J. Org. Chem. 1983,48, 1271-1275 5.87. Compound IIi (4-F) on pyrolysis at 248 "C for 6.5 h gave 87.5% conversion; bp 122-124 "C (3 mm). Anal. Calcd for C, 54.25; H, 5.06. Found C, 54.25; H, 5.10. CgHl$"OS: Compound IIj (4-1) on pyrolysis at 220-235 "C for 1.5 h gave 95% conversion; mp 87.5-88.8 "C [vacuum sublimed at 106 "C (0.7 mm)]. Anal. Calcd for CgHloINOS: C, 35.19; H, 3.28. Found: C, 35.22; H, 3.33. 0 - P h e n y l NJV-Dimethylthiocarbamates. Compounds of this class required for pyrolytic conversion to compounds of series I1 above were prepared by reaction of the corresponding phenol in a nitrogen atmosphere with NaH and NJV-dimethylthiocarbamoyl chloride in a manner analogous to that described for these compounds by Newman and The following physical constanta and analytical data were observed for previously unreported compounds. 0-p-n-Butoxyphenyl NJV-dimethylthiocarbamate, mp 69-70.5 "C (ethanol). Anal. Calcd for C13H19N02S:C, 61.63; H, 7.56. Found C, 61.78; H, 7.60. O-pEthoxyphenyl NjV-dimethylthiocarbamate, mp 85.5-86.5 "C (ethanol). Anal. Calcd for Cl1Hl5NO2SC, 58.64; H, 6.71. Found: C, 58.51; H, 6.83. 0-p-Ethylphenyl NJV-dimethylthiocarbamate, mp 59-62.5 "C (ethanol). Anal. Calcd for C11H15NOS: C, 63.12; H, 7.22. Found: C, 62.97; H, 7.37. 0-p-Fluorophenyl NJV-dimethylthiocarbamate, mp 77-78.2 "C (ethanol). Anal. Calcd for CgHl$"OS: C, 54.25; H, 5.06. Found: C, 54.32; H, 5.15. O-pIodophenyl NjV-dimethylthiocarbamate, mp 109.5-110.5 "C (ethanol). Anal. Calcd for C9HlJNOS: C, 35.19; H, 3.28. Found C, 35.15; H, 3.36. N,N-Dimethylbenzamides (111). The compounds of this series were the same as those employed in an earlier investigation? Infrared Spectra. The spectra were taken on Perkin-Elmer Model 567 and 180 grating spectrometers. The carbonyl stretching frequencies were measured at 25 "C in NaCl cells of 0.1-, 1.0-, ~
~~
1271
and 5.0-mm thickness by using CCll and CHC13 as solvents. Concentrations were chosen to give absorption between 70% and 75%. The instrument calibrations were verified by using water vapor and indene standard spectra. Peak positions were determined by averaging the results of three measurements and are believed to be accurate to f0.5 cm-'. The hydroxyl frequency shifts of phenol by the compounds were measured in solutions of CCll contained in NaCl cells of 5.0-mm path length, the concentrations of compounds of series 1-111 and phenol being 1.6 X and 2.0 X 10" mol/L, respectively. Peak positions were determined with an accuracy of k 3 cm-'.
Acknowledgment. We are indebted t o Mrs. Z. Sustekovi a n d A. Farkasovi for operational assistance. Registry No. Ia, 84694-98-4;Ib, 7305-10-4;IC,73986-55-7;Id, 5461-74-5;Ie, 7305-08-0; If, 84694-99-5; Ig, 84695-00-1; Ih, 696990-0; Ii, 3983-30-0;Ij, 7541-20-0; Ik, 84695-01-2;11,7305-03-5;Im, 7308-55-6; In, 38491-27-9; Io, 84695-02-3; Ip, 52916-82-2; Ir, 14100-44-8;Is, 7244-70-4; IIa, 84695-03-4; IIb, 13511-98-3;IIc, 84695-04-5;IId, 13511-96-1;IIe, 7322-85-2; IIf, 84695-05-6;IIg, 7304-68-9; IIh, 69734-16-3;IIi, 84695-06-7;IIj, 84695-07-8;IIk, 7304-69-0;111, 7305-13-7; IIm, 13511-93-8;IIn, 13511-90-5;110, 19290-43-8;IIp, 7305-12-6;IIIq, 67024-50-4; IIIb, 7291-00-1; IIIc, 14062-78-3;IIId, 011-74-5; IIIf, 25771-25-9; IIIg, 24167-56-4; IIIi, 24167-53-1; IIIj, 14062-80-7;IIB, 18469-37-9;IIIp, 24167-50-8;1115, 7291-01-2; phenol, 108-95-2;NjV-dimethylcarbamoyl chloride, 79-44-7; 0-(p-n-butoxyphenyl) N,N-dimethylthiocarbamate, 84695-08-9; 0-(p-ethoxyphenyl) N,N-dimethylcarbamate, 84695-09-0; 0-(p-ethylphenyl) NjV-dimethylcarbamate, 8469510-3; 0-(p-fluorophenyl) NjV-dimethylcarbamate, 84695-11-4; 0-(p-iodophenyl) NjV-dimethylcarbamate, 84695-12-5.
