Boopathy Gnanaprakasam

Direct Synthesis of Imines from Alcohols and Amines with Liberation of H2

Imines are important compounds because of their diverse reactivity, which has led to widespread applications in laboratory and industrial synthetic processes. Traditionally, imines are synthesized from the reaction of ketones or aldehydes with amines in the presence of an acid catalyst. Imines have also been prepared by the self-condensation of amines upon oxidation and by the oxidation of secondary amines. The catalytic N-alkylation of amines and ammonia with alcohols is thought to involve imines as transient intermediates that undergo rapid hydrogenation. The development of an efficient, general method for the synthesis of imines from alcohols and amines is very desirable because of its potential versatility and wide scope. The formation of imines by coupling alcohols with amines in the presence of stoichiometric amounts of oxidants has been reported, but it is limited to activated alcohols and leads to the generation of stoichiometric amounts of waste. Recently, interesting oxidative coupling reactions of alcohols with primary amines under O2 were reported, but the reactions were also limited to activated (benzylic) alcohols, and a maximum turnover number of 50 was reported. 7] We now report a general, efficient, and environmentally benign method for the direct synthesis of imines by the reaction of alcohols with amines. This reaction occurs with liberation of H2 gas and water, high turnover numbers, and no waste products. Furthermore, the reaction proceeds under neutral conditions and no hydrogen acceptor is needed [Eq. (1)]. Remarkably, hydrogenation of the imine does not take place. We have previously reported the catalytic dehydrogenative coupling of primary alcohols to give esters, the dehydrogenation of secondary alcohols to give ketones, and the hydrogenation of esters to give alcohols. These reactions are catalyzed by de-aromatized 2-(di-tert-butylphosphinomethyl)-6-(diethylaminomethyl)pyridine (PNN) and 2,6-bis(diisopropylphosphinomethyl)pyridine (PNP) pincertype Ru complexes 1 and 2, respectively (Scheme 1).

Direct Hydrogenation of Amides to Alcohols and Amines under Mild Conditions

The selective, direct hydrogenation of amides to the corresponding alcohols and amines with cleavage of the C-N bond was discovered. The expected products of C-O cleavage are not formed (except as traces in the case of anilides). The reaction proceeds under mild pressure and neutral, homogeneous conditions using a dearomatized, bipyridyl-based PNN Ru(II) pincer complex as a catalyst. The postulated mechanism involves metal-ligand cooperation by aromatization-dearomatization of the heteroaromatic pincer core and does not involve hydrolytic cleavage of the amide. The simplicity, generality, and efficiency of this environmentally benign process make it attractive for the direct transformations of amides to alcohols and amines in good to excellent yields.

Synthesis of Amides from Esters and Amines with Liberation of H2 under Neutral Conditions

Efficient synthesis of amides directly from esters and amines is achieved under mild, neutral conditions with the liberation of molecular hydrogen. Both primary and secondary amines can be utilized. This unprecedented, general, environmentally benign reaction is homogeneously catalyzed under neutral conditions by a dearomatized ruthenium-pincer PNN complex and proceeds in toluene under an inert atmosphere with a high turnover number (up to 1000). PNP analogues do not catalyze this transformation, underlining the crucial importance of the amine arm of the pincer ligand. A mechanism is proposed involving metal-ligand cooperation via aromatization-dearomatization of the pyridine moiety and hemilability of the amine arm.

Synthesis of Peptides and Pyrazines from β‐Amino Alcohols through Extrusion of H2 Catalyzed by Ruthenium Pincer Complexes: Ligand‐Controlled Selectivity

Peptides constitute one of the most important families of compounds in chemistry and biology. Short peptides have found intriguing biological and synthetic applications. For example, the conformational rigidity of cyclic peptides makes them attractive for drug discovery and biomedical research. Several cyclic peptides that show intriguing biological activity are found in nature. Cyclic peptides have been discovered that are novel antibiotics, enzyme inhibitors, and receptor antagonists. Among them are the smallest cyclopeptides, 2,5diketopiperazines derivatives, which are commonly found as natural products. These compounds exhibit high-affinity binding to a large variety of receptors and show a broad range of biological acitivities, including antimicrobial, antitumoral, antiviral, and neuroprotective effects. 2,5-diketopiperazine derivatives are synthesized in solution or on the solid phase from commercially available and appropriately protected chiral a-amino acids in processes that are usually not atom-economical and generate considerable amounts of waste. Large libraries of cyclic peptides are accessible through solid-phase split-and-pool synthesis, and various methods were developed for their syntheses. Very recently, the synthesis of diketopiperazines from amino acids under microwave irradiation was reported. Green, atom-economical methods for the generation of peptides are highly desirable. We have developed several reactions catalyzed by PNN and PNP Ru pincer complexes based on pyridine, bipyridine, 13] and acridine and have discovered a new mode of metal–ligand cooperation based on ligand aromatization–dearomatization. For example, the PNN Ru pincer complex 1 (Scheme 1) catalyzes the direct synthesis of amides from alcohols and amines with liberation of H2 [17] (Scheme 2, Eq. (1)). Several reports on amide formation by dehydrogenative coupling of amines with alcohols appeared later. Unlike complex 1, the analogous PNP complex 2 (or complex 3 in the presence of an equivalent of base) catalyzes the coupling of amines with alcohols to form imines rather than amides with liberation of H2 and H2O (Scheme 2, Eq. (2)). Herein we report a novel method for peptide synthesis, which involves dehydrogenative coupling of b-amino alcohols with extrusion of H2 catalyzed by complex 1. This environmentally benign and atom-economical reaction proceeds under neutral reaction conditions without the use of toxic reagents, activators, condensing agents, or other additives. With the analogous PNP complex 2, a strikingly different reaction takes place, which leads to pyrazines with extrusion of H2 and H2O. Initially, we were interested to see whether coupling of bamino alcohols with amines can be accomplished and whether racemization would be involved. Reaction of (S)-2-amino-3phenylpropan-1-ol (4), benzylamine, and 1 mol% of the catalyst 1 in toluene at reflux for six hours led to (S)-2-aminoN-benzyl-3-phenylpropanamide 5 in 58% yield after column chromatography (Scheme 3). The specific rotation of amide 5 obtained from the catalysis is essentially the same as reported (+ 16.08). The neutral reaction conditions likely help to prevent racemization. Scheme 1. PNNand PNP-type pincer ruthenium complexes.