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

Bartolo Gabriele; Pierluigi Plastina; Giuseppe Salerno; Mirco Costa

doi:10.1055/s-2005-864819

LETTER

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

Bartolo Gabriele*^a, Pierluigi Plastina^b, Giuseppe Salerno^b, Mirco Costa^c
^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;

Abstract

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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

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References

<A NAME="RD36704ST-1">1</A> Gabriele B. Salerno G. Plastina P. Costa M. Crispini A. Adv. Synth. Catal. 2004, 346: 351

<A NAME="RD36704ST-2">2</A> Gabriele B. Salerno G. Veltri L. Costa M. J. Organomet. Chem. 2001, 622: 84

<A NAME="RD36704ST-3">3</A> 2-Ynylamines 3 were easily prepared starting from 2-yn-1-olacetates according to a literature procedure, see: Imada Y. Yuasa M. Nakamura I. Murahashi S. J. Org. Chem. 1994, 59: 2282

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.

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.

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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.

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).