Synthesis of Certain 5,6-Diamino-as-triazines: Precursors for Fused Heterocyclic Systems' Cherng-Chyi Tzeng, Nancy C. Motola, and Raymond P. Panzica* Departments of Medicinal Chemistry and Chemistry, University of Rhode Island, Kingston, Rhode Island 02881 Received August 3, 1982 An improved synthesis of 6-amino-as-triazine-3,5-dione (1) and selective thiation of this heterocycle provides two key intermediates, 6-amino-3-oxo-as-triazine-5-thione (2) and 6-amino-as-triazine-3,E-dithione (3). Methylation of 2 and 3 under basic conditions leads to their methylmercapto derivatives,which on treatment with methanolic ammonia furnish 5,6-diamino-as-triazine-3-one (6a) and 5,6-diamino-3-(methylthio)-as-triazine (7a),respectively, in good overall yield. o-Diamino heterocycles have attracted considerable attention as synthons to fused heterocyclic systems. Of interest t o us are t h e 5,6-diamino-us-triazines, which are potential precursors to novel 5 6 and 6 6 fused heterocycles. Recently, several investigators described a n d used such intermediates to synthesize the imidaz0[4,5-e]-us-triazine~~~ a n d u-triazolo[4,5-e]-as-triazine4 ring systems. Without exception, the us-triazines used in these studies were alkylated at either t h e N2 or C 3 positions, a n d all b u t one contained alkylated exocyclic amino groups. W e now re(1) Presented in part a t the 183rd National Meeting of the American Chemical Society, Las Vegas, March 1982, ORGN 170. (2) Kaji, K.; Kawase, M. Chem. Pharm. Bull. 1976,24, 2274. (3) Yoneda, F.:Nomchi, M.; Noda, M.; Nitta, Y. Chem. Pharm. Bull. 1978,26, 3154. (4) Kaji, K.;Nagashima, H.; Oda, H.; Kawase, M. Heterocycles 1976, 4, 1846.
port t h e preparation of t h e diamines 5,6-diamino-as-triazine-3-one (6a) and 5,6-diamino-3-(methylthio)-as-triazine (7a, Scheme I). T h e advantages offered by 6a and 7a are that ring closure and simple chemical modification can lead to the parent imidazo- and u-triazolo[4,5-e]-as-triazine and pyrazino[2,3-e]-us-triazine ring systems. 6-Amino-us-triazine-3,5-dione (1) was chosen as t h e starting material for this project. T h e reported synthetic procedure for l5 gave low yields especially on scale-up and at times did not work. Faced with this dilemma, we explored more effective routes for t h e preparation of this heterocycle. It was found t h a t when 6-bromo-as-triazine-3,5-dione5 was heated a t 80 "C in a steel reaction vessel with liquid ammonia and a catalytic amount of fine copper powder, 1 was obtained in 98% yield. (5)Chang, P. K. J. Org. Chem. 1961,26, 1118.
0022-3263/83/1948-1271$01.50/00 1983 American Chemical Society
1272 J. Org. Chem., Vol. 48, No. 8, 1983
alkylating agent, (mmol) methyl iodide (80)
Tzeng et al.
Table I. S-Alkylation of 6-Amino-3-oxo-as-triazine-5-thione ( 2 ) and 6-Amino-as-triazine-3,5-dithione (3) at Room Temperature reac1N abs tion starting mat1 NaOH, EtOH, time, product: (mmol) mL mL h % yield MP,b "C 2 (35)
35
250
2.55 (s, 3, SCH,), 5.88 (br s, 2, NH,), 11.92 ( v br s, 1,NH)d allyl bromide (3.6) 2 (3.2) 3.2 50 4 4b (58) 175-177 3.81 (d, 2, SCH,, J = 7 Hz), 5.10-6.10 ( m , 3, SCH,CH=CH,),e 5.70 (br s, 2, NH,), 11.63 ( v br s, 1 , NH) benzyl bromide (8.3) 2 (7) 10.5 100 16 4~ (84.3) 176-178 4.48 (s, 2, SCH,), 5.82 (br s, 2, NH,), 7.3-7.70 (m, 5, C,H,), 11.81 (br s, 1 , NH) p-nitrobenzyl 2 (3) 3 50 24 4df ( 7 0 ) 160-161 4.63 (s, 2, SCH,), 5.88 (s, 2,NH,), 7.79 and 8.26 bromide (3.6) (AB q , 4, CH,C,H,NO,, J A B = 8.5 Hz), 11.83 (br s, 1 NH) methyl iodide (48) 3 (12.5) 30 250 4 5 (81.7) 171-173 2.50 (s, 3, SCH,), 2.52 (s, 3, SCH,), 6.44 (br s, 2 , NH,) a Satisfactory analyses (C, H, N, S; 20.4%) were obtained for 4a-d and 5 . For compounds 4a-d slow decomposition be+ins at this temperature range. ' Recrystallized from 95% ethanol. d v br s = very broad singlet. e Me,SO-d,/D,O. Acidified water treatment omitted and compound recrystallized from AR acetone.
