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A generalized approach to the optimization and implementation of Buchwald-Hartwig reactions in flow is reported, through the combination of three key factors: a highly active palladium catalyst; a universal approach for continuous work-up and purification, and a methodology for catalyst recycling and reuse. The palladium N-heterocyclic carbene (NHC) pre-catalyst [Pd(IPr*)(cin)Cl] 4 (IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene; cin = η3-cinnamyl) is an excellent choice for continuous Buchwald-Hartwig reactions, due to its inherent high activity and stability. In preparation for running this reaction in flow (published concurrently), a detailed study has been carried out into its water stability, ultimately allowing the recycling of the catalyst in the organic phase up to 3 times in batch mode. A “right-first-time” work-up methodology has also been developed, resulting in a universal protocol that allows the selective extraction of the Buchwald-Hartwig product into the aqueous stream as a salt, while retaining the aryl bromide starting material in the organic stream with the catalyst, thus negating the requirement for further purification. It is therefore envisaged that this approach will particularly amenable to exploitation in the Pharmaceutical industry. An optimized, scalable synthesis of [Pd(IPr*)(cin)Cl] is also reported on multi-hundred gram scale.

The use of the ITent-based series of Pd-N-heterocyclic carbenes precatalysts (Tent= Tentacular) enables the Buchwald–Hartwig amine arylation reaction in apolar alkane solvents. The use of such solvents is rare because of their poor solvation properties. Nonetheless, they could be of interest for industrial applications, as they can be disposed of in an energetically favorable manner and may potentially simplify product isolation. The excellent solubility of the precatalysts permitted the desired products to be obtained in yields ranging from 75 to 96 %, even with deactivated and functionalized coupling partners.

Over the past few decades, furopyridines have emerged as key structural subunits prevalent in a number of natural products and structural analogues associated with interesting biological activities. Consequently, considerable efforts have been devoted to the synthesis of these fused heterocyclic scaffolds. This review covers the main methodologies reported in the literature for the preparation of furopyridines.

The direct S-arylation of unactivated arylsulfoxides catalyzed by [Pd(IPr*)(cin)Cl] is described. Several arylmethylsulfoxides were coupled to various aryl halides in moderate to good yields (17 examples, 34–85%). Scope, limitations, and reaction mechanism are discussed.

International audience; The furopyridine framework was chosen as a target for a lithiation study, in order to define the most effective conditions leading to the total functionalization of the heterocycle. Consequently, a detailed procedure for successive regioselective lithiations/electrophilic trapping of furo[3,2-b]pyridines is described and afforded several polyfunctionalized derivatives in good overall yields. A Pd-catalyzed cross-coupling reaction is also described and easily yielded the 7,7'-bifuro[3,2-b]pyridine.

The use of the ITent-based series of Pd-N-heterocyclic carbenes precatalysts (Tent= Tentacular) enables the Buchwald–Hartwig amine arylation reaction in apolar alkane solvents. The use of such solvents is rare because of their poor solvation properties. Nonetheless, they could be of interest for industrial applications, as they can be disposed of in an energetically favorable manner and may potentially simplify product isolation. The excellent solubility of the precatalysts permitted the desired products to be obtained in yields ranging from 75 to 96 %, even with deactivated and functionalized coupling partners.

The preparation of the novel, well-defined [Pd(IPr*)(3-Cl-pyridinyl)Cl2] complex is described. The steric parameters of the ligand as well as its reactivity in the Buchwald–Hartwig amination were directly compared to other [Pd(NHC)(3-Cl-pyridinyl)Cl2] and [Pd(IPr*)(LX)Cl)] precatalysts (LX = cinnamyl or acac). The title complex exhibits similar catalytic activity to [Pd(NHC)(3-Cl-pyridinyl)Cl2] congeners (NHC = IPr and SIPr) at room temperature. However, it also showed improved reactivity at low catalyst loading and high temperature (as low as 0.025 mol %). On the other hand, it proved to be as efficient as the previously reported [Pd(IPr*)(cinnamyl)Cl] complex, pointing to the most likely existence of a similar catalytically active species.

The well-defined [Pd(IPr*)(cinnamyl)Cl] complex is reported as one of the best N-heterocyclic carbene (NHC)-based pre-catalysts for the Buchwald–Hartwig amination reaction. This catalytic system displays high efficiency for the coupling of numerous (hetero)aryl chlorides, with a wide range of amines, at room temperature or at extremely low catalyst loading (as low as 0.025 mol%).

