "C nucleophilic displacement of bromide is followed by cyclisation, and the salt (16) is formed directly (yield 37%). Unambiguous formulation of the derived base as 5-phenylimidazo[2,l-b]- thiazole (17) is not possible from spectrometric examination alone (Table); it is also necessary to know that the product is not the 6-phenyl compound (7Aa). 2-Aminobenzothiazole is reported,8 without proof, to undergo endo-N reaction with ethyl chloroacetate.The work in Scheme 3 establishes that such is the case in the reactions of 2-aminothiazoles with ethyl bromo- acetate. Experimental 1.r. spectra were recorded on a Perkin-Elmer 1750 Fourier Transform spectrometer using solutions in CHCI, and 'H n.m.r. spectra on a Bruker WH300 (300 MHz) spectrometer using solutions of the salts (3) and (6) in (CD,),SO and solutions of the other compounds in CDC1,. Mass spectra were obtained by in-beam electronic-impact unless stated otherwise.Solvents were dried and distilled before use in preparing the salts (3);THF refers to tetrahydrofuran, and petroleum to light petroleum, b.p. 85-95 "C. The amines (1A-E) are known compound^;^ the amine (lF), whose preparation was inadvertently omitted from a paper dealing with its derivatives, was obtained as follows. 2-Chloro-3- phenylpropanal (10.1 g) was added during 15 min to a stirred 644 J. CHEM. SOC. PERKIN TRANS. I 1989 Scheme 1. Imidazo[2,1-b] thiazoles from 2-aminothiazoles and a-bromo ketones Reaction at endo-N (3) (4) (5) IIvi IIiv for (3 Ad)] V vii or1, 11 ,1 H Reagents: i, Me2C0 or CHCI,, 20 "C, or THF, 50 "C; ii, NaHC0,-H,O-CHCl,, 20 "C; iii, (CF,CO),O-PhMe, 20 "C; iv, 2-ThienylCOC1-C5H,N, 20 "C; v, EtOH or MeOH, heat; vi, HCONMe,, 120 "C; vii, EtOH, 78 OC; viii, PhMe, 110 "C;ix, Na,CO,; x, KOH-EtOH Compounds A B C D E F R' H Me CH,CO,Et PhCH, H H R2 H H H H Et PhCH, Compounds a b C d e f R3 Ph C6H4F-p C6H4Br-p C6H4N02-p 2-Thien yl Me Compounds prepared (references are given to known compounds; the rest are new) (3) (4) Aa" Aa Abb Ad' Af Ba Ba Bd Bf Ca Ca Dc Dc Ea Ea Ee Ee Ef Fb Fb (5) (6) (7)(8) Aa Aa"Vd Aaa*d Aa Ab Ab Ad Af Afd Ba Bad'" Bad.' Bd Bd Bf Bfd Ca Ca Ca Ca Dc Ea Ea Ea Ea Ee Ee Ee Ef Ef " Ref.2. Ref. 5. 'Not fully characterised. Ref. 3. Ref. 1 suspension of dry MgSO, (10g) in a solution of thiourea (4.51 and variations from the general procedures are noted under the g) in Me,CO (50ml) which was boiled under reflux during the individual products.An abbreviated form is used in reporting addition and then for a further 2h. The mixture was diluted with the products' characteristics. Thus a standard entry such as ice-water (150ml), basified with Na2C0,, and extracted with 2-amino-4-methyl-3-phenylacylthiazoliumbromide (3Ba) (yield CHCI,. The CHCI, solution was washed with brine, and then 81%), m.p. 211-212 OC (from EtOH) (Found: C, 45.8;H,4.1; extracted with 5~ HCl. Basification of the acid solution, and