Our next concern was thiation of 1 to provide a good yield of either 6-amino-3-oxo-as-triazine-5-thione (2) or 6-amino-as-triazine-3,5-dithione (3). Studies involving the thiation of as-triazine-3,5-diones have demonstrated that the C5 position is the initial site of reaction.6-*0 One of them8 carefully examined the conditions required for C5monothiation of as-triazine-3,5-dione (6-azauracil)" using phosphorus pentasulfide (P2S5)/pyridineand found that the best results were obtained when the as-triazine:P2S5 ratio was 2:l and the pyridine had a water content of ca. 0.1% . Larger amounts of P2S5decreased the C5-monothiated derivative and increased the formation of the C3,C5-dithiated product. Thiation of 1 under similar conditions furnished 2 in 48% yield. Although the yield of 2 was not high, it was the same as that reported for its pyrimidine counterpart.12 A reversal of the l:P2S5ratio provided 3, but in poor yield (ca. 30%). When 2 replaced 1, a 75% yield of 3 was realized; however, overall it was comparable to the direct dithiation of 1. Since 3 was a critical intermediate to 7a, we sought alternate methods t o increase the yield of this heterocycle. Neither Lawesson's reagent13 nor increasing the amount of P2S5to 4 equiv (1:4 l:P2S5)helped. A search of the literature revealed that addition of elemental sulfur14 (6) Gut, J.; Prystag, M.; Jon@, J. Collect. Czech. Chem. Commun. 1961, 26, 986. (7) Zee-Cheng, K. Y.; Cheng, C. C. J. Org. Chem. 1962,27, 976. (8) Mizuno, Y.; Ikehara, M.; Watanabe, K. A. Chem. Pharm.Bull. 1962, 10, 647. (9) Cristescu, C.; Sitaru, S. Reu. Roum. Chim.1971, 16, 135. (10) Wasti, K.; Joullie, M. M. J. Chem. Soc., Perkin Trans. 2 1976, 2521. (11) Mizuno and co-workerss depicted the differences in the UV spectra of 3-oxo-as-triazine-5-thione, 5-oxo-as-triazine-3-thione, and astriazine-3,5-thione. When sulfur resides on the C3 position, i.e., the 5-oxo-thione derivative, the maxima for the pH 1and neutral spectra are similar to those exhibited by the parent dione (6-azauracil, maxima between 260 and 270 nm). On the other hand, when sulfur is attached to C5 the maxima appear at higher wavelengths (320 nm). Alkylation of the C-SR) causes a hypsochromic shift.6 The same UV C5 thione (C=S spectral characteristics were observed (see Table 111) for 2, 3, 4a, and 5. (12) Taylor, E. C.; Garcia, E. E. J. Org. Chem. 1964, 29, 2121. (13) Pedenen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S. 0. Bull. SOC.Chim.Belg. 1978, 87, 223.
-
4
4aC (76)
'H NMR, 6
237-239
Scheme I
. "'"rJ0 S
S. N H -2
H -3
1
1
RS
"Nx:;r, c H3
H,CS 4 2 : R=CH, b: R=CH,-CH=CH, 5: R=CH,-C,H, R= CH,-C,H,N02
5
I:
t
1
2Nxlsc
RlR2
6a: -b :
R,,R,=H R,=H.R2=CH, 5 : R,,R,=CH,
H,
5 :R,,R,=H b : R,=H,R2=CH, 4 : R,= H, R,-CH2-C,H5
to the reaction medium could increase the yield of the thiated heterocycle from about 20% to 40%. Using a 1:P2S5:S8 ratio of 2:4:0.5 in pyridine containing 0.1% water, 3 was obtained in 69% yield. In an effort to optimize this yield, we increased the amt. of water in pyridine to 0 . 3 4 4 % .g To our surprise, instead of 3 we obtained 2 in very good (73%) yield. Apparently, the water content of (14) Schmidt, U.; Luttringhaus, A.; Trefzger, H. Justus Liebigs Ann. Chem. 1960,631, 129.
