Communication Cite This: J. Am. Chem. Soc. 2018, 140, 2460−2464
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Electrochemical Difluoromethylarylation of Alkynes Peng Xiong,†,§ He-Huan Xu,†,§ Jinshuai Song,‡ and Hai-Chao Xu*,† †
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, Innovation Center of Chemistry for Energy Materials and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, People’s Republic of China ‡ Fujian Institute of Research on Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, People’s Republic of China S Supporting Information *
Scheme 1. Radical Difluoromethylation Reactions
ABSTRACT: An unprecedented radical difluoromethylarylation reaction of alkynes has been developed by discovering a new difluoromethylation reagent, CF2HSO2NHNHBoc. This air-stable and solid reagent can be prepared in one step from commercially available reagents CF2HSO2Cl and NH2NHBoc. The CF2H radical, generated through ferrocene-mediated electrochemical oxidation, participates in an unexplored alkyne addition reaction followed by a challenging 7-membered ring-forming homolytic aromatic substitution step to afford fluorinated dibenzazepines. he importance of fluorine-containing moieties in pharmaceuticals, agrochemicals and performance materials has fuelled an ever-increasing interest in developing new reagents and efficient synthetic strategies for the preparation of organofluorine compounds.1 Recently, the development of new radicalbased fluoroalkylation methods has gained much attention.2 Fluorinated alkyl radicals are reactive toward many π-systems, which makes radical fluoroalkylation potentially broadly applicable. The difluoromethyl group (CF2H) can serve as a hydrogenbonding donor and thus has been employed as a lipophilic isostere in drug design for functionalities such as amide, alcohol, thiol and hydroxamic acid.3 However, compared to the plethora of literatures on trifluoromethylation, there have only been a few published studies on the development of radical difluoromethylation reactions, possibly because CF2H radical is more difficult to produce and also less reactive than CF3 radical.2,4 A number of research groups have succeeded in forming CF2H radical from various precursors through visible light-promoted reduction with Ru, Ir, Cu or organic catalysts (Scheme 1a).5 Hu reported the preparation of CF2HSO2Na (E) that can be used for silver-catalyzed oxidative radical difluoromethylation.6 Furthermore, Baran pioneered the generation of CF2H radical from [Zn(CF2HSO2)2] (F) using tBuOOH as the oxidant.7 The results of these studies have enabled the radical-based difluoromethylation of isocyanides, alkenes and arenes.5−7 However, the same synthetic strategy has not been applied to alkynes.8 Nonetheless, Hu reported a versatile method for the preparation of CF2Hsubstituted alkenes from PhSO2CF2I and terminal alkynes through a two-step process involving addition and reductive cleavage of the PhSO2 group.8a Organic electrochemistry has been demonstrated to be an attractive tool for the generation of reactive intermediates such as radical and radical ions due to its tunability over electron transfer processes and use of electrons as traceless reagents.9,10
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© 2018 American Chemical Society
In this regard, Blackmond and Baran demonstrated that the direct electrolysis in a divided cell could serve as a more efficient oxidation strategy than the use of a peroxide reagent in arene functionalization reactions employing zinc sulfinates as the radical precursors.11 Electrolysis in a undivided cell is usually more attractive than in a divided cell because of its ease of operation and simplicity of setup. In addition, the C-radical species generated on the electrode surface through direct electrolysis are prone to dimerization, overoxidation to a cation, or reaction with the electrode leading to electrode passivation. One way to mitigate such problems and expand the applications of electrochemically generated radical species is the employment of a redox mediator.12 We have recently developed electrochemical methods to generate amidyl radicals from N−H precursors.13 Encouraged by these results and inspired by the work on the generation of alkyl radicals through oxidative decomposition of sulfinates7,11 and sulfonyl hydrazines,14 we report herein the preparation of CF2HSO2NHNHBoc (1) as a new precursor to CF2H radical and its application in an unprecedented, ferrocene-mediated electrochemical alkyne functionalization reaction to construct fluorinated dibenzazepines (Scheme 1b, top). Received: January 11, 2018 Published: February 6, 2018 2460
DOI: 10.1021/jacs.8b00391 J. Am. Chem. Soc. 2018, 140, 2460−2464
Communication
Journal of the American Chemical Society
