J. CHEM. SOC. PERKIN TRANS. I 1992 Azoles. Part 8.' Metallation and Bromine -Lithium Exchange Reactions of Polyhalogenothiazoles Salah Athmani, Andrew Bruce (in part) and Brian lddon The Ramage Laboratories, Department of Chemistry and Applied Chemistry, University of Satford, Satford, M5 4WT, UK ~ ~~ ~ 2,4-Dichloro- and 2,4-dibromo-thiazole were deprotonated at position-5 with LiNPr,' in THF at -78 "C and the resulting lithium compound was quenched with various reagents, to yield various trisubstituted thiazoles. 2,5-Dibromo-4-chlorothiazole reacted with n-butyllithium in TH F at -78 "Cat position-5 and the resulting lithium derivative gave 2-bromo-4-chloro-5-substitutedthiazoles when quenched with the appropriate reagent. Both the 2-and 5-bromine-atoms were reactive in diethyl ether.2,5- Dibromo- thiazole failed to deprotonate at position-4 under various reaction conditions, whereas treatment of 2,4,5-tribromothiazole with 1 mole equivalent of n-butyllithium in THF at -90 "C, followed by addition of dimethyl disulfide after 30 min, gave a high yield of the 2,5-bis(methylthio)-compound. The tribromo- compound was also treated with 1 mole equivalent of n-butyllithium or methyllithium under various reaction conditions and the products formed after hydrolysis were analysed by H N MR spectroscopy. The 5-bromine-atom is the most reactive and greater selectivity is obtained with methyllithium. Many common organic compounds are readily poly- or per-brominated and the bromine atoms provide useful 'handles' for the introduction of other substituents via bromine --lithium exchange techniques2 Previously we have demonstrated that the bromine atoms in readily available l-protected 2,4,5- tribromoimidazoles can be replaced stepwise in the order 2 -5 -4.3-6 Similar work has been carried out with 1- and 2-protected dibromo- 1,2,3-tria~oles.~ We now report an extension of our work to polyhalogenothiazoles.Discussion In diethyl ether at -78 "C, 2,4-dibromothiazole 5 reacts with n- butyllithium exclusively by bromine -lithium exchange at position-2,'*' whilst 2,5-dibromo-4-(trifluoromethyl)thiazole3 is reported' to undergo bromine lithium exchange with n- butyllithium in hexane at -60 "C at both position-2 and position-5. Similarly, 2-bromothiazole (more readily available than the parent heter~cycIe)~*~'~-'~ and its derivative^^.','^ react with n-butyllithium in diethyl ether at low temperatures to give the corresponding thiazol-2-yllithium compound.With LiNPr,' (LDA), 2-bromothiazole is deprotonated at position-5, to give 2-bromothiazol-5-yllithi~m.'~~'By contrast with 5-bromo- thiazole and its derivatives, which undergo bromine -lithium exchange reactions with n-butyllithium'.' or pheny1lit hi um ' without difficulty, 4- bromo t hiazole is me tal- lated with n-butyllithium at position-2.' However, a number of substituted 4-bromothiazoles undergo bromine -lithium exchange reactions to yield the corresponding thiazol-4-yllithium c~rnpound.~.'~.'~ The difference in the reactivities of bromine atoms at C-4 and C-5 in imida~oles~-~ and thiazoles can be attributed to the effect of a nitrogen lone pair on N-3 (the 'ALP effect'' 7, which destabilises a developing negative charge at C-4.2-Aminothiazole and thiazolidine-2,4-dione are commer-cially available. Bromination of the former compound yields 2- amino-5-bromothiazole1* which can be converted into 2,5- dibromothiazole 1 via diazotisation and treatment of the resulting diazonium salt with sodium bromide in the presence of a copper salt (Sandmeyer reaction).' ' Treatment of thiazolidine-2,4-dione with either phosphoryl trichloride or phosphoryl tribromide (an expensive reagent) gives 2,4-di- R 1 R=H 2 R=CI 3 R=CF3 CI OHC2AR 21 R=NMe2 22 R=piperidino R MeS &%Me 23 R=CI 24 R=Br CI R2kBr 25 R=H 26 R=CHO 27 R=C02H 28 R=C(OH)Pb 29 R=SiMe3 X RXAx 4 X=CI,R=H 5 X=Br,R=H 6 X=R=Br 7 X=CI,R=CHO 8 X=CI,R=C02H 9 X = CI, R = CO2Et 10 X = CI, R = CH(0H)Ph 11 X = CI, R = C(0H)Phz 12 X=CI,R=SMe 13 X = CI, R = SiMe3 14 X = CI, R = SnMe3 15 X = Br, R = CHO 16 X = Bt, R = C02H 17 X = Br, R = C(0H)Php 18 X = Br, R = SMe 19 X = Br, R = SiMe3 20 X = Br, R = SnMe3 chloro-4 or 2,4-dibromo-thiazole 5, respectively.l9 The di- bromo compound is unstable, losing bromine slowly on storage at ambient temperature.Bromination of 2,4-dichlorothiazole 4 with bromine in acetic acid gives 2,5-dibromo-4-chlorothiazole 2,20whilst further bromination of the 2,4-dibromo compound 5 similarly gives 2,4,5-tribromothiazole We chose to study the metallation and bromine -lithium exchange reactions of these readily available starting materials particularly with the synthesis of 4-halogenothiazole-5-carbaldehydesin mind.These aldehydes are key intermediates for the synthesis of thienothiazoles, through their reaction with ethyl 2-mercapto- acetate (see ref. 1 for the analogous synthesis of thieno-imidazoles), and several novel heterocyclic systems. 2,4-Dichloro-4 and 2,4-dibromo-thiazole 5 were deproto- nated at position-5 with LDA in anhydrous tetrahydrofuran (THF) at -78 "C and the resulting thiazol-5-yllithium com- pounds were quenched with either carbon dioxide, ethyl chloroformate, benzaldehyde, benzophenone, chlorotrimethyl- silane, or chlorotrimethylstannane, to give compounds 8-1 1 and 13 and 14, or 16,17,19 and 20, respectively (see Table 1 for details) (compounds 14 and 20 are very unstable; consequently their purification and analysis proved extremely difficult).In an attempt to prepare 2,4-dichlorothiazole-5-carbaldehyde7 2,4-dichlorothiazol-5-yllithium was quenched with N,N-dimethyl- formamide (DMF). The product isolated, however, was shown (see Experimental section) to be 4-chloro-2-(dimethylamino)-thiazole-Scarbaldehyde 21. Quenching of this thiazol-5-yllithium compound with N-formylpiperidine gave an analog- ous product 22. Since the completion of our work Sawhney and Wilson21 have reported the synthesis of a series of 2-(dialkylamino)thiazole-5-carbaldehydesby this method.A final quench with water rather than acid is essential if compounds such as 21 and 22 are to be isolated.21 These reactions proceed via initial formation of 2,4-dichlorothiazole-5-carbaldehyde7, which undergoes nucleophilic displacement of its activated 2-chlorine atom with the liberated secondary amine. 2,4-Dichlorothiazole-Scarbaldehyde7 did not react with N,N-dimethylformamide (neat) at ambient temperature during 5 h, nor did 2,4-dichlorothiazole 4.22*23When 2,4-dibromothiazol- 5-yllithium was quenched with DMF, then acid was added to the reaction mixture, it gave 2,4-dibromothiazole-5-carb-aldehyde 15. When 2,4-dichloro-and 2,4-dibromo-thiazol-5-yllithium were quenched with dimethyl disulfide, they gave compound 23 or 24, respectively, presumably through reaction of the initially formed 2,4-dihalogeno-5-(methylthio)thiazole,12 or 18, with the liberated methylthiolate (MeS-) anion.Successive treatment of 2,5-dibromothiazole 1 with LDA in THF (at 0 "C) and dimethyl disulfide resulted in a quantitative return of starting material. A previous attempt to metallate