Synthesis of nucleosides using ketene dithioacetals

摘要

2309J. CHEM. SOC. PERKIN TRANS. I 1988 Synthesis of Nucleosides Using Ketene Dithioacetals Masataka Yokoyama," Katsushi Kumata, Naoyuki Yamada, Hidehiko Noro, and Yuka Sudo Department of Chemistry, Faculty of Science, Chiba University, Ya yoi-cho, Chiba City, 260,Japan Several unnatural pyrazole and 1,2,4-triazoIe nucleosides are synthesized in a regio- and stereo- selective manner by the reaction of readily available ketene dithioacetals with 1-ribofuranosyl-hydrazine. Ketene dithioacetals are conveniently synthesized in large quantities from the reaction of active methylene compounds with carbon disulphide followed by alkylation. These compounds are readily soluble in a variety of organic solvents and the alkylthio groups are convertible into amino, alkyl, and other groups by reaction with the corresponding nucleophiles. Using these reactions, a wide variety of heterocycles2 and naturally occurring products have been synthesized.We have also reported the synthesis of pharmaceutically important oxazoles, pyrazoles, pyrimidine^,^ and heterocycles containing an amino acid m~iety.~ In this paper, the work is extended to the synthesis of nucleosides which have recently received considerable attention as antiviral agents.6 Results and Discussion The synthetic methodology of nucleosides is generally classified into two categories: i, direct fusion of the base moiety and ribose derivatives such as ribofuranosyl ~hloride,~ribofuranosyl acetate,* or methyl ribofuranoside and ii, construction of the base moiety starting from 1-functionalised riboses such as ribofuranosylamine, ribofuranosyl isocyanate, ribofuranosyl isothiocyanate, ribofuranosylurea, ribofuranosylthiourea, and ribofuranosyl azide.lo Recently, Townsend et al. have reported the synthesis of nucleosides using ribofuranosylhydrazine.' ' From their results, this hydrazine derivative reacts with ketene dithioacetals to afford the corresponding nucleosides regio- selectively because it exists mainly in a hydrazone form.' Several nucleosides were prepared starting from ketene dithioacetals. Further, we found that the present reaction formed the p-anomer of nucleosides exclusively, a result that may be attributed to the steric hindrance between the isopropylidene and the hydrazino moieties of the N,N-disubstituted hydrazinoribose intermediate (3).The five ketene dithioacetals (1) derived from cyanoacetamide and malononitrile were refluxed with 2,3-0-isopropylidene-~- ribofuranosylhydrazine (2) in absolute ethanol to give the corresponding nucleosides (4) in moderate yields as shown in Table I (Scheme 1). The yield is based on the 2,3-0-isopropylidene-D-ribose used. Deprotection of (4) was carried out with acetic acid in the usual way to afford the corresponding nucleoside (5). In a similar way, compounds (7)and (9)were synthesized using the modified ketene dithioacetals (6) and (8), respectively (Schemes 2 and 3).The results for compound (7) are summarized in Table 2. Compound (9) was further deprotected by treatment with formic acid to give the corresponding nucleoside (10).The structures of compounds (4), (7), and (9)were determined by spectral and analytical evidence and their p-anomer structures were assigned on the basis of differences in chemical shifts between the two