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.
Highlights
1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p-substituted arenes and alkynes
As direct palladium-catalyzed cross-coupling of iodo-BCPs can suffer from competing ring fragmentation,[8] approaches to all-carbon disubstituted BCPs from iodo-BCPs have to date necessitated lithiation of the iodide, followed by cross-coupling as the nucleophilic com
BCPs 1 k and 1 i were synthesized in excellent yields from reaction of [1.1.1]propellane with commercially available ethyl iodopropanoate 6 (80 %), and iodoquinoline 7 (85 %),[8] using Et3B initiation and photoredox catalysis (Ir(ppy)3/blue LEDs), respectively
Summary
With optimized conditions in hand (Table 1, Entries 8/9), the scope of the aryl Grignard coupling partner was examined (Figure 2) using p-trifluoromethylbenzyl (1 a) and 4-N-Bocpiperidyl (1 b) iodo-BCPs as representative substrates Both electron-rich and moderately electron-poor Grignard reagents gave good to excellent yields of the coupled products for para-substituted aryl organometallics (2 b–2 m, 53–83 %), with the reaction of 4-trimethylsilylphenylmagnesium bromide delivering an excellent yield of 2 m on 2.7 mmol scale (90 %). A variety of heteroaryl Grignards underwent success-
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