l-(ethoxymethyl)-5-methylthio-2-(phenylthio)imida-zole in position-4 with LDA in THF at -70 "Csimilarly failed but metallation of this compound was achieved with potassium diisopropylamide-lithium t-butoxide (KDA).24 However, KDA failed to metallate 2,5-dibromothiazole in position-4; again starting material was recovered. When 2,5-dibromo-4-chlorothiazole 2 was treated with 1 mole equivalent of n-butyllithium in diethyl ether at -78 "C the product composition, after quenching of the reaction mixture with water, was dependent on time, presumably as a result of transmetallation reactions occurring after generation of the kinetically controlled initial product(s).Both the 2- and 5-bromine atoms are reactive. After 12 s, the yellow oil obtained was shown by 'H NMR spectroscopic analysis to be a mixture containing 5-bromo-4-chloro- 30, 2-bromo-4-chloro-25, and 4-chloro-thiazole 32 (proportions 7: 10:0.9). As time elapsed the amount of 4-chlorothiazole 32 (with two doublets, J 2.0 Hz, at 6 7.07 and 8.6725) increased until, after 30 min, it became the exclusive hydrogen-bearing product.1 -Protected tribromoimidazoles (in Et20)3*5 and 2,5-dibromo-4-(trifluoro-methy1)thiazole 3 (in he~ane)~ similarly react with 1 mole equivalent of n-butyllithium at both the 2- and 5-positions. However, when 2,5-dibromo-4-chlorothiazole 2 was treated X X Br/kJ 30 X=CI 32 X = CI 31 X=Br 33 X=Br J. CHEM. SOC. PERKIN TRANS. I 1992 with 1 mole equivalent of n-butyllithium, but in THF (at -90 "C) instead of diethyl ether as the solvent, and the reaction mixture was quenched with water, the only isolable hydrogen- bearing product was 2-bromo-4-chlorothiazole 25 (6 at 7.13 for 5-H). 2-Bromo-4-chlorothiazol-5-yllithiumalso reacted with carbon dioxide, benzophenone, and chlorotrimethylsilane, to give (after hydrolysis) compounds 27-29, respectively.Quenching of this lithium derivative with either DMF or N-formylpiperidine failed to yield any 2-bromo-4-chlorot hiazole- Scarbaldehyde 26; these reactions gave only intractable black residues. Dimethyl disulfide as the quenching reagent gave compound 23, identical with the sample prepared as described before. When 2,4,5-tribromothiazole 6 was treated with 1 mole equivalent of n-butyllithium in diethyl ether, the product composition (by 'H NMR spectroscopy), after treatment of the resulting mixture with 2 mol dm-3 hydrochloric acid, was shown to be dependent on time and temperature. After 10 min at -78 "C,a mixture of 2,4-dibromo- 5 and 4-bromo-thiazole 33 (ratio 10:5.5) was obtained. After 30 min at -78 "C, the ratio of these products changed to 3: 10 whilst, after 10 min at -90 "C, a mixture of 2,4-dibromo- 5, 4,5-dibromo-31, and 4-bromo-thiazole 33 (proportions 10:4.55: 5.45) was obtained.When 2,4,5-tribromothiazole 6 was treated successively at -78 "C with 1 mole equivalent each of n-butyllithium and dimethyl disulfide (after 30 min), 4-bromo-2,5-bis(methyl- thio)thiazole 24 was obtained in 71% yield, identical with the sample prepared as described before from 2,4-dibromothiazole 5. As is the case with 1-protected tribromoimida~oles,~*~*~2,4,5-tribromothiazole 6 was found to be more selective in its reactions with methyflithiurn, in diethyl ether at -90 "C. After 20 min, quenching of the reaction mixture with 2 mol dm-3 hydrochloric acid gave a mixture of 2,4-dibromo-5 and 4- bromothiazole 33 (ratio 10: 1).Unlike 1-protected tribromo- imidazoles, which react with ethylmagnesium bromide selectively at the 2- bromine-a tom, 3,5 2,4,5-tribromothiazole 6 failed to