C S I R O
P U B L I S H I N G
Australian Journal of Chemistry Volume 52, 1999 © CSIRO Australia 1999
A journal for the publication of original research in all branches of chemistry and chemical technology
w w w. p u b l i s h . c s i r o . a u / j o u r n a l s / a j c All enquiries and manuscripts should be directed to The Managing Editor Australian Journal of Chemistry CSIRO PUBLISHING PO Box 1139 (150 Oxford St) Collingwood Telephone: 61 3 9662 7630 Vic. 3066 Facsimile: 61 3 9662 7611 Australia Email: [email protected]
Published by CSIRO PUBLISHING for CSIRO Australia and the Australian Academy of Science
Aust. J. Chem., 1999, 52, 63–67
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An Adventitious Synthesis of 2,20 -Dipyrryl Disulfides Raju Adhikari,A Dionne Jones,A Andris J. LiepaA,B and Maureen F. MackayC A B C
CSIRO Molecular Science, Private Bag 10, Clayton South MDC, Vic. 3169. Author to whom correspondence should be addressed. School of Chemistry, La Trobe University, Bundoora, Vic. 3083.
Condensation of 1,2-diketones and a cyanothioacetamide gave hydroxy thiolactams which failed to give the expected 3-cyano methylene thiolactams on dehydration. Disulfides and a thiosulfonate were obtained from the dehydrations. A possible mechanism for their formation is proposed. The crystal structure of the disulfide 4,40 ,5,50 -tetramethyl-1,10 -diphenyl-2,20 -disulfanediyldi-1H -pyrrole-3-carbonitrile (9) has been determined by X-ray diffraction.
Introduction 1
A diverse array of biological activity is associated with α,β-unsaturated lactones, hence analogous unsaturated lactams were envisaged as less common structures which might also have the potential for biological activity. Although compounds incorporating a 3-cyanosubstituted methylene lactam (4; R1 /R2 = various groups, X = O) have been described,2,3 neither the synthesis nor the biological properties of related methylene thiolactams (4; X = S) have been reported. Consequently, such sulfur analogues present a synthetic target of interest in their own right as well as offering molecules with unexplored biological activity.
The inspiration for a plausible pathway to these compounds was provided by a convenient procedure reported for the preparation of simple hydroxy lactams (3; R1 = alkyl, R2 = H or alkyl, X = O). Such compounds form readily as the result of a condensation between 2-cyanoacetamide (2; R = H, X = O) and 1,2-diketones (1)4 (Scheme 1). Further, it was found5 that under acidic conditions, dehydration of analogous N -aryl-substituted intermediates (3; R = aryl, X = O) gives rise to methylene lactams (4; R = aryl, X = O). Consequently, it was envisaged that a similar reaction Manuscript received 24 June 1998
sequence, commencing with a cyanothioacetamide (2; X = S) in place of a cyanoacetamide (2; X = O), could provide the required methylene thiolactam (4; R = aryl, X = S). Results and Discussion Accordingly, 2-cyano-N -phenylthioacetamide (2; R = Ph, X = S) was prepared by a literature procedure6 (with some minor modifications). Condensation of (2; R = Ph, X = S) with butane-2,3-dione readily gave the previously unknown hydroxy thiolactam (7) (Scheme 2) in 54% yield and base-catalysed (morpholine) condensation with cyclohexane-1,2-dione gave the ring-fused analogue (8) in 40% yield. These compounds were characterized by the usual spectroscopic methods and elemental analyses. Notwithstanding the successful analogy to this point with the known lactam preparation, attempts to dehydrate either of these hydroxy thiolactams under a variety of conditions failed to give the desired methylene thiolactams. Instead, several unexpected products were obtained. Formic acid had been found5 to be a convenient dehydrating agent for converting hydroxy lactams (3; X = O) into methylene lactams (4; X = O). However, an attempted dehydration of the hydroxy thiolactam (7) by heating in formic acid did not give the expected analogous product. Instead, the reaction produced a complex mixture from which an orange crystalline material was separated as the only major component in 16% yield. The proton n.m.r. spectrum of this compound was disarmingly simple and included singlets at δ 2 · 30 and 2 · 06, as well as absorption due to aromatic protons, resonances which integrated in the relative ratio of 3 : 3 : 5. However, this product was clearly not the expected methylene lactam. The spectroscopic
q CSIRO 1999
0004-9425/99/010063$05.00 10.1071/CH98112
.
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evidence suggested the possibility that the elimination of a molecule of water from (3; R1 = CH3 , R2 = H, X = S) combined with some reductive process might have given rise to either a pyrrole (5) or a thiophen (6), although neither an SH nor an NH resonance was evident. Since such possible alternatives could not be conveniently distinguished by spectroscopic means, the material was subjected to analysis by X-ray crystallography. Surprisingly, the product (9) (Scheme 2) was in fact found to be a pyrrole disulfide. Similarly, reaction of the hydroxy thiolactam (8) with formic acid at room temperature was found to form the analogous tetrahydroindole disulfide (10) in 27% yield. Formation of these products from the hydroxy thiolactam may be rationalized as follows. It appears that under the acidic reaction conditions the alcohol (3) becomes protonated and subsequently eliminates water to give a sulfenylium ion. This could be reduced by formic acid to a transient pyrrolethiol (5) (Scheme 3) which could readily undergo oxidative dimerization
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to form the observed disulfide products (9) and (10) (Scheme 2).
Reduction of the hydroxy lactams in the presence of formic acid to give the dimeric products is not exceptional as the acid is known to act as a reducing agent under certain conditions.7 Moreover, in the reaction of (7) with formic acid, prior addition of 2-mercapto-1methylimidazole considerably enhanced the formation of the pyrrole giving (9) in greater than 59% yield, this combination presumably acting as a superior reducing agent; however, no unsymmetrical disulfide product was isolated. On the other hand, these dimeric pyrroles were also isolated when dehydration was attempted under conditions which did not include the presence of a recognizable reductant. Phosphorus oxychloride–pyridine is a useful combination for generating exocyclic double bonds from cyclic tertiary alcohols.8,9 When the effect of this reagent upon (8) was investigated, the tetrahydroindole disulfide (10) was again isolated in 36% yield as well as the thiosulfonate (11) in 15% yield. These products can be accounted for by postulating the formation of a sulfenyl chloride (12) (Scheme 3) as an intermediate followed by hydrolysis during workup to the corresponding sulfenic acid. Such acids are known10 to readily disproportionate to give disulfides and thiosulfonates, accounting for the simultaneous formation of (10) and (11). Testing of these compounds for potential as crop protection chemicals failed to reveal any significant activity. Experimental Melting points were determined on a Reichert Kofler hotstage micro melting point apparatus and are uncorrected. Microanalyses were performed by the National Analytical Laboratory, Melbourne. Infrared spectra were recorded on a Perkin Elmer 842 spectrophotometer (cm−1 ) and refer to paraffin mulls. 1 H and 13 C n.m.r. spectra were recorded at 200 and 50 · 3 MHz respectively on a Bruker AC-200 spectrometer, or at 500 and 125 · 7 MHz on a Bruker AM 500 instrument. Chemical shifts (δ) are measured in ppm with tetramethylsilane
