Access to 3D Alicyclic Amine-Containing Fragments through Transannular C-H Arylation

Abstract

In this Letter, we adapt a recently reported Pd-catalyzed transannular C(sp³)-H arylation of alicyclic amines for applications in fragment-based drug discovery (FBDD). We apply this method to the synthesis of a series of 6-arylated 3-azabicyclo[3.1.0]hexanes that are rule-of-three compliant fragments. Several modifications were made to the Pd-catalyzed C-H arylation method to enhance its utility in fragment synthesis. These include the use of microwave heating to shorten reaction times to under 1 h and the development of new approaches for directing group cleavage. Finally, we demonstrate that this fragment library falls within desirable physicochemical space for FBDD applications.

Keywords: amines; arylation; directed C–H functionalization; directing group; fragment based drug discovery; microwave; palladium.

Figure 1

Substrate scope with modified reaction conditions. ^aReaction conducted with S-1 (0.52 mmol). ^b Reaction conducted with S-1 (1.04 mmol). ^c Yields from the original conditions reported in reference . ^d Reaction conducted for 100 min.

Figure 2

Plot of molecular weight versus ClogP

Figure 3

PMI plot for the C-6 arylated amines and amides synthesized. The average distance from the plane of best fit (PBF score) is denoted by the color of the markers (blue ≤ 0.50, 0.50 < green ≤ 0.75, 0.75 < red ≤ 1.00)

Scheme 1

Proposed synthesis of fragments through C–H functionalization