Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Organophosphine-Catalyzed Difluoroalkylation of Alkenes Liang Zhao,*,†,§ Yang Huang,†,§ Ze Wang,† Erlin Zhu,† Ting Mao,† Jia Jia,† Jiwei Gu,‡ Xiao-Fei Li,*,† and Chun-Yang He*,† †
Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, Generic Drug Research Center of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China ‡ School of Medicine, Washington University in St. Louis, St. Louis, Missouri 63110, United States
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S Supporting Information *
ABSTRACT: Atom transfer radical addition and Heck-type reaction between alkenes and ethyl iododifluoroacetate by using organophosphine compounds as catalysts have been developed. The reaction proceeds under mild reaction conditions with excellent functional group tolerance and high chemo- and regioselectivities. Mechanistic study indicates that the reaction might be initiated via noncovalent interactions between an organophosphine catalyst and a carbon−iodine bond. ifluoromethylene (CF2) is an important fluorinated motif found in many biologically active compounds and functional materials. The selective incorporation of a difluoromethylene group can modify biologically relevant properties of a compound, such as metabolic stability, basicity, lipophilicity, and bioavailability.1,2 The traditional route to such compounds uses fluorinating agents such as DAST or its derivatives to convert a ketone into the corresponding difluoroalkyl group.3 A number of useful and elegant catalytic chemistries for latestage installation of a difluoroalkyl group into organic compounds have been developed since 2010,4 including nucleophilic chemistry,5 electrophilic chemistry,6 radical difluoroalkylation,7 and metal−difluorocarbene coupling (MeDiC).8 Among the four catalytic modes mentioned above, there is growing recognition of the significance of radical chemistry in difluoroalkylation reaction. Transition metal catalysts and photoexcited catalysts are identified as two of the most effective systems for generating difluoroalkyl radical intermediates under mild reaction conditions. As a milestone in the realm of radical fluoroalkylation, Melchiorre’s group realized a new electron transfer process for generateing perfluoroalkyl radical species by visible-light irradiation of in situ-formed electron donor−acceptor (EDA) complexes, which arose from the interaction of activated substrates and perfluoroalkyl iodides. They advanced this EDA complex activation concept to develop a photochemical aromatic perfluoroalkylation of α-cyano aryl acetates9 and enantioselective perfluoroalkylation of β-ketoesters.10 Expending upon their pioneering researches, our group reported a catalyst-free approach for installing trifluoromethyl and perfluoroalkyl groups within uracils and cytosines.11 However, in the
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© XXXX American Chemical Society
achieved precedents, specific substrates or an excess of amines was required to generate the photochemical activity of EDA complexes.12 Therefore, the development of new catalyst systems based on noncovalent interaction attracted a great deal of our interest. On the other hand, organophosphine was found to be an efficient electron donor. Given their excellent performance in organic chemistry, especially in transition metal-catalyzed reactions,13 exploitation of their new features has attracted intense interest. Normally, the reaction catalyzed by organophosphine species was proceeded via a nucleophilic process, and rare examples of radical chemistry were reported.14 We envisioned that the catalytic amount of organophosphine would combine with ethyl iododifluoroacetate to form a noncovalent interaction, which could induce a radical intermediate, thus leading to the discovery of unprecedented transformations (Scheme 1). To verify this hypothesis and study the organophosphine catalysis reaction, we chose alkenes and ICF2COOEt as Scheme 1. Reaction Design Based on the Noncovalent Interactions between P and the C−I Bond
Received: July 4, 2019
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DOI: 10.1021/acs.orglett.9b02314 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
slightly decreased when the loading amount of the catalyst or additive was decreased (Table 1, entries 14 and 15). The effect of the reaction temperature was also investigated, and an only 46% yield was obtained when the reaction was performed at 60 °C (Table 1, entry 16). As a control, no desired product was observed in the absence of DPPM (Table 1, entry 17), and an 84% yield without DMPU (Table 1, entry 18), which indicates that an organophosphine-catalyzed process was involved in the reaction. With the optimized reaction conditions in hand, the scope of this organophosphine-catalyzed atom transfer radical addition (ATRA) was evaluated using abundant structurally diverse terminal alkenes. As shown in Scheme 2, the reaction exhibited