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as an internal standard. The 15 N n.m.r. spectrum was recorded at 50 · 7 MHz on a Bruker AM 500 instrument without nuclear Overhauser effect in CDCl3 at 305 K with nitromethane as external standard and is uncorrected for susceptibility. Positive values of δ 15 N denote absorption at higher frequencies than the standard. High- and low-resolution chemical ionization (c.i.) mass spectra and fast atom bombardment (f.a.b.) mass spectra were obtained on a Jeol JMS-DX303 mass spectrometer, with the M+1 ion (if observed) and principal ion peaks with intensity >10% reported. Analytical thin-layer chromatography was performed on polyester-backed plates precoated with silica gel 60 (SIL G/UV254 ). Radial thin-layer chromatography was performed on a Harrison Research Chromatron (7924T) with 4-mm thick silica plates (silica gel 60 PF254 , Merck No. 7749). Light petroleum refers to the fraction with a b.p. of 40–60◦ . 2-Cyano-N -phenylethanethioamide (2; R = Ph, X = S) To a stirred solution of sodium ethoxide [prepared from sodium (7 · 8 g, 0 · 34 mol) and dry ethanol (200 ml)] at 5–10◦ (internal temperature) under argon was added ethyl cyanoacetate (39 · 0 g, 0 · 34 mol) dropwise. On completion of the addition, phenyl isothiocyanate (46 · 0 g, 0 · 34 mol) was added dropwise whilst maintaining the temperature between 5–10◦ . The reaction mixture was refluxed for 2 h, cooled in ice– water and a solution of sodium hydroxide (136 g, 3 · 4 mol) in water (450 ml) added. The reaction mixture was then left overnight and heated to reflux for 2 h. The solution was cooled to room temperature, extracted with ether, chilled and carefully acidified with concentrated hydrochloric acid. The precipitated yellow solid was collected by filtration, washed with water and dried under vacuum yielding 58 · 6 g (98%) of (2; R = Ph, X = S), m.p. 104–106◦ (lit.6 111◦ ). 1 H n.m.r. δ (200 MHz, CDCl3 /(CD3 )2 SO) 11 · 37, br s, NH; 7 · 67–7 · 63, m, 2H; 7 · 33–7 · 11, m, 3H; 3 · 91, s, 2H. 5-Hydroxy-4,5-dimethyl-1-phenyl-2-thioxo-2,5-dihydro-1H pyrrole-3-carbonitrile (7) To a stirred, cooled (ice–water) solution of (2) (2 · 0 g, 11 · 4 mmol) in dimethylformamide (10 ml) was added butane2,3-dione (1 · 0 g, 11 · 6 mmol) dropwise. The reaction mixture was left in the bath for 30 min, allowed to warm to room temperature and diluted with water. The resulting solution was extracted with ether, and the combined extracts were washed with water, dried (MgSO4 ) and evaporated under vacuum to give (7) (2 · 4 g). Crystallization from dichloromethane/light petroleum gave a bright yellow crystalline solid (1 · 5 g, 54%), m.p. 175–177◦ . An analytical sample was obtained by drying in the presence of P2 O5 under vacuum at 40◦ for 2 days (Found: C, 63 · 9; H, 5 · 0; N, 11 · 1; S, 13 · 4. C13 H12 N2 OS requires C, 63 · 9; H, 5 · 0; N, 11 · 5; S, 13 · 1%). ν max (Nujol) 3402s, 2239m (CN), 1636m, 1594w, 1589w, 1488m, 1419s, 1299s, 1166m, 1117w, 1097w, 1007w, 965w, 825w, 755w cm−1 . 1 H n.m.r. δ (500 MHz, CDCl3 ) 7 · 57–7 · 30, m, 5 aromatic H; 3 · 80, s, OH; 2 · 36, s, CH3 ; 1 · 48, s, CH3 . 13 C n.m.r. δ (CDCl3 ) 188 · 7; 168 · 8; 135 · 8; 129 · 5; 129 · 2; 128 · 9; 116 · 3; 112 · 3; 98 · 1; 22 · 0; 13 · 2. 15 N n.m.r. δ (CDCl3 ) −112 · 3, CN; −194 · 9, NCS. Mass spectrum: m/z 245 (M+1, 100%), 229 (20), 227 (25). 4,40 ,5,50 -Tetramethyl-1,10 -diphenyl-2,20 -disulfanediyldi-1Hpyrrole-3-carbonitrile (9) (A) A stirred solution of (7) (700 mg, 2 · 9 mmol) in formic acid (5 ml) was left at room temperature for 30 min and then gently warmed at 60◦ for a few minutes. After cooling, the reaction mixture was diluted with water (10 ml) and extracted with ether. The combined extracts were washed with water (3×50 ml), dried (MgSO4 ) and evaporated under vacuum to
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give an orange foam (638 mg). Radial chromatography on silica (commencing with CH2 Cl2 /light petroleum (1 : 1) and progressing to CH2 Cl2 ) gave (9) as the major product as a yellow foam (119 mg). Crystallization from CH2 Cl2 /light petroleum gave (9) as orange crystals (108 mg, 16%), m.p. 184–186◦ (Found: C, 68 · 6; H, 4 · 9; N, 12 · 0; S, 14 · 3. C26 H22 N4 S2 requires C, 68 · 7; H, 4 · 9; N, 12 · 3; S, 14 · 1%). ν max (Nujol) 2220m, 1595w, 1554w, 1491m, 1270w, 1169w, 760w, 696w cm−1 . 1 H n.m.r. δ (200 MHz, CDCl3 ) 7 · 47–7 · 26, m, 10 aromatic H; 2 · 30, s, 2×CH3 ; 2 · 06, s, 2×CH3 . 13 C n.m.r. δ (CDCl3 ) 136 · 8; 135 · 6; 128 · 9; 128 · 7; 123 · 8; 120 · 0; 114 · 6; 107 · 6; 11 · 5; 10 · 2. Mass spectrum: m/z 259 (10%), 257 (11), 230 (17), 229 (100), 228 (43), 227 (54). (B) To a mixture of (7) (500 mg, 2 · 1 mmol) and 2-mercapto1-methylimidazole (480 mg, 4 · 2 mmol) was added formic acid (10 ml) and the mixture was stirred at room temperature for 4 h. The orange solution was diluted slowly with water and the precipitate collected by filtration, washed with water and dried in air to give (9) as an orange-yellow solid (283 mg, 59%), m.p. 180–183◦ . The 1 H n.m.r. spectrum of the product was identical with the material described above. An additional impure sample of (9) (149 mg) was obtained by extracting the filtrate as in (A) above. 7a-Hydroxy-1-phenyl-2-thioxo-2,4,5,6,7,7a-hexahydro-1H indole-3-carbonitrile (8) To a stirred, cooled (ice) solution of (2; R = Ph, X = S) (2 · 0 g, 11 · 4 mmol) in dimethylformamide (10 ml) were added cyclohexane-1,2-dione (1 · 4 g, 12 · 5 mmol) and a few drops of morpholine. The reaction mixture was allowed to warm to room temperature overnight, diluted with water (30 ml) and extracted with dichloromethane (3×30 ml). The combined extracts were washed with water (3×50 ml), dried (MgSO4 ) and evaporated under vacuum to give a brown viscous oil (2 · 5 g). Radial chromatography on silica (commencing with ethyl acetate/light petroleum (1 : 4) and progressing to 1 : 1) and subsequent trituration of the product with dichloromethane afforded (8) as a bright yellow solid (1 · 2 g, 40%), m.p. 176– 178◦ (Found: MH+• , 271 · 0895. C15 H14 N2 OS requires MH+• , 271 · 0827). ν max (Nujol) 3394s, 2240m (CN), 1634m, 1592w, 1495w, 14045s, 1313m, 1294m, 1259w, 1175w, 1119w, 1086w, 1066w, 1011w, 699m cm−1 . 1 H n.m.r. δ (200 MHz, CDCl3 ) 7 · 54–7 · 28, m, 5 aromatic H; 3 · 60, br s, OH (D2 O); 3 · 13–2 · 95, m, 1H; 2 · 81–2 · 58, m, 1H; 2 · 30–2 · 10, m, 2H; 1 · 80–1 · 35, m, 4H. 13 C n.m.r. δ (CDCl3 /(CD3 )2 SO) 188 · 9; 172 · 0; 136 · 1; 129 · 2; 128 · 5; 125 · 9; 112 · 2; 112 · 1; 96 · 5; 37 · 9; 27 · 9; 27 · 0; 21 · 0. Mass spectrum: m/z 271 (M+1, 100%), 245 (10). 1,10 -Diphenyl-4,40 5,50 ,6,60 ,7,70 -octahydro-2,20 -disulfanediyldi1H -indole-3-carbonitrile (10) A stirred solution of (8) (700 mg, 2 · 6 mmol) in formic acid (20 ml) was left at room temperature for 20 h. The reaction mixture was diluted with cold water (40 ml) and the precipitate collected by filtration and washed with water to give a yellow solid (530 mg). The filtrate, on extraction with ether, was found by thin-layer chromatography (silica; CH2 Cl2 /light petroleum (1 : 2)) to contain unreacted (8). Radial chromatography on silica (commencing with CH2 Cl2 /light petroleum (1 : 8) and progressing to 1 : 4) gave (10) as a yellow solid (232 mg). Recrystallization from dichloromethane/ethanol gave an orange crystalline solid (180 mg, 27%), m.p. 227–228◦ (Found: MH+• , 507 · 1589. C30 H27 N4 S2 requires MH+• , 507 · 1599). ν max (Nujol) 2216m, 1595w, 1550w, 1496m, 761m, 704m cm−1 . 1 H n.m.r. δ (200 MHz, CDCl3 ) 7 · 63–7 · 13, m, 10 aromatic H; 2 · 78–2 · 47, m, 4H; 2 · 41, br s, 4H; 2 · 06–1 · 69, m, 8H. 13 C n.m.r. δ (CDCl3 ) 138 · 5; 136 · 3; 128 · 9; 128 · 4; 124 · 1; 122 · 5; 114 · 4; 106 · 0; 23 · 2, 22 · 7, 21 · 9, 8×CH2 . Mass spectrum: m/z 507 (M+1, 10%), 283 (21), 255 (100), 253 (40).
