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Received 00th January 20xx, Accepted 00th January 20xx

A Simple Access to β-Trifluoromethyl-Substituted Ketones via Copper-Catalyzed Ring-Opening Trifluoromethylation of Substituted Cyclopropanols

Dzmitry G. Kananovich,*a Yulia A. Konik,b Dzmitry M. Zubrytski,b Ivar Järvinga and Margus Lopp*a

DOI: 10.1039/x0xx00000x

Tertiary cyclopropanols react rapidly with Togni reagent in methanol at room temperature in the presence of catalytic amounts (3 mol%) of CuCl affording β-trifluoromethyl ketones in 65-73% isolated yields. Ring opening in 1,2-dialkylsubstituted cyclopropanols gives a mixture of isomeric β-trifluoromethyl ketones in about 50% combined yields. Dedicated to Prof. Oleg G. Kulinkovich on the occasion of his 68th birthday The growing importance of organofluorine compounds in agrochemistry, material science and especially their wide use in biomedical applications1 encourages the development of new and efficient methodologies for the synthesis of fluorinated organic molecules. Despite a considerable progress in the field of trifluoromethylation reactions in recent decades,2 introduction of CF3 group into aliphatic chain remote from any directing/activating functionalities still remains a challenging task. Thus, the known strategies for the preparation of β-trifluoromethyl-substituted ketones 1 are mostly based on the modifications of fluorinated starting materials.3 Examples of the direct one-step introduction of the trifluoromethyl functionality to -position of carbonyl group are rare.4 Here we propose a straightforward synthesis of β-trifluoromethyl substituted ketones 1 from easily available cyclopropanols 2.5 When acting as synthetic equivalents of homoenolate anions,6 cyclopropanols 2 may undergo direct electrophilic trifluoromethylation to afford ketones 1 (Scheme 1). Among the reagents known to result in electrophilic trifluoromethylation,2g,7 we selected Togni’s hypervalent iodine reagents2b,2k,8 3 and 4. This selection was made on the basis of our knowledge that cyclopropanols react readily with hypervalent iodine compounds such as phenyliodonium dicarboxylates9 giving in some cases minor amounts of β-acyloxyketone by-products.


Department of Chemistry, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia. E-mail: [email protected]; [email protected] b. Department of Organic Chemistry, Belarusian State University, Leningradskaya 14, 220050, Minsk, Belarus. Electronic Supplementary Information (ESI) available: Experimental procedures This journaldata. is © See TheDOI: Royal Society of Chemistry 20xx and spectral 10.1039/x0xx00000x

Unlike phenyliodonium dicarboxylates which react rapidly with cyclopropanols in methanol to afford products of oxidative cleavage of the strained three-carbon ring,9 the reaction of 1-propylcyclopropanol 2a with both reagents 3 and 4 did not occur in methanol-d4 at all (Table 1, entry 1). It is known that reagents 3 and 4 can be activated by Lewis acid.2k,10 However, the reaction of cyclopropanol 2a with reagent 3 in the presence of Zn(OTf)2 in CDCl3 proceeded slowly and gave a complex mixture of unidentified ketone products after 4 days, without any traces of the desired β-trifluoromethyl ketone 1a (Table 1, entry 2).

Scheme 1 A novel approach to β-trifluoromethyl ketones 1

The reagents 3 and 4 can also be activated with copper salts.2k To our delight, when 20 mol% of unpurified “olivegreen” copper(I) chloride was introduced into the methanol solution containing both 2a and 3, a reaction occurred to produce the desired trifluoromethyl ketone 1a in 55% yield and propyl vinyl ketone (5a) as a main by-product in 30% yield (Table 1, entry 3; see also Table S1 in the Supporting Information for the details). Reagent 4 was less efficient affording 1a in only 23% yield (entry 4). When copper(II) chloride (20 mol%) was used as a catalyst in the case of reagent 3, trifluoromethyl ketone 1a in 68% yield together with 20% of 1-chloro-3-hexanone 6a as a major by-product were obtained (entry 5). Again, reagent 4 was considerably less effective under the same reaction conditions (entry 6). Therefore, in the following experiments only reagent 3 was employed. Other sources of Cu(II), such as copper(II) sulfate and copper(II) acetate, gave 1-methoxy-3-hexanone as the main

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product, without any traces of ketone 1a (entries 7, 8). In the experiment with a stoichiometric amount of copper(II) chloride only 25% of ketone 1a was produced, together with 60% yield of β-chloroketone 6a (entry 9). In the course of this experiment a rapid precipitation of insoluble CuCl was visually observed, pointing to the conclusion that the Cu(II) salt was reduced to Cu(I) under the reaction conditions.

