Reductive amination plays a paramount role in pharmaceutical and medicinal chemistry owing to its synthetic merits and the ubiquitous presence of amines among biologically active compounds. It is one of the key approaches to C–N bond construction due to its operational easiness and a wide toolbox of protocols. Recent studies show that at least a quarter of C–N bond-forming reactions in the pharmaceutical industry are performed via reductive amination. This Review concisely compiles information on 71 medical substances that are synthesized by reductive amination. Compounds are grouped according to the principle of action, which includes drugs affecting the central nervous system, drugs affecting the cardiovascular system, anticancer drugs, antibiotics, antiviral and antifungal medicines, drugs affecting the urinary system, drugs affecting the respiratory system, antidiabetic medications, drugs affecting the gastrointestinal tract, and drugs regulating metabolic processes. A general synthetic scheme is provided for each compound, and the description is focused on reductive amination steps. The green chemistry metric of reaction mass efficiency was calculated for all reactions.

A comparative study of various widely used methods of reductive amination is reported. Specifically, such reducing agents as H2, Pd/C, hydride reagents [NaBH4, NaBH3CN, NaBH(OAc)3], and CO/Rh2(OAc)4 system were considered. For understanding the selectivity and activity of the reducing agents reviewed herein, different classes of starting materials were tested, including aliphatic and aromatic amines, as well as aliphatic and aromatic aldehydes and ketones. Most important advantages and drawbacks of the methods, such as selectivity of the target amine formation and toxicity of the reducing agents were compared. Methods were also considered from the viewpoint of green chemistry.

Borrowing hydrogen or the hydrogen autotransfer amination is a powerful approach to create single C–N bonds, starting from stable and readily available substrates: amines and alcohols. It is considered as one of the most atom-efficient and green methods to synthesize complex amines. Herein, we attempted to arrange the array of the existing data in a comprehensive and structured manner and determine correlations between the experimental conditions and catalysis outcome both within different groups of catalysts and between the defined groups using the machine analysis. For each type of N-nucleophiles (aromatic, aliphatic, and heteroaromatic amines, amides), the most efficient working conditions were suggested, including attributing the optimal base and temperature regime for each metal.

A catalyst of a new type, cyclobutadiene complex [(C 4 Et 4 )Rh(p-xylene)]PF 6 , was found to promote selective reductive amination in the presence of carbon monoxide under mild conditions (1−3 bar, 90 °C). The reaction demonstrated perfect compatibility with a wide range of functional groups prone to reduction by conventional reducing agents. The developed system represents the first systematic investigation of cyclobutadiene metal complexes as catalysts.

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Tertiary amines represent a key class of organic molecules with multiple industrial, synthetic, and analytical applications. The focus of this review is on different approaches towards the synthesis of the C 3 and C 3V symmetrical tertiary amines. Generally, symmetrical tertiary amines can be prepared

An interesting catalytic dichotomy was discovered: switching between simple ligand-free catalysts leads to fundamentally different outcomes of reductive reaction between amines and α-carbonylcyclopropanes. Whereas a rhodium catalyst leads to the traditional reductive amination product, ruthenium catalysis enables a novel reaction of pyrrolidine synthesis via ring expansion. The protocols do not require an external hydrogen source and employ carbon monoxide as a deoxygenative agent. The developed methodologies are perfectly compatible with a number of synthetically important functionalities such as ester, carboxyl, bromo, and Cbz moieties.

Development of novel, sustainable catalytic methodologies to provide access to amines represents a goal of fundamental importance. Herein we describe a systematic study for the construction of a variety of amines catalyzed by a well-defined homogeneous iridium complex using carbon monoxide as a reducing agent. The methodology was shown to be compatible with functional groups prone to reduction by hydrogen or complex hydrides.