Synfacts 2021; 17(06): 0619
DOI: 10.1055/s-0040-1720656
Synthesis of Heterocycles

Multigram Electrosynthesis of Enecarbamates and Related Building Blocks

(Pfizer) Contributor(s):
Paul Richardson
Tereschenko OD, Perebiynis MY, Knysh IV, Vasylets OV, Sorochenko AA, Slobodyanyuk EY, Rusanov EB, Borysov OV, Kolotilov SV, Ryabukhin SV, *, Volochnyuk DM. * Enamine Ltd, Kyiv, National Academy of Sciences of Ukraine, Kyiv, and Taras Shevchenko National University of Kyiv, Ukraine
Electrochemical Scaled-up Synthesis of Cyclic Enecarbamates as Starting Materials for Medicinal Chemistry Relevant Building Blocks.

Adv. Synth. Catal. 2020;
362: 3229-3242
DOI: 10.1002/adsc.202000450
 

Significance

Chemistry within a drug-discovery environment presents an interesting dichotomy in that whereas new chemical space is highly desirable, medicinal chemists typically rely on a suite of robust reactions for their synthetic endeavors, particularly when planning parallel (library) campaigns. Given this, the complexity and novelty of the molecules synthesized arise from the building blocks that are used, with a wide variety of diverse and unique collections of these becoming more accessible from commercial sources (A. Tomberg, J. Boström Drug Discov. Today 2021, 25, 2174). The current report describes a simple cost-effective electrochemical synthesis of a series of cyclic enecarbamates on a multigram scale and their subsequent elaboration into diverse functionalized building blocks for utilization in drug-discovery programs.


#

Comment

Prior to this report, the dihydrooxa­azine 3 was unknown in the literature and, of the compounds reported, only the tetrahydropyridine 4 was commercially available. Optimization of the Shono oxidation focused on the development of a multigram protocol as opposed to a systematic evaluation of reaction variables. Notably, an electrolysis galvanostatic mode was employed on scale because of the ease of controlling a constant current as opposed to a constant potential. Bu4N+BF4 was selected as the electrolyte owing to its ability to catalyze the subsequent conversion of 2 into 3, and inexpensive graphite electrodes were used. The enecarbamates were subjected to [2+1] cyclo­additions (10, 11), and electrophilic substitutions (12, 13), with further functionalization of the latter products achieved through elimination (14) or recyclization after deprotection and treatment with hydrazine (15).


#
#

Publication History

Article published online:
18 May 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany