Titanium-Promoted Cross-Coupling for the Selective Synthesis of Polysubstituted, Conjugated Amides

Abstract

α,β-Unsaturated amides are important building blocks and are key structural elements in a number of biologically active natural products. Despite their importance and prevalence, few methods exist to prepare conjugated amides directly and modularly. To address this gap, a titanium-promoted coupling of alkynes and isocyanates has been developed. The method is highly stereoselective, producing only the E isomer with good chemoselectivity and regioselectivity (>95/5), for unsymmetrical internal alkynes that contain a steric bias. The reactive titanacyclopentene intermediate formed from the coupling of the alkyne and isocyanate was additionally reacted with various electrophiles to access tetrasubstituted enamides.

Stereoselective Formal Hydroamidation of Si-Substituted Arylacetylenes with DIBAL-H and Isocyanates: Synthesis of (E)- and (Z)-α-Silyl-α,β-unsaturated Amides

“…The crude product was purified by silica gel column chromatography (EtOAc/hexanes = 1:4) to provide 9b in 82% yield (24.7 mg, 0.0825 mmol) as a white solid. This compound has been previously reported, and the spectral data match the described data: 1 H NMR (CDCl 3 , 400 MHz) δ 7.99 (s, 1H), 7.55–7.50 (m, 3H), 7.47–7.42 (m, 2H), 7.38–7.36 (m, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.22–7.15 (m, 4H), 7.10 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 6.9 Hz, 2H); 13 C­{ 1 H} NMR (CDCl 3 , 100 MHz) δ 164.9, 138.2, 137.8, 135.8, 134.8, 134.6, 130.4, 130.0, 129.9, 128.9, 128.9, 128.8, 128.2, 124.4, 119.9.…”

“…The crude product was purified using silica gel column chromatography (EtOAc/hexanes = 1:4) to produce the desired acrylamide product 4aa in >98% yield (88.3 mg, 0.299 mmol) as a white solid. This compound has been previously reported, and the spectral data match the described data: 10 1 H NMR (DMSO-d 6 , 400 MHz) δ 10.01 (s, 1H), 7.69 (d,J = 7.3 Hz,2H),7.56 (s,1H),2H),5H), 7.05 (t, J = 7.3 Hz, 1H), 0.05 (s, 9H); 13 C{ 1 H} NMR (DMSO-d 6 , 100 MHz) δ 171. 6, 144.3, 142.6, 139.5, 137.7, 128.6, 128.3 , 128.1, 128.1, 123.2, 119.6, 0.1. (Z)-N-(4-Methoxyphenyl)-3-phenyl-2-(trimethylsilyl)acrylamide (4ab).…”

“…Martin and co-workers reported the Ni-catalyzed hydroamidations of alkynes with isocyanates in the presence of Mn and i -PrBr as the hydride source, which occurs through a β-hydride elimination (Scheme b) . Ti-mediated alkyne-isocyanate coupling using i -PrMgCl as a reductant provided ( E )-tri- or tetrasubstituted acrylamides via a titanacyclopropene intermediate (Scheme c) . During our studies, Wu and Chen reported the synthesis of ( E )-disubstituted acrylamides by treating isocyanates with alkenylaluminum reagents (Scheme d) .…”

“…9 Ti-mediated alkyneisocyanate coupling using i-PrMgCl as a reductant provided (E)-tri-or tetrasubstituted acrylamides via a titanacyclopropene intermediate (Scheme 1c). 10 During our studies, Wu and Chen reported the synthesis of (E)-disubstituted acrylamides by treating isocyanates with alkenylaluminum reagents (Scheme 1d). 11 Despite its practicality, there are compelling issues that need to be solved, including the substrate scope, which is limited to terminal alkynes, relatively long reaction times, and moderate yields.…”

Synthesis of Monofluoroalkenes: A Leap Forward

“…Rahaim and Chenniappan reported the titanium-promoted cross-coupling reaction between alkynes and isocyanates to give α,β-unsaturated amides via the formation of titanacycles (titanacyclopentenes) and their subsequent reaction with an electrophile. 221 On example was reported using diphenylacetylene and phenyl isocyanate with N-fluorobenzenesulfonimide as the electrophile to give 3-fluoro-N,2,3-triphenylacrylamide in low yield exclusively as the E isomer in what is essentially a fluorocarbamoylation reaction (Scheme 232).…”