Article Cite This: J. Org. Chem. 2018, 83, 10445−10452
pubs.acs.org/joc
Copper-Catalyzed Bromodifluoroacetylation of Alkenes with Ethyl Bromodifluoroacetate Dengke Li,*,†,‡,§ Tingting Mao,†,‡ Jinbo Huang,†,‡ and Qiang Zhu*,†,‡ †
J. Org. Chem. 2018.83:10445-10452. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 09/07/18. For personal use only.
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 § College of Chemistry and Environmental Science, Qujing Normal University, Qujing 655011, Yunnan, China S Supporting Information *
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 byproducts generated from hydrodifluoroacetylation and/or direct alkenyl C−H difluoroacetylation are not observed. Mechanistic studies confirm that the 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 been 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 (BrCF2CO 2Et) 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 fluorinecontaining 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 II5a,6 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 a functional group (Br) for further diversification.7 In 2011, Stephenson and co-workers developed an elegant visible-light-mediated 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 centered radical could be formed from BrCF2CO2Et in the presence of copper catalyst;6b−d,h,8 however, Cu-catalyzed regio- and chemoselective bromodifluoroacetylation of alkenes (type III over I and II, Scheme 1) has not been realized yet.9
■
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 °C 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 either of them (entries 4 and 5). Additives B2Pin2 and NaHCO3 were also vital for the
Scheme 1. Difluoroacetylation of Alkenes with Ethyl Bromodifluoroacetate
Received: June 14, 2018 Published: June 22, 2018 © 2018 American Chemical Society
10445
DOI: 10.1021/acs.joc.8b01434 J. Org. Chem. 2018, 83, 10445−10452
Article
The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14
[Cu] (mol %) CuI (5) CuI (7.5) CuI (10) CuI (7.5) CuI (7.5) CuI (7.5) CuCl (7.5) CuBr (7.5) Cu(OAc)2 (7.5) CuCl2 (7.5) CuI (7.5) CuI (7.5) CuI (7.5)
Scheme 2. Scope of Alkenesa
additive (equiv)
yield (%)
NaHCO3 (1.5) NaHCO3 (1.5) NaHCO3 (1.5) NaHCO3 (1.5) NaHCO3 (1.5) NaHCO3 (1.5)
87 92 84 n.d. n.d.b
