N-Alkylation of Amines by C1-C10 Aliphatic Alcohols Using A Well-Defined Ru(II)-Catalyst. A Metal-Ligand Cooperative Approach.

A Ru(II)-catalyzed efficient and selective N-alkylation of amines by C1-C10 aliphatic alcohols is reported. The catalyst [Ru(L1a)(PPh3)Cl2] (1a) bearing a tridentate redox-active azo-aromatic pincer, 2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline (L1a) is air-stable, easy to prepare, and showed wide functional group tolerance requiring only 1.0 mol % (for N-methylation and N-ethylation) and 0.1 mol % of catalyst loading for N-alkylation with C3-C10 alcohols. A wide array of N-methylated, N-ethylated, and N-alkylated amines were prepared in moderate to good yields via direct coupling of amines and alcohols. 1a efficiently catalyzes the N-alkylation of diamines selectively. It is even suitable for synthesizing N-alkylated diamines using (aliphatic) diols producing the tumor-active drug molecule MSX-122 in moderate yield. 1a showed excellent chemo-selectivity during the N-alkylation using oleyl alcohol and monoterpenoid ß-citronellol. Control experiments and mechanistic investigations revealed that the 1a-catalyzed N-alkylation reactions proceed via a borrowing hydrogen transfer pathway where the hydrogen removed from the alcohol during the dehydrogenation step is stored in the ligand backbone of 1a, which in the subsequent steps transferred to the in situ formed imine intermediate to produce the N-alkylated amines.

Oxygen Dependent Switchable Selectivity during Ruthenium Catalyzed Selective Synthesis of C3-Alkylated Indoles and Bis(indolyl)methanes.

Herein, we report a ligand-centered redox-controlled oxygen-dependent switchable selectivity during ruthenium-catalyzed selective synthesis of C3-alkylated indoles and bis(indolyl)methanes (BIMs). A wide variety of C3-alkylated indoles and BIMs were prepared selectively in moderate to good isolated yields by coupling a wide variety of indoles and alcohols, catalyzed by a well-defined, air-stable, and easy-to-prepare Ru(II)-catalyst (1a) bearing a redox-active tridentate pincer (L1a). Catalyst 1a efficiently catalyzed the C3-alkylation of indoles under an argon atmosphere while, under an oxygen environment, exclusively producing the BIMs. A few drug molecules containing BIMs were also synthesized efficiently. 1a exhibited excellent chemoselectivity with alcohols containing internal carbon-carbon double bonds. Mechanistic investigation revealed that the coordinated azo-aromatic ligand actively participates during the catalysis. During the dehydrogenation of alcohols, the azo-moiety of the ligand stores the hydrogen removed from the alcohols and subsequently transfers the hydrogen to the alkylideneindolenine intermediate, forming the C3-alkylated indoles. While under an oxygen environment, the transfer of hydrogen from the ligand scaffold to the molecular oxygen generates H2O2, leaving no scope for hydrogenation of the alkylideneindolenine intermediate, rather than it undergoing 1,4-Michael-type addition forming the BIMs.

Zn(II)-Catalyzed Selective N-Alkylation of Amines with Alcohols Using Redox Noninnocent Azo-Aromatic Ligand as Electron and Hydrogen Reservoir.

We report a sustainable and eco-friendly approach for selective N-alkylation of various amines by alcohols, catalyzed by a well-defined Zn(II)-catalyst, Zn(La)Cl2 (1a), bearing a tridentate arylazo scaffold. A total of 57 N-alkylated amines were prepared in good to excellent yields, out of which 17 examples are new. The Zn(II)-catalyst shows wide functional group tolerance, is compatible with the synthesis of dialkylated amines via double N-alkylation of diamines, and produces the precursors in high yields for the marketed drugs tripelennamine and thonzonium bromide in gram-scale reactions. Control reactions and DFT studies indicate that electron transfer events occur at the azo-chromophore throughout the catalytic process, which shuttles between neutral azo, one-electron reduced azo-anion radical, and two-electron reduced hydrazo forms acting both as electron and hydrogen reservoir, enabling the Zn(II)-catalyst for N-alkylation reaction.

