The synthesis of 3-azabicyclo[3.2.0]heptyl boropinacolates and trifluoroborates via the [2 + 2] photocycloaddition of the corresponding alkenyl boronic derivatives and maleimides or maleic anhydride is described. Optimization of the reaction conditions (i.e., wavelength, concentration of the reagents, photosensitizer) was carried out, and the scope and limitations of the method were studied. Alkenyl boronic acid pinacolates were found to be more suitable for the [2 + 2] cycloaddition, providing better reaction outcomes compared to the trifluoroborates. The utility of this approach was shown by the preparation of bi-and trifunctional building blocks (21 examples), which could be easily synthesized on up to 60 g scale. These cycloadducts provide a convenient entry into the 3-azabicyclo[3.2.0]heptane scaffold through the C−C coupling or oxidative deborylation reactions.
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).
An approach to di- and trihetera[3.3.n]propellanes (n = 2–4 ), advanced morpholine and piperazine analogues, is developed. The key step of the reaction sequence included a [3 + 2] cycloaddition reaction of unsaturated vicinal dicarboxylic acid derivatives and in situ generated azomethine ylide resulting in the formation of the pyrrolidine ring. One more heteroaliphatic ring (i.e., pyrrolidine or tetrahydrofuran) was annelated by nucleophilic cyclization of the appropriate 1,4-dielectrophilic intermediates. There were 11 examples of the title products obtained in 3–5 steps on a multigram scale with 10–72% overall yields. Additionally, molecular structures of homologous dihetera[3.3.n]propellanes, analogues of morpholine, were obtained from X-ray diffraction studies and analyzed using exit vector plots (EVPs). It was shown that the scaffolds obtained are somewhat larger as compared to the parent morpholine and bicyclic 3-oxa-7-azabicyclo[3.3.0]octane. Moreover, despite very similar chemical structures, they provide a very distinct spatial position of heteroatoms, which is clearly seen from the conformation adopted by a formal eight-membered ring including both N and O atoms (i.e., crown, boat–chair, twist chair–chair, and boat–boat for the oxaza[3.3.2]-, -[3.3.3]-, -[4.3.3]propellanes, and 3-oxa-7-azabicyclo[3.3.0]octane, respectively).
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