N, 9.1.C1,H,,BrN20S requires C, 46.0; H, 4.2;N, 8.9%) is extraction with CHC1, afforded 2-amino-5-benzylthiazole (1F) shortened to (3Ba) (81), m.p. 211-212 (EtOH) (45.8, 4.2, 8.9. (8.68g), m.p. 110-1 12 "C (from CHCI,) (Found C, 63.1;H, 5.3; C1,H1 ,BrN20S, 46.0, 4.2, 8.9).Full characterisations of the N, 14.9.CloHl0N2S requires C,63.1;H, 5.3;N,14.7%); m/z 190 products are recorded elsewhere.' * (M+,100%). General procedures are illustrated by the preparations of the The Thiazolium Salts (3).-A solution of PhCOCH,Br (7.96 series (3Aa)-(8Aa); analogues are listed after each preparation, g) in Me,CO (30 ml) was added during 30 min to a stirred J. CHEM. SOC. PERKIN TRANS. I 1989 Scheme 2. Verification of reaction at endo-N of 2-aminothiazoles (Scheme 1) Alternative structures, reaction at em-N r-------I I R3COCHzBr + I (2) Comparison of i.r. c--O bonds (v,.,,.Jcm-') (for solutions in CHCl,) Letters denoting R' and R2groups are as Scheme 1.Compounds (12), (13), and (14) are models for structures (3,(lo), (ll),respectively. V Compound v(CF,CO) v(R'C0) 1633 Aa 1 630 1700 1635 Ba 1 630 1700 1632 Ca 1 630 1 700 (1 730, C0,Et) (12) 1 632 (5) Dc 1635 1704 Ea 1632 1 702 R' 1 690 Ee 1632 1 680 1 690 Fb 1632 1 706 iR2 C'NCOCF,I Me (13) v(Thieny1-CO) v(R3CO) 1 625 1 580 1 702 1625 1580 1 705 1 624 1580 1700 (1 730, C02Et) Me 1580 1 703 1 584 1 678 (14) Ref. 6. Scheme 3. Related reactions of 2-aminothiazoles Letters denoting R' and R2 groups are as in Scheme 1. Compound Br Ph NH I ii __cA + Y --J-O+CH iii ii _cBrCH2 COzE t -Br-(20B) (21B) Y / crn-' (CHCt3) 1635 ,1749 1580,1746 Reagents: i, THF, 20 OC; ii, NaHCOJ-H20-CHCl,, 20 "C; iii, Me,CO, 20 "C; iv, (CF,CO),@PhMe, 20 "C; v, 2-ThienylCOC1-C5H5N, 20 "C J.CHEM. SOC. PERKIN TRANS. I 1989 Table. 'H N.m.r. spectra of imidazo[2,1-b]thiazoles Positions (6 values, solutions in CDCl,) of signals, singlets unless shown otherwise Compound (7Aa) (7Ab) (7Af) (7Ba) (7Bd) 7(Bf) (7Ca) (7Ea) (7Ee) (7Ef) (15) 2-H 6.83" 6.84" 6.75" 6.4Ib 6.52b 6.33b 6.7Ib 6.92" 3-H 7.46" 7.46" 7.33" 7.15' 7.1 1 7.04' 7.68 " 5-H 7.75 7.70 7.20 7.63 7.78 7.09b 7.69 7.63 7.53 7.0tib (7.53, 6-H) a d, J ca 4.5 Hz. Split by small coupling (J ca. 0.9 Hz) to neighbouring Me. 't, J 1.3 Hz). Substituent shifts of 2-H (basic value 6.72), 3-H (7.33), and 5-H (7.23) signals Substituent 2-Et 3-Me 3-CHZCOzEt 6-Me 6-Ph 6-C,H,F-p 6-C,H,NOz-p 2-Thienyl 2-H -0.42 -0.12 +0.03 +0.11 f0.12 +0.22 +0.08 3-H -0.30 0.00 f0.13 +0.13 cu.+0.2d 5-H -0.13 -0.11 -0.06 -0.03 +0.52 +0.47 +0.67 +0.43 Assessed from spectrum of compound (7Ad) in (CD,),SO. solution of 2-aminothiazole (4.01 g) in Me,CO (30 ml) at 20 "C, and stirring was continued for 1d. The precipitate was collected, washed with cold Me,CO, and crystallised from MeOH to give 2-amino-3-phenacylthiazoliumbromide (3Aa) (9.71 g), m.p. 186-188 (lit.,, 197--198); 6 5.81 (2 H, s, CH,); vmax.1 687 cm-'; m/z (f.a.b.), 219 [(M -Br)+, loo%]. Analogues (prepared in Me,CO unless otherwise stated): 2-Amino-3-p-fluorobenzoylmethylthiazoliumbromide (3Ab) (prepared in THF at 50 "C) (79), m.p. 236-237 (lit.," 235-237) (MeOH).2-Amino-3-p-nitrobenzoylmethylthiazolium bromide (3Ad) (83), m.p. 260-270 (decomp.). 