Dual Incorporation of Trifluoromethyl and Cyano Groups into Pyrazole Pharmcophores via Silver-Catalyzed Cycloaddition Reaction of Trifluorodiazoethane

Open AccessCCS ChemistryCOMMUNICATION7 Dec 2022Dual Incorporation of Trifluoromethyl and Cyano Groups into Pyrazole Pharmcophores via Silver-Catalyzed Cycloaddition Reaction of Trifluorodiazoethane Cheng-Feng Gao, Yin Zhou, Hai Ma, Yue Zhang, Jing Nie, Fa-Guang Zhang and Jun-An Ma Cheng-Feng Gao Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for Synthetic Biology, Ministry of Education, Tianjin Collaborative Innovation Centre of Chemical Science and Engineering, Tianjin University, Tianjin 300072 Google Scholar More articles by this author , Yin Zhou Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for Synthetic Biology, Ministry of Education, Tianjin Collaborative Innovation Centre of Chemical Science and Engineering, Tianjin University, Tianjin 300072 Google Scholar More articles by this author , Hai Ma Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700 Google Scholar More articles by this author , Yue Zhang Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for Synthetic Biology, Ministry of Education, Tianjin Collaborative Innovation Centre of Chemical Science and Engineering, Tianjin University, Tianjin 300072 Google Scholar More articles by this author , Jing Nie Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for Synthetic Biology, Ministry of Education, Tianjin Collaborative Innovation Centre of Chemical Science and Engineering, Tianjin University, Tianjin 300072 Google Scholar More articles by this author , Fa-Guang Zhang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for Synthetic Biology, Ministry of Education, Tianjin Collaborative Innovation Centre of Chemical Science and Engineering, Tianjin University, Tianjin 300072 Google Scholar More articles by this author and Jun-An Ma *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for Synthetic Biology, Ministry of Education, Tianjin Collaborative Innovation Centre of Chemical Science and Engineering, Tianjin University, Tianjin 300072 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202201923 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The dual incorporation of two important functional groups—trifluoromethyl and cyano moieties into one heterocyclic core in a single-step reaction represents an appealing but largely unaddressed synthetic challenge. Here we demonstrate that a silver-catalyzed [3 + 2] cycloaddition reaction of dicyanoalkenes with trifluorodiazoethane (CF3CHN2) could render a facile construction of a unique category of pyrazoles that are simultaneously adorned by trifluoromethyl and cyano groups. Changing the location pattern of the cyano group in starting dicyanoalkene material allows regiodivergent access to two series of previously elusive trifluoromethyl cyanopyrazoles with an exquisite level of regiocontrol. Thus, this method could be applied in the preparation of cyano-analogues of CF3-containing drugs (Celecoxib) and agrochemicals (Penthiopyrad and Fluazolate). Notably, several cyano-analogues of Celecoxib demonstrate enhanced inhibitory activity towards cyclooxygenase-2 (COX-2), thereby laying a good foundation for developing new lead-based anti-inflammatory agents. Download figure Download PowerPoint Introduction Both trifluoromethyl and cyano groups have proved to be versatile moieties in the design and development of numerous active pharmaceutical ingredients, agrochemicals, drugs, and organic functional materials.1–10 In particular, trifluoromethyl- and cyano-functionalized pyrazoles have emerged as two of the most widespread heterocyclic cores in a broad spectrum of applied disciplines (Figures 1a and 1b), thus, stimulating continuously intense interest in their synthetic methodology development.11–17 Note that the dual incorporation of both trifluoromethyl and cyano groups into the pyrazole ring has proved to be very useful in the development of agrochemicals and bioactive molecules (Figure 1c).18–25 However, almost all