Addition of α-Aminonitriles to α,β-Unsaturated Carbonyl Compounds: A One-pot Synthesis of Polysubstituted Pyrrolidines

Abstract

The vinylogous addition of deprotonated N-alkyl-α-aminonitriles to α,β-unsaturated carbonyl compounds yields cyclic intermediates which can be reduced to form polysubstituted pyr­rolidines in a one-pot reaction sequence. Since the cyano substituent is lost in the reduction step, the aminonitriles serve as easily accessible (N-alkylamino)-substituted carbanion equivalents.

pyrrolidines - α-aminonitriles - Michael additions - reductions - heterocycles

References

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10

According to Treibs and Derra, the von Miller-Plöchl-synthesis gives good results only for α,N-diaryl-α-aminonitriles; see ref. [8]

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14

Under identical conditions, N-benzylaminoacetonitrile does not react with crotonaldehyde. Presumably, the basicity of KHMDS is insufficient in this case.

15

General Procedure for the Preparation of Pyrrolidines 5a-h: To a solution of the α-aminonitrile (2.8 mmol) in THF (27 mL) was added a freshly prepared solution of KHMDS (3.1 mmol, 1.1 equiv) in THF (5 mL) at -78 °C under argon. After 3 min, a solution of the α,β-unsaturated carbonyl compound (3.1 mmol, 1.1 equiv) in THF (5 mL) was added and the mixture was stirred for 30 min. A mixture of EtOH (167 mmol, 60 equiv) and HOAc (17 mmol, 6 equiv) was added and the mixture was warmed to 0 °C. After addition of NaBH₃CN (8.5 mmol, 3 equiv), the mixture was stirred at r.t. overnight. The reaction mixture was partitioned between 1 N NaOH and EtOAc, the organic layer was separated and washed with a mixture of brine and 1 N NaOH (9:1). The organic layer was 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 evaporation of the solvent in vacuo gave a crude product, which was purified by column chromatography or preparative TLC. Note: Some of the products were too lipophilic for an extraction with aq HCl. They were directly purified by chromatographic methods.

16

Spectroscopic Data of Compound trans -5d: ¹H NMR (400 MHz, CDCl₃): δ = 7.82-7.86 (m, 3 H), 7.77 (s, br, 1 H,
H-1′), 7.54 (dd, 1 H, J = 8.6 Hz, 1.6 Hz, H-3′), 7.42-7.49 (m, 2 H), 3.32 (d-pseudo-t, 1 H, J _t = 9 Hz, J _d = 2.9 Hz, H-5a), 2.75 (d, 1 H, J = 8.6 Hz, H-2), 2.42 (pseudo-q, br, 1 H, J = 9 Hz, H-5b), 2.17-2.35 (m, 2 H, H-3, H-4a), 2.18 (s, 3 H, NMe), 1.45-1.54 (m, 1 H, H-4b), 0.99 (d, 3 H, J = 6.7 Hz, 3-CH₃). Irradiation at δ = 2.75 ppm (H-2) enhances the signals at δ = 7.77 ppm (H-1′, 3%), 7.54 ppm (H-3′, 1%), 2.42 ppm (H-5b, 1%), 2.18 ppm (NMe, 3%) and 0.99 ppm (3-CH₃, 2%). ¹³C NMR (100.6 MHz, CDCl₃): δ = 139.18 (C-2′), 133.39, 133.09 (C-4a′,C-8a′), 128.16, 127.67, 127.63, 126.99, 125.85, 125.69, 125.49 (C-1′, C-3′-C-8′), 80.10 (C-2), 55.65 (C-5), 42.47 (C-3), 40.70 (NMe), 31.24 (C-4), 18.23 (3-CH₃). ESI-MS: m/z = 226.2 [M + H]⁺ (100%). Spectroscopic Data of Compound cis -5d: ¹H NMR (400 MHz, CDCl₃): δ = 7.79-7.86 (m, 3 H), 7.75 (s, 1 H, H-1′), 7.40-7.50 (m, 3 H), 3.47 (d, 1 H, J = 8.2 Hz, H-2), 3.29 (ddd, 1 H, J = 2.2 Hz, 7.8 Hz, 9.4 Hz, H-5a), 2.50 (m, 1 H, H-3), 2.36 (ddd, 1 H, J = 1.4 Hz, 7.8 Hz, 9.4 Hz, H-5b), 2.30 (s, 3 H, NMe), 2.11-2.20 (m, 1 H, H-4a), 1.52-1.63 (m, 1 H, H-4b), 0.60 (d, 3 H, J = 7.0 Hz, 3-CH₃). Irradiation at δ = 3.47 ppm (H-2) enhances the signals at δ = 7.75 ppm (H-1′, 2%), 7.41 ppm (H-3′, 2%), 2.50 (H-3, 3%), 2.36 (H-5b, 1%) and 2.30 (NMe, 2%). ¹³C NMR (100.6 MHz, CDCl₃): δ = 138.20 (C-2′), 133.36, 132.69 (C-4a′, C-8a′), 127.75, 127.58, 127.39, 127.08, 126.79, 125.75, 125.30 (C-1′, C-3′-C-8′), 74.74 (C-2), 56.26 (C-5), 41.29 (NMe), 37.43 (C-3), 32.67 (C-4), 18.77 (3-CH₃). ESI-MS: m/z = 226.2 [M + H]⁺ (100%).

The assignment of the relative stereochemistry of the products 5 was either based on X-ray crystallography, NOE measurements or on comparison of ¹H chemical shifts with literature data:

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