Communication Cite This: J. Am. Chem. Soc. 2018, 140, 9061−9065
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Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents Minyan Wang, Xinghui Pu, Yunfei Zhao, Panpan Wang, Zexian Li, Chendan Zhu, and Zhuangzhi Shi* State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
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S Supporting Information *
ABSTRACT: A copper-catalyzed system has been introduced for the enantioselective defluoroalkylation of linear 1-(trifluoromethyl)alkenes through C−F activation to synthesize various gem-difluoroalkenes as carbonyl mimics. For the first time, arylboronate-activated alkyl Grignard reagents were uncovered in this cross-coupling reaction. Mechanistic studies confirmed that the tetraorganoborate complexes generated in situ were the key reactive species for this transformation.
M
odern drug discovery relies on improvements in chemical synthesis to address the many challenges that result from the design of new pharmaceutical agents. One such challenge arises from the presence of important but sensitive functional groups in pharmaceutical compounds, such as carbonyl moieties,1 which are easily reduced to the corresponding alcohols during phase I metabolism by mammalian NAD(P)H-dependent reductases leading to diminished bioavailability.2 gem-Difluoroalkenes have emerged as a useful carbonyl mimic that has steric and electronic profiles that are similar to those of ketones, aldehydes, and esters, and consequently, they have been used extensively as carbonyl isosteres.3 Therefore, a commonly used synthetic strategy to prevent in vivo metabolism involves the replacement of a carbonyl in drug candidates with the corresponding gem-difluoroalkene moiety.4 For instance, gemdifluoromethylene−artemisinins have been designed to mimic artemisinin and show better antimalarial activity.5 Furthermore, this motif has proved beneficial in diverse downstream transformations; thus, rapid the construction of various novel gem-difluoromethylene−artemisinin derivatives is an attractive target (Figure 1a).6 Typically, the α-position of a gemdifluoromethylene substituent on a drug candidate is an alkyl-substituted chiral carbon center.7 In this context, various strategies that can access gem-difluoroalkenes have been actively pursued, and some elegant methods for the formation of alkyl-substituted gem-difluoroalkenes have been reported.6,8 Defluorinative alkylation9 of α-trifluoromethyl alkenes is one of the most promising processes owing to the ready availability of substrates10 as well as the high efficiency of the reactions. This transformation historically requires the addition of carbon (RLi or RMgBr) nucleophiles in an SN2′ manner through the cleavage of a C−F bond.11 Very recently, a catalytic variant was developed by using a photocatalyst in conjunction with alkylradical precursors (Figure 1b).12 However, control over the © 2018 American Chemical Society
Figure 1. Development of an enantioselective defluoroalkylation protocol to construct gem-difluoroalkene carbonyl mimics.
enantioselectivity in defluorinative functionalization still remains a challenge.13 To the best of our knowledge, the corresponding defluoroalkylation reaction has not been developed. Here, we report a mild and operationally simple strategy for a copper-catalyzed enantioselective defluoroalkylation of linear 1-trifluoromethyl alkenes using commercially available alkyl Grignard reagents (Figure 1c). Organoboronatederived “ate” complexes14 with alkyl Grignard reagents or alkyllithium reagents have been widely applied in transitionmetal-catalyzed cross-coupling reactions in which an aryl group is usually the coupling partner (Figure 1d).8a,15 Remarkably, the key to our success is the discovery of the reactivity of arylboronate-activated alkyl Grignard reagents. To begin our studies, we chose (E)-4-(3,3,3-trifluoroprop-1en-1-yl)-1,1′-biphenyl (1a) and EtMgBr (2a) as the model substrates (Table 1). In presence of 7 mol % CuTc, 8 mol % NHC ligand L1, and 20 mol % NaOtBu at room temperature Received: May 10, 2018 Published: July 10, 2018 9061
DOI: 10.1021/jacs.8b04902 J. Am. Chem. Soc. 2018, 140, 9061−9065
Communication
Journal of the American Chemical Society Table 1. Reaction Developmenta
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14
[Cu] CuTc CuTc CuTc CuTc CuTc CuTc CuTc CuTc CuBr CuBr CuBr CuBr CuBr −
base t
NaO Bu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOPh − NaOMe
Table 2. Substrate Scopea
activator
L*
ee (%)b
yield (%)c
− − − − − − − − − PhBpin PhBnep PhBnep PhBnep −
L1 L2 L3 L4 L5 L6 L7 L8 L8 L8 L8 L8 L8 L8
10 2 30 18 0 2 44 49 52 83 90 92 92 0
58 42 51 32 82 23 52 7 12 50 62 90 (87)d 15 0
a
Reaction conditions: 7 mol % [Cu], 8 mol % NHC ligand, 20 mol % base, 1a (0.20 mmol), 2a (0.60 mmol), activator (0.20 mmol) in 1 mL of toluene for 24 h under argon. bEnantiomeric excesses were determined by chiral HPLC analysis. cYields were determined by GC analysis. dIsolated yield. PhBpin = phenylboronic acid pinacol ester; PhBnep = phenylboronic acid neopentyl glycol ester.
