Synthesis of All‐Carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron‐Catalyzed Kumada Cross‐Coupling

Abstract

1,3‐Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p‐substituted arenes and alkynes. Access to all‐carbon disubstituted BCPs via cross‐coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3‐C‐disubstituted BCPs from 1‐iodo‐bicyclo[1.1.1]pentanes (iodo‐BCPs) by direct iron‐catalyzed cross‐coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo‐BCPs as electrophiles in cross‐coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3‐C‐disubstituted BCPs including various drug analogues.

Strain-release 2-azaallyl anion addition/borylation of [1.1.1]propellane: synthesis and functionalization of benzylamine bicyclo[1.1.1]pentyl boronates

“…Anderson demonstrated the straightforward synthesis of BCP iodides (2) under Atom Transfer Radical Addition catalysis 12,13 and developed an Fe-catalyzed Kumada coupling with aryl Grignards to access all-carbon 1,3-disubstituted BCP products (Scheme 1a, bottom right). 14 Uchiyama reported the silaboration of 1 to give isolable intermediate 3, which could be subsequently arylated under Pd catalysis (Scheme 1a, bottom le). 15 This work was the rst to demonstrate arylation of BCP boronates; however, the arylation protocol requires preactivation of the boronate with stoichiometric tert-butyllithium, which highlights the synthetic difficulty of functionalizing BCP Bpin compounds.…”

“…Since the functionalization of tertiary iodides generally requires organometallic reagents (e.g. t-BuLi, Grignard reagents), 12,14 we explored BCP carbanion capture with other electrophiles with the hope of accessing bench-stable, functionalized BCP benzylamines that could be readily elaborated to more complex substrates. We were particularly attracted to the idea of accessing pinacol boronates, which are both bench-stable and highly versatile synthetic handles.…”

General and Practical Route to Diverse 1,3-(Difluoro)alkyl bicyclo[1.1.1]-Aryl Pentanes Enabled by an Fe-Catalyzed Multicomponent Radical Coupling

“…From these studies, it is clear that subtle changes to the relative concentrations among the three components is crucial for overall efficiency. Control experiments show the importance of the unique iron precatalyst and ligand combination to achieve good yields (entries [9][10][11][12]. Finally, to Table 1.…”

“…The Baran 9 and Molander 10 groups have reported the use of substituted redox-active esters in Fe-and Ni-catalyzed BCP-aryl crosscouplings with aryl zinc reagents and aryl halides, respectively. Finally, Anderson 11 has the reported the use of BCP-iodides to cross-couple with (hetero)aryl Grignard reagents under iron catalysis.…”