Fluorinated β‐Diketones in Reactions with Diazocyclopropane Generated in situ

Abstract

Treatment of 1,1‐di‐ and 1,1,1‐trifluoroalkane‐2,4‐diones 10−13 with cyclopropyldiazonium intermediates 2 and 3, generated in situ through the decomposition of N‐cyclopropyl‐N‐nitrosourea 1 by treatment with moist K2CO3, did not result in the expected azo coupling of the cyclopropyldiazonium ion, but afforded the corresponding oxaspiropentanes 14−17 as products of the addition of diazocyclopropane (3) onto one of the carbonyl groups. In addition, the reaction proceeded selectively on the carbonyl groups adjacent to the di‐ or trifluoromethyl substituents. 1,1‐Difluoroacetone reacted analogously with diazocyclopropane (3) generated in situ, giving stable 2‐(difluoromethyl)‐2‐methyloxaspiropentane in approximately 50% yield. The resulting oxaspiropentanes 14−17, on heating or in the presence of lithium iodide, rearranged selectively into cyclobutanones 20−23, while in the presence of Al2O3 they formed mixtures of approximately equal amounts of the corresponding cyclobutanones and the 1‐vinylcyclopropanols 24−27. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Fluoroalkyl‐Containing 1,2‐Disubstituted Cyclobutanes: Advanced Building Blocks for Medicinal Chemistry

“…All the compounds shown in Figure 1 demonstrate the 1,3‐substitution pattern of the fluorinated cyclobutane fragment; this is partially related to their more or less satisfactory synthetic accessibility. The known approaches to install the fluoroalkyl group onto the cyclobutane ring relied on deoxofluorination [30–33] or decarboxylative trifluoromethylation [34] of carboxylic acids, the addition of the Ruppert‐Prakash reagent or its CHF 2 ‐substituted analog to C=O and C=N bonds, [35,36] fluoride‐mediated nucleophilic substitution, [37] metal‐catalyzed C( sp 3 )−Br [38] and C( sp 3 )−H [39] trifluoromethylation, direct side‐chain C(sp 3 )−H fluorination, [40] rearrangement of fluoroalkyl‐substituted cyclopro panes, [41–43] difluoromethylation of cyclobutene with CHF 2 I, [44] and other methods. Meanwhile, the corresponding 1,2‐disubstituted fluorinated counterparts have been largely underrepresented in the literature to date [39,41,44] .…”

3‐Fluoroalkyl (CF3, CHF2, CH2F) Cyclobutane‐Derived Building Blocks for Medicinal Chemistry: Synthesis and Physicochemical Properties

“…Incorporation of the fluoroalkyl groups into the cyclobutane ring relied on deoxofluorination [39–42] or decarboxylative trifluoromethylation [43] of carboxylic acids, the addition of the Ruppert‐Prakash reagent or its CHF 2 ‐substituted analogue to cyclobutanones or its imines, [44,45] nucleophilic substitution with fluoride anion, [46] metal‐catalyzed C( sp 3 )−Br [47] or C( sp 3 )−H [48,49] trifluoromethylation, difluoromethylation of cyclobutene with CHF 2 I, [50] and other methods [51–53] . Previously, we have disclosed the synthesis and evaluation of physicochemical properties of trans ‐1,2‐disubstituted cyclobutane derivatives 7 a and 7 b bearing mono‐, di‐ and trifluoromethyl groups (Scheme 1, A ), which have been largely underrepresented in the literature to date [54] .…”

“…[33][34][35][36][37][38] Incorporation of the fluoroalkyl groups into the cyclobutane ring relied on deoxofluorination [39][40][41][42] or decarboxylative trifluoromethylation [43] of carboxylic acids, the addition of the Ruppert-Prakash reagent or its CHF 2 -substituted analogue to cyclobutanones or its imines, [44,45] nucleophilic substitution with fluoride anion, [46] metal-catalyzed C(sp 3 )À Br [47] or C(sp 3 )À H [48,49] trifluoromethylation, difluoromethylation of cyclobutene with CHF 2 I, [50] and other methods. [51][52][53] Previously, we have disclosed the synthesis and evaluation of physicochemical properties of trans-1,2-disubstituted cyclobutane derivatives 7 a and 7 b bearing mono-, di-and trifluoromethyl groups (Scheme 1, A), which have been largely underrepresented in the literature to date. [54] In this work, we have aimed at the extending the accessible diversity of fluoroalkyl-substituted cyclobutane building blocks by multigram preparation of diastereomerically pure cis-and trans-1,3-disubstituted counterparts, i. e. amines cis-/ trans-8-10 and carboxylic acids cis-/trans-11-13, as well as their physicochemical characterization by measurement of pK a and LogP values (Scheme 1, C).…”