Functionalization of remote C(sp3)-H bonds enabled by copper-catalyzed coupling of O-acyloximes with terminal alkynes

Zhaodong Li,Qian Wang,Jieping Zhu,Rubén O Torres-Ochoa

doi:10.1038/s41467-020-14292-2

Zhaodong Li, Qian Wang + Show 2 more

Open Access

https://doi.org/10.1038/s41467-020-14292-2

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Abstract

Transition metal catalyzed Sonogashira cross-coupling of terminal alkynes with aryl(vinyl) (pseudo)halides has been successfully extended to alkyl halides for the synthesis of functionalized internal alkynes. The direct alkynylation of remote unfunctionalized sp3 carbon by terminal alkynes remains difficult to realize. We report herein an approach to this synthetic challenge by developing two catalytic remote sp3 carbon alkynylation protocols. In the presence of a catalytic amount of Cu(I) salt and a tridentate ligand (tBu3-terpyridine), O-acyloximes derived from cycloalkanones and acyclic ketones are efficiently coupled with terminal alkynes to afford a variety of γ- and δ-alkynyl nitriles and γ-alkynyl ketones, respectively. These reactions proceed through a domino sequence involving copper-catalyzed reductive generation of iminyl radical followed by radical translocation via either β-scission or 1,5-hydrogen atom transfer (1,5-HAT) and copper-catalyzed alkynylation of the resulting translocated carbon radicals. The protocols are applicable to complex natural products.

Highlights

Transition metal catalyzed Sonogashira cross-coupling of terminal alkynes with aryl(vinyl)halides has been successfully extended to alkyl halides for the synthesis of functionalized internal alkynes
Depending on the structure of oximes, the iminyl radicals can evolve to a carbon radical through either β-scission[17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32] or 1,5hydrogen atom transfer (1,5-HAT) process[33,34,35,36,37,38,39]
We report the successful realization of this endeavor by developing synthesis of γ- and δ-alkynyl nitriles 4 and γ-alkynyl ketones 5 from simple oxime esters 1 or 2 and terminal alkynes 3 (Fig. 1f)

Summary

Results

Oxime esters derived from C-3 mono- and disubstituted cyclobutanones underwent alkynylation smoothly to afford the corresponding γ-alkynylated nitriles (4v–4af). Oxime esters derived from less strained cyclopentanones and dihydrofuran-3(2H)-one underwent similar transformation to afford δ-alkynylated nitriles (4al, 4am, 4an) in good yields. Reaction of 2a (R1 = R2 = Ph) with 3a (R = Ph) under aforementioned standard conditions afforded only a trace amount of 5a, with the unfunctionalized ketone being isolated as the major product. This result was not unexpected considering the reversibility of 1,5-HAT of iminyl radicals to benzylic radicals[35]. After an exhaustive optimization of reaction conditions (see Supplementary Methods, Tables 8–14), we found that stirring a DCE solution of 2a (0.1 mmol) with 3a (0.2 mmol) at 45 °C in the presence of (CuOTf)2·C6H6 (0.05 equiv), tBu3-TERPY (0.1 equiv), and K2CO3 (2 equiv) provided the desired internal alkyne t Bu

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Discussion

Methods