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Reaction of (8) with Phosphorus Oxychloride to Give (10) and S -(3-Cyano-1-phenyl-4,5,6,7-tetrahydro-1H -indol2-yl) 3-Cyano-1-phenyl-4,5,6,7-tetrahydro-1H -indole-2thiosulfonate (11) Phosphorus oxychloride (2 · 4 g, 15 · 5 mmol) was added dropwise to a stirred, cooled solution of (8) (500 mg, 1 · 8 mmol) in pyridine (5 ml). After 5 min, the reaction mixture was removed from the cooling bath and left stirring at room temperature for 1 · 5 h. The reaction mixture was then carefully poured into ice/water (50 ml) with stirring. Attempted extraction of the resulting solution with ether (20 ml) produced a precipitate which was collected by filtration and washed with water and a small quantity of ether to give a yellow solid (230 mg). Thinlayer chromatography (silica; CH2 Cl2 /light petroleum (1 : 2)) of the solid indicated that a mixture containing two compounds had been isolated. The combined filtrate and washings were extracted by the addition of dichloromethane/ether (20 ml, 1 : 1). The organic phase was separated, washed with saturated sodium bicarbonate (2×50 ml), water (2×50 ml), dried (MgSO4 ), and evaporated under vacuum to give more of the mixture isolated previously as a yellow solid (192 mg). The isolated solids were combined and subjected to radial chromatography on silica (commencing with CH2 Cl2 /petroleum ether (1 : 2) and progressing to 2 : 1). Subsequent recrystallization from dichloromethane/ethanol gave (10) as orange crystals (165 mg, 36%), m.p. 226–228◦ (dec). Compound (11) was obtained as the second component of the mixture after chromatography. Recrystallization from dichloromethane/ethanol gave (11) as yellow crystals (70 mg, 15%), m.p. 176–179◦ (Found: MH+• , 538 · 1482. C30 H27 N4 O2 S2 requires MH+• , 538 · 1497). ν max (Nujol) 2220w (CN), 1597w, 1560w, 1496m, 1342m, 1129m, 785w, 703m. 1 H n.m.r. δ (200 MHz, CDCl3 ) 8 · 00–6 · 86, m, 10 aromatic H; 2 · 91–1 · 60, m, 8×CH2 . 13 C n.m.r. δ (CDCl3 ) 140 · 6; 139 · 8; 135 · 4; 134 · 9; 129 · 8, 129 · 1, 128 · 9, 10 aromatic C; 124 · 1; 123 · 9; 114 · 4; 112 · 2; 105 · 7; 104 · 3, 23 · 2, 22 · 4, 21 · 9, 21 · 7, 8×CH2 . The sample was not stable to c.i. mass spectrometric analysis. F.a.b. m/z 539 (M+H, 8%), 524 (14), 507 (22), 378 (13), 304 (15), 269 (51), 263 (100), 223 (24).
Crystallography Crystal Data for (9) C26 H22 N4 S2 , M 454 · 6, monoclinic, a 12 · 992(2), b 11 · 172(1), c 17 · 082(2) ˚ A, β 102 · 15(1)◦ , V 2423 · 9(8) ˚ A3 , D c (Z = 4) −3 1 · 246 g cm , F (000) 1056, µ(Cu Kα) 21 · 4 cm−1 . Space group P 21 /c. Accurate cell dimensions were determined at 291(2) K by least-squares refinement of 25 automatically centred reflections in the range 36◦ < 2θ < 68◦ , measured with Cu Kα (graphite-monochromatized) radiation (λ 1 · 5418 ˚ A).
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for which I > 3σ(I ) considered observed. The non-hydrogen atoms were refined with anisotropic temperature factors; the positional coordinates of the C 7 and C 70 methyl hydrogen atoms were calculated and all other hydrogen-atom coordinates refined, the atoms being given isotropic temperature factors. The function minimized in the refinement was Σ w (F o − F c )2 , with w = [σ 2 (F )+0 · 0052F 2 ]−1 . At convergence the conventional reliability indices for the observed data were R ∗ 0 · 043 and wR 0 · 070 with S 0 · 907 (362 variables). The maximum and minimum residual electron-density peak heights were +0 · 24 and −0 · 19 e ˚ A−3 . An extinction parameter was applied to the F c terms with SHELX-76;11 the extinction coefficient was 1 · 30(7)×10−6 . Final atomic parameters are given in Table 1;† Fig. 1 was prepared from the output of ORTEP-II13 and shows the atomic labelling scheme used. Table 1.