substrates to investigate the atom transfer radical addition (ATRA) reaction between them. Usually, this protocol requires radical initiators such as peroxide,15 Et3B,16 or UV light17 and suffers from the limited substrate scope. Recently, transition metal18 and photoredox catalysis19 have emerged as attractive alternatives, which are recognized as more efficient strategies. Herein, we demonstrate an organophosphinecatalyzed difluoroalkylation of alkenes. The advantages of this protocol are the simple catalytic system, excellent functional group tolerance, and high chemo- and regioselectivities. Accordingly, we conducted this reaction with 1-allyl-4methylbenzene (1a) and ethyl iododifluoroacetate (2) in the presence of a phosphine catalyst. To our delight, after the solvents had been screened (Table 1, entries 1−5), an 82%
Scheme 2. 1,2-Addition of Ethyl Iododifluoroacetate to Alkenesa,b
Table 1. Representative Results for the Optimization of the Organophosphine-Catalyzed Difluoroalkylation of 1-Allyl-4methylbenzenea
entry
catalyst
additive (equiv)
solvent
yield of 3a (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14c 15 16d 17 18
PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 X-Phos DPPE DPPM DPPP DPPM DPPM DPPM DPPM − DPPM
− − − − − K2CO3 (1) KOAc (1) DMPU (1) DMPU (1) DMPU (1) DMPU (1) DMPU (1) DMPU (0.5) DMPU (0.5) DMPU (0.2) DMPU (0.5) DMPU (0.5) −
toluene MeCN THF DMF DMSO THF THF THF THF THF THF THF THF THF THF THF THF THF
− − 82 47 − − 16 85 82 87 90 83 98 (94) 85 86 46 − 84
a
Reaction conditions: 1 (0.3 mmol, 1.0 equiv), 2 (0.6 mmol, 2.0 equiv), DPPM (0.03 mmol, 0.1 equiv), DMPU (0.15 mmol, 0.5 equiv), THF (2 mL), 80 °C, 20 h. bYield of isolated product. c Reaction conditions: 1 (10 mmol, 1.0 equiv), 2 (20 mmol, 2.0 equiv), DPPM (1 mmol, 0.1 equiv), DMPU (5 mmol, 0.5 equiv), THF (30 mL), 80 °C, 30 h.
a
Reaction conditions (unless otherwise specified): 1a (0.3 mmol, 1.0 equiv), 2 (0.6 mmol, 2.0 equiv), organophosphine (0.03 mmol, 0.1 equiv), solvent (2.0 mL), 80 °C, 20 h. bNMR yield determined by 19F NMR using fluorobenzene as the internal standard. The number in parentheses is the yield of the isolated product. cDPPM (0.015 mmol, 5 mol %) was used. dThe reaction was performed at 60 °C.
excellent functional group tolerance. Allylbenzenes containing methoxyl, fluoride, hydroxyl, esters, aldehyde, and even bromo substituents generally were compatible with the reaction and provided difluoroalkylated ATRA products in excellent yields (3a−j). Then, we turned our attention to the aliphatic olefins. We were pleased to find that the alkenes containing alkyl, cycloalkyl, alkoxy, alkoxycarbonyl (3k−o), and even cyano (3p) substituents proved to be highly efficient, providing the corresponding difluoroalkylated analogues in good to excellent yields. Importantly, the reliability and scalability of this protocol can also be demonstrated by gram-scale synthesis of 3p (75%, 2.38 g). Overall, compared to radical initiator-mediated addition of difluoroalkyl radicals onto styrene, which features a complex reaction system,18b,c this new organophosphine-catalyzed difluoroalkyl radical addition onto styrene afforded only the Heck-type products. As shown in Scheme 3, electron neutral, rich, and poor styrenes all performed as successful substrates,
yield was obtained when the reaction was performed in THF at 80 °C for 20 h using PPh3 as a catalyst (Table 1, entry 3). Then, various bases were added to the reaction system with the purpose of improving the efficiency of the reaction (Table 1, entries 6−8). However, the reaction was suppressed in the presence of inorganic bases, and the yield was slightly improved when DMPU [1,3-dimethyl-3,4,5,6-tetrahydro2(1H)-pyrimidinone] was used as an additive. We found that the additive DMPU could reduce the level of formation of HCF2COOEt. Further optimization of the reaction conditions by examining different organophosphine compounds (Table 1, entries 9−12) showed that all tested catalysts performed well, and DPPM [dis(diphenylphosphino)methane] gave the best result (90%). Decreasing the loading amount of DMPU could improve the yield to 98% (Table 1, entry 13). The yields B
DOI: 10.1021/acs.orglett.9b02314 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 3. Organophosphine-Catalyzed Heck-Type Reaction of Ethyl Iododifluoroacetate with Alkenesa,b
Scheme 4. Mechanistic Investigation
a
Reaction conditions: 4 (0.3 mmol, 1.0 equiv), 2 (0.6 mmol, 2.0 equiv), DPPM (0.03 mmol, 0.10 equiv), DMPU (0.15 mmol, 0.5 equiv), DMF (2 mL), 90 °C, 20 h. bYield of isolated product. c Reaction conditions: 4b (5 mmol, 1.0 equiv), 2 (10 mmol, 2.0 equiv), DPPM (0.5 mmol, 0.1 equiv), DMPU (2.5 mmol, 0.5 equiv), DMF (15 mL), 90 °C, 24 h.
