Reactions of tetrasulfur tetranitride with aryl dibromomethyl ketones: one-pot synthesis of 3-aroylformamido-4-aryl-1,2,5-thiadiazoles and their reactions

摘要

253J. CHEM. soc. PERKIN TRANS. 1 1995 Reactions of Tetrasulfur Tetranitride with Aryl Dibromomethyl Ketones: One-pot Synthesis of 3-Aroylformamido-4-aryl-I ,2,5-thiadiazoles and their Reactions Kyongtae Kim," Jaeeock Cho and Sung Cheol Yoon Department of Chemistry, Seoul National University, Seoul 757-742,Korea Heating of dibromomethyl aryl ketones with tetrasulfur tetranitride (S,N,) at 11 5 "C without a solvent gave 3-aroylformamido-4-aryl-1,2-5-thiadiazoles8 as major products (1 2-71 ) and 3,5-diaroyl-l,2.4- thiadiazoles 2 as minor products in certain cases. The structures of compounds 8 were determined based on the X-ray analysis of 3-benzoylformamido-4-phenyl-l,2,5-thiadiazole 8a and comparison with an authentic sample of comound 8a. as well as all the spectroscopic and analytical data of compounds 8.Oxidation of compounds 8 with m-chloroperbenzoic acid in chloroform at room temperature gave compounds 2 (0-66). whereas reduction of compounds 8 with sodium boranuide in a mixture of chloroform-ethanol at room temperature gave 3-amin0-4-aryl-l.2.5-thiadiazoles 10 (71 -93). Treatment of 3-(3-nitrobenzoylformamido)-4-(3-nitrophenyl)-l,2,5-thiadiazole 8d with either sodium hydroxide in aqueousp-dioxane at reflux or sodium hydride in chloroform at room temperature gave 3-amino-4- (3-nitrophenyl) -1.2.5-thiadiazole 1Od in 56 and 80yield, respectively. Previously we have shown that the reactions of tetrasulfur tetranitride (S4N,) with monohalogenomethyl aryl ketones or the corresponding alkyl ketones 1 without a-hydrogens in the alkyl groups in chlorobenzene at 110-1 15 "C gave 3,5-diaroyl- and 3,5-diacyl-l,2,4-thiadiazoles2, respectively as major products.' Since only minute amounts of 1,2,4-thiadiazole were Ar = Awl, Bu', adamantyl 2 reported to be formed in the reactions of dibenzyl ketone with X = CI, Br S,N,,' it was believed that the halogen atom at the a-position of the ketones 1 played an important role in the formation of the 1,2,4-thiadiazoles. On the other hand, 3-aryl- or 3-alkyl-4-aryl- 1,2,5-thiadiazoles4 were formed by the reactions of alkyl aryl ketoximes 3 having at least two hydrogens u to the oxime functionality with S4N4 in p-dioxane at refl~x.~ This result was in contrast with those obtained from the reactions of diaryl ketoximes with S,N4 in toluene at reflux from which the corresponding diarylimino sulfides, diaryl ketones, and/or 4 (R = H) +Arh+Brli I/arylamide, arylimine, and aminosulfenamide were i~olated.~ 4 (R = H) -ArC(=N-OH)CH2X kS/Nx-ClThe synergism between a halogen atom and an oxime functionality was also observed in the reactions of aryl 5 6 monohalogenomethyl ketoximes 5 with S4N, in p-dioxane at Scheme 1 Reagents and conditions: i, S4N4, C,H,CI, 110-1 15 'C;re flu^.^ From the reactions of compounds 5 (X = C1) were ii,S,N,, p-dioxane, heat obtained 1,2,5-thiadiazoles 4 (R = H) in excellent yields except for the reactions of p-anisyl chloromethyl ketoxime 5 (Ar = p-MeOC,H4, X = CI), whereas those of compounds 5 (X = Br) from orangish yellow to dark.Heating was continued until no under the same conditions as in the reactions of the chloro spot corresponding to S,N4 was observed on TLC silica gel; analogues afforded compounds 4 (R = H) and 3-aryl-4-R,of S,N, 0.75 (benzene). Chromatography of the reaction 6.Interestingly, the total yields of mixture gave the corresponding 3-aroylformamido-4-aryl-bromo-l,2,5-thiadiazoles the two products, 4 and 6, obtained from the reactions of 1,2,5-thiadiazole 8 as a major product and compound 2 as a compounds 5 (X = Br) were comparable to those of the single minor product depending on starting compound 7, in addition products 4 (R = H) obtained from the corresponding oxime 5 to unchanged substrate 7 and a complex mixture. Attempts (X = Cl), which stimulated us to investigate further the effects were made to reduce the amount of unchanged starting material of the halogen atoms in the reactions of aryl dibromomethyl 7 by increasing the concentration of S4N,.However, yields of ketones 7 with S4N4.Our results are described herein. compounds 8 decreased drastically and separation of the reaction mixture by chromatography was troublesome due to Results and Discussion OH Reactions of Dibromides 7 with S,N,.-Compounds 7 were ArC(=O)CHBr2 t S,N, -i Ar+amp;fA' t 2 prepared according to the literature method^.