react with this reagent in THF, either at ambient (during 5 h) or reflux temperature (overnight); starting material was recovered in each case. Experimenta1 IR spectra were recorded for liquid films or Nujol mulls between sodium chloride plates with a Perkin-Elmer 297 or 1710 FT spectrometer; 'H NMR spectra were recorded with a Perkin-Elmer R32 (90 MHz) or a Bruker AC300 (300.13 MHz) instrument with tetramethylsilane as internal standard; low- resolution mass spectra were obtained using a Finnigan 4500 machine, and high-resolution mass spectra were recorded with a Kratos Concept 1s mass spectrometer, both operating at 70 eV.Reported molecular weights (obtained by low-resolution mass spectrometry) are given for the isotopes "Br, 35Cl and l2OSn. Isotopic abundance ratios were as expected for the compounds containing these elements. Camlab Polygram silica G/UV,S4 plates were used for TLC, flash chromatography was carried out on silica gel 60 (Merck 9385), and medium-pressure column chromatography on silica gel (Merck 7736). Light petroleum had a boiling range of 6@80 "C unless stated otherwise. Ether refers to diethyl ether. Solvents and reagents were dried by standard procedures. In all cases organic extracts were combined, dried (MgS04), and evaporated under reduced pressure on a rotary evaporator.Small-scale distillations were carried out with a Kugelrohr microdistillation apparatus and the 'b.p.' temperatures recorded are those of the oven at the time of distillation. M.p.s were recorded with a Buchi m.p. apparatus and are uncorrected. Table I Polysubstituted thiazoles prepared by metallation and bromine -+ lithium exchange reactions of polyhalogenothiazoles c-n f CA09R5 -0Found (%) Required (7;) rn 'H NMR data (&value) 70 Compound R' R4 RS Quench reagent Yield (x) M.p. or B.p." ("C) v,,,/cm-' (Assignment) (Assignment) C H N FoundM' Formula C H N RequiredM 8 CI CI CO,H co2 40 117-1 18 (A)" 1699 (CO) and 196.91 14 C4HC12N02S 196.9 105 2854-3586br (OH) 9 CI CI C0,Et CIC0,Et 66 156-1 57 (B) 1740 (CO) 1.35 (3 H, t.Me) and 32.3 2.3 5.7 225 C,H,CI,NO,S 32.0 2.2 6.2 225 4.36 (2 H, q, CH2) 10 CI CI CH(0H)Ph PhCHO 74 150 at 0.2 mmHg 3300-3400br (OH) 3.32 (IH, s, OH), 6.02 46.4 2.9 5.3 259 C,,H,CI,NO2S 46.2 2.7 5.4 259 (1 H. s. CH) and 7.34- 7.40 (5 H, m, ArH) I1 CI CI C(OH)Ph, Ph2CO 25 128-129 (C)c 3400-3550br (OH) 3.62 (1 H, s, OH) and 57.2 3.2 4.0 335 C,,HlICIZNOS 57.2 3.3 4.2 335 7.20-7.50 (10 H, m, ArH) 13 CI CI SiMe, CISiMe, 71 90at 0.2 mmHg 0.35 (9 H, s, SiMe,) 31.3 4.05 6.2 225 C,H,CI,NSSi 31.9 4.0 6.2 225 14 CI CI SnMc, CISnMe, 69 55-57 (D) 0.43 (9 H, s, SnMe,) 317 C,H,CI,NSSn 317 15 Br Br CHO DMF 54 80-81 (E) 1661 (CO) 9.79 (1 H, s, CHO) 17.1 0.2 5.0 269 C4HBr2NOS 17.7 0.4 5.2 269 16 Br Br CO,H co2 68 178-179 (A) 1699 (CO) and 17.2 0.5 4.3 285 C4HBr2N02S 16.7 0.35 4.9 285 2854-3586br (OH) 17 Br Br C(OH)Ph, Ph2C0 46 122-123 (D) 3300-3583br (OH) 3.72br (I H, s, OH) and 45.3 2.5 3.1 423 C,,H,,Br2NOS 45.2 2.6 3.3 423 7.34 (10 H, m, ArH) 19 Br Br SiMe, CISiMe, 66 130 at 2.0 mmHg 0.37 (9 H, s, SiMe,) 312.8571 C,H,Br,NSSi 3 12.8593 20 Br Br SnMe, CISnMe, 48 79-80 (D) 0.37 (9 H, s, SnMe,) 404.7845 C,H,Br,NSSn 404.7845 21 NMc, CI CHO DMF 76 105-107 (D)'." 