providing the corresponding CF2CO2Et analogues in good yields (5a−j). The amenability of bromide and chloride on the styrene rings to this organophosphine protocol affords a highly valuable opportunity for application in the development of medicine (5h and 5i). Branched alkenes could also be applied to the reaction. As for a terminal branched alkene bearing an aryl group, a 91% yield can be obtained (5k), while a disubstituted compound was the major product when the branched alkene was bearing a methyl group (5l). It is noteworthy that the conjugated alkene underwent the reaction smoothly, thus providing 5m in good yield. A moderate yield was obtained, when cyclic alkene 1,2-dihydronaphthalene was examined (5n). An only 28% yield was obtained when prop-1en-1-ylbenzene was treated (5o) due to the influence of the steric effect. When the reaction was performed on a gram scale (5b), a comparable yield still can be obtained, thus demonstrating the synthetic utility of the protocol. To gain insight into the mechanism of this transformation, a series of experiments were performed. The reaction was completely suppressed when the mixture was treated with radical inhibitor 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) under the standard reaction conditions (Scheme 4a). This experiment suggests radical intermediates were involved in this reaction. Then, several experiments were performed to trap the reactive radical species. When 2 was treated with αcyclopropylstyrene (7) in the presence or absence of 1a under the standard reaction conditions, ring opening product 8 was formed (Scheme 4b). Optical absorption spectra of the reactants showed that the absorption was obviously strengthened between 350 and 370 nm (Scheme 4c; for details, see the
Supporting Information), which indicated a noncovalent interaction occurred between DPPM and I-CF2CO2Et (2). To improve our understanding of the reaction mechanism, we switched to a simpler reaction system (Table 1, entry 3). A control experiment indicated that 1,1-difluoroalkylphosphonium salt was not generated; meanwhile, compounds 9 and 10 were detected during this process (Scheme 4d), which further confirmed the radical intermediate was initiated by organophosphine. Finally, the reaction was monitored by 31P NMR (Scheme 4e), and a new signal was detected at ∼25 ppm at room temperature or 80 °C in THF and DMF (for details, see the Supporting Information). C
DOI: 10.1021/acs.orglett.9b02314 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters ORCID
On the basis of these preliminary results, a plausible mechanism was proposed in Scheme 5 for this transformation.
Chun-Yang He: 0000-0002-0599-7335 Author Contributions
Scheme 5. Proposed Reaction Mechanism
§
L.Z. and Y.H. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (81760624 and 21702241), Programs of Guizhou Province (2017-1225 and 2018-1427), the Young Elite Scientists Sponsorship Program by Cast of the China Association for Science and Technology (2015-41), and Zunyi Medical University. The authors thank Prof. Xingang Zhang and Prof. Zhang Feng for helpful discussions. Special thanks to Dr. Jiwei Gu from Washington University for his revision of the manuscript.
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Initially, noncovalent interactions between P and I occurred. Then, the difluoroalkyl radical was generated at 80 °C. Two pathways are feasible for the propagation step. (1) The newly formed radical then reacted with 1 and generated a carbon radical intermediate B, which abstracted an iodine atom from RFI to afford desired product 3 and regenerated the RF radical. (2) For styrenes, the benzylic radical species (B) was more stable and less reactive, which would like to generate a cation (C) via a SET process, and only a thermodynamically stable product (5) was obtained by following deprotonation. In addition, a catalytic cycle might also be involved during the reaction; intermediate A, which was confirmed by a previous report,14 was generated via the interaction between P and 2. Then, The PR′3-I• radical reacts with carbon radical intermediate B, which can convert to PR′3; meanwhile, the desired products (3 and 5) were generated. In summary, the development of ATRA of a simple alkene via an organophosphine-catalyzed process has been firmly accomplished as a reliable and versatile methodology. In particular, a Heck-type difluoroalkylated product was furnished when sytrenes performed the reaction. The significant advantages of this method are the high efficiency, excellent functional group tolerance, and synthetic simplicity, thus providing a facile route for further application in pharmaceuticals and life sciences. Mechanistic study indicates that the reaction might be initiated via noncovalent interactions between the phosphine catalyst and carbon−iodine bond.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02314. Experimental procedures and spectral data for all new compounds (PDF)
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DOI: 10.1021/acs.orglett.9b02314 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.9b02314 Org. Lett. XXXX, XXX, XXX−XXX