^,' A mixture of 7the appropriate amount of both a compound 7 and S,N, was 0 kS.N slowly heated to 115 "C, during which time the compound 7 8 melted and S4N4was dissolved in it concomitant with initiation Conditions for reaction of dibromo ketones 7 with S,N, to of the reaction. The colour of the solution turned gradually prepare glyoxylamides 8.i, 115 "C. Table 1 Synthesisof 3-aroylfo1mamido-4-aryl-l,2,5-thiadiazoles8 Entry (substrate) Ar Time (t/h) Yield Product ()" By-Yield product ()" 7a Ph 5 8a 13 7b 4-CIC6H4 10 8b 12 2a 2 7c 7d 7e 7f 4-BrC6H, 3-0,NC6H44-0,NC6H4 4-NCCGH4 10 10 10 10 8c 8d 8e 8f 28 48 69 59 2b 2c 2d 11 12 10 7h 7i 7g 2-Naphthyl 5 2-Thienyl 6 3-Br,CHCOC,H4 10 8g Sh 8i 52 15 71 Isolated yield based on the amount of compound 7 consumed the presence of much tarry material. The yields of products 8 are summarized in Table 1, Structural IdentiJication of Products 8.--'H NMR spectra of the compounds 8 showed a singlet due to NH between S, 9.73 and 11.98.All aryl protons appeared as a multiplet in the region 8, 6.67-9.25 except for those of 8h, which exhibited a double doublet at BH 7.94 with J = 4.9 and 1.2 Hz and at 6, 8.57 with J = 4.0 and 1.2 Hz. A multiplet at S,7.13-7.3 1 was assigned to the four protons at C-4 and C-5 of two thienyl groups. IR spectroscopy of compounds 8 exhibited a band in the range ilmax 3240-3350 cm-', indicating the presence of an NH band. Compounds 8a. 8d. 8g and 8i showed two strong bands, at v,,, 1675-1678 and 16941698 cm-', which indicated the presence of two different carbonyl groups, whereas compounds 8b, 8c, 8e, 8f and 8h showed the corresponding bands at v,,, 1640-1669 and 1672-1718 cm~'.13C NMR (50.3 MHz; CDCI,) spectroscopy of compound 8d exhibited sixteen peaks consisting of a weak peak at amp; 185.39, indicating the presence of a carbonyl carbon of the benzoyl group, together with other peaks at 6, 122.07, 124.30, 124.40, 128.68, 130.51, 130.68, 132.96, 133.55, 133.92. 135.76, 147.70, 147.91, 149.00, 153.03 and 162.32. Mass spectroscopy of each compound 8 showed a corresponding molecular-ion peak and elemental analysis of each compound 8 was in good agreement with the corres- ponding structure. In spite of their reasonable spectroscopic and analytical data being available, a difficulty in assigning the correct structures of compounds 8 was encountered. In particular, it was cumbersome to rationalize the formation of the products obtained from the subsequent chemical reactions of compounds 8 (vide infra). The structural ambiguity was finally solved by X-ray crystallography.X-Ray analysis of compound 8a showed clearly the presence of two adjacent carbonyl groups bonded to the phenyl group and the nitrogen atom, respectively, as shown in Fig. 1. The structure of compound 8a was also confirmed by comparison with that of PhC(=O)C02H + SOCl, -PhC(=O)COCI 9 H2NWPh -8a9+ kS/N 1Oa Reagents and conditions: i, Et,N, CHCI,. room temp. an authentic sample which was prepared by the reaction of benzoylformyl chloride 9 with 3-amino-4-phenyl-l,2,5-thia-diazole 10a (vide infra). Selected bond lengths for compound 8a are given in Table 2.Oxidation of Compounds 8 with m-Chloroperbenzoic Acid (MCPBA).-Before the X-ray analysis of compound 8a, J. CHEM. SOC. PERKIN TRANS. 1 1995 Table 2 Selected bond lengths (A) for compound 8a" S(1)-N( I) 1.635 C(9tN(3) 1.401 S(l)-N(2) 1.611 C(8tN(3) 1.355 N(1)-C(I0) 1.313 C(8tO(l) 1.221 N(2jC(9) 1.330 C(7)-C(8) 1.510 C(9tC(lO) 1.467 C(7)-0(2) 1.216 a Crystallographic numbering scheme, see Fig. I. W4) Fig. 1 ORTEP view of compound Sa oxidation of compounds 8 with MCPBA was carried out in order to obtain information about the structure of compounds 8. Reaction of a compound 8 (1 mol equiv.) with MCPBA (5 rnol equiv.) in chloroform for 7 h at room temperature gave compounds 2 as the only identifiable products in moderate yields.The structural identification of products 2b2e was made based on the structure of the parent 2a, which was the only previously known compound among the 1,2,4-thiadiazoles 2 OH 8 Reagenls and conditions: i, MCPBA,CHCI,. room temp prepared. The yields of products 2 and the reaction times are summarized in Table 3. It has been known for some time that 3,5-disubstituted 1,2,5- thiadiazoles are oxidized to form the corresponding 1,2,5- thiadiazole I-oxides by either MCPBA 8.9 or dinitrogen tetraoxide.' However. the formation of compounds 2 from the oxidation of the glyoxylamides 8 by MCPBA suggests that the initial oxidation might not occur in the same way. Further study is necessary in order to elucidate the mechanism of the formation compounds 2 from substrates 8.Reduction of Compound.s 8 by Sodium Boranuide (NaBH4).