the previous approaches could only introduce one structural motif in each step, either via conducting functional group interconversion with trifluoromethyl pyrazoles or performing trifluoromethylation with cyanopyrazoles (Figure 1d).26–44 In sharp contrast, the dual incorporation of trifluoromethyl and cyano groups into one heterocyclic core in a single step has not been achieved, albeit the fact that this convergent strategy would provide a more concise method to access the interesting CF3- and CN-pyrazoles. Herein, we present our discovery, which shows that two classes of previously elusive trifluoromethyl- and cyano-functionalized pyrazoles could be readily constructed via a silver-catalyzed direct [3 + 2] cycloaddition reaction of dicyanoalkenes with trifluorodiazoethane in a one-pot operation (Figure 1e). This new synthetic method is operationally simple and uses readily accessible starting materials. The reaction has wide substrate scope and excellent regioselectivity, and it can be scaled up easily. Importantly, the potential application of this transformation has been exemplified via the synthesis of cyano-analogues of CF3-containing drugs (Celecoxib) and agrochemicals (Penthiopyrad and Fluazolate). Preliminary in vitro cyclooxygenase inhibition assay indicated that one N1-aryl-3-CF3-4-cyano pyrazole exhibited potent activity as a selective cyclooxygenase-2 (COX-2) inhibitor, thus, holding great promise for the development of novel non-steroidal anti-inflammatory agents. Figure 1 | Development of a dual incorporation method for the synthesis of trifluoromethyl pyrazole-carbonitriles. (a) Selected bio-active trifluoromethyl pyrazoles. (b) Selected bio-active pyrazole-carbonitriles. (c) Selected bio-active trifluoromethyl pyrazole-carbonitriles. (d) Previous studies for the stepwise construction of CF3- and CN-pyrazoles. (e) This work: Dual incorporation of two star-motifs into pyrazoles in one-pot. Download figure Download PowerPoint Experimental Methods Safety note 2,2,2-Trifluorodiazoethane (CF3CHN2) is potentially explosive! Although no accident occurred in the course of this study, stringent safety precautions were necessary for all reactions of CF3CHN2. The CF3CHN2 in different solutions were prepared according to known procedures.30 Experiments related to cyanide compounds were performed under fume-hood conditions. The aqueous phase was treated with NaClO(aq) to quench any cyanide by-products formed. General procedure A for the synthesis of 3-trifluoromethyl pyrazole-4-carbonitriles 2 To an oven-dried sealed tube (10 mL) equipped with a magnetic stirring bar was added 1,2-dicyanoalkene 1 (0.2 mmol, 1.0 equiv) and AgCl (1.4 mg, 0.05 equiv). Next, N2CHCF3 in a stock solution of dimethylformamide (DMF; 2.0 mL, 1.0 mmol, 0.5 mol/L, 5.0 equiv) and tetramethylethylenediamine (TMEDA; 69.7 mg, 0.6 mmol) were added and stirred at room temperature for 12 h. Then the reaction mixture was diluted with EtOAc, washed with saturated NH4Cl solution, and the water layer was extracted twice with EtOAc. The aqueous phase was treated with NaClO(aq) to quench the formed cyanide by-products, then the combined organic layers were dried with anhydrous MgSO4, filtered, and evaporated in vacuo. The crude product was purified by column chromatography (silica gel 300–400 mesh, Qingdao Marine Chemical Inc., Qingdao, China) on silica gel (C189172, 17 mm × 254 mm, Beijing Synthware Glass Inc., Beijing, China) to afford the corresponding 3-CF3-pyrazole-4-carbonitrile 2. General procedure B for the synthesis of 5-trifluoromethyl pyrazole-3-carbonitriles 4 To an oven-dried sealed tube (10 mL) equipped with a magnetic stirring bar was added 1,1-dicyanoalkene 3 (0.2 mmol, 1.0 equiv) and Ag2O (2.3 mg, 0.05 equiv). N2CHCF3 in a stock solution of tetrahydrofuran (2.0 mL, 1.0 mmol, 0.5 mol/L, 5.0 equiv) and TMEDA (69.7 mg, 0.6 mmol) were added and stirred at room temperature for 12 h. Then the reaction mixture was diluted with EtOAc, washed with saturated NH4Cl solution, and the water layer was extracted twice with