Rapid progress in the fields of organometallic chemistry and homogeneous catalysis has made it possible for synthetic chemists to consider using ubiquitous yet unreactive C-H bonds as starting points to construct complex organic molecules. However, a majority of the C-H functionalization reactions currently in use require noble transition metal catalysts and harsh reaction conditions, so researchers have placed a priority on the development of mild and cost-effective catalysts. Given this situation, we wondered whether earth-abundant first-row transition metals could emulate the reactivity of a noble transition metal catalyst and carry out similar C-H functionalization reactions at a lower cost and under milder conditions. We also wondered whether we could use first-row transition metals to achieve hitherto unknown, but useful, C-H functionalization reactions. This Account summarizes our research on the development of three different types of C-H functionalization reactions using low-valent cobalt catalysts: (1) hydroarylation of alkynes and olefins, (2) ortho C-H functionalization with electrophiles, and (3) addition of arylzinc reagents to alkynes involving 1,4-cobalt migration. Although synthetic chemists have previously paid little attention to cobalt in designing catalytic C-H functionalization reactions, earlier studies, particularly those on stoichiometric cyclometalation, inspired us as we developed the hydroarylation and ortho C-H functionalization reactions. In these transformations, we combined a cobalt precatalyst, a ligand (such as phosphine or N-heterocyclic carbene (NHC)), and Grignard reagent to generate low-valent cobalt catalysts. These novel catalysts promoted a series of pyridine- and imine-directed hydroarylation reactions of alkynes and olefins at mild temperatures. Notably, we observed branched-selective addition to styrenes, which highlights a distinct regioselectivity of the cobalt catalyst compared with typical rhodium and ruthenium catalysts. The combination of a cobalt-NHC catalyst and a Grignard reagent allows directed aromatic C-H functionalizations with electrophiles such as aldimines, aryl chlorides, and alkyl chlorides or bromides. This second reaction has a particularly broad scope, allowing us to introduce secondary alkyl groups at the ortho position of aryl imines, a difficult reaction to carry out by other means. Serendipitously, we found that a cobalt-Xantphos complex catalyzed the third type of C-H functionalization: the addition of an arylzinc reagent to an alkyne to afford ortho-alkenylarylzinc species through a 1,4-cobalt migration. This "migratory arylzincation" allowed us to quickly construct a diverse group of functionalized benzothiophenes and benzoselenophenes. Collectively, our studies of cobalt catalysis have provided cost-effective catalysts and milder conditions for existing C-H functionalizations and have led to some unprecedented, attractive chemical transformations.

Ternary catalytic systems consisting of cobalt salts, phosphine ligands, and Grignard reagents promote addition of arylpyridines and imines to unactivated internal alkynes with high regio- and stereoselectivities. Deuterium-labeling experiments suggest that the reaction involves chelation-assisted oxidative addition of the aryl C-H bond to the cobalt center and insertion of the C-C triple bond into the Co-H bond, followed by reductive elimination of the resulting diorganocobalt species.

Cobalt-phosphine and cobalt-carbene catalysts have been developed for the hydroarylation of styrenes via chelation-assisted C-H bond activation, to afford branched and linear addition products, respectively, in a highly regioselective fashion. Deuterium-labeling experiments suggested a mechanism involving reversible C-H bond cleavage and olefin insertion steps and reductive elimination as the rate- and regioselectivity-determining step.

We report here cobalt-N-heterocyclic carbene catalytic systems for the ortho alkylation of aromatic imines with alkyl chlorides and bromides, which allows the introduction of a variety of primary and secondary alkyl groups at room temperature. The stereochemical outcomes of the reaction of secondary alkyl halides suggest that the present reaction involves single-electron transfer from a cobalt species to the alkyl halide to generate the corresponding alkyl radical. A cycloalkylated product obtained by this method can be transformed into unique spirocycles through manipulation of the directing and cycloalkyl groups.

A cobalt-N-heterocyclic carbene catalyst, in combination with an appropriate Grignard reagent, promotes a chelation-assisted aromatic C-H functionalization reaction via addition to an aromatic aldimine.

Chelation-assisted C À H activation followed by insertion of an unsaturated molecule offers a straightforward, regioselective, and atom-economical method for CÀC bond formation. [1] While rare-transition-metal catalysts (e.g. Ru, Rh, Pd) have played major roles in this and related types of CÀH bond functionalization, the development of cost-effective alternatives has attracted increasing interest.[2] We recently developed cobalt-phosphine and cobalt-carbene catalysts that promote ortho alkenylation and ortho alkylation reactions of aryl pyridine and imine derivatives by insertion of alkynes and styrenes, respectively.[3] These reactions represent the recent emergence of cobalt catalysis for CÀH bond functionalization; [4][5][6] cobalt catalysis is attractive because of the low cost of the catalysts as well as the unique reactivities or selectivities often achieved. [7] We report herein a significant expansion of the scope of this chemistry, achieved with cobalt-phenanthroline (L1 or L2) catalysts, which allow the ortho alkylation of aromatic imines with a variety of olefins under mild reaction conditions (Scheme 1). [8][9][10] From the screen of the cobalt catalysts for the addition of the acetophenone imine 1 a (PMP = p-methoxyphenyl) to vinyltrimethylsilane (2 a, 1.2 equiv), we identified 1,10-phenanthroline (L1) as an inexpensive and effective ligand (Table 1). Thus, the reaction took place smoothly at room temperature (20 8C) in the presence of a cobalt catalyst generated from CoBr 2 (5 mol %), L1 (5 mol %), and tBuCH 2 MgBr (40 mol %) to afford the alkylation product 3 a within 6 hours, in 85 % yield upon isolation (Table 1, entry 1). No dialkylation product was observed. The roomtemperature conditions are in stark contrast to those used for the related reactions of imines under rhodium or ruthenium catalysis, which typically require heating at 130-150 8C. [8,9] Among other phenanthroline-type ligands, bathophenanthroline performed as efficiently as L1 (Table 1, entries 2-4). The use of other Grignard reagents such as MeMgCl and Me 3 SiCH 2 MgCl led to lower yields (Table 1, entries 5 and 6). Little conversion was observed when the amount of tBuCH 2 MgBr was reduced to 20 mol % (Table 1, entry 7). The cobalt-phosphine and cobalt-carbene catalysts developed previously by our group [3] were much less effective (Table 1, entries 8-10).The optimized catalytic system was applicable to a wide variety of aromatic imines (Table 2). Tolerated substituents on the aromatic ring included methoxy (3 b, 3 j), chloro (3 d, 3 f), fluoro (3 i), trifluoromethyl (3 g), and cyano (3 h) groups (Table 2, entries 1, 3, and 5-9), although the product yields in the latter two cases were modest. An imine derived from 4-bromoacetophenone did not participate in the reaction but afforded a product resulting from the cross-coupling at the CÀ Br bond with the Grignard reagent (< 5 %). Imines derived Scheme 1. ortho Alkylation of aromatic imines with a cobalt-phenanthroline catalyst. [a] Reaction was performed on a 0.3 mmol scale at 0.3 m...

An ortho-arylation reaction of aromatic imines with aryl chlorides has been achieved using a cobalt-N-heterocyclic carbene catalyst in combination with a neopentyl Grignard reagent. The reaction takes place at room temperature to afford biaryl products in moderate to good yields.

A mild and efficient route for the synthesis of quinolines and polycyclic quinolines via Friedländer annulation, utilizing molecular iodine (1 mol%) as a new catalyst, is described.