A very straightforward synthesis of [Pd(IPr*)(acac)Cl] has been developed from commercially available Pd(acac)2 and the easily prepared IPr*·HCl (acac = acetylacetonate; IPr* = N,N′-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene). The reactivity of the resulting complex [Pd(IPr*)(acac)Cl] (1) as a highly active PdII precatalyst for the Buchwald–Hartwig arylamination coupling has been explored. A wide range of substrates with varying electronic and steric demands of both coupling partners has been screened successfully. The chemoselectivity of the reaction was also explored by using aryl heterodihalides.

The efficient preparation of [Pd(Amphos)(cinnamyl)Cl)] and [Pd(Amphos)(TFA)(κ2-N,C-C6H4-CH2NMe2)] (Amphos = 4-(di-tert-butylphosphino)-N,N-dimethylaniline and TFA = trifluoroacetate), two new well-defined palladium precatalysts, is reported. These complexes prove highly active in the Buchwald–Hartwig amination reaction, allowing the coupling of a wide range of (hetero)aryl chlorides, including unactivated, neutral, and sterically hindered substrates, with a wide range of amines, including primary and secondary amines. Finally, the catalytic systems have proven efficient at low catalyst loadings ranging from 0.1 to 0.3 mol %.

A detailed procedure for successive regioselective lithiations of furo[2,3-c]pyridine is described by using n-BuLi and the [n-BuLi/LiDMAE] superbase. Several polysubstituted furo[2,3-c]pyridines have been efficiently synthesized and some of them were engaged in Pd- or Ni-catalyzed coupling reactions leading to 2,2'- or 7,7'-bifuro[2,3-c]pyridine ligands.

Over the past few decades, furopyridines have emerged as key structural subunits prevalent in a number of natural products and structural analogues associated with interesting biological activities. Consequently, considerable efforts have been devoted to the synthesis of these fused heterocyclic scaffolds. This review covers the main methodologies reported in the literature for the preparation of furopyridines.

This chapter presents an overview of developments using Pd–NHC systems in cross-coupling catalysis. The reactions examined are the major Pd-mediated transformations including those discovered by the 2010 Nobel Prize in Chemistry winners.

The title catalysts can be synthesized in eight steps from inexpensive and readily available 2-nitro-m-xylene.

The furopyridine framework was chosen as a target for a lithiation study, in order to define the most effective conditions leading to the total functionalization of the heterocycle. Consequently, a detailed procedure for successive regioselective lithiations/electrophilic trapping of furo[3,2-b]pyridines is described and afforded several polyfunctionalized derivatives in good overall yields. A Pd-catalyzed cross-coupling reaction is also described and easily yielded the 7,7'-bifuro[3,2-b]pyridine.

A straightforward and scalable eight-step synthesis of new N-heterocyclic carbenes (NHCs) has been developed from inexpensive and readily available 2-nitro-m-xylene. This process allows for the preparation of a novel class of NHCs coined ITent ("Tent" for "tentacular") of which the well-known IMes (N,N′-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene), IPr (N,N′-bis(2,6-di(2-propyl)phenyl)imidazol-2-ylidene) and IPent (N,N′-bis(2,6-di(3-pentyl)phenyl)imidazol-2-ylidene) NHCs are the simplest and already known congeners. The synthetic route was successfully used for the preparation of three members of the ITent family: IPent (N,N′-bis(2,6- di(3-pentyl)phenyl)imidazol-2-ylidene), IHept (N,N′-bis(2,6-di(4-heptyl) phenyl)imidazol-2-ylidene) and INon (N,N′-bis(2,6-di(5-nonyl)phenyl) imidazol-2-ylidene). The electronic and steric properties of each NHC were studied through the preparation of both nickel and palladium complexes. Finally the effect of these new ITent ligands in Pd-catalyzed Suzuki-Miyaura and Buchwald-Hartwig cross-couplings was investigated. Tentacular NHCs: A straightforward, scalable eight-step synthesis of N-heterocyclic carbenes (NHCs) has been developed using inexpensive and readily available 2-nitro-m-xylene, allowing the preparation of a class of NHCs designated ITent ("Tent" for "tentacular"). The electronic and steric properties of each NHC were studied through the preparation of both nickel and palladium complexes, and the effect of these new ITent ligands in Pd-catalyzed Suzuki-Miyaura and Buchwald-Hartwig cross-couplings was investigated.

