Synthesis of 1-Substituted Cyclopropylamines via Formal Tertiary C_sp³–H Amination of Cyclopropanes

Abstract

A novel and facile approach to synthesis of 1-substituted cyclopropylamines via phosphine-catalyzed formal tertiary Csp3 –H amination of cyclopropanes was described. The indoles, pyrroles, imidazoles, uracils, 2-pyridone, pyrimidin-4­(3H)-one, and phthalimide had been proven as good aminating partners. The present protocol features transition-metal-free, excellent regioselectivity, high-atom-economy, and mild reaction conditions and a broad range of substrates. The practicability of this protocol can also be demonstrated with late-stage modification of bioactive molecules, scaled up reaction, and divergent derivatization. Notably, the method has been used in the formal synthesis of the hormone-sensitive lipase (HSL) inhibitor. The mechanistic aspects were elucidated by both experimental and computational studies.

Synthesis of Cyclopropylamines through an Electro-Induced Hofmann Rearrangement

“…22 The Curtius rearrangement of cyclopropane-1carbonyl azides was used for the synthesis of 1-subtituted cyclopropylamines, especially for the synthesis of amino acids containing cyclopropane rings (Scheme 2f). 23 Finally, C(sp 3 )-H activation strategies were used for the synthesis of cyclopropylamines either through a formal phosphine catalyzed direct amination of cyclopropyl alkynones (Scheme 2g) 24 or a palladium(II)-catalyzed intramolecular tandem aminoalkylation leading to three-membered-ring fused indolines in good yields. 25 An efficient synthesis of -substituted cyclopropyl amines from ketones homoenolates was also recently reported (Scheme 2h).…”

2‐Hydroxypyridines as N‐ and O‐Nucleophiles in Organic Synthesis

“…Compared with transition metal catalytic systems, there are relatively few reports of organo-catalyzed chemoselective Nallylation of 2-hydroxypyridines. [46] In 2022, we accomplished the first bifunctional Lewis base catalyzed asymmetric N-allylic alkylation of 2-hydroxypyridines 1 with Morita-Baylis-Hillman(MBH) carbonates 77 (Scheme 21). [47] In most cases, this chemoselective N-allylation delivered high yields and enantioselectivities.…”

Cyclopropanation ofN-vinylimidesviaa redox-neutral photocatalysed radical addition/anionic cyclisation process

“…8 Owing to their great importance in organic synthesis and drug discovery, general and modular access to structure-specific cyclopropylamines from readily available substrates under mild conditions with broad functional group compatibility is still highly desirable. 9…”