Copper-Catalyzed Direct C–H Alkylation of Polyfluoroarenes by Using Hydrocarbons as an Alkylating Source

Abstract

Construction of carbon–carbon bonds is one of the most important tools in chemical synthesis. In the previously established cross-coupling reactions, prefunctionalized starting materials were usually employed in the form of aryl or alkyl (pseudo)­halides or their metalated derivatives. However, the direct use of arenes and alkanes via a 2-fold oxidative C–H bond activation strategy to access chemoselective C­(sp2)–C­(sp3) cross-couplings is highly challenging due to the low reactivity of carbon–hydrogen (C–H) bonds and the difficulty in suppressing side reactions such as homocouplings. Herein, we present the new development of a copper-catalyzed cross-dehydrogenative coupling of polyfluoroarenes with alkanes under mild conditions. Relatively weak sp3 C–H bonds at the benzylic or allylic positions, and nonactivated hydrocarbons could be alkylated by the newly developed catalyst system. A moderate-to-high site selectivity was observed among various C–H bonds present in hydrocarbon reactants, including gaseous feedstocks and complex molecules. Mechanistic information was obtained by performing combined experimental and computational studies to reveal that the copper catalyst plays a dual role in activating both alkane sp3 C–H bonds and sp2 polyfluoroarene C–H bonds. It was also suggested that the noncovalent π–π interaction and weak hydrogen bonds formed in situ between the optimal ligand and arene substrates are key to facilitating the current coupling reactions.

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

“…However, the development of efficient methods can be challenging due to the requirement of directing groups and control of selectivity. In the case of reactions for applications in the synthesis of bioactive compounds, an additional challenge is the frequent presence of heterocycles containing metal-coordi- nating atoms, such as nitrogen and sulfur, that can compete with ligands and directing groups for coordination with the metal, leading to poor selectivity [313]. On the other hand, such heterocyclic moieties present in bioactive compounds, or their synthetic intermediates may eventually play the role of a directing group, thus providing an opportunity for convenient and straightforward transformations based on metal-mediated C-H activation [314].…”

“…The reaction requires the activation of both the C(sp 2 )-H bond of the fluoroarene and the C(sp 3 )-H bond of the alkane, thus it is challenging due to the possibility of homocoupling and overall alkylation. A cross-dehydrogenative coupling of polyfluoroarenes and alkanes was achieved by the use of a Cu(I) salt and a β-ketimide ligand in the presence of di-tert-butyl peroxide as the oxidant (Scheme 80A) [313]. The choice of a proper ligand was suggested to be a crucial issue to achieve selectivity and facilitate the reaction due to interactions with the arene substrates.…”

Copper‐Catalyzed Cross‐Dehydrogenative Coupling Reactions

“…In 2020, Xie et al reported the catalytic dehydrogenative coupling between polyfluoroarenes (62) and alkanes (63) using copper as catalyst. [37] The strategy involved the formation of C(sp 2 )À C(sp ) bond by the coupling of C(sp )À H/C(sp 3 )À H under mild condition [CuBr SMe 2 (10 mol%), 64 (15 mol%) as ligand DTBP (4 equiv. ), t BuONa (80 mol%), C 6 H 6 at 60-80°C for 24 h], affording the products in high yields (Scheme 20).…”

“…An efficient procedure for the construction of triaryl carbon centers through arylation of copper-mediated cross-dehydrogenative coupling between heteroaryl C(sp 2 )À H (36, 57) and tertiary C(sp 3 )À H (56) bond was demonstrated by Tang et al [36] The substrate scope studies of this protocol under optimized conditions [CuBr ( (62) and alkanes (63) using copper as catalyst. [37] The strategy involved the formation of C(sp 2 )À C(sp ) bond by the coupling of C(sp )À H/C(sp 3 )À H under mild condition [CuBr SMe 2 (10 mol%), 64 (15 mol%) as ligand DTBP (4 equiv. ), t BuONa (80 mol%), C 6 H 6 at 60-80°C for 24 h], affording the products in high yields (Scheme 20).…”

“…An intramolecular catalytic C(sp 2 )À H/C(sp 2 )À H dehydrogenative cross-coupling of 2-arylbenzaldehyde (77) using Cu(0)/Selectfluor was developed by Bao et al [39] The strategy could (Reproduced from Ref. [37] Copyright (2020), with permission from American Chemical Society.) synthesize xanthone derivatives (78) using mol% Cu(0), equiv.…”