Nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts enabled by NN2 pincer ligand

Abstract

Alkynes are amongst the most valuable functional groups in organic chemistry and widely used in chemical biology, pharmacy, and materials science. However, the preparation of alkyl-substituted alkynes still remains elusive. Here, we show a nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts. Key to the success of this coupling is the development of an easily accessible and bench-stable amide-type pincer ligand. This ligand allows naturally abundant alkyl amines as alkylating agents in Sonogashira reactions, and produces diverse alkynes in excellent yields under mild conditions. Salient merits of this chemistry include broad substrate scope and functional group tolerance, gram-scale synthesis, one-pot transformation, versatile late-stage derivatizations as well as the use of inexpensive pre-catalyst and readily available substrates. The high efficiency and strong practicability bode well for the widespread applications of this strategy in constructing functional molecules, materials, and fine chemicals.

Direct Deaminative Functionalization

“…With few exceptions, transformations of amines into other functional groups rely on preactivation strategies, thus requiring a minimum of two distinct transformations to accomplish one desired interconversion (Figure A). The classical example of this is conversion of the amino group to a diazonium ion, , with more recent protocols employing Katrizky-type pyridinium salts − or electron-rich imines. , A rare instance of a direct deaminative functionalization was recently reported by Cornella, , in which in situ formation of a pyridinium ion allows deaminative functionalization via an S N Ar mechanism for electron-poor (hetero)­aromatics. The rarity of one-step amine diversification processes is a stark reminder of the inadequacies in this area of synthetic chemistry.…”

A porphyrin-triazatruxene dyad for ratiometric two-photon fluorescent sensing of intracellular viscosity

“…18 The dyad was synthesized by connecting a triazatruxene unit (TAT-E) 22 with a meso-brominated porphyrin derivative (ZnPor-Br) via a Sonogashira cross-coupling reaction. 27 The A3B-type intermediate ZnPor-Br was prepared by a cyclic condensation reaction of a benzaldehyde derivative with two different dipyrromethanes, 28 followed by bromination and metalation. The dyad and new intermediates were characterized by NMR spectroscopy, mass spectrometry and elemental analysis (Scheme S1 and Fig.…”

Nickel-Catalyzed Deaminative Allenylation of Amino Acid Derivatives: Catalytic Activity Enhanced by an Amide-Type NN2 Pincer Ligand

“…Inspired by the elegant transformation of Katritzky salts and our recent work on nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts, we disclose herein the general and efficient deaminative allenylation of amino acid derivatives with terminal alkynes by nickel catalysis under mild conditions (Scheme B). Key to the success of this challenging coupling is the development of a novel, electron deficient, and sterically encumbered amide-type NN 2 pincer ligand, which enables rapid access to allenes in a convenient and straightforward manner.…”

“…In addition, the racemic product obtained in the reaction of enantioenriched 1a further illustrated the involvement of radical species in this process (Scheme S1). To gain more insight into the reaction mechanism, Ni-alkynyl species Int-1 was prepared according to our previous method . To our delight, it exhibited excellent catalytic activity under otherwise identical conditions, affording product 3c in 80% yield (Scheme c).…”

“…The initial step of this coupling is likely relevant to the alkyl radical produced from pyridinium salt 1 through thermal decomposition or nickel-promoted inner-sphere single-electron transfer . However, other alternative routes, such as the reaction of complex A with 2 equiv of a terminal alkyne to form a more electron-rich Ni bis­(acetylide) intermediate to initiate the process, cannot yet be completely ruled out. , …”