-To a solution of a glyoxylamide 8 (1 rnol equiv.) in a mixture of chloroform and ethanol (1 : 1) was added sodium boranuide (2 mol equiv.), and the mixture was stirred at room temperature for 1 h. TLC (silica gel) showed no spot corresponding to substrate 8, and a new spot with higher R,-value than that of compound 8 was observed. The new spot, identified as that of the corresponding 3-amino-4-aryl- 1,2,5-thiadiazole 10, was J. CHEM. SOC. PERKIN TRANS. 1 1995 Table 3 Formation of 3,5-diaroyl-l,2,4-thiadiazoles2 Compound Ar Time (t/h) Yield ()" 8a Ph 7 ze' 39 8b 4-CIC6H4 48 b 8c 4-BrC6H, 48 b 8d 3-OZNC6H4 7 2c 59 8e 4-02NCbH4 7 2d 63 8f 4-NCC6H4 7 2f 66 8h8g 2-Naphthyl 2-Thienyl 7 7 2g b 43 "Isolated yield.Only compounds 8b, 8c and 8h were recovered, in 77, 82 and 43 yield, respectively. Known compound.' Table 4 Synthesis of 3-amino-4-aryl-1,2,5-thiadiazoles10 Compound Ar Yield () a 1Oa Ph 78 lob 4-CIC6H4 92 1oc 4-BrC6H4 91 1Od 3-0ZNC6H4 89 IOe 4-OZNC6H4 93 1Of 4-NCC6H4 86 1 2-Naphthyl 84 10h 2-Thienyl 71 a Isolated yield. *Known compounds separated by chromatography as the only identifiable product. The yields of products 10 are summarized in Table 4. Only a few 3-amino-4-aryl-l,2,5-thiadiazoles,such as 3-amino-4-phenyl-10a,I0 3-amino-4-(4-bromophenyl)-lOc," 3-10 Reagents und conditions: i, NaBH,, CHC1,-EtOH, room temp.amino-4-(2-thienyl)-10h,' ' and 3-amino-4-(p-tolyl)- 1,2,5-thia- diazole,' have previously been reported. They were obtained from the reactions of substituted acetylenes with S,N, in refluxing toluene in 3-9 yield. Consequently, treatment of glyoxylamides 8 with NaBH, would be a good synthetic method for compounds 10. Treatment of Compound8d with Acids and Bases.--In order to study the stability of compounds 8 under both acidic and basic conditions, compound 8d (0.313 mmol) was chosen as a model, and was treated with conc. hydrochloric acid (2 cm3) in p-dioxane (30 cm3) at room temperature for 24 h. Essentially no change was observed on TLC. However, 3-amino-4-(3- nitrophenyl)-l,2,5-thiadiazole10d was obtained in 71 yield after refluxing of the mixture for 6 h.In the meantime, attempted analysis of compound 8d with sodium hydroxide in a mixture of water and p-dioxane (1 :5) at room temperature for 24 h gave only a 6 yield of compound 10d, with 72 recovery of substrate 8d. However, complete hydrolysis of compound 8d occurred after 6 h reflux under the same conditions, to give an isolated yield of compound lod, after chromatography, of 56. In addition, treatment of compound 8d with sodium hydride in chloroform for 1 h at room temperature, followed by chromatography, gave compound 1Od in 80 yield. Similar treatment of compound 8d with sodium hydride under the same conditions as in the foregoing reaction, followed by addition of methyl iodide, did not give any methylated products and only compound 1Od was isolated, in 80 yield.In conclusion, compound 8d undergoes hydrolysis to give compound 1Od by treatment with either hydrochloric acid in p-dioxane or sodium hydroxide in aqueous p-dioxane at reflux, and the hydrolysis takes place rapidly even at room temperature by treatment with sodium hydride in chloroform. Experimental All m.p.s were determined on a Fisher-Johns melting point apparatus and are uncorrected. IR spectra were obtained on a Perkin-Elmer Model 283 spectrophotometer for samples as KBr pellets or thin films. 'H NMR spectra were determined on either a Bruker 80 MHz or a Varian EM 360 A 60 MHz spectrometer using tetramethylsilane as internal standard. J Values are given in Hz.l3C NMR spectra were recorded on a Varian VXR-200s spectrometer operating at 50.3 MHz. Mass spectra were obtained by electron impact at 70 eV on a Varian MAT 7 1 1 spectrometer. Elemental analyses were determined by Korea Basic Science Center. Column chromatography was performed on silica gel (Merck, 70-230 or 24MOO mesh, ASTM). Light petroleum refers to the fraction with distillation range 30-70 OC. Neutrality was determined using Hydrion pH test paper. Tetrasulfur tetranitride was prepared by the reaction of sulfur monochloride with ammonia gas at room temperature. ' MCPBA (5040) was obtained from Aldrich. Aryl dibromo- methyl ketones, 7a-d and 7g, were prepared by the literature methods, and compounds 7e, f, h, i were prepared by a method analogous to that in the literature:I3 2,2-dibromo-l-phenyleth- anone 7a, m.p.36-37 "C (lit,,I3 36 "C); 2,2-dibromo-1-(4- chloropheny1)ethanone 7b,m.p. 92-93 "C (lit.,', 93-94 "C); 2,2- dibromo-l-(4-bromophenyl)ethanone742, m.p. 91-92 "C (lit.,', 93-94 "C); 2,2-dibromo- 1-(3-nitrophenyl)ethanone 7d, m.p. 54-55 "C (Iit.,l3 55-56 "C); 2,2-dibromo-l-(4-nitrophenyl)eth-anone 7e, m.p. 5455 "C (from EtOH) (Found: C, 29.7; H, 1.6; N, 4.3; Br, 49.4. C,H,Br,NO, requires C, 29.75; H, 1.6; N, 4.3; Br, 49.5); v,,,(KBr)/cm-' 1696, 1601, 1528, 