methyl groups of the isopropylidene moiety in the 'H n.m.r. spectra As = 0.21 for (4a), A6 = 0.20 for (7), and A8 = 0.12 for (9).13 The presence of a sugar moiety at Table 1. Preparation of compound (4) (4) R' R2 (44 CONH, Me (4b) CONH2 Bn (W CN CH2TMS (44 CN Me (4e) CN Bn R1 M.p. ("C) Yield () 154-1 55 63 59-60 51 53-54 34 159-160 30 41-43 27 HoDNHdH H:p"' RO OR (4)R, R = CMe2 (5) R=H Scheme 1. R' and RZ are given in Table 1 R1InR2 (71 Scheme 2.R' and R2 are given in Table 2 position 1of 1,2-pyrazole or 1,2,4-triazole can be determined on the basis of the 3Jc,Hsplitting in the 13C n.m.r. spectra.I4 The 13C n.m.r. spectrum of (4a) which was measured by proton decoupling and n.0.e. showed a quartet peak and a broad peak 2310 J. CHEM. SOC. PERKIN TRANS. I 1988 nitrile with iodomethyltrimethylsilane, methyl iodide, and Table 2. Preparation of compound (7) benzyl chloride, respectively. 2-Carbamoyl-3,3-bis(benzylthio)acrylonitrile (1b). White (7) R' R2 M.p. ("C) Yield () powder (92), m.p. 125-127 "C (Found: C, 63.45; H, 4.75; N, (74 CONH, Ph 167-169 20 8.2. C1,Hl,N,OS, requires C, 63.50; H, 4.74; N, 8.23); (7b) CONH, Bu 154-155 25 vmax.(KBr) 3 350, 3 150 (NH,), 2 990 (CH), 2 200 (CN), and (7c) CN Ph 136-137 23 (decomp.) (74 CN Bu ca.-3 24 6,( 1 640 cm-' (CO); 100 MHz, CDCl,) 4.04 (2 H, S, SCH,Ph), U 4.12 (2 H, s, SCH,Ph), 5.8Ck-6.10 (2 H, br, CONH,), and 7.G 7.20 (10 H, m, 2 x Ph); m/z 340 (M+). 2-Cyano-3,3-bis(trimethylsilylmethyl)thioacrylonitrile(lc). A mixture of disodium 2-cyano-3,3-disulphidoacrylonitrile hydrate (2.4 g, 10 mmol) and iodomethyltrimethylsilane(TMSCH,I) (4.5 g, 21 mmol) was refluxed in water (50 ml) containing a small amount of ethanol (5 ml) for 3 h. The resultant mixture was cooled and extracted with ethyl acetate. The extract was dried (Na,S04) and evaporated to give yellow RO OR (9) R, R = CMe2 (1O)R.R = H for C-3 and C-5, respectively.An alternative structure (4a') is ruled out by this result. The 13C n.m.r. spectrum of (9)showed a similar result. 0 t-( Ox0 These structures were further supported by the following reactions; compounds (4a) and (9) were desulphurized with Raney nickel to give 5-amino- 1-(2',3'-0-isopropylidene-P-~-ribofuranosyl)pyrazole-4-carboxamide' and 5-amino- 1 -(2',3'- 0-isopropylidene- P-D-ri bofuranosy1)- 1,2,4- triazole, respect-ively. The latter compound was converted into 5-amino-l-(P-~- ribofuranosyl)-1,2,4-triazolel6 on treatment with acetic acid. Experimental Microanalysis was performed with a Perkin-Elmer elemental 240 analyser at the Chemical Analysis Center of Chiba University. I.r., mass, u.v., 'H n.m.r., and 13C n.m.r.spectra were measured with Hitachi 215, RMU 6MC, EPS-3T, JEOL MH- 100, and JMN-GX-270 spectrometers, respectively. Wakogel C- 200 was used for column chromatography and Wakogel B-5F was used for t.1.c. Preparation of Ketene Dithioacetals (l).