PDF icon Download PDF
Synlett 2005(6): 0935-0938  
DOI: 10.1055/s-2005-864819
LETTER
© Georg Thieme Verlag Stuttgart · New York

A New Synthesis of 4-Dialkylamino-1,5-dihydropyrrol-2-ones by Pd-Catalyzed Oxidative Aminocarbonylation of 2-Ynylamines

Bartolo Gabriele*a, Pierluigi Plastinab, Giuseppe Salernob, Mirco Costac
a Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
b Dipartimento di Chimica, Università della Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
c Dipartimento di Chimica Organica e Industriale, Università di Parma, 43100 Parma, Italy
e-Mail: b.gabriele@unical.it;
Further Information

Publication History

Received 8 December 2004
Publication Date:
23 March 2005 (online)

   Permissions and Reprints All articles of this category
Preview

Abstract

A novel synthesis of γ-lactam derivatives 4 is reported, based on PdI2-catalyzed oxidative monoaminocarbonylation of 2-ynylamines, followed by in situ conjugate addition of a secondary amine and lactamization. Tetramic acids can be easily obtained from 4 by acid-catalyzed hydrolysis at room temperature.

Key words

aminocarbonylation - carbonylation - γ-lactams - palladium - tetramic acids

4

Typical Procedure for the Oxidative Aminocyclo-carbonylation of 2-Ynylamines 3. All carbonylations were carried out in a 250 mL stainless steel autoclave with magnetic stirring. In a typical experiment, the autoclave was charged in the presence of air with PdI2 (15.0 mg or 30.0 mg, 4.2·10-2 or 8.3·10-2 mmol), KI (70.0 mg or 138.0 mg, 0.42 mmol or 0.83 mmol), and a solution of 3 (4.2 mmol) and the amine (8.4 mmol) in MeOH (8.4 mL). While the mixture was stirred, the autoclave was charged with CO (16 atm) and air (4 atm), and then heated at 100 °C with stirring for 15-20 h (see Table [1] ). After cooling, the autoclave was degassed and opened. Pure products 4 were isolated by column chromatography (neutral Al2O3, hexane-EtOAc from 8:2 to 7:3 as the eluent) after removal of the solvent by rotary evaporation.