Iron-Catalyzed Metal-Ligand Cooperative Approach toward Sustainable Synthesis of Azines and N-Acylhydrazones in Air.

Herein, we describe a metal-ligand cooperative approach for the sustainable synthesis of various aldazines, ketazines, and N-acylhydrazones via dehydrogenative functionalization of alcohols with hydrazine hydrate using a simple, easy-to-prepare iron catalyst featuring a redox noninnocent tridentate arylazo backbone. Our catalyst is compatible with both primary and secondary alcohols to produce a wide variety of substituted aldazines, ketazines, and N-acylhydrazones in good isolated yields in air. A series of control experiments are performed to elucidate the reaction mechanism.

Ruthenium-Catalyzed Dehydrogenative Functionalization of Alcohols to Pyrroles: A Comparison between Metal-Ligand Cooperative and Non-cooperative Approaches.

Herein, we report the synthesis and characterization of two ruthenium-based pincer-type catalysts, [1]X (X = Cl, PF6) and 2, containing two different tridentate pincer ligands, 2-pyrazolyl-(1,10-phenanthroline) (L1) and 2-arylazo-(1,10-phenanthroline) (L2a/2b, L2a = 2-(phenyldiazenyl)-1,10-phenanthroline; L2b = 2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline), and their application in the synthesis of substituted pyrroles via dehydrogenative alcohol functionalization reactions. In catalyst [1]X (X = Cl, PF6), the tridentate scaffold 2-pyrazolyl-(1,10-phenanthroline) (L1) is apparently redox innocent, and all the redox events occur at the metal center, and the coordinated ligands remain as spectators. In contrast, in catalysts 2a and 2b, the coordinated azo-aromatic scaffolds are highly redox-active and known to participate actively during the dehydrogenation of alcohols. A comparison between the catalytic activities of these two catalysts was made, starting from the simple dehydrogenation of alcohols to further dehydrogenative functionalization of alcohols to various substituted pyrroles to understand the advantages/disadvantages of the metal-ligand cooperative approach. Various substituted pyrroles were prepared via dehydrogenative coupling of secondary alcohols and amino alcohols, and the N-substituted pyrroles were synthesized via dehydrogenative coupling of aromatic amines with cis-2-butene-1,4-diol and 2-butyne-1,4-diol, respectively. Several control reactions and spectroscopic experiments were performed to characterize the catalysts and establish the reaction mechanism.

Ligand centered redox enabled sustainable synthesis of triazines and pyrimidines using a zinc-stabilized azo-anion radical catalyst.

Herein, we report ligand-centered redox controlled Zn(II)-catalyzed multicomponent approaches for synthesizing pyrimidines and triazines. Taking advantage of the ligand-centered redox events and using a well-defined Zn(II)-catalyst (1a) bearing (E)-2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline (L1a) as the redox-active ligand, a wide variety of substituted pyrimidines and triazines were prepared via dehydrogenative alcohol functionalization reactions. Pyrimidines were prepared via two pathways: (i) dehydrogenative coupling of primary and secondary alcohols with amidines and (ii) dehydrogenative coupling of primary alcohols with alkynes and amidines. Triazines were prepared via dehydrogenative coupling of alcohols and amidines. Catalyst 1a is well tolerant to a wide range of substrates yielding the desired pyrimidines and triazines in moderate to good isolated yields. A series of control reactions were performed to predict the plausible mechanism, suggesting that the active participation of the ligand-centered redox events enables the Zn(II)-complex 1a to act as an efficient catalyst for synthesizing these N-heterocycles. Electron transfer processes occur at the azo-aromatic ligand throughout the catalytic reaction, and the Zn(II)-center serves only as a template.

Metal-ligand cooperative approaches in homogeneous catalysis using transition metal complex catalysts of redox noninnocent ligands.