-Compound (la) was prepared by reaction of ethyl cyanoacetate with carbon disulphide followed by methylation.' A mixture of ethyl cyanoacetate (120 g, 1.1 mol), carbon disulphide (161 g, 2.1 mol), and aqueous ammonia (28; 360 ml) was stirred at room temperature for 8 h. The crude product was collected and recrystallized from water-acetone to give light yellow prisms (83 g, 40), m.p., 147-148 "C. This product was methylated with methyl iodide in water to give pale yellow needles. Recrystal- lization from ethanol gave white needles (7773, m.p. 84deg;C.Similarly, compound (1b) was prepared by benzylation instead of methylation. Compounds (lc), (la), and (le) were prepared by the alkylation of disodium 2-cyano-3,3-disulphidoacrylo-plates of (lc) (96) as white plates (recrystallized from hexane- ethyl acetate), m.p. 68-69 "C (Found: C, 45.65; H, 7.0; N, 8.9. C,,H,,N,S,Si, requires C, 45.81; H, 7.05; N, 8.90); v,,,,(KBr) 2 925, 2860 (CH), and 2 200 cm-' (CN); 6,(100 MHz, CDCl,) 0.18 (18 H, s, 2 x SiMe,), and 2.50 (4 H, s, 2 x SCH,Si); m/z 314 (M+). 2-Cyano-3,3-bis(methylthio)acryfonitrile(la).This compound was prepared according to ref. 17 (8673, m.p. 83-84deg;C; v,,,.(KBr) 2 980 (CH) and 2 200 cm-' (CN); 6,(100 MHz, CDCl,) 2.70 (6 H, s, 2 x Me); m/z 170 (M+).2-Cyano-3,3-bis(benzylthio)acrylonitrile(le). White powder (recrystallized from hexane-ethyl acetate) (7573, m.p. 87- 88 "C (Found: C, 67.1; H, 4.4; N, 8.65. C1,H,,N2S, requires C, 67.09; H, 4.34; N, 8.70); v,,,.(KBr) 2 200 cm-' (CN); 6,(100 MHz, CDCI,) 4.32 (4 H, s, 2 x SCH,Ph) and 7.30 (10 H, m, Ph); m/z 322 (M'). 2,3-O-Isopropylidene-~-ribofuranosylhydrazine (2).-The procedure by L.B. Townsend '' was modified as follows. A mixture of 2,3-0-isopropylidene-~-ribose (1.14 g, 6 mmol), ' * anhydrous hydrazine (1.8 ml, 60 mmol; 97 reagent grade), and absolute ethanol (6 ml) was stirred overnight at room temperature under nitrogen. The solvent of the reaction mixture was removed by aspirator and the residue was evaporated with dry ethanol (4 x 4 ml) and dry toluene (1 ml) under a vacuum pump (1 mmHg) below 50 "C in order to remove the excess of hydrazine.The pale yellow syrup thus obtained was used without purification in the next step. 5-Amino-4-carbamoyl-3-methylthio-1-(2',3'-O-isopropylidene-P-D-ribofuranosy1)pyrazole(4a).-A solution of (la) (376 mg, 2 mmol) and (2) (1.22 g, 6 mmol) in absolute ethanol (12 ml) was refluxed for 10 h. The solvent was evaporated off to give a yellow syrup and the syrup was dissolved in methylene dichloride and purified by t.1.c. on silica gel (eluant AcOEt-MeOH, 1O:l) to afford white crystals (8) (428 mg, 62.4), m.p. 154 "C (Found: C, 45.1; H, 5.8; N, 16.05. C13H,,N40,S requires C, 45.34; H, 5.85; N, 16.27); v,,,,(KBr) 3 380, 3 300 (OH, NH,), 2 950, 2 900 (CH), and 1 640 cm-' (CO); 6,(270 MHz, CDCl,) 1.37 (3 H, s, Me), 1.58 (3 H, s, Me), 2.53 (3 H, s, SMe), 3.84, 3.69 (2 H, AB pattern, CH,OH, J,,,,.12.5 Hz, J4,,,,7 Hz), 4.48 (1 H, s,OH), 4.87 (1 H,dd,4'-H, J3,,4,3 Hz, J4,,5,7HZ), 5.02(1 H,dd,2'-H, J29.3, ~Hz, J,,,2,2 Hz), 5.26 (1 H, dd, 3'-H, J,*,3,6 Hz, J3,,4,3 Hz), 5.80 (1 H, d, J,.,,.2 Hz), 5.90 (2 H, br, NH, exch.D,O), and 6.10 (2 H, br, CONH,, exch. D,O); 6, (67.8 Hz, CDCl,) 16.0 (SMe), 25.0,26.9 (2 x Me), 63.6 (C-5'), 81.8 (C-37, 84.2 (C-2'), 88.1 (C-4'), 91.6 (C-1'), 96.4 (CMe,), 113.2 (C-5), 145.5 (C-3), 152.2 (C-4), and 166.3 (CO). m/z (in beam) 344(M + 1)'; h,,,.(99 EtOH) 212 (E 16 OOO) and 225 nm (5 800); cz,, -76.8" (c 0.35, EtOH).Compounds (4b), (k),(a),and (4e) were prepared from compounds (lb), (lc), (Id), and (le) by the same method as above. J. CHEM. SOC. PERKIN TRANS. I 1988 5-Amino-3-benzylthio-4-carbamoyl-1-(2rsquo;,3lsquo;-O-isopropylidene-P-D-ribofuranosy1)pyrazole(4b). White powder (Found: C, 54.1; H, 5.8; N, 13.15. C,,H,,N,O,S requires C, 54.27; H, 5.75; N, 13.32); v,,,.