Cobalt‐Catalyzed C4‐Selective Direct Alkylation of Pyridines

Abstract

A pyridine core is a ubiquitous structural motif found in many biologically active natural products and pharmaceuticals. The regioselective functionalization of pyridines, [1] such as the C2selective addition of highly reactive nucleophiles and C2selective deprotonation with a strong base followed by reactions with electrophiles, [2] has long been investigated by many researchers. Catalytic CÀH bond functionalization of pyridines provides atom- [3] and step-economical [4] methods for accessing various functionalized pyridines, and thus has attracted recent interest. [5][6][7][8][9][10][11][12][13][14][15][16] In many reports, a Lewis basic sp 2 nitrogen atom in the pyridine ring was utilized as the directing group, and CÀH bond activation by transition-metal catalysts occurred selectively at the C2 position. [5,7] In contrast, reports on the C3-or C4-selective catalytic CÀH bond functionalization of pyridines without an additional directing group are limited. [8][9][10][11] Thus, further studies into the development of new catalysts for C3-or C4-selective direct functionalization of pyridines are highly desirable. In 2010, Nakao, Hiyama, and co-workers, [10a] and Ong et al. [10b] independently reported the first C4-selective direct functionalization of pyridines through an oxidative addition/insertion/ reductive elimination sequence catalyzed by Ni 0 and bulky Lewis acids. There remains room for improvement in the C4selective direct functionalization of pyridines, however, especially in terms of catalyst loading.To realize the C4-selective alkylation of pyridines, we searched for a new catalyst system based on a different strategy, catalytic nucleophilic addition/rearomatization. [14][15][16] Our working hypothesis is shown in Scheme 1. Hydrometalation of alkenes with a metal hydride catalyst (I) would afford an alkyl-metal species (II). If the alkyl-metal species (II) has sufficient nucleophilicity, its addition to pyridine may afford a dihydropyridine intermediate (III). To realize an atom-economical catalytic process, rearomatization of pyridine without any oxidants and regeneration of the metalhydride catalyst (I) are required.We first screened various metal salts and hydride sources that fulfilled the requirements for Scheme 1. Selected results from the optimization studies are summarized in Table 1.

Alkylation of Pyridines at Their 4‐Positions with Styrenes plus Yttrium Reagent or Benzyl Grignard Reagents

“…For example, nucleophilic addition of organometallic reagents to pyridines takes place mostly at their 2-or 4-positions, among which the former appears more feasible, but the selectivity is often difficult to control. [1][2][3][4][5] A similar issue is also found in the alkylation of pyridines through CÀH bond activation, in which the reaction preferentially occurs at the 2-position of pyridines, [11,12] likely facilitated by the initial interaction between the metal reagents and the pyridine nitrogen. Thus, the highly regioselective substitution of pyridines at the 4-position has been less frequently encountered [4,5,12] and still calls for newer, simpler, or more dependable methods using inexpensive reagents.…”

“…Table 1 shows optimization of the above reaction, using 2-ethylpyridine (1 a) and styrene (2 a) as representative substrates and YCl 3 , BuLi, and DIBAL-H as reagents under the conditions shown in Equation (1). The reaction with one equivalent each of these reagents gave only a trace amount of the desired product 4 a ( [11][12][13][14] proved unsatisfactory. Table 2 summarizes the results of the preparation of 4-substituted pyridines under the optimal conditions determined in entry 7, Table 1.…”

“…[1,9] In addition to these, new syntheses through CÀH bond activation of pyridines have recently appeared. [10][11][12] When the synthesis starts with pyridines, an issue on the regioselection and its selectivity for the introduction of a side chain or a functional group arises. For example, nucleophilic addition of organometallic reagents to pyridines takes place mostly at their 2-or 4-positions, among which the former appears more feasible, but the selectivity is often difficult to control.…”

Studies on the Nature of Active Cobalt Species for the Production of Methane and Propylene in Catalytic Dehydrogenation of Propane

“…Low-valent cobalt catalysts are known to be efficient in C-H functionalization, such as hydroarylation of olefins [7,8], C-H/electrophiles coupling [9,10], addition of arylzinc reagents to alkynes [11,12]. For these reactions, it is speculated that the mechanism proceeds through a Co 1? intermediate and an oxidative addition/reductive elimination pathway.…”

Branch Selective Murai-type Alkene Hydroarylation Reactions

“…A Co-catalyzed protocol reported by Matsunaga, Kanai, and co-workers enables formal C-4-and branch-selective hydroarylation between styrenes and pyridines. 36 …”