J. Org. Chem., Vol. 48, No. 8, 1983 1273
5,6-Diamino-as-triazines
Table 11. Synthesis of Certain 5-(Alkylamino)- and 5-(Arylalkylamino)-6-amino-3-substituted-as-triazines at Room Temperature reaction time, product: h % yield
st art ing mat1 (mmol) 4a 1 . 3 )
40% aq
48
6b(76)
27gb
H2O
4a 4 . 4 )
dimethylamine ( 1 5 )
48
6c ( 7 6 )
243-244
MeOH
4a 3 . 0 )
benzylamine ( 0 . 5 )
48
6d(82)
281-282
H,O
4a 4 . 4 )
furfurylamine ( 0 . 6 )
48
6e ( 4 9 )
288b
abs EtOH
5 (2.0)
40% aq methylamine (100)
3
7b(87)
216-218
EtOAc
5 (2.9)
benzylamine ( 5 )
12
7c (86)
248-24gd
EtOAc
amine (mL) . , methylamine (100)
crystallizing solvent
MP. "C
Satisfactory analyses (C, H, N , S; t 0 . 4 % ) were obtained for 6b-c and 7b-c. collapses t o a singlet in the presence of D,O. Decomposition.
the pyridine used is as critical as the ratio of as-triazine to PzS5. Dry pyridine that had been distilled and stored over potassium hydroxide (KOH) or a fresh bottle of ACS pyridine (ca. 0.1% HzO) gave consistent yields (65439%) of 3 with a 1:PzS5:S?ratio of 2:4:0.5,whereas wet pyridine and the same conditions afforded 2. For purification of the thiated azines, we found that silylation of the crude reaction product, distillation of the silylated heterocycle, and subsequent hydrolysis with AR methanol provided analytically pure products. Also the use of ammonium hydroxide (NH40H)instead of sodium hydroxide (NaOH) in the workup of 2 or 3 led to pure products. Two studies6J5that examined the pK, values of as-triazine-3,5-dione, 3-oxo-as-triazine-5-thione, 5-oxoas-triazine-3-thione, and as-triazine-3,5-thione have shown the N3 proton of these heterocycles to be quite acidic. A comparison of the lH NMR data on 1-3 supported this finding. Thus, a weak base such as NH40H dissolved only the desired thiated heterocycle, leaving the contaminates behind. Acidification of the ammonium salt furnished the pure heterocycle. The S-alkylated derivatives 4a-d and 5 (Table I) were conveniently prepared from 2 and 3, respectively. That methylation of 2 or 3 occurred on sulfur rather than nitrogen was confirmed by the UV and lH NMR spectral data. The chemical shift of the methyl signals in the lH NMR of 4a (6 2.55) and 5 (6 2.50 and 2.52) indicated the methyl groups were attached to sulfur16J7and the characteristic hypsochromic shift6$8in the UV spectra further supported S-methylation of these as-triazines. The similarity of UV data of 4b-d to those of 4a established sulfur as the site of alkylation for these analogues. The C5 methylthio group of 6-amino-5-(methylthio)as-triazine-3-one (4a)is quite reactive and was smoothly displaced by amines a t room temperature to provide 6b-c (Table 11). Quantitative conversion of 4a to 5,6-di(15) Gut,J.; Prystas, M.; JonU, J.; Sorm, F. Collect. Czech. Chem. Commun. 1961,26, 974. (16) Townsend, L. B. 'Synthetic Procedures in Nucleic Acid Chemistry";Zorbach, W. W., Tipson, S., Eds.; Wiley: New York, 1973; Vol. 11, Chapter 7. (17) Chen, S.-F.; Panzica, R. P. J. Org. Chem. 1981, 46, 2467.
'H NMR. 6 2 . 8 0 ( d , 3 , N H C H , ) , C5 . 4 2 (br s, 2, NH,), 7 . 6 2 ( v br q, 1,NHCH,), 1 0 . 5 9 (br s, 1, N2H) 3 . 1 5 (s, 6 , N(CH,),), 5 . 2 5 (br s, 2, NH,), 1 0 . 9 6 ( v br s, 1, N 2 H ) 4 . 6 6 (d, 2, NHCH,),C 5 . 7 8 (br s, 2, NH,), 7 . 4 5 (s, 5 , C,H,), 8 . 3 2 (v br t , 1, NHCH,), 11.08 (br s, 1,N2H) 4 . 6 4 (d, 2 , NHCH,),c 5 . 7 4 (br s, 2, NH,), 6.47 (m, 2, H3',H4'), 7 . 6 8 fm. 1. H 5 ' ) . 8.17 (v br t. 1. NHCH,), 11.02'iv br s,'l, N2H)' 2 . 4 0 (s, 3, SCH,), 2 . 8 4 (d, 3, NHCH,),c 5 . 9 4 ( b r s , 2 , NH,) 7 . 3 8 ( v br q , 1,NHCH,) 2 . 3 4 (s, 3, SCH,), 4 . 5 4 (d, 2 , NHCH,), 6 . 0 6 (br s, 2, NH,), 7 . 2 9 (s, 5 , C,H,), 7 . 8 0 ( v br t, 1,NHCH,)
Slow decomposition.