EtOAc. The aqueous phase was treated with NaClO(aq) to quench the formed cyanide-by-products. Then the combined organic layers were dried with anhydrous MgSO4, filtered, and evaporated in vacuo. The crude product was purified by column chromatography, as described above, on a silica gel to afford the corresponding 5-CF3-pyrazole-3-carbonitrile 4. Results and Discussion Optimization studies In preliminary experiments, we investigated the cycloaddition reaction of 2-phenylmaleonitrile Z- 1a with CF3CHN2 at room temperature. After a series of optimizing experiments, we were pleased to observe that the desired 3-trifluoromethyl-4-cyano-1H-pyrazole 2a could be obtained in up to 94% yield with exclusive regioselectivity using 5 mol % silver chloride (AgCl) as a catalyst and TMEDA as the base (Table 1a) (for detailed optimization studies, see the Supporting Information Tables S1–S10).45,46 Notably, this discovery represented an impressive example of successfully reducing the stoichiometric amount of silver salt to catalytic silver-enabled diazo-cycloaddition transformations, thereby largely improving the practicality of this protocol. Interestingly, using 2-phenylfumaronitrile E- 1a in this reaction could also render the smooth formation of 2a in 95% yield with identical excellent regioselectivity (Table 1b). This observation circumvents the troublesome issue of separating E/Z mixtures of alkenyl 1,2-dinitriles 1 to the more readily accessible (Z/E)-2-phenylbut-2-enedinitrile 1a was used in subsequent studies. Changing the AgCl to different silver salts such as Ag2O, AgOAc, and Ag2CO3, promoted the transformation with comparable results (entries 2–4). Other metal salts such as CuCl, FeCl3, ZnCl2, CoCl2, NiCl2, and MgCl2 were also tested in this reaction, which generally produced pyrazole 2a in 65–80% yields (entries 5–10). Notably, the complete omission of AgCl from the reaction system still allowed the formation of 2a in up to 80% yield (entry 11). In comparison, the reaction was almost fully inhibited when TMEDA was omitted (entry 12), implying a crucial role of TMEDA in promoting the reaction. Switching TMEDA to an array of organic and inorganic bases proved viable with the formation of desired pyrazole 2a in variable (57–91%) yields (entries 13–20). This [3 + 2] cycloaddition reaction was also compatible with other reaction medium such as acetonitrile (entry 21). Reducing the amount of TMEDA to 1 equivalent would harm the yield of 2a to 53% (entries 21 and 22), while decreasing the loading of CF3CHN2 to smaller excess resulted in acceptable yields (entries 24–26). Furthermore, we used a two-chamber system to conduct in situ generation of CF3CHN2 from trifluoroethylamine hydrochloride and sodium nitrite, which delivered 2a in 47% yield (see the Supporting Information Figure S1, procedure C for details). Table 1 | Optimizing the Silver-Catalyzed Cycloaddition Reaction Conditions Entrya Variation from the Standard Conditions Yield (%)b 1 None 95 2 Ag2O instead of AgCl 90 3 AgOAc instead of AgCl 91 4 Ag2CO3 instead of AgCl 89 5 CuCl instead of AgCl 70 6 FeCl3 instead of AgCl 67 7 ZnCl2 instead of AgCl 73 8 CoCl2 instead of AgCl 80 9 NiCl2 instead of AgCl 65 10 MgCl2 instead of AgCl 75 11 AgCl was not added 80 12 TMEDA was not added Trace 13 Et3N instead of TMEDA 87 14 DIPEA instead of TMEDA 81 15 DABCO instead of TMEDA 86 16 DBU instead of TMEDA 57 17 DMAP instead of TMEDA 89 18 KOAc instead of TMEDA 90 19 K2CO3 instead of TMEDA 91 20 Cs2CO3 instead of TMEDA 81 21 MeCN instead of DMF 90 22 2 equiv of TMEDA was used 71 23 1 equiv of TMEDA was used 53 24 4 equiv of CF3CHN2 was used 83 25 3 equiv of CF3CHN2 was used 76 26 2 equiv of CF3CHN2 was used 61 Note: TMEDA, tetramethylethylenediamine; DIPEA, N,N-diisopropylethylamine; DABCO, 1,4-diazabicyclo[2.2.2]octane; DBU, 1,8-diazabicyclo(5.4.0)undec-7-ene; DMAP, 4-dimethylaminopyridine. aCF3CHN2 in a stock solution of DMF (1.0 mmol, 0.5 mol/L, 5.0 equiv) was mixed with the 2-phenylbut-2-enedinitrile 1a (31.8 mg, 0.2 mmol), silver salt AgCl (1.4 mg, 0.01 