A Novel One-Pot, Three-Component
Synthesis of Dialkyl 5-(Alkylamino)-1-aryl-1H-pyrazole-3,4-dicarboxylates

Mehdi Adib; Bagher Mohammadi; Hamid Reza Bijanzadeh

doi:10.1055/s-0028-1087365

LETTER

A Novel One-Pot, Three-Component Synthesis of Dialkyl 5-(Alkylamino)-1-aryl-1H-pyrazole-3,4-dicarboxylates

Mehdi Adib*^a, Bagher Mohammadi^a, Hamid Reza Bijanzadeh^b
^a School of Chemistry, University College of Science, University of Tehran, P.O. Box 14155-6455, Tehran, Iran
Fax: +98(21)66495291; e-Mail: madib@khayam.ut.ac.ir;
^b Department of Chemistry, Tarbiat Modarres University, P.O. Box 14115-175, Tehran, Iran

Abstract

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Abstract

A novel, one-pot, and three-component synthesis of dialkyl 5-(alkylamino)-1-aryl-1H-pyrazole-3,4-dicarboxylates is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by hydrazinecarboxamides to afford the title compounds in good yields.

Key words

5-amino-1-aryl-1H-pyrazole-3,4-dicarboxylates - three-component reactions - isocyanides - cyclizations - heterocycles

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References and Notes

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Synthesis of Dimethyl 5-( tert -Butylamino)-1-phenyl-1 H -pyrazole-3,4-dicarboxylate (5a) The procedure for the preparation of dimethyl 5-(tert-butylamino)-1-phenyl-1H-pyrazole-3,4-dicarboxylate (5a) is described as an example. To a magnetically stirred solution of N′,2-diphenyl-1-hydrazinecarboxamide (0.455 g, 2 mmol) and dimethyl acetylenedicarboxylate (0.284 g,
2 mmol) in dry acetone (10 mL) was added dropwise a solution of tert-butyl isocyanide (0.166 g, 2 mmol) in dry acetone (2 mL) at ambient temperature over 10 min. Then the reaction mixture was stirred for 36 h. The solvent was removed, and the residue was purified by column chromatography using n-hexane-EtOAc (5:1) as eluent. The solvent was removed and the product was obtained as colorless oil; yield 0.48 g (72%). IR (KBr): 3423 (NH), 1745, 1697 (C=O), 1597, 1557, 1543, 1510, 1483, 1443, 1420, 1391, 1364, 1271, 1221, 1132, 1094, 1072, 1047, 941, 791, 758, 692 cm^-¹. ^¹H NMR (500.1 MHz, CDCl₃): δ = 1.46 [s, 9 H, C(CH₃)₃], 3.81 and 3.86 (2 s, 6 H, 2 × OCH₃), 5.63 (br s, 1 H, NH), 7.33 (t, J = 7.5 Hz, 1 H, CH), 7.42 (dd, J = 8.2, 7.5 Hz, 2 H, 2 × CH), 7.49 (d, J = 8.2 Hz, 2 H, 2 × CH). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 29.06 [C(CH₃)₃], 51.37 [NC(CH₃)₃], 51.42 and 53.17 (2 × OCH₃), 100.25 (N₂C=C), 122.76, 127.71 and 129.14 (3 × CH), 135.25, 139.41 and 155.73 (3 × C), 162.34 and 164.18 (2 × C=O). MS: m/z (%) = 331 (18) [M⁺], 316 (56), 300(6), 284 (100), 275 (7), 252 (8), 243 (17), 214 (4), 185 (4), 143 (6), 77 (28), 57 (8), 41 (8). Anal. Calcd (%) for C₁₇H₂₁N₃O₄ (331.37): C, 61.62; H, 6.39; N, 12.68. Found: C, 61.6; H, 6.5; N, 12.6.
Dimethyl 5-(Cyclohexylamino)-1-phenyl-1 H -pyrazole-3,4-dicarboxylate (5c)
Yield 0.51 g (72%); colorless crystals, mp 76 ˚C. IR (KBr): 3440 (NH), 1742 and 1688 (C=O), 1565, 1549, 1508, 1481, 1450, 1421, 1367, 1288, 1260, 1236, 1190, 1161, 1136, 1105, 1095, 1070, 792, 765, 696 cm^-¹. ^¹H NMR (500.1 MHz, CDCl₃): δ = 1.21-2.13 [m, 10 H, CH(CH ₂)₅], 3.62-3.66 (m, 1 H, NHCH), 3.81 and 3.83 (2 s, 6 H, 2 × OCH₃), 5.44 (d, J = 7.6 Hz, 1 H, NH), 7.33 (t, J = 7.4 Hz, 1 H, CH), 7.41 (dd, J = 7.4, 7.7 Hz, 2 H, 2 × CH), 7.47 (d, J = 7.7 Hz, 2 H, 2 × CH). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 24.74, 25.87 and 33.22 (3 × CH₂), 51.23 (NCH), 51.37 and 53.08 (2 × OCH₃), 99.32 (N₂C=C), 123.23, 127.97 and 129.15 (3 × CH), 135.96, 139.24 and 156.34 (3 × C), 161.89 and 163.98 (2 × C=O). MS: m/z (%) = 357 (94) [M⁺], 342 (28), 324 (15), 314 (53), 282 (100), 275 (50), 256 (12), 243 (10), 167 (11), 149 (26), 77 (42), 69 (15), 55 (17). Anal. Calcd (%) for C₁₉H₂₃N₃O₄ (357.41): C, 63.85; H, 6.49; N, 11.76. Found: C, 63.8; H, 6.5; N, 11.7.