1650 (CO) 3.19 (6 H, s, NMe,) and 38.2 3.6 14.2 190 C,H,CIN,OS 37.9 3.7 14.7 I90 9.73 (1 H, s.CHO) 22 Piperidino CI CHO N-Formylpipcridine 71 91-92 (D) 1661 (CO) 1.68 (6 H, m, CH,), 3.57br 46.6 4.8 12.3 230 C9HI ICIN2OS 46.8 4.8 12.2 230 (4 H, m, CH,), and 9.73 (1 H, s, CHO) 23 SMe CI SMc Me2S2 42,' 78 Yellow oil'.g 2.38 (3 H, s, 5-SMe) and 28.6 2.9 6.5 21 I CSH,CINS3 28.4 2.8 6.6 21 I 2.64 (3 H,s, 2-SMe) 24 SMc Br SMc Mc2S2 76,h 71 Yellow oily 2.39 (3 H, s, 5-SMe) and 23.9 2.45 5.4 255 CSH,BrNS, 23.4 2.4 5.5 255 2.64 (3 H, s, 2-SMe) 27 Br CI CO2H C02 47 16&-161 (A) 168O(CO) and 240.8597 C4HBrCIN02S 240.8600 2700-33 1Obr (OH) 28 Br CI C(OH)Ph, Ph,CO 59 l3&138 (E) 32963582br (OH) 3.58 (1 H, s, OH) and 50.65 3.0 3.5 379 C16Hl,BrCINOS 50.5 2.9 3.7 379 7.30-7.42 (10 H, m, ArH) 61 29 Br CI SiMc, CISiMc, 95 at 0.5 mmHg 0.34 (9 H, s, SiMe,) 27.0 3.5 5.2 269 C6H9BrCINSSi 26.6 3.35 5.2 269 ~ ~~ ~~~ ~ ~ ~~~~ ~~~ ~ 'Recrystallisation solvents: A water; B ethanol; C light petroleum-ethyl acetate; D light petroleum; E light petroleum (40-60 "C); Liquids distilled using Kugelrohr distillation apparatus." Synthesized" as a minor isomer by treatment of 2.4.5-trichlorothiazole with BuLi followed by carbonation of the reaction mixture (no details, including absence of a m.p.) -the major product was 4,5-dichlorothiazole-2-carboxylicacid. L. Andrew Bruce, Honours BSc. Degree in Applied Chemistry final year Dissertation, 1989. yield 84% and m.p. 108 "C (from light petroleum-zthyl acetate). From 2,4-dichlorothiazole. J From 2,5-dibromo-4-chIorothiazole.R Purified by column chromatography on silica. Light petroleum (4&60 C)eluted the 3 product. From 2,4-dibromothiazolc. From 2,4,5-tribromothiazolc. 4 218 Microanalytical (for C, H and N) results were supplied by Butterworth Laboratories Ltd of Teddington.The following compounds were prepared by literature procedues: 2-amino-5-bromothiazole (617;), m.p. 95-96 "C (from toluene) (lit.,' ' 34% and m.p. 93-94 "C,lit.,' 59% and m.p. 80 "C); 2,5-dibromothiazole 1 (50%), m.p. 44-46 "C (from EtOH) (1it.,l8 65% and m.p. 4W7 "C);2,4-dichlorothiazole 4 (65%), m.p. 4243 "C(from aq. EtOH) (Iit.,l9 51% and m.p. 42- 43 "C);2,4-dibromothiazole5 (38.5%), m.p. 81-82 "C(sublimed at 90 "C and 1.00 mmHg) (Iit.,l9 60% and m.p. 82 "C); 2,5-dibromo-4-chlorothiazole 2 (58%), b.p. 78 "C at 1.1 mmHg (lit.,20 73% and b.p. 78 "C at 1.1 mmHg); and 2,4,5-tribromothiazole 6 (87%), m.p. 36 "C(sublimed at 45 "Cand 0.2 mmHg) (lit.,20 87% and m.p. 36 "C). Reactions of 2,4-Dichloro-4 and 2,4-Dibromo-thiazole 5 with LDA.-General reaction. n-Butyllithium in hexane (1.1 rnol equiv.) was syringed dropwise through a rubber septum cap into a round-bottomed flask containing a stirred solution of diisopropylamine (1.1 rnol equiv.) in anhydrous THF (1 5 cm') at -78 "C (internal temperature) under nitrogen and the resulting solution was allowed to warm up to 0 "C,then cooled again to -78 "C.A solution of either 2,4-dichloro- 4 or 2,4- dibromo-thiazole 5 (0.5 g) in anhydrous THF (10 cm') was added dropwise at such a rate that the temperature did not exceed -70 "C.The resulting solution was stirred at -78 "Cfor 30 min. Then the quenching reagent (1.1 rnol equiv.) was syringed in dropwise as a solution in THF (10 cm') and the mixture was allowed to warm up to ambient temperature.Water (10 cm') was added and extraction with ether (3 x 50 cm3) gave the crude product. Solids were crystallised whilst liquids were either distilled (Kugelrohr apparatus) or purified by chrom- atography on a silica column. For the synthesis of carboxylic acids an excess of Cardice was added to the reaction mixture prior to quenching with water. Addition of 10% hydrochloric acid caused precipitation of the crude products. After quenching with chlorotrimethylsilane or chlorotrimethylstannane, reaction mixtures were washed with saturated aq. sodium hydrogen carbonate (30 cm') before extraction with ether. Details of the products are given in Table 1. Reactions of 2,5-Dibromo-4-chlorothiazole 2 with n-Butyl- lithium.