mmol), and base TMEDA (69.7 mg, 0.6 mmol) and stirred at room temperature for 12 h unless otherwise indicated. bYield of isolated pyrazole 2a. Scope of the reaction Next, the substrate scope with respect to 1,2-dicyanoalkenes 1 was examined under the optimized conditions (Scheme 1, left). Methyl, tert-butyl, and methoxyl groups substituted at the phenyl ring of 1,2-dicyanoalkenes were well accommodated to give the corresponding cycloadducts 2b– 2d in 92–95% yields. The structure of product 2b was further confirmed to be 3-trifluoromethyl-4-cyano-1H-pyrazole using X-ray crystallographic analysis. Also, the biphenyl-derived substrate was a good reaction partner, yielding pyrazole 2e. A series of halogen atoms, including fluorine, chlorine, and bromine, substituted at different positions of the benzene ring were all well-tolerated in this transformation (products 2f– 2k). Introducing strong electron-withdrawing groups such as trifluoromethyl, cyano, and nitro groups into the phenyl-derived substrates proved to be equally applicable (products 2l– 2n). Furthermore, 2-naphthyl-, 1-naphthyl-, 2-thienyl-, 3-thienyl-, and 2-furyl-substituted 1,2-dicyanoalkenes participated in the [3 + 2] cycloaddition process with constant good results (products 2o– 2s). Finally, 5-carboxylic ester and 5-vinyl group-functionalized 3-CF3-4-CN-pyrazoles 2t and 2u were readily obtained in 82% and 90% yield, respectively. Noteworthily, excellent regioselectivity was observed constantly in all tested examples, demonstrating the remarkable regio-control capability of this catalytic system. However, alkyl-substituted 1,2-dicyanoalkenes proved to be relatively unstable under the current developed conditions, with no desired detectable cycloadducts. Scheme 1 | Substrate scope of 3-CF3-4-CN-1H-pyrazoles 2 and 5-CF3-3-CN-1H-pyrazoles 4. a20 mol % of Ag2O was used for these reaction examples. Download figure Download PowerPoint The broad functional group compatibility, excellent regioselectivity, and mild reaction conditions of this platform prompted us to examine the applicability of 1,1-dicyanoalkenes 3 (Scheme 1, right). To our delight, the corresponding target 3-cyano-5-trifluoromethyl-1H-pyrazoles 4a was obtained in up to 91% yield as a single regioisomer by only a slight modification of the reaction conditions (see the Supporting Information). The silver catalyst proved to be more important for this system as only a 65% yield of 4a was obtained when Ag2O was removed. 2-Aryl-1,1-dicyanoalkenes bearing alkyl and alkoxyl groups on the phenyl ring were well tolerated to furnish the pyrazole products 4b– 4f in good yields. Importantly, a gram-scale experiment was performed and afforded 1.0 grams of pyrazole 4b in 80% yield with exclusive regioselectivity. Substrates bearing different halogen atoms located at various positions of the phenyl ring were all accommodated and provided 4g– 4l in 63–81% yield, among which compounds 4i– 4k demonstrated potential insecticidal activity.18 Strong electron-withdrawing substituents (such as CF3, NO2, and CN) on the phenyl ring were also compatible, albeit requiring a slightly increased amount of silver catalyst (products 4m– 4o). We were pleased to observe that 2-naphthyl, 1-naphthyl, and heteroarenes including pyridine-, indole-, furan-, and thiophene-derived substrates, were all suitable and led to the formation of the corresponding pyrazoles with complete regio-control (products 4p– 4u). Furthermore, alkyl group-substituted alkenyl dinitrile was tested and delivered the cycloadduct 4v in decent yield. The incorporation of ester moiety was also feasible and offered 3-cyano-5-trifluoromethyl-1H-pyrazole-4-carboxylate 4w in 69% yield. Finally, the ferrocene-derived substrate could react with CF3CHN2 smoothly and gave product 4x in 72% yield. Notably, the presence of one more alkenyl group in the starting dipolarophile did not impede the progress of the cycloaddition event, as exemplified by the smooth liberation of 3-vinyl-pyrazole 4y from the corresponding 3-phenylallylidene malononitrile. In