Multigram Synthesis of Heterabicyclo[n.1.0]alkan‐1‐yl Trifluoroborates

Abstract

An approach to the synthesis of oxa‐ and azabicyclo[n.1.0]alkan‐1‐yl trifluoroborates on a multigram scale was developed. Two synthetic strategies were evaluated: the first based on the lithiation–borylation of the corresponding 2‐bromoallyl derivatives, and the other relying on regioselective hydroboration of the appropriate hetera‐substituted enynes. The second method appeared to be more efficient in terms of scalability and substrate scope. Further steps included ring closing‐metathesis, mild palladium‐catalyzed cyclopropanation with diazomethane, and reaction with KHF2 and furnished the title compounds in up to 50 g scale in a single run (10–41 % overall yield, 4–5 steps).

[3+2] Cycloaddition of Alkynyl Boronates and in situ Generated Azomethine Ylide

“…All other data corresponded to those reported in literature. [27] General procedure for the Suzuki reaction…”

“…Known approaches towards these compounds fall into three different categoriesintermolecular nucleophilic substitution, [25] CÀ B bond formation via Suzuki-Miyaura borylation of the corresponding enol triflate, [26] and intramolecular ring-closing metathesis (Scheme 1, A-C). [27] Our previous experience indicates that N-benzyl-1-methoxy-N-(((trimethylsilyl)oxy)methyl)methanamine (1) is one of the best precursors of azomethine ylide for the construction of the pyrrolidine core. [28][29][30][31] While compound 1 has been extensively used in the reactions with alkene derivatives to form 3substituted pyrrolidines, its reactivity towards triple bonds remained only limitedly explored (Scheme 1, D).…”

“…While various 2‐ and 3‐borylated pyrrolidines are well‐known, [22] Δ 3 ‐pyrroline‐3‐boronate and its derivatives have been scarcely represented in literature to date. Known approaches towards these compounds fall into three different categories – intermolecular nucleophilic substitution, [25] C−B bond formation via Suzuki‐Miyaura borylation of the corresponding enol triflate, [26] and intramolecular ring‐closing metathesis (Scheme 1, A–C) [27] …”

Expedient Synthesis of 6‐Functionalized Azabicyclo[4.1.0]heptane Derivatives

“…Later, an increased outcome of the target boronate was achieved through palla-dium-catalyzed cyclopropanation of an unsaturated pinacol boronate with diazomethane (Scheme 1, C). [31] Several recent works reported the use of tandem metal-catalyzed cyclizations for the construction of the target bicyclic system (Scheme 1, D-F). [32,33,34] In this work, we report synthesis of a series of novel 6functionalized azabicyclo[4.1.0]heptane-derived medicinally relevant building blocks starting from a common readily available precursor -1-benzyl-4-hydroxymethyl-1,2,3,6-tetrahydropyridine (3) -that in turn can be prepared from commercially available 4-(hydroxymethyl)pyridine (1) (Scheme 2).…”

“…Subsequently, Simmons–Smith cyclopropanations of N ‐protected 4‐piperidinone silyl enol ether [28] and unsaturated boronates [29,30] with diiodomethane and ZnEt 2 were reported (Scheme 1, B ). Later, an increased outcome of the target boronate was achieved through palladium‐catalyzed cyclopropanation of an unsaturated pinacol boronate with diazomethane (Scheme 1, C ) [31] . Several recent works reported the use of tandem metal‐catalyzed cyclizations for the construction of the target bicyclic system (Scheme 1, D – F ) [32,33,34] …”