This doublet
amino-as-triazine-3-one (6a) was accomplished with methanolic ammonia a t room temperature. An alternate and step-saving route to 6a involves ammonolysis of 2.798 Treatment of 6-amino-3,5-bis(methylthio)-as-triazine (5) with liquid ammonia at 50 "C furnished 7a. When 5 was subjected to the same reaction conditions employed for the conversion of 4a to 6a, it took 2 weeks for the reaction to reach completion. As in the thiation of 1, nucleophilic displacement on 5 occurred preferentially at C5.9J8J9 Experimental Section Melting points were determined on a Thomas-Hoover melting point apparatus and are uncorrected. The infrared spectra were obtained in pressed potassium bromide disks on a Beckman IR-8 spectrometer. The 'H NMR spectra were recorded on a Varian A-60 or a Varian EM-390 spectrometer. AU samples were dissolved in dimethylde sulfoxide, and the chemical shifts are expressed in parts per million with respect to tetramethylsilane. The ultraviolet absorption spectra were obtained on a Beckman DB-GB grating spectrometer. Mass spectra were determined with a Du Pont 490 spectrometer. Thin-layer chromatography was run on precoated (0.25 mm) silica gel 60 F-254 plates manufactured by EM Laboratories, Inc., and short-wave ultraviolet light (254 nm) was used to detect the UV-absorbing spots. Evaporations were performed with a Buchi Rotovapor at 40 "C unless otherwise stated. Elemental analyses were performed by M-H-W Laboratories, Phoenix, AZ. Recently purchased gallon or pint bottles of ACS pyridine whose maximum water content is specified as 0.1% were used in the thiation of 3. For the thiation of 2 (method B), enough water was added to the ACS pyridine to raise the content to ca. 0.4%.
B-Amino-as-triazine-3,5-dione (1). 6-Bromo-as-triazine3,5-dione5(50 g, 260 mmol), copper powder (130 mg), and liquid ammonia (400 mL) were heated in a glass-lined, stainless steel reaction vessel at 80 "C for 48 h. After the reaction cooled, the excess ammonia was vented off, and the residual solid was dissolved in hot water (400 mL). The cool, blue solution was carefully acidified to pH 4 with concentrated HCl and the resulting precipitate collected by filtration. This material was resuspended in distilled water (500mL) and dissolved by the dropwise addition of concentrated NH,OH, the solution filtered, and the colorless (18) Libermann, D.; Jaquier, R. Bull. SOC.Chim. Fr. 1961, 386. (19) Piskala, A. Collect. Czech. Chem. Commun. 1975, 40,2340.
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Tzeng et al.
Table 111. Ultraviolet Spectral Data for Certain 6-Amino-as-triazines" compd pH ina ax, nm 10-3e 352 6.65 8.23 303 6.78 243.5 6.16 b 357 7.83 304 6.56 245 10.77 329 11 6.80 245.5 shc 3 1 12.50 329 sh 22.85 299.5 7.37 255 sh b 12.18 333.5 sh 22.37 300.5 6.73 255 sh 325 11 9.90 15.25 281 4a 1 348.5 sh 3.07 7.10 287 10.49 235 2.85 350 b 7.23 284 2 37 11.69 11 3.80 349 272.5 4.40 237 10.25 5 1 308 8.57 269 17.43 350 b 3.46 264 19.58 11 338 3.39 262 17.89 6a 1 315 3.10 240 sh 6.74 307.5 2.80 b 249.5 sh 6.08 225.5 12.81 11 301 3.03 247 sh 6.23 227.5 10.17 320 sh la 1 2.83 257.5 22.32 4.97 324 b 14.62 250 11 320 4.76 14.23 250 a Each compound was dissolved in AR methanol (10 mg/100 mL), and from this stock solution the final diluMethanol. tion was made with the appropriate solvent. sh = shoulder; supplementary material available: full UV data for compounds 4b-d, 6b-e, and 7b-c. 2
1
