Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. 2019, 21, 196−200
Irradiation-Induced Cobaloxime-Catalyzed C−H Monofluoroalkylation of Styrenes at Room Temperature Wei-Ke Tang,†,∥ Zhuo-Wei Xu,†,∥ Jun Xu,*,‡ Fei Tang,† Xiao-Xuan Li,† Jian-Jun Dai,‡ Hua-Jian Xu,*,†,‡ and Yi-Si Feng*,†,§
Org. Lett. 2019.21:196-200. Downloaded from pubs.acs.org by UNITED ARAB EMIRATES UNIV on 01/09/19. For personal use only.
†
Anhui Province Key Laboratory of Advance Catalytic Materials and Reaction Engineering, School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei 230009, P. R. China ‡ School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, P. R. China § Anhui Provincial Laboratory of Heterocyclic Chemistry, Maanshan 243110, P. R. China S Supporting Information *
ABSTRACT: A cobaloxime-catalyzed photochemical synthesis of allyl monofluorides from styrenes is described herein. This method is characterized by mild reaction conditions, low-cost catalyst, and broad substrate scope. Furthermore, this convenient method will provide a facile synthesis toward novel monofluoroalkylated natural product and pharmaceutical derivatives. Mechanistic investigations indicate that a monofluoroalkyl radical is involved in the catalytic cycle.
T
Scheme 1. (a) Synthesis of Monofluoroalkylated Alkenes; (b) Cobaloxime-Catalyzed Heck-Type Reaction
he allylic monofluoride moieties play a unique role in various fields of current research1 due to their ability to confer desired properties, such as higher metabolic and conformational stability, increased lipophilicity, and increasing the strength of the interaction with target proteins.2 Therefore, it shows a great potential as a fluorinated synthon in organic synthesis3 and is a valuable structure skeleton in many bioactive compounds and medicines (Figure 1).4 However, despite their potential use in
Figure 1. Examples of bioactive allyl fluorides.
various fields, only limited methods are available for their synthesis.5 Thus, the development of a novel method that allows for the synthesis of diverse allyl monofluorides is eagerly anticipated. In the past years, lots of efforts have been made in the preparation of allyl difluorides6 or trifluorides.7 However, the incorporation of alkyl groups containing a single fluorine into alkenes has been studied to a lesser extent and remained still as a challenge. In this context, an example of nickel-catalyzed monofluoromethylation of vinyl boronic acid or styryl silane has been elegantly developed by Wang’s group (Scheme 1, eq 1).8 Recently, our group also reported a monofluoroalkylation reaction of cinnamic acids using an Eosin Y catalytic system (Scheme 1, eq 1).9 Those works represent an efficient strategy for the construction of allylic monofluoride units. However, the © 2018 American Chemical Society
direct C−H monofluoroalkylation of alkenes are relatively underdeveloped despite their potential importance. The only example of the nickel-catalyzed direct monofluoromethylation of styrenes was reported by Wang’s group (Scheme 1, eq 2).10 Although those works represent very promising advances, the use of complex extra ligands or additives imposed restrictions on its application in synthetic chemistry. Received: November 15, 2018 Published: December 14, 2018 196
DOI: 10.1021/acs.orglett.8b03656 Org. Lett. 2019, 21, 196−200
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa,b
Visible-light photoredox catalysis has recently attracted extensive attention because the process serves as an environmentally friendly method for promoting selective radical reactions.11 In this context, the cobaloxime-catalyzed reactions have received increasing attention because of unique advantages,12 such as cobaloxime-catalyst is inexpensive compared to other transition metals, which show a higher catalytic reactivity. In general, the regeneration of a cobalt(I) species is the key step for the reaction, which is often effected under base or reductive conditions (namely by Zn or by the stoichiometric use of reductants NaBH4) (Scheme 1, eq 3).12d,e,13,14 Herein, we report below the successful development of visiblelight-induced C−H bond monofluoroalkylation of alkenes using inexpensive (triphenyltin)cobaloxime catalyst at room temperature without complex extra ligands or additives. The mild reaction conditions, wide substrate scopes, and excellent E selectivity deliver an ideal tool for the late-stage monofluoroalkylation of biologically active molecules. A notable feature of the method does not require the addition of a base or reductants to regenerate a cobalt(I) species, broadening the scope of cobaloxime-catalyzed coupling reactions. Initially, we investigated the model reaction of styrene 1a with ethyl bromofluoroacetate 2a as a cheap and abundant monofluoro-methylating agent using 36 W blue LED as the source of visible light. Various commonly used photocatalysts such as Ru(phen)3Cl3, Ru(bpy)3Cl2·H2O, Eosin Y, or Rhodamine B were tested with acetonitrile as a solvent in order to achieve monofluoroalkylation of styrene. Unfortunately, no product 3a could be obtained, while the hydromonofluoromethylation product 3a′ was obtained as the single products (Table 1, entries 1−5). Next, (triphenyltin)cobaloxime was evaluated for this transformation, as this photocatalyst is known as a useful reagent for radical generation from bromides. To our satisfaction, reactions using [Co] as catalyst were observed to generate the single monofluoroalkane product 3a despite incomplete alkene conversion (Table 1, entry 6). Thus, monofluoroalkylation of alkenes were focused on the use of [Co] as an effective photocatalyst. To increase the yield, various solvents and bases were screened to improve the reaction efficiency. The solvents screen indicated that dichloromethane (DCM) was the best medium for this transformation (Table 1, entry 7). Other solvents, such as hexane, THF, DMSO, and DMF, were less effective (see the Supporting Information for details). Subsequently, various inorganic and organic bases including K2CO3 and NEt3 were tested. However, none of them gave higher yield (Table 1, entries 8 and 9). Delightfully, further study of styrene 1a coupling with the ethyl bromofluoroacetate 2a catalyzed by [Co] was met with very encouraging results under base-free conditions (Table 1, entry 10). The optimal results were obtained only by using cobalt catalyst in DCM furnishing the monofluoromethylated styrene in good yield (80% isolated yield) within 20 h. The importance of the cobalt catalyst and irradiation was established by control experiments, in which the same reaction system did not give higher than 8% yield of product in the dark at rt or 100 °C (Table 1, entries 11 and 12). Additionally, the reaction stopped completely when it was carried out in the presence of air (Table 1, entry 13). Having found optimal reaction conditions, we set out to examine the scope of the photocatalytic monofluoroalkylation of styrenes in batch. As shown in Scheme 2, satisfactory stereoselectivity with E isomers was achieved in most cases. A series of para-substituted alkenes bearing either electron-donating or electron-withdrawing functional groups gave high yields of the
yield (%)b entry
PC (X mol %)
1 2 3 4 5 6 7 8 9 10 11 12c 13d
Ru(phen)3Cl3 (5) Ru(bpy)3Cl2 (5) Ir(ppy)2 (5) Eosin Y (5) Rhodamine B (5) [Co] (10) [Co] (10) [Co] (10) [Co] (10) [Co] (10) [Co] (10) [Co] (10)
base (3 equiv) i
Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt K2CO3 NEt3
solvent (2 mL)
3a
3a′
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN DCM DCM DCM DCM DCM DCM DCM
trace trace trace trace trace 41 79 38 43 80 0