Palladium complex PAL is an efficient catalyst at extremely low loading for the amination reaction of numerous aryl/pyridyl chlorides with primary or secondary amines at reflux temperature, or at some higher loading at room temperature.

The bigger the better: The new well-defined [Pd(IPr*)(cin)Cl] pre-catalyst is described. This complex proves to be highly active in the Suzuki-Miyaura cross-coupling for the synthesis of tetra-ortho-substituted biaryls under mild conditions. IPr* is reported as the largest N-heterocyclic carbene (NHC) to date for [Pd(NHC)(cin)Cl] complexes, explaining the high reactivity observed for this complex in this challenging transformation.

Palladium hydroxide dimers were prepared by reactions of CsOH with monomeric [Pd(NHC)(η3-allyl)Cl] starting materials. The dimers represent species proposed as intermediates in important cross-coupling reactions. These complexes were tested for their catalytic activity in Suzuki–Miyaura coupling and Buchwald–Hartwig aryl amination. The hydroxide complexes were susceptible to hydrogenolysis on exposure to H2 gas. Following H2O elimination and β-hydride elimination of an additional cinnamyl ligand, a Pd(0) species is formed which can react with other available ligands.

A new and efficient method to prepare bifunctionalized furopyridines, pyrazines, and pyridines is reported.

The scope and the limitations of 3-chloro-2-pyridinyl lithium condensation to aldehydes were envisioned de- pending on metallation conditions or condensation time and temperatures. The procedure was applied to various aromatic, aliphatic or functionalized aldehydes to afford a new and efficient access to 2-(polyhydroxyalkyl)pyridines. n Scheme 1. Selective functionalization of 3-chloropyridine induced by (n-BuLi/LiDMAE) superbase. In this previous study, we described the regioselective C- 2 functionalization of 3-chloropyridine (2) performed by a metallation at -60°C for 1h, in hexane as solvent, with super- base (n-BuLi/LiDMAE) (3 eq). Condensation reactions were afforded using various representative electrophiles, one was a carbonyl reagent (tBuCHO, 60% isolated yield). In agree- ment with these results, we reported here a detailed investi- gation to extend the scope of this condensation using a vari- ety of functionalized aldehydes. The best determined condi- tions led us to define an improved protocol for introducing polyhydroxylated moieties on pyridinic ring allowing the synthesis of 1a-b.

An efficient and rapid synthesis of furo[3,2-b]pyridine 1 is described using a one-pot Sonogashira coupling/heteroannulation sequence. Regioselective lithiation of this synthon was performed leading to various 2-substituted furo[3,2-b]pyridines. Some of them were used as substrates for short functional synthesis of polyheterocycles.

The scope and the limitations of 3-chloro-2-pyridinyl lithium condensation to aldehydes were envisioned de- pending on metallation conditions or condensation time and temperatures. The procedure was applied to various aromatic, aliphatic or functionalized aldehydes to afford a new and efficient access to 2-(polyhydroxyalkyl)pyridines. n Scheme 1. Selective functionalization of 3-chloropyridine induced by (n-BuLi/LiDMAE) superbase. In this previous study, we described the regioselective C- 2 functionalization of 3-chloropyridine (2) performed by a metallation at -60°C for 1h, in hexane as solvent, with super- base (n-BuLi/LiDMAE) (3 eq). Condensation reactions were afforded using various representative electrophiles, one was a carbonyl reagent (tBuCHO, 60% isolated yield). In agree- ment with these results, we reported here a detailed investi- gation to extend the scope of this condensation using a vari- ety of functionalized aldehydes. The best determined condi- tions led us to define an improved protocol for introducing polyhydroxylated moieties on pyridinic ring allowing the synthesis of 1a-b.

A highly effective solvent-free protocol for the Buchwald–Hartwig amination of unactivated aryl chlorides is described. The effect of various [Pd(NHC)] pre-catalyst systems on the reactivity has been studied. [Pd(IPr*)(cin)Cl] is reported as the complex of choice for the transformation.

Herein, we report an efficient method for the double functionalisation of lithiated halogenopyridines, -pyrazines or -furopyridines through a convenient one-pot electrophilic trapping/nucleophilic substitution sequence.