Xincheng Li

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.

A highly diastereo- and enantioselective copper(I)-catalyzed Henry reaction using a bis(sulfonamide)-diamine ligand.

A series of bis(sulfonamide)-diamine (BSDA) ligands were synthesized from commercially available chiral α-amino alcohols and diamines. The chiral BSDA ligand 3a, coordinated with Cu(I), catalyzes the enantioselective Henry reaction with excellent enantioselectivity (up to 99%). Moreover, with the assistance of pyridine, a CuBr-3a system promotes the diastereoselective Henry reaction with various aldehyde substrates and gives the corresponding syn-selective adduct with up to a 99% yield and 32.3:1 syn/anti selectivity. The enantiomeric excess of the syn adduct was 97%.

Highly Regioselective Migration of the Sulfonyl Group: Easy Access to Functionalized Pyrroles

The development of new reactions for the synthesis of diverse molecular frameworks is a challenging task in the field of modern organic chemistry. Chemistry of pyrroles continues to attract the interest of chemists, and new synthetic methods of these compounds occupy an important area of synthetic organic chemistry. In search of new routes for the synthesis of pyrroles through the design of new building blocks such as N-sulfonyl-protected azaenyne derivatives 1 (Scheme 1), we

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.

A Class of Benzene Backbone-Based Olefin-Sulfoxide Ligands for Rh-Catalyzed Enantioselective Addition of Arylboronic Acids to Enones

A class of readily available and easily tunable benzene backbone-based olefin-sulfoxide ligands was developed for the rhodium-catalyzed asymmetric conjugate addition reaction of arylboronic acids to enones with up to 97% yield and 97% ee.

Rhodium-catalyzed asymmetric conjugate addition of arylboronic acids to nitroalkenes using olefin-sulfoxide ligands.

An efficient rhodium/olefin-sulfoxide catalyzed asymmetric conjugate addition of organoboronic acids to a variety of nitroalkenes has been developed, where 2-methoxy-1-naphthyl sulfinyl functionalized olefin ligands have shown to be highly effective and are applicable to a broad scope of aryl, alkyl, and heteroaryl nitroalkenes.

Cyclization and N-iodosuccinimide-induced electrophilic iodocyclization of 3-aza-1,5-enynes to synthesize 1,2-dihydropyridines and 3-iodo-1,2-dihydropyridines.

Metal-free cyclization and N-iodosuccinimide-induced electrophilic iodocyclization of readily available 3-aza-1,5-enynes have been developed. The reactions selectively give 1,2-dihydropyridines and 3-iodo-1,2-dihydropyridines involving an aza-Claisen rearrangement and a 6π-electrocyclization step. Furthermore, the reaction could be carried out in 10 g scale for the synthesis of 1,2-dihydropyridines.

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.

A New Type of Bis(sulfonamide)-Diamine Ligand for a Cu(OTf)(2)-Catalyzed Asymmetric Friedel-Crafts Alkylation Reaction of Indoles with Nitroalkenes

Chiral bis(sulfonamide)-diamine served as new type of ligand for a Cu(OTf)(2)-catalyzed asymmetric Friedel-Crafts alkylation reaction of indoles with nitroalkenes. The desired products were obtained with up to 99% yield and 97% ee.

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.