850761-36-3Relevant articles and documents
Nickel-Mediated Alkoxycarbonylation for Complete Carbon Isotope Replacement
Ton, Stephanie J.,Neumann, Karoline T.,N?rby, Peter,Skrydstrup, Troels
supporting information, p. 17816 - 17824 (2021/11/04)
Many commercial drugs, as well as upcoming pharmaceutically active compounds in the pipeline, display aliphatic carboxylic acids or derivatives thereof as key structural entities. Synthetic methods for rapidly accessing isotopologues of such compounds are highly relevant for undertaking critical pharmacological studies. In this paper, we disclose a direct synthetic route allowing for full carbon isotope replacement via a nickel-mediated alkoxycarbonylation. Employing a nickelII pincer complex ([(N2N)Ni-Cl]) in combination with carbon-13 labeled CO, alkyl iodide, sodium methoxide, photocatalyst, and blue LED light, it was possible to generate the corresponding isotopically labeled aliphatic carboxylates in good yields. Furthermore, the developed methodology was applied to the carbon isotope substitution of several pharmaceutically active compounds, whereby complete carbon-13 labeling was successfully accomplished. It was initially proposed that the carboxylation step would proceed via the in situ formation of a nickellacarboxylate, generated by CO insertion into the Ni-alkoxide bond. However, preliminary mechanistic investigations suggest an alternative pathway involving attack of an open shell species generated from the alkyl halide to a metal ligated CO to generate an acyl NiIII species. Subsequent reductive elimination involving the alkoxide eventually leads to carboxylate formation. An excess of the alkoxide was essential for obtaining a high yield of the product. In general, the presented methodology provides a simple and convenient setup for the synthesis and carbon isotope labeling of aliphatic carboxylates, while providing new insights about the reactivity of the N2N nickel pincer complex applied.
Electrochemical Scaled-up Synthesis of Cyclic Enecarbamates as Starting Materials for Medicinal Chemistry Relevant Building Bocks
Tereshchenko, Oleksandr D.,Perebiynis, Maryana Y.,Knysh, Irina V.,Vasylets, Olesia V.,Sorochenko, Anna A.,Slobodyanyuk, Eugeniy Y.,Rusanov, Eduard B.,Borysov, Oleksandr V.,Kolotilov, Sergey V.,Ryabukhin, Sergey V.,Volochnyuk, Dmitriy M.
supporting information, p. 3229 - 3242 (2020/07/06)
The electrochemical Shono oxidation of Boc-protected cyclic amines was revised. The conditions for scalable electrochemical synthesis of cyclic enecarbamates were found. The developed protocol included recycling of the full range of used reagents, favoring to E-factor reduction according to Green Chemistry requirements. The method opened the way for the convenient preparation of previously uncommon materials, which could become useful synthetic intermediates. Their synthetic potential was evaluated in [2+1] and [2+2] cycloadditions as well as electrophilic functionalization. Moreover, functionalized enecarbamates with carbonyl groups in β-position were used as latent 1,3-bielectrophiles in classical heterocyclizations. In a case of the hydrazine, the corresponding unusually decorated pyrazoles were prepared. The proposed methodology is a straightforward tool for the design and synthesis of Medicinal Chemistry relevant building blocks. As examples, 5-fluoro pipecolic and 3-fluoro isonipecotic acids were synthesized starting from Boc-protected esters of the pipecolic and the isonipecotic acids respectively; the 5-step approach to pyrazole containing α-aminoacids with different linkers between the aminoacidic and pyrazole moieties was elaborated based on the cheapest commercially available racemic and chiral cyclic α-aminoacids; the convenient approach to the functionalized tetrahydropyrido[3,4-d]pyridazines was proposed starting from Boc-protected ester of the isonipecotic acids. (Figure presented.).
Cobalt-Catalyzed Cross-Coupling of 3- and 4-Iodopiperidines with Grignard Reagents
Gonnard, Laurine,Gurinot, Amandine,Cossy, Janine
supporting information, p. 12797 - 12803 (2015/09/01)
A cobalt-catalyzed cross-coupling between 3- and 4-iodopiperidines and Grignard reagents is disclosed. The reaction is an efficient, cheap, chemoselective, and flexible way to functionalize piperidines. This coupling was used as the key step to realize a short synthesis of (±)-preclamol. Some mechanistic investigations were conducted that highlight the formation of radical intermediates. Scaffold synthesis: A cobalt-catalyzed cross-coupling between iodopiperidines and Grignard reagents is reported (see scheme; PG=protecting group). A large variety of 3- and 4-substituted piperidines were synthesized and the method was applied to a short synthesis of (±)-preclamol. This work constitutes one of the rare examples of cross-couplings involving 3-halogeno piperidines.