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Table 1 Selected results of the optimization experimentsa

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Reagent 3 or 4 3 3 4 3 4 3 3 3 3 3 3 3 3 3 3 3 3

Catalyst (mol%) — 100% Zn(OTf)2 20% CuClc 20% CuClc 20% CuCl2·2H2O 20% CuCl2·2H2O 20% CuSO4·5H2O 20% Cu(OAc)2·2H2O 100% CuCl2·2H2O 20% CuClg 20% CuBr 20% CuI 10% CuClh 10% CuClh 10% CuClh 5% CuClh 1% CuClh 1% CuCl2·2H2Oh


observed in 19F NMR spectra. Lowering the catalyst amount did View Article Online DOI:1a 10.1039/C5CC02386F not noticeably alter the yield of product (entry 16). It is noteworthy that even 1 mol% amount of CuCl catalyst was effective to afford 1a in 78% yield (entry 17). At such lower catalyst loadings air-sensitive CuCl can be replaced by stable copper(II) chloride and Cu(I) species can be generated in situ (entry 18). A brief solvent screening (entries 13-15) showed that the originally selected methanol was a better choice than aprotic chloroform and acetonitrile. The trifluoromethylation reaction is fast and completes within ca. 20 min by using 5% catalyst loadings (monitored by NMR).

1ab [%] no reaction 0 55d 23d 68e 12d 0f 0f 25e 80d 65 30 80e 70 60 83 78 74


Typical reaction conditions: 2a (0.05 mmol), 3 or 4 (0.05 mmol), solvent (0.5 mL), 20 h, r.t. Experiments in entries 10-18 were carried out under argon. b Yields were determined by 1H and 19F NMR spectroscopy using internal standard. c Unpurified CuCl was used. d Propyl vinyl ketone 5a was formed as a main by-product. e 1-Chloro-3-hexanone 6a was formed as a main byproduct. f 1-Methoxy-3-hexanone was formed as a main product. g Purified CuCl was employed. h LiCl was used as an additive.

We supposed that Cu(I) species are the actual reaction catalyst and the Cu(II) impurities in the CuCl have a negative impact on the reaction efficiency (the case of “olive-green” reagent, entry 3). That’s why we turned to purified Cu(II)-free copper(I) chloride. Indeed, by using the purified CuCl (20 mol%) under inert atmosphere ketone 1a was formed in a noticeably better yield (80%; entry 10). Other copper(I) halides were less efficient mostly due to lower conversion of the starting cyclopropanol 2a (entries 11, 12). As the final improvement, in order to generate homogeneous copper(I) catalyst, we introduced LiCl as an additive to the reaction mixture (entry 13). Although the yield of product 1a remained nearly the same, addition of LiCl allowed to suppress formation of vinyl ketone by-product 5a (>4% yield) as well as some fluorine-containing impurities

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Scheme 2 Synthesis of β-CF3 ketones 1b-l and reactions of 1,2-disubstituted cyclopropanols 2m-o. Figures in parentheses are yields of isolated products. Ratio of isomers 1na-b, 1oa-b was determined by 19F NMR analysis of the reaction mixtures

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The scope of the reaction has also been investigated (Scheme 2). 1-Substituted cyclopropanols 2b-l bearing various functionalities in R group were allowed to react with reagent 3 in 1 mmol scale, in the presence of 3 mol% of CuCl. Mostly, the reaction proceeded with equal efficiency, not depending on the nature of R group. The corresponding β-trifluoromethyl substituted ketones 1b-l were isolated in 65-73% yields. Inspection of 1H NMR spectra of the reaction mixtures showed presence of the corresponding vinyl ketones (

Simple access to β-trifluoromethyl-substituted ketones via copper-catalyzed ring-opening trifluoromethylation of substituted cyclopropanols.

Tertiary cyclopropanols react rapidly with Togni reagent in methanol at room temperature in the presence of catalytic amounts (3 mol%) of CuCl affordi...
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