Advances in the Synthesis of Cyclopropylamines" that outlines recent methodological breakthroughs in the field."> Advances in the Synthesis of Cyclopropylamines" that outlines recent methodological breakthroughs in the field."> Advances in the Synthesis of Cyclopropylamine

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Advances in the Synthesis of Cyclopropylamine

16 May 2025

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Cyclopropylamines represent a significant subclass of substituted cyclopropanes, incorporating both the distinctive electronic and steric characteristics of cyclopropanes and a donor nitrogen atom. These compounds serve dual roles: as constituents in various biologically active molecules and as crucial synthetic intermediates, particularly in ring-opening and cycloaddition reactions. The field has witnessed substantial methodological developments over three decades. A comprehensive SciFinder analysis (Figure 1) of aminocyclopropane scaffold synthesis reveals over 34,000 references, comprising more than 23,000 patents and 10,000 scientific publications, reflecting the compound class's growing significance in chemical research.

Figure 1. Annual Distribution of Publications and Patents Related to Nitrogen-Substituted Cyclopropane Synthesis from SciFinder (1970−2023)

Cyclopropylboronic acid has gained prominence due to its accessibility and notable stability toward air and moisture. This compound has been successfully employed in the synthesis of N-cyclopropyl heterocycles from 2- and 4-hydroxypyridines (Figure 2).

Figure 2. Copper-Catalyzed Coupling of Cyclopropylboronic Acid with Hydroxypyridine Derivatives

A significant advancement was the observation that bis[2-(N,N-dimethylaminoethyl)]ether forms complexes with Grignard reagents, thereby moderating their reactivity and controlling the direct addition of EtMgBr to nitriles. This methodology was successfully demonstrated in a large-scale synthesis utilizing 8 kg of 2-cyanopyridine, producing cyclopropylamine of sufficient purity for direct amide coupling with Boc-L-alanine, achieving an overall yield of approximately 50% (Figure 3).

Figure 3. Large-Scale Cyclopropanation of 2-Cyanopyridine

Professor Sophie Rousseaux's research group from Department of Chemistry, University of Toronto, discovered that zinc homoenolates, traditionally used as nucleophiles, can also act as electrophiles at the carbonyl position (C1) in the presence of nucleophilic amines, allowing the efficient synthesis of trans-cyclopropylamines with good yields and high diastereoselectivities (Figure 4).

Figure 4. Effects of Zinc Salts on Cyclopropanol-Amine Reactions

AmBeed’s Featured Building Blocks

The synthetic advances discussed in both studies highlight the importance of key intermediates such as pyridine derivatives, nitriles, and cyclopropylamines. At AmBeed, we offer a diverse catalog of high-purity reagents to support your research in this area:
· Pyridines - Versatile heterocycles widely used in medicinal chemistry and as ligands in metal-catalyzed reactions.
· 2-Cyanopyridine - A valuable nitrile-functionalized pyridine used in heterocycle synthesis and pharmaceutical intermediate development.
· Cyclopropylamine - A strained-ring amine core featured in bioactive compounds and synthetic intermediates, including those discussed in the two articles above.

Whether you're exploring new synthetic routes or optimizing existing ones, AmBeed provides reliable chemical building blocks to advance your innovation.

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References

[1]Bertus P, Caillé J. Advances in the Synthesis of Cyclopropylamines[J]. Chemical Reviews, 2025, 125(6): 3242-3377.

[2]Mills L R, Barrera Arbelaez L M, Rousseaux S A L. Electrophilic zinc homoenolates: synthesis of cyclopropylamines from cyclopropanols and amines[J]. Journal of the American Chemical Society, 2017, 139(33): 11357-11360.

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