Final atomic coordinates and equivalent isotropic temperature factors for C26 H22 N4 S2 (9) Values for C and N have been multiplied by 104 ; values for S have been multiplied by 105 . Estimated standard deviations are in parentheses. B eq = (8π 2 /3)Σi Σj a i *a j *a i .a j Atom
x
y
z
B eq (˚ A)2
N(1) C(2) C(3) C(4) C(5) S(1) N(2) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) N(10 ) C(20 ) C(30 ) C(40 ) C(50 ) S(10 ) N(20 ) C(60 ) C(70 ) C(80 ) C(90 ) C(100 ) C(110 ) C(120 ) C(130 ) C(140 )
9425(2) 8385(2) 8056(2) 8888(2) 9722(2) 76480(6) 6223(3) 7037(3) 8845(3) 10801(3) 10058(2) 10384(3) 11009(3) 11307(3) 10977(4) 10367(3) 5339(2) 6334(2) 6705(2) 5930(3) 5096(3) 70130(6) 8556(3) 7728(3) 6021(4) 4072(3) 4660(2) 4481(3) 3797(4) 3328(3) 3512(3) 4192(3)
1564(2) 1233(3) 594(3) 528(3) 1139(3) 16927(7) −359(3) 68(3) −48(4) 1310(5) 2278(3) 3395(3) 4084(4) 3662(4) 2552(4) 1851(4) 2467(2) 2967(3) 2948(3) 2448(3) 2150(3) 33629(7) 3626(4) 3347(3) 2243(5) 1584(5) 2335(3) 1231(4) 1116(5) 2088(6) 3208(5) 3341(4)
4154(1) 4133(2) 3435(2) 3019(2) 3473(2) 48041(5) 2972(2) 3189(2) 2221(2) 3332(3) 4758(2) 4559(2) 5141(3) 5906(3) 6105(3) 5526(2) 3192(1) 3374(2) 2667(2) 2053(2) 2397(2) 43102(5) 2545(3) 2606(2) 1200(2) 2027(3) 3746(2) 4029(3) 4559(3) 4801(3) 4513(3) 3991(2)
3 · 11(6) 3 · 09(6) 3 · 43(7) 3 · 79(8) 3 · 50(7) 3 · 72(2) 6 · 43(1) 4 · 22(8) 5 · 83(1) 5 · 37(11) 3 · 23(7) 4 · 08(9) 5 · 03(10) 5 · 76(12) 6 · 49(10) 4 · 93(10) 3 · 37(6) 3 · 20(7) 3 · 52(7) 3 · 93(8) 3 · 69(7) 3 · 76(2) 6 · 58(11) 4 · 30(9) 5 · 98(12) 5 · 30(11) 3 · 62(7) 4 · 99(10) 6 · 44(14) 6 · 11(12) 6 · 24(13) 4 · 88(10)
Structure Determination
Description of the Structure of 4,4 0 ,5,5 0 -Tetramethyl-1,1 0 diphenyl-2,2 0 -disulfanediyldi-1 H-pyrrole-3-carbonitrile (9)
Intensity data were measured with Cu Kα radiation from a cleaved specimen of dimensions c. 0 · 128 by 0 · 180 by 0 · 305 mm aligned on a Rigaku-AFC four-circle diffractometer, recorded by an ω–2θ scan with 2θ scan rate 2 · 0◦ min−1 , and 10s stationary background counts. Three reference reflections monitored every 100 reflections showed no decay. Data to a 2θmax 130◦ yielded 4074 unique terms; corrections for Lorentz and polarization effects were applied; analytical absorption corrections were made with SHELX-7611 (transmission factors 0 · 659–0 · 802). The structure was solved by direct methods with 12 SHELXS-86 and the least-squares refinements were carried out with SHELX-7611 on a VAX8800 computer with the 2792 terms
The molecule has approximate twofold symmetry and the torsion angles N(1)–C(2)–S(1)–S(10 ) of 85 · 6(3)◦ and N(10 )– C(20 )–S(10 )–S(1) of 80 · 5(3)◦ show that the S–S bridge is approximately orthogonal to the pyrrole rings, while the C(2)– S(1)–S(10 )–C(20 ) torsion angle of 58 · 4(2)◦ illustrates the twist about the S–S bond. The pyrrole and phenyl rings are planar to within experimental error and their relative orientations are given by the torsion angles C(2)–N(1)–C(9)–C(14) and C(20 )–N(10 )–C(90 )–C(140 ) of 67 · 2(4) and 71 · 7(4)◦ respectively. The S(1)–S(10 ) bond distance of 2 · 140(1) ˚ A is significantly longer than that usually observed for the S–S bond while the C(2)–S(1) and C(20 )–S(10 ) bond lengths of 1 · 720(4) and
∗
R = Σ ||Fo | − |Fc ||/Σ |Fo |, wR = (Σ w||Fo | − |Fc ||2 /Σ w|Fo |2 )1/2 . † Crystallographic data for compound (9), namely tables of structure factor amplitudes, bond distances and angles, anisotropic thermal parameters and hydrogen atom parameters, have been deposited. Copies can be obtained from the Australian Journal of Chemistry (until 31 December 2004), P.O. Box 1139, Collingwood, Vic. 3066.
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Acknowledgments We thank E. I. DuPont de Nemours and Co., Agricultural Products Department, for the evaluation of fungicidal activity. We also thank Mr I. Vit for measurement of mass spectra and Mr R. I. Willing for measurement of 1 H and 15 N n.m.r. spectra.
References 1
2
3 4
Fig. 1. Perspective view and atom labelling of the structure of (9). Thermal ellipsoids are at the 50% probability level. Hydrogen atoms are denoted by spheres of arbitrary radius. 1 · 714(3) ˚ A are significantly shorter than values tabulated by Van Wart, Shipman and Scheraga.14 It has been suggested that the double-bond character indicated by the C–S bond lengths, the lengthening of the S–S bond and the near-orthogonality of C–C–S angles is consistent with pπ–dπ interactions between the aromatic carbon atom and the sulfur.15 Although the C–S–S angles of 102 · 7(1) and 102 · 9(1)◦ are smaller than other reported values, they are consistent with the dihedral angle of 44 · 4(2)◦ between the two pyrrole rings. A similar situation was also noted for 2,2-diaminodiphenyl disulfide.15 There is delocalization around the pyrrole rings with the mean N–C bond length of 1 · 384(4) ˚ A (mean deviation 0 · 006 ˚ A) and the C–C bond lengths range from 1 · 373(4) to 1 · 408(4) ˚ A and the angles have a mean value of 108 · 0(3)◦ (mean deviation 1 · 3◦ ). The C(6)–N(2) and C(60 )–N(20 ) bond lengths of 1 · 149(5) and 1 · 146(4) ˚ A and the C(3)–C(6)–N(2) and C(30 )–C(60 )–N(20 ) angles of 178 · 2(3) and 177 · 4(3)◦ are similar to other reported values for cyano groups.
5 6 7 8 9 10 11
12
13 14 15
Davidson, B. S., Chem. Rev., 1993, 93, 1771; Hopper, A. T., and Witiak, D. T., J. Org. Chem., 1995, 60, 3334; Rao, Y. S., Chem. Rev ., 1964, 64, 353. Diehl, D. R., Helber, M. J., and Rossi, L. J., U.S. Pat. Appl. US 5,283,165 (Cl. 430–522; G03C1/84), 01 February 1994; Appl. 995,436, 23 December 1992 (Chem. Abstr ., 1994, 121, 95864p). Fallert, M., and Hartke, K., Arch. Pharm. (Weinheim, Ger.), 1986, 319, 1098 (Chem. Abstr ., 1987, 106, 102014g). Hubert, R., and Hartke, K., Chem. Ber ., 1975, 108, 3262. Liepa, A. J., unpublished data. Grabenko, A. D., Kulaeva, L. N., and Pel’kis, P. S., Zh. Obshch. Khim., 1962, 32, 2248. Paquette, L. A., ‘Encyclopedia of Reagents for Organic Synthesis’ Vol. 4, p. 2593 (Interscience: New York 1995). Barton, D. H. R., Campos-Neves, A. da S., and Cookson, R. C., J. Chem. Soc., 1956, 3500. Sauers, R. R., J. Am. Chem. Soc., 1959, 81, 4873. Hogg, D. R., in ‘Comprehensive Organic Chemistry’ (Ed. D. N. Jones) Vol. 3, p. 269 (Pergamon: Oxford 1979). Sheldrick, G. M., SHELX-76, Program for Crystal Structure Determination, University of Cambridge, Cambridge, U.K., 1976. Sheldrick, G. M., SHELXS-86, Structure Solution Package, University of G¨ ottingen, Federal Republic of Germany, 1986. Johnson, C. K., ORTEP-II, Report ORNL-5138, Oak Ridge National Laboratory, Tennessee, 1976. Scheraga, H. A., Shipman, L. L., and Van Wart, H. E., J. Phys. Chem., 1975, 79, 1436. Bryant, M. W. R., and Lee, J. D., Acta Crystallogr., Sect. B , 1970, 26, 1729.