1510, 1344, 1322, 1267, 994, 866, 854 and 786; 6,(80 MHz; CDCI,) 6.62 (1 H, s, CH) and 8.30 (4 H, s, ArH); 4-(2,2-dibromoace~yl)benzonitrile 7f, m.p. 98-99 "C (from EtOH) (Found: C, 35.5; H, 1.6; N, 4.6; Br, 52.7.C,H,Br,NO requires C, 35.7; H, 1.7; N, 4.6; Br, 52.75); v,,,(film)/cm-' 2224, 1690, 1408, 1293, 1270, 995, 864 and 755; 6amp;0 MHz; CDCI,) 7.55 (1 H, s, CH) and 8.02 (4 H, dd, J 7.2 and 26.7, ArH); 2,2-dibromo-l-(2-naphthyl)ethanone 7g, m.p. 99-100 "C (lit.,13 101-102 "C); 2,2-dibromo-1-(2- thieny1)ethanone 7h, oily liquid (Found: C, 25.3; H, 1.35; Br, 56.1. C,H,Br,OS requires C, 25.4; H, 1.4; Br, 56.3); v,,,(film)/cm-' 1661, 1507 and 1405; SH(80 MHz; CDC13) 6.44 (1 H, s, CH), 7.04-7.19 (1 H, m, ArH) and 7.62-7.98 (2 H, m, ArH); 1,3-bis(dibrornoacetyl)benzene7i, oily liquid (Found: C, 25.0; H, 1.2; Br, 66.7. Cl0H,Br4O, requires C, 25.1; H, 1.3; Br, 66.9); v,,,(film)/cm-' 1693, 1593, 1281, 1179, 907, 731 and 628; aH(8O MHz; CDCI,) 7.59 (2 H, s, CH), 7.69 (1 H, t, J 8.0, ArH), 8.32 (2 H, d, J 8.0, ArH) and 8.75 (1 H, s.ArH). General Procedure for the Reactions of Aryl Dibromomethyl Ketones with S4N4.-A mixture of an aryl dibromomethyl ketone (6-1 1 mmol) and S4N4 (0.3-0.5 mol equiv.) was slowly heated to 115 "C. Heating was continued until no spot corresponding to S4N4 was observed on TLC R,0.75 (benzene). The reaction mixture was cooled to room temperature. Hot ethyl acetate (20 cm3) was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel (7amp;230 mesh, 2 x 12 cm). Elution with hexane (100 cm3) gave sulfur, and a series of solvents were then used to elute the other products (see below).3-Benzoylformamido-4-phenyi-l12,5-thiadiazole8a. In accord- ance with the above general procedure, a mixture of compound 7a (2363mg, 8.50 mmol) and S4N, (509mg, 2.76mmol) was heated for 5 h. Chromatography of the reaction mixture with a mixture of hexane-benzene (1 : 1) as eluent gave unchanged compound 7a (1.829mg, 77 recovery). Elution next with chloroform gave the titlecompound8a (37mg, 13) as a solid, m.p. 137-138.5OC(from CCI,) (Found: C, 62.1;H, 3.5;N, 13.45;S, 10.5.C16H,,N302S requires C, 62.1;H, 3.6;N, 13.6; S, 10.4); v,,,(KBr)/cm-' 3240, 1694, 1675, 1592, 1528, 1500, 1461,1446,1425, 1268, 1170,885,859,780,752 and 7O2;dH(80 MHz; CDCI,) 7.39-8.49(10 H, m, Ph) and 9.81(1 H, s,NH); m/z 309 (1.8, M'), 204 (15.1), 121 (29.7), 119 (72.5), 117(IOO), 105 (80.7) and 77 (28.6).3-(4-Chlorobenzoylformamido)-4-(4-chlorophenyl)-1,2,5-thia-diazole8b. In accordance with the above general procedure, a mixture of substrate 7b (2291mg, 7.33mmol) and S,N, (523 mg, 2.84mmol) was heated for 10 h. Chromatography of the reaction mixture with a mixture of hexane-benzene (3:1) as eluent gave unchanged compound 7b (1.657mg, 72 recovery) and 2-bromo-1-(4-~hlorophenyl)ethanone (1 00 mg, 0.428 mmol). Elution with benzene then gave 3,5-bis(4-chlorobenzoyl)-l,2,4-thiadiazole 2a (6 mg, 273,m.p. 200-202deg;C (lit.,' 20amp;202"C). Elution next with a mixture of hexane+thyl acetate (3: 1) gave the title compound8b (47mg, 12) as a yellowish grey solid, m.p.149-151"C (from CC14) (Found: C, 50.8;H, 2.35;N, 11.3;S, 8.6.C16Hamp;12N3O2S requires C, 50.8;H, 2.4;N, 11 .l; S, 8.5); v,,,(KBr)/cm-' 3350, 1715, 1651, 1581, 1416, 1402, 1400,1294, 1278, 1260, 1145, 1093, 101 1, 820, 786 and 559; SH60 MHz; (CD,),SO-CDCI, 7.52-8.36 (8 H, m, ArH) and 11.85 (1 H, s, NH); miz 378 (0.2, M'), 240 (5.7), 238 (15.6), 141(30.8),139(100) and 11 1 (26.7). 3-(4-Bromobenzoylformamido)-4-(4-bromophenyl)-1,2,5-thia-diazole8c. In accordance with the above general procedure, a mixture of substrate 7c (4002mg, 11.22mmol) and S4N4 (1009 mg, 5.48mmol) was heated for 10 h. Chromatography of the reaction mixture with a mixture of hexane-benzene (1 : 1) as eluent gave unchanged compound 7c (3477mg, 87 recovery) and 2-bromo-l-(4-bromophenyl)ethanone(22mg, 5).Elution with benzene then gave 3,5-bis(4-bromobenzoyl)-l,2,4-thiadia-zole 2b (40mg, 1 l), m.p. 119-120OC (lit.,' 12amp;121 "C). Elution next with chloroform gave the title compound8c (105 mg, 28) as a solid, m.p. 167-169"C (from CCl,) (Found: C, 41.1; S, 7.0. C16HgBr,N302S requires C, 41.1;H, 1.9;N, 9.1; H, 1.9;N, 9.0;S, 6.9); v,,,(film)/cm-' 3342, 1711, 1657, 1580, 1521, 1502, 1396, 1292, 1280, 1147, 1072, 1010, 821,790, 781 and 560; dH60 MHz; (CD3),SO-CDCI, 7.73-8.40(8 H, m, ArH)and 10.6(1 H,s,NH);m/z469(6.7,M+ + 2),467(14.1, M +),465 (6.5), 183 (1 00) and 155 (32.9). J CHEM. SOC. PERKIN TRANS, 1 1995 162.32,153.03,149.00, 147.91, 147.70, 135.76, 133.92, 133.55, 132.96, 130.68, 130.51,128.68, 124.40, 124.30 and 122.07;m/z399(0.2, M'), 249(0.5), 150(100), 134(9.9), 104(28.8)and76(22.5).3-(4-Nitrobenzoylformamido)-4-(4-nitrophenyl)-1,2,5-thiadia-zole 