Organocatalytic Nucleophilic Ring Opening of Cyclopropanecarbaldehydes by Benzenethiols: Tandem Synthesis of Benzo[b]thiepines

Abstract

An unprecedented nucleophilic ring opening of cyclopropanecarbaldehydes with benzenethiols proceeds regioselectively under the catalysis of 40 mol% proline to afford fair to good yields of 4-phenylthio-substituted butyraldehydes. If o-thiosalicyl­aldehydes are employed, a tandem homoconjugate addition-aldol reaction occurs, which constitutes an expedient entry to pharmaceutically valuable 2,3-dihydrobenzo[b]thiepine-4-carbaldehydes.

Key words

ring opening - tandem reactions - heterocycles - regio­selectivity - aldol reactions

References and Notes

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14

General Procedure for the Ring Opening of Cyclopropanecarbaldehydes 1 by Nucleophilic Attack with Benzenethiols 2
A mixture of cyclopropanecarbaldehyde 1 (1 mmol), benzenethiol 2 (1.2 mmol), (S)-proline (46 mg, 0.4 mmol), and 4 Å MS (500 mg) in THF (2 mL) was stirred at r.t. for 3 d, then H₂O (5 mL) was added to quench the reaction. The aqueous phase was extracted with Et₂O (100 mL), and the organic phase was dried over Na₂SO₄, filtrated, and concentrated. The residue was purified by column chromatography (silica gel, PE-EtOAc) to afford 4a-p as pale yellow oil. All new compounds have been isolated in pure form and characterized by spectral data (^¹H NMR, ^¹³C NMR, and MS).
Selected Data for Compounds 4
Compound 4a: yield 55%. ^¹H NMR (400 MHz, CDCl₃): δ = 9.66 (1 H, s, CHO), 7.30-7.18 (10 H, m, ArH), 4.16 (1 H, dd, J = 6.9, 8.3 Hz, SCH), 2.48 (2 H, t, J = 7.3 Hz, COCH₂), 2.30-2.15 (2 H, m, H-3). ^¹³C NMR (125 MHz, CDCl₃): δ = 201.1, 141.0, 134.3, 132.4, 128.7, 128.5, 127.7, 127.4, 127.2, 52.6, 41.7, 28.5. GC-MS (EI): m/z = 256.1 [M]⁺.

15

Typical procedure for the tandem synthesis of benzo[b]-
thiepines 6 was operated as described in ref. 14, except for replacing benzenethiols 2 with o-salicylaldehydes 5. The reaction gave 6 as off-white crystal solids. All new compounds have been isolated in pure form and charac-terized by spectral data (^¹H NMR, ^¹³C NMR, and MS).
Selected Data for Compounds 6
Compound 6e: yield 56%; mp 120-121 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 9.62 (1 H, s, CHO), 7.40-6.84 (8 H, m, ArH, and CH=C), 4.26 (1 H, dd, J = 3.2, 11.4 Hz, SCH), 3.79 (3 H, s, OCH₃), 3.26-3.02 (2 H, m, CH₂), 2.37 (3 H, s, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 194.9, 159.0, 150.4, 141.8, 137.5, 136.0, 135.2, 134.7, 134.5, 132.9, 130.9, 128.0, 114.2, 55.4, 52.6, 37.3, 21.0. ESI-HRMS: m/z calcd for C₁₉H₁₈O₂S: 310.1028; found: 310.1031.

17

For comparision, we also conducted the tandem reaction with the ‘best’ substrate 1c under Anand’s condition (ref. 12). After refuxing in EtOH for 3 h, the reaction afforded a mixture of products, from which 6g was isolated in 13% yield.

18

Enantiomeric excess was determined chromatographically as follows: Diacel CHIRALPAK AS-H, hexane-2-PrOH (80:20), flow rate 0.6 mL/min, λ = 254 nm.

19

A single crystal of 6e suitable for X-ray diffraction analysis was obtained by recrystallization from CH₂Cl₂-n-hexane. Crystallographic data have been deposited with the Cambridge Crystallographic Data Center as supplementary publication number CCDC 726088.