Minyan Li

Palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions with aryl chlorides.

A regioselective arylation of 1,1,3-triaryl-2-azaallyl anions with aryl chlorides is described. The palladium-NIXANTPHOS-based catalyst affords diarylmethylamine derivatives in good yield and without product isomerization. A gram scale sequential one-pot ketimine synthesis/arylation protocol was also developed.

Synthesis of diarylmethylamines via palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions

Diarylmethylamines are of great interest due to their prevalence in pharmaceutical chemistry. As a result, new methods for their synthesis are in demand. Herein, we report a versatile protocol for the synthesis of diarylmethylamine derivatives involving palladium-catalyzed arylation of in situ generated 2-azaallyl anion intermediates. The 2-azaallyl anions are generated by reversible deprotonation of readily available aldimine and ketimine precursors. Importantly, the arylated aldimine and ketimine products do not undergo isomerization under the reaction conditions. Scale-up of the arylation and hydrolysis of the resulting products to furnish diarylmethylamines were also successfully performed.

Nickel-catalyzed arylation of heteroaryl-containing diarylmethanes: exceptional reactivity of the Ni(NIXANTPHOS)-based catalyst

Nickel(0)-catalyzed cross-coupling of heteroaryl-containing diarylmethanes with both aryl bromides and chlorides has been achieved.

Palladium-Catalyzed C-H Arylation of α,β-Unsaturated Imines: Catalyst-Controlled Synthesis of Enamine and Allylic Amine Derivatives.

A unique chemo- and regioselective α- and γ-arylation of palladium azapentadienyl intermediates is presented. Two distinct catalysts and sets of conditions successfully controlled the regioselectivity of the arylation. These methods provide the first umpolung C-H functionalization of azapentadienyl palladium intermediates and enable the divergent synthesis of allylic amine and enamine derivatives, which are of significant interest in the pharmaceutical industry.

Transition-metal-free chemo- and regioselective vinylation of azaallyls

Direct C(sp3)–C(sp2) bond formation under transition-metal-free conditions offers an atom-economical, inexpensive and environmentally benign alternative to traditional transition-metal-catalysed cross-coupling reactions. A new chemo- and regioselective coupling protocol between 3-aryl-substituted-1,1-diphenyl-2-azaallyl derivatives and vinyl bromides has been developed. This is the first transition-metal-free cross-coupling of azaallyls with vinyl bromide electrophiles and delivers allylic amines in excellent yields (up to 99%). This relatively simple and mild protocol offers a direct and practical strategy for the synthesis of high-value allylic amine building blocks that does not require the use of transition metals, special initiators or photoredox catalysts. Radical clock experiments, electron paramagnetic resonance studies and density functional theory calculations point to an unprecedented substrate-dependent coupling mechanism. Furthermore, an electron paramagnetic resonance signal was observed when the N-benzyl benzophenone ketimine was subjected to silylamide base, supporting the formation of radical species upon deprotonation. The unique mechanisms outlined herein could pave the way for new approaches to transition-metal-free C–C bond formations. Cross coupling under transition-metal-free conditions is an attractive and economic alternative to traditional transition-metal-catalysed methods. Metal-free coupling of azaallyls has now been demonstrated with vinyl bromide electrophiles, delivering allylic amines in excellent yields. Moreover, mechanistic evidence supports dual reaction pathways triggered by azaallyl anions and radicals.

Umpolung Synthesis of Diarylmethylamines via Palladium‐ Catalyzed Arylation of N‐Benzyl Aldimines

An umpolung synthesis of diarylmethylamine derivatives is presented. This reaction entails a Pd catalyzed arylation of 1,3-diaryl-2-azaallyl anions, in situ generated from N-benzyl aldimines. A Pd(NIXANTPHOS)-based catalyst together with hindered silylamide bases enabled the coupling of aldimines with aryl bromides in good to excellent yields without product isomerization. Moreover, regioselectivity in the arylation of unsymmetrical 1,3-diaryl-2-azaallyl anions was studied. This method is suitable for a gram scale synthesis of diarylmethylamine derivatives at room temperature without use of a glovebox.

Palladium-Catalyzed Selective α-Alkenylation of Pyridylmethyl Ethers with Vinyl Bromides

An efficient palladium-catalyzed α-alkenylation of pyridylmethyl ethers with vinyl bromides is presented. A Pd/NIXANTPHOS-based catalyst system enables a mild and chemoselective coupling between a variety of pyridylmethyl ethers and vinyl bromides in good to excellent yields. Under the mild conditions, β,γ-unsaturated products are obtained without isomerization or Heck byproducts observed.

Palladium-Catalyzed α-Arylation of Methyl Sulfonamides with Aryl Chlorides

A Palladium-catalyzed α-arylation of sulfonamides with aryl chlorides is presented. A Buchwald type precatalyst formed with Kwongs indole-based ligand enabled this transformation to be compatible with a large variety of methyl sulfonamides and aryl chlorides in good to excellent yields. Importantly, under the optimized reaction conditions, only mono-arylated products were observed. This method has been applied to the efficient synthesis of sumatriptan, which is used to treat migraines.

Arylation of Azaarylmethylamines with Aryl Chlorides and a NiBr2/NIXANTPHOS-based Catalyst

A nickel-catalyzed coupling of azaarylmethylamines with aryl chlorides has been achieved. NIXANTPHOS together with low cost NiBr2 was successfully developed and optimized to exhibit high reactivity at 2.5 mol % loading. Under optimized reaction conditions, aryl(azaaryl)methylamine products were afforded in good to excellent yields (22 examples, up to 98% yield).

Chemoselective synthesis of aryl(pyridinyl)methanol derivatives through Ni-NIXANTPHOS catalyzed α-arylation and tandem arylation/rearrangement of pyridylmethyl ethers

An efficient synthesis of aryl(pyridyl)-methanol derivatives using a nickel-NIXANTPHOS catalyst is described. Combinations of the Ni-NIXANTPHOS catalyst, solvent, and reaction temperature achieved chemoselective arylation and tandem arylation/rearrangement of pyridylmethyl ethers. A large variety of aryl halides were tolerated (55 examples, up to 96% yield). The scalability of the reaction is demonstrated. The order of the tandem arylation and [1,2]-Wittig rearrangement was probed by comparative studies.