(KBr) 3 400,3 200 (OH, NH,), 2 960,2 920 (CH), and 1 640 cm-rsquo; (CO); 6,(270 MHz, CDCI,) 1.37 (3 H, s, Me), 1.57(3 H, s, Me), 3.60,3.76 (2 H, AB pattern, CH,OH, J,,,,.12.5 Hz, J4,,5,7 Hz), 4.16 (2 H, s, PhCH,), 4.44 (1 H, s, OH),4.56 (1 H, dd,4lsquo;-H, J3r.432 Hz, J4r.5rsquo;7 Hz),4.96 (1 H,dd, 2lsquo;-H, J1*,2,2 Hz, J2r.3, 6 Hz), 5.1 7 ( 1 H ,dd, 3rsquo;-H, J,,,3,6 Hz, J3t ,4,2 Hz), 5.79 ( 1 H, d, 1 rsquo;-H, J,.,,.2 Hz), 5.90 (2 H, s, NH,), 6.20 (2 H, s, CONH,), and 7.26 (5 H, s, Ph); m/z (in beam) 420 (Mrsquo;); h,,,.(99 EtOH) 210 (E 91 400) and 260 nm (24 700); a,, -44.4rsquo; (c 0.35, EtOH).5-Amino-4-cyano-3-(trimethylsily1)rnethylthio-1 -(2rsquo;,3rsquo;-0- isopropylidene-P-D-ribofuranosyl)pyrazole(4c). White powder (Found: c,48.05; H, 6.55; N, 13.95. C16H26N404SSi requires c, 48.22; H, 6.58; N, 14.06); v,,,.(KBr) 3 350, 3 200 (OH, NH,), 2 950,2 860 (CH), and 2 220 cm-rsquo; (CN); 6,( 100 MHz, CDCl,) 0.12 (9 H, s, SiMe,), 1.30 (3 H, s, Me), 1.48 (3 H, s, Me), 2.16 (2 H, s, CH,TMS), 3.60 (2 H, m, CH,OH), 4.20 (1 H, s, OH), 4.30 (1 H,m,4rsquo;-H),4.70(1 H,d,2rsquo;-H, J2,,3,4Hz),4.90(1 H,d,3rsquo;-H, J2,,3* 4Hz),5.20(2H,br,NH2),and5.5O(1H,d,lrsquo;-H,J,,,,.2Hz);rn/z (in beam) 398 (Mrsquo;); h,,,.(99 EtOH) 217 (E 25 900) and 235 nm (14 400); .ID -53.4rsquo; (c 0.27, EtOH).5-Amino-4-cyano-3-methylthio-1-(2rsquo;,3rsquo;-O-isopropylidene-p-~-ribofuranosy1)pyrazole (4d). White powder (Found: C, 47.8; H, 5.55; N, 17.35. Cl,Hl,N,04S requires C, 47.84; H, 5.56; N, 17.17); v,,,,(KBr) 3 450,3 350,3 180 (OH, NH,), 2 980,2 920 (CH), and 2 220 cm-lsquo; (CN); 6,(100 MHz, CDC1,) 1.36 (3 H, S, 231 1 crystallized from hexane-ethyl acetate) (Found: C, 60.5; H, 4.6; N, 12.8. C,,H,,N,OS requires C, 60.53; H, 4.62; N, 12.83); vmax.(KBr)3 360,3 140 (NH,) 2 200 (CN), and 1 680 cm-rsquo; (CO); amp;,(lo0 MHz, CDCI,) 1.60 (3 H x 1/9, s, SMe), 1.84 (3 H x 8/9, s, SMe), 5.90 (2 H, br, NH,), 7.10 (2 H, m, Ph), and 7.30 (3 H, m, Ph); m/z 218 (M+).N.m.r.data showed (6a) to be a 9: 1 mixture of E-and 2-forms. 3-Butyl-2-carbamoyl-3-(methylthio)acrylonitrile (6b).-A THF solution of butylmagnesium chloride (2.2 mmol) was added dropwise to a solution of (la) (0.188 g, 1 mmol) in dry THF (10 ml) and the mixture was stirred at the same temperature for 2 h and then at room temperature for 10 h. The reaction mixture was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and the extract was dried (Na,S04) and evaporated to give a pale yellow oil, which was purified by t.1.c. on silica gel (eluant AcOEt-hexane, 1:1) to afford white crystals (40), m.p. 78- 80 lsquo;C (Found: C, 54.5; H, 7.1; N, 14.1. C,H,,N,OS requires C, 54.52; H, 7.1 1; N, 14.13); v,,,.(KBr) 3 400,3 280 (NH,), 2 960, 2 920, 2 860 (CH), 2 200 (CN), and 1 650 cm-rsquo; (CO); 6,(100 MHz, CDC1,) 0.94 3 H, t, (CH,),Me, J4 Hz, 1.20-1.70 (4 H, m, CH,CH,CH,Me, J 4 Hz), 2.34 (3 H, s, SMe), 2.70 (2 H, br, CH,CH,CH,Me), and 5.80 (2 H, br, CONH,); m/z 198 (Mrsquo;). 2- Cyano-3-methylthio- 3-phenylacrylonitrile ((ic).