P U B L I S H I N G
Australian Journal of Chemistry Volume 52, 1999 © CSIRO Australia 1999
A journal for the publication of original research in all branches of chemistry and chemical technology
w w w. p u b l i s h . c s i r o . a u / j o u r n a l s / a j c All enquiries and manuscripts should be directed to The Managing Editor Australian Journal of Chemistry CSIRO PUBLISHING PO Box 1139 (150 Oxford St) Collingwood Telephone: 61 3 9662 7630 Vic. 3066 Facsimile: 61 3 9662 7611 Australia Email: [email protected]
Published by CSIRO PUBLISHING for CSIRO Australia and the Australian Academy of Science
Aust. J. Chem., 1999, 52, 63–67
Short Communications
An Adventitious Synthesis of 2,20 -Dipyrryl Disulfides Raju Adhikari,A Dionne Jones,A Andris J. LiepaA,B and Maureen F. MackayC A B C
CSIRO Molecular Science, Private Bag 10, Clayton South MDC, Vic. 3169. Author to whom correspondence should be addressed. School of Chemistry, La Trobe University, Bundoora, Vic. 3083.
Condensation of 1,2-diketones and a cyanothioacetamide gave hydroxy thiolactams which failed to give the expected 3-cyano methylene thiolactams on dehydration. Disulfides and a thiosulfonate were obtained from the dehydrations. A possible mechanism for their formation is proposed. The crystal structure of the disulfide 4,40 ,5,50 -tetramethyl-1,10 -diphenyl-2,20 -disulfanediyldi-1H -pyrrole-3-carbonitrile (9) has been determined by X-ray diffraction.
Introduction 1
A diverse array of biological activity is associated with α,β-unsaturated lactones, hence analogous unsaturated lactams were envisaged as less common structures which might also have the potential for biological activity. Although compounds incorporating a 3-cyanosubstituted methylene lactam (4; R1 /R2 = various groups, X = O) have been described,2,3 neither the synthesis nor the biological properties of related methylene thiolactams (4; X = S) have been reported. Consequently, such sulfur analogues present a synthetic target of interest in their own right as well as offering molecules with unexplored biological activity.
The inspiration for a plausible pathway to these compounds was provided by a convenient procedure reported for the preparation of simple hydroxy lactams (3; R1 = alkyl, R2 = H or alkyl, X = O). Such compounds form readily as the result of a condensation between 2-cyanoacetamide (2; R = H, X = O) and 1,2-diketones (1)4 (Scheme 1). Further, it was found5 that under acidic conditions, dehydration of analogous N -aryl-substituted intermediates (3; R = aryl, X = O) gives rise to methylene lactams (4; R = aryl, X = O). Consequently, it was envisaged that a similar reaction Manuscript received 24 June 1998
sequence, commencing with a cyanothioacetamide (2; X = S) in place of a cyanoacetamide (2; X = O), could provide the required methylene thiolactam (4; R = aryl, X = S). Results and Discussion Accordingly, 2-cyano-N -phenylthioacetamide (2; R = Ph, X = S) was prepared by a literature procedure6 (with some minor modifications). Condensation of (2; R = Ph, X = S) with butane-2,3-dione readily gave the previously unknown hydroxy thiolactam (7) (Scheme 2) in 54% yield and base-catalysed (morpholine) condensation with cyclohexane-1,2-dione gave the ring-fused analogue (8) in 40% yield. These compounds were characterized by the usual spectroscopic methods and elemental analyses. Notwithstanding the successful analogy to this point with the known lactam preparation, attempts to dehydrate either of these hydroxy thiolactams under a variety of conditions failed to give the desired methylene thiolactams. Instead, several unexpected products were obtained. Formic acid had been found5 to be a convenient dehydrating agent for converting hydroxy lactams (3; X = O) into methylene lactams (4; X = O). However, an attempted dehydration of the hydroxy thiolactam (7) by heating in formic acid did not give the expected analogous product. Instead, the reaction produced a complex mixture from which an orange crystalline material was separated as the only major component in 16% yield. The proton n.m.r. spectrum of this compound was disarmingly simple and included singlets at δ 2 · 30 and 2 · 06, as well as absorption due to aromatic protons, resonances which integrated in the relative ratio of 3 : 3 : 5. However, this product was clearly not the expected methylene lactam. The spectroscopic
q CSIRO 1999
0004-9425/99/010063$05.00 10.1071/CH98112
.
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evidence suggested the possibility that the elimination of a molecule of water from (3; R1 = CH3 , R2 = H, X = S) combined with some reductive process might have given rise to either a pyrrole (5) or a thiophen (6), although neither an SH nor an NH resonance was evident. Since such possible alternatives could not be conveniently distinguished by spectroscopic means, the material was subjected to analysis by X-ray crystallography. Surprisingly, the product (9) (Scheme 2) was in fact found to be a pyrrole disulfide. Similarly, reaction of the hydroxy thiolactam (8) with formic acid at room temperature was found to form the analogous tetrahydroindole disulfide (10) in 27% yield. Formation of these products from the hydroxy thiolactam may be rationalized as follows. It appears that under the acidic reaction conditions the alcohol (3) becomes protonated and subsequently eliminates water to give a sulfenylium ion. This could be reduced by formic acid to a transient pyrrolethiol (5) (Scheme 3) which could readily undergo oxidative dimerization
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to form the observed disulfide products (9) and (10) (Scheme 2).
Reduction of the hydroxy lactams in the presence of formic acid to give the dimeric products is not exceptional as the acid is known to act as a reducing agent under certain conditions.7 Moreover, in the reaction of (7) with formic acid, prior addition of 2-mercapto-1methylimidazole considerably enhanced the formation of the pyrrole giving (9) in greater than 59% yield, this combination presumably acting as a superior reducing agent; however, no unsymmetrical disulfide product was isolated. On the other hand, these dimeric pyrroles were also isolated when dehydration was attempted under conditions which did not include the presence of a recognizable reductant. Phosphorus oxychloride–pyridine is a useful combination for generating exocyclic double bonds from cyclic tertiary alcohols.8,9 When the effect of this reagent upon (8) was investigated, the tetrahydroindole disulfide (10) was again isolated in 36% yield as well as the thiosulfonate (11) in 15% yield. These products can be accounted for by postulating the formation of a sulfenyl chloride (12) (Scheme 3) as an intermediate followed by hydrolysis during workup to the corresponding sulfenic acid. Such acids are known10 to readily disproportionate to give disulfides and thiosulfonates, accounting for the simultaneous formation of (10) and (11). Testing of these compounds for potential as crop protection chemicals failed to reveal any significant activity. Experimental Melting points were determined on a Reichert Kofler hotstage micro melting point apparatus and are uncorrected. Microanalyses were performed by the National Analytical Laboratory, Melbourne. Infrared spectra were recorded on a Perkin Elmer 842 spectrophotometer (cm−1 ) and refer to paraffin mulls. 1 H and 13 C n.m.r. spectra were recorded at 200 and 50 · 3 MHz respectively on a Bruker AC-200 spectrometer, or at 500 and 125 · 7 MHz on a Bruker AM 500 instrument. Chemical shifts (δ) are measured in ppm with tetramethylsilane
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as an internal standard. The 15 N n.m.r. spectrum was recorded at 50 · 7 MHz on a Bruker AM 500 instrument without nuclear Overhauser effect in CDCl3 at 305 K with nitromethane as external standard and is uncorrected for susceptibility. Positive values of δ 15 N denote absorption at higher frequencies than the standard. High- and low-resolution chemical ionization (c.i.) mass spectra and fast atom bombardment (f.a.b.) mass spectra were obtained on a Jeol JMS-DX303 mass spectrometer, with the M+1 ion (if observed) and principal ion peaks with intensity >10% reported. Analytical thin-layer chromatography was performed on polyester-backed plates precoated with silica gel 60 (SIL G/UV254 ). Radial thin-layer chromatography was performed on a Harrison Research Chromatron (7924T) with 4-mm thick silica plates (silica gel 60 PF254 , Merck No. 7749). Light petroleum refers to the fraction with a b.p. of 40–60◦ . 2-Cyano-N -phenylethanethioamide (2; R = Ph, X = S) To a stirred solution of sodium ethoxide [prepared from sodium (7 · 8 g, 0 · 34 mol) and dry ethanol (200 ml)] at 5–10◦ (internal temperature) under argon was added ethyl cyanoacetate (39 · 0 g, 0 · 34 mol) dropwise. On completion of the addition, phenyl isothiocyanate (46 · 0 g, 0 · 34 mol) was added dropwise whilst maintaining the temperature between 5–10◦ . The reaction mixture was refluxed for 2 h, cooled in ice– water and a solution of sodium hydroxide (136 g, 3 · 4 mol) in water (450 ml) added. The reaction mixture was then left overnight and heated to reflux for 2 h. The solution was cooled to room temperature, extracted with ether, chilled and carefully acidified with concentrated hydrochloric acid. The precipitated yellow solid was collected by filtration, washed with water and dried under vacuum yielding 58 · 6 g (98%) of (2; R = Ph, X = S), m.p. 104–106◦ (lit.6 111◦ ). 1 H n.m.r. δ (200 MHz, CDCl3 /(CD3 )2 SO) 11 · 37, br s, NH; 7 · 67–7 · 63, m, 2H; 7 · 33–7 · 11, m, 3H; 3 · 91, s, 2H. 5-Hydroxy-4,5-dimethyl-1-phenyl-2-thioxo-2,5-dihydro-1H pyrrole-3-carbonitrile (7) To a stirred, cooled (ice–water) solution of (2) (2 · 0 g, 11 · 4 mmol) in dimethylformamide (10 ml) was added butane2,3-dione (1 · 0 g, 11 · 6 mmol) dropwise. The reaction mixture was left in the bath for 30 min, allowed to warm to room temperature and diluted with water. The resulting solution was extracted with ether, and the combined extracts were washed with water, dried (MgSO4 ) and evaporated under vacuum to give (7) (2 · 4 g). Crystallization from dichloromethane/light petroleum gave a bright yellow crystalline solid (1 · 5 g, 54%), m.p. 175–177◦ . An analytical sample was obtained by drying in the presence of P2 O5 under vacuum at 40◦ for 2 days (Found: C, 63 · 9; H, 5 · 0; N, 11 · 1; S, 13 · 4. C13 H12 N2 OS requires C, 63 · 9; H, 5 · 0; N, 11 · 5; S, 13 · 1%). ν max (Nujol) 3402s, 2239m (CN), 1636m, 1594w, 1589w, 1488m, 1419s, 1299s, 1166m, 1117w, 1097w, 1007w, 965w, 825w, 755w cm−1 . 1 H n.m.r. δ (500 MHz, CDCl3 ) 7 · 57–7 · 30, m, 5 aromatic H; 3 · 80, s, OH; 2 · 36, s, CH3 ; 1 · 48, s, CH3 . 13 C n.m.r. δ (CDCl3 ) 188 · 7; 168 · 8; 135 · 8; 129 · 5; 129 · 2; 128 · 9; 116 · 3; 112 · 3; 98 · 1; 22 · 0; 13 · 2. 15 N n.m.r. δ (CDCl3 ) −112 · 3, CN; −194 · 9, NCS. Mass spectrum: m/z 245 (M+1, 100%), 229 (20), 227 (25). 4,40 ,5,50 -Tetramethyl-1,10 -diphenyl-2,20 -disulfanediyldi-1Hpyrrole-3-carbonitrile (9) (A) A stirred solution of (7) (700 mg, 2 · 9 mmol) in formic acid (5 ml) was left at room temperature for 30 min and then gently warmed at 60◦ for a few minutes. After cooling, the reaction mixture was diluted with water (10 ml) and extracted with ether. The combined extracts were washed with water (3×50 ml), dried (MgSO4 ) and evaporated under vacuum to
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give an orange foam (638 mg). Radial chromatography on silica (commencing with CH2 Cl2 /light petroleum (1 : 1) and progressing to CH2 Cl2 ) gave (9) as the major product as a yellow foam (119 mg). Crystallization from CH2 Cl2 /light petroleum gave (9) as orange crystals (108 mg, 16%), m.p. 184–186◦ (Found: C, 68 · 6; H, 4 · 9; N, 12 · 0; S, 14 · 3. C26 H22 N4 S2 requires C, 68 · 7; H, 4 · 9; N, 12 · 3; S, 14 · 1%). ν max (Nujol) 2220m, 1595w, 1554w, 1491m, 1270w, 1169w, 760w, 696w cm−1 . 1 H n.m.r. δ (200 MHz, CDCl3 ) 7 · 47–7 · 26, m, 10 aromatic H; 2 · 30, s, 2×CH3 ; 2 · 06, s, 2×CH3 . 13 C n.m.r. δ (CDCl3 ) 136 · 8; 135 · 6; 128 · 9; 128 · 7; 123 · 8; 120 · 0; 114 · 6; 107 · 6; 11 · 5; 10 · 2. Mass spectrum: m/z 259 (10%), 257 (11), 230 (17), 229 (100), 228 (43), 227 (54). (B) To a mixture of (7) (500 mg, 2 · 1 mmol) and 2-mercapto1-methylimidazole (480 mg, 4 · 2 mmol) was added formic acid (10 ml) and the mixture was stirred at room temperature for 4 h. The orange solution was diluted slowly with water and the precipitate collected by filtration, washed with water and dried in air to give (9) as an orange-yellow solid (283 mg, 59%), m.p. 180–183◦ . The 1 H n.m.r. spectrum of the product was identical with the material described above. An additional impure sample of (9) (149 mg) was obtained by extracting the filtrate as in (A) above. 7a-Hydroxy-1-phenyl-2-thioxo-2,4,5,6,7,7a-hexahydro-1H indole-3-carbonitrile (8) To a stirred, cooled (ice) solution of (2; R = Ph, X = S) (2 · 0 g, 11 · 4 mmol) in dimethylformamide (10 ml) were added cyclohexane-1,2-dione (1 · 4 g, 12 · 5 mmol) and a few drops of morpholine. The reaction mixture was allowed to warm to room temperature overnight, diluted with water (30 ml) and extracted with dichloromethane (3×30 ml). The combined extracts were washed with water (3×50 ml), dried (MgSO4 ) and evaporated under vacuum to give a brown viscous oil (2 · 5 g). Radial chromatography on silica (commencing with ethyl acetate/light petroleum (1 : 4) and progressing to 1 : 1) and subsequent trituration of the product with dichloromethane afforded (8) as a bright yellow solid (1 · 2 g, 40%), m.p. 176– 178◦ (Found: MH+• , 271 · 0895. C15 H14 N2 OS requires MH+• , 271 · 0827). ν max (Nujol) 3394s, 2240m (CN), 1634m, 1592w, 1495w, 14045s, 1313m, 1294m, 1259w, 1175w, 1119w, 1086w, 1066w, 1011w, 699m cm−1 . 1 H n.m.r. δ (200 MHz, CDCl3 ) 7 · 54–7 · 28, m, 5 aromatic H; 3 · 60, br s, OH (D2 O); 3 · 13–2 · 95, m, 1H; 2 · 81–2 · 58, m, 1H; 2 · 30–2 · 10, m, 2H; 1 · 80–1 · 35, m, 4H. 13 C n.m.r. δ (CDCl3 /(CD3 )2 SO) 188 · 9; 172 · 0; 136 · 1; 129 · 2; 128 · 5; 125 · 9; 112 · 2; 112 · 1; 96 · 5; 37 · 9; 27 · 9; 27 · 0; 21 · 0. Mass spectrum: m/z 271 (M+1, 100%), 245 (10). 1,10 -Diphenyl-4,40 5,50 ,6,60 ,7,70 -octahydro-2,20 -disulfanediyldi1H -indole-3-carbonitrile (10) A stirred solution of (8) (700 mg, 2 · 6 mmol) in formic acid (20 ml) was left at room temperature for 20 h. The reaction mixture was diluted with cold water (40 ml) and the precipitate collected by filtration and washed with water to give a yellow solid (530 mg). The filtrate, on extraction with ether, was found by thin-layer chromatography (silica; CH2 Cl2 /light petroleum (1 : 2)) to contain unreacted (8). Radial chromatography on silica (commencing with CH2 Cl2 /light petroleum (1 : 8) and progressing to 1 : 4) gave (10) as a yellow solid (232 mg). Recrystallization from dichloromethane/ethanol gave an orange crystalline solid (180 mg, 27%), m.p. 227–228◦ (Found: MH+• , 507 · 1589. C30 H27 N4 S2 requires MH+• , 507 · 1599). ν max (Nujol) 2216m, 1595w, 1550w, 1496m, 761m, 704m cm−1 . 1 H n.m.r. δ (200 MHz, CDCl3 ) 7 · 63–7 · 13, m, 10 aromatic H; 2 · 78–2 · 47, m, 4H; 2 · 41, br s, 4H; 2 · 06–1 · 69, m, 8H. 13 C n.m.r. δ (CDCl3 ) 138 · 5; 136 · 3; 128 · 9; 128 · 4; 124 · 1; 122 · 5; 114 · 4; 106 · 0; 23 · 2, 22 · 7, 21 · 9, 8×CH2 . Mass spectrum: m/z 507 (M+1, 10%), 283 (21), 255 (100), 253 (40).
