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Ammonium Iodide-induced Non-radical Regioselective Sulfenylation of Flavones via a C-H Functionalization Process Wannian Zhao, Ping Xie, Zhaogang Bian, Aihua Zhou, Haibo Ge, Min Zhang, Yingcai Ding, and Lian Zheng J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 20 Aug 2015 Downloaded from http://pubs.acs.org on August 20, 2015
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The Journal of Organic Chemistry
Ammonium
Iodide-induced
Non-radical
Regioselective
Sulfenylation of Flavones via a C-H Functionalization Process Wannian Zhao,† Ping Xie,§ Zhaogang Bian,† Aihua Zhou,*† Haibo Ge,*‡ Min Zhang,† Yingcai Ding† and Lian Zheng† †
Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang City, Jiangsu, 212013, China;
§
Scientific Information Research Institute, Jiangsu University (Library), Xuefu Road 301, Zhenjiang City, Jiangsu, 212013, China;
‡
Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis IN 46202 (USA)
Abstract: A novel and highly regioselective ammonium iodide-induced non-radical sulfenylation method for the construction of C-S bond was developed via C-H functionalization. With DMSO or R1SO2NHNH2 as a sulfenylating agent, MeS- and R1Ssubstituted flavone derivatives were obtained in good yields. This method enriches current C-S bond formation chemistry, making it a highly valuable and practical method in pharmaceutical industry.
Introduction Organic molecules containing a C-S bond widely exist in nature, possessing a variety of valuable biological activities.1 Therefore, considerable efforts have been devoted to the development of efficient synthetic methods of constructing C-S bond between biologically relevant molecules and sulfenylating sources.2 Traditionally, a C-S bond is achieved by the condensation of an alkyl halide with a metal thiolate.3 Later, transition metalcatalyzed couplings between vinyl/aryl halides and sulfenylating sources such as thiols, sulfonyl chlorides, and disulfides have been developed.4 One shortcoming of these methods is that prefunctionalized reactants are needed for these reactions. Recently, direct formation of C-S bond via C-H bond functionalization has emerged as an efficient method which enables superior step and atom-economic transformations (see DMSO example in Scheme 1).5 Although no prefunctionalized reactants
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are needed, these reactions often suffer from the high loading of transition metal catalysts, additives and harsh reaction conditions sometimes. Very recently, metal-free sulfenylation processes via direct functionalization of unreactive C-H bonds were also developed,6 DMSO, R1SO2NHNH2, R1SO2Na and R1SO2H were often used as sulfenylating agents in these processes (Scheme 1).7,8 Compared with smelly and unstable thiols, these sulfenylating agents are stable, odorless and readily available. Scheme 1. Representative sulfenylation methods
In this paper, we reported a novel and regioselective sulfenylation method via direct C-H functionalization, in which ammonium iodide (NH4I) was employed as a catalyst instead of previously reported iodine (I2) (Scheme 1). Both DMSO and alkyl/arylsulfonyl hydrazines were used as sulfenylating agents. Although TBAI(Bu4NI)/TBHP(t-BuOOH)-mediated sulfonylation methods have been reported to construct (C-SO2R) bond recently,9 sulfonylation is different from sulfenylation (CS bond construction) in which no oxygen atoms are connected with sulfur atom. More importantly, no oxidants were needed in our sulfenylation approach. Flavone is a well-known natural product class in drug discovery with carbonyl-conjugated olefin function in its structure, its electron-rich ring enables it to undergo direct C-H bond functionalization with electrophiles (DMSO or R1SO2NHNH2) to form MeS- and R1S-substituted flavone derivatives. To the best of our knowledgement, there are no reports until now.
Results and Discussion Based on previous reports of C-S bond construction,10 we first investigated suitable reaction conditions for the couplings of flavone with DMSO. Flavone 1a and DMSO were used as the representative reactants, and different catalysts and solvents were screened for the reaction. (Table 1).
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The Journal of Organic Chemistry
First, CuI, CuBr2 or FeCl3 was used as a catalyst for the coupling, and none of these reactions gave the expected product 2a (entries 1-3) at 95 oC. Using NaI or TBAI as a catalyst didn’t generate product 2a (entries 4 and 5) either. When I2 was selected as a catalyst, the reaction product 2a was obtained in 10% yield (entry 6). When NH4I (1.0 equiv.) was employed with water as a Table 1. Screening reactions for the sulfenylationa
Entry
Catalyst
Solvent
Temp.(oC)
Yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
CuI CuBr2 FeCl3 NaI TBAI I2 NH4Ib NH4I I2 NH4I NH4I NH4Cl NH4I NH4I NH4I NH4I NH4I
------------H2O H2O MeCN --H2O H2O DCE MeCN EtOAc THF Toluene
95 95 95 95 95 95 95 95 135 135 135 135 135 135 135 135 135
0 0 0 0 0 10 trace
