Synthesis of 2-Aryl-Substituted Chromans by Intramolecular C-O Bond Formation

Abstract

A synthetic route for the preparation of 2-aryl-substituted chromans from commercially available starting materials and utilizing either a palladium- or copper-catalyzed intramolecular cyclization of aryl bromides is described. Chromans with stereocontrol at C-2 can thus be obtained via a palladium-catalyzed asymmetric allylic etherification procedure utilizing a chiral indole-phosphine oxazoline (IndPHOX) ligand.

Key words

intramolecular cyclization - chromans - chalcones - palladium - copper

References and Notes

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11

General Procedure for Palladium-Catalyzed Intramolecular Cyclization: To a mixture of Pd(OAc)₂ (2.4 mg, 0.0105 mmol), ligand 11 (3.1 mg, 0.0105 mmol) and Cs₂CO₃ (0.17 g, 0.525 mmol), compound 9 (0.35 mmol) in toluene (1.2 mL) was added. After stirring under 90 ˚C for reported time, the reaction mixture was cooled to r.t., diluted with Et₂O, and filtered through a pad of celite. The resulting solution was purified by silica gel chromatography (n-hexane-EtOAc, 30:1).

12

The by-product was 1-(furan-2-yl)-3-phenylpropan-1-one, isolated in 22% yield. For the reaction mechanism, see reference 7b.

14

General Procedure for Copper-Catalyzed Intramolecular Cyclization: To a mixture of CuI (2.8 mg, 0.015 mmol), 2-aminopyridine (2.8 mg, 0.03 mmol) and NaOMe (12 mg, 0.225 mmol), compound 9 (0.15 mmol) in diglyme (0.7 mL) was added. After stirring under 100 ˚C for reported time, the reaction mixture was cooled to r.t., quenched with H₂O, and extracted with Et₂O. The extracts were washed with brine and dried over MgSO₄. The solvent was removed in vacuo and the residue was purified by column chromatography (n-hexane-EtOAc, 30:1).

17

The reported ee is the average value of three entries.

18

2-(2-Bromophenyl)chroman (20): [α]_D ^²0 +71.2 (c = 0.95, CHCl₃, 89% ee). ^¹H NMR (300 MHz, CDCl₃): δ = 7.54-7.61 (m, 2 H), 7.36 (td, J = 7.7, 1.2 Hz, 1 H), 7.10-7.19 (m, 3 H), 6.86-6.93 (m, 2 H), 5.38 (td, J = 10.2, 2.2 Hz, 1 H), 3.00-3.10 (m, 1 H), 2.75-2.83 (m, 1 H), 2.31-2.39 (m, 1 H), 1.85-1.94 (m, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 155.4, 141.3, 133.0, 130.0, 129.4, 128.1, 127.8, 127.7, 122.3, 121.8, 120.8, 117.2, 77.3, 29.1, 25.5. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₅H₁₃ONaBr: 311.0047; found: 311.0015.

19

[α]_D ^²0 +27.7 (c = 0.5, CH₂Cl₂, 87% ee).

22

2-([1,1′-Biphenyl]-2-yl)chroman (22): [α]_D ^²0 -36.5 (c = 0.40, CHCl₃, 89% ee). ^¹H NMR (300 MHz, CDCl₃): δ = 7.64-7.67 (m, 1 H), 7.25-7.46 (m, 8 H), 7.00-7.11 (m, 2 H), 6.80-6.88 (m, 2 H), 5.05-5.10 (m, 1 H), 2.71-2.78 (m, 2 H), 2.01-2.09 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 155.8, 141.2, 141.0, 139.3, 130.4, 129.8, 129.6, 128.5, 128.2, 128.0, 127.5, 127.4, 126.7, 122.2, 120.5, 117.3, 75.2, 30.1, 25.9. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₂₁H₁₈ONa: 309.1255; found: 309.1263.