One-Pot Michael Addition/Radical Cyclization Reaction of N-Acryloyl Indoles

Abstract

From N-acryloyl indoles, ten examples of 1,2-annulated ­indole products were generated in a one-pot procedure via a Michael addition and radical cyclization mediated by Mn(OAc)₃.

Key words

indoles - radical reaction - heterocycles - alkaloids - Michael addition

• References and Notes

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• 12 General Experimental Procedure: One-Pot Michael Addition, Radical Cyclization (15a–j, 16) To an argon-flushed round-bottom flask was added half of the total volume of THF (0.15 M) required followed by NaH (60% dispersed in mineral oil, 1.5 equiv). The 1,3-dicarbonyl species (1.5 equiv) was added dropwise via syringe with stirring under argon. The resultant mixture was stirred for 15 min at which point the desired indole (1 equiv), dissolved in the other half-volume of THF, was added via syringe or cannula. The Michael addition was monitored by TLC. Once TLC confirmed complete consumption of starting indole, Mn(OAc)₃(7 equiv) was added to the round-bottom flask followed by AcOH (0.12 M). The flask was equipped with a reflux condenser and put back under an argon atmosphere. The reaction was brought to 110 °C and refluxed until the mixture changed color from a dark brown to now containing obvious white solid in a yellow/orange solution. At this point, TLC analysis always indicated complete consumption of starting materials. The crude reaction mixture was allowed to cool to r.t. and then diluted with a large excess of EtOAc. The solution was vacuum filtered through a thick pad of Celite and then flushed with even more EtOAc. The solvent was removed under reduced pressure with added toluene to aid in the removal of AcOH. The obtained dried crude product was purified with flash column chromatography (EtOAc in hexanes). The desired fractions of the column were collected to a separatory funnel and washed twice with 1 M NaOH solution and then followed with a brine wash. The organic layer was collected, dried with MgSO₄, and concentrated in vacuo to yield product. Product 15a Following the general experimental procedure, 15a was synthesized from acyl-indole 14a (0.30 g, 1.51 mmol), NaH (0.091g, 2.27 mmol), dimethyl malonate (0.30 g, 2.27 mmol, 0.26 mL) in 10 mL of THF then Mn(OAc)₃ (2.80 g, 10.6 mmol) in AcOH (13 mL). Compound 15a was isolated as a yellow solid (0.33 g, 65%); R_f = 0.40 (20% EtOAc in hexanes); mp 126–129 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.50 (d, J = 8.2 Hz, 1 H), 7.50 (d,   = 7.7 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 1 H), 3.83 (s, 3 H), 3.79 (s, 3 H), 2.90 (ddq, J = 12.6, 6.5, 6.3 Hz, 1 H), 2.84 (dd, J = 13.0, 4.4 Hz, 1 H), 2.39 (t, J = 13.0 Hz, 1 H), 2.16 (s, 3 H), 1.42 (d, J = 6.8 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 170.9, 170.4, 169.0, 134.5, 131.1, 128.2, 125.7, 124.0, 118.6, 117.9, 116.8, 55.7, 53.6, 37.5, 35.4, 15.7, 9.2 IR 3027, 2954, 1785, 1702, 1456, 1386, 1385, 1308, 1245, 751. HRMS: m/z calcd for C₁₈H₁₉NO₅: 329.1263; found [M⁺]: 329.12682. Product 15d Following the general experimental procedure, 15d was synthesized from acryloyl indole 14d (0.25 g, 1.35 mmol), dimethyl malonate (0.27 g, 2.02 mmol, 0.23 mL), NaH (0.081 g, 2.02 mmol) in 9 mL of THF. Following completion of the Michael addition was then added Mn(OAc)₃ (2.53 g, 9.40 mmol) and AcOH (11 mL). Compound 15d was isolated as a pale orange solid (0.18 g, 45%); R_f = 0.27 (20% EtOAc in hexanes); mp 109–113 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.48 (d, J = 8.2 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.39–7.31 (m, 1 H), 7.28 (m, 1 H), 6.68 (s, 1 H), 3.89 (s, 3 H), 3.77 (s, 3 H), 2.80 (ddd, J = 13.3, 6.7, 4.5 Hz, 1 H), 2.72 (dd, J = 13.6, 4.5 Hz, 1 H), 2.51 (t, J = 13.5 Hz, 1 H), 1.43 (d, J = 6.8 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.0, 169.6, 168.8, 135.4, 133.0, 129.3, 125.5, 124.3, 120.8, 116.8, 109.2, 55.7, 53.7, 42.0, 36.4, 35.3, 15.9. IR: 2956, 2923, 2852, 1746, 1708, 1437, 1300, 1144, 1063, 836 cm^–1. HRMS: m/z calcd for C₁₇H₁₇NO₅: 315.11067; found [M⁺]: 315.11120.
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