Compatibility Assessment of Unactivated Internal Alkynes in ­Rhodium-Catalyzed [2+2+2] Cycloadditions

Abstract

Functionalized 1,2,4,5-tetrasubstituted benzenes are synthetically difficult or laborious to access. The Rh-catalyzed [2+2+2] cycloaddition of a diyne and internal alkyne offers a seemingly straightforward route to these scaffolds; however, this has been largely restricted to alkynes bearing activating (coordinating) functional groups, with very few examples of unactivated alkynes. In this work, we disclose an assessment of Rh-catalyzed [2+2+2] cycloadditions employing unactivated internal alkynes, focusing on the structural diversity and compatibility of both alkyne and diyne components. The limitations of this method are disclosed, with exceptionally bulky alkynes and specific functional groups undergoing side reactions. Furthermore, the practicalities of gram-scale reactions and catalyst recovery/reuse are demonstrated.

Key words

cycloaddition - catalysis - rhodium - alkynes - arenes

Publication History

Received: 13 February 2024

Accepted after revision: 11 March 2024

Accepted Manuscript online:
11 March 2024

Article published online:
28 March 2024

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• 26 Representative Procedure for the Synthesis of 4An oven-dried microwave vial was charged with 2-(hex-1-yn-1-yl)thiophene (15.0 mg, 100 μmol, 1.0 equiv), [Rh(COD)(MeCN)₂]BF₄ (7.6 mg, 20.0 μmol, 20 mol%), and rac-BINAP (24.9 mg, 40.0 μmol, 40 mol%). The vial was sealed, evacuated, and backfilled with N₂. Dry acetone (0.5 mL) was introduced into the vial, and the mixture was heated to 60 °C. A solution of 4-methyl-N,N-di(prop-2-yn-1-yl)benzenesulfonamide (148 mg, 600 μmol, 6.0 equiv) in acetone (0.5 mL) was prepared and this was added via syringe pump to the heated Rh solution over 15 h. The mixture was allowed to stir at 60 °C for the duration of the slow addition followed by a further 1 h (16 h, total reaction time). The vial was then allowed to cool to RT, before filtering through Celite® (washing with acetone) and concentrating in vacuo to give a residue that was purified by flash column chromatography (silica, 0–5% Et₂O in PhMe) to yield the desired product 4 as a yellow solid (37.9 mg, 92%). ¹H NMR (400 MHz, CDCl₃): δ 7.81–7.76 (m, 2 H), 7.35–7.30 (m, 3 H), 7.14 (s, 1 H), 7.08 (s, 1 H), 7.06 (dd, J = 5.14, 3.50 Hz, 1 H), 6.94 (dd, J = 3.51, 1.20 Hz, 1 H), 4.62 (s, 2 H), 4.60 (s, 2 H), 2.68–2.60 (m, 2 H), 2.41 (s, 3 H), 1.51–1.38 (m, 2 H), 1.33–1.19 (m, 2 H), 0.83 (t, J = 7.31 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 143.8, 143.8, 142.3, 141.6, 136.2, 133.8, 133.8, 130.0, 127.8, 127.1, 126.7, 125.5, 125.2, 123.7, 53.7, 53.9, 34.0, 33.3, 22.6, 21.6, 14.0. IR (ATR, film): 2924, 1344, 1161, 1098, 1061, 810, 702, 665, 615, 550 cm^–1. HRMS (ESI): m/z calcd for [C₂₃H₂₅NO₂S₂ + H]⁺: 412.1400; found: 412.1391.