Introduction to Spatial Anion Control for Direct C–H Arylation

Abstract

C–H activation of functionally rich molecules without the need for directing groups promises shorter organic syntheses and late-stage diversification of molecules for drug discovery. We highlight recent examples of palladium-catalyzed nondirected functionalization of C–H bonds in arenes as limiting substrates with a focus on the development of the concept of spatial anion control for direct C–H arylation.1 C–H Activation and the CMD Mechanism2 Nondirected C–H Functionalizations of Arenes as Limiting Substrates3 Nondirected C–H Arylation4 Spatial Anion Control for Direct C–H Arylation5 Coordination Chemistry with Spatial Anion Control6 Conclusion

Control over Anion Coordination on Pd(II), Cu(I), and Ag(I) with Regioisomeric Phosphine‐Carboxylate Ligands

“…A related design of rigid backbones for carboxylates was used in our earlier work on bis(carboxylate) systems (Figure 1d). [67][68][69][70] To achieve the appropriate geometries for binding of both donors in the carboxylate-phosphine system, a disubstituted benzene is used as a spacer group. We hypothesized that the different geometric constraints imposed by the three potential substitution patterns on the central benzene group (1,2-, 1,3-, and 1,4À ) might selectively favor the three coordination modes of the carboxylate group (cis-k 1 , k 2 , and trans-k 1 , respectively).…”

“…[42,59] Furthermore, the design of rigid backbones that offer precise control over anion coordination geometry can be an enabling factor for catalytic reactivity. For example, our group showed that spatial anion control on palladium by using rigid bis(carboxylate) ligands can enable, under ambient conditions, direct CÀ H arylation of non-activated arenes as limiting [60][61][62][63][64][65][66] reactants (Figure 1d), [67][68][69][70] a reaction that is otherwise a challenge even at elevated temperatures. [71][72][73][74][75] Although the nature and the binding mode of polyatomic anions, such as carboxylates, is of high relevance for transition metal catalysis in general, the ligand systems that offer precise control over anion binding geometry are underdeveloped in the area of coordination chemistry.…”

Site‐Selective C−H Arylation of Diverse Arenes Ortho to Small Alkyl Groups

“…However, in a few cases, significant functionalization next to small alkyl substituents was observed and, in the case of indoprofen methyl ester, arylation next to the methylene group was preferred (Figure 2a, right). Endocyclic methylene substituents are present in a diverse range of pharmaceutically relevant arene classes, but substrate‐limited arylations of non‐activated arenes are rare [49, 58–60] and, in particular, sites ortho to alkyl groups are not readily accessible [48, 49] . Therefore, in order to study the observed selectivity, we started the investigation by using lactone 1 a (phthalide), which possesses an electronically similar arene, but lacks the extended structure of indoprofen, which might potentially influence the selectivity.…”

Site‐Selective C−H Arylation of Diverse Arenes Ortho to Small Alkyl Groups

“…[58] However, in a few cases, significant functionalization next to small alkyl substituents was observed and, in the case of indoprofen methyl ester, arylation next to the methylene group was preferred (Figure 2a, right). Endocyclic methylene substituents are present in a diverse range of pharmaceutically relevant arene classes, but substrate-limited arylations of non-activated arenes are rare [49,[58][59][60] and, in particular, sites ortho to alkyl groups are not readily accessible. [48,49] Therefore, in order to study the observed selectivity, we started the investigation by using lactone 1 a (phthalide), which possesses an electronically similar arene, but lacks the extended structure of indoprofen, which might potentially influence the selectivity.…”