gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF₃SiMe₃–NaI System

Abstract

Difluorocyclopropanation of alkenyl trifluoroborates using TMSCF 3 -NaI system was reported for the first time. The developed method allowed preparation of monocyclic, spiroand fused-bicyclic gem-difluorocyclopropanes bearing addi-groups. [20][21][22][23][24] Nonetheless, the addition of difluorocarbene equivalent derived from TMSCF 3 to alkenylboronic derivatives was unknown until the present study. Scheme 1. Difluorocyclopropanation of alkenylboronic derivatives.In this work, application of TMSCF 3 -NaI system in refluxing THF (66°C) for the synthesis of gem-difluorocyclopropyl boronic derivatives and its effectiveness for multigram scale synthesis is reported (Scheme 1). It is shown that alkenyl trifluoroborates are optimal substrates for the preparation of aliphatic derivatives which facilitate isolation of the target products. The studied reaction scope included substrates bearing secondary N-Boc protected amine, ester, ether, phenyl and cyclopropyl moieties and provided products with spiro-and fused-bicyclic molecular topologies. Results and DiscussionOur study commenced with testing TMSCF 3 -NaI system in reaction with substrate 5a (Scheme 2), for which the difluorocyclopropanation using XCF 2 CO 2 Na (X = Cl, Br) at 180°C and 150°C, Scheme 2. Attempted difluorocyclopropanation of alkenyl boronic derivatives using the TMSCF 3 -NaI system. 2218Scheme 3. Preparation of trifluoroborate salts 7 from pinacolboronates 9.Scheme 4. Synthesis of pinacolboronates 9e (A) and 9p (B).

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…In the last decade, a significant attention was paid to the difluorocyclopropanation of functionalized alkenes with the CF 3 SiMe 3 -NaI system originally introduced by Prakash, Hu, and co-workers. [496] This reagent system was applied successfully to the alkenes bearing a protected secondary amino, [497] pyrazole, [498,499] trifluoroborate, [500] protected hydroxyl, and other functional groups [501] (Scheme 64). In some of the aforementioned cases, a modification of the original method proposed by our group, "slow addition protocol", was required.…”

The preparation and properties of 1,1-difluorocyclopropane derivatives

“…When the same reaction was attempted on the bromine-free analog, the yield was only 22% [ 43 ]. The difluorocyclopropanation of an alkenyl trifluoroborate using the TMSCF 3 –NaI system afforded the boronate derivative 37 [ 44 ]. The reagent was also used for the synthesis of organic spiro compounds, containing selectively fluorinated cyclopropanes 38a , b [ 45 ], for the preparation of 6,6-difluoro-3-azabicyclo[3.1.0]hexane ( 39 ) (on a 10 g scale) [ 46 ], and of the epothilone B analog 40 [ 47 ] ( Table 2 ).…”

“…Consequently, difluorocarbene is generated, when diazirine 44 is heated above 165 °C. Moreover, Scheme 17: Cyclopropanation of (Z)-2-butene in the presence of difluorodiazirine (44).…”

Cycloadditions of Alkenylboronic Derivatives

“…Recently, difluorocyclopropanation of various alkenyl trifluoroborates 56 with the CF 3 SiMe 3 -NaI system has been described by our group (Scheme 24). 58 Lowering the temperature of the reaction to 66 °C (refluxing THF) allowed a significant extension of the reaction scope, including substrates with NBoc-protected secondary amino, ester, ether, and ketal functions. Mono-and fused bicyclic, as well as spirocyclic difluorocyclopropanes 57 could be obtained in 60-90% yields on up to 50 g scale.…”