-Malono-nitrile (660 mg, 10 mmol) at 0 lsquo;C was added to ethanol (50 ml) containing sodium metal (460 mg, 20 mmol) and the mixture Me), 1.56 (3 H, s, Me), 2.44 (3 H, s, SMe), 3.70 (2 H, m, CH,OH), was stirred for 30 min at room temperature.Methyl dithio- 4.10(1 H,m,4rsquo;-H),4.38(1H,s,OH),4.80-5.18(4H,m,2rsquo;-H,benzoate (1.68 g, 10 mmol) was added to the reaction mixture at 3rsquo;-H, NH,), and 5.60 (1 H, d, 1rsquo;-H, J1,,,,2 Hz); m/z (in beam) 326 (Mrsquo;); hma,,(99rdquo;/0 EtOH) 214 (E 22 O00) and 236 nm (10 500); .ID -77.9rdquo; (C 0.65, EtOH).5- Amino- 3- benzylthio-4-cyano- 1 -(2rsquo;-3rsquo;-O-isopropylidene-p-D-ribofuranosy1)pyrazole (4e). White powder (Found: C, 56.65; H, 5.5; N, 13.65. Cl,H,,N404S requires C, 56.70; H, 5.51; N, 13.92); v,,,.(KBr) 3 400,3 300,3 200 (OH, NH,), 2 920,2 850 (CH), and 2 200 cm-I (CN); 6,(100 MHz, CDC1,) 1.30 (3 H, S, Me), 1.48 (3 H, s, Me), 3.44 (2 H, m, CH,OH), 4.00 (2 H, s, CH,Ph),4.20(1 H, s, OH),4.56(1 H,m,4rsquo;-H),4.65 (1 H,dd, 2lsquo;- H, J1,,,, 2 Hz, J2,,3r 4 Hz), 4.90-5.10 (3 H, m, 3rsquo;-H, NH,), 5.50 (1 H, d, 1rsquo;-H, J,,,,,2 Hz), and 7.00 (5 H, s, Ph); m/z (in beam) 402 (Mrsquo;); hm,,,(99 EtOH) 215 (E 62600) and 258 nm (44200); .ID -37.5rsquo; (C 0.82, EtOH). 5-Amino-4-carbamoyl- 3-methylthio- 1 -(p-D-ribofuranosy1)-pyrazole (5a).-A mixture of (4a) (344 mg, 1 mmol) and 10 acetic acid (2 ml) was refluxed for 3.5 h and then evaporated under reduced pressure with water and ethanol several times to give (5a) as a white powder, m.p.162 lsquo;C (decomp.) (Found: C, 39.45; H, 5.3; N, 18.44. CloH16N405S requires C, 39.47; H, 5.30; N, 18.41); v,,,,(KBr) 3 400-3 150 (NH,, OH), 2 950-2 870 (CH), and 1 640 cm-rsquo; (CO); 6,(100 MHz, CDC13-C5D,N) 2.38 (3 H, s, SMe), 3.98 (2 H, m, CH,OH),4.40(1 H, m,4rsquo;-H),4.74 (1 H, m, 2rsquo;-H), 5.10 (1 H, m, 3rsquo;-H), and 5.70-7.40 (6 H, m, 3-OH, 2 x NH,, 1rsquo;-H); m/z (in beam) 304 (Mrsquo;);h,,,.(99 EtOH) 215 (E 23 600) and 255 nm (9 500); .ID -49.4rsquo; (c 0.16, EtOH). Prepararinn oflsquo; Modijied Ketene Dithioacetals (6).--2-Carb- amoyl-3-methylthio-3-phenylacrylonitrile(6a). A mixture of oil- free sodium hydride (30 mmol), cyanoacetamide (0.84 g, 10 mmol), and dry tetrahydrofuran (20 ml) was refluxed for 1 h.To the reaction mixture was added methyl dithiobenzoate (2.0 g, 12 mmol) below 0deg;C. The reaction mixture was quenched by water, washed with benzene, and the resulting aqueous solution was stirred with methyl iodide (1 ml, 15 mmol) at room temperature for 4 h and then extracted with ethyl acetate to give pale yellow crystals (62), m.p. 202-203 lsquo;C (decomp.) (re- Orsquo;C, the mixture was stirred for a further 3 h at room temperature and methyl iodide (2 ml) was then added. The resulting solution was stirred at room temperature for 15 h and evaporated to give a yellow oil, which was dissolved in ethyl acetate.The ethyl acetate solution was washed with water several times, dried (Na,SO,), and subjected to column chromatography on silica gel (eluant CHCl,) to give (6c) (0.62 g, 30), m.p. 86-87rsquo;C (Found: C, 65.9; H, 4.05; N, 14.0. C,,H,N,S requires C, 65.98; H, 4.03; N, 13.99); v,,,.(KBr) 3050 (Ph), 2900 (CH), and 2200 cm-rsquo; (CN); 6,(100 MHz, CDCI,) 2.16 (3 H, s, SMe) and 7.20-7.50 (5 H, m, Ph); m/z 200 (Mrsquo;).Compound (6d)was prepared from methyl dithiopentanoate and malononitrile by the method used in the preparation of (6c). 3-Butyl-2-cyano-3-(methylthio)acrylonitrile(6d).Dark red oil (95), b.p. 125-127 lsquo;C/1 mmHg (Found: C, 59.8; H, 6.65; N, 15.55. C,H,,N,S requires C, 59.97; H, 6.71; N, 15.54); v,,,.