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Reaction of (8) with Phosphorus Oxychloride to Give (10) and S -(3-Cyano-1-phenyl-4,5,6,7-tetrahydro-1H -indol2-yl) 3-Cyano-1-phenyl-4,5,6,7-tetrahydro-1H -indole-2thiosulfonate (11) Phosphorus oxychloride (2 · 4 g, 15 · 5 mmol) was added dropwise to a stirred, cooled solution of (8) (500 mg, 1 · 8 mmol) in pyridine (5 ml). After 5 min, the reaction mixture was removed from the cooling bath and left stirring at room temperature for 1 · 5 h. The reaction mixture was then carefully poured into ice/water (50 ml) with stirring. Attempted extraction of the resulting solution with ether (20 ml) produced a precipitate which was collected by filtration and washed with water and a small quantity of ether to give a yellow solid (230 mg). Thinlayer chromatography (silica; CH2 Cl2 /light petroleum (1 : 2)) of the solid indicated that a mixture containing two compounds had been isolated. The combined filtrate and washings were extracted by the addition of dichloromethane/ether (20 ml, 1 : 1). The organic phase was separated, washed with saturated sodium bicarbonate (2×50 ml), water (2×50 ml), dried (MgSO4 ), and evaporated under vacuum to give more of the mixture isolated previously as a yellow solid (192 mg). The isolated solids were combined and subjected to radial chromatography on silica (commencing with CH2 Cl2 /petroleum ether (1 : 2) and progressing to 2 : 1). Subsequent recrystallization from dichloromethane/ethanol gave (10) as orange crystals (165 mg, 36%), m.p. 226–228◦ (dec). Compound (11) was obtained as the second component of the mixture after chromatography. Recrystallization from dichloromethane/ethanol gave (11) as yellow crystals (70 mg, 15%), m.p. 176–179◦ (Found: MH+• , 538 · 1482. C30 H27 N4 O2 S2 requires MH+• , 538 · 1497). ν max (Nujol) 2220w (CN), 1597w, 1560w, 1496m, 1342m, 1129m, 785w, 703m. 1 H n.m.r. δ (200 MHz, CDCl3 ) 8 · 00–6 · 86, m, 10 aromatic H; 2 · 91–1 · 60, m, 8×CH2 . 13 C n.m.r. δ (CDCl3 ) 140 · 6; 139 · 8; 135 · 4; 134 · 9; 129 · 8, 129 · 1, 128 · 9, 10 aromatic C; 124 · 1; 123 · 9; 114 · 4; 112 · 2; 105 · 7; 104 · 3, 23 · 2, 22 · 4, 21 · 9, 21 · 7, 8×CH2 . The sample was not stable to c.i. mass spectrometric analysis. F.a.b. m/z 539 (M+H, 8%), 524 (14), 507 (22), 378 (13), 304 (15), 269 (51), 263 (100), 223 (24).
Crystallography Crystal Data for (9) C26 H22 N4 S2 , M 454 · 6, monoclinic, a 12 · 992(2), b 11 · 172(1), c 17 · 082(2) ˚ A, β 102 · 15(1)◦ , V 2423 · 9(8) ˚ A3 , D c (Z = 4) −3 1 · 246 g cm , F (000) 1056, µ(Cu Kα) 21 · 4 cm−1 . Space group P 21 /c. Accurate cell dimensions were determined at 291(2) K by least-squares refinement of 25 automatically centred reflections in the range 36◦ < 2θ < 68◦ , measured with Cu Kα (graphite-monochromatized) radiation (λ 1 · 5418 ˚ A).
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for which I > 3σ(I ) considered observed. The non-hydrogen atoms were refined with anisotropic temperature factors; the positional coordinates of the C 7 and C 70 methyl hydrogen atoms were calculated and all other hydrogen-atom coordinates refined, the atoms being given isotropic temperature factors. The function minimized in the refinement was Σ w (F o − F c )2 , with w = [σ 2 (F )+0 · 0052F 2 ]−1 . At convergence the conventional reliability indices for the observed data were R ∗ 0 · 043 and wR 0 · 070 with S 0 · 907 (362 variables). The maximum and minimum residual electron-density peak heights were +0 · 24 and −0 · 19 e ˚ A−3 . An extinction parameter was applied to the F c terms with SHELX-76;11 the extinction coefficient was 1 · 30(7)×10−6 . Final atomic parameters are given in Table 1;† Fig. 1 was prepared from the output of ORTEP-II13 and shows the atomic labelling scheme used. Table 1.
