Synlett 2009(7): 1118-1122  
DOI: 10.1055/s-0029-1216630
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Selenium-Substituted Pyrroles and Pyrazol-3-ones

Orazio A. Attanasi*a, Lucia De Crescentini*a, Fabio Mantellinia, Francesca Marinib, Simona Nicolinia, Silvia Sternativob, Marcello Tiecco*b
a Istituto di Chimica Organica, Università degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti, 24, 61029 Urbino (PU), Italy
Fax: +39(0722)303441; e-Mail: [email protected]; e-Mail: [email protected];
b Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Università di Perugia, 06123 Perugia, Italy
Further Information

Publication History

Received 20 November 2008
Publication Date:
02 April 2009 (online)

Abstract

An approach to the synthesis of 4-(phenylseleno)pyrroles, 4-(phenylseleno)pyrazol-3-ones, and 4-(1,3-benzoselenazol-2-ylthio)pyrazol-3-ones is described. Their formation passes through hydrazonic intermediates obtained by the reaction between 1,2-diaza-1,3-butadienes and 1-(phenylseleno)ketones, phenylselenol, or 2-mercaptobenzoselenazole, respectively.

    References and Notes

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  • 12a

    Synthesis of the α-Seleno Ketones 2a,bCompound 2a Phenyl selenyl chloride (5.0 mmol) was added at r.t. to acetone (4 mL), and the solution was stirred for 30 min. The reaction mixture was poured into H2O and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered, and evaporated under vacuum. The crude product 2a (89% yield) was used without further purification.
    Compound 2b The phenylselenyl sulfate was generated from (PhSe)2 (1.7 mmol) and (NH4)2S2O8 (2.3 mmol) in MeCN (20 mL) at 80 ˚C. After 30 min the 1-phenylethanone (1.7 mmol) was added. The mixture was stirred overnight at the same temperature, then was poured into an aq solution of NaHCO3 and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered, and evaporated under vacuum. The residue was purified by flash chromatography (elution mixture: PE-CH2Cl2 = 85:15) to yield 2b in 40% yield.

  • 12b Spectral data of 2a and 2b are identical to those already described in the literature: Houllemare D. Ponthieux S. Outurquin F. Paulmier C. Synthesis  1997,  101 
  • 15 Attanasi OA. De Crescentini L. Filippone P. Foresti E. Mantellini F. J. Org. Chem.  2000,  65:  2820 
  • 18a Attanasi OA. Filippone P. Mei A. Santeusanio S. Synthesis  1984,  671 
  • 18b Attanasi OA. Filippone P. Mei A. Santeusanio S. Synthesis  1984,  873 
13

General Procedure for the Synthesis of β-(Phenylseleno)-hydrazones 3a,b To a magnetically stirred solution of 1,2-diaza-1,3-butadiene 1a as a mixture of E/Z isomers [¹8] (1.0 mmol) and 1-(phenyl-seleno)acetone [¹²] (2a) or 1-phenyl-2-(phenylseleno)-ethanone [¹²] (2b, 1.0 mmol) in THF (5 mL) at r.t., a catalytic amount (0.1 mmol) of NaH was added. The reaction mixture was magnetically stirred for 1.0-1.5 h until the disappearance of the starting 1. β-(Phenylseleno)hydrazones 3a,b were obtained by chromatography on SiO2 column (elution mixtures: cyclohexane-EtOAc) and by subsequent crystallization from Et2O-light PE (40-60). The reaction between 1b,c and 2a,b gave complicated mixtures.
Data for Ethyl 2-[ N-(Aminocarbonyl)ethanehydra-zonoyl]-2,5-dideoxy-3- Se -phenyl-3-selenopent-4-ulosonate (3a)
Yield 294.5 mg (74%) obtained as yellow solid; mp 148-152 ˚C. IR (Nujol): νmax = 3420, 3291, 3195, 1765, 1720, 1690 cm. ¹H NMR (400 MHz, DMSO-d 6): δ = 1.08 (t, 3 H, J = 6.8 Hz), 1.85 (s, 3 H), 2.32 (s, 3 H), 3.44 (d, 1 H, J = 11.6 Hz), 3.97-4.02 (m, 2 H), 4.70 (d, 1 H, J = 11.6 Hz), 6.38 (s, 2 H), 7.38-7.47 (m, 5 H), 9.30 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 13.8 (q), 15.2 (q), 27.7 (q), 49.3 (d), 53.8 (d), 60.8 (t), 125.5 (s), 128.8 (d), 129.1 (d), 136.2 (d), 142.4 (s), 156.9 (s), 169.3 (s), 202.0 (s); during the MS analysis, we have observed only the signals of pyrrole 4a. Anal. Calcd for C16H21N3O4Se: C, 48.25; H, 5.31; N, 10.55. Found: C, 48.19; H, 5.39; N, 10.63.

