Deconstructive diversification of cyclic amines

Abstract

Deconstructive functionalization involves C–C bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis 1 and olefin metathesis 2 , 3 have allowed each carbon in C–C double bonds to be viewed as a functional group. Despite the significant advances in deconstructive functionalizations involving scission of C–C double bonds, there are very few methods that achieve C( sp 3 )–C( sp 3 ) single bond cleavage/functionalization, especially in relatively unstrained cyclic systems. Here, we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, important moities in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C( sp 3 )–N/C( sp 3 )–C( sp 3 ) single bond cleavage followed by C( sp 3 )–halogen bond formation. The resulting acyclic haloamines serve as versatile intermediates that are transformed into a variety of structural motifs through substitution reactions. In this way, skeletal remodeling of cyclic amines, which constitutes a scaffold hop, can be achieved. The value of this deconstructive strategy has been demonstrated through the late-stage diversification of proline-containing peptides.

Transition‐Metal‐Free Deconstructive Lactamization of Piperidines

“…This can be achieved either by a two‐step or one‐pot protocol, but under transition‐metal‐free conditions and using only cheap and environmentally friendly reagents. We designed the title chemical transformation inspired by the seminal work of the Sarpong group, in which they developed a silver‐mediated deconstructive functionalization of piperidines into pyrrolidines in two sequential steps and alternatively in a one‐pot protocol (Scheme ).…”

“… Silver‐mediated deconstructive dehomologation of piperidines developed by Sarpong [Eq. (1)], and the transition‐metal‐free deconstructive lactamization of piperidines proposed here [Eq. (2)].…”

Transition‐Metal‐Free Deconstructive Lactamization of Piperidines

“…[11a] In this work, we introduce asimple protocol that permits the transformation of piperidines to 2-pyrrolidinones via the deconstructive functionalization of ap iperidinesC (sp 3 )-C(sp 3 )single bond to pyrrolidinonesC(sp 2 )-N "single" bond. This can be achieved either by atwo-step or one-pot protocol, but under transition-metal-free conditions and using only cheap and environmentally friendly reagents.W ed esigned the title chemical transformation inspired by the seminal work of the Sarpong group, [12] in which they developed as ilver-mediated deconstructive functionalization of piperidines into pyrrolidines in two sequential steps and alternatively in aone-pot protocol (Scheme 1).…”

“…Silver-mediated deconstructive dehomologation of piperidines developedb ySarpong [Eq. (1)], [12] and the transition-metal-free deconstructive lactamization of piperidines proposed here [Eq.…”

“…High chemical yields were obtained for the lactamization of piperidines 1 and 11 to give lactams 5 and 9,r espectively. We thought that m-CPBAc ould be compatible with the oxidizing reagents employed for the dual oxidation, then a" one-pot" protocol was applied to piperidines 1 and 11 providing acceptable yields of lactams 5 and 9.T he regioselectivity in the Baeyer-Villiger reaction was tested with piperidines substituted at the C-4 position (12,14,16,18,20,22, 24,and 28,T able 2).…”