addition, several perfluorinated diazo compounds were prepared and examined, and the corresponding products 5a– 5h were obtained in moderate to good yields with excellent regioselectivity by employing different bases (Scheme 2a). However, when difluorodiazoethanes were used,47–51 no cycloadducts were observed, probably due to the competitive deprotonation at the CF2H moiety and the starting dicyanoalkenes were fully recovered. Scheme 2 | Synthesis of perfluorinated cyanopyrazoles and the subsequent synthetic applications of trifluoromethylated cyanopyrazoles. (a) Application of perfluorinated diazo compounds. (b) Preparation of cyano analogue of Fluazolate. (c) Preparation of cyano analogue of Penthiopyrad. (d) Preparation of cyano analogues of Celecoxib. Download figure Download PowerPoint Synthetic utility and biological activity assay The synthetic utility of this silver-enabled dual incorporation protocol was showcased by the preparation of several analogues of agrochemicals and drugs (Schemes 2b–2d). As shown in Scheme 2b, employing 1,2-dicyano alkene 1v as the starting material to react with CF3CHN2 under standard conditions generated the corresponding 3-CF3-4-CN-1H-pyrazole 2v in 76% yield with excellent regioselectivity. Subsequent methylation provided 4-CN-5-CF3-pyrazole 6 in 43% yield, which possessed similar core structures compared with the herbicide Fluazolate.52 Direct N-methylation of 4w with iodomethane under basic conditions gave the corresponding 3-CF3-5-CN-pyrazole 7 in 81% yield (Scheme 2c). Subsequent hydrolysis and amidation could afford 3-CF3-5-CN-pyrazole-carboxamide 9 as the major product in practical yield, a cyano-analogue of the fungicide Penthiopyrad.53 Furthermore, the nucleophilic aromatic substitution of 1-fluoro-4-nitrobenzene with pyrazole 2b offered the corresponding N1-aryl-pyrazole 10 (Scheme 2d).54,55 Moreover, reduction and diazotization were smooth, leading to primary amine 11 and diazonium salt 12 in high yields, respectively. Treatment of diazonium salt 12 with sodium azide afforded the azide product 13 in 71% yield, which might perform as a potential azido bioisostere of the drug Celecoxib.56 More importantly, sulfonamide 15 (as a cyano-analogue of Celecoxib) was obtained in good yield via a one-pot sulfonylation/amination sequential process.57 In this context, the structures of the compounds 6, 7, 11, and 13 were confirmed by X-ray crystallographic analysis. Furthermore, we performed a preliminary in vitro activity evaluation towards COX-2 with compounds 10, 11, 13, 15 and the drug Celecoxib (Figures 2a and 2b). To our great delight, treating the lipopolysaccharide (LPS)-induced RAW264.7 (murine macrophage) cells with the obtained N1-aryl-3-CF3-4-CN-pyrazoles for 48 h caused significant inhibition of COX-2 expression. Particularly, compound 11 exhibited an even better COX-2 potency at lower concentrations than Celecoxib (compound 11: 0.1 μM vs Celecoxib: 10 μM) in an in vitro inhibitory activity assay, demonstrating that compound 11 effectiveness against COX-2 was >100 times than the positive control Celecoxib agent; thus, holding high promise for further development as an anti-inflammatory drug.58,59 Figure 2 | Inhibitory activity evaluation toward COX-2. RAW264.7 cells were treated with compounds 10, 11, 13, 15, and Celecoxib at indicated concentrations for 48 h. The data were analyzed using one-analysis of variance (ANOVA) followed by Tukey’s test. **p < 0.01, ***p < 0.001 versus LPS-induced cells without pyrazole treatment. ###p < 0.001 versus normal cells with LPS-induced cells. Download figure Download PowerPoint Mechanistic studies To provide insight into the reaction mechanism, several control and deuterium labeling experiments were conducted (Scheme 3). The cycloaddition of 3-phenylpropiolonitrile 16 with CF3CHN2 proceeded very slowly to afford the adduct 2b in low yield (Scheme 3a). We also treated 1,2-dicyanoalkene 1a and 1,1-dicyanoalkene 3a under the standard reaction conditions, but in the absence of CF3CHN2, and did not detect any formed 