under an argon atmosphere in toluene, defluoroalkylation product 3aa was generated in 58% yield with 10% ee (entry 1). To improve the result, we evaluated various ligands, but only NHC-type ligands were effective (entries 2−8). Among the tested ligands, bidentate NHC ligand L816 provided the best enantioselectivity (7% yield, 49% ee, entry 8). A range of copper salts were also tested, and CuBr afforded the best yield and enantioselectivity (12% yield, 52% ee, entry 9). Interestingly, the reaction efficacy was enhanced by the addition of PhBpin as an activator, which provided the desired product in 50% yield and 83% ee (entry 10). The enantiomeric excess of 3aa could be increased to a high level by using PhBnep as the activator (62%, 90% ee, entry 11). Under these conditions, using a catalytic amount of NaOPh as the base increased the yield to 90% with 92% ee, and no defluoroarylation byproduct was detected (entry 12). Finally, control experiments revealed that in the absence of base, the yield dramatically decreased (entry 13), and the reaction was unsuccessful using 2a directly (entry 14). With the optimized reaction conditions in hand, we first examined the scope of this defluoroalkylation reaction. Crosscoupling reactions of EtMgBr (2a) with a broad range of 1(trifluoromethyl)alkenes 1 were examined (Table 2). In most cases, this novel defluoroalkylation reaction proceeded efficiently to give the corresponding gem-difluoroalkenes in moderate to good yields with excellent enantioselectivities. Ortho-substituted substrates 1g lead to the best results (3ga,
a
Reaction conditions: 7 mol % CuBr, 8 mol % L8, 20 mol % PhONa, 1a (0.20 mmol), 2a (0.60 mmol), PhBnep (0.20 mmol) in 2 mL of toluene, at room temperature, 24 h, under argon; Isolated yields with ee values were determined by chiral HPLC. bAt 0 °C. cUsing 10 mol % CuBr and 12 mol % L8.
91%, 95% ee), suggesting that the increased steric congestion does not impair the reactivity. Notably, the chemoselectivity of the chiral copper catalyst was not affected by halo substituents, such as Cl and Br, on the substrates (3ia−3na), highlighting the potential uses of this process in combination with further conventional cross-coupling transformations. Naphthalenecontaining substrates were also well-tolerated in the present reaction conditions, and they afforded products 3oa−3pa in 73−78% yields and 89−93% ees. Notably, the couplings of substrates with heterocyclic aromatic motifs like benzofuran (1q), benzo[b]thiophene (1r), and even isoquinoline (1s) were also tolerable and afforded 3qa−3sa in 88−99% ees. To 9062
DOI: 10.1021/jacs.8b04902 J. Am. Chem. Soc. 2018, 140, 9061−9065
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Journal of the American Chemical Society
phenylboroxine with Et2Zn in toluene (Figure 2b).21 With the increase of EtMgBr, the 11B NMR spectrum showed three
further explore functional group compatibility of this method, an additive-based robustness screen was also performed.17 We next examined the scope of this defluoroalkylation process with respect to the Grignard reagents. Grignard reagents possessing longer (3ab−3ad) alkyl chains also resulted in excellent enantioselectivity. However, the enantioselective defluoroalkylation with MeMgBr failed (not shown in the table). Bulky Grignard reagents, such as iPrMgBr (3ae, 96%, 96% ee) and cPentMgBr (3af, 73%, 92% ee), also provided good results under these conditions. Unfortunately, hindered tBuMgCl only generated product 3ag in low yield. This defluoroalkylation process is not only limited to (het)aryl-substituted trifluoromethylalkenes, alkyl-substituted substrate 4 was also effective and provided desired product 5 in 80% yield and 83% ee (Scheme 1a). The bulky substituent Scheme 1. Further Investigationsa
Figure 2. 11B NMR studies of the reaction intermediates.