8e. In accordance with the above general procedure, a mixture of compound 7e (2025mg, 6.27mmol) and SIN, (501 mg, 2.72mmol) was heated for 10h. Chromatography of the reaction mixture with a mixture of hexane-benzene (1 :4)as eluent gave unchanged compound 7e (1 113mg, 55 recovery). Elution with chloroform gave 3,5-bis(4-nitrobenzoyl)-1,2,4-thiadiazole 2d (53 mg, lo), m.p. 119-121"C (from CCI,) (Found: C, 50.1; H, 2.1;N, 14.7;S, 8.5. C16H8N,06S requires C, 50.0; H, 2.1;N, 14.6;S, 8.3",); v,,,(KBr)/cm-' 1672, 1655, 1599,1346,1315,1278,1194,1119,1002,872,850,826and719; dH(60 MHz; CDC1,) 8.60 (2 H, d, 58.4,ArH) 8.69(4H, s, ArH) and 9.03 (2 H, d, J 8.4,ArH); m/z 384 (0.2, M+), 150 (loo),104 (26) and 76 (19.6).Elution with a mixture of hexane-ethyl acetate (1 : 1) gave the title compound8e (393 mg, 69) as a yellow solid, m.p. 182-184OC (from CC1,-acetone) (Found: C, 48.25;H, 2.3;N, 17.4;S, 8.2.CI6HgN,O,S requires C, 48.1;H, 2.3;N, 17.5; S, 8.0); v,,,(film)/cm-' 3346, 1718, 1668, 1592, 1528, 1509, 1349, 1314, 1263, 1150, 874, 855,781,739 and 558; SH80 MHz; CDCI3-(CD3),SO 8.06 (2 H, d, J 8.8,ArH) 8.31 (4H, s, ArH), 8.33 (2 H, d,J8.8, ArH) and 11.64(1 H, s, NH);m/z 399 (2.4, M'), 249 (7.0), 248 (9.2), 232 (12.2), 222 (17.3), 150(loo), 104 (35.6), 134(6.4), 120 (16.2) and 76 (27.2).3-(4-Cyanobenzoylformarnido)-4-(4-~~anophenyl)-1,2,5-thia-diazole8f. In accordance with the above general procedure, a mixture of compound If (2042mg, 6.74mmol) and S4N, (507 mg, 2.75mmol) was heated for 10 h. Chromatography of the reaction mixture with benzene as eluent gave unchanged 7f (846 mg, 41 recovery). Elution next with a mixture of hexanethyl acetate (1 : 1) gave the title compound8f (422mg, 59) as an orangish solid, m.p. 222-224"C (from CC1,-acetone) (Found: C, 60.2;H, 2.4;N, 19.5;S, 9.1.C,,H,N,O,S requires C, 60.2; H, 2.5;N,19.5;S, 8.9); v,,,(KBr)/cm-' 3345,2230, 1718, 1669,1530, 1510,1494,1406,1264, and1154,864,854,834,745 571;SH(80MHz; CDCl,) 7.80 (2 H, d, J8.0, ArH), 7.84 (2 H, d, J8.8,ArH),8.01(2H,d,J8.0,ArH),8.24(2H,d,J8.8,ArH) and 11.62(1 H, s, NH); m/z 359 (2.9, M'), 229 (11.3), 130 (100)and 102 (41.5).4-(2-Naphthyl)-3-(2-naphthylcarbonylformamido)-1,2,5-thia-diazole8g. In accordance with the above general procedure, a mixture of substrate 7g (2044mg, 6.23mmol) and S4N, (506 mg, 2.75mmol) was heated for 5 h. Chromatography of the reaction mixture with a mixture of hexane-benzene (1 : 1) as eluent gave unchanged compound 7g (1837mg, 90). Elution zole 8d. In accordance with the above general procedure, a mixture of substrate 7d (2059mg, 6.38mmol) and S,N, (503 mg, 2.73mmol) was heated for 10 h. Chromatograhy of the reaction mixture with a mixture of hexane-benzene (1 :1) as eluent gave unchanged compound 7d (1 128mg, 55 recovery).Elution with chloroform gave 3,5-bis(3-nitrobenzoyl)-1,2,4-thiadiazole 2c (71 mg, 12), m.p. 116117deg;C (from CCI,) (Found: c,50.2;H, 2.2;N, 14.4;s,8.6.CI6H8N,O6S requires C, 50.0;H, 2.1;N, 14.6;S, 8.3); v,,,(film)/cm-l 3083, 1675, 1660, 1609, 1528, 1349, 1266, 1090,904,849.720,697 and 678; cSH(6O MHz; CDCI,) 7.92-9.81(8 H, m, ArH); mjz 384 (3.9, M'), 150 (loo), 104(39.4)and 76 (43.1). Elution next with a mixture of hexane-ethyl acetate (3:2)gave the title compound amp;I(276mg, 48) as a yellow solid, m.p. 179.5-181"C (from CCI,-CHC13) (Found: C, 48.0;H, 2.1;N,17.7;S, 8.2. C,,H,N,O,S requires C, 48.1; H, 2.3;N, 17.5;S, 8.0); v,,,(KBr)/cm-' 3319, 1691, 1677. 1610, 1532, 1350,1260, 1179, 1100,915, 785 and 734; S,200 MHz; (CD3),SO 7.63-8.79(8 H, m, ArH) and 11.98(1 H, s, NH); Sc(CD3),SO 185.39, 3-(3-Nitrobenzoylforrnarnido)-4-(3-nitrophenyl)-1,2,5-thiadia-with a mixture of hexane-ethyl acetate (1 : 1) gave the title compound8g (67 mg, 52) as a pale brown solid, m.p.89-90"C (from light petroleum-CCI,) (Found: C, 70.5;H, 3.6;N, 10.4; S, 8.0. C,,H,,N,O,SrequiresC, 70.4;H, 3.7;N,10.3;S, 7.8); v,,,(KBr)/cm '3240, 1694, 1677, 1621, 1530, 1501, 1480, 1280, 1121, 833, 816, 798 and 740;6,(80 MHz; CDCI,) 7.49-8.27(13 H, m, ArH), 9.25(1 H, s, ArH) and 9.98(1 H, s,NH); miz 409 (6.8,M'), 155 (100) and 127 (57.8). 