5

1-Benzyl-5,5-dimethyl-4-(morpholin-4-yl)-1,5-dihydropyrrol-2-one (4a): yellow solid (0.78 g, 65% yield based on 3a); mp 144-145 °C. IR (KBr): ν = 2961 (m), 1651 (s), 1601 (m), 1454 (w), 1414 (w), 1232 (w), 1115 (m), 707 (w) cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.34-7.16 (m, 5 H, Ph), 4.89 (s, 1 H, =CH), 4.55 (s, 2 H, NCH 2Ph), 3.78-3.71 (m, 4 H, CH2OCH2), 3.25-3.19 (m, 4 H, CH2NCH2), 1.33 (s, 6 H, CMe2). 13C NMR (75 MHz, CDCl3): δ = 171.0, 170.1, 139.7, 128.3, 127.4, 126.8, 92.4, 66.2, 63.7, 48.1, 41.4, 24.4. MS (EI, 70 eV): m/z (%) = 286 (100) [M+], 271 (10), 182 (10), 181 (46), 166 (9), 138 (13), 108 (10), 91 (61). Anal. Calcd for C17H22N2O2 (286.37): C, 71.30; H, 7.74; N, 9.78. Found: C, 71.44; H, 7.72; N. 9.79.
1-Benzyl-5,5-dimethyl-4-(piperidin-1-yl)-1,5-dihydropyrrol-2-one (4a′): yellow oil (0.66 g, 55% yield based on 3a). IR (film): ν = 2933 (w), 1656 (s), 1579 (s), 1391 (m), 1236 (w), 1025 (w), 708 (w) cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.35-7.15 (m, 5 H, Ph), 4.80 (s, 1 H, =CH), 4.54 (s, 2 H, NCH 2Ph), 3.62-3.13 (m, 4 H, CH2NCH2), 1.75-1.45 (m, 6 H, NCH2CH 2CH 2CH 2CH2), 1.33 (s, 6 H, CMe2). 13C NMR (75 MHz, CDCl3): δ = 171.7, 170.0, 140.0, 128.2, 127.4, 126.7, 89.7, 63.8, 49.2, 41.4, 25.4, 24.3, 24.1. MS (EI, 70 eV): m/z (%) = 285 (20) [M+ + 1], 284 (100) [M+], 269 (16), 193 (21), 180 (19), 179 (49), 162 (16), 151 (14), 150 (26), 136 (56), 109 (19), 108 (15), 91 (66), 84 (26), 67 (14). Anal. Calcd for C18H24N2O (284.40): C, 76.02; H, 8.51; N, 9.85. Found: C, 76.13; H, 8.50; N. 9.87.
1-Benzyl-5-ethyl-5-methyl-4-(morpholin-4-yl)-1,5-dihydropyrrol-2-one (4b): yellow solid (0.95 g, 75% yield based on 3b); mp 136-137 °C. IR (KBr): ν = 2968 (m), 1657 (s), 1585 (s), 1395 (m), 1239 (m), 1120 (m), 1031 (w), 905 (w), 782 (w), 711 (w) cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.40-7.15 (m, 5 H, Ph), 4.94 (s, 1 H, =CH), 4.68 (distorted d, J = 16.1 Hz, 1 H, NCHHPh), 4.26 (distorted d, J = 16.1 Hz, 1 H, NCHHPh), 3.78-3.68 (m, 4 H, CH2OCH2), 3.27-3.17 (m, 4 H, CH2NCH2), 1.86-1.60 (m, 2 H, CH 2CH3), 1.28 (s, 3 H, CH 3CCH2CH3), 0.56 (t, J = 7.3 Hz, 3 H, CH2CH 3). 13C NMR (75 MHz, CDCl3): δ = 171.7, 167.3, 139.3, 128.0, 127.5, 126.6, 93.8, 67.3, 66.0, 47.6, 41.2, 28.6, 24.2, 7.4. MS (EI, 70 eV): m/z (%) = 300 (46) [M+], 285 (15), 272 (38), 271 (35), 181 (15), 180 (10), 167 (25), 139 (21), 92 (9), 91 (100), 65 (10). Anal. Calcd for C18H24N2O2 (300.40): C, 71.97; H, 8.05; N, 9.33. Found: C, 72.12; H, 8.03; N. 9.35.
1-Benzyl-5-ethyl-4-(morpholin-4-yl)-1,5-dihydropyrrol-2-one (4c): yellow oil (0.84 g, 70% yield based on 3c). IR (film): ν = 1657 (s), 1600 (s), 1407 (m), 1231 (m), 1115 (m), 705 (w) cm-1. 1H NMR (300 MHz, acetone-d 6): δ = 7.39-7.15 (m, 5 H, Ph), 4.95 (distorted d, J = 15.4 Hz, 1 H, NCHHPh), 4.87 (s, 1 H, =CH), 4.15 (t, J = 3.6 Hz, 1 H, HCCH2CH3), 4.01 (distorted d, J = 15.4 Hz, 1 H, NCHHPh), 3.77-3.49 (m, 4 H, CH2OCH2), 3.19-2.99 (m, 4 H, CH2NCH2), 1.96-1.60 (m, 2 H, CH 2CH3), 0.63 (t, J = 7.3 Hz, 3 H, Me). 13C NMR (75 MHz, acetone-d 6): δ = 173.0, 166.2, 139.7, 129.2, 128.7, 127.8, 94.5, 66.7, 58.9, 49.05, 43.5, 22.4, 6.1. MS (EI, 70 eV): m/z (%) = 286 (45) [M+], 271 (4), 258 (55), 257 (27), 229 (5), 221 (6), 207 (13), 193 (9), 181 (5), 167 (21), 166 (11), 153 (16), 147 (6), 135 (7), 125 (17), 108 (7), 91(100), 73 (22), 65 (10), 53 (6). Anal. Calcd for C17H22N2O2 (286.17): C, 71.30; H, 7.74; N, 9.78. Found: C, 71.44; H, 7.73; N. 9.76.
1-Benzyl-4-(morpholin-4-yl)-5-(2-phenylethyl)-1,5-dihydropyrrol-2-one (4d): yellow oil (1.19 g, 78% yield based on 3d). IR (film): ν = 2961 (w), 2920 (w), 2854 (m), 1664 (s), 1599 (s), 1443 (m), 1405 (m), 1234 (m), 1115 (m), 706 (m) cm-1. 1H NMR (300 MHz, acetone-d 6): δ = 7.40-6.96 (m, 10 H, 2 Ph), 4.92 (s, 1 H, =CH), 4.83 (distorted d, J = 15.4 Hz, 1 H, NCHHPh), 4.32 (distorted d, J = 15.4 Hz, 1 H, NCHHPh), 4.26 (t, J = 3.5 Hz, 1 H, HCCH2CH2Ph), 3.74-3.52 (m, 4 H, CH2OCH2), 3.20-3.01 (m, 4 H, CH2NCH2), 2.41-2.23 (m, 2 H, CH2CH 2Ph), 2.16-1.84 (m, 2 H, CH 2CH2Ph). 13C NMR (75 MHz, acetone-d 6): δ = 173.1, 166.4, 142.7, 140.0, 129.3, 129.2, 129.1, 128.9, 127.9, 126.5, 94.5, 66.8, 59.2, 49.0, 44.3, 32.4, 28.9. MS (EI, 70 eV): m/z (%) = 362 (2) [M+], 341 (1), 259 (16), 258 (100), 193 (3), 168 (6), 167 (62), 91 (59), 73 (8), 65 (5). Anal. Calcd for C23H26N2O2 (362.46): C, 76.21; H, 7.23; N, 7.73. Found: C, 76.09; H, 7.24; N. 7.71.

