1978 1169 Intermediates in the Halogenation of Some 2-Aminothiazoles By Luciano Forlani and Alessandro Medici, lstituto di Chimica Organica, Viale Risorgimento 4,401 36 Bologna, Italy Halogenation of 2-aminothiazoles in various solvents to produce 2-amino-5-halogenothiazoles proceeds via an addition-elimination mechanism. The addition products (A2-thiazolines) have been isolated and characterized by their n.m.r. spectral properties. The high regiospecificity and stereospecificity of the addition step are dis-cussed. In these reactions, the behaviour of the C(4)-C(5) double bond in 2-aminothiazoles is similar to that of the double bond in ethylenes. ofHALOGENATION2-aminothiazoles occurs at the 5-position, and is considered to be an aromatic electro- philic substitution, activated by the amino-group.English reported the isolation of an aminothiazole ' bromide-perbromide ' in the bromination of 2-amino- thiazole in water in the presence of hydrogen bromide. Garreau isolated a partially saturated bromothiazole derivative in the bromination of 2-amino-4,lj-dimethyl- thiazole. We report here the isolation of the A2-thiazoline intermediates (2) in the halogenation (bromin- ation and chlorination) of the 2-aminothiazoles (1). RESULTS AND DISCUSSION When methanolic bromine is added dropwise to a methanolic solution of 2-aminothiazole (1) at 0 "C, the bromine solution is instantaneously decolourized. The H structure (2a; X = Br, R3 = Me) to the white product, arising from addition of the nucleophilic part of the solvent (R3O) to (la) during the bromination.2-Aminothiazole and 2-amino-5-bromothiazole do not react with methanol, even in the presence of large amounts of hydrogen bromide. 2-Amino-5-bromo-thiazole (3a) is obtained in reasonable yield by heating the hydrobromide (2a; X = Br, R3 = Me) (as a solid or in solution), and reduction of this hydrobromide with zinc in acetic acid yields the starting thiazole (la). Other adducts (2b-e; X = Br, R3 = Me) have been obtained similarly Scheme 1; see Table for yields, physical properties, and lH n.m.r. spectra for the starting aminothiazoles (1)and the adducts (2) 3. The signals due to the thiazoline ring protons in (2) are shifted to higher field compared with the starting aminothiazoles (1).(1) (2) (3) SCHEME1 a; R1 = R2= H b; R1=R2=Me C; R' = H, R2 = Bu' d; R' = H, R2 = PhCH, R3 = Me, Et, HI or HO*CH,.CH,; X = Br or C1 immediate disappearance of the U.V. absorption maximum (in methanol) due to the 2-aminothiazole (A,,,. 257 nm; E 9.05 x lo4)is not accompanied by the appearance of the maximum due to the expected 2- amino-5-bromothiazole (3a; X = Br) (Amx. 268 nm; E 8.01 x lo4) which appears only after heating. In preparative runs, a white compound, soluble only in polar solvents (alcohols, water, or dimethyl sulphoxide), was obtained on removing the solvent under reduced pressure. Attempts to purify the crude solid by column chromatography or crystallization failed. The solid did not give free iodine from aqueous potassium iodide.The purity of this compound could be improved by adding 1 equiv. of methanolic hydrogen bromide to the reaction mixture initially. We have assigned the A2-thiazoline hydrobromide J. P. English, D. J. Clark, D. Seeger, R. H. Ebel, and J. W. Clapp, J. Amer. Chem. SOC.,1946, 68,453. 13C N.m.r. data (in CD30D) confirm structure (2): compound (2a), 6 173.09 (s, C-2), 99.06 (d, C-4), and 52.90 (d, C-5) p.p.m.; compound (2b), 6 171.66 (s, C-2), 99.93 (d, C-4), and 53.00(d, C-5) p.p.m., values in agree- ment with those for other A2-thiazoline derivatives3 The reaction giving compounds (2) is stereospecific ; no isomers were detectable. Experiments carried out in CD,OD (see later) show that C(4)H and C(5)H do not undergo exchange during the bromination.No coupling is observed between these protons; the dihedral angle between these bonds in (2) is probably ca. go", the protons being bonded to sP3 carbon atoms in a trans-arrange-ment. Bromination of 2-acetylaminothiazole in methanol also yields (2a; X = Br, R3 = Me), deacetylation occurring during the bromination. Y. Garreau, Compt. rend., 1954, 564. L. Forlani, A. Medici, M. Ricci, and P. E. Todesco, Synthesis, 1977, 320. 