-General reaction.1.6 rnol dm-3 n-Butyllithium in hexane (1.13 cm', 1.8 mmol) was syringed dropwise through a rubber septum cap into a round-bottomed flask containing a stirred solution of 2,5-dibromo-4-chlorothiazole 2 (0.5 g, 1.8 mmol) in anhydrous THF (10 cm3) at -90 "C (internal temperature) under nitrogen and the resulting mixture was stirred at this temperature for a further 30 min. The quenching reagent (1.8 mmol) was added as a solution in THF (10 cm') and the mixture was allowed to warm up slowly to ambient temperature. After quenching of the mixture with an excess of 2 rnol dm-3 hydrochloric acid, it was treated as described in the previous general reaction. Details of the products are given in Table 1.Attempted Deprotonation of 2,5-Dibromothiazole 1.-(a) With LDA ut -90 "C. 1.6 mol dm-' n-Butyllithium in hexane (1.40 cm', 2.25 mmol) was syringed through a rubber septum cap into a round-bottomed flask containing a stirred solution of diisopropylamine (0.23 g, 0.32 cm', 2.25 mmol) in anhydrous THF (10 cm') cooled at -90 "C(internal temperature) under nitrogen and the resulting mixture was stirred for 30 min at this temperature. A solution of 2,5-dibromothiazole (0.5 g, 2.06 mmol) in THF (10 cm3) was added and the mixture was stirred at -90 "C for a further 30 min. Then a solution of dimethyl disulfide (0.21 g, 0.25 cm', 2.25 mmol) in THF (10 cm') was added and the mixture was allowed to warm up slowly to J. CHEM. SOC. PERKIN TRANS.I 1992 ambient temperature. Work-up as described before gave only starting material (100% recovery), identified by its m.p. and IR and 'H NMR spectra. (b) With LDA ut 0°C. Deprotonation was carried out as described in (a) but at 0°C. Work-up, after quenching with dimethyl disulfide, as before gave a quantitative recovery of starting material. (c) With KDA at -78 "C.Deprotonation was carried out as described in (a) but with KDA24 instead of LDA and at -78 "C.Work-up, after quenching with dimethyl disulfide, as described in (a) gave only starting material (1000/, recovery). Reactions of 2,4,5-Tribromothiazole 6 with n-Butjdlithium OY Methyllithiurn.-(a) 1.3 rnol dm-3 n-Butyllithium in hexane (0.71 cm', 0.93 mmol) was dissolved in anhydrous THF (15 cm') and added dropwise to a stirred solution of 2,4,5-tribromothiazole (0.3 g, 0.93 mmol) in anhydrous THF (10 cm') at -78 or -90 "C (internal temperature) under nitrogen and the resulting mixture was stirred for a further 10 or 30 min at this temperature.Then an excess of 2 rnol dmP3 hydrochloric was added and extraction with ether (3 x 50 cm3) gave the crude product, which was analysed by 'H NMR spectroscopic analysis. See Discussion section for results. (b) The above reaction was repeated but using methyllithium in place of the n-butyllithium (reaction temperature -90 "C; the time before hydrolysis was 20 min). The result is given in the Discussion section. (c) The experiment described in (a) was repeated but the reaction mixture was quenched (after 30 min at -90 "C) with a solution of dimethyl disulfide (0.1 g, 1.06 mmol) in anhydrous THF (10.0 cm3), then allowed to warm up slowly to ambient temperature.An excess of water was added and extraction with ether (3 x 50 cm') gave the crude product, which was chromatographed on silica. Light petroleum (40-60 "C) eluted 4-bromo-2,5-bis(methylthio)thiazole24 as a yellow oil (0.17 g, 7l%), identical with the sample prepared as described before. Attempted Reactions of 2,4,5-Tribromothiazole 6 )r*ith Ethjd- magnesium Bromide.