Gold-Catalysed Cycloisomerisation of Ynamides To Access 2,2-Disubstituted Tetrahydrothiophene Motifs

Abstract

Ynamides bearing a tethered allyl sulfoxide undergo a gold-catalysed cycloisomerisation to afford tetrahydrothiophene-2-carboxamides and their benzo-fused analogues. The reactions are initiated by a formal 7-endo-dig cyclisation and accommodate a range of different substituents. The use of N-allyl ynamides provided a route into novel spirocyclic ε-lactam structures.

Key words

gold - ynamides - isomerization - ylides - regioselectivity - thiophenecarboxamides

Publication History

Received: 28 January 2021

Accepted after revision: 13 March 2021

Accepted Manuscript online:
13 March 2021

Article published online:
07 April 2021

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• 12 Cycloisomerisation of Ynamides: General Procedure AuPicCl₂ (5.0 mol%, 5 μmol) was added to a 0.2 M solution of the appropriate ynamide in DCE (0.1 mmol) in a flame-dried Schlenk tube under argon, and the mixture was heated at 70 °C. Upon completion of the reaction (TLC), the crude mixture was passed through a small plug of silica to remove gold residues. The solvent was then evaporated, and the residue was purified by column chromatography (hexanes–EtOAc). 1-Allyl-N-benzyl-N-(methylsulfonyl)-1,3-dihydro-2-benzothiophene-1-carboxamide (4b) Purified by column chromatography [silica gel, hexanes–EtOAc (7:3)] as a yellow viscous oil; yield: 31 mg (81%). IR (neat): 2925 (w), 1679 (s), 1351 (s), 1162 (s) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.92 (s, 3 H) overlaps with 3.01–2.95 (m, 1 H), 3.10 (dd, J = 14.2, 7.4 Hz, 1 H), 4.19 (d, J = 14.2 Hz, 1 H), 4.33 (d, J = 16.0 Hz, 1 H), 4.41 (d, J = 14.2 Hz, 1 H), 4.83 (d, J = 16.0 Hz, 1 H), 4.92–5.05 (m, 2 H), 5.46–5.64 (m, 1 H), 7.14–7.31 (m, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 238.0, 43.3, 47.2, 50.6, 69.0, 120.1, 125.2, 125.3, 127.8, 127.9, 128.4, 128.5, 128.6, 132.2, 135.6, 140.2, 141.0, 175.1. MS (TOF ES⁺): m/z = 410 (100%) [M + Na]⁺. HRMS (TOF ES⁺): m/z calcd for C₂₀H₂₁NNaO₃S₂: 410.0861; found: 410.0859. N,3-Diallyl-N-(methylsulfonyl)-2-thiaspiro[4.5]decane-3-carboxamide (9) Colourless viscous oil; yield: 21.3 mg (60%); IR (neat): 2924 (s), 2852 (m), 1681 (s), 1352 (s), 1165 (s) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.21–1.63 (m, 10 H), overlaps with 1.53 (d, J = 13.6 Hz, 1 H), 2.55 (dd, J = 14.4, 7.2 Hz, 1 H), 2.70 (dd, J = 14.4, 5.8 Hz, 1 H), 2.69 (d, J = 10.7 Hz, 1 H), 2.77 (d, J = 10.7 Hz, 1 H), 2.96 (d, J = 13.6 Hz, 1 H), 3.28 (s, 3 H), 4.39–4.56 (m, 2 H), 5.05–5.20 (m, 2 H), 5.25–5.42 (m, 2 H), 5.63–5.81 (m, 1 H), 5.86–6.03 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 23.0, 24.0, 26.1, 34.6, 37.8, 43.3, 44.5, 45.8, 46.5, 47.7, 62.3, 119.5, 132.5, 132.8, 174.6. MS (TOF ES⁺): m/z = 380 (100%). HRMS (TOF ES⁺): m/z calcd for C₁₇H₂₇NNaO₃S₂: 380.1330; found: 380.1338.
• 13 To complement the 2-thiaspiro[4.5]decane motif 5 accessed from ynamides 2, their alkyne precursor was tested under the conditions previously developed for the reaction of terminal alkynes (see ref. 5), providing access to a 2-thiaspiro[5.5]undecan-4-one motif (see SI).
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• 16 Attempts to extrude sulfur dioxide from 13 were unsuccessful with no conversion even in diphenyl ether at 280 °C.