Rapid functionalization of multiple C–H bonds in unprotected alicyclic amines

• Published in: Nature chemistry Vol. 12; no. 6; pp. 545 - 550
• Main Authors: Chen, Weijie, Paul, Anirudra, Abboud, Khalil A., Seidel, Daniel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2020; NATURE PORTFOLIO; Nature Publishing Group
• Subjects: 639/638/403/933; 639/638/549/933; Allyl Compounds - chemistry; Amines; Amines - chemistry; Analytical Chemistry; Anions; Aza Compounds - chemistry; Biochemistry; Carbon - chemistry; Chemistry; Chemistry and Materials Science; Chemistry, Multidisciplinary; Chemistry/Food Science; Hydrocarbons, Alicyclic - chemistry; Hydrogen - chemistry; Hydrogen Bonding; Hydrogen bonds; Imines; Inorganic Chemistry; Intermediates; Molecular Structure; Organic Chemistry; Oxidants; Oxidizing agents; Physical Chemistry; Physical Sciences; Protecting groups; Science & Technology; ACTIVATION; PIPERIDINE; NITROGEN; OPPORTUNITIES; C(SP)-H ARYLATION; ANTAGONISTS; DISCOVERY; CYCLIC AMINES
• ISSN: 1755-4330; 1755-4349; 1755-4349
• DOI: 10.1038/s41557-020-0438-z

The synthesis of valuable bioactive alicyclic amines containing variable substituents in multiple ring positions typically relies on multistep synthetic sequences that frequently require the introduction and subsequent removal of undesirable protecting groups. Although a vast number of studies have aimed to simplify access to such materials through the C–H bond functionalization of feedstock alicyclic amines, the simultaneous introduction of more than one substituent to unprotected amines has never been accomplished. Here we report an advance in C–H bond functionalization methodology that enables the introduction of up to three substituents in a single operation. Lithiated amines are first exposed to a ketone oxidant, generating transient imines that are subsequently converted to endocyclic 1-azaallyl anions, which can be processed further to furnish β-substituted, α,β-disubstituted, or α,β,α′-trisubstituted amines. This study highlights the unique utility of in situ-generated endocyclic 1-azaallyl anions, elusive intermediates in synthetic chemistry. The preparation of unprotected alicyclic amines containing variable substituents in multiple ring positions typically requires multistep synthetic sequences. Now, an advance in C–H bond functionalization methodology that enables the convenient preparation of elusive endocyclic 1-azaallyl anions allows the introduction of up to three substituents in a single operation.