Catalysis offers a straightforward route to prepare various value-added molecules starting from readily available raw materials. The catalytic reactions mostly involve multi-electron transformations. Hence, compared to the inexpensive and readily available 3d-metals, the 4d and 5d-transition metals get an extra advantage for performing multi-electron catalytic reactions as the heavier transition metals prefer two-electron redox events. However, for sustainable development, these expensive and scarce heavy metal-based catalysts need to be replaced by inexpensive, environmentally benign, and economically affordable 3d-metal catalysts. In this regard, a metal-ligand cooperative approach involving transition metal complexes of redox noninnocent ligands offers an attractive alternative. The synergistic participation of redox-active ligands during electron transfer events allows multi-electron transformations using 3d-metal catalysts and allows interesting chemical transformations using 4d and 5d-metals as well. Herein we summarize an up-to-date literature report on the metal-ligand cooperative approaches using transition metal complexes of redox noninnocent ligands as catalysts for a few selected types of catalytic reactions.

Iron-Catalyzed Alkyne-Based Multicomponent Synthesis of Pyrimidines under Air.

An iron-catalyzed sustainable, economically affordable, and eco-friendly synthetic protocol for the construction of various trisubstituted pyrimidines is described. A wide range of trisubstituted pyrimidines were prepared using a well-defined, easy to prepare, bench-stable, and phosphine-free iron catalyst featuring a redox-noninnocent tridentate arylazo pincer under comparatively mild aerobic conditions via dehydrogenative functionalization of alcohols with alkynes and amidines.

Nickel-Catalyzed [4 + 2] Annulation of Nitriles and Benzylamines by C-H/N-H Activation.

Nickel-catalyzed [4 + 2] annulation of benzylamines and nitriles via C-H/N-H bond activation, providing straightforward atom-economic access to a wide variety of multisubstituted quinazolines, is reported. Mechanistic investigation revealed that the in situ formed amidines from the coupling of benzylamines and nitriles direct the nickel catalyst to activate the ortho-C-H bond of the phenyl ring of the benzylamine.

Nickel catalyzed sustainable synthesis of benzazoles and purines via acceptorless dehydrogenative coupling and borrowing hydrogen approach.

Herein we report nickel-catalyzed sustainable synthesis of a few chosen five-membered fused nitrogen heterocycles such as benzimidazole, purine, benzothiazole, and benzoxazole via acceptorless dehydrogenative functionalization of alcohols. Using a bench stable, easy to prepare, and inexpensive Ni(ii)-catalyst, [Ni(MeTAA)] (1a), featuring a tetraaza macrocyclic ligand (tetramethyltetraaza[14]annulene (MeTAA)), a wide variety of polysubstituted benzimidazole, purine, benzothiazole, and benzoxazole derivatives were prepared via dehydrogenative coupling of alcohols with 1,2-diaminobenzene, 4,5-diaminopyrimidine, 2-aminothiphenol, and 2-aminophenol, respectively. A wide array of benzimidazoles were also prepared via a borrowing hydrogen approach involving alcohols as hydrogen donors and 2-nitroanilines as hydrogen acceptors. A few control experiments were performed to understand the reaction mechanism.

Oxygen-Dependent Ligand-Controlled Iron-Catalyzed Chemoselective Synthesis of Olefins and Vinyl Nitriles.

An oxygen-dependent ligand-controlled chemoselective synthesis of vinyl nitriles and E-olefins by coupling a variety of alcohols and benzyl cyanides, catalyzed by a well-characterized, air-stable, easy-to-prepare Fe(II) catalyst (1a) bearing a redox-active arylazo pincer (L1a) is reported. The azo-moiety of the ligand backbone acts as an electron and hydrogen reservoir, enabling catalyst 1a to efficiently produce a broad spectrum of vinyl nitriles and E-olefins in moderate to good yields selectively under an oxygen and argon atmosphere, respectively.