4-(2-Thienyl)-3-(2-thienylcarbonylformamido)-1,2,5-thiadia-zole 8h. In accordance with the above general procedure, a mixture of substrate 7h (2018mg, 7.11 mmol) and S,N, (501 mg, 2.72mmol) was heated for 6h.Chromatography of the reaction mixture with a mixture of hexane-benzene (1 : 1) as eluent gave unchanged compound 7h (1432mg, 71 recovery). Elution with methylene dichloride gave the title compound8h (48 mg, 15) as a pale brown solid, m.p. 48-51"C (from hexane-CCl,) (Found: C, 45.0;H, 2.4;N,13.0;S, 30.1. Cl2H,N3O2S3 requires C, 44.9;H, 2.2;N, 13.1;S, 29.9); v,,,(film)/cm-' 3330, 1706, 1640, 1530,1497,1441,1406, 1355, 1265, 1219, 1158, 1050,990,860,800,754 and 735;dH(80MHz; J. CHEM SIX. PERKIN TRANS. I 1995 CDCl,) 7.13-7.31 (4 H, m, thienyl ArH), 7.94 (1 H, dd, J 4.9 and 1.2, thienyl ArH), 8.57 (1 H, dd, 34.0 and 1.2, thienyl ArH) and 9.89 (1 H, s, NH); m/z 321 (2.5, M'), 210 (9.0), 111 (100) and 83 (9.6).3-3-( Dibromoacetyl)benzoylfbrmmido-4-3-(dibromo-acetyl)phenyl- 1,2,5-thiadiazoIe 8i. In accordance with the above general procedure, a mixture of substrate 7i (2088 mg, 4.37 mmol) and S4N4 (511 mg, 2.77 mmol) was heated for 10 h. Chromatography of the reaction mixture with benzene as eluent gave unchanged compound 7i (1 554 mg, 74 recovery). Elution with a mixture of hexane-ethyl acetate (1 :1) gave the title compound8i (282 mg, 71) as a pale yellow solid, m.p. 142- 145 "C (from CCl,) (Found: C, 34.05; H, 1.6; N, 5.9; S, 4.5. C,,H,,Br,N,O,S requires C, 34.0; H, 1.1; N, 5.95; S, 4.5); v,,,(KBr)/cm-' 3250, 1698, 1678, 1594, 1530, 1289, 1245, 1161, 687 and 631;6,(80 MHz; CDCl,) 6.67 (1 H, s, CH), 6.68 (1 H, s, CH), 7.55-7.82 (2 H, m, ArH), 7.99-8.65 (5 H, m, ArH), 9.08 (1 H, m, ArH) and 9.73 (1 H, s, NH).General Procedure for the Reaction of Compounds 8 with MCPBA.-A solution of a mixture of compound 8 and MCPBA in chloroform (20 cm3) was stirred at room temperature for 7 h and was then poured into an excess of 5 aq. sodium carbonate. The mixture was extracted with chloroform (30 cm3 x 3). The combined organic layer was washed with water three times and dried on anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was chromatographed on silica gel (230- 400mesh, 2 x 12cm). 3,5-Dibenzoyl-l,2,4-thiadiazole2e. In accordance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8a (159 mg, 0.514 mmol) and MCPBA (463 mg) was chromatographed.Elution with a mixture of hexane-benzene (1:3) gave the title compound 2e (59 mg, 3973, m.p. 67 "C (lit.,' 65-66 "C). 3,5-Bis(3-nitrobenzoyl)-l,2,4-thiadiazole2c. In accordance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8d (153 mg, 0.383 mmol) and MCPBA (328 mg) was chromatographed. Elution with a mixture of hexane-ethyl acetate (3: 1) gave the title compound 2c (87 mg, 59). 3,5-Bis(4-nitrobenzoyl)-l,2,4-thiadiazole2d. In accordance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound amp; (143 mg, 0.358 mmol) and MCPBA (317 mg) was chromatographed.Elution with a mixture of hexane-ethyl acetate (1 : 1) gave the title compound 2d (86 mg, 63). 3,5-Bis(4-cyanobenzoyl)-1,2,4-thiadiazole 2f. In accordance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8f (148 mg, 0.412 mmol) and MCPBA (355 mg) was chromatographed. Elution with a mixture of hexane-ethyl acetate (1 : 1) gave the title compound 2f (93 mg, 6673, m.p. 159-161 "C (from CCl,) (Found: C, 62.6; H, 2.5; N, 16.3; s,9.5. C18H,N,0,S requires C, 62.8; H, 2.3; N, 16.3; S, 9.3); v,,,(KBr)/cm-' 2231, 1681, 1645, 1604, 1408, 1324, 1289, 1216, 1007, 905, 872 and 764; ad80 MHz; CDCI,) 7.86 (2 H, d, J8.8, ArH), 7.88 (2 H, d, J 8.8, ArH), 8.41 (2 H, d, J 8.8, ArH) and 8.73 (2 H, d, J 8.8, ArH); m/z 344 (3.5, M'), 130 (51.5), 102 (27.6) and 40 (100).3,5-Di(2-naphthoyl)-1,2,4-thiadiazole2g. In accordance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8g (137 mg, 0.335 mmol) and MCPBA (338 mg) was chromatographed. Elution with benzene gave the title compound 2g (57 mg, 43), m.p. 118- 120 "C (from CCI,) (Found: C, 73.1; H, 2.15; N, 7.3; S, 8.3. C2,H14N202S requires C, 73.1; H, 2.0; N, 7.1; S, 8.1); v,,,(film)/cm-' 1658, 1645, 1615, 1589, 1462, 1390, 1348, 1270, 1170, 1120, 1095, 1001,820 and 754; amp;(80 MHz; CDCl,) 7.34 8.02 (10 H, m, ArH), 8.25-8.50 (2 H, m, ArH), 8.92 (1 H, m, ArH) and 9.45 (1 H, m, ArH); m/z 394 (7.6, M'), 155 (100) and 127 (89.7).Reaction of Compound 8b with MCPBA.--In accordance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8b (257 mg, 0.679 mmol) and MCPBA (584 mg) was chromatographed. Elution with chloroform gave unchanged substrate 8b (197 mg, 77 recovery). No 3,5-bis(4-chlorobenzoyl)-1,2,4-thiadiazole was isolated. Reaction of Compoundamp; with MCPBA.--In accordance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8c (235 mg, 0.503 mmol) and MCPBA (433 mg) was chromatographed. Elution with chloroform gave unchanged substrate 8c (193 mg, 82 recovery). No 3,5-bis(4-bromobenzoyl)-l,2,4-thiadiazolewas isolated.Reaction of Compound 8h with MCPBA.-In accordance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8h (202 mg, 0.629 mmol) and MCPBA (533 mg) was chromatographed. Elution with benzene gave unchanged substrate 8h (86 mg, 43 recovery). No 3,5-bis(2-thienylcarbonyl)-l,2,4-thiadiazolewas isolated. General Procedure for the Reaction of Compounds 8 with Sodium Boranuide.