3-Acetonyl-2- aminothiazolium bromide (3Af) (prepared from filtered solu- tions of the reactants in Me,CO, followed by copious washing of the product with cold Me,CO and prolonged drying over P205at 20"C/3 mmHg) (81), m.p. 139-140 (30.5, 3.8, 11.7. C,H,BrN,OS, 30.43, 3.8, 11.8). Product (3Ba), see entry in earlier section about abbreviated form. 2-Amino-4-methyl-3-p- nitrobenzoylmethylthiuzolium bromide (3Bd) [prepared as for the salt (3Af)l (82), m.p. 265-270 (decomp.) (40.3, 3.3, 11.8. C, ,H,,BrN,O,S, 40.2,3.4,11.7). 3-Acetonyl-2-amino-4-methyl-thiazolium bromide (3Bf) [prepared as for the salt (3Af)l (86), m.p. 235-238 (33.6, 4.3, 11.2. C,H,,N,OS, 33.5; 4.4, 11.15). 2-Amino-4-ethoxycarbonq~lmethyE-3-phenacylthiuzoliumbromide (3Ca) (79), m.p.148-149 (EtOH) (46.8, 4.4, 7.1. C15H17- BrN,OS, 46.75; 4.4,7.3). 2-Amino-4-benzyl-3-p-bromophenacyl-thiazolium bromide (3Dc) (prepared in THF at 50 "C) (80), m.p. 253-255 (MeOH) (46.4, 3.5, 6.0. C,,H,,Br,N,OS, 46.2, 3.4, 6.0). 2-Amino-5-ethyl-3-phenacylthiazoliumbromide (3Ea) (pre- pared in CHC1, at 20°C) (78), m.p. 170-172 (EtOH) (47.95, 4.8, 8.7. C, ,HI ,BrN,OS, 47.7, 4.6, 8.55). 2-Amino-5-ethyl-3-(2-thenoylrnethy1)thiazoliumbromide (3Ee) (prepared in CHCl, at 20°C) (73), m.p. 173-174 (EtOH), (39.6, 3.8, 8.2. C,,H,3- BrN,OS,, 39.6, 3.9, 8.4). 3-Acetonyl-2-amino-5-ethylthiazoliurn bromide (3Ef) [prepared as for the salt (3Af)l (79), m.p.126- 127 (36.1, 4.9, 10.3. C,H,,BrN,OS, 36.2, 4.9, 10.6). 2-Arnino-5- benzyl-3-p-juorophenucylthiazolium bromide (3Fb) (prepared in THF at 50 "C) (83), m.p. 179-180 (Pr'OH) (53.0, 4.0, 6.8. C,,H,,FBrN,OS, 53.1, 4.0, 6.9). The Imines (4).-A suspension of 2-amino-3-phenacylthi- azolium bromide (3Aa) (4.05 g) in l~ NaHCO, (100 m1)- CHCl, (100 ml) was stirred vigorously at 20 "C for 20 min. The aqueous layer was extracted with more CHCl,; the CHCl, solutions were combined, washed with brine, dried, filtered, and concentrated at 20 OC/15 mm to a volume of ca. 8 ml. Petroleum (60 ml) was added and the solution was concentrated (on a Rotovac, without external heating or cooling) at 15 mmHg for ca. 30 min, during which time crystalline material was deposited.This was collected and dried to give 2-irnino-3- phenacyl-2,3-dihydrothiazole(4Aa) (2.9 1g),m.p. 105-106 (60.4, 4.8,12.6. C,,H,,N20S, 60.5,4.6,12.8); 6 5.21 (2 H, s, CH,), 6.01 (1 H, d, J 4.5 Hz, 5-H), and 6.73 (1 H, d, J 4.5 Hz, 4-H); v,,,, 3 345 (NH), 1 704 (CO), and 1 590 (CN) cm-l; m/z (c.i.) 219 [(M + l)+, loo%]. Analogues: 2-Imino-4-methyl-3-phenacyl-2,3-dihydrothiazole (4Ba) (76), m.p. 96-98 (62.2, 5.0, 11.9. C,,H,,N,OS, 62.0, 5.2, 12.1). 