peaks at −12, −14, and −16 ppm, consistent with tetraorganoborate anions21a such as [BEt4]− and [BPhEt3]− with different counterion, most likely [BrMg(solv)x]+ (Figure 2c). Addition of the rest of the reaction components to this 1B/3Mg mixture immediately lead a decrease in the intensity of the signal at −14 and −16 ppm (Figure 2d). At the end of the reaction (∼10 h), the signals at −16 and −14 ppm in the 11 B NMR spectrum almost vanish and the intensity of the signal of Et3B increases while that of the peak at −12 ppm remains constant (Figure 2e). To further clarify the role of these formed boronate complexes, we tried to synthesize these compounds separately. Interestingly, performing the reaction of Et3B and PhMgBr (1:1) formed a boronate probably with [BPhEt3]− species, consistent with the left peak at −12 ppm (Figure 2f). After addition of 1.0 equiv EtMgBr to the above system, the middle and right peaks increased, indicating these two compounds should contain [BEt4]− anion or related structure (Figure 2g). Pleasingly, the mixture of EtBnep and EtMgBr (1:3) only generated the boronate at −16 ppm, confirming our speculation (Figure 2h). Finally, this boronate mixture with a different proportion of each component compared to 1B/3Mg could also be produced from a pregenerated PhBEt2 and EtMgBr (Figure 2i). We found the reaction efficacy was closely related to the boronate complexes at −14 and −16 ppm. As shown in Scheme 2, the use of Et3B as ethyl source did not work (entry 1) and the combination of Et3B and PhMgBr only gave the desired product 3aa in trace amount (entry 2). As long as the mixture contains the compound at −14 and/or −16 ppm (Figure 2g−i), excellent enantioselectivities in the product 3aa were observed in which the more the coupling components, the higher the yield that could be detected (entries 3−5). Notably, reducing the proportion of PhBnep to 0.5 equiv only led to a slightly lower yield and ee (entry 6), however, employing 0.2 equiv or 1.5 equiv PhBnep in our reaction affected the result dramatically (entries 7−8). On the basis of the above experimental results, a possible mechanism has been proposed as shown in Figure 3. Similar to the known process of boron-to-zinc transmetalation,21 the B− Mg transmetalation between PhBnep and EtMgBr can form EtBnep (I) and PhMgBr along with a byproduct PhBEt2 (II).
a
For details, see Supporting Information.
adjacent to the olefin is crucial for the enantioselectivity of products, and long alkyl chain substituted substrates lead to dramatically decreased ee value.18 This method could be applied to 1,3-diene substrate 6, which afforded chiral 1,4diene 7 in 51% yield and 93% ee with perfect regioselectivity. Moreover, our preliminary experiments revealed that the reaction between enyne 8 and Grignard reagent 2a could form desired 1,1-difluoropenta-1,4-enyne 9 in 67% yield with 71% ee. As shown in Scheme 1b, the reduction of the formed 3aa with Red Al afforded E-fluoroalkene 10 as the major product. Alternatively, utilizing our recently developed method of copper-catalyzed hydrodefluorination of gem-difluoroalkenes with water could afford Z-fluoroalkene 11 in 94% yield with no erosion of the ee.19 The double bond in 3aa could be hydrogenated to yield CF2H-substituted alkane12 in 84% yield. Finally, cross-coupling of 3aa with excess methyl Grignard reagent, MeMgBr, proceeded in the presence of a nickel catalyst to provide methylation product 13 in high yield. With a series of experiments, we investigated the pivotal role of the activator. As demonstrated by 11B NMR, the 2:1 ratio of PhBnep (δ = 27 ppm) and EtMgBr in toluene generated two new compounds confirmed as Et3B (δ = 87 ppm) and PhBEt2 (δ = 78 ppm)20 in line with B−Zn transmetalation of 9063
DOI: 10.1021/jacs.8b04902 J. Am. Chem. Soc. 2018, 140, 9061−9065
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Scheme 2. Mechanistic Studiesa
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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/jacs.8b04902. Experimental procedures, characterization data, and spectra of new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Zhuangzhi Shi: 0000-0003-4571-4413
a
For details, see Supporting Information.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the “1000-Youth Talents Plan”, the National Natural Science Foundation of China (grant 2167020084), and the National Natural Science Foundation of Jiangsu Province (grant BK20170632) for their financial supports.
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REFERENCES
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Figure 3. Proposed mechanism.
The formed EtBnep can convert to BEt3 and further to [BEt4]+Y− or related compounds IV with addition of EtMgBr. On the other hand, the reaction of the CuBr precatalyst with NaOPh and the chiral NHC ligand forms catalytically active species A. Because both yield and enantioselectivity are much lower without PhBnep (Table 1, entry 9), an intermediate B is possible to generate through counterion exchange22 between salts A and IV instead of a simple transmetalation (B′). Then complex B can undergo enantioselective addition to substrate 1 producing species C. Subsequent boron-assisted β-F elimination19,23 from C furnishes chiral product 3 and regenerates BEt3 and the copper catalyst. Considering that 3.0 equiv alkyl Grignard reagents is enough for this reaction, we speculate that PhBnep only partially converts into BEt3, which can realize the catalytic cycle with EtMgBr (Scheme 2, entry 6). Additional investigation is necessary to fully elucidate the nature of this interaction. In summary, we have developed an enantioselective coppercatalyzed system that can activate the C−F bonds of 1(trifluoromethyl)alkenes through a defluoroalkylative process to produce various gem-difluoroalkenes. Given the importance of carbonyl mimics in drug discovery, we anticipate that this strategy will simplify the synthesis and structural elaboration of chiral gem-difluoroalkene targets for interdisciplinary research. Further mechanistic studies of this system, especially the arylboronate-activated alkyl Grignard reagents, are the subject of ongoing research in our laboratory. 9064
DOI: 10.1021/jacs.8b04902 J. Am. Chem. Soc. 2018, 140, 9061−9065
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