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Synlett 2004(5): 0787-0790  
DOI: 10.1055/s-2004-817774
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Short Synthesis of Polysubstituted Pyrrolidines via α-(Alkylidene­amino)nitriles

Nino Meyer, Till Opatz*
Insitut für Organische Chemie, Johannes Gutenberg-Universität Mainz, 55099 Mainz, Germany
Fax: +49(6131)3924786; e-Mail: opatz@uni-mainz.de;
Further Information

Publication History

Received 9 December 2003
Publication Date:
10 February 2004 (online)

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Abstract

α-(Alkylideneamino)nitriles can be deprotonated under mild conditions. Their conjugated anions react with enones in a 1,4-addition to yield δ-keto-α-(alkylideneamino)nitriles which in turn can be reduced to form pyrrolidines in a one-pot reaction sequence.

Key words

pyrrolidines - Michael additions - reductions - imines - combinatorial chemistry

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10

General Procedure for the Preparation of α-(Alkylideneamino)nitriles 3a-c: To a solution of the aminonitrile (10 mmol) in dry CH2Cl2 (20 mL) were added MgSO4 (1.1 equiv) and the aldehyde (1.1 equiv). The suspension was stirred overnight. The MgSO4 was filtered off and the organic phase was partitioned between a sat. NaHCO3 solution and CH2Cl2. The organic layer was dried over Na2SO4 and the solvent was evaporated in vacuo. Recrystallization yielded the pure imines. In the case of products 3a and 3b, aminoacetonitrile sulfate was used and 1 equiv of Et3N was added to the reaction mixture.

13

General Procedure for the Preparation of Pyrrolidines 8a-g: To a solution of the α-(alkylideneamino)nitrile (1.45 mmol) in THF (5 mL) was added a solution of DBU (1.59 mmol, 1.1 equiv) in THF (2 mL) under argon at r.t. After addition of a solution of methyl vinyl ketone (1.59 mmol, 1.1 equiv) in THF (3 mL), the mixture was stirred for 90 min. The reaction was stopped by addition of a mixture of EtOH (87 mmol, 60 equiv) and HOAc (11.6 mmol, 8 equiv). After NaBH3CN (5.8 mmol, 4 equiv) was added, the mixture was stirred at r.t. overnight. The reaction mixture was washed twice with 1 N NaOH and the combined aqueous phases were reextracted with EtOAc. The combined organic layers were extracted three times with 1 N HCl and the combined aqueous phases were made alkaline by addition of NaOH. Extraction with CH2Cl2, drying over Na2SO4 and evapora-tion of the solvent in vacuo gave a crude product, which was further purified by column chromatography, preparative TLC or HPLC if necessary. Note: Compounds 8f and 8g were too lipophilic for an efficient extraction with 1 N HCl. They were directly purified by chromatographic methods.

14

Under identical conditions, compounds 3a and 3b could not be reacted cleanly with α,β-unsaturated aldehydes.

15

Spectroscopic Data of Compound cis -8e: 1H NMR (400 MHz, CDCl3): δ = 7.28-7.21 (m, 2 H, Ph), 7.19-7.10 (m, 3 H, Ph), 6.92 (d, 1 H, J 2 ′ ,6 ′ = 1.8 Hz, H-2′), 6.90 (dd, 1 H, J 5 ′ ,6 ′ = 8.1 Hz, J 2 ′ ,6 ′ = 1.8 Hz, H-6′), 6.83 (d, 1 H, J 5 ′ ,6 ′ = 8.1 Hz, H-5′), 3.90, 3.88 (2 s, 6 H, OCH3), 3.81 [d, 1 H, J = 14.1 Hz, CH2C6H3 (OMe)2], 3.75 [d, 1 H, J = 14.1 Hz, CH2C6H3 (OMe)2], 2.93-2.81 (m, 2 H, CH2Ph, H-2), 2.74-2.60 (m, 1 H, H-5), 2.38 (dd, 1 H, J gem = 12.4 Hz, J vic = 9.2 Hz, CH2Ph), 1.81-1.70 (m, 1 H, H-4a), 1.67-1.44 (m, 2 H, H-3a, H-3b), 1.42-1.30 (m, 1 H, H-4b), 1.07 (d, 3 H, J = 6.0 Hz, CH3). Irradiation (transient NOE) at δ = 2.68 ppm (H-5) enhances the signals at δ = 6.90 ppm (H-6′, 0.8%), 6.83 ppm (H-5′, 0.2%), 3.81 ppm [CH2C6H3 (OMe)2, 1.1%], 3.75 ppm [CH2C6H3 (OMe)2, 1.0%], 2.83 ppm (H-2, 0.6%), 1.72 ppm (H-4a, 2.2%), 1.55 ppm (H-3, 0.8%), 1.35 ppm (H-4b, 0.6%), 1.07 ppm (CH3, 1.1%). 13C NMR (100.6 MHz, CDCl3): δ = 148.60, 147.87 (C-3′, C-4′), 140.30 (C-1 Ph), 137.28 (C-1′), 129.18, 128.08, 125.77 (Ph), 121.14 (C-6′), 112.56 (C-2′), 110.65 (C-5′), 66.11 (C-2), 60.09 (C-5), 56.28 [CH2C6H3 (OMe)2], 55.85 (OCH3), 42.46 (CH2Ph), 31.55 (C-4), 28.80 (C-3), 20.80 (CH3).
Spectroscopic Data of Compound trans -8e: 1H NMR (400 MHz, CDCl3): δ = 7.26-7.20 (m, 2 H, Ph), 7.18-7.12 (m, 1 H, Ph), 7.05 (d, 2 H, J = 7 Hz, H-2, H-6 Ph), 6.98 (br s, 1 H, H-2′), 6.92 (dd, 1 H, J 5 ′ ,6 ′ = 8.1 Hz, J 2 ′ ,6 ′= 1.3 Hz, H-6′), 6.83 (d, 1 H, J 5 ′ ,6 ′ = 8.1 Hz, H-5′), 3.92 [d, 1 H, J = 13.6 Hz, CH2-C6H3 (OMe)2], 3.90, 3.89 (2 s, 6 H, OCH3), 3.62 [d, 1 H, J = 13.6 Hz, CH2C6H3(OMe)2], 3.17-3.05 (m, 2 H, H-2, H-5), 2.96 (dd, 1 H, J gem = 12.9 Hz, J vic = 3.5 Hz, CH2Ph), 2.36 (dd, 1 H, Jgem = 12.9 Hz, J = 10.0 Hz, CH2Ph), 2.05-1.92 (m, 1 H, H-4a), 1.83-1.70 (m, 1 H, H-3a), 1.56-1.46 (m, 1 H, H-3b), 1.44-1.33 (m, 1 H, H-4b), 0.99 (d, 3 H, J = 6.2 Hz, CH3). 13C NMR (100 MHz, CDCl3): δ = 148.87, 147.69 (C-3′, C-4′); 140.49 (C-1 Benzyl), 136.52 (C-1′), 129.26, 128.12, 125.67 (Benzyl); 120.35 (C-6′); 111.72 (C-2′); 110.71 (C-5′); 61.91 (C-2); 55.89 (OCH3); 55.40 (C-5); 51.71 [CH2C6H3(OMe)2]; 37.63 (CH2Ph); 30.77 (C-4); 27.55 (C-3); 16.76 (CH3).