Last of the gem-Difluorocycloalkanes: Synthesis and Characterization of 2,2-Difluorocyclobutyl-Substituted Building Blocks

An efficient approach to synthesis of previously unavailable 2-substituted difluorocyclobutane building blocks was developed and applied on a multigram scale. The key step of the synthetic sequence included deoxofluorination of O-protected 2-(hydroxylmethyl)­cyclobutanone. Dissociation constants (pK...

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Published inJournal of organic chemistry Vol. 84; no. 13; pp. 8487 - 8496
Main Authors Chernykh, Anton V, Melnykov, Kostiantyn P, Tolmacheva, Nataliya A, Kondratov, Ivan S, Radchenko, Dmytro S, Daniliuc, Constantin G, Volochnyuk, Dmitriy M, Ryabukhin, Sergey V, Kuchkovska, Yuliya O, Grygorenko, Oleksandr O
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 05.07.2019
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Organic
Physical Sciences
Science & Technology
CYCLOADDITION REACTIONS
POTENT
PHARMACEUTICALS
DRUG DISCOVERY
FLUORINE
INHIBITORS
DERIVATIVES
EVP
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Summary:An efficient approach to synthesis of previously unavailable 2-substituted difluorocyclobutane building blocks was developed and applied on a multigram scale. The key step of the synthetic sequence included deoxofluorination of O-protected 2-(hydroxylmethyl)­cyclobutanone. Dissociation constants (pK a) and log P values for 2,2-difluorocyclobutaneamine and 2,2-difluorocyclobutanecarboxylic acid or their derivatives were measured and compared with the values obtained for the corresponding 3,3-difluorocyclobutane derivatives and nonfluorinated counterparts. Three-dimensional structures of 2,2- and 3,3-difluorocyclobutanamines were compared using exit vector plot analysis of X-ray crystallographic data.
Bibliography:ObjectType-Article-1
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ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.9b00719