4-Ethoxycarbonylmethyl-2-imino-3-phenacyl-2,3-dihydro-thiazole (4Ca) (59), m.p. 62-64 (59.4,5.4,9.0. C,,H,,N,S, 59.2, 5.3, 9.2), v,,,, 1734, 1708, and 1594 cm-'. 4-Benzyl-3-p-bromophenacyl-2-imino-2,3-dihydrothiuzole(4Dc) (72), m.p. 148-149 (low temperature crystallisation from MeOH) (55.7, 4.0,7.2.C, ,H, ,BrN,OS, 55.8,3.9,7.2). 5-Ethyl-2-imino-3-phen- acyl-2,3-dihydrothiazole(4Ea) (80), m.p. 142-1 43 (63.6, 5.8, 11.65.Cl3HI4N20S, 63.4,5.75,11.4). 5-Ethyl-2-imino-3-(2-then-oylmethyl)-2,3-dihydrotlziazole(4Ee) (81), m.p. 84-85 (52.2,4.8, 11.0. C, 1H,2N,0S,, 52.35, 4.8, 11.1). 5-BenzyI-3-p-Juoro- phenacyl-2-imino-2,3-dihydrothiazole(4Fb) (78), m.p. 1 19-120 (low temperature crystallisation from MeOH) (66.0, 4.7, 8.7. C,,H,,FN,OS, 66.3, 4.6, 8.6). The Trifluoroucetylimines (5).-Trifluoroacetic anhydride (2.05 g) was added to a stirred solution of the imine (4Aa) (1.02 g) in dry PhMe (25 ml) at 20°C. After 2 d the solution was poured into brine (50 ml)-CHCI, (50 ml), and the mixture was basified to pH 9 with 1~ NaHCO,.Extraction of the aqueous layer with more CHCl,, and work-up of the combined CHCl, solutions gave 3-phenacyl-2-triJluoroacetylimino-2,3-dihydro-thiazole (5Aa) (1.15 g), m.p. 146-147 (CHC1,-petroleum) (49.9, 2.75, 8.8. C,,H,F,N,O,S, 49.7, 2.9, 8.9); m/z 314 (M+, 12%), 245 (47), 105 (loo), and 77 (46); v,,,, in Scheme 2. Analogues: 4-Methq~l-3-phenacyl-2-tr~~uoroacet~~lin~ino-2,3-dihydrothiazole (5Ba) (76), 169-170 (petroleum) (51.0, 3.3, 8.6. C,,H,,F,N,O,S, 51.2, 3.4, 8.6); m/z 328 (M+,31%), 259 (7), and 105 (1 00). 4-Ethoxycarbonylrnethyl-3-phenacyl-2-tr~jluoro-acetylimino-2,3-dihydrothiuzole(5Ca) (58), 1 18-1 20 (petro- leum) (51.1, 3.7, 7.1. C,,H,,F,N,O,S, 51.0, 3.8, 7.0); m/z 400 (M+,60%), 331 (75), and 105 (100). 4-Benzyl-3-p-brornophen-acy1-2-trifluoroacetylimino-2,3-dihydrothiazole(5Dc)(79), 194- 196 (EtOH) (49.7, 3.0, 5.7.C,,H,,BrF,N,O,S, 49.7, 2.9, 5.8); m/z 483 (M+, 50%) 414 (50), and 183 (100%). 5-Ethyl-3- phenacyl-2-trifluoroacetylimino-2,3-dilzydrotkiazole(5Ea) (65), 131-132 (CHC1,-petroleum) (52.75, 3.75, 8.3. C, 5H1,F3-N,O,S, 52.6, 3.85, 8.2); m/z 342 (M', 31%), 273 (loo), and 105 (87). 5-Ethyl-3-(2-thenoylrnethyl)-2-trifluoroacetylimino-2,3- J. CHEM. SOC. PERKIN TRANS. I 1989 dihydrothiazofe (5Ea) (65), 13 1-132 (CHC1,-petroleum) (52.75,3.75,8.3. Cl,H,3F,N20,S, 52.6,3.85,8.2);m/z 342 (M+, 31%), 273 (loo), and 105 (87). 5-Ethyf-3-(2-thenoyfmethyf)-2-trijiuoroacetyfimino-2,3-dihydrothiuzole(5Ee) (69), m.p. 106- 107 (CHC1,-petroleum) (44.9, 3.2,7.8.C13H1 1F3N202S2, 44.8, 3.2, 8.05); mlz (ci.) 349 [(M + l)', 1000/,]and 279 (42). The 2-Thenoyfimines (8).