1170 We have been able to obtain the free A2-thiazoline from the hydrobromide (unstable and difficult to purify) only in the case of compound (2a; X = Br, R3 = Me), by neutralization with NaHCO,: m.p. 73-75 "C, n.m.r. (in CD,OD; int.ref. Me,Si), 6 5.95 (1 H, s, 4-H), 5.64 (1 H, s, 5-H), and 3.42 (3 H, s, OMe); m/e 210 (M+);picrate, m.p. 183-185 "C. Bromination of 2-aminothiazole occurs similarly in ethanol and ethylene glycol to give the adducts (2a; X = Br; R3 = Et and HOCH,CH,), respectively (Table). We have also obtained an adduct arising from addition of bromine and methanol to the C(4)-C(5) double bond on bromination of 2-amino-3-methyl J.C.S. Perkin I shifted to higher field than in the starting 2-amino-5- bromothiazole (6 7.43), as would be expected on change of Br 'r--ramp;NH2.HBrH--Me0 (4) hybridization (from sP2to sp3)of C-4. We have assigned structure (4) to the product isolated from this further bromination, and this assignment is confirmed by 13C n.m.r.results: G(CD,OD) 179.49 (s, C-2), 100.08 (d, 2-Alkylaminothiazoles (1) and intermediates (2) in their halogenation in R30H at 0 "C; yields and n.m.r. data N.m.r. in CD30D (int. rcf. Me,Si) X Yield (yo) b M.p./"C 93-94 6(5-H) 6.47 6(4-H) 6.93 6(alkyl) Br 95 e e 90 83-85 d 72-73 131-132 126-127 6.49 6.46 6.49 5.69 7.06 6.95 6.98 6.11 3.03 (6 H, s) 0.9-1.7 (8 H, m), 3.6 (1 H, m) 4.46 (2 H, s),7.36 (5 H, s) Br Br Br Br 85 85 90 95 166-168 122-124 116-1 18 102-104 5.73 5.73 5.77 5.71 6.16 6.13 6.16 6.06 3.44 (6 H, s) 0.9-2 (9 H, m) 4.81 (2 H, s), 7.30 (5 H, s) Rr 80 130-132 5.76 6.05 Br 90 118-1 21 5.90 5.97 5.80f 6.00f c1 95 109-1 11 5.75 5.87 Br 95 105-107 5.84 5.83f 6.23 6.33f 3.70 (3 H, s) 3.59 (3 H, s) f ~(0~3)' 3.52 (3 H, s) 3.47 (3 H, s)3.53 (3 H, s) 3.50 (3 H, s) 1.20 (3 H, t),3.53 (2 H, q) 3.5-3.8 (4 H, m) 3.53 (3 H, s) 3.53 (3 H, s)f 1 H, s, except where noted.By recrystallization of commercial product (E.G.A.). 1 H, d, J4,54.2 Hz. B.y. at 15 mmHg.See ref. 3. f In (CD,),SO. N-Methylthiazolium nitrate derivative. thiazolium nitrate (Table), but attempts to obtain the 2-amino-5-bromo-3-methylthiazoliumnitrate by heating failed. Bromination or chlorination of 2-aminothiazole in water (in the presence or absence of HBr or HC1) also gives white crystals of the adducts (2a; R3 = H, X = Br or C1) (Table). Iodine is not liberated from aqueous potassium iodide, showing the absence of free halogen.Bromination of 2-aminothiazole in acetic acid (the at 15 "C leads to immediate decolourization of the bromine solution, but 2-amino-5-bromothiazole is not observed. Addition of light petroleum to the reaction mixture causes precipitation of an unstable solid. It was possible to record only its n.m.r. spectrum (in CD,OD) which was analogous to that for compound (2a; X = Br, R3 = Me). Similar behaviour is observed in the bromination of 2-aminothiazole in tetrahydrofuran at -20 "C. ,) most commonly used solvent in such halogenations Methanolic bromine methanolic solution of and a white solid is solvent under reduced n.m.r. (CD,OD; int. 4-H), and 3.88 (3 H, is rapidly decolourized by a the 2-amino-5-bromothiazole, obtained on removal of the pressure; m.p.117-118 "C, ref. Me,Si) 6 5.82 (1 H, s, s, OMe). The (4)H signal is C-4), and 56.20 (s, C-5) p.p.m. N.m.r. analysis of solutions of the adducts (2) in CD30D shows that exchange between OCH, and OCD, groups occurs for the few minutes at room temperature, although it does not occur for the free thiazolidine obtained from compound (2a; X = Br, R3 = Me) or for (2b) and for the 3-methyl- thiazolidinium nitrate analogue of (2a), even after long reaction times. In all cases deuterium exchange for C(4)H and C(5)H is not observed. Furthermore, compound (2a; X = Br, R3 = H) is converted (in 2 days at room temperature) into compound (2a; X = Br, R3 = CD,O) simply by dissolution in CD30D. These exchanges probably occur by some acid-catalysed tautomeric equilibrium, which is possible only when R2 = H and the ring nitrogen atom is not methylated.Scheme 2 represents a reasonable pathway for this reaction. The lH n.m.r. signals of the thiazolidine ring protons are not affected by the exchange; stereospecific addition of the nucleophilic part of the solvent probably occurs to the positively charged species (5). In conclusion the halogenation of 2-aminothiazoles occurs by an addition-elimination pathway, the first H. Erlenmeyer and H. Kiefler, Helv. Chim. Ada, 1945, 28, 985; H. C. Beyerman, P. H. Berben, and J. S. Bontekoe, Rec. Trav. chim., 1954, 73, 325. step of which is attack by halogen on the C(4)-C(5) double bond, followed by stereospecific addition of the nucleophile.The fact that 2-(NN-dimethylamino)-thiazole (lb) reacts readily is evidence against the possibility that the reaction occurs on the imino-form of the thiazoles (arising from a tautomeric equilibrium 5). The regioselectivity of the present reactions (halogen- ation only at the 5-position) is in agreement with direct conjugation between the 5-position and the 2-amino group,g and by the presence of the sulphur atom which probably plays an important role in stabilizing a bromo- nium ion intermediate' such as (6) and promoting the H H H stituted thioureas and a-bromoacetaldehyde.* 2-N-Alkyl- amino-5-bromothiazoles 39 obtained from ( la), ( lc), and ( Id) and 2-amino-5-chlorothiazolehave already been des- cribed.5-Bromo-2- (NN-dimethylamino) thiazole hydro-bromide was also prepared by bromination of 2(NN-dimethyl- amino)thiazole in acetic acid * in 70 yield ; m.p. 35-36 "C; n.m.r. (CDCl,; int. ref. Me,Si): 6 7.05 (1H, s, 4-H) and 3.04 (6 H, s, Me). M.p.s and b.p.s are uncorrected. 1H and l3C n.m.r., and U.V. spectra were recorded respectively with JEOL (60 MHz), JEOL MS-D 100, and Perkin-Elmer (257) instru-ments. Solvents were purified by the usual procedure^.^ Deuteriated solvents (Merck) were used without purification. H U SCHEME2 stereospecificity of the reactions. However, the form- ation of the adducts (2) emphasizes the lack of aro-maticity of the thiazoles (l),and indicates that the H behaviour of the C(4)-C(5) double bond is similar to that usually observed for ethylene derivatives. EXPERIMENTAL 2-N-Alkylaminothiazoles ( 1) were obtained by the cyclization (in the presence of bromine) between sub-s M.SClim, M. SClim, 0. TCtu, G. Drillen, and P. Rumpf,Bull. Soc. chim. France, 1965, 3, 3527; J. Elguero, C. Marzin, A. R. Katritzky, and P. Linda, ' The Tautomerism of Hetero- cycles,' Academic Press, New York, 1976; L. Forlani, A. Medici, and P. E. Todesco, Tetrahedron Letters, 1976, 201. L. Forlani, A. Medici, and L. Lunazzi, Tetrahedron Lettevs, 1977, 4525. Halogenations were carried out at 0 "C, in an ice-water bath, with equimolecular solutions of reagents in the selected solvent. The same compounds were obtained from runs carried out at room temperature, but the purity of the materials is better at 0 "C. The hydrobromides (2) were obtained by removing the solvent in vucuo or by precipit-ation (in water), 2-Amino-5-halogenothiazole hydro-halides (3)were obtained by heating the reaction mixtures at ca. 70 "C for several hours. Neutralization with sodium hydrogen carbonate yields the free 2-amino-amp;halogeno-thiazoles which are identical to those obtained by halogen- ation of 2-aminothiazoles in acetic acid at 70 "C., We thank Dr. D. Macciantelli (C.N.R. Ozzano) for recording the 13C n.m.r. spectra. This work was carried out with financial assistance from C.N.R. (Roma). 7/1917 Received, 2nd November, 19771 G. Bellucci, G. Berti, R. Bianchini, G. Ingrosso, and E. Mastrorilli, Gazzetta, 1976, 106, 955. R. H. Wiley, D. C. England, and L. C. Behr, Org. Reactions, 1951, 6, 367. 0 A. Weissberger, ' Techniques of Organic Chemistry,' Inter- science, New York, vol. VIII, 1955.
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