Copper‐Catalyzed Remote C(sp³)−H Trifluoromethylation of Carboxamides and Sulfonamides

Abstract

Reported herein is an unprecedented protocol for trifluoromethylation of unactivated aliphatic C(sp3)−H bonds. With Cu(OTf)2 as the catalyst, the reaction of N‐fluoro‐substituted carboxamides (or sulfonamides) with Zn(CF3)2 complexes provides the corresponding δ‐trifluoromethylated carboxamides (or sulfonamides) in satisfactory yields under mild reaction conditions. A radical mechanism involving 1,5‐hydrogen atom transfer of N‐radicals followed by CF3‐transfer from CuII−CF3 complexes to the thus formed alkyl radicals is proposed.

Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated δ C–H Cyanation

“…However, recently, the first examples of d C-C formation have been enabled by intercepting this radical translocation to afford acyclic, d-functionalized amides. [11][12][13][14][15][16][17][18][19][20] Nonetheless, development of enantioselective methods for termination of an HAT pathway remains an ongoing challenge [21][22][23][24] -both for the classic d C-H amination as well as for recent interrupted methods for d C-H functionalization. In fact, with the exception of a single example of d C-H arylation from our lab (65% ee), 25 all known remote C-H functionalizations via N-radical relays are racemic.…”

Trifluoromethylation of Alkyl Radicals: Breakthrough and Challenges†

“…The catalytic cycle in Scheme 5 paved the road for the design of copper‐catalyzed methods of radical trifluoromethylation. For example, by replacing NFSI with N‐fluoro‐substituted amides or sulfonamides ( 6 ) and taking advantage of 1,5‐H migration of N‐radicals, the copper‐catalyzed reaction led to remote aliphatic C–H trifluoromethylation of carboxamides and sulfonamides (to afford products 7 ), [ 6 ] as shown in Scheme 6. Furthermore, the use of alkenes ( 8 ) in place of alkylarenes 4 as substrates resulted in the aminotrifluoromethylation of alkenes (to give 9 ) with high regioselectivity opposite to those driven by CF 3 radical addition.…”

Enantioselective Copper-Catalyzed Cyanation of Remote C(sp3)-H Bonds Enabled by 1,5-Hydrogen Atom Transfer

“…Starting from the pioneering work of Hofmann (Hofmann, 1883), known as Hofmann–Lӧffler–Freytag (HLF) reaction with N-haloamines used as precursors to generate N-centered radical (Hofmann, 1883, Lӧffler and Freytag, 1909, Wolff, 1963, Neale, 1971, Mackiewicz and Furstoss, 1978), the selective cleavage of remote C(sp 3 )-H bonds via 1,5-HAT process is well documented (Robertson et al., 2001, Čeković, 2003, Chiba and Chen, 2014, Stateman et al., 2018, Chu and Rovis, 2016, Chu and Rovis, 2018, Martínez and Muñiz, 2015, Wappes et al., 2016, Choi et al., 2016, Xia et al., 2018, Na and Alexanian, 2018). Although the early examples utilize transition metal to facilitate electron transfer, to further expand the scope of this remote C(sp 3 )-H functionalization process, many domino processes involving a metal-catalyzed cross-coupling pathway have developed (Scheme 1A) (Zhou and Andrus, 2002, Zhang et al., 2016, Zhang et al., 2019a, Zhang et al., 2019b, Zhang et al., 2019c; Wang et al., 2018, Groendyke et al., 2016, Li et al., 2018, Liu et al., 2019, Bao et al., 2019). With the generation of N-centered radical initiating remote hydrogen transfer, the following cross-coupling reactions enabled by the recapture of in situ -generated carbon radical could be achieved with transition metals (Groendyke et al., 2016, Li et al., 2017, Li et al., 2018, Liu et al., 2019, Bao et al., 2019, Zhang et al., 2019a, Zhang et al., 2019b, Zhang et al., 2019c, Yu et al., 2014).…”

“…Although the early examples utilize transition metal to facilitate electron transfer, to further expand the scope of this remote C(sp 3 )-H functionalization process, many domino processes involving a metal-catalyzed cross-coupling pathway have developed (Scheme 1A) (Zhou and Andrus, 2002, Zhang et al., 2016, Zhang et al., 2019a, Zhang et al., 2019b, Zhang et al., 2019c; Wang et al., 2018, Groendyke et al., 2016, Li et al., 2018, Liu et al., 2019, Bao et al., 2019). With the generation of N-centered radical initiating remote hydrogen transfer, the following cross-coupling reactions enabled by the recapture of in situ -generated carbon radical could be achieved with transition metals (Groendyke et al., 2016, Li et al., 2017, Li et al., 2018, Liu et al., 2019, Bao et al., 2019, Zhang et al., 2019a, Zhang et al., 2019b, Zhang et al., 2019c, Yu et al., 2014). As our continuous efforts on selective cleavage of remote aliphatic C(sp 3 )-H via a 1,5-HAT process (Scheme 1B) (Wang et al., 2017a, Wang et al., 2017b), we envisioned that the recapture of in situ -generated carbon radical of 1,5-HAT by chiral metal catalyst, followed by reductive elimination from the chiral metal complex would realize enantioselective C(sp 3 )–H functionalizations, thus providing a convenient entry to optically pure δ-cyano amines and their pharmaceutical derivatives (Figure 1) (Sugimoto et al., 2000, van de Waterbeemd et al., 2001, Abdel-Rahman et al., 2002).…”