filtrate acidified to pH 4 with concentrated HCl. The solid was collected by filtration, washed with distilled water (2 x 20 mL), and air-dried to furnish 32.8 g (98.4%) of 1: mp >300 "C (lit.4 mp 310-315 "C); 'H NMR 6 5.90 (br s, 2, NHd, 10.8 (br s, 1, N2H), A,- (pH 1)298 nm (4.411, 230.5 11.6 (br s, 1,N4H); UV (t x sh (6.60), ,A, (MeOH) 299 nm (4.48), 228.5 sh (6.75), ,A, (pH 1) 296 nm (4.06), 11) 287.5 nm (3.59), 239.5 sh (6.34) [lit! A-_ (pH . A,, (pH 11) 289 nm (4.0511. Anal. Calcd for CIHINIOB: C. 28.13: H. 3.15: N. 43.74. Found: c,28.04; H, 3.30; N: 43.83. 6-Amino-3-oxo-as-triazine-5-thione (2). Method A. To a suspension of 6-amino-as-triazine-3,5-dione (I, 17 g, 133 mmol) in ACS pyridine (425 mL, Fisher) was added Pass (14.9 g, 67 "01, Alfa), and the mixture was stirred and heated at reflux for 3 h. The reaction mixture was allowed to cool, and the pyridine was removed in vacuo to furnish a dark brown residue. This residue was covered with water (ca. 300 mL) and boiled for 30 min, and the suspension was allowed to stand at 5 "C overnight. The dark solid was collected by filtration, washed with cold water (3 X 100 mL), and dried in vacuo for 12 h at 100 "C to provide 12 g (64%) of crude 2. This was added to an excess of hexamethyldisilazane (HMDS, 150 mL) containing a catalytic amount of ammonium sulfate, and heated at 140 OC for 24 h under anhydrous conditions. I
I
,
I
I
The excess HMDS was distilled off under diminished pressure (water aspirator), and the dark, oily residue was then distilled in vacuo. The orange silyl derivative of 2 distilled between 144 and 150 "C (0.25-0.15 mmHg). The cold, silyl derivative was hydrolyzed with AR methanol (50 mL), and 2 precipitated as a bright yellow sQlid. The solid was collected by filtration, washed with AR methanol (2 X 50 mL), and air-dried to furnish 9 g (48% overall yield) of analytically pure 2: mp 242-244 "C (slow decomposition); MS (EI, 70 eV, probe 300 "C, source 200 "C), 144 (M'); 'H NMR 6 5.94 (br s, 2, NH2), 11.45 (br s, 1, N2H), 13.2 (v br s, 1, N4H). Anal. Calcd for C3H4N40S:C, 24.99; H, 2.80; N, 33.87; S,22.24. Found: C, 24.99; H, 2.94; N, 33.96; S,22.10. Method B. A mixture of 1 (2.56 g, 20 mmol), flowers of sulfur (S& (1.28 g, 5 mmol), P2S5 (8.89 g, 40 mmol), water (0.5 mL), and ACS pyridine (180 mL, Fisher) was heated at reflux for 3 h with vigorous stirring. After this period, the solvent was removed under diminished pressure (water bath, 65 "C) and the residual solid was covered with water (150 mL) and boiled for 10 min on a steam bath. The suspension was allowed to cool to room temperature, and the solid was collected by filtration and washed with two 50-mL portions of water. This solid was then resuspended in distilled water (150 mL) and concentrated NH40H was added dropwise with stirring until pH 10 was reached. The mixture was treated with Norit and filtered through a Celite pad. The filtrate was carefully acidified to pH 4 with 6 N HC1. A yellow precipitate formed during the acidification procedure. The mixture was allowed to stand at room temperature for 1 h, and then the solid was collected by filtration. The yellow solid was washed with cold, distilled water (2 x 20 mL) and air-dried to provide 2.1 g of 2 (72.9%), identical in all respects (UV, 'H NMR, and elemental analyses) with 2 prepared by method A. 6-Amino-as -triazine-3,5-dithione (3). Method A. Phosphorus pentasulfide (8.89 g, 40 "01) was added to a stirred, warm solution of 2 (2.88 g, 20 mmol) in 200 mL of ACS pyridine (Fisher). The mixture was heated at reflux for 7 h. After this period, the mixture was allowed to cool and stand at room temperature for 16 h. The clear, reddish-brown solution was decanted from the reaction flask and the pyridine removed under diminished pressure (water bath, 60 "C). The resulting residue was covered with 200 mL of distilled water, boiled for 10 min, and allowed to stand at 4 "C for 18 h. The precipitate was collected by filtration, resuspended in 140 mL of distilled water, and basified to pH 10 by the dropwise addition of concentrated NH40H. The mixture was treated with Norit and filtered through a Celite pad, and the pad was washed with two portions (2 x 20 mL) of basic water (pH 10). The combined filtrate was carefully acidified with 6 N HCl to pH 4. Upon acidification, 3 began to precipitate as an orange solid. The solid was collected by filtration, washed with cold, distilled water (3 X 50 mL), and air-dried to furnish 2.4 g of 3 (75%): mp >300 "C; 'H NMR 6 6.57 (v br s, 2,NH2),12.96 (br s, 1, N2H), 14.18 (br s, 