Polyhalogenated Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acids

Abstract

Herein we report the highly selective radical chlorination of 2,2-difluorobicyclo[1.1.1]­pentane-1,3-dicarboxylic acid. Together with radical hydrodechlorination by TMS3SiH, four new bicyclo[1.1.1]­pentane cages carrying two fluorine and one to three chlorine atoms in bridge positions have been obtained. The exact positions of all halogen atoms have been confirmed by X-ray diffraction. The acidity constants (pK a) for all new derivatives have been determined by capillary electrophoresis, and these experimental values show excellent agreement with pK as predicted by DFT methods. Extensive DFT calculations have been used to rationalize the selective formation of four out of nine possible F2Cl1–4 isomers of bridge-halogenated bicyclo[1.1.1]­pentanes and to obtain relative strain energies for all possible isomers.

Rapid Access to 2-Substituted Bicyclo[1.1.1]pentanes

“…Considering the thermodynamic dependence of HAT rates and the high BDE of H–Cl (103 kcal mol –1 ), we postulated that chlorine radicals could be suitable for accomplishing this difficult BCP bridge C–H abstraction. In particular, we were inspired by studies demonstrating that chlorine gas could activate the strong methylene C–H bonds of BCPs to generate di- and trisubstituted chlorinated products in moderate yields under photochemical conditions. − In our proposed monobromination protocol, we would generate high-energy radicals by photolysis of N -chlorosuccinimide (NCS) under visible-light conditions, which would then abstract the BCP bridge C–H bonds of 1 leading to a BCP bridge radical 2 . This radical would then abstract a bromine atom from a brominating agent to give our desired 2-brominated BCP 3 .…”

“…Although current approaches have enabled the introduction of some drug-like substituents at the bridge position, they suffer from long step counts and often lack modularity as they require preinstallation of the desired 2-substituents prior to BCP core construction. − Conversely, direct functionalization of the bridge BCP C–H bonds would dramatically streamline the synthesis of these 2-substituted BCP scaffolds, enabling rapid library generation of these sought-after structures for drug development. While appealing, BCP C–H activation represents a significant synthetic challenge due to the high BDEs (bond dissociation energies) of the methylene C–H bonds (estimated BDE ∼106 kcal mol –1 ), meaning no general methods exist to convert these strong bonds to useful functional handles in good efficiency. , Furthermore, selectivity for the monofunctionalized bridge BCP is difficult, given that past BCP C–H functionalization strategies all favor the difunctionalization or bridgehead-substituted product over the desired bridge-functionalized BCP. − A third challenge to modular bridge functionalization is the lack of cross-coupling procedures that can elaborate 2-substituted BCPs, which are hindered by the high s character of the bridge C–X bonds, and corresponding intermediates, compared to typical alkyl systems (hybridization of bridge C–H ∼ sp 2.5 ) . To overcome these long-standing issues, we hypothesized that a programmable platform for 2-substituted BCP synthesis could be achieved through radical-mediated C–H functionalization and metallaphotoredox cross coupling (Figure B).…”

Rapid Access to 2-Substituted Bicyclo[1.1.1]pentanes

“…Furthermore, ortho-, meta-and para-substituents on the aryl ring were amenable to our reaction conditions (16,22,23). The conditions were applicable to a range of potentially sensitive functional groups and useful synthetic handles, such as tertiary amines (24), carbamates (20 and 25), nitriles (26) and aryl chlorides (19 and 27). Notably, acidic functionality such as NH bonds, which are commonly problematic in transition-metal catalyzed reactions, 14 could also be accommodated in this reaction (25).…”

“…20,21 Furthermore, selectivity for the mono-functionalized bridge BCP is difficult given that past BCP C-H functionalization strategies all favor the difunctionalization or bridgehead-substituted product over the desired bridge-functionalized BCP. [21][22][23][24] A third challenge to modular bridge functionalization is the lack of cross-coupling procedures that can elaborate 2-substituted BCPs, which are hindered by the high s character of the bridge C-X bonds, and corresponding intermediates, compared to typical alkyl systems (hybridization of bridge C-H ~sp 2.5 ) 25 . To overcome these long-standing issues, we hypothesized a programmable platform for 2-substituted BCP synthesis could be achieved through radical-mediated C-H functionalization and metallaphotoredox cross coupling (Figure 1B).…”

“…In particular, we were inspired by studies demonstrating that chlorine gas could activate the strong methylene C-H bonds of BCPs to generate di-and trisubstituted chlorinated products in moderate yield under photochemical conditions. [22][23][24] In our proposed monobromination protocol, we would generate high energy radicals by photolysis of Nchlorosuccinimide (NCS) under visible light conditions, which would then abstract the BCP bridge C-H bonds of 1 leading to a BCP bridge radical 2. This radical would then abstract a bromine atom from a brominating agent to give our desired 2-brominated BCP 3.…”