14

General Procedure for the Synthesis of 4-(Phenylseleno)-pyrroles 4a-c and 2-Oxohydrazones 5a,b To a magnetically stirred solution of 1,2-diaza-1,3-butadienes 1a-c as a mixture of E/Z isomers [¹8] (2.0 mmol) and 1-(phenylseleno)acetone [¹²] (2a, 1.0 mmol) or 1-phenyl-2-(phenylseleno)ethanone [¹²] (2b, 1.0 mmol) in THF (5 mL) at r.t., a stoichiometric amount (1.0 mmol) of NaH was added. The reaction mixture was magnetically stirred for 6.0-8.0 h until the disappearance of the starting 1. 4-(Phenyl-seleno)pyrroles 4a-c and 2-oxohydrazones [¹4] 5a,b were separated by chromatography on SiO2 column (elution mixtures: cyclohexane-EtOAc), and they were crystallized from Et2O-light PE (40-60) or EtOAc-light PE (40-60), respectively.
Ethyl 1-[(Aminocarbonyl)amino]-2,5-dimethyl-4-(phenylseleno)-1 H -pyrrole-3-carboxylate (4a) Yield 266.5 mg (70%) obtained as light yellow solid; mp 182-184 ˚C. IR (Nujol): νmax = 3518, 3374, 3193, 1727, 1704 cm. ¹H NMR (400 MHz, DMSO-d 6): δ = 1.04 (t, 3 H, J = 7.2 Hz), 2.10 (s, 3 H), 2.28 (s, 3 H), 4.03 (q, 2 H, J = 7.2 Hz), 6.38 (s, 2 H), 7.15-7.19 (m, 2 H), 7.49-7.53 (m, 2 H), 7.73-7.75 (m, 1 H), 9.29 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 10.8 (q), 13.9 (q), 14.2 (q), 58.8 (t), 98.5 (s), 110.3 (s), 118.7 (s), 125.3 (s), 128.2 (d), 128.8 (d), 134.2 (s), 145.9 (d), 156.9 (s), 164.3 (s). MS: m/z (%) = 383 (23) [M+ + 3], 381 (100) [M+ + 1], 379 (57) [M+ - 1], 378 (21) [M+ - 2], 377 (22) [M+ - 3], 375 (2) [M+ - 5]. Anal. Calcd for C16H19N3O3Se: C, 50.53; H, 5.04; N, 11.05. Found: C, 50.48; H, 5.21; N, 10.96.