1, N4H). Anal. Calcd for C3H4N4S2:C, 22.49; H, 2.52; N, 34.97; S,40.02. Found: C, 22.49; H, 2.89; N, 34.87; S,39.78. Method B. 6-Amino-as-triazine-3,5-dione (1, 2.56 g, 20 mmol), P2S5 (8.89 g, 40 mmol), and flowers of sulfur (1.28 g, 5 mmol) were added to 180 mL of ACS pyridine, and the mixture was heated at reflux for 5 h with vigorous stirring. The reaction mixture was allowed to cool and stand at room temperature for 16 h. The reaction was worked up in a manner similar to that described in method A. This procedure provided 2.2 g of 3 (68.8%), identical in all respects (UV, IR, 'H NMR) to 3 prepared by method A. General Procedure for t h e S-Alkylation of 6-Amino-3oxo-as-triazine-5-thione(2) a n d 6-Amino-as-triazine-3,5dithione (3). To a stirred suspension of 2 in absolute ethanol at 40 "C was added 1 N sodium hydroxide. Upon addition of the sodium hydroxide solution, 2 dissolved, and depending upon the concentration of this heterocycle after several minutes a small quantity would precipitate as the sodium salt. The stirred solution was cooled to room temperature, and the desired alkylating agent was added in one portion. With the exception of 4a, minutes after the addition of the alkylating agent the S-alkylated derivative began to precipitate. The reaction was monitored by TLC, and when the reaction was complete, the excess solvent was removed under diminished pressure to provide a crystalline residue. The solid was triturated with cold water and collected by filtration.
J. Org. Chem. 1983,48,1275-1281 This material was resuspended in acidified water (1 mL of 0.1 N HC1 in 100 mL of distilled water) and allowed to stand at 4 OC for 16 h. The crystalline S-alkylated derivative was collected by filtration,washed with cold distilled water, and air-dried. These derivatives were of sufficient purity for elemental analyses but could be recrystallized as indicated in Table I. A similar set of conditions was employed for the methylation of 3. Like 4a, 5 remained in solution. When the reaction was complete, the solvent was evaporated under diminished pressure, and the residue was crystallized from 95% ethanol to furnish 5. 5,6-Diamino-as-triazine-t-one(64. Method A. 6-Amino5-(methylthio)-as-triazine-3-one (4a, 4.75 g, 30 mmol) was suspended in methanolic ammonia (30 mL, saturated at -5 OC) and kept at room temperature for 24 h in a pressure bottle. During this time, 4a dissolved, and 6a gradudy began to precipitate out of solution. The excess gases were vented, and the solvent was removed under diminished pressure. The residual off-white solid was recrystallized from distilled water to afford a quantitative yield (3.81 g) of 6a: mp 268 OC (slow decomposition); MS (EI, 70 eV, probe 300 "C, source 200 "C), 127 (M'); 'H NMR 6 5.88 (br s, 2,6-NHz),7.0-8.40 (v br s, 2, 5-NHz),10.77 (v br, s, 1,N2H). Anal. Calcd for C3H5N50:C, 28.35; H, 3.97; N, 55.10. Found: C, 28.57; H, 4.08; N, 55.26. Method B. 6-Amino-3-oxo-as-triazine5thione(2,720 mg,4.99 mmol) and liquid ammonia (ca. 15 mL) were heated (oil bath) and stirred in a glass-lined stainless steel reaction vessel at 90 OC for 5 h. The vessel was cooled to room temperature, and the excess ammonia was vented off to provide a yellow residue, which was dissolved in hot methanol (30 mL) and filtered through Celite, and the solvent was removed under diminished pressure. Recrystallition from water furnished 520 mg (82%)of 6a, identical (W,IR,chromatographicmobilities,and a mixture melting point) with 6a prepared by method A. 5,6-Diamino-3-(methylthio)-as-triazine (7a). 6-Amino3,5-bis(methylthio)-as-triazine (5, 1.88 g, 10 mmol) and liquid ammonia (20 mL) were heated in a glass-lined stainless steel reaction vessel at 50 "C for 24 h. The reaction vessel was allowed to cool to room temperature, and the excess gases were vented
1275
off. Crystallization of the resulting residue from distilled water furnished 7a: 1.52 g (97%);mp 200-202 OC, 'H NMR 6 2.38 (8, 3, SCH3), 5.96 (8, 2, 6-NHz), 7.12 (br, 8, 2, 5-NHz).
