Developing ligands for palladium(II)-catalyzed C-H functionalization: intimate dialogue between ligand and substrate

Abstract

Homogeneous transition-metal-catalyzed reactions are indispensable to all facets of modern chemical synthesis. It is thus difficult to imagine that for much of the early 20th century, the reactivity and selectivity of all known homogeneous metal catalysts paled in comparison to their heterogeneous and biological counterparts. In the intervening decades, advances in ligand design bridged this divide, such that today some of the most demanding bond-forming events are mediated by ligand-supported homogeneous metal species. While ligand design has propelled many areas of homogeneous catalysis, in the field of Pd(II)-catalyzed C-H functionalization, suitable ligand scaffolds are lacking, which has hampered the development of broadly practical transformations based on C-H functionalization logic. In this Perspective, we offer an account of our research employing three ligand scaffolds, mono-N-protected amino acids, 2,6-disubstituted pyridines, and 2,2'-bipyridines, to address challenges posed by several synthetically versatile substrate classes. Drawing on this work, we discuss principles of ligand design, such as the need to match a ligand to a particular substrate class, and how ligand traits such as tunability and modularity can be advantageous in reaction discovery.

Figure 1

“Privileged” chiral ligands for asymmetric transition metal catalysis.

Figure 2

“Privileged” achiral ligands for high kinetic reactivity in transition metal catalysis.

Figure 3

Selected examples of commercially available BINOL derivatives.

Figure 4

(a) Modular synthesis of chiral PHOX-type ligands. (b) Representative PHOX ligands.

Figure 5

Aryl- and alkylcarboxylic acids, representative starting material classes that are abundant in quantity and rich in structural diversity

Figure 6

Ligand scaffolds discussed in this section.

Figure 7

Relevant examples of Pd(II)(Py)_nL_n complexes that have been characterized by X-ray diffraction.^,–

Scheme 1

Application of a diverse array of catalyst/ligand structures to asymmetric transformations of olefins. (a) Asymmetric hydrogenation of olefins by Noyori^, and Pfaltz. (b) Asymmetric epoxidation of olefins by Sharpless^, and Jacobsen. (c) Ligand structures.

Scheme 2

Application of sterically bulky, electron-rich phosphine ligands in the Suzuki–Miyaura cross-coupling of unactivated arylchlorides with boronic acids, as reported independently by the groups of (a) Buchwald and (b) Fu.

Scheme 3

Novel retrosynthetic disconnections enabled by our methodology: routes to (a) the kinamycins and (b) (+)-lithospermic acid.

Scheme 4

Diverse Pd(II)-catalyzed C–H functionalization of (a) benzoic acids^– and (b) benzoic acid–derived N-aryl amides^– reported by our group.

Scheme 5

Enantioselective Pd(II)-catalyzed C–H activation using a chiral ligand.

Scheme 6

(a) Disastereoselective C(sp³)–H iodination of gem-dimethyl groups using a removable chiral oxazoline auxiliary. (b) General catalytic cycle for C–H iodination via Pd(II)/Pd(IV) catalysis. (c) Model for diastereocontrol, including proposed transition state structure.

Scheme 7

General catalytic cycle for C–H/R–BX_n cross-coupling via Pd(II)/Pd(0) catalysis.

Scheme 8

(a) Racemic route to dimeric palladacycle 122 from prochiral starting material 120. (b) Initial hypothesis for achieving stereoinduction in the C–H cleavage step through use of a chiral carboxylate ligand.

Scheme 9

Catalytic enantioselective C(sp³)–H activation of 151.

Scheme 10

Working stereomodel, as supported by computational studies.^,–

Scheme 11

Enantioselective C(sp²)–H olefination of diphenylacetic acid derivative 162.

Scheme 12

General catalytic cycle for C–H olefination via Pd(II)/Pd(0) catalysis.

Scheme 13

Ligand-promoted diolefination of hydrocinnamic acid (197). The mono-olefinated product (35% conv.) was also observed by ¹H NMR, but was not isolated.

Scheme 14

Ligand-promoted ortho-C–H functionalization of phenethyl alcohols: (a) olefination and (b) carbonylation. (c) General catalytic cycle C–H carbonylation via Pd(II)/Pd(0) catlaysis; Nu = generic nucleophile.

Scheme 15

Ligand-promoted ortho-C–H olefination of (a) benzylsulfonamides (204) and (b) phenethylethers (206).

Scheme 16

Ligand-promoted meta-C–H olefination of hydrocinnamic acid derivative 209 using an end-on template approach.

Scheme 17

(a) Initial discovery of Pd(II)-mediated C–H olefination using stoichiometric complex 211 by Fujiwara and Moritani in 1967. (b) Distribution of positional isomers (ortho-, meta- and para215) in the stoichiometric Pd(II)-mediated C–H olefination of toluene 214.

Scheme 18

Representative examples of tactics for controlling positional selectivity in C–H olefination: (a) intermolecular ortho-C–H olefination of N-(p-tolyl)acetamide (216) by de Vries and van Leeuwen (b) intramolecular C–H olefination of N-methyl indole substrate 219 by Stoltz.

Scheme 19

Sequential C–H functionalization route to tetra-substituted arene 240.

Scheme 20

Equilibrium species observed based on structural and spectroscopic studies.

Scheme 21

(a) Ligand-promoted methylene C(sp³)–H arylation of butanoic acid derivative 244. (b) General catalytic cycle for C–H arylation with aryl iodides via Pd(II)/Pd(IV) catalysis.

Scheme 22

Literature precedents for pyridine C–H functionalization with Pd(II) catalysts: (a) C2-selective C–H olefination of pyridine N-oxide (248); (b) C4-selective C–H/R–B(OH)₂ cross-coupling of 2,3,5,6-tetrafluoropyridine (251).

Scheme 23

Postulated coordination equilibrium of pyridine with Pd(II): unproductive N-bound (left) and productive π-bound (right).

Scheme 24

Expedient synthesis of (±)-preclamol using C3-selective C–H arylation.