Exploiting the sp2 character of bicyclo[1.1.1]pentyl radicals in the transition-metal-free multi-component difunctionalization of [1.1.1]propellane

Abstract

Strained bicyclic substructures are increasingly relevant in medicinal chemistry discovery research because of their role as bioisosteres. Over the last decade, the successful use of bicyclo[1.1.1]pentane (BCP) as a para-disubstituted benzene replacement has made it a highly valuable pharmacophore. However, various challenges, including limited and lengthy access to useful BCP building blocks, are hampering early discovery research. Here we report a single-step transition-metal-free multi-component approach to synthetically versatile BCP boronates. Radicals derived from commonly available carboxylic acids and organohalides perform additions onto [1.1.1]propellane to afford BCP radicals, which then engage in polarity-matched borylation. A wide array of alkyl-, aryl- and alkenyl-functionalized BCP boronates were easily prepared. Late-stage functionalization performed on natural products and approved drugs proceeded with good efficiency to generate the corresponding BCP conjugates. Various photoredox transformations forging C-C and C-N bonds were demonstrated by taking advantage of BCP trifluoroborate salts derived from the BCP boronates.

Figure 1.. One-step, multi-component access to diverse BCP boronates.

a. Representative BCP-containing drug candidates reported in recent years. b. Proposed kinetic barriers: polarity-matching requirement leads to favorable reactivity between strained sp²-like alkyl radicals with Bpin acceptors. c. This work: Leveraging lower kinetic barrier of radical addition to [1.1.1]propellane and favorable borylation reactivity between BCP radicals and Bpin acceptors to accomplish a simple transition metal-free multi-component reaction to afford the synthetically useful BCP boronates.

Figure 2.. Strain-induced increase in s character in alkyl radicals leads to favorable borylations in competition experiments.

A positive correlation between the degree radical s character and borylation efficiency is demonstrated by competition experiments between radicals with varies s characters. See supplementary information section 8.1 for more details and discussion. a. Competition experiments were performed between BCP redox-active ester 1f and other alkyl bearing redox-active esters with B₂pin₂ in DMA under 390 nm light irradiation. b. Results indicate that higher s character in the radical leads to more favorable borylation with B₂pin₂.

Figure 3.. One-pot synthesis of BCP-BF₃K 6 and its diversification by photoredox-mediated processes.

BCP trifluoroborate 6 can be synthesized in a one-pot manner from RAE without the need of column chromatography. The synthetic applications of 6 is demonstrated by several photoredox transformation: (i) hydroalkylation with acrylonitrile; (ii) hydroalkylation with dehydroalanine to yield an amino acid derivative; (iii) Minisci heteroarylation; (iv) single-electron mediated Chan-Lam C–N coupling; (v) 1,2-dicarbofunctionalization of vinyl boronic pinacol ester. See supplementary information section 7 for details on reaction conditions. [Ir]= Ir[dF(CF₃)ppy]₂(bpy)PF₆. ^aYield by using isolated 4k.

Figure 4.. Mechanistic investigations into the radical intermediacy and origin of chemoselectivity.

a. Addition of TEMPO completely shut down product formation, and TEMPO-adducts were formed. b. Radical clock experiments confirmed the radical nature of the two reactions and suggested slow addition between radical and [1.1.1]propellane. c. UV-vis studies indicate that at 390 nm, radical precursors are the only absorbing species, and there is no noticeable formation of an EDA complex. Thus, initiation is carried out by excitation of the RAE/organohalides. d. Electronic effect on BCP radical borylation vs. oligomerization: significant through-space effect on the BCP radical such that electron-rich BCP radical tends to undergo borylation whereas electron-poor BCP tends to oligomerize to form [2]staffane as the major product. e. Proposed mechanism based on literature and observations. The chain initiation involves light-mediated excitation of the radical precursor. Chain propagation involves four steps: i) radical addition to [1.1.1]propellane; ii) and ii’) the BCP radical formed coordinates to the Bpin acceptor; iii) and iii’) B–B/Si–B bond undergoes homolytic cleavage to generate BCP-Bpin; iv) and iv’) B/Si radical from the bond cleavage event initiates the next chain cycle.