-A mixture of a compound 8(1 mol equiv.) and NaBH, (2 mol equiv.) in a solution of a mixture of chloroform-ethanol (1 : 1; 20 cm3) was stirred at room temperature for 1 h. The mixture was poured into water (100 cm3) and extracted with ethyl acetate (30 cm3 x 3). The combined extracts were dried on anhydrous magnesium sulfate.After removal of the solvent under reduced pressure, the residue was chromatographed on silica gel (230400 mesh, 1 x 12 cm). 3-Amino-4-phenyl-1,2,5-thiadiazole10a. In accordance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8a (98 mg, 0.317 mmol) and NaBH, (26 mg, 0.687 mmol) was chromatographed. Elution with chloroform gave the title compound 10a (44 mg, 78), m.p. 99-100 "C (lit.," 10@-102 "C). 3-Amino-4-(4-chlorophenyl)-1,2,5-thiadiazole lob. In accord- ance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8b (201 mg, 0.531 mmol) and NaBH, (40 mg, 1.06 mmol) was chromatograhed. Elution with chloroform gave the title compound 10b (104 mg, 92) m.p.126128 "C (from CCl,) (Found: C, 45.9; H,2.9; N, 20.0; s, 15.35. C8H,C1N3S requires C, 45.4; H, 2.9; N, 19.85; S, 15.15); v,,,(KBr)/cm-' 3418, 3300, 3200, 1621, 1516, 1496, 1440, 1094, 1019, 865 and 835; amp;(80 MHz; CDCl3) 4.81 (2 H, S, NHJ, 7.46 (2 H, d, J 8.3, ArH) and 7.73 (2 H, d, 58.3, ArH); m/z 213 (31.8, M+ + 2), 211 (90.2, M+), 171 (18.9), 169(53.8), 139(12.5). 137(33.6), 102 (18.9) and 74(100). 3-Amino-4-(4-bromophenyl)-1,2,5-thiadiazoleLOc. In accord-ance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound amp; (153 mg, 0.328 mmol) and NaBH, (25 mg, 0.661 mmol) was chromatographed. Elution with chloroform gave the title compound 1Oc (76 mg, 91), m.p.131-133deg;C (lit.," 134-135 "C). 3-Amino-4-(3-nitrophenyl)-1,2,5-thiadiazole10d. In accord- ance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8d (1 54 mg, 0.386 mmol) and NaBH, (29 mg, 0.767 mmol) was chromatographed. Elution with chloroform gave the title 258 compound 1Od (76 mg, 89), m.p. 114-116deg;C (from CCI,) (Found: C, 43.4; H, 2.9; N, 25.4; S, 14.6. C8H,N402S requires C, 43.2; H, 2.7; N, 25.2; S, 14.4); v,,,(KBr)/crn-' 3420, 3305, 1630, 1524, 1441, 1352, 869 and 789; S,(80 MHz; CDCI,) 4.85 (2 H, s, NH,), 7.59-7.79 (1 H, m, ArH), 8.10-8.36 (2 H, m, ArH) and 8.65-8.71 (1 H, m, ArH); m/z 222 (loo, M+), 180 (19.5), 175 (54.6), 174 (46.8), 148 (1.3), 122 (10.7) and 74 (97.9).3-Amino-4-(4-nitrophenyl)-1,2,5-thiadiazole1Oe. In accord- ance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8e (143 mg, 0.358 mmol) and NaBH, (27 mg, 0.714 mmol) was chromatographed. Elution with chloroform gave the title compound 10e (74 mg, 9373, m.p. 206206 "C (from CH2C12- CCl,) (Found: C, 43.2; H, 2.8; N, 25.4; S, 14.6. C8H,N40,S requires C, 43.2; H, 2.7; N, 25.2; S, 14.4); v,,,(KBr)/cm-' 3480, 3421, 3306, 1632, 1599, 1350, 859 and 831; 6,(80 MHz; CDCI,) 5.96 (2 H, s, NH,), 7.97 (2 H, d, J9.6, ArH) and 8.24 (2 H, d, J9.6, ArH); m/z 222 (45, M'), 180 (15.5), 150 (14), 148 (1.8), 130 (23.5), 122 (11.4) and 74 (100). 3-Amino-4-(4-cyanophenyl)-1,2,5-thiadiazole1Of.In accord- ance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8f (1 16 mg, 0.323 mmol) and NaBH, (26 mg, 0.687 mmol) was chromatographed. Elution with chloroform gave the title compound 1Of (56 mg, 8673, m.p. 155-157 "C (from CCI,) (Found: C, 53.6; H, 3.0; N, 27.9; S, 16.0. C9H6N,S requires C, 53.45; H, 3.0; N, 27.7; S, 15.85); v,,,(film)/cm-' 3470, 3348, 3230,2248, 1645, 1610, 1532,1448, 1410, 1332, 1312, 1270,878 and 840; 6,(80 MHz; CDCI,) 4.82 (2 H, s, NH,), 7.77 (2 H, d, J 8.0, ArH) and 7.95 (2 H, d, J 8.0, ArH); m/z 202 (98.0, M'), 160 (30.0),128 (20.6), 102 (16.7) and 74 (100). 3-Amino-4-(2-naphthyl)- 1,2,5-thiadiazole 1Og. In accordance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8g (163 mg, 0.398 mmol) and NaBH, (30 mg, 0.793 mmol) was chromatographed.Elution with chloroform gave the title compound log (76 mg, 84), m.p. 92-94 "C (from hexane-CC1,) (Found: C, 63.5; H, 4.0; N, 18.7;S, 14.3. C, ,H,N,S requires C, 63.4; H, 4.0; N, 18.5; S, 14.1); v,,,(KBr)/cm-' 3440, 3282, 1624, 1514, 1506, 1492, 904, and 825; 6,(80 MHz; CDCI,) 4.67 (2 H, s, NH,) and 7.48- 8.24 (7 H, m, ArH); m/z 227 (loo, M'), 185 (22.1), 153 (38.3), 127 (13.8) and 126 (14.6). 3-Amino-4-(2-thienyl)- 1,2,5-thiadiazole 10h. In accordance with the above general procedure, the residue obtained from a stirred solution of a mixture of compound 8h (151 mg, 0.470 mmol) and NaBH, (36 mg, 0.952 mmol) was chromatographed. Elution with chloroform gave the title compound 10h (61 mg, 71), m.p. 116-1 17 "C (lit.,', 117-1 18 "C).Treatment of Compound amp;I with Conc. Hydrochloric Acid.