Abstract
Abstract1,3‐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
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
Access to aryl-BCPs featuring substituents not tolerated under Kumada coupling could be achieved by ipso-substitution[26] of aryl silane 2 m (Scheme 2 b), for example with halides suitable for further elaboration by cross-coupling (10, 11),[27] or an electronwithdrawing acetyl group (12).[28]
Summary
[e] Using 10 mol % Fe(acac) mol % TMEDA. The unsubstituted 3-pyridyl Grignard reagent gave 2 v in a modest 27 % yield, significant improvement was observed with more electron-rich pyridines (2 w–2 y, 35–55 %), reactions of 2-pyridyl Grignard reagents were unsuccessful. Cross-couplings of benzofuran, N-Bocindoline, N-Boc-indole, N-methyl indazole, and N-phenyl carbazole organometallics were successful, giving good yields of the heteroarylated products 2 z–2 ad (46–67 %). The scope of the iodo-BCP coupling partner was investigated in couplings with PMPMgBr. An N-Boc azetidine-substituted BCP gave product 2 ae in excellent yield (73 %). Heteroarylsubstituted iodo-BCPs proved good substrates, affording the bis-arylated BCP 2 ai in 69 % yield, and double crosscoupled product 2 aj in 64 % yield. The chemistry was applied to more complex iodides, with quinoline 2 ak and nicotinic www.angewandte.org
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
