Regio- and Diastereoselective Cycloaddition of Azomethine Ylides with Benzylidenemalononitrile: Assembly of a New Set of Multisubstituted 4,4-Dicyanopyrrolidine-2-carboxylate and Nornicotine Scaffolds

Abstract

Regio- and diastereoselective 1,3-dipolar cycloaddition reaction of azomethine ylides derived from N-benzylideneiminoglycinates in the presence of catalytic quantities of silver salts with benzylidenemalononitriles (Knöevenagel adducts) is reported. The reaction of azomethine ylides with benzylidenemalononitriles gave a new class of 3,5-aryl/heteroaryl-substituted 4,4-dicyanopyrrolidine-2-carboxylate (proline) and nornicotine scaffolds having three stereocenters, with very good diastereoselectivity. The stereochemistry of representative major diastereomers was confirmed by single crystal X-ray structure analyses.

Key words

1,3-dipolar cycloaddition - pyrrolidine - regioselectivity - stereoselective synthesis - ylides

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• 12 General Procedure: Under a nitrogen atmosphere, AgOAc (10 mol%) in anhydrous CH₂Cl₂ (1 mL) was stirred for 30 min. To this mixture were sequentially added a solution of N-benzylideneiminoglycinates (0.5 mmol) and benzylidenemalononitrile (0.5 mmol) in CH₂Cl₂ (4 mL), and Et₃N (40 mol%), and the mixture was stirred for 12 h at r.t. in the absence of light. The reaction mixture was filtered through a Celite pad, the filtrate was evaporated, and the residue was purified by column chromatography. In all the cases, attempts were made to separate the major and minor isomers. The major isomer was obtained in pure form in the majority of the reactions, but it did not prove possible to isolate the minor isomers in pure form. In some cases, it was not possible to separate the major and minor isomers. Analytical Data for 7b: By following the general procedure, 7b was obtained after purification by silica column chromatography (EtOAc–hexane, 30:70). White solid; mp 170–172 °C. FT-IR (KBr): 3343, 2902, 1737, 1247 cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 7.57 (d, J = 8.1 Hz, 2 H), 7.46 (d, J = 8.1 Hz, 2 H), 7.31–7.27 (m, 4 H), 4.92 (s, 1 H), 4.51 (d, J = 8.1 Hz, 1 H), 4.15 (d, J = 8.1 Hz, 1 H), 3.76 (s, 3 H), 2.97 (br. s, 1 H), 2.41 (s, 6 H). ¹³C NMR (CDCl₃, 100 MHz): δ = 173.4, 140.1, 139.6, 130.6, 130.0, 129.7, 129.6, 128.3, 127.2, 113.8, 111.7, 70.4, 61.0, 58.1, 53.1, 50.9, 21.3, 21.2. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₂N₃O₂: 360.1712; found: 360.1716. Analytical Data for 7c: By following the general procedure described above, 7c was obtained after purification by silica column chromatography (EtOAc–hexane, 30:70). White solid; mp 99–101 °C. FTIR (KBr): 3345, 2983, 1731, 1218 cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 7.58 (d, J = 8.1 Hz, 2 H), 7.46 (d, J = 8.1 Hz, 2 H), 7.30–7.27 (m, 4 H), 4.93 (s, 1 H), 4.47 (d, J = 8.1 Hz, 1 H), 4.26–4.16 (m, 2 H), 4.13 (d, J = 8.1 Hz, 1 H), 2.96 (br. s, 1 H), 2.41 (s, 6 H), 1.21 (t, J = 7.1 Hz, 3 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 172.8, 140.0, 139.5, 130.7, 129.9, 129.8, 129.6, 128.3, 127.2, 113.9, 111.7, 70.4, 62.2, 61.2, 58.2, 50.9, 21.3, 21.3, 14.1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₄N₃O₂: 374.1869; found: 374.1873. The cycloaddition reaction of azomethine ylides with 10a,b gave single isomers 11a,b and 12a,b. At this stage, it was not possible to assign the stereochemistry of the newly formed C3-center in the products 11a,b and 12a,b. The diastereomeric ratios given for the products 11a,b and 12a,b are based on their respective starting materials 10a,b obtained from 7a,c.