Chunxiang Wang

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

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. 2] The iron-catalyzed [2+2+2] cycloaddition to form pyridines remains a great challenge in this field, 4] although significant efforts have been made in various catalytic systems (e.g. Co, Ru, Rh, Ni, Ti, Zr/Ni) in the last few decades. Guerchais and co-workers described a stoichiometric reaction between an Fe complex (Scheme 1, structure A) and alkynes with a 73 % yield. Meanwhile, Zenneck and co-workers developed a cycloaddition reaction catalyzed by an Fe complex (Scheme 1, structure B), 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. 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”). The formation of a metallacycle intermediate 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, 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—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 2a 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 FeCl3 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 3a were obtained when FeCl3/dppe was used as the catalyst in a 1:1 ratio (6 % yield, entry 2). Given that the amount of ligand can strongly affect the catalytic efficiency, different metal/ligand ratios were screened. The yield was dramatically improved to 97% when a 1:2 mixture of metal and ligand was used (entry 3), however, further increasing the ratio to 1:3 drastically decreased the yield (entry 4, 38%). Sequential investigations of other iron salts, solvents, and ligands (entries 5–9) showed that the combination of FeBr2 or FeI2 with 1,3-bis(diphenylphosphino)propane Scheme 1. Iron catalysts used for the [2+2+2] cycloaddition to form pyridines. TMS= trimethylsilyl.

Iron-Catalyzed Cycloaddition Reaction of Diynes and Cyanamides at Room Temperature

An iron-catalyzed [2 + 2 + 2] cycloaddition reaction of diynes and cyanamides at room temperature is reported. Highly substituted 2-aminopyridines were obtained in good to excellent yields with high regioselectivity. Insights toward the reaction process were investigated through in situ IR spectra and control experiments. In this iron-catalyzed cycloaddition reaction, the active iron species was generated only in the presence of both alkynes and nitriles. The lower reaction temperature, broad substrates scope, and inversed regioselectivity make it a complementary method to the previously developed iron catalytic system.

Rhodium‐Catalyzed CH Annulation of Nitrones with Alkynes: A Regiospecific Route to Unsymmetrical 2,3‐Diaryl‐Substituted Indoles

The direct C-H annulation of anilines or related compounds with internal alkynes provides straightforward access to 2,3-disubstituted indole products. However, this transformation proceeds with poor regioselectivity in the synthesis of unsymmetrically 2,3-diaryl substituted indoles. Herein, we report the rhodium(III)-catalyzed C-H annulation of nitrones with symmetrical diaryl alkynes as an alternative method to prepare 2,3-diaryl-substituted N-unprotected indoles with two different aryl groups. One of the aryl substituents is derived from N=C-aryl ring of the nitrone and the other from the alkyne substrate, thus providing the indole products with exclusive regioselectivity.

From Propargylamides to Oxazole Derivatives: NIS-Mediated Cyclization and Further Oxidation by Dioxygen

NIS-mediated iodocyclization of N-sulfonyl propargylamides for the synthesis of various oxazolidines and iodoalkylidenedihydrooxazoles via a 5-exo-dig process is developed. The resulting iodoalkylidenedihydrooxazoles can be further transformed into the corresponding oxazoles in the presence of dioxygen.

Rhodium-Catalyzed (2+2+2) Cycloaddition of Oximes and Diynes To Give Pyridines

Oximes and diynes undergo efficient cycloaddition in the presence of a catalytic amount of a cationic rhodium(I)/dppf complex (see scheme). Spontaneous dehydration of the initially formed cycloadducts leads to the formation of a variety of substituted pyridines in moderate to good yields. The transformation could also be achieved in a one-pot procedure using aldehydes.

Synthesis of Tetrasubstituted Pyrroles from Terminal Alkynes and Imines

Tetrasubstituted pyrroles can be obtained via the reaction of terminal alkynes and imines using (n)BuLi as the base in one step with high chemoselectivity (method 1). Alternatively, the intermediate propargylamines can also react with imines to afford tetrasubstituted pyrroles when using LiHMDS as the base (method 2), which provides a complementary method to construct the pyrroles with different substituents.

Rhodium‐Catalyzed Cyclization of Diynes with Nitrones: A Formal [2+2+5] Approach to Bridged Eight‐Membered Heterocycles

N-aryl-substituted nitrones were employed as five-atom coupling partners in the rhodium-catalyzed cyclization with diynes. In this reaction, the nitrone moiety served as a directing group for the catalytic C-H activation of the N-aryl ring. This formal [2+2+5] approach allows rapid access to bridged eight-membered heterocycles with broad substrate scope. The results of this study may provide new insight into the chemistry of nitrones and find applications in the synthesis of other heterocycles.

Ruthenium-Catalyzed C-C Bond Cleavage of 2H-Azirines: A Formal [3+2+2] Cycloaddition to Fused Azepine Skeletons.

2H-azirines can serve as three-atom synthons by C-C bond cleavage, however, it involves a high energy barrier under thermal conditions (>50.0 kcal mol(-1) ). Reported is a ruthenium-catalyzed [3+2+2] cycloaddition reaction of 2H-azirines with diynes, thus leading to the formation of fused azepine skeletons. This approach features an unprecedented metal-catalyzed C-C bond cleavage of 2H-azirines at room temperature, and the challenging construction of aza-seven-membered rings from diynes. The results of this study provide a new reaction pattern for constructing nitrogen-containing seven-membered rings and may find applications in the synthesis of other complex heterocycles.

Nickel-catalyzed [3 + 2] cycloaddition of diynes with methyleneaziridines via C–C bond cleavage

A Ni-catalyzed [3 + 2] cycloaddition via C-C bond cleavage of methyleneaziridines under mild conditions was developed. This reaction gave substituted pyrroles with excellent regioselectivity and a pendant alkyne unit, which is advantageous for further derivatization.

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

One ring to bind them: An efficient method for synthesizing highly functionalized pyridine derivatives from diynes and nitriles is described. The reaction system involves Cp*Ru(COD)Cl/tppts-catalyzed [2+2+2] cycloaddition in pure water. Without being accompanied by diyne dimerization or trimerization byproducts, the desired products can be obtained in moderate to high yields.