16

General Procedure for the Synthesis of α-(Phenylseleno)-hydrazones 6a-c and α-(1,3-Benzoselenazol-2-ylthio)-hydrazones 6d-f A solution of 1,2-diaza-1,3-butadienes 1a-c as a mixture of E/Z isomers [¹8] (1.0 mmol) and phenylselenol(2c) or 2-mercaptobenzselenazole (2d, 1.0 mmol) in THF (5 mL) was magnetically stirred at r.t., for 0.1-24.0 h until the disappearance of the starting 1. Ηydrazones 6a-c were obtained by chromatography on SiO2 column (elution mixtures: cyclohexane-EtOAc) and by subsequent crystallization from Et2O-light PE (40-60), while hydrazones 6d-f were crystallized from Et2O-light PE
(40-60), after the evaporation of the reaction solvent. The conversion of α-(1,3-benzoselenazol-2-ylthio)hydrazones 6d-f into the corresponding hydrazino forms occurred in one week, directly in the NMR tube, using DMSO-d 6 as solvent.
Methyl 3-[(Aminocarbonyl)hydrazono]-2-(phenylseleno)-pentanoate (6b)
Yield 247.5 mg (72%) obtained as white solid; mp 124-126 ˚C. IR (Nujol): νmax = 3454, 3299, 3191, 1793, 1697 cm. ¹H NMR (400 MHz, DMSO-d 6): δ = 0.93 (t, 3 H, J = 7.6 Hz), 2.33-2.38 (m, 2 H), 3.60 (s, 3 H), 4.94 (s, 1 H), 6.18 (br s, 2 H), 7.30-7.32 (m, 3 H), 7.54-7.56 (m, 2 H), 9.44 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6) : δ = 9.6 (q), 21.0 (t), 50.1 (d), 52.5 (q), 128.1 (s), 128.2 (d), 129.1 (d), 134.1 (d), 145.8 (s), 156.8 (s), 169.8 (s). MS: m/z (%) = 345 (8)[M+ + 3], 343 (35) [M+ + 1], 341 (17) [M+ - 1], 340 (6) [M+ - 2], 339 (6) [M+ - 3], 337 (1) [M+ - 5], 317 (3), 315 (15), 313 (9), 312 (4), 311 (4), 270 (6), 268 (30), 266 (15), 265 (6), 264 (6), 262 (2), 186 (100). Anal. Calcd for C13H17N3O3Se: C, 45.62; H, 5.01; N, 12.28. Found: C, 45.48; H, 5.17; N, 12.41.
Ethyl 3-[(Aminocarbonyl)hydrazono]-2-(1,3-benzo-selenazol-2-ylthio)butanoate (Hydrazono Form of 6d)
Yield 372.5 mg (93%) obtained as white solid; mp 144-146 ˚C. IR (Nujol): νmax = 3463, 3313, 3200, 1790, 1692 cm. ¹H NMR (400 MHz, DMSO-d 6): δ = 1.20 (t, 3 H, J = 7.2 Hz), 1.98 (s, 3 H), 4.16-4.24 (m, 2 H), 5.51 (s, 1 H), 6.28 (br s, 2 H), 7.29 (t, 1 H, J = 8.0 Hz), 7.44 (t, 1 H, J = 8.0 Hz), 7.78 (d, 1 H, J = 7.2 Hz), 8.04 (d, 1 H, J = 6.8 Hz), 9.55 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6) : δ = 13.9 (q), 14.5 (q), 57.4 (t), 61.9 (d), 122.5 (d), 124.6 (d), 125.3 (d), 126.4 (d), 138.3 (s), 140.5 (s), 153.6 (s), 156.6 (s), 166.1 (s), 167.5 (s); MS: m/z (%) = 400 (1) [M+ + 3], 398 (5) [M+ + 1], 396 (2) [M+ - 1], 397 (1) [M+ - 2], 396 (1) [M+ - 3], 328 (9), 326 (45), 324 (19), 323 (8), 322 (8), 320 (1), 313 (31), 311 (100), 309 (60), 308 (24), 307 (23), 305 (3); Anal. Calcd for C14H16N4O3SSe: C, 42.11; H, 4.04; N, 14.03. Found: C, 42.31; H, 4.11; N, 14.20.
Ethyl 3-[2-(Aminocarbonyl)hydrazino]-2-(1,3-benzo-selenazol-2-ylthio)but-2-enoate (Hydrazino Form of 6d)
¹H NMR (400 MHz, DMSO-d 6): δ = 1.11 (t, 3 H, J = 7.2 Hz), 2.30 (s, 3 H), 4.09 (q, 2 H, J = 7.2 Hz), 6.28 (s, 2 H), 7.21 (t, 1 H, J = 8.0 Hz), 7.39 (t, 1 H, J = 8.0 Hz), 7.75 (d, 1 H, J = 6.8 Hz), 7.96 (d, 1 H, J = 8.0 Hz), 8.60 (s, 1 H), 11.08 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 14.3 (q), 16.4 (q), 59.9 (t), 82.3 (s), 122.4 (d), 123.7 (d), 125.0 (d), 126.1 (d), 137.8 (s), 156.8 (s), 157.8 (s), 168.7 (s), 172.4 (s), 180.3 (s).

17

General Procedure for the Synthesis of 4-(Phenylseleno)-pyrazol-3-ones 7a,b, 8a and 4-(1,3-benzoselenazol-2-ylthio)pyrazol-3-ones 7c,d, 8b
α-(Phenylseleno)- or α-(1,3-benzoselenazol-2-ylthio)hydra-zones (6a-c and 6d-f, 1.0 mmol) were dissolved in a mixture of THF (5 mL)-MeOH (5 mL), and a stoichiometric amount of NaH (1.0 mmol) was added. The reaction mixture was magnetically stirred for 0.1-0.3 h until the disappear-ance of the starting 6. Pyrazol-3-ones 7a-d were obtained from 6a,b,d,e, respectively, while pyrazol-3-ones 8a,b were obtained from 6c,f, respectively. Products 7a-d and 8a,b were purified by chromatography on SiO2 column (elution mixtures: EtOAc-MeOH) and by subsequent crystallization from Et2O-light PE (40-60).
5-Ethyl-4-(phenylseleno)-1,2-dihydro-3 H -pyrazol-3-one (7b)
Yield 252.1 mg (94%) obtained as white solid; mp 120-122 ˚C. IR (Nujol): νmax = 3369, 3116, 1735, 1702, 1636 cm. ¹H NMR (400 MHz, DMSO-d 6): δ = 1.03 (t, 3 H, J = 7.6 Hz), 2.35-2.41 (m, 2 H), 7.18-7.32 (m, 4 H), 7.46 (br s, 1 H), 7.57-7.59 (m, 1 H), 8.65 (br s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 13.1 (q), 20.8 (d), 125.2 (s), 127.7 (d), 128.9 (d), 129.5 (d), 130.8 (s), 158.6 (s), 164.4 (s). MS: m/z (%) = 270 (20)[M+ + 3], 268 (100) [M+ + 1], 266 (39) [M+ - 1], 265 (19) [M+ - 2], 264 (21) [M+ - 3], 262 (2) [M+ - 5]. Anal. Calcd for C11H12N2OSe: C, 49.45; H, 4.53; N, 10.48. Found: C, 49.49; H, 4.47; N, 10.41.