3-phenylpropiolonitrile (Scheme 3b). In addition, using cinnamonitrile 17 as the dipolarophile to react with CF3CHN2 did not furnish the desired cycloadducts (Scheme 3c). These results indicated that two cyano groups were critical for this cycloaddition reaction to occur. When AgCl was combined with a weak base such as potassium dihydrogen phosphate (KH2PO4), 2,4-dihydro-3H-pyrazole-3,3-dicarbonitrile 18 was obtained in 80% yield (Scheme 3d). Subsequently, treatment of compound 18 with Ag2O under the standard conditions could smoothly deliver pyrazole product 4a. Besides, we monitored the reaction of CF3CHN2 with Ag2O and TMEDA via 19F- and 1H-NMR spectroscopies and observed the appearance of a new signal at −47.9 ppm (19F-NMR) and the disappearance of the H-signal of CF3CHN2 at 5.19 ppm (1H-NMR), pointing to the generation of silver trifluorodiazoethylide species. However, no new signals in the 19F- and 1H-NMR were observed in the presence of CF3CHN2 with AgCl and TMEDA. Direct trapping of a stoichiometric silver-promoted reaction with D2O gave the corresponding deuterated product D- 4a (Scheme 3e). Based on these preliminary results and previous studies,60–67,a a plausible mechanism was proposed for the formation of cycloadducts 2 and 4 (Scheme 3f): CF3CHN2 interacted with silver oxide to form the corresponding trifluorodiazoethane-silver complexes Int-I. Subsequent [3 + 2] cycloaddition of this silver complex with 1,1-dicyanoalkenes 3 proceeded to give the pyrazoline intermediate Int-II. Finally, base-promoted cyanide elimination and pyrazolyl silver hydrolysis ( Int-III) occurred to give the corresponding aromatized pyrazole product 4. On the other hand, CF3CHN2 might have reacted directly with 1,2-dicyanoalkenes 1 to give pyrazoline intermediate Int-IV, promoted by TMEDA and AgCl, in which the silver catalyst could coordinate with the cyano group as a Lewis acid. Subsequent steps, including 1,3-hydrogen shift, base-promoted cyanide elimination, and another 1,3-hydrogen shift, could lead to the formation of final pyrazole product 2. The reaction was regioselectivity in the cycloaddition to and to an in of the with Scheme 3 | experiments and proposed mechanism for the formation of cycloadducts. (a) evaluation of (b) the of alkene to (c) evaluation of (d) intermediate (e) Download figure Download PowerPoint We have developed a silver-catalyzed [3 + 2] cycloaddition reaction of dicyanoalkenes with This transformation the dual incorporation of two important structural into one heterocyclic core in a single step, thus, convergent and regiodivergent access to previously elusive CF3- and pyrazoles with excellent under mild reaction conditions. the potential application of this cycloaddition reaction was demonstrated via a step in the and synthesis of cyano-analogues of CF3-containing drugs (Celecoxib) and agrochemicals (Penthiopyrad and Fluazolate). COX-2 inhibitory activity was obtained with 3-trifluoromethyl compared with the drug Celecoxib. A more on the and further application of this cycloaddition reaction is in our a be that base-promoted cycloaddition is also in these reactions when silver salt is yield for 2a and 65% yield for 4a without the of silver salt under otherwise reaction Supporting Information Supporting Information is and the optimization studies, of all new of and X-ray crystallographic The X-ray crystallographic for structures in this have been at the Centre under ( ( ( ( ( ( and ( These data are of from the of is no of interest to Information This is by the Science of China and the Key and Development of China and and Tianjin Science and This is to the of the Institute of at in Google Scholar 2. of with Introduction of Google Scholar Zhou of in of and Google Scholar 4. and in the and Application of for Google Scholar of to the Google Scholar of to Google Scholar Synthetic in 1, Google Scholar of the Google Scholar of in Google Scholar of and Google Scholar of as Google Scholar as and A Google Scholar Ma of Google Scholar to A for the Synthesis of Google Scholar and of Google