Vitamin B₁₂ Catalyzed Radical Cyclizations of Arylalkenes

Abstract

The use of vitamin B₁₂ for synthetic organic transformations has been extensively studied. Herein, we report the intra­molecular cyclization reaction of a series of arylalkene substrates catalyzed by vitamin B₁₂. These reactions proceed in good yields in environmentally benign solvents and do not require the use of a ­toxic heavy metal catalyst. Variation of the reaction pH can predictably alter the product distribution.

Key words

vitamin B₁₂ - radical cyclization - arylalkenes

References and Notes

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14

Solvents used for cyclization reactions were deoxygenated under reduced pressure (10 min) and purged with N₂; this was repeated three times before storage under argon. When t-BuOH was used as a solvent, it was distilled over CaH₂. All cyclizations were conducted on a 0.1 mmol scale, and initiated in the dark before covering the flask with aluminum foil. Representative procedures are provided for a select set of substrates.
A flask was charged with 1d (20.3 mg, 0.116 mmol) and vitamin B₁₂ (12.8 mg, 0.009 mmol) and purged with Ar. Degassed t-BuOH (15 mL) was added, followed by a Ti(III) citrate solution, pH 6.0 (8 mL) prepared as previously described. [2] The purple solution was stirred in the dark for 24 h. The reaction was poured into H₂O (50 mL) and extracted with hexane (3 × 50 mL). The combined organic layers were washed with H₂O (2 × 75 mL), dried with MgSO₄, filtered and concentrated, yielding 15.9 mg of total product (1:14 mixture of 2d and 3d, 75%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.07 (s, 3 H), 1.41 (s, 3 H), 1.75 (s, 3 H), 3.12 (t, J = 7.9 Hz, 1 H), 4.01 (m, 2 H), 4.79 (m, 1 H), 4.95 (pentet, J = 1.5 Hz, 1 H), 5.73 (dd, J = 3.6, 1.3 Hz, 1 H), 6.19 (t, J = 2.9 Hz, 1 H), 6.53 (dd, J = 2.6, 1.3 Hz, 1 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 23.0 (CH₃), 23.8 (CH₃), 28.6 (CH₃), 41.4 (Cq), 48.7 (CH₂), 60.5 (CH), 96.7 (CH), 111.5 (CH), 113.1 (CH), 113.6 (CH₂), 143.0 (Cq). HRMS (EI): m/z calcd for C₁₂H₁₇N [M⁺]: 175.1361; found: 175.1360.
A flask was charged with 7b (29.4 mg, 0.090 mmol) and vitamin B₁₂ (12.4 mg, 0.009 mmol) and purged with Ar. Degassed MeCN (20 mL) was added followed by aqueous Ti(III) citrate pH 8.0 (7 mL). The purple solution was stirred in the dark for 23 h, then poured into H₂O (50 mL) and extracted with hexane (3 × 50 mL). The combined organic layers were washed with H₂O (2 × 75 mL), dried with MgSO₄, filtered and concentrated yielding 20.0 mg of product 8b (68%) as a colorless oil. Both diastereomers were separated by HPLC and the stereochemistry of the major isomer was determined using NOE after assignment of the protons by HMQC and COSY spectroscopy. ¹H NMR (500 MHz, CDCl₃, major diastereomer): δ = 1.47 (s, 3 H), 3.63 (m, 2 H), 3.77 (d, J = 8.8 Hz, 1 H), 3.87 (d, J = 7.7 Hz, 1 H), 3.98 (dt, J = 1.8, 7.4 Hz, 1 H), 4.22 (d, J = 8.8 Hz, 1 H), 6.84-6.90 (m, 3 H), 7.05-7.35 (m, 12 H). Minor diastereomer: δ = 1.57 (s, 3 H), 3.16 (d, J = 11.4 Hz, 1 H), 3.38 (m, 1 H), 3.52 (dd, J = 10.2, 9.7 Hz, 1 H), 3.85 (dd, J = 8.1, 8.3 Hz, 1 H), 3.91 (d, J = 8.6 Hz, 1 H), 4.21 (d, J = 8.7 Hz, 1 H), 7.05-7.35 (m, 15 H). ¹³C NMR (125.6 MHz, CDCl₃, major diastereomer): δ = 18.7 (CH₃), 47.9 (CH₂), 55.0 (CH), 77.0 (CH₂), 85.0 (CH₂), 125.7 (CH), 126.0 (CH), 126.7 (CH), 127.5 (CH), 128.0 (CH), 128.1 (CH), 128.9 (CH), 144.4 (Cq). HRMS (EI): m/z calcd for C₂₄H₂₄O [M⁺]: 328.1827; found: 328.1826
A flask was charged with 7d (18.8 mg, 0.093 mmol) and vitamin B₁₂ (13.2 mg, 0.01 mmol) and purged with Ar. Degassed MeCN (20 mL) was added, followed by aqueous Ti(III) citrate pH 6.0 (8 mL). The dark red solution was stirred in the dark for 24 h, and then the reaction was poured into H₂O (50 mL) and extracted with hexane (3 × 60 mL). The combined organic layers were washed with H₂O (2 × 75 mL), dried with MgSO₄, filtered and concentrated yielding 15.4 mg of product 9d (82%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.37 (s, 3 H), 1.48 (s, 3 H), 3.11 (t, J = 8.1 Hz, 1 H), 3.82 (d, J = 8.6 Hz, 1 H), 4.05 (t, J = 8.8 Hz, 1 H), 4.18 (d, J = 8.7 Hz, 1 H), 4.15 (t, J = 8.2 Hz, 1 H), 4.70 (s, 1 H), 4.89 (s, 1 H), 7.25-7.35 (m, 3 H), 7.48-7.50 (m, 2 H). ¹³C NMR (125.6 MHz, CDCl₃): δ = 19.8 (CH₃), 24.2 (CH₃), 57.5 (CH), 71.4 (CH₂), 82.7 (CH₂), 112.4 (CH₂), 126.5 (CH), 127.4 (CH), 128.1 (CH), 128.6 (CH), 146.5 (Cq). HRMS (EI): m/z calcd for C₁₄H₁₈O [M⁺]: 202.1358; found: 202.1357.