---( a) A solution of 2,4,5- tri bromo t hiazole (0.3 g, 0.93 mmol) in anhydrous THF (10 cm') was added dropwise to a stirred solution of ethylmagnesium bromide [prepared from magnesium (0.023 g, 0.93 mg-atom) and bromoethane (0.1 g, 0.93 mmol)] in anhydrous THF (20 cm') at ambient temperature and the resulting mixture was stirred for a further 5 h.Then 2 mol dm-' hydrochloric acid (10 cm3) was added and extraction of the product with ether (3 x 50 cm') gave starting material (80% recovery). (b) The experiment described in (a) was repeated but the reaction mixture was heated under reflux overnight before hydrolysis. Work-up gave only starting material (80%recovery). Acknowledgements We thank the Algerian Government for financial support (to S. A.), Mrs. Ruth Howard for recording the low-resolution mass spectra, Mrs. Valerie Boote (University of Manchester) for recording the high-resolution mass spectral data, and Mr.M. A. Stuckey for recording 'H NMR spectra at 300 MHz. References 1 Part 7, B. Iddon, N. Khan and B. L. Lim, J. Chrtii. Soc., Porkiti Truns. I, 1987, 1457. 2 B. Iddon and B. J. Wake field, in Broniitic. Cotiipoinirls: Clicwii.s/rj-cnirl Applicutions, ed. D. Price, B. Iddon and B. J. Wakefield, Elsevier, Amsterdam, 1988. ch. 4, p. 181. 3 B. Iddon, in Stirdies iti 0rg:rrnic. Chrniistt.j- 35: Clitwiis/rj. of He/cw)c*j.c.lie* Conipounrls, ed. J. Kovac and P. Zalupsky, Elsevier, Amsterdam, 1988, p. 24. J. CHEM. SOC. PERKIN TRANS. 1 1992 4 B. Iddon, Heterocycles, 1985,23,417. 5 B. Iddon and N. Khan, J. Chem. Soc., Perkin Trans. I, 1987, 1445. 6 B. Iddon and N. Khan, J. Chem. Soc., Perkin Trans. I, 1987,1453. 7 A. Dondoni, A.R. Mastellari, A. Medici, E. Negrini and P. Pedrini, Synthesis, 1986, 757. 8 A. Dondoni, G. Fantin, M. Fogagnolo, A. Medici and P. Pedrini, J. Org. Chem., 1988,53, 1748. 9 P. T. Kaye, G. D. Meakins, C. Willbe and P. R. Williams, J. Chem. Soc.. Perkin Trans. I, 1981,2335. 10 A. Medici, P. Pedrini and A. Dondoni, J. Chem. Soc., Chem. Commun., 1981,655. 11 H. C. Beyerman, P. H. Berben and J. S. Bontekoe, Reel. Trau. Chim. Pays-Bas, 1954,73,325. 12 R. P.Kurkjy and E. V. Brown, J. Am. Chem. SOC.,1952,74,6260. 13 A. Dondoni, G. Fantin, M. Fogagnolo, A Medici and P. Pedrini, Synthesis, 1987,998. 14 A. R. Katritzky, K. S. Laurenzo and D. I. Relyea, Can.J. Chem., 1988, 66,1617. 15 S. C. Dillender, T. D. Greenwood, M. S. Hendi and J. F. Wolfe, J. Org. Chem., 1986,51, 1184. 16 B. M. Mikhailov and V. P. Bronovitskaya, Zh. Obshch. Khim., 1956, 26,66 (Chem. Absfr., 1956, SO, 13874). 17 K. L. Kirk, J. Heterocjd. Chem., 1985,22, 57. 18 P. Roussel and J. Metzger, Bull. Soc. Chim.Fr., 1962, 2075 (see also ref. 7). 19 P. Reynaud, M.Robba and R. C. Moreau, Bull. SOL'.Chim. Fr., 1962, 1735. 20 F. E. Herkes and T. A. Blazer, J. Hererocjd Chem., 1976, 13, 1297. 21 I. Sawhney and J. R.H. Wilson, J. Chem. Soc., Perkin Trans. I, 1990, 329. 22 L. Joseph and A. H. Albert, J. Hererocycl. Clrem., 1966,3, 107. 23 J. J. DAmico, S. T. Webster, R. H. Campbell and C. E. Twine, J. Org. Chem., 1965,30, 3618. 24 B. Iddon and B. L. Lim, J. Chem. SOL'.,Perkin Trans. I, 1983, 279; J. Chem. Soc., Chem. Commun., 1981,1095. 25 E. J. Vincent, R. Phan-Tan-Luu, J. Metzger and J. M. Surzur, Bull. Soc. Chim. Fr., 1966,3524. Paper 1/04859G Received 20th September 1991 Accepted 10th October 1991
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