Palladium-Catalyzed Directed C(sp3)-H Arylation of Saturated Heterocycles at C-3 Using a Concise Optimization Approach

Abstract

Saturated heterocycles, such as THFs, pyrrolidines, piperidines and THPs, are essential components of many biologically active compounds. Examples of C-H functionalization on these important ring systems remain scarce, especially at unactivated positions. Here we report the development of conditions for the palladium-catalyzed stereoselective C(sp³)-H arylation at unactivated 3-positions of 5- and 6-membered N- and O-heterocycles with aminoquinoline directing groups. Subtle differences in substrate structures altered their reactivity significantly; and different conditions were required to achieve high yields in each case. Successful conditions were developed using a short empirical optimization approach to cover reaction space with a limited set of variables. Excellent cis-selectivity was achieved in all cases, except for the THP substrate where minor trans-products were formed through a different palladacyclic intermediate. Here, differences in reactivity and selectivity with other directing groups were examined.

Keywords: C–H arylation; Homogeneous catalysis; N Heterocycles; O Heterocycles; Palladium.

Scheme 1

Directed C(sp³)–H arylation: acyclic, cyclic and heterocyclic substrates.

Figure 1

Substrate classes in this study optimized through a concise optimization protocol, posing questions of stereoselectivity or mono vs. bis‐arylation (DG = CONHQ, X = Boc, Cbz).

Figure 2

Process and parameters used for optimization of the C–H arylation for each substrate. [a] Reactions were performed at 0.3 m concentration with respect to amide. [b] Using preferred solvent and Pd source from round 1; 1 equiv. Ag₂CO₃, 30 mol‐% PivOH. [c] Using preferred solvent, Pd source and base from rounds 1 and 2.

Scheme 2

Selected scope of aryl iodides compatible with the C–H arylation reaction of THF carboxamide 1.

Scheme 3

Selective removal of the 8‐aminoquinoline directing group to afford either the trans‐acid 3 or cis‐acid 4.

Scheme 4

Selected scope of aryl iodides compatible with the C–H arylation reaction of N‐Boc‐pyrrolidinecarboxamide 5.

Scheme 5

Selected scope of aryl iodides compatible with the C–H arylation reaction of N‐Cbz‐piperidinecarboxamide 7.

Scheme 6

Selected scope of aryl iodides compatible with the C–H arylation reaction of N‐Boc‐piperidinecarboxamide 9. [a] 36 h reaction time.

Scheme 7

Deprotection of 10b to form amine 11 or 3‐arylpipecolinic acid derivative 12.

Figure 3

Comparison of optimal yields and product ratios of different directing groups on THP carboxamides, following the standard optimization procedure, yields and diastereomeric ratio (dr) quoted as observed in the crude reaction mixture against an internal standard after 18 h reaction time.

Scheme 8

Selected scope of aryl iodides compatible with the C–H arylation reaction of THP carboxamide 11, yield and dr of products on isolation after a 24 h reaction time.

Scheme 9

Viable conformations of the palladacyclic intermediate formed from THP carboxamide 13.

Scheme 10

Isolated yields for the mono and di‐selective β‐C–H arylations of cyclopentanecarboxamide 17.

Scheme 11

Isolated yields for the mono and bis‐selective β‐C–H arylations of propionamide 20.