(neat) 2950, 2920, 2860 (CH), and 2200 cm-rsquo; (CN); 6,( 100 MHz, CDCl,) 0.95 -3 H, t, (CH,),Me, J4 Hz, 1.2amp; 1.60 (4 H, m, CH,CH,CH,Me), 2.50 (3 H, s, SMe), and 2.70 (2 H, t, CH,CH,CH,Me J 4 Hz); m/z 180 (Mrsquo;).Compounds (7a), (7b), (7c), and (7d) were prepared from starting compounds (6a), (6b), (amp;), and (6d)by the method used in the preparation of (4a). 5-Amino-4-carbamoyl-3-phenyl-1-(2rsquo;,3rsquo;-O-isopropylidene-P-D-ribofuranosyl)pyrazole (7a). White powder (from CH,Cl,) (Found; C, 57.8; H, 6.0; N, 14.85. C,,H,,N,O, requires C, 57.75; H, 5.92; N, 14.96); v,,,.(KBr) 3 450, 3 350 (OH, NH,) 2 960, 2 910 (CH), and 1 640 cm-rsquo; (CO); amp;,(lo0 MHz, CDCI,) 1.32 (3 H, s, Me), 1.54 (3 H, s, Me), 3.68 (2 H, m, CH,OH), 4.36 (1 H, S, OH), 4.92 (1 H, dd, T-H, J2,,3,6 Hz, Jl,,2f Hz), 4.50 (1 H, m, 4rsquo;-H), 5.20( 1 H, dd, 3rsquo;-H, J2P.386 Hz, J2,,3,2 Hz), 5.36 (2 H, s, NH,), 5.90 (2 H, br, CONH,), and 7.30 (5 H, m, Ph); m/z (in beam) 374 (M+);h,,,,(99 EtOH) 210 (E 42 800), 231 (31 700), and 255 nm (31 700); .ID -86.3rsquo; (c 0.28, EtOH).5-Amino- 3- butyl-4-carbamojd- 1 -( 2rsquo;,3rsquo;-O-isopropylidene-p-D-ribofuranosyI)pyrazole (7b). White powder (from CH,CI,) (Found: c, 54.1; H, 7.3; N, 15.75. C16H26N405 requires c, 54.22; H, 7.39; N, 15.81); v,,,.(KBr) 3 450, 3 330, 3 140 (OH, NH,), 2 950, 2 910, 2 850 (CH), and 1 630 cm-rsquo; (CO); 6,(100 MHz, CDCI,) 0.92 3 H, t, (CH,),Me, J6 Hz, l.l(L1.60 (4 H, m, CH,CH,CH,Me), 1.32 (3 H, s, Me), 1.48 (3 H, s, Me), 2.68 (2 H, t, CH,CH,CH,Me, J 6 Hz), 3.36 (1 H, s, OH), 3.60 (2 H, m, CH,OH), 3.8G5.00 (4 H, m, 1rsquo;-H, 4lsquo;-H, NH,), and 5.80 (2 H, br, NH,); m/z (in beam) 354 (amp;I+);h,,,.(99 EtOH) 208.5 (E 19 500), 225sh (7 400), and 257 nm (9 600); .ID -10.2rdquo;(c 0.29, EtOH).5- Amino-4-cyano-3-phenyl- 1 -(2rsquo;,3rsquo;-O-isopropylidene-P-~-ribofuranosy1)pyrazole (7c). White powder (from AcOEt-hexane) (Found: C, 60.65; H, 5.6; N, 15.65. C18H,oN404 requires C, 60.66; H, 5.66; N, 15.72);vmax.(KBr)3 400, 3 300, 3 240 (OH, NH,), 2960, 2900, 2 850 (CH), and 2200 cm-rsquo; (CN); 6,(100 MHz, CDCl,) 1.24 (3 H, S, Me), 1.48 (3 H, S, Me), 3.50 (2 H, m, CH,OH), 4.10 (1 H, s, OH), 4.70 (1 H, m, 4rsquo;-H), 4.94 (1 H, s, OH), 5.16 (2 H, br, NH,), 5.52 (1 H, m, 3rsquo;-H), 5.60 (1 H, d, 1rsquo;-H,JIl,,,2 Hz), and 7.04 (5 H, m, Ph); m/z (in beam) 356 (amp;I+);hma,.(99, EtOH) 236 (E 9790) and 275sh; nm .ID-34.9O (C 0.49, EtOH).5-Amino-3-butyl-4-cyano-1-(2rsquo;,3rsquo;-O-isopropylidene-P-~-ribo-furanosyl)pyrazole (7d). Pale yellow oil, m.p. ca. -3 ldquo;C (Found: C, 57.1; H, 7.1; N, 16.55. Cl,H,4N404 requires C, 57.13; H, 7.19; N, 16.66);v,,,.(neat) 3 40amp;3 150 (NH,, OH), 2 950-2 830 (CH), and 2 200 cm-rsquo; (CN); 6,(100 MHz, CDCI,) 0.90 3 H, t (CH,),Me, J 4 Hz, 1.30 (3 H, s, Me), 1.1G1.65 (4 H, m, CH,CH,Me), 1.48 (3 H, s, Me), 2.44 (2 H, t, CH,CH,CH,Me, J 4 Hz), 3.60 (2 H, m, CH,OH), 4.00 (1 H, m, 4rsquo;-H), 4.10-4.50 (3 H, br, NH,, OH),4.84 (1 H, d, 2rsquo;-H, J2*,,,6 Hz), 5.04 (1 H, d, 3rsquo;-H, J2,,3,6Hz), and 5.60 (1 H, d, 1rsquo;-H, J1,,,,2 Hz); m/z (in beam) 336 (Mrsquo;); h,,,.(99 EtOH) 236 nm (E 7 830); .ID -93.5rdquo; (C 0.51, EtOH). Dimethyl N-Cyanodithiocarbonimidate(8).-Compound (8) was readily synthesized from the reaction of cyanamide with carbon disulphide followed by methylation according to the literat~re;rsquo;~ (KBr) 2980, 2920 (CH), and 2 200 cm-rsquo;v,,,.