Final atomic coordinates and equivalent isotropic temperature factors for C26 H22 N4 S2 (9) Values for C and N have been multiplied by 104 ; values for S have been multiplied by 105 . Estimated standard deviations are in parentheses. B eq = (8π 2 /3)Σi Σj a i *a j *a i .a j Atom
x
y
z
B eq (˚ A)2
N(1) C(2) C(3) C(4) C(5) S(1) N(2) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) N(10 ) C(20 ) C(30 ) C(40 ) C(50 ) S(10 ) N(20 ) C(60 ) C(70 ) C(80 ) C(90 ) C(100 ) C(110 ) C(120 ) C(130 ) C(140 )
9425(2) 8385(2) 8056(2) 8888(2) 9722(2) 76480(6) 6223(3) 7037(3) 8845(3) 10801(3) 10058(2) 10384(3) 11009(3) 11307(3) 10977(4) 10367(3) 5339(2) 6334(2) 6705(2) 5930(3) 5096(3) 70130(6) 8556(3) 7728(3) 6021(4) 4072(3) 4660(2) 4481(3) 3797(4) 3328(3) 3512(3) 4192(3)
1564(2) 1233(3) 594(3) 528(3) 1139(3) 16927(7) −359(3) 68(3) −48(4) 1310(5) 2278(3) 3395(3) 4084(4) 3662(4) 2552(4) 1851(4) 2467(2) 2967(3) 2948(3) 2448(3) 2150(3) 33629(7) 3626(4) 3347(3) 2243(5) 1584(5) 2335(3) 1231(4) 1116(5) 2088(6) 3208(5) 3341(4)
4154(1) 4133(2) 3435(2) 3019(2) 3473(2) 48041(5) 2972(2) 3189(2) 2221(2) 3332(3) 4758(2) 4559(2) 5141(3) 5906(3) 6105(3) 5526(2) 3192(1) 3374(2) 2667(2) 2053(2) 2397(2) 43102(5) 2545(3) 2606(2) 1200(2) 2027(3) 3746(2) 4029(3) 4559(3) 4801(3) 4513(3) 3991(2)
3 · 11(6) 3 · 09(6) 3 · 43(7) 3 · 79(8) 3 · 50(7) 3 · 72(2) 6 · 43(1) 4 · 22(8) 5 · 83(1) 5 · 37(11) 3 · 23(7) 4 · 08(9) 5 · 03(10) 5 · 76(12) 6 · 49(10) 4 · 93(10) 3 · 37(6) 3 · 20(7) 3 · 52(7) 3 · 93(8) 3 · 69(7) 3 · 76(2) 6 · 58(11) 4 · 30(9) 5 · 98(12) 5 · 30(11) 3 · 62(7) 4 · 99(10) 6 · 44(14) 6 · 11(12) 6 · 24(13) 4 · 88(10)
Structure Determination
Description of the Structure of 4,4 0 ,5,5 0 -Tetramethyl-1,1 0 diphenyl-2,2 0 -disulfanediyldi-1 H-pyrrole-3-carbonitrile (9)
Intensity data were measured with Cu Kα radiation from a cleaved specimen of dimensions c. 0 · 128 by 0 · 180 by 0 · 305 mm aligned on a Rigaku-AFC four-circle diffractometer, recorded by an ω–2θ scan with 2θ scan rate 2 · 0◦ min−1 , and 10s stationary background counts. Three reference reflections monitored every 100 reflections showed no decay. Data to a 2θmax 130◦ yielded 4074 unique terms; corrections for Lorentz and polarization effects were applied; analytical absorption corrections were made with SHELX-7611 (transmission factors 0 · 659–0 · 802). The structure was solved by direct methods with 12 SHELXS-86 and the least-squares refinements were carried out with SHELX-7611 on a VAX8800 computer with the 2792 terms
The molecule has approximate twofold symmetry and the torsion angles N(1)–C(2)–S(1)–S(10 ) of 85 · 6(3)◦ and N(10 )– C(20 )–S(10 )–S(1) of 80 · 5(3)◦ show that the S–S bridge is approximately orthogonal to the pyrrole rings, while the C(2)– S(1)–S(10 )–C(20 ) torsion angle of 58 · 4(2)◦ illustrates the twist about the S–S bond. The pyrrole and phenyl rings are planar to within experimental error and their relative orientations are given by the torsion angles C(2)–N(1)–C(9)–C(14) and C(20 )–N(10 )–C(90 )–C(140 ) of 67 · 2(4) and 71 · 7(4)◦ respectively. The S(1)–S(10 ) bond distance of 2 · 140(1) ˚ A is significantly longer than that usually observed for the S–S bond while the C(2)–S(1) and C(20 )–S(10 ) bond lengths of 1 · 720(4) and
∗
R = Σ ||Fo | − |Fc ||/Σ |Fo |, wR = (Σ w||Fo | − |Fc ||2 /Σ w|Fo |2 )1/2 . † Crystallographic data for compound (9), namely tables of structure factor amplitudes, bond distances and angles, anisotropic thermal parameters and hydrogen atom parameters, have been deposited. Copies can be obtained from the Australian Journal of Chemistry (until 31 December 2004), P.O. Box 1139, Collingwood, Vic. 3066.
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Acknowledgments We thank E. I. DuPont de Nemours and Co., Agricultural Products Department, for the evaluation of fungicidal activity. We also thank Mr I. Vit for measurement of mass spectra and Mr R. I. Willing for measurement of 1 H and 15 N n.m.r. spectra.
References 1
2
3 4
Fig. 1. Perspective view and atom labelling of the structure of (9). Thermal ellipsoids are at the 50% probability level. Hydrogen atoms are denoted by spheres of arbitrary radius. 1 · 714(3) ˚ A are significantly shorter than values tabulated by Van Wart, Shipman and Scheraga.14 It has been suggested that the double-bond character indicated by the C–S bond lengths, the lengthening of the S–S bond and the near-orthogonality of C–C–S angles is consistent with pπ–dπ interactions between the aromatic carbon atom and the sulfur.15 Although the C–S–S angles of 102 · 7(1) and 102 · 9(1)◦ are smaller than other reported values, they are consistent with the dihedral angle of 44 · 4(2)◦ between the two pyrrole rings. A similar situation was also noted for 2,2-diaminodiphenyl disulfide.15 There is delocalization around the pyrrole rings with the mean N–C bond length of 1 · 384(4) ˚ A (mean deviation 0 · 006 ˚ A) and the C–C bond lengths range from 1 · 373(4) to 1 · 408(4) ˚ A and the angles have a mean value of 108 · 0(3)◦ (mean deviation 1 · 3◦ ). The C(6)–N(2) and C(60 )–N(20 ) bond lengths of 1 · 149(5) and 1 · 146(4) ˚ A and the C(3)–C(6)–N(2) and C(30 )–C(60 )–N(20 ) angles of 178 · 2(3) and 177 · 4(3)◦ are similar to other reported values for cyano groups.
5 6 7 8 9 10 11
12
13 14 15
Davidson, B. S., Chem. Rev., 1993, 93, 1771; Hopper, A. T., and Witiak, D. T., J. Org. Chem., 1995, 60, 3334; Rao, Y. S., Chem. Rev ., 1964, 64, 353. Diehl, D. R., Helber, M. J., and Rossi, L. J., U.S. Pat. Appl. US 5,283,165 (Cl. 430–522; G03C1/84), 01 February 1994; Appl. 995,436, 23 December 1992 (Chem. Abstr ., 1994, 121, 95864p). Fallert, M., and Hartke, K., Arch. Pharm. (Weinheim, Ger.), 1986, 319, 1098 (Chem. Abstr ., 1987, 106, 102014g). Hubert, R., and Hartke, K., Chem. Ber ., 1975, 108, 3262. Liepa, A. J., unpublished data. Grabenko, A. D., Kulaeva, L. N., and Pel’kis, P. S., Zh. Obshch. Khim., 1962, 32, 2248. Paquette, L. A., ‘Encyclopedia of Reagents for Organic Synthesis’ Vol. 4, p. 2593 (Interscience: New York 1995). Barton, D. H. R., Campos-Neves, A. da S., and Cookson, R. C., J. Chem. Soc., 1956, 3500. Sauers, R. R., J. Am. Chem. Soc., 1959, 81, 4873. Hogg, D. R., in ‘Comprehensive Organic Chemistry’ (Ed. D. N. Jones) Vol. 3, p. 269 (Pergamon: Oxford 1979). Sheldrick, G. M., SHELX-76, Program for Crystal Structure Determination, University of Cambridge, Cambridge, U.K., 1976. Sheldrick, G. M., SHELXS-86, Structure Solution Package, University of G¨ ottingen, Federal Republic of Germany, 1986. Johnson, C. K., ORTEP-II, Report ORNL-5138, Oak Ridge National Laboratory, Tennessee, 1976. Scheraga, H. A., Shipman, L. L., and Van Wart, H. E., J. Phys. Chem., 1975, 79, 1436. Bryant, M. W. R., and Lee, J. D., Acta Crystallogr., Sect. B , 1970, 26, 1729.
