Elaboration of the Oxazepine Ring System via CuI/l-Proline-Catalyzed Intramolecular Aryl Amination

Abstract

A two-step approach for assembling oxazepines is described, which started from 2-aminophenols and substituted 2-bromobenzyl bromides and used CuI/l-proline-catalyzed coupling reaction as the key step.

Key words

cross-coupling - aryl bromide - ethers - oxazepines

References and Notes

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1

These authors contributed equally to this paper.

8

Typical Procedure for Etherification
To a flask containing 2-aminophenol (21 mmol) and Na₂CO₃ (40 mmol) was added DMF (20 mL), DMSO (20 mL), and H₂O (2 mL). At 0 ˚C a solution of 2-bromobenzyl bromide (10 mmol) in DMF (5 mL) was added dropwise. After the mixture was stirred for about 4 h, it was filtered. The filtrate was partitioned between EtOAc and H₂O. The organic phase was separated, and the aqueous layer was extracted with EtOAc. The combined organic phase was washed with H₂O and brine, dried over Na₂SO₄, and concentrated. The residual oil was loaded on a silica gel column and eluted with 1:10 EtOAc-PE to afford the etherification product.

9

Typical Procedure for Coupling
A Schlenk tube was charged with the above ether (0.5 mmol), CuI (0.05 mmol), l-proline (0.1 mmol), and DABCO˙6H₂O (5.0 mmol), evacuated, and backfilled with Ar. Then, DMSO (4 mL) and H₂O (1 mL) were added. The reaction mixture was heated at 90 ˚C until the starting material disappeared (monitored by TLC). The cooled mixture was partitioned between EtOAc and H₂O. The organic phase was separated, and the aqueous layer was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The crude product was purified by column chromatography on silica gel to provide the coupling product.

10

Selected Data for 6c
^¹H NMR (300 MHz, CDCl₃): δ = 7.78 (dd, J = 1.8, 8.1 Hz, 1 H), 7.69 (d, J = 2.1 Hz, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 6.99 (dd, J = 1.5, 7.8 Hz, 1 H), 6.74 (td, J = 1.8, 7.8 Hz, 1 H), 6.59 (td, J = 1.2, 8.1 Hz, 1 H), 6.46 (dd, J = 1.8, 8.1 Hz, 1 H), 4.31 (s, 2 H), 3.84 (s, 1 H), 1.48 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 165.0, 161.2, 114.3, 138.6, 130.8, 130.4, 129.6, 127.4, 124.4, 121.8, 120.3, 119.4, 118.7, 80.8, 47.1, 28.1. ESI-MS: m/z = 298.1 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₈H₂₀NO₃ [M + H]⁺: 298.1438; found: 298.1432.

11

Selected Data for 6f
^¹H NMR (300 MHz, CDCl₃): δ = 8.41 (d, J = 8.1 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.40-7.53 (m, 3 H), 7.31 (dd, J = 1.2, 7.8 Hz, 1 H), 7.18 (d, J = 8.1 Hz, 1 H), 6.82 (td, J = 1.2, 7.2 Hz, 1 H), 6.69 (td, J = 1.5, 7.8 Hz, 1 H), 6.51 (dd, J = 1.2, 7.8 Hz, 1 H), 4.52 (s, 2 H), 3.75 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 153.3, 144.6, 139.2, 134.2, 127.6, 127.1, 126.6, 126.2, 126.1, 125.8, 124.4, 123.6, 122.0, 121.8, 119.2, 118.8, 46.9. ESI-MS: m/z = 248.1 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₇H₁₄NO [M + H]⁺: 248.1070; found: 248.1068.

12

Selected Data for 6h
^¹H NMR (300 MHz, CDCl₃): δ = 7.05-7.18 (m, 3 H), 6.97-6.99 (m, 1 H), 7.00 (d, J = 8.1, 1 H), 6.39 (dd, J = 1.5, 8.1 Hz, 1 H), 6.27 (d, J = 1.2 Hz, 1 H), 4.35 (s, 2 H), 3.56 (s, 1 H), 2.08 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 158.5, 142.9, 138.2, 133.9, 131.7, 128.9, 128.0, 124.1, 121.7, 120.4, 119.9, 118.9, 46.8, 20.5. ESI-MS: m/z = 212.0 [M + H]⁺.

13

Selected Data for 6m
^¹H NMR (300 MHz, CDCl₃): δ = 7.02 (dd, J = 4.2, 5.1 Hz, 1 H), 6.91 (d, J = 4.2 Hz, 1 H), 6.59-6.70 (m, 3 H), 6.53 (t, J = 7.8 Hz, 1 H), 4.45 (s, 2 H), 3.68 (s, 3 H), 1.99 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 158.9, 152.4, 145.0, 136.6, 133.1, 125.9, 125.3, 120.9, 119.7, 118.0, 113.2, 113.1, 55.6, 46.3, 17.7. ESI-MS: m/z = 242.0 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₅H₁₆NO₂ [M + H]⁺: 242.1179; found: 242.1176.