Microwave-Assisted, Palladium-Catalyzed Intramolecular Direct Arylation for the Synthesis of Novel Fused Heterocycles

Abstract

An efficient synthesis of novel fused heterocycles has been established via microwave-assisted palladium-catalyzed intramolecular direct arylation. The acyclic aryl bromides are readily available from microwave-assisted one-pot annulation of N-(2-bromobenzyl)-2-aminophenols and ethyl 2-bromoalkanoates. The intramolecular direct arylation is then performed in the presence of palladium(II) acetate and dppf (10 mol% each) in toluene using potassium carbonate (2 equiv) as the base under microwave heating (150 °C, 1 h) to afford the products in 43-99% yields. Steric effect is observed for Ar-Ar bond formation, giving a substantial amount of the debromination byproduct.

Key words

3,4-dihydro-3-oxo-2H-1,4-benzoxazine - direct arylation - heterocycles - microwave - palladium

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17

General Procedure for Pd-Catalyzed Direct Arylation: A 10 mL pressurized process vial was charged with the bromide 8 (0.50 mmol), Pd(OAc)₂ (0.05 mmol), dppf (0.05 mmol), and K₂CO₃ (1.00 mmol) and it was sealed with a cap containing a silicon septum. The vial was then evacuated and backfilled with N₂ (repeated for several times) through the cap using a needle. To the degassed vial was added degassed anhyd toluene (3 mL) through the cap using a syringe. The loaded vial was then placed into the microwave reactor cavity and was heated at 150 °C for 1 h. After cooled to r.t. H₂O (5 mL) was added to the reaction vial. The resultant mixture was then extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine, dried over anhyd Na₂SO₄, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to furnish the product (see Table [3] and Scheme [4] for details). Spectroscopic data for 7e: IR (KBr): 1672, 1236 cm^-1. ¹H NMR (400 MHz, CDCl₃): d = 8.49 (d, J = 7.6 Hz, 1 H), 7.43-7.32 (m, 3 H), 7.16 (d, J = 8.4 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 1 H), 5.13 and 4.61 (ABq, J = 14.8 Hz, 2 H), 4.54 (q, J = 6.8 Hz, 1 H), 1.57 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): d = 164.6, 143.9, 132.2, 129.0, 128.5, 127.6, 127.5, 127.2, 126.8, 126.6, 124.4, 122.8, 116.2, 73.4, 42.6, 15.5. MS (ESI⁺): m/z (%) = 308 (100) [M + Na⁺]. Anal. Calcd for C₁₆H₁₂ClNO₂: C, 67.26; H, 4.23; N, 4.90. Found: C, 67.28; H, 4.22; N, 4.88. The ¹H NMR and ¹³C NMR of 7a-f and 16 can be obtained from the authors upon request.