Parallel Minisci Reaction of gem-Difluorocycloalkyl Building Blocks

Abstract

Parallel Minisci reactions of nonfluorinated and gem-difluorinated C₄-C₇ cycloalkyl building blocks (trifluoroborates and carboxylic acids) with a series of electron-deficient heterocycles were studied. A comparison of the reaction's outcome revealed better product yields in the case of carboxylic acids as the radical precursors in most cases, albeit these reagents were used with three-fold excess under optimized conditions. The nature of the heterocyclic core was found to be important for successful incorporation of the cycloalkyl fragment. The impact of the CF₂ moiety on the oxidation potential of fluorinated cycloalkyl trifluoroborates and the reaction outcome, in general, was also evaluated.

Figure 1

(A) Structural motifs that are increasingly popular in drug discovery. (B) Experimental and marketed drugs designed by a combination of fluorine atoms, saturated rings, and heteroaromatic fragments.

Scheme 1. (A) General Scheme for the Minisci Reaction; (B) Major Developments on the Minisci Reaction; and (C) the Key Transformation of This Work

Scheme 2. Synthesis of Compound Library 4{1–5,1–10} and Heatmap of the Reaction Yields According to LC–MS [(A)—for Trifluoroborates 2, (B)—for Carboxylic Acids 3]

Figure 2

(A) LC–MS-based and isolated yields of products 4 as functions of building blocks 2/3 (A) and heterocycles 1 (B).

Figure 3

Regioselectivity of the Minisci reaction with heterocycles 1{1–5}.

Scheme 3. Plausible Reaction Pathways Based on the Literature Data^,

Figure 4

E_a,p values of trifluoroborates 2{1–10} obtained from CVA as compared to E(Ag²⁺/Ag⁺) and E(SO₄^•–/SO₄^2–) (recalculated from the literature values^, vs ferrocene).