-Thiophene-2-carbonyl chloride (0.68 g) was added to a stirred solution of the imine (4Aa) (1.01 g) in dry pyridine (10 ml) at 20 "C. After 2 d the solution was poured into ice-water (40 ml), and extracted with AcOEt. CCl, (50 ml) was added to the material so obtained, and the mixture was evaporated at 80 "C/15 mmHg. The evaporation with CCl, was repeated, and the residue was crystallised from EtOH to give 3-phenucyf-2-(2-thenoylimino)-2,3-dihydrothiazole (8Aa) (1.11 g), m.p. 161-162 (58.4, 3.5,8.4. C16H12N202S2, 58.5, 3.7, 8.5); 6 5.70 (2 H, s, CH,), 6.76 and 7.06 (each 1 H, d, J4.5 Hz, thiazole 5-H and 4-H respectively, 7.03,7.38, and 7.78 (each 1 H, d of d, J4.7 and 4.3,4.7 and 0.9,4.3 and 0.9 Hz, thiophene 4-H, 3-H, and 5-H), 7.58 (2 H, t), 7.70 (1 H, t), and 8.10 (2 H, d) (all J values 7.9 Hz, phenyl 3-H and 5-H, 4-H, and 2-H, and 6-H); vmax.in Scheme 2.Analogues: 4-Ethoxycarbonyfmethyf-3-phenucyf-2-(2-thenoyf-imino)-2,3-dihydrothiazofe(8Ca) (69), m.p. 123-125 (EtOH) (57.9, 4.2, 6.8. C20H18N204S2, 57.95, 4.4, 6.8). 5-Ethyl-3- phenacyf-2-(2-thenoyfimino)-2,3-dihydrothiazofe(8Ea) (7 l), m.p. 145-146 (CHC1,-petroleum) (60.65, 4.4, 7.7. c18H1 6NZ02S2, 60.65,4.5,7.85).5-Ethyf-2-(2-thenoyfimino)-3-(2-thenoyfmethyl)-2,3-dihydrothiazofe (8Ee) (67), m.p. 136-137 (CHC1,-petro-feum) (53.1, 4.0, 7.7. C,6H,,N202S,, 53.0, 3.9, 7.7). The Imiduzothiazolium Sufts (6).-A solution of 2-amino-3- phenacylthiazolium bromide (3Aa) (5.25 g) in MeOH (150 ml) was boiled under reflux for 3 h, concentrated at 80°C to ca.50 ml, filtered, and cooled slowly. Collection of the crystalline material gave 6-phenyl-7H-imidazo[2.l-b]thiazoliumbromide (6Aa) (4.05 g), m.p. 125-127 (lit.,2 123-124); S[(CD,),SO] 7.55, 8.16 (each 1 H, d, J4.7 Hz), and 8.47 (1 H, s) (2-H, 3-H, and 5-H, respectively), and 7.39 (1 H, t), 7.50 (2 H, t), and 7.82 (2 H, d) (J values 7.4 Hz, phenyl 4-H, 3-H and 5-H, and 2-H and 6-H); m/z (f.a.b.) 201 [(A4-Br)', loo%]. Analogues: 6-p-F/uorophenyf-7H-imiduzo[2,1-b] thiazolium bromide (6Ab) (87), m.p. 222-223 (MeOH) (60.1, 3.8, 12.9. CllH7BrFN2S, 60.3, 3.7, 12.8); m/z 219 (100%). 6-Methyl-7H- irnidazoC2,l -b]thiazofium bromide (6Af) (84), m.p.17&17 1 (EtOH) (33.0, 3.1, 12.85. C6H7BrN2S, 32.9, 3.2, 12.8); m/z 139 (100%). 3-Methyl-6-phenyl-7H-imidazo[2.l-b]thiazolium bromide (6Ba) (90), m.p. 223-225 (lit.,' 198-224, and lit.,, 310) (MeOH); m/z 215 (100%). 3-Methyl-6-p-nitrophenyl-7H-imid-uzo~2,l-b]thiazofium bromide (6Bd) (88), m.p. 250 (MeOH) (42.5, 3.2, 12.1. C12HloBrN,02S, 42.4, 3.0, 12.35); m/z 260 (100%). 3,6-Dimethyl-7H-imidazo[2,1-b]thiuzofium bromide (6Bf) (87), m.p. 250 (MeOH) (36.2, 3.8, 11.9. C7H,BrN2S, 36.1, 3.9, 12.0); m/z 153 (100%). 3-Ethoxycurbonylmethyl-6-phenyl-7H-imidazo[2,l-b]thiuzofiumbromide (6Ca) (85), m.p. 165-166 (CHCI,) (48.9, 4.2, 7.6. C, ,H,,BrN,02S, 49.05, 4.1, 7.6); m/z 287 (100%). 2-Ethyf-6-phenyf-7H-imidazo[2,1-b]thi-azolium bromide (6Ea) (80), m.p.122-123 (EtOH) (50.4, 4.3, 9.1. C, ,H13BrN2S, 50.5,4.25, 9.05); m/z 229 (100%). 2-Ethyl-6- methyl-7H-imiduzo[2,l-b]thiazofiumbromide (6Ef) (84), m.p. 126-127 (EtOH) (38.8,4.4,11.1. C,H, ,BrN,S, 38.9,4.5, 11.35); m/z 167 (100%). The Imiduzo[2,l-b] thiazofes.