positions of ring B (4−14), though monosubstitution at the meta position resulted in regioisomers (14). Substrates in which ring B carried multiple substituents were suited precursors to highly decorated dibenzazepines (15−18). Furthermore, ring B could also be an aromatic heterocycle such as thiophene (19), benzothiophene (20), pyridine (21) and quinoline (22). On the other hand, ring A could be a substituted phenyl moiety (23−28) or a pyridine (29, 30). The reaction was also compatible with substrates bearing an ester (31) or a methyl group (32) at the benzylic position, and with those that carried an acetyl instead of a trifluoroacetyl group on the nitrogen (29, 30, 32 and 33). Reaction of 34 bearing an alkyne moiety on ring B under the standard conditions led to the stereroselective formation of 35, a stereoisomer of 3 (Scheme 2). These results demonstrated that the geometry of the trisubstituted alkene in the dibenzazepine product could be controlled by the position of the alkyne moiety in the starting amide. Further studies (Scheme 3) revealed that under slightly modified reaction conditions the reagent 1 could be used for the functionalization of electron-deficient alkenes (36, 37), enynes (40a−g, 44)19 or even an endiyne (42). In the latter case, four C−C bonds and three rings were formed in a single operation. Additionally, enyne 44 underwent efficient C(sp3)−H functionalization to give the tricyclic product 45.19 The electrolytic reaction of 2 could be performed on a gram scale with good yield (Scheme 4).18 On the other hand, the dibenzazepine product 3 could be further derivatized by removing its trifluoroacetyl group with NH3 in MeOH, followed by the reaction of the resultant secondary amine with benzoyl chloride to furnish amide 46. Alternatively, the oxidation of the amine intermediate could afford imine 47, which could participate in the Ugi reaction20 to generate 48. Considering the versatility of the Ugi reaction, a compound library could be easily prepared for structure−activity studies. To shine light on the reaction mechanism, alkene 49 was synthesized as a radical clock and subjected to the standard electrolysis conditions. The ring opening product 50 bearing a CF2H group was obtained in 69% yield (Scheme 5, top), providing evidence for the involvement of CF2H radical during the electrolysis. In addition, cyclic voltammetry experiments revealed that Cp2Fe+ could oxidize reagent 1 when a base such as Na2HPO4 or LiOMe was present with the latter being much more efficient (see the Supporting Information, Figure S1). Based on the mechanistic studies and literature report,14,21 a possible mechanism for the electrochemical synthesis of dibenzazepines was proposed using amide 2 as a model substrate (Scheme 5, bottom). The electrolytic process begins with the anodic oxidation of Cp2Fe that produces Cp2Fe+. In the meanwhile, MeOH is reduced at the cathode to generate H2 and MeO−. Hence, the oxidation of I, the conjugate base of 1, by Cp2Fe+ generates diazene III, probably via the intermediacy of N-radical II. In an undivided cell, Cp2Fe+ may also get reduced at the cathode to give Cp2Fe, leading to reduced current efficiency. CF2H radical is subsequently generated from the decomposition of III14,21 and reacts with the alkyne moiety in 2 to furnish the vinyl radical IV.22 Vinyl radical 7-ortho cyclization onto phenyl rings has been reported to be difficult due to competing side reactions such as 6-ipso cyclization and H atom abstraction reactions.17 Computational studies (Scheme 5 and Figure S2) suggested that, for the current reaction, the 7-ortho cyclization (path a) was kinetically favored over the alternative 6-ipso cyclization (path b) or 1,5-H atom abstraction (path c).23 Hence, C-radical IV undergoes 7-ortho cyclization with the
The dibenzazepine moiety, which serves as a core scaffold in many bioactive molecules including commercial drugs such as Mianserin, Epinastine and Mirtazapine (Scheme 1b, bottom),15 was formed in a challenging homolytic aromatic substitution (HAS)16 process featuring the formation of a seven-membered ring.17 To begin, the reagent 1 was prepared in one step by reacting commercially available CF2HSO2Cl and NH2NHBoc.18 This radical precursor is an easy-to-handle and bench-stable solid. One noted advantage of using 1 to promote electrochemical difuoromethylation was that the reaction could be performed in an undivided cell. We have recently found ferrocene (Cp2Fe) to be a highly efficient mediator for the electrochemical activation of N−H bonds to generate amidyl radicals.13b Interestingly, this inexpensive organometallic compound also promoted the oxidation and subsequent alkyne functionalization of reagent 1 in an undivided cell equipped with a reticulated vitreous carbon (RVC) anode and a Pt cathode. Hence, electrolyzing 1 and amide 2 bearing a terminal alkyne moiety as the radical acceptor at 70 °C in MeOH containing 10 mol % Cp2Fe as the mediator and Na2HPO4 as a basic additive led to the formation of fluorinated dibenzazepine 3 in 70% yield as the sole alkene stereoisomer (Table 1, entry 1). Table 1. Optimization of Reaction Conditionsa
entry
deviation from standard conditions
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14
none no Cp2Fe no Na2HPO4 reaction at rt no electricity 0.1 F mol−1 Na2CO3 as the base NaHCO3 as the base NaH2PO4 as the base (p-BrC6H4)3N as the catalyst (p-MeC6H4)3N as the catalyst nBu4NBF4 as the supporting electrolyte Et4NOTs as the supporting electrolyte Et4NPF6 as the supporting electrolyte
70c 18 (
