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Synlett 2007(10): 1557-1560  
DOI: 10.1055/s-2007-982553
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 4-Substituted 1,5-Dihydropyrrol-2-ones and 5,6-Dihydro-1H-pyridin-2-ones by Negishi Cross-Coupling Reactions: Short Access to the Antidepressant (±)-Rolipram

Dominik Albrecht, Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax: +49(89)28913315; e-Mail: thorsten.bach@ch.tum.de;
Further Information

Publication History

Received 18 April 2007
Publication Date:
06 June 2007 (online)

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Abstract

A straightforward access to the title compounds was ­established by Pd-catalyzed Negishi cross-coupling reactions of the readily available bromides 3 and 6 with various functionalized zinc reagents (71-97% yield).

Key words

catalysis - cross-coupling - heterocycles - lactams - palladium - zinc

    References and Notes

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7

Typical Procedure for the Bromide Formation with Oxalyl Bromide To a solution of DMF (6.4 mL, 82.3 mmol) in dry CH2Cl2 (100 mL) oxalyl bromide (6.8 mL, 73.4 mmol) was added slowly at 0 °C. The reaction mixture was stirred at this temperature until gas formation ceased. Then, 1-tert-butyl-piperidine-2,4-dione (8, 5.24 g, 31.0 mmol) dissolved in dry CH2Cl2 (50 mL) was added to the solution at 0 °C. The reaction mixture was stirred for 1 h at 0 °C and for 1 h at r.t. After neutralization with sat. aq NaHCO3 solution, H2O (20 mL) and CH2Cl2 (20 mL) were added. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The organic layers were combined, washed with sat. aq NaCl solution (20 mL) and dried over MgSO4. After filtration the solvent was evaporated under reduced pressure. After purification by flash chromatography (pentane-EtOAc, 9:1) 4-bromo-1-tert-butyl-5,6-dihydro-1H-pyridin-2-one (4, 5.98 g, 25.9 mmol, 84%) was obtained as colorless liquid. R f = 0.25 (cyclohexane-EtOAc, 9:1). IR (film): νmax = 2974, 2868, 1652, 1625, 1461, 1411, 1364, 1352, 1319, 1258, 1242 cm-1. 1H NMR (360 MHz, CDCl3): δ = 1.40 (s, 9 H), 2.68 (dt, 3 J = 6.8 Hz, 4 J = 1.4 Hz, 2 H), 3.44 (t, 3 J = 6.8 Hz, 2 H), 6.17 (t, 4 J = 1.4 Hz, 1 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 28.6 (q), 35.6 (t), 42.2 (t), 57.0 (s), 129.5 (d), 135.7 (q), 164.3 (s) ppm. HMRS (EI): m/z calcd for C8H11BrNO [M - CH3]+: 216.0024; found: 216.0019. Anal. Calcd for C9H14BrNO: C, 46.57; H, 6.08; N, 6.03. Found: C, 46.53; H, 6.07; N, 6.12.

11

Representative Cross-Coupling Procedure To a solution of Pd2(dba)3 (20 mg, 22.7 µmol) and RuPhos (40 mg, 90.8 µmol) in dry dimethylacetamide (2 mL) 4-bromo-1-tert-butyl-5,6-dihydro-1H-pyridin-2-one (4, 105 mg, 0.454 mmol) was added at r.t. After stirring for 10 min a solution of the organozinc reagent (0.903 mmol) prepared according to procedure A was added at once. After the reaction mixture was stirred at r.t. for 14 h the solvent was removed under reduced pressure. Purification by flash chromatography (pentane-EtOAc, 19:1) yielded 4-butyl-1-tert-butyl-5,6-dihydro-1H-pyridin-2-one (9a, 92.0 mg, 0.441 mmol, 97%) as a colorless liquid. R f = 0.18 (cyclohexane-EtOAc, 9:1). 1H NMR (360 MHz, CDCl3): δ = 0.85 (t, 3 J = 7.2 Hz, 3 H), 1.44-1.21 (m, 13 H), 2.07 (t, 3 J = 7.5 Hz, 2 H), 2.13 (t, 3 J = 6.6 Hz, 2 H), 3.31 (t, 3 J = 6.6 Hz, 2 H), 5.55 (s, 1 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 13.8 (q), 22.3 (t), 28.7 (q), 28.8 (t), 29.2 (t), 35.5 (t), 41.8 (t), 56.3 (s), 122.4 (d), 153.3 (s), 167.1 (s) ppm. HMRS (EI): m/z calcd for C13H23NO: 209.1780; found: 209.1782. Anal. Calcd for C13H23NO: C, 74.59; H, 11.07; N, 6.69. Found: C, 74.22; H, 11.30; N, 6.55.

22

Representative Deprotection Procedure 4-(3-Cyclopentyloxy-4-methoxy-phenyl)-2-oxo-2,5-dihydro-pyrrole-1carboxylic acid tert-butyl ester (11i, 36 mg, 96.4 µmol) was dissolved in CH2Cl2 (2 mL) at r.t. and TFA (37 µl, 482 µmol) was added. After the reaction mixture was stirred at r.t. for 30 min the solvent and TFA were removed under reduced pressure. Purification by flash chromatography (EtOAc-MeOH, 9:1) yielded 4-(3-cyclopentyloxy-4-methoxy-phenyl)-1,5-dihydro-pyrrol-2-one (25.0 mg, 91.5 µmol, 95%) as colorless crystals. R f = 0.55 (EtOAc-MeOH, 9:1); mp 203-205 °C. 1H NMR (360 MHz, CDCl3): δ = 1.60-1.63 (m, 2 H), 1.81-1.95 (m, 6 H), 3.87 (s, 3 H), 4.37 (s, 2 H), 4.76-4.80 (m, 1 H), 6.29 (s, 1 H), 6.85 (d, 3 J = 8.4 Hz, 1 H), 7.01-7.04 (m, 2 H), 7.14 (s, br, 1 H) ppm. 13C NMR (90.6 MHz, CDCl3): δ = 24.2 (t), 32.9 (t), 48.5 (t), 56.2 (q), 81.0 (d), 111.9 (d), 112.8 (d), 118.2 (d), 119.2 (d), 124.9 (s), 148.1 (s), 152.3 (s), 157.9 (s), 175.8 (s) ppm. HMRS (EI): m/z calcd for C16H19NO3: 273.1365; found: 273.1361.