A Three-Component Synthesis of (1,3-Oxazol-2-yl)-1,2-dihydro(iso)quinoline and its further Structural Diversifications

Abstract

A Reissert-type three-component synthesis of 1,3-oxazol-2-yl-1,2-dihydro(iso)quinoline is developed using α-isocyano β-phenyl propionamide as an isonitrile input. The structure of this multicomponent adduct is further diversified taking advantage of the rich chemistry of oxazole.

aminooxazole - isocyanide - isonitrile - isoquinoline - multicomponent reaction - Reissert reaction - Ugi reaction

References

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The role of molecular sieve is unknown. It may remove adventitious water or act as a scavenger of HCl produced in situ. It is worthy of note that the same reaction did not occur in the presence of triethylamine.

<A NAME="RG45404ST-13">13</A>

Typical Procedure for the Synthesis of 4.
To a solution of isoquinoline (1, 97.0 µL, 105.7 mg, 0.82 mmol) in dry CH₂Cl₂ (2.0 mL) at -40 °C were added powdered molecular sieves (4 Å, 200 mg) and methyl chloroformate (2, 155.0 mg, 126.7 µL, 1.64 mmol,) successively. The resulting yellow solution was stirred for 5 min and a solution of α-isocyano β-phenyl propionamide (3, 200.0 mg, 0.82 mmol) in dry CH₂Cl₂ (3.0 mL) was added drop-wise. After being stirred for 1.5 h, the reaction was quenched by addition of sat. aq NaHCO₃ solution and extracted with CH₂Cl₂. The combined organic extracts were washed with HCl (2 N), sat. aq NH₄Cl solution, dried over Na₂SO₄, and the volatile was evaporated under reduced pressure. The crude product was purified by flash chromatography (heptane-EtOAc = 6:4) to give 4 as a yellowish solid (263.0 mg, 76%): mp 110-112 °C. IR: 1713, 1633, 1440, 1347, 1235, 1113, 970 cm^-1. ¹H NMR (300 MHz, CDCl₃): two rotamers, δ = 7.27-7.06 (9 H, m), 6.95, 6.91 (1 H, d, J = 7.7 Hz), 6.41, 6.29 (1 H, br s), 5.82 (1 H, d, J = 7.7), 5.75 (1 H, d, J = 7.7), 3.75, 3.71 (2 H, s), 3.66 (3 H, s), 3.53 (4 H, m), 2.74 (4 H, m). MS (ESI): m/z (%) = 454 (100) [M + Na⁺].

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