Parallel Synthesis of 1,2,3,4-Tetrahydro-β-carbolines Using Microwave Irradiation

Abstract

Novel soluble polymer supported synthesis of 1,2,3,4-tetrahydro-β-carboline derivatives in the microwave oven is reported. Commercially available Fmoc-protected tryptophan was directly anchored to MeO-PEG-OH via an ester linkage in the presence of DCC and DMAP. One pot cyclocondensation of polymer-bound tryptophan with a variety of aldehydes and ketones has been carried out under microwave irradiation to provide immobilized 1,2,3,4-tetra-hydro-β-carboline derivatives. The desired products were then liberated from the soluble matrix in good yield and good purity.

Key words

1,2,3,4-tetrahydro-β-carbolines - combinatorial chemistry - liquid-phase method - scaffold - microwave-assisted combinatorial synthesis

References

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11

A typical procedure for the synthesis of 4 (Table [1] , entry 13) is the following. A mixture of PEG-bound indole 2 (510 mg), 10 mL of chloroform, p-TSA (2 mg) and acetone (5 equiv) was irradiated in a microwave oven (Sharp domestic microwave oven) with an output at 100% (900 W) for 15 min. Upon completion of the reaction, cold diethyl ether (20 mL) was added to the reaction mixture to precipitate the PEG-bound β-carboline. The precipitate was then collected on a sintered glass funnel and thoroughly washed with diethyl ether (20 mL × 3). The resulting PEG-bound β-carboline was cleaved at r.t. by using KCN (20 mg) in 10 mL of methanol. After completion of reaction, the detached MeO-PEG-OH was precipitated by adding diethyl ether. The polymer was filtered, and the combined filtrate was dried to offer the corresponding crude product in 95% yield with 89% HPLC purity. The data for 4 (entry 13, Table [1] ) is as follows. ¹H NMR (300 MHz, CDCl₃): δ = 7.81 (bs, 1 H), 7.47 (d, J = 7.5 Hz, 1 H), 7.32 (d, J = 7.5 Hz, 1 H), 7.14 (m, 2 H), 3.96 (dd, J = 11.1, 4.3 Hz, 1 H), 3.83 (s, 3 H), 3.13 (dd, J = 15.1, 4.3 Hz, 1 H), 2.79 (dd, J = 15.1, 11.1 Hz, 1 H), 1.57 (s, 3 H), 1.50 (s, 3 H); ¹³C NMR (75 M Hz, CDCl₃): δ = 173.9, 139.7, 135.8, 127.0, 121.9, 119.7, 118.2, 110.8, 106.2, 52.9, 52.3, 51.2, 29.6, 28.4, 26.3. MS (EI): m/z = 258 (M⁺). HRMS (EI): Calcd for C₁₅H₁₈N₂O₂: 258.1358. Found: 258.1360.