(CN); 6,(100 MHz, CDCl,) 2.60 (6 H, s, 2 x Me); m/z 146 (amp;I+1. 5- Amino-3-methylthio- 1 -(2rsquo;,3rsquo;-O-isopropylidene-P-~-ribo-furanosy1)- 1,2,4-triazole (9).-The reaction was carried out by the same procedure as for compound (4). Purification was performed by t.1.c. work-up using AcOEt-EtOH (95 :5) as eluant; white powder (36), m.p. 147 ldquo;C (Found: C, 43.7; H, 5.95; N, 18.5. CllH18N404S requires C, 43.70; H, 6.00; N, 18.53);v,,,.(KBr) 3 410,3 310,3 210 (NH,), 2 960, and 2 910 cm-rsquo; (CH); 6,(270 MHz, CDCl,-C,D,N) 1.32 (3 H, s, Me), 1.44 (3 H, s, Me), 2.46 (3 H, s, SMe), 3.70, 3.81 (2 H, AB pattern, C HZOH, J5 ,,5*,12Hz,J4*,5t3.3 H~),4.38 (1 H, dd,4rsquo;-H, J4t, 5* 3.3Hz, J3P.4rsquo;2 Hz),4.99 (1 H, dd, 2rsquo;-H, J2e.3lsquo;6Hz,J,,,2,2Hz), 5.2 1(1 H, dd, 3rsquo;-H,J2T.3rsquo;6Hz,J38,4r2 Hz),5.91 (1 H, d, 1rsquo;-H,J,,,,, 2 Hz), and 6.10 (2 H, br, NH,, exch.D,O); 6J67.8 MHz, CDC13-C5D5N) 13.4 (SMe),24.7, 26.5 (2 x Me), 62.7 (CH,), 81.4 (C-3rsquo;), 83.9 (C-27, 87.7 (C-4rsquo;), 91.5 (C-1rsquo;), 95.5 (CMe,), 156.0 (C-5),and 159.1 (C- 3); m/z (in beam) 302 (M+);h,,,.(99 EtOH) 236.8 (E 16 OOO) and 306.5 nm (1 700); .ID -58.2O (c 0.52, EtOH). 5-Amino-3-methylthio- 1 -(P-D-ribofuranosyl)- 1,2,4-triazole (lo).-A mixture of compound (9) (300 mg, 1 mmol) and 50 formic acid (2 ml) was stirred at room temperature for 5 days.The reaction mixture was evaporated under reduced pressure and then purified by column chromatography on silica gel using AcOEt-EtOH (95:5) as eluant to give a white powder (50), m.p. 160-161 ldquo;C (Found: C, 36.6; H, 5.4;N, 21.4. C8H1,N4O4S requires C, 36.64; H, 5.38; N, 21.36); v,,,,(KBr) 3 300, 3 200 (OH, NH,), and 2 900 cm-rsquo; (CH); 6,(100 MHz, CDC1,- C,D,N) 2.22 (3 H, s, SMe),3.70 (2 H, m, CH,OH), 4.10 (1 H, m, J. CHEM. SOC. PERKIN TRANS. I 1988 4rsquo;-H), 4.40 (1 H, m, 2rsquo;-H), 4.70 (1 H, m, 3rsquo;-H), 5.40-5.60 (3 H, br, 3-OH, together with H,O), 5.80 (1 H, d, 1rsquo;-H, .Ilr,,,2 Hz), and 6.70 (2 H, s, NH,); m/z (in beam) 262 (W);h,,,.(99EtOH) 207 (E 11 SOO), 220sh (7 400), and 240sh nm (3 200); .ID-50.5rdquo; (C 0.16, EtOH).Desulphurization of Compound (4a).-A solution of com-pound (4a) (0.34 g, 1 mmol) and activated Raney nickelZo (1.5 ml) in 2-methoxyethanol (10 ml) was refluxed for 3 h. The reaction mixture was filtered through Celite and the filtrate was evaporated to give a white residue which was dried under vacuum (2-3 mmHg). Recrystallization from methanol- hexane gave 5-amino-1-(2rsquo;,3rsquo;-O-isopropylidene-~-~-ribo-furanosyl)pyrazole-4-carboxamide in quantitative yield as white prisms, m.p. 179-180 ldquo;C (lit.,rsquo;, 181 ldquo;C); 6,(100 MHz, CDCI,) 1.30 (3 H, s, Me), 1.42 (3 H, s, Me), 3.69 (2 H, m, CH,OH), 4.32 (1 H, m, 4rsquo;-H), 4.98 (1 H, m, 3rsquo;-H), 5.25 (1 H, dd, 2rsquo;-H), J1,,2, 2 Hz, J2,,39 6 Hz), 5.94 (1 H, d, 1rsquo;-H, Jl,,Zr 2 Hz), 6.0-6.5 (4 H, br, 2 x NH,), and 7.50 (1 H, s, 3-H); h,,,.(99, EtOH) 236.5 (E 12 300) and 255 nm (13 800); .ID -123rdquo; (c 0.61, EtOH).5- Amino- 1 -(P-D-ribofuranosy1)-1,2,4-triazole.