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.

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.

Zn(II)-Catalyzed Multicomponent Sustainable Synthesis of Pyridines in Air.

Herein, we report a Zn(II)-catalyzed solvent-free sustainable synthesis of tri- and tetra-substituted pyridines using alcohols as the primary feedstock and NH4OAc as the nitrogen source. Using a well-defined air-stable Zn(II)-catalyst, 1a, featuring a redox-active tridentate azo-aromatic pincer, 2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline (La), a wide variety of unsymmetrical 2,4,6-substituted pyridines were prepared by three-component coupling of primary and secondary alcohols with NH4OAc. Catalyst 1a is equally compatible with the four-component coupling. Unsymmetrical 2,4,6-substituted pyridines were also prepared via a four-component coupling of a primary alcohol with two different secondary alcohols and NH4OAc. A series of tetra-substituted pyridines were prepared up to 67% yield by coupling primary and secondary alcohols with 1-phenylpropan-1-one or 1,2-diphenylethan-1-one and NH4OAc. The 1a-catalyzed reactions also proceeded efficiently upon replacing the secondary alcohols with the corresponding ketones, producing the desired tri- and tetra-substituted pyridines in higher yields in a shorter reaction time. A few control experiments were performed to unveil the mechanistic aspects, which indicates that the active participation of the aryl-azo ligand during catalysis enables the Zn(II)-complex to act as an efficient catalyst for the present multicomponent reactions. Aerial oxygen acts as an oxidant during the Zn(II)-catalyzed dehydrogenation of alcohols, producing H2O and H2O2 as byproducts.

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.

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.