Chemo- and Regioselective Asymmetric Friedel–Crafts Reaction of Furans and Thiophenes with α,β-Unsaturated Aldehydes through Dual Activation

Abstract

A highly chemo- and regioselective Friedel–Crafts alkylation reaction of furans and thiophenes has been developed, which relies on the activation from the remote conjugated Mukaiyama silyl enol ether motif. Excellent enantioslectivity is generally obtained in reactions with α,β-unsaturated aldehydes under the well-established iminium ion catalysis of a chiral secondary amine.

Key words

Friedel–Crafts alkylation - furans - thiophenes - iminium ion catalysis - α,β-unsaturated aldehydes - dual activation

• References and Notes


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• 12 The reaction was carried out with α,β-unsaturated aldehyde 3 (0.15 mmol) and silyl enol ether 2 (0.1 mmol) in CHCl₃ (1.0 mL) in the presence of secondary amine catalyst C4 (4.9 mg, 0.02 mmol) and TFA (2.2 mg, 0.02 mmol) at –20 °C. After completion, the solution was concentrated, and the residue was dissolved in MeOH (2 mL), then NaBH₄ (5.7 mg, 0.15 mmol) was added in one portion at r.t. After completion, the solution was concentrated and purified by flash chromatography on silica gel (PE–EtOAc) to afford the chiral product 4. Isolated products have been fully characterized by ¹H NMR and ¹³C NMR spectroscopy (see the Supporting Information). (S,Z)-3-(5-{2-[(tert-Butyldimethylsilyl)oxy]prop-1-en-1-yl}furan-2-yl)-3-(4-nitrophenyl)propan-1-ol (4d) Yield: 35.0 mg (84%), yellow oil; the enantiomeric excess was determined to be 95% by HPLC analysis [Chiralpak AD-H column (5% 2-PrOH–n-hexane, 1.0 mL/min), UV (220 nm), t _R (minor) = 11.32 min, t _R (major) = 13.22 min]; [α]_D ²⁰ = +13.5 (c 0.80 in CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.14 (d, J = 8.8 Hz, 2 H), 7.41 (d, J = 8.8 Hz, 2 H), 6.35 (d, J = 3.2 Hz, 1 H), 6.13 (d, J = 3.2 Hz, 1 H), 5.34 (s, 1 H), 4.29 (t, J = 7.8 Hz, 1 H), 3.66–3.57 (m, 2 H), 2.39–2.33 (m, 1 H), 2.12–2.07 (m, 1 H), 1.95 (s, 3 H), 1.40 (s, 1 H), 0.95 (s, 9 H), 0.21–0.20 (m, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 151.7, 151.6, 150.4, 148.9, 128.7, 123.8, 108.0, 106.6, 98.7, 60.1, 41.2, 37.1, 25.9, 23.4, 18.4, -3.1 ppm. ESI-HRMS: m/z calcd for C₂₂H₃₁NO₅Si + Na⁺: 440.1864; found: 440.1868.
• 13 To the best of our knowledge, there is only one example involving the Friedel–Crafts reaction of 2-methoxythiophene under aminocatalytic conditions, see: Huang Y. Walji AM. Larsen CH. MacMillan DW. C. J. Am. Chem. Soc. 2005; 127: 15051
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