A Simple and Highly Efficient Iron Catalyst for a [2+2+2] Cycloaddition to Form Pyridines

Abstract

Transition-metal-catalyzed[2+2+2] cycloaddition reactions that use two alkynes and a nitrile is the most straightforward and powerful strategy for the construction of multisubstituted pyridines with high atom efficiency. [1,2] The iron-catalyzed [2+2+2] cycloaddition to form pyridines remains a great challenge in this field, [3,4] although significant efforts have been made in various catalytic systems (e.g. Co,[5] Ru, [6] Rh, [7] Ni, [8] Ti, [9] Zr/Ni [10] ) in the last few decades. Guerchais and co-workers described a stoichiometric reaction between an Fe I complex (Scheme 1, structure A) and alkynes with a 73 % yield.[4a] Meanwhile, Zenneck and co-workers developed a cycloaddition reaction catalyzed by an Fe 0 complex (Scheme 1, structure B), [4b,c] however, this approach gave low chemoselectivity and had a complicated procedure for catalyst preparation. A very recent example revealed that no pyridine products were observed from alkynes under iron catalyst even when nitrile was used as the solvent.[11] Therefore, the development of a simple and highly efficient iron catalyst to exclusively generate pyridine compounds would be a useful contribution to this area. Herein, we disclose the [2+2+2] cycloaddition of diynes and unactivated nitriles at room temperature using a simple iron salt as the catalyst precursor, thus resulting in the production of pyridines with up to 98 % yield of isolated product.Two important steps are generally involved in [2+2+2] cycloaddition: 1) formation of a metallacycle intermediate by oxidative cyclization and 2) subsequent reductive elimination to produce pyridines (the "common mechanism").[2] The formation of a metallacycle intermediate [12,13] from a low-valent metal species plays a crucial role in the whole process. Inspired by an investigation by Holland and co-workers revealing that alkynes bind more tightly than phosphines to low-valent iron center, [14] we envisioned that low-valent iron catalysts generated in situ from an inorganic iron salt and phosphine ligands might initiate the reaction through ligand exchange, and thereby promote the oxidative cyclization between an alkyne and an alkyne or a nitrile followed by the formation of metallacycle intermediate (Scheme 1, Step 2). Considering that the formation of benzene rings can be somewhat inhibited in the presence of a certain amount of nitrile compounds [4a] -the nature of the ligand has a dramatic effect on the reaction product-it is possible to generate pyridines with high efficiency when the appropriate iron salt and ligand are used.Initially, diyne 1 a and benzonitrile 2 a were used as model substrates for the optimization of the cycloaddition reaction conditions, and the results are summarized in Table 1. In the first instance, we employed the iron salt FeCl 3 as the catalyst precursor, 1,2-bis(diphenylphosphino)ethane (dppe) as the ligand, and 2 a as the solvent (Table 1, entries 1-4). No desired product was observed in the absence of dppe, as expected, and only trace amounts of 3 a were obtained when FeCl 3 /dp...

Ruthenium‐catalyzed [2+2+2] Cycloaddition of Diynes with Nitriles in Pure Water

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The transition metal-catalyzed [2+2+2] cycloaddition of two alkyne molecules and a nitrile, particularly involving catalysis by Co, Ru, Rh, Ni, Ti, and Fe species, [1][2][3][4][5][6] has been widely investigated as a valuable tool for the synthesis of substituted pyridines. [7,8] However, highly diluted conditions and techniques of slow addition are generally required to suppress the competing side reactions, such as dimerization and trimerization of the diynes.

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Recent advances in the iron-catalyzed cycloaddition reactions

“…Recently, Wang and co-workers [82] reported an ironcatalyzed [2+2+2] cycloaddition of diynes and unactivated…”

A Serendipitous Discovery: Nickel Catalyst for the Cycloaddition of Diynes with Unactivated Nitriles

“…A variety of transition-metal complexes (i.e., Co, Ru, Rh, Ni, and Fe) catalyze the cycloaddition of alkynes and nitriles to form pyridines. [1][2][3][4][5][6][7] Most of the catalysts generate pyridines through a mechanism that involves initial oxidative coupling of the alkynes and then subsequent insertion of the nitrile (i.e., formation of A, Scheme 1). [4d, 8] In contrast, nickelmediated cycloadditions are thought to undergo heterooxidative coupling between a single alkyne and the heteroatom-containing substrate, such as a nitrile, before insertion of the second alkyne (i.e., formation of B, Scheme 1).…”

“…[1][2][3][4][5][6][7] Most of the catalysts generate pyridines through a mechanism that involves initial oxidative coupling of the alkynes and then subsequent insertion of the nitrile (i.e., formation of A, Scheme 1). [1][2][3][4][5][6][7] Most of the catalysts generate pyridines through a mechanism that involves initial oxidative coupling of the alkynes and then subsequent insertion of the nitrile (i.e., formation of A, Scheme 1).…”