12

A mixture of pure 4a (0.6 g, 2.1 mmol) in 2 N HCl (10 mL) was stirred at r.t. for 2 h. The crude mixture was extracted several times with Et2O and the collected organic layers were dried over Na2SO4. After filtration and removal of the solvent by rotary evaporation, 1-benzyl-5,5-dimethyl-pyrrolidine-2,4-dione (5a) was purified by column chromatography (neutral Al2O3) using as eluent 6:4 hexane-EtOAc (colorless solid, 0.45 g, 99% based on 4a). Mp 114-116 °C. IR (KBr): ν = 2973 (m), 1768 (s), 1686 (s), 1407 (m), 1359 (m), 1201 (m), 1107 (w), 701 (m) cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.36-7.22 (m, 5 H, Ph), 4.61 (s, 2 H, NCH2), 3.15 (s, 2 H, CH2C=O), 1.22 (s, 6 H, CMe2). 13C NMR (75 MHz, CDCl3): δ = 209.3, 168.2, 137.9, 128.7, 127.9, 127.6, 68.8, 42.9, 39.2, 23.3. MS (EI, 70 eV):
m/z (%) = 217 (44) [M+], 146 (20), 132 (13), 106 (55), 92 (8), 91 (100), 70 (16), 65 (16). Anal. Calcd for C13H15NO2 (217.26): C, 71.87; H, 6.96; N, 6.45. Found: C, 71.74; H, 6.95; N. 6.47.

13

In a typical experiment, the autoclave was charged in the presence of air with PdI2 (30.0 mg, 8.3·10-2 mmol), KI (138.0 mg, 0.83 mmol), and a solution of 3a (730.0 mg, 4.2 mmol) and morpholine (730.0 mg, 8.4 mmol) in MeOH (8.4 mL). While the mixture was stirred, the autoclave was charged with CO (16 atm) and air (4 atm), and then heated at 100 °C with stirring for 15 h. After cooling, the autoclave was degassed, and 1% HCl (15 mL) was slowly added to the crude reaction with stirring. After additional stirring at r.t. for 2 h, the hydrolyzed mixture was extracted several times with Et2O, and the collected organic layers were dried over Na2SO4. After filtration and removal of the solvent by rotary evaporation, tetramic acid 5a was purified as described in ref. 12 (0.50 g, 55% yield based on 3a).