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Copper-Catalyzed Bromodifluoroacetylation of Alkenes with Ethyl Bromodifluoroacetate Dengke Li, Tingting Mao, Jinbo Huang, and Qiang Zhu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01434 • Publication Date (Web): 22 Jun 2018 Downloaded from http://pubs.acs.org on June 22, 2018
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The Journal of Organic Chemistry
Copper-Catalyzed Bromodifluoroacetylation of Alkenes with Ethyl Bromodifluoroacetate Dengke Li,*, a, b Tingting Mao,a Jinbo Huang,a and Qiang Zhu*, a a
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health,
Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China. b
College of Chemistry and Environmental Science, Qujing Normal Univeisity, Qujing 655011, Yunan,
China. E-mail:
[email protected];
[email protected] RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: A Cu-catalyzed regioselective bromodifluoroacetylation of alkenes, using ethyl bromodifluoroacetate (BrCF2CO2Et) as a difluoroacetylating reagent, has been disclosed. The reaction proceeds under mild conditions, and possible by-products generated from hydrodifluoroacetylation and/or direct alkenyl C‒H difluoroacetylation are not observed. Mechanistic studies confirm that atom transfer radical addition (ATRA) process is involved in this alkene difunctionalization reaction.
INTRODUCTION Incorporating fluorine atom or fluorine-containing groups into molecules of medicinal interest has recognized as a common strategy to enhance their lipophilicity, metabolic stability, and bioavailability.1 Among the numerous fluorinating methods, difluoroacetylation using inexpensive and bench stable ethyl bromodifluoroacetate (BrCF2CO2Et) as a fluorinated building block has been studied extensively,2 owing to the versatility of the ester group for further transformations.3 Meanwhile, alkenes are among the most useful chemical feedstock in organic synthesis and fluorination across the double bond has become one of the most straightforward strategies for the preparation of fluorine-containing molecules.2,
4
In general, three types of products could be obtained by reacting alkenes with
BrCF2CO2Et (Scheme 1).5-7 Products of type I5 and type II6,
5a
are generated from
hydrodifluoroacetylation and direct C‒H difluoroacetylation, respectively, in which bromide is not present in the fluorinated alkyl or alkenyl products. The type III reaction is bromodifluoroacetylation of alkene, which is not only more atom economical, but also provides functional group (Br) for further diversification.7 In 2011, Stephenson and the co-workers developed an elegant visible-light-mediated
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ATRA reaction of halogenated compounds including BrCF2CO2Et with olefins.7a-c Later on, similar photoredox strategies were developed using different photocatalysts to generate the same type of difunctionalized products.7d-e However, limitations of these approaches, such as high cost of Ru- or Ir-based photocatalysts make less expensive and more practical approaches still highly desirable. It has been well-established that difluoroacetyl centred radical could be formed from BrCF2CO2Et in the presence
of
copper
catalyst,8,
6b-d,
h
however,
Cu-catalyzed
regio-
and
chemo-selective
bromodifluoroacetylation of alkenes (type III over I and II, Scheme 1) has not been realized yet.9
Scheme 1. Difluoroacetylation of Alkenes with Ethyl Bromodifluoroacetate
RESULTS AND DISCUSSION We set out on the investigation by reacting pent-4-en-1-yl benzoate (1a) with BrCF2CO2Et (2a) in the presence of CuI (5.0 mol%), 1,10-phenanthroline (phen, 10 mol%), bis(pinacolato)diboron (B2Pin2, 10 mol%), and NaHCO3 (1.5 equiv) (Table 1). To our delight, the desired bromodifluoroacetylation product 3a was isolated in 87% yield when the reaction was performed in CH3CN at 100 oC for 12 h (entry 1, Table 1). It was notable that product of neither type I nor type II was detected. Increasing the loading of CuI to 7.5 mol% could improve the yield of 3a to 92%. Control experiments revealed that both copper catalyst and the ligand phen were indispensable, and no desired product was detected in the absence of neither of them (entries 4-5). Additives B2Pin2 and NaHCO3 were also vital for the formation of 3a (entries 6-7).8g-i, 10 Screening of other Cu(I) and Cu(II) species suggested that CuI was superior to other copper catalysts (entries 8-11). Replacing NaHCO3 with other inorganic or organic bases, such as Na2CO3, K2CO3, NaOAc, Bipy (68%) and DAFO (65%) was proven less effective for the current bromodifluoroacetylation reaction (entries 12-14). Other solvents, such as DMF
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The Journal of Organic Chemistry
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