Bicyclo[1.1.1]pentane‐Derived Building Blocks for Click Chemistry

Abstract

Syntheses of bicyclo[1.1.1]pentane‐derived azides and terminal alkynes – interesting substrates for click reactions – are described. With a few exceptions, these compounds were prepared in two or three steps starting from common synthetic intermediates – the corresponding carboxylic acids. The key step in the synthesis of 1‐azidobicyclo[1.1.1]pentanes is a copper‐catalysed diazo‐transfer reaction with imidazole‐1‐sulfonyl azide. The preparation of bicyclo[1.1.1]pentyl‐substituted alkynes relies on a Seyferth–Gilbert homologation with dimethyl 1‐diazo‐2‐oxopropylphosphonate (Ohira–Bestmann reagent). Both types of target compounds were found to be suitable substrates for click reactions, and thus they are promising building blocks for medicinal, combinatorial and bioconjugate chemistry. A practically important side result of this study was a multigram preparation of Boc‐monoprotected 1,3‐diaminobicyclo[1.1.1]pentane – a representative bicyclic conformationally restricted diamine derivative.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…Silaboration of [1.1.1] propellane was also reported; a possibility to address both the functionalities in the molecule of bicyclo[1.1.1]pentane 90 chemoselectively was demonstrated. [415] Other recent interesting developments in the synthesis of BCP-derived building blocks include: 1) radical ring opening of [1.1.1]propellane leading to bicyclo[1.1.1]pentyl iodides or bromides with fairly large substrate scope; [416,417] 2) reactions of [1.1.1]propellane with 2-aryl-1,3-dithianes allowing for the preparation of BCP-substituted ketones; [418] 3) similar synthesis of BCP-substituted benzylamines; [419] 4) and 5) synthesis of BCPderived building blocks for click chemistry (i. e. azides and terminal alkynes) via diazo transfer and Seyferth -Gilbert homologation, respectively [102,420] (Scheme 51).…”

Nickel-Catalyzed Decarboxylative Cross-Coupling of Bicyclo[1.1.1]pentyl Radicals Enabled by Electron Donor–Acceptor Complex Photoactivation

“…In further investigations using 4-((4-bromophenyl)­sulfonyl)­morpholine as a standard aryl bromide, the method was demonstrated to be amenable to a wide range of BCP RAEs with varying bridgehead substitutions ( 24 – 31 ). In particular, very few BCP–aryl compounds with amino-( 27 ), − Cl-( 28 ), CF 3 -( 29 ), CN-( 30 ), and F-( 33 ) bridgehead substitutions have been reported, and to our knowledge, none have been prepared via direct cross-coupling. Furthermore, the current method is proven to be more versatile than that of VanHeyst, Qi, and co-workers, who were unsuccessful in employing NHBoc-, CF 3 -, and CN-BCP trifluoroborates in Ni/photoredox cross-coupling.…”

Selected Topics in the Syntheses of Bicyclo[1.1.1]Pentane (BCP) Analogues

“…Compared to the abundant publications describing the preparation of 1‐halobicyclo[1.1.1]pentane analogues, the usage of functionalized bicyclo[1.1.1]pentanes in transition metal catalyzed cross‐couplings has been scarce (Scheme ). In 1999, Szeimies and co‐workers reported the first example in this field (Scheme A) .…”

“…A number of BCP‐containing analogues containing polyfluoroalkyl substituents [e. g. trifluoromethyl (−CF 3 , Figure , 97 a – l ), difluoromethyl (−CF 2 H, Figure , 98 ), trifluoroethyl (−CH 2 CF 3 , Figure , 99 ), and difluoroethyl (−CF 2 CH 3 , Figure , 100 a – b )] on the bridge‐head positions have also been prepared. Selective examples are summarized in Figure .…”