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...

Iron Catalysis in Organic Synthesis

“…1232 The transformation was achieved using a catalyst system consisting of iron(II) iodide and 1,3-bis-(diphenylphosphino)propane (DPPP). Zinc powder was required to activate the iron species by reduction.…”

Iron Catalysis in Synthetic Chemistry

“…In 2006, Holland and co-workers (18) revealed that alkyne binding to a low-valent iron metal center is particularly stronger than that of phosphine. Inspired by this report, Wan and co-workers (19) developed an iron catalyst comprising of readily available FeI 2 and dppp [1,3-bis(diphenylphosphino)propane] as the phosphine ligand in the presence of Zn dust, which served as the reducing agent (Scheme 11). Efficient synthesis of pyridines was observed only at rt starting from diynes and a slight excess of nitriles in THF an unsymmetrical diyne and acetonitrile indicated a ferracyclopentadiene intermediate that might not be involved in the overall catalytic system.…”

“…In 2002, Nguyen and co-workers (38) reported the olefin cyclopropanation using μ-oxo-bis[(salen)iron(III)] complexes [salen = N,N´-bis (3,5- (16)(17)(18)(19)(20) (Scheme 20). Thus, this (salen)iron complex (16) can be used as an efficient, selective, and inexpensive metal alternative to a widely used ruthenium(II) salen complex.…”

Iron-Catalyzed Formation of 2-Aminopyridines from Diynes and Cyanamides

“…4 Shortly after our initial report, Wan and co-workers published an iron-catalyzed synthesis of pyridines from diynes and nitriles (eq 2). 5 Unfortunately, relatively high catalyst loadings were required in both systems. In addition, these systems either gave pyridines in moderate yields (former) or required ten to twenty molar equivalents of nitrile (latter).…”