--(a) From the salts (6). A solution of 6-pheny1-7H-imidazoC2,l-b]thiazolium bromide (6Aa) (3.24 g) in 2~ Na,CO, (60 ml) -€HC13 (60ml) was stirred vigorously at 20 "C for 20 min. Extraction of the aqueous layer with more CHCl,, and work-up of the combined CHCI, solutions gave 6-phenylimidazo[2,l-b] thiazole (7Aa) (1.95 g), 647 m.p. 146-147 (lit.,2 145-146), and lit.,' 144-145 (from CHC1,-petroleum); m/z (ci) 200 (M', 100%); 'H n.m.r.signals (of all imidazothiazoles) in Table 1. Analogues prepared similarly: 6-p-Ffuorophenyfimidazo-[2,l-b]thiazofe (7Ab) (84), m.p. 99-100 (CHC1,-petroleum) (60.4, 3.2, 12.8. CllH,FN2S, 60.5, 3.2, 12.8); m/z 218 (100%). 6-MethylimidazoC2,l -b]thiazole (7Af) (79), b.p. 106-107/3 mmHg (lit.,, 83-85/0.1 mmHg); m/z 138 (100%). 3-Methyl-6- phenyl-imidazo[2,l-b]thiazole (7Ba) (80), m.p. 113-1 14 (lit.,' 113.5, and lit.,, 112-113.3) (petroleum); m/z 214 (100%). 3,6- Dimethylimidazo[2,1-b]thiazole (7Bf) (84), b.p. 1 15-1 17/3 mmHg (lit.,, 86-88/0.35 mmHg), m.p. 63-64 (lit.,, 96-97); m/z 152 (100%). 3-Ethoxycurbonyfrnethyl-6-phenyZimidazo[2,1-blthiazofe (7Cr) (73), m.p. 71-72 (petroleum) (62.7, 4.8, 10.0. C,,H,,N,O2S, 62.9, 4.9, 9.8); m/z (c.i.) 287 (100%). 2-Ethyl-6- phenyfimidazoC2,l -b]thiazofe (7Ea) (88), m.p.125-1 27 (CHC1,-petroleum) (68.25, 5.2, 12.1. C13H12N1S, 68.4, 5.3, 12.25); m/z 228 (100%). 2-Ethyf-6-methyfimidazo[2,l-b]thiuzofe (7Ef) (87), b.p. 86-88/0.4 mmHg (57.8, 5.85, 16.9. C,H,,N2S, 57.8, 6.05, 16.85); m/z (ci) 167 (100%). A solution of KOH (0.51 g) in EtOH (10 ml) was added to a stirred solution of 3-methyl-6-p-nitrophenyl-7H-imidazo-[2,l-b]thiazolium bromide (2.95 g) in EtOH (150 m 1) at 20 "C. After 30 min the solvent was removed at 40 "C/15 mmHg, and the residue was boiled with AcOEt (100 ml). Filtration of the hot solution, concentration of the filtrate to ca. 20 ml, and slow cooling of the solution gave 3-methyl-6-p-nitrophenyfimidazo-C2,l-blthiazole (7Bd) (1.61 g), m.p. 240-242 (55.4, 3.5, 16.3.C12H,N,0,S, 55.6,3.5, 16.2); m/z (ci) 260 [(M + l)+, 100741. (b) From the salt (3Ad). A solution of 2-amino-3-p-nitro- benzoylmethylthiazolium bromide (3Ad) (10.07 g) in dimethyl- formamide (200 ml) was kept at 120 "C for 15 min, filtered, and cooled slowly. The yellow crystalline product was collected, washed with dimethylformamide and then acetone, and dried to give 6-p-nitrophenyfimiduzo[2,l-b]thiazofe(7Ad) (6.25 g), m.p. 250 (54.0, 2.75, 17.2. CllH7N302S, 53.9, 2.9, 17.1); S[(CD3)2SO] 7.35 (1 H, d, J4.5 Hz, 2-H), 8.00 (1 H, d, J4.5 Hz, 3-H), and 8.52 (1 H, s, 5-H); m/z 245 (M', 100%) and 199 (41). (c) From the imines (4). A solution of 2-imino-3-phenacyl-2,3-dihydrothiazole (4Aa) (1.62 g) in EtOH (100 ml) was boiled under reflux for 1 h.Evaporation afforded 6-phenylimidazo- [2,1-b]thiazole (7Aa) (1.25 g), m.p. and mixed m.p. 145-146. Similarly the imines (4Ba), (4Ca), and (4Ea) gave the imidazothiazoles (7Ba), (7Ca), and (7Ea) in yields of 80-85%. A solution of 5-ethyl-2-imino-3-(2-thenoylmethyl)-2,3-di-hydrothiazole (4Ee) in EtOH was refluxed for 2 h. The residue obtained by evaporation was shown by 'H n.m.r. to consist largely of the starting material. A solution of the imine (4Ee) (2.06 g) in PhMe (80 ml) was boiled under reflux for 4 h, and then evaporated at 100°C/15 mmHg). The residue was dis- solved in CHCI,, and treated with activated charcoal. Evapor- ation, and crystallisation from CHC1,-petroleum gave 2-ethyl- 6-(2-thienyl)imiduzo[2,l-b]thiuzole(7Ee) (1.08 g), m.p.116- 118 (56.3, 4.35, 11.9. C,,H1,N2S2, 56.4, 4.3, 11.95); m/z (M', 100%) and 129 (48). The Trijiuoroacetyfimine (12D).-A mixture of 2-amino-4-benzylthiazole (1D)(3.92 g) and Me1 (4.2 g) was stirred at 50 "C for 2 h, and then evaporated at 15 mmHg. The material so obtained crystallised from MeOH to give 2-amino-4-benzyf-3- methylthiazofium iodide (5.52 g), m.p. 19W191 (40.1, 4.2, 8.35. CllH,,IN,S, 39.8, 3.9, 8.4). This salt (3.35 g) was stirred-vigorously with 2~ NaOH (100 ml) at 20 "C for 1 h. Isolation with CHCI,, gave a product (1.58 g) [S 3.15 (3 H, s, NMe), 3.62 (2 H, s, CH,), 5.35 (1 H, s, 5-H), 6.17 (1 H, C=NH), and 7.28 (5 H, s, Ph)] formulated as 4-benzyl-2-imino-3-methyl-2,3-dihydrothiazole; this on treatment with trifluoroacetate anhydride as described for the products (5), afforded 4-benzyf- 3-methyl-2-tri~uoroacetylimino-2,3-dihydrothiazole(12D) (1.92 g), m.p.137-139 (Pr'OH) (52.1,3.6,9.3.C,3H11F3N20S,52.0, 3.7, 9.3); m/z300 (M', 15%) and 231. 5-Phenylimidazo[2,1-b]thiazole(17).-A solution of Br, (20.2 g) in dry CH,Cl, (20 ml) was added during 1 h in to a stirred solution of phenylacetaldehyde (distilled immediately before use, b.p. 58-60 OC/3 mmHg; 15.1 g) in dioxane (100m1)-CH,Cl, (100ml) at 0 "C. A solution of NaHCO, (15g) in water (100ml) was added, and stirring was continued for 30 min. The layers were separated, and the aqueous layer was extracted with more CH,Cl, (100ml).The CH,Cl, solutions were combined, washed with brine ( x 3),and dried (MgSO,). Removal of solvent at 20OC/15 mmHg gave material (17.6g) shown by 'H n.m.r. examination to be 2-bromo-2-phenyl- ethanal (15)[S 6.02 (1 H, d, CHBr) and 9.32 (1 H, d, CHO)] of 94% purity. A solution of this aldehyde (13.62g) in dry THF (10ml) was added during 30 min to a stirred solution of 2-aminothiazole (6.41g) in THF (25ml) at 2OoC, and stirring was continued for 1 h. The insoluble material was collected, and washed with a little cold THF. Crystallisation from EtOH gave 5-phenyl-7H-imidazo[2,1-b]thiazoliumbromide (16)(6.62g), m.p. 240-241 (47.1, 3.1, 9.9.C,,H,BrN,S, 47.0,3.2, 10.0);S[(CD,),SO] 7.70 (1 H, d, J4.5,2-H), 8.03 (1 H, s, 6-H), and 8.41(1H, d, J 4.5,3-H); m/z(f.a.b.) 201 [(M-Br)', 100%].Basification of the foregoing salt (2.15g) by the general procedure (NaHCO,) gave 5-phenylimidazo[2,l-b]thiazole(15)(1.25g), b.p. 141-143/15 mmHg, m.p. 87-88 (66.1, 3.9,13.9. C,,H,N,S, 66.0, 4.0, 14.0); m/z200(M+, 100%). Products from 2-Aminothiazoles and Ethyl Brom0acetate.