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

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.

pyrrolidines - Michael additions - reductions - imines - combinatorial chemistry

References

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<A NAME="RG35003ST-10">10</A>

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.

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<A NAME="RG35003ST-13">13</A>

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.

<A NAME="RG35003ST-14">14</A>

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

<A NAME="RG35003ST-15">15</A>

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).

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