-Desulphuriz-ation of (9) was carried out by the same method as that of (4a). The white powder obtained was deprotected by refluxing for 2 days with 50 acetic acid to give a white powder. lsquo;H N.m.r. and U.V.data were superimposable on those reported by J. T. Witkowski et all6 Acknowledgements We thank the Ministry of Education, Science and Culture, Japan, for financial support in the form of a Grant-in-Aid for Scientific Research and Prof. M. Funabashi (College of Art and Science, Chiba University) for his assistance in the research of literature.References 1 B. Myboh, L. W. Singh, and 1. H. Junjappa, Synthesis, 1982, 307; S. Apparao, A. Rahman, and I. H. Junjappa, Tetrahedron Lett., 1982, 23,971; M. Yokoyama, M. Tohnishi, and T. Imamoto, Chem. Lett., 1982, 1933; K. T. Patts, M. J. Cipulls, P. Ralli, and G. Theodoridis, J. Org. Chem., 1982,47, 3027; B. Cazes and S. Julia, Tetrahedron Lett., 1978,4065; E. J. Corey and H. K. Chen, Tetrahedron Lett., 1973,38 17. 2 M. Yokoyama and T. Imamoto, Synthesis, 1984, 797; T. Yoshinori and Y. Matsuda, J.Synth. Org. Chem., 1985, 43, 669 (in Japanese). 3 A. I. Mayer, T. A. Tait, and D. L. Comins, Tetrahedron Lett., 1978, 4657. 4 M. Yokoyama, K. Tsuji, and T. Imamoto, Bull. Chem. SOC.Jpn., 1984,57, 2954; M. Yokoyama, K. Tsuji, and M. Kushida, J. Chem. SOC., Perkin Trans. I, 1986, 67. 5 M. Yokoyama, K. Kumata, H. Noro, and A. Kogo, Synthesis, in the press. 6 R. K. Robins, Chem. Eng. News, 1986,27, 28; J. T. Witkowski, R. K. Robins, R. W. Sidwell, and L. N. Simon, J. Med. Chem., 1972, 15, 1150; R. W. Sidwell, J. H. Huffman, G. P. Khare, L. B. Allen, J. T. Witkowski, and R. K. Robins, Science, 1972, 177, 705; J. T. Witkowski, R. K. Robins, G. P. Khare, and R. K. Sidwell, J. Med. Chem., 1973,16,935; N. J. Leonard and S. P. Hiremath, Tetrahedron Lett., 1986, 42, 1917. 7 J. Davoll and B. A. Lowy, J. Am. Chem. Soc., 1951,73,1650; J. J. Fox, N. Yung, J. Davoll, and G. B. Brown, J. Am. Chem. SOC., 1956, 78 21 17; K. A. Watanabe and J.J. Fox, J. Heterocycl. Chem., 1969, 6, 109; N. Yamaoka, K. Aso, and K. Matsuda, J. Org. Chem., 1965,30, 145;G. A. Haward, B. Lythgoe, and A. R. Todd, J. Chem. Soc., 1947, 1052; T. Ueda and H. Ohtsuka, Chem. Pharm. Bull., 1973,21, 1530. 8 M. J. Robins and R. K. Robins, J. Am. Chem. SOC., 1965,87,4934; U. Niedballa and H. Vorbruggen, J. Org. Chem., 1974,39, 3654. 9 Y. Furukawa, K. Imai, and M. Honjo, Tetrahedron Lett., 1968,4655. J. CHEM. SOC. PERKIN TRANS. I 1988 10 G. Shaw, R. N. Warrener, M. H. Maguire, and P. K. Ralph, J.Chem. SOC.,1958, 2294; N. J. Cusack, H. Hildick, D. H. Robinson, and G. Shaw, J. Chem.SOC.,Perkin Trans. I, 1973,1720; T. Naito, M. Hirata, T. Kawakami, and M. Sano, Chem. Pharm. Bull., 1961, 9, 703; T. Naito and M. Sano, Chem. Pharm. Bull., 1961,9, 709. 11 0.L. Acevedo, S. H. Krawczyk, and L. B. Townsend, J. Org. Chem., 1986, 51, 1050. 12 R. R. Schmidt, J. Karg, and W. Guillard, Angew. Chem., Int. Ed. Engl., 1975, 14, 64. 13 B. Rayner, C.Tapiero, and J. L. Inbach, Carbohydr. Res., 1976,47,195. 14 The method was developed by T. Somorai et al.; T. Somorai, Gy. Jerkovich, and P. Dvortsak, J.Heterocycl. Chem., 1982, 19, 1157. 15 R. R. Schmidt, J. Karg, and W. Guillard, Angew. Chem., Int. Ed. Engl., 1975, 14, 64. 16 F. Mercedes, R. K. Robins, and J. T. Witkowski, J. Carbohydr. Nucleosides, Nucleotides, 1976, 3, 169. 17 T. Takeshima, M. Yokoyama, N. Fukada, and M. Akano, J. Org. Chem., 1970,35, 2438. 18 M. Kiso and A. Hasagawa, Carbohydr. Rex, 1976, 95, 52. 19 L. S. Wittenbrook, C. L. Smith, and R. J. Timmons, J. Org. Chem., 1973 38, 465. 20 E. C. Horning, Org. Synth., Coll. Vol. 3, 1967, 181. Received 9th February 1987; Paper 71239