Palladium-Catalyzed Intramolecular Hydroarylation of 2-Bromobenzyl Propargyl Ethers: A New Access to Exocyclic Isochromans

Abstract

An efficient, stereo- and regioselective palladium-catalyzed 6-exo-dig intramolecular hydroarylation of propargyl ethers which provides a concise access to functionalized isochromans in high yields has been developed. A wide range of substrates possessing aromatic, aliphatic and heteroaromatic alkynes can be efficiently transformed into the targeted isochromans. Irrespective of the nature of the substrates, the cyclization follows highly selective ­stereo- and regiochemistry.

palladium - isochroman - carbocyclization - 6-exo-dig regiochemistry - acetylene

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14

General Procedure for Sonogashira Coupling of O-Propargylated Benzyl Alcohol with Aryl Iodide 6a-f: To a solution of aryl iodide (1.0 mmol), Pd(PPh₃)₂Cl₂ (3 mol%), and CuI (3 mol%) in freshly distilled Et₃N was slowly added a solution of alkyne 3 (1.1 mmol) in Et₃N and the resulting suspension was magnetically stirred for 6 h. H₂O (50 mL) was added to the reaction mixture, the residue was extracted into EtOAc (4 × 15 mL), and the extract was dried over anhyd Na₂SO₄. Removal of the solvent under reduced pressure gave the crude product, which was further purified by column chromatography on silica gel using EtOAc-petroleum ether as eluent to afford pure product. Analytical Data for 1-[3-(2-Bromo-4,5-dimethoxybenzyl-oxy)prop-1-ynyl]-4-methylbenzene (6b): colorless solid; mp 54-56 ˚C. IR (KBr): 808, 1085, 1160, 1211, 1260, 1450, 1508, 2854, 2924 cm . ^¹H NMR (500 MHz, CDCl₃): δ = 2.33 (s, 3 H, Me), 3.84 (s, 3 H, OMe), 3.86 (s, 3 H, OMe), 4.44 (s, 2 H, OCH₂), 4.67 (s, 2 H, OCH₂), 7.00 (s, 1 H, ArH), 7.02 (s, 1 H, ArH), 7.10 (d, J = 8.4 Hz, 2 H, ArH), 7.34 (d, J = 7.65 Hz, 2 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 21.6, 56.1, 56.3, 58.6, 71.0, 84.3, 86.9, 112.4, 113.4, 115.4, 119.6, 129.1, 129.2, 131.8, 138.7, 148.5, 149.1. MS (EI): m/z 376.4 [M+H]⁺. Anal. Calcd for C₁₉H₁₉BrO₃: C, 60.81; H, 5.10. Found: C, 60.85; H, 5.07.

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19

General Procedure for the Synthesis of Isochromans 7a-n: Pd(PPh₃)₄ (3 mol%) and HCOONa (1.5 equiv) were added to a pressure tube and the tube was flushed with nitrogen. The requisite propargyl ether (0.4 mmol) dissolved in DMF (4.5 mL) was added, followed by distilled H₂O (1.5 mL). The pressure tube was exposed to microwave irradiation for 1 min using an unmodified microwave oven operating at 300 W. The reaction mixture was cooled and was irradiated again for the same time. After fifteen of such successive irradiations and cooling sequences, the reaction mixture was diluted with EtOAc. The organic phase was washed with brine, dried (anhyd Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by chromatogra-
phy (petroleum ether-EtOAc as eluent) and the yields are shown in Table  [4] .
Analytical Data for 6,7-Dimethoxy-4-(4-methylbenzylidene)-isochroman (7b): pale yellow solid; mp 186-188 ˚C. IR (KBr): 1088, 1109, 1234, 1353, 1457, 1513, 1602, 2844, 2930 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.36 (s, 3 H, Me), 3.88 (s, 3 H, OMe), 3.94 (s, 3 H, OMe), 4.73 (s, 2 H, OCH₂), 4.74 (s, 2 H, OCH₂), 6.52 (s, 1 H, ArH), 6.99 (s, 1 H, ArH), 7.12 (d, J = 7.65 Hz, 2 H, ArH), 7.17 (d, J = 8.4 Hz, 2 H, ArH), 7.21 (s, 1 H, =CH). ^¹³C NMR (125 MHz, CDCl₃): δ = 21.3, 56.0, 56.1, 66.8, 68.4, 106.1, 107.2, 121.3, 124.8, 127.8, 129.1, 129.2, 131.4, 134.0, 136.8, 148.4, 148.2. MS (EI): m/z 297.50 [M+H]⁺. Anal. Calcd for C₁₉H₂₀O₃: C, 77.00; H, 6.80. Found: C, 76.96; H, 6.82.