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After 2 h from the beginning of the reaction, TLC analysis of the reaction mixture clearly indicated formation of an intermediate in good yield. The reaction was quenched by rapid evaporation of the solvent and the intermediate was purified by a rapid column chromatography using n-hexane-EtOAc (1:1) as eluent. The solvent was removed and the intermediate precipitated from H₂O-EtOH (1:1).
Dimethyl 2-(Anilinocarbonyl)-5-(cyclohexylamino)-1-phenyl-2,3-dihydro-1 H -pyrazole-3,4-dicarboxylate (10c)
White powder, mp 79-81 ˚C. IR (KBr): 3381 and 3300 (NH), 1745, 1710 and 1685 (C=O), 1624, 1599, 1537, 1495, 1443, 1365, 1313, 1259, 1198, 1088, 1053, 1030, 1005, 781, 754, 692 cm^-¹. ^¹H NMR (500.1 MHz, CDCl₃): δ = 1.17-1.91 [m, 10 H, CH(CH ₂)₅], 3.17-3.25 (m, 1 H, NHCH), 3.58 and 3.73 (2 s, 6 H, 2 × OCH₃), 5.63 (s, 1 H, NCH), 7.11 (t, J = 7.5 Hz, 1 H, CH), 7.21 (d, J = 8.5 Hz, 1 H, NH), 7.25 (t, J = 7.4 Hz, 1 H, CH), 7.34 (dd, J = 7.8, 7.5 Hz, 2 H, 2 × CH), 7.38 (dd, J = 8.4, 7.4 Hz, 2 H, 2 × CH), 7.44 (d, J = 7.7 Hz, 2 H, 2 × CH), 7.47 (d, J = 8.4 Hz, 2 H, 2 × CH), 8.20 (s, 1 H, NHCO). ^¹³C NMR (125.8 MHz, CDCl₃): δ = 24.04, 24.13, 25.06, 32.28 and 34.68 (5 × CH₂), 50.62 (NHCH), 52.20 and 53.10 (2 × OCH₃), 62.79 (NCH), 83.40 (N₂C=C), 119.17, 122.28, 123.85, 126.90, 129.01 and 129.27 (6 × CH), 137.51 and 145.79 (2 × C), 157.16 and 159.71 (N₂ C=C and C=O, urea), 166.28 and 171.07 (2 × C=O, ester). MS: m/z (%) = 479 (20) [M⁺ + 1], 463 (10) [M - CH₃], 446 (12) [M - OCH₃], 419 (46) [M - CO₂CH₃], 386 (11) [M - PhNH], 343 (8) [M - (CO₂CH₃ + Ph)], 326 (10) [M - (CO₂CH₃ + PhNH)], 300(100) [M - (CO₂CH₃ + PhNHCO)], 252 (69), 225 (15) [PhN=NCOPh⁺], 218 (30), 186 (25), 170 (58), 119 (34) [PhNCO⁺], 91 (34), 77 (62), 55 (88). Anal. Calcd (%) for C₂₆H₃₀N₄O₅ (478.55): C, 65.26; H, 6.32; N, 11.71. Found: C, 65.0; H, 6.6; N, 11.4.