4-(1,3-Benzoselenazol-2-ylthio)-5-methyl-1,2-dihydro-3 H -pyrazol-3-one (7c) Yield 309.1 mg (99%) obtained as white solid; mp 192-194 ˚C. IR (Nujol): νmax = 3398, 3328, 1739, 1697, 1673, 1655 cm. ¹H NMR (400 MHz, DMSO-d 6): δ = 2.02 (s, 3 H), 7.01 (s, 1 H), 7.15 (t, 1 H, J = 7.6 Hz), 7.35 (t, 1 H, J = 8.0 Hz), 7.69 (d, 1 H, J = 8.0 Hz), 7.86 (d, 1 H, J = 8.0 Hz), 8.39 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 13.4 (q), 80.7 (s), 122.1 (d), 123.2 (d), 124.9 (d), 125.8 (d), 138.0 (s), 153.1 (s), 157.3 (s), 165.8 (s), 184.2 (s). MS: m/z (%) = 313 (28) [M+ + 3], 311 (100) [M+ + 1], 309 (52) [M+ - 1], 308(18) [M+ - 2], 307(18) [M+ - 3], 305 (1) [M+ - 5]. Anal. Calcd for C11H9N3OSSe: C, 42.59; H, 2.92; N, 13.54. Found: C, 42.39; H, 3.01; N, 13.28. 3-Methyl-5-oxo- N -phenyl-4-(phenylseleno)-2,5-dihydro-1 H -pyrazole-1-carboxamide (8a) Yield 292.1 mg (78%) obtained as white solid; mp 144-147 ˚C. IR (Nujol): νmax = 3342, 3191, 1721, 1687 cm. ¹H NMR (400 MHz, DMSO-d 6): δ = 2.12 (s, 3 H), 6.98 (t, 1 H, J = 7.2 Hz), 7.24-7.28 (m, 5 H), 7.45 (br s, 1 H), 7.51-7.68 (m, 4 H), 11.98 (br s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 13.0 (q), 110.4 (s), 119.1 (d), 122.1 (d), 127.7 (d), 127.8 (d), 129.0 (d), 129.5 (d), 130.8 (s), 139.1 (s), 147.3 (s), 154.2 (s), 164.8 (s). MS: m/z (%) = 375 (20) [M+ + 3], 373 (100) [M+ + 1], 371 (41) [M+ - 1], 370 (19) [M+ - 2], 369 (21) [M+ - 3], 367 (3) [M+ - 5]. Anal. Calcd for C17H15N3O2Se: C, 54.85; H, 4.06; N, 11.29. Found: C, 54.96; H, 4.17; N, 11.36.
4-(1,3-Benzoselenazol-2-ylthio)-3-methyl-5-oxo- N -phenyl-2,5-dihydro-1 H -pyrazol-1-carboxamide (8b)
Yield 417.1 mg (97%) obtained as white solid; mp 246-248 ˚C. IR (Nujol): νmax = 3351, 3186, 1706, 1683 cm. ¹H NMR (400 MHz, DMSO-d 6): δ = 2.10 (s, 3 H), 7.05 (t, 1 H, J = 7.6 Hz), 7.17 (t, 1 H, J = 7.6 Hz), 7.32-7.51 (m, 4 H), 7.54 (d, 2 H, J = 8.0 Hz), 7.72 (d, 1 H, J = 8.0 Hz), 7.88 (d, 1 H, J = 8.0 Hz), 12.21 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 13.4 (q), 81.2 (s), 119.0 (d), 122.2 (d), 122.7 (d), 123.4 (d), 124.9 (d), 125.8 (d), 129.0 (d), 138.0 (s), 138.7 (s), 149.6 (s), 152.8 (s), 157.2 (s), 165.8 (s), 183.3 (s). MS: m/z (%) = 430 (14) [M+ + 3], 428 (45) [M+ + 1], 426 (35) [M+ - 1], 425 (12) [M+ - 2], 424 (13) [M+ - 3], 422 (2) [M+ - 5], 313 (15), 311 (55), 309 (26), 308 (10), 307 (10), 305 (2), 215 (100). Anal. Calcd for C18H14N4O2SSe: C, 50.35; H, 3.29; N, 13.05. Found: C, 50.39; H, 3.31; N, 13.23.