Diastereoselective Synthesis of Functionalized Indolines Using in situ Generated Allyl Boronic Species

Abstract

A new three-component coupling protocol for preparation of functionalized indolines, with a high degree of diastereoselectivity, has been developed. The protocol is based on the in situ homologation of vinyl boronic acids to allylboronic acids, using TMSCHN₂ as carbon source, and subsequent coupling reaction with indoles to give 2-substituted indolines. The scope of the method was exemplified in several examples.

Key words

allyl boronic species - indolines - vinyl boronic acids - diastereoselective - multicomponent reaction

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• 14a General Procedure for Homoallylation of IndolinesA microwave vial was charged with the indole (0.25 mmol, 1 equiv) and the corresponding vinyl boronic acid (0.625 mmol, 2.5 equiv). The flask was flushed with argon and sealed. The degassed solvent (2.5 mL) was added, followed by the addition of water (3 mmol, 1.2 equiv). Next, a 2 M TMSCHN₂ solution in n-hexanes was added (1.25 mmol, 5 equiv) under vigorous stirring. The final mixture was heated at 60 °C for 8 h in a Biotage Initiator microwave reactor, or in a sand-bath at 60 °C when specified. The reactions where monitored by TLC analysis and quenched in methanol when the reaction was completed or when no more conversion was observed. The volatiles were removed under reduced pressure and the residue obtained was purified by flash column chromatography using petroleum ether/ethyl acetate.Characterization Data for Compound 4ePrepared according to the general procedure under conventional heating on a sand-bath in 77% yield (0.19 mmol), obtained as a yellow oil. ¹H NMR (600 MHz, CDCl₃): δ = 6.71 (d, J = 2.3 Hz, 1 H), 6.56 (dd, J = 8.6, 2.6 Hz, 1 H), 6.52 (d, J = 8.2 Hz, 1 H), 5.70 (dt, J = 16.9, 10.1 Hz, 1 H), 5.17 (dd, J = 10.2, 2.3 Hz, 1 H), 5.07 (dd, J = 17.1, 2.0 Hz, 1 H), 3.91 (ddd, J = 9.0, 8.6, 8.2 Hz, 1 H), 3.73 (s, 3 H), 3.03 (dd, J = 15.5, 8.2 Hz, 1 H), 2.81 (dd, J = 15.6, 9.0 Hz, 1 H), 2.00 (ddd, J = 10.1, 8.6, 4.9 Hz, 1 H), 1.64–1.78 (m, 4 H), 1.57 (d, J = 12.8 Hz, 1 H), 1.45–1.52 (m, 1 H), 1.23–1.32 (m, 1 H), 1.17–1.23 (m, 1 H), 1.07–1.16 (m, 2 H), 1.01 (qd, J = 12.4, 3.5 Hz, 1 H). ¹³C NMR (151 MHz, CDCl₃): δ = 153.1, 144.6, 137.6, 130.6, 118.1, 111.8, 111.6, 109.4, 60.6, 55.9, 55.5, 38.7, 34.6, 32.1, 28.3, 26.6, 26.6, 26.5. IR (ATR): 3368 (w), 2923 (s), 2851 (s), 1635 (w), 1599 (m), 1491 (s), 1465 (m), 1448 (m), 1433 (m), 1295 (w), 1233 (s, br), 1138 (s), 1034 (s), 1000 (m), 992 (w), 912 (m), 886 (w), 832 (m), 797 (m), 729 (m) cm^–1. HRMS (ESI⁺): m/z calcd for C₁₈H₂₈N₁O₁ ⁺ [M + H]⁺: 272.2018; found: 272.2014.Characterization Data for Compound 4fPrepared according to the general procedure under conventional heating on a sand-bath in 74% yield (0.18 mmol), obtained as a light-yellow oil. ¹H NMR (600 MHz, CDCl₃): δ = 6.69–6.73 (m, 1 H), 6.57 (dd, J = 8.2, 2.6 Hz, 1 H), 6.52 (d, J = 8.2 Hz, 1 H), 5.58 (dt, J = 17.1, 9.9 Hz, 1 H), 5.14 (dd, J = 10.4, 2.1 Hz, 1 H), 5.10 (dd, J = 17.3, 1.8 Hz, 1 H), 3.73 (s, 3 H), 3.64 (q, J = 8.4 Hz, 1 H), 3.05 (dd, J = 15.5, 8.6 Hz, 1 H), 2.79 (dd, J = 15.5, 8.6 Hz, 1 H), 2.09–2.16 (m, 1 H), 1.36–1.50 (m, 2 H), 1.19–1.29 (m, 2 H), 0.86–0.94 (m, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 152.9, 144.3, 139.9, 130.2, 117.1, 111.6, 111.4, 109.1, 63.3, 55.7, 49.6, 34.4, 33.3, 20.1, 13.9. IR (ATR): 3365 (w), 3074 (w), 2955 (m), 2930 (m), 2871 (m), 2831 (w), 1638 (w), 1599 (m), 1490 (s), 1465 (m), 1453 (s), 1433 (m), 1377 (w), 1293 (m), 1233 (s, br), 1138 (s), 1033 (s), 998 (w), 913 (m), 861 (w), 841 (m), 797 (m), 734 (m), 676 (m) cm^–1. HRMS (ESI⁺): m/z calcd for C₁₈H₂₈N₁O₁ ⁺ [M + H]⁺: 274.2172; found: 274.2171.