General Procedure for the Preparation of 5-(Alkylamino)and 5-(Arylalkylamino)-6-amino-3-substituted-as-triazines. Either 4a or 5 was stirred with the appropriate alkylamine or arylalkylamine at room temperature to furnish the corresponding 5-alkylamino or 5-arylalkylaminoderivatives (Table 11). For the preparation of 6c,liquid dimethylamine was used, and the reaction was run in a glass-lined stainless steel bomb. Compounds 6d and 6e were synthesized by suspending 4a in 100 mL of absolute ethanol and adding 1.5 equiv of benzylamine and furfurylamine, respectively. With the exceptions of 6c and 7c, the workups were similar. The excess solvent was removed in vacuo or under diminished pressure and the resulting solid recrystallized as indicated in Table II. In the case of 6c, the exceas gases were vented off, and the residue was crystallized form AR methanol. For 712, the reaction mixture was poured into ethyl ether and washed with three portions of water. The ether layer was then allowed to evaporate overnight and the crystalline residue recrystallized from ethyl acetate.
Acknowledgment. We thank Prof. Elie Abushanab for many helpful discussions and Ms. Sylvia Stoner for technical assistance. Registry No. 1, 18802-38-5; 2, 84582-84-3;3,84582-85-4;4a, 84582-86-5; 4b, 84582-87-6; 4c, 84582-88-7; 4d, 84582-89-8; 5, 84582-90-1; 6a, 84582-91-2; 6b, 84582-92-3;6c, 84582-93-4;6d, 84602-16-4; 6e, 84602-17-5; 7a, 84582-94-5; 7b, 84582-95-6; 7c, 84582-96-7; 6-bromo-as-triazine-3,5-dione, 4956-05-2; methyl iodide, 74-88-4;allyl bromide, 106-95-6;benzyl bromide, 100-39-0; p-nitrobenzyl bromide, 100-11-8; methylamine, 74-89-5; dimethylamine, 124-40-3; benzylamine, 100-46-9;furfurylamine, 617-89-0. Supplementary Material Available: Additional UV absorption data (3 pages). Ordering information is given on any current masthead page.
P hotocycloaddition Reactions of 3-Phenyl-1,2-benzisothiazole and Alkynes M. Sindler-Kulyk a n d D. C. Neckers* Department of Chemistry, Bowling Green State University, Bowling Green, Ohio 43403 Received July 26, 1982
Photocycloaddition reactions of 3-phenyl-1,2-benzisothiazole(1) and the electron-rich alkynes ethoxyacetylene
(%a), ethoxypropyne (2b),and (diethy1amino)propyne (212)gave substituted 3,4-benzo-2,6-thiazabicyclo[3.2.3]hepta-3,g-dienes (3a, 3b, 6) in one-step processes presumably via the l,4-benzothiazepines 13 and 14. I n continuation of our work1i2 on photocycloaddition reactions of fused heterocyclic compounds, we report herein a one-step photochemical synthesis of substituted 3,4-benzo-2,6-thiazabicyclo[3.2.0] hepta-3,6-dienes by irradiating 3-phenyl-l,2-benzisothiazole (1) in t h e presence (1) (a) Neckers, D. C.; Dopper, J. H.; Wynberg, H. J. Org. Chem. 1970, 35, 1582. (b) Dopper, J. H.; Neckers, D. C. Ibid. 1971, 36, 3755. (c) Tmemans, A. H. A,; Neckers, D. C. Ibid. 1977,42,2374. (d) Tinnemans, A. H. A.; Neckers, D. C. Ibid. 1978,43,2493. (e) Ditto, S. R.; Davis, P. D.; Neckers, D. C. Tetrahedron Lett. 1981, 22, 521. (f) Davis, P. D.; Neckera, D. C. J.Org. Chem. 1980,45,456. ( 9 ) Davis, P. D.; Neckers, D. C.; Blount, J. R. Ibid. 1980, 45, 462. (h) Davis, P. D.; Neckers, D. C. Tetrahedron Lett. 1978, 2979. (2) (a) Sindler-Kulyk, M.; Neckers, D. C. Tetrahedron Lett. 1981,22, 525,259. (b) Sindler-Kulyk, M.; Neckers, D. C.; Blount, J. R. Tetrahedron 1981. 3377.
of electron-rich alkynes. Previous results from our laboratory, as well as other^,^ have indicated t h e viability of *2, ,2, cycloadditions with the 2,3-bond of fused heterocyclic compounds such as benzo[b] thiophene, benzo[ 61furan, a n d indole, followed by a thermal cyclobutene-butadiene rearrangement, in generating benzo[ b]thiepines, benzo[b]oxepines, a n d benzo[b]azepines. O n t h e basis of these observations, we postulated t h a t irradiation of fused heteroaromatic compounds such as benzothiazole or benzisothiazole with alkynes might provide t h e pharmacologically interesting benzothiazepines. Contrary t o our expectation, initial attempted photocycloadditions in the presence of both alkynes and alkenes
+
(3) Reinhoudt, D. N.; Kouwenhoven, C. G. Tetrahedron 1974,30,2431.
0022-3263/83/1948-1275$01.50/0 0 1983 American Chemical Society