- The compounds shown in Scheme 3 were obtained using the general procedures described earlier (work in Scheme 1).The products were: 2-Amino-3-ethoxycarbonylmethylthiazoliumbromide (HA) (72),m.p. 142-144 (EtOH) (31.6, 4.2, 10.4. C,H BrN,02S, 31.5, 4.2,10.5). 2-Amino-3-ethoxycarbonyl-methyl-4-methylthiazolium bromide (18B)(89),m.p. 168-169 (EtOH) (34.0, 4.6, 10.1. CsHl,BrN,O,S, 34.2, 4.7, 10.0). 2-Amino-3-ethoxycarbonylmethyl-5-ethylthiazolium bromide (HE)(78),m.p.141-143 (EtOH) (36.55, 5.0, 9.4. C9H15-BrN,02S, 36.6,5.1,9.5).3-Ethoxycarbonylmethyl-2-imino-2,3-J. CHEM. SOC. PERKIN TRANS. I 1989 dihydrothiazole(19A)(58),b.p. 97-102 (bath te,mp.)/3 mmHg, m.p. 64-65 (45.2,5.3,15.0.C,HloN,0,S,45.1, 5.4, 15.0); 6 1.31 (3 H, t, J 7.2)and 4.25(2 H, q, J 7.2)(CO,Et), 4.46 (2 H, s, NCH,), 5.82(1H, d, J4.4Hz, 5-H), and 6.42 (1 H, d, J4.4Hz, 4-H); v,,,. 1748 cm-'; m/z186 (M', 52%) and 1 145 (100). 3-Ethoxycarbonylmethyl-2-imino-4-methyl-2,3-dihydrothiazole (19B)(72),b.p. 105-110 (bath temp.)/3 mmHg, m.p. 67-69 (48.1, 6.0, 14.1. CSHl,N,O,S, 48.0, 6.0, 14.0). 3-Ethoxy- carbonylmethyl-5-ethyl-2-imino-2,3-dihydrothiazole(19C)(65), b.p. 108-111 (bath temp.)/3 mmHg, m.p.88-90 (50.6, 6.55, 13.0.C,H1,N2O2S, 50.45, 6.6, 13.1). 3-Ethoxycarbonylmethyl- 4-methyl-2-trifluoroacetylimino-2,3-dihydrothiazole(20B)(76), m.p. 86-87 (petroleum) (40.6,3.5,9.3.C10HllF3N203,40.5, 3.7, 9.45); v,,,. 1 749(C0,Et) and 1 635 cm-I (COCF,); m/z296 (M', 31%) and 227 (100). 3-Ethoxycarbonylmethyl-4-methyl-2-(2-thenoylimino)-2,3-dihydrothiazole 89-90(21B)(72), (EtOH) (50.5, 4.1,11.6. C,,H,,N,OS,, 50.4, 4.2, 11.75); vmaX.1 746 (C0,Et) and 1580 cm-' (thenoyl); m/z(ci) 239 [(M+ l)+,33x1 and 148 (100). References 1 H. Kondo and F. Nagasawa, J. Pharm. SOC.Jpn., 1937,57, 308. 2 B. Kickhofen and F. Krohnke, Chem. Ber., 1955,88, 1109. 3 S. Sano, J. Pharm. SOC.Jpn., 1972, 92, 51. 4 G. Kernpler, J. Spindler, H.-3. Fiebig, and G. Sarodnick, J. Prakt. Chem., 1971, 313,977. 5 R. Barone, M. Chanon, and R. Gallo in 'Thiazole and Its Derivatives,'ed. J. V. Metzger, Wiley, New York, 1979, Part 2, ch. VI. 6 T. N. Birkinshaw, S. A. Harkin, P. T. Kaye, G. D. Meakins, and A. K. Smith, J. Chem. SOC.,Perkin Trans. I, 1982, 939. 7 H. Erlenmeyer, C. Becker, E. Sorkin, H.Bloch, and E. Suter, Helv. Chim. Acta, 1947,30, 2058. 8 C. F. H.Allen and J. A. Vanallan, J. Org. Chem., 1948, 13, 603. 9 A. V. Dombrovskii, A. M.Yurkevich, and A. P. Terentev, Zh. Obshch. Khim., 1957,27, 3047 (Chem. Abstr., 1958, 52, 8087). 10 S. R. R. Musk, C. A. Robertson, and L. S. Woodhouse, Part I1 Theses, University of Oxford, 1987. 11 Netherlands Appl. 6 505 806 (Chem. Abstr., 1966, 64, 11 213). Received25th July 1988;Paper 8/02997K