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.

Key words

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

References

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12

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.

13

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⁺].