Nef Reaction of Nitropyrrolidines: Novel Synthesis of Hydroxypyrrolidine Derivatives

Abstract

A general synthetic route to hydroxypyrrolidine derivatives using the first Nef reaction of nitropyrrolidines with chromium(II) chloride as a key step is presented.

Key words

cycloadditions - heterocycles - Nef reaction - pyrrol­idines - reductions

References and Notes

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12

General Procedure for the Preparation of Compounds 8: The appropriate pyrrolidine derivative 7 (10 mmol) was dissolved in anhyd CH₂Cl₂ (30 mL) and pyridine (1 mL) was added. The solution was cooled to 0 °C and then methyl chloroformate (1.13 g, 0.93 mL, 12 mmol) was added. The orange mixture was stirred for another 16 h, allowing the temperature to rise to r.t. The reaction mixture was extracted with dilute HCl and aq NaHCO₃, dried over MgSO₄, and the solvent was evaporated to yield the product which was purified by recrystallization from Et₂O.

14

General Procedure for Nef Reaction of 8a-h: Potassium dichromate dihydrate (2.0 g) was dissolved in 6 M HCl acid (30 mL) and zinc powder (3.3 g) was added under an argon atmosphere. After the complete dissolution of zinc the formed chromium(II) chloride solution was transferred via syringe to the refluxing solution of nitro compound (1 mmol) in MeOH (30 mL) under argon. After 1 h reflux, the reaction mixture was cooled and evaporated to half of its volume. It was extracted with CH₂Cl₂. The organic phase was washed with aq NaHCO₃ solution, brine, dried over MgSO₄, then evaporated to yield a colorless oil, which was further purified by column chromatography.
Selected data for representative examples are as follows:
2-Ethoxycarbonyl-1-methoxycarbonyl-5-(4-methoxy-phenyl)pyrrolidine-4-one (9b): pale yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.49 (dd, J = 8.9 Hz, 2 H, 2′-Ar, 6′-H), 6.95 (dd, J = 8.9 Hz, 2 H, 2′-Ar, 6′-H), 4.95 (br s, 1 H, H-5), 4.88 (dd, J = 3.5, 5.7 Hz, 1 H, H-2), 4.25 (q, J = 7.1 Hz, 2 H, OCH₂), 3.83 (s, 3 H, OMe), 3.69 (br s, 3 H, OMe), 3.00 (br dd, J = 3.5, 18.0 Hz, 1 H, H-3), 2.77 (dd, J = 5.7, 18.0 Hz, 1 H, H-3), 1.35 (t, 3 H, Me). ¹³C NMR (75 MHz, CDCl₃): δ = 206.3 (q), 171.9 (q), 159.4 (q), 157.0 (q), 126.7 (2 × CH), 114.2 (2 × CH), 66.0 (CH), 61.6 (CH₂), 55.5 (CH), 55.2 (Me), 52.8 (Me), 38.6 (CH₂), 14.2 (Me).
2-Ethoxycarbonyl-1-methoxycarbonyl-3-(4-methoxy-phenyl)-5-phenylpyrrolidine-4-one (9f): ¹H NMR (300 MHz, CDCl₃): δ = 7.67 (d, J = 7.5 Hz, 2 H, 2′-Ph, 6′-H), 7.38 (t, J = 7.5 Hz, 2 H, 3′-Ph, 5′-H), 7.30 (t, 1 H, 4′-Ph), 7.06 (d, J = 8.6 Hz, 2 H, 3′-Ar, 5′-H), 6.86 (d, J = 8.6 Hz, 2 H, 2′-Ar, 6′-H), 5.11 (br s, 1 H, H-5), 4.72 (d, J = 8.6 Hz, 1 H, H-3), 4.25 (q, J = 7.1 Hz, 2 H, OCH₂), 3.94 (d, J = 8.6 Hz, 1 H, H-2), 3.76 (s, 3 H, ArOMe), 3.62 (br s, 3 H, CO₂Me), 1.24 (t, 3 H, Me). ¹³C NMR (75 MHz, CDCl₃): δ = 204.9 (q), 171.2 (q), 159.4 (q), 136.1 (q), 131.1 (q), 129.4 (2 × CH), 128.7 (2 × CH), 128.3 (CH), 126.0 (2 × CH), 125.0 (q), 114.4 (2 × CH), 77.2 (CH), 66.5 (CH), 63.0 (CH), 61.7 (CH₂), 55.2 (Me), 53.3 (Me), 14.1 (Me).