- (a) At room temperature. A mixture of compound 8d (125 mg, 0.313 mmol) and conc. hydrochloric acid (2 cm3)in p-dioxane (30 cm3) was stirred for 24 h. The mixture was poured into water (150 cm3), and neutralized with 5 aq. sodium carbonate. The aqueous solution was extracted with ethyl acetate (30 cm3 x 3). The extracts were washed with water and dried over magnesium sulfate. Removal of the solvent, followed by chromatography of the residue on silica gel (23amp; 400 mesh) with a mixture of hexanethyl acetate (3: 1) as eluent, gave unchanged starting material 8d (1 18 mg, 94 recovery).(b) At rejux. A mixture of compound 8d (138 mg, 0.346 mmol) and conc. hydrochloric acid (2 cm3) in p-dioxane (30 cm3) was stirred for 6 h. The reaction mixture was cooled to room temperature and worked up as described in (a). Chromato- graphy (silica gel, 230-400 mesh, 1 x 12 an) of the residue with chloroform as eluent gave compound 1Od (55 mg, 71). J. CHEM. SOC. PERKIN TRANS. 1 1995 Treatment of Compound 8d with Sodium Hydroxide.--(a) At room temperature. A mixture of compound 8d (126 mg, 0.316 mmol) and sodium hydroxide (pellet, 3 1 mg) in a mixture of p-dioxane-water (5: 1; 30 cm3)was stirred at room temperature for 24 h. The reaction mixture was poured into water (1 50 cm3), and was neutralized with 10 aq.hydrochloric acid. The aqueous solution was extracted with ethyl acetate (30 cm3 x 3). The extracts were washed with water and dried over magnesium sulfate. Removal of the solvent, followed by chromatography (silica gel, 230-400 mesh, 1 x 12 cm) of the residue with chloroform as eluent, gave compound 1Od (4 mg, 6). Elution next with a mixture of hexane-ethyl acetate (3 : 1) gave starting material 8d (91 mg, 72 recovery). (b) At reflux. A mixture of compound 8d (142 mg, 0.356 mmol) and sodium hydroxide (pellet, 33 mg) in a mixture of p-dioxane-water (5 : 1; 30 cm3) was refluxed for 6 h. The reaction mixture was worked up as described in (a). Chromatography using chloroform as eluent gave 1Od (44mg, 56) as the only identifiable product.Treatment of Compound 8d with Sodium Hydride.-To a mixture of compound 8d (137 mg, 0.343 mmol) and sodium hydride (13 mg, 41.7 mmol) was added chloroform (30 cm3), and the mixture was stirred for 1 h. TLC silica gel; hexane- ethyl acetate (3 : l) showed a single spot, of which the R,-value (0.45 hexane-ethyl acetate (3: l)} was higher than that (0.34) of starting material 8d.The mixture was extracted with ethyl acetate (30 cm3 x 3) and the extracts were dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (230-400 mesh, 1 x 12 cm). Elution with chloroform gave compound 1Od (61 mg, 80). X-Ray Structure Determination of Compound Sa.-Crystal data: C,,H,,N,O,S, M = 309.3, monoclinic, space group P2,c, a = 4.827(1), b = 19.465(2), c = 15.476(2) A, V = 1451.5(3) A3, Z = 4, D, = 1.42 g cm-,, fl(M0-K~)= 2.7 an-'.Data were measured on an Enraf-Nonius CAD-4 diffractometer with graphite-monochromated Mo-Ka radiation using 420 scans for 1690 reflections with 735 reflections having F, 30(F0). Crystals were grown from hexane. Positional parameters and their estimated standard deviations, and bond distances and angles, have been deposited at the Cambridge Crystallographic Data Centre.* Acknowledgements We are grateful for the financial support from the Center for Biofunctional Molecules (CBM) and the Basic Science Research Institute Program, Ministry of Education (BERI-94- 315). * See Instructions for Authors, in the January issue. References 1 J. Cho and K. Kim, J. Heierocycl. Chem., 1992,29, 1433. 2 S. Mataka, A. Hosoki and M. Tashiro, J.Heterocycf, Chem., 1980, 17, 1681. 3 J. Cho and K. Kim, J. Chem. SOC., Perkin Trans. I, 1993,2345. 4 S.Mataka, K. Takahashi, S.Ishi-i and M. Tashiro, J. Chem. SOC., Perkin Trans. I, 1979,2905. 5 K. Kim and J. Cho, Heterocycles, 1994,38, 1859. 6 R. M. Cowper and L. H. Davison, Org. Synth., 1957, Coll. Vol. 11, p. 480. 7 J. J. Klingenberg, Org. Synth., 1957, Coll. Vol. IV, p. 110. 8 S. Karady, J. S. Amato, D. Dortmund and L. M. Weinstock, Heterocycles, 1981, 16, 1561. J. CHEM. soc. PERKIN TRANS. I 1995 9 P. J. Dunn and C. W. Rees, J. Chem. SOC., Perkin Trans. I, 1989, 13 V. P. Kravets, G. I. Chervenyuk and G. V. Grinev, J. Org. Chem. 2485. USSR (Engl. Transl.), 1966,2, 1238. 10 S. Mataka, K. Takahashi, Y. Yamada and M. Tashiro, J. Heterocycl. Chem., 1979, 16, 1009. 11 S. Mataka, K. Takahashi and M. Tashiro, Heterocycles, 1983, 20, 20 17. 12 Gmelin's Handbook of Inorganic Chemistry, Sulfur-Nitrogen Paper 4/03603D Compounds, Part 2B, ed. B. Heibel, Springer-Verlag, Berlin, 8th Received 14th June 1994 edn., 1984, ch. 5, p. 127. Accepted 19th September 1994