Cyclopropyl-substituted amines are privileged scaffolds in medicinal chemistry due to thir inherent ring strain and conformational rigidity, which helps to enhance metabolic stability, increases BBB-permeability and introduces unique binding profiles to bioactive molecules with such structural motifs. Building upon the seminal 2007 work by Bertus and Szymoniak¹, who first demonstrated titanium- and Lewis acid-mediated cyclopropanation of imides, we report a significant expansion of this methodology to access previously unknown mono- and dicyclopropyl-substituted amines via optimized synthetic protocols.

Our systematic investigation of the Kulinkovich cyclopropanation reaction, employing MeTi(OiPr)₃, EtMgBr, and BF₃*Et₂O, has successfully yielded a diverse array of aliphatic cyclopropyl-amines from readily available cyclic imides. Most significantly, we report the first synthesis of bis-cyclopropyl derivatives, accessed through either direct dicyclopropanation or the complementary Szymoniak route depending on substrate compatibility. The methodology demonstrates excellent efficiency for 5- and 6-membered heterocyclic systems, including pyrrolidine, piperidine, morpholine, thiomorpholine and piperazine derivatives, with yields ranging from 70-85% on each step.

Another critical advancement which we introduce is the debenzylation protocol, which enables isolation of pure, non-benzylated cyclopropyl-amines through modified catalytic hydrogenation conditions in presence of strong acid (HCl), which allowed us to achieve up to 85% purity of the target products using simple purification procedures. The scalability of our approach is exemplified by the successful preparation of bis-cyclopropyl piperazine amine on a 20-gram scale with maintained reproducibility.

Current limitations include reduced reactivity of fluorine-substituted substrates and larger 7-membered ring systems. Aromatic imides (phthalimide derivatives) also remain challenging objects due to competing ring-opening pathways and problematic lactam-to-amine reduction steps.

Serhii Kinakh

Enamine Ltd

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