15

General Procedure for Reduction of 9a-h: LiAlH₄ (0.4 g, 10 mmol) was suspended in anhyd THF (5 mL) under an argon atmosphere. A solution of ketopyrrolidine 9 (2 mmol) in anhyd THF (5 mL) was added via syringe. The reaction mixture was heated under reflux for 2 h and then cooled. EtOAc (2 mL) and sat. aq NH₄Cl solution (4 mL) were added. The precipitate was filtered off and washed with Et₂O. The organic layer was washed with brine, dried over MgSO₄ and evaporated in vacuo to yield a waxy solid. In the cases when a mixture of two diastereomer was obtained, the mixture was separated by column chromatography.
Selected data for representative examples are as follows:
4-Hydroxy-2-hydroxymethyl-5-(4-methoxyphenyl)-1-methylpyrrolidine (11b): ¹H NMR (500 MHz, CDCl₃): δ = 7.30 (d, J = 8.6 Hz, 2 H, 2′-Ar, 6′-H), 6.90 (d, J = 8.6 Hz, 2 H, 3′-Ar, 5′-H), 4.02 (t, J = 4.1 Hz, 1 H, H-4), 3.80 (s, 3 H, OMe), 3.76 (dd, J = 2.8, 10.8 Hz, 1 H, OCH₂), 3.50 (d, J = 4.1 Hz, 1 H, H-5), 3.47 (dd, J = 1.8, 10.8 Hz, 1 H, OCH₂), 2.75 (dddd, J = 0.9, 1.8, 2.8, 6.1 Hz, 1 H, H-2), 2.38 (ddd, J = 4.2, 6.1, 14.2 Hz, 1 H, H-3), 1.91 (ddd, J = 0.9, 4.6, 14.2 Hz, 1 H, H-3), 2.21 (s, 3 H, NMe). ¹³C NMR (125 MHz, CDCl₃): δ = 159.0(q), 129.4 (2 × CH), 113.7 (2 × CH), 76.2 (CH), 72.9 (CH), 64.8 (CH), 61.5 (CH₂), 55.1 (Me), 38.1 (Me), 35.6 (CH₂). IR (neat): 3359, 2943, 2787, 1612, 1513, 1443, 1246, 1173, 1034 cm^-1.
4-Hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)-1-methyl-5-phenylpyrrolidine (Major Isomer) (10f): ¹H NMR (500 MHz, CDCl₃): δ = 7.39 (d, J = 7.8 Hz, 2 H, 2′-Ph, 6′-H), 7.35 (t, J = 7.8 Hz, 2 H, 3′-Ph, 5′-H), 7.29 (t, J = 7.8 Hz, 1 H, 4′-Ph), 7.26 (d, J = 8.5 Hz, 2 H, 2′-Ar, 6′-H), 6.87 (d, J = 8.5 Hz, 2 H, 3′-Ar, 5′-H), 4.10 (dd, J = 3.3, 5.8 Hz, 1 H, H-4), 3.83 (d, J = 5.8 Hz, 1 H, H-5), 3.78 (s, 3 H, OMe), 3.77 (dd, J = 2.8, 11.3 Hz, 1 H, OCH₂), 3.49 (dd, J = 1.3, 11.3 Hz, 1 H, OCH₂), 3.29 (dd, J = 3.3, 7.8 Hz, 1 H, H-3), 2.66 (ddd, J = 1.3, 2.7, 7.8 Hz, 1 H, H-2), 2.26 (s, 3 H, NMe). ¹³C NMR (125 MHz, CDCl₃): δ = 158.3 (q), 137.2 (q), 133.7 (q), 129.0 (2 × CH), 128.8 (2 × CH), 128.4 (2 × CH), 114.2 (2 × CH), 79.5 (CH), 75.8 (CH), 73.0 (CH), 58.8 (CH), 55.2 (Me), 53.3 (Me), 38.5 (CH₂). IR (KBr): 3425, 2956, 2914, 2802, 1612, 1513, 1470, 1450, 1401, 1341, 1302, 1261, 1246, 1064, 1030 cm^-1.
Minor Isomer (11f): ¹H NMR (500 MHz, CDCl₃): δ = 7.45 (t, J = 7.6 Hz, 2 H, 3′-Ph, 5′-H), 7.36 (m, 4 H, Ar), 7.29 (t, 1 H, 4′-Ph), 6.84 (d, J = 8.8 Hz, 2 H, 3′-Ar, 5′-H), 4.19 (t, J = 3.4 Hz, 1 H, H-4), 3.91 (d, J = 3.3 Hz, 1 H, H-5), 3.77 (s, 3 H, OMe), 3.71 (dd, J = 3.9, 10.3 Hz, 1 H, H-3), 3.58 (dd, J = 3.7, 11.4 Hz, 1 H, OCH₂), 3.39 (dd, J = 1.8, 11.4 Hz, 1 H, OCH₂), 3.22 (ddd, J = 1.8, 3.7, 10.3 Hz, 1 H, H-2), 2.41 (s, 3 H, NMe). ¹³C NMR (125 MHz, CDCl₃): δ = 158.9 (q), 137.9 (q), 136.5 (q), 130.3 (2 × CH), 128.4 (2 × CH), 128.3 (2 × CH), 113.6 (2 × CH), 77.7 (CH), 76.0 (CH), 70.0 (CH), 57.1 (CH), 55.1 (Me), 54.4 (Me), 38.3 (CH₂). IR (neat): 3428, 2959, 2810, 1615, 1517, 1472, 1450, 1408, 1342, 1249, 1060 cm^-1.