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Regioselective Palladium-Catalyzed C-H Bond Trifluoroethylation of Indoles: Exploration and Mechanistic Insight Hao Zhang, Haoyang Wang, Yixin Luo, Chaohuang Chen, Yimiao Cao, Pinhong Chen, Yin-Long Guo, Yu Lan, and Guosheng Liu ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03220 • Publication Date (Web): 29 Jan 2018 Downloaded from http://pubs.acs.org on January 30, 2018
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ACS Catalysis
Regioselective Palladium-Catalyzed C-H Bond Trifluoroethylation of Indoles: Exploration and Mechanistic Insight ‡
Hao Zhang,† Hao-Yang Wang,*† Yixin Luo, Chaohuang Chen,† Yimiao Cao,† Pinhong Chen,† YinLong Guo,† Yu Lan*‡ and Guosheng Liu*† †
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, China, 200032 ‡ School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P. R. China Supporting Information ABSTRACT:
A selective palladium-catalyzed trifluoroethylation reaction of indoles has been developed. The CH bond activation process, using CF3CH2I as the fluoroalkyl source, can be employed to prepare a variety of 2-CF3CH2 substituted indoles. Moreover, because it displays a wide functional group tolerance, the process can be employed to synthesize CF3CH2-containing bioactive indoles through latestage trifluoroethylation. The results of a preliminary mechanistic study and DFT calculations show that a β-diketone, acting as an ionic palladium ligand, plays an important role in governing the efficiency of the palladium-catalyzed trifluoroethylation reaction by accelerating the oxidative addition step. In contrast, transfer of the indole N-H proton in the palladium center is involved in the rate-determining step. Key words: C-H activation, Trifluoroethylation, Indoles, Palladacycle, Catellani Reaction
Introduction The indole motif is present in a large number of therapeutic substances.1 Many bioactive compounds and drugs in this group, such as oxypertine, acemetacin and panobinostat, contain a 2methylindole moiety (Scheme 1a).2 Owing to the unique properties bestowed by fluorine atom and fluorine-containing groups, organofluorine molecules have been extensively studied and widely applied as pharmaceutical agents and agricultural chemicals.3 Consequently, a common approach to developing new drugs in the pharamceutical industry involves the introduction of fluorine into bioactive lead compounds. In this regard, 2trifluoroethylindoles, in which the CF3 group is appended to the 2methyl group of 2-methylindoles, have gained the recent interest of workers in the field of medicinal chemistry and biochemistry.4 For instance, a variety of 2-trifluoroethylindole derivatives such as 1-3 (Scheme 1b) have been investigated as antitumor, nervous system, and reproductive control agents.5 Because of this high level of interest,6 increasing attention is being given to the development of new and efficient methods to prepare 2-trifluoroethylindoles, which avoid the use of multi-step sequences uncovered in earlier studies. For example, Antonchick recently developed an elegant three-component reaction that generates 2-CF3CH2-substituted indoles through a seqential radical process and Fischer indole synthesis.7 One of the most
Scheme 1. Direct C-H Trifluoroethylation of indoles. attractive methods developed to date for the preparation of indoles involves highly regioselective transitionmetal-catalyzed C-H functionalization of indoles.8 Based on this precedence, we envisioned that direct trifluoroethylation reactions of indoles would be a highly competitive strategy for the synthesis of 2CF3CH2-substituted indoles. Importantly, a method of this type would enable direct late-stage trifluoroethylation of bioactive indoles as part of protocols to construct CF3CH2-contianing indole
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libraries. Herein, we reported a novel palladium-catalyzed direct trifluoroethylation of C-H bond of indoles using CF3CH2I as a trifluoroethyl source (Scheme 1c). Recently, Bach and coworkers reported an elegant study of a ligand free palladiun-catalyzed C-H bond alkylation of indoles,9 which takes place through a modified Catellani pathway.10 This finding suggested that replacement of normal alkylhalides by CF3CH2I in the Bach's process would enable generation of 2-C-H trifluoroethylation of indoles (Scheme 1d). In contemplating this proposal, some important issues need to be considered. Firstly, studies of the Catellani reaction by Lautens10b showed that the use of an electron-rich phosphine ligand significantly increases the nucleophilicity of palladacycle intermediates and, as a result, enhances the rates of oxidative addition (OA) of alkyl- and arylhalides. Secondly, in a manner that is different from the Catellani reaction, which is initiated by oxidative addition of ArI to Pd(0), Bach's indole alkylation process begins with aminopalladation (AP) of norbornene. Thus, the presence of electron-donating phosphine ligands would suppress the initial AP step and result in inhibition of the overall reaction. Notably, Bach's alkylation method utilizes ligand-free conditions, in which the Pd(II) complex Int.II exhibits relatively low nucleophilicity, causing the oxidative addition step to be rate-limiting (Scheme 1d).9b Finally, results of our recent study of ortho C-H trifluoroethylation reactions of aryl iodides showed that, because of the unique electronic and steric nature of the CF3CH2 group, oxidative addition of CF3CH2I to palladacycle complex is much slower than that of normal alkyl halide and, as result, it is the rate-limiting step in the pathway.11 Thus, it is reasonable to conclude that oxidative addition of CF3CH2I to the palladacycle complex Int.II would be difficult in the absence of electron-rich ligands. Taken together, the above considerations suggest that the key AP and OA steps in the pathway for C-H bond trifluoroethylation reactions of indoles would respond to ligands in an opposite way. Specifically, the reasoning suggests that both Catellani's (phosphine ligand) and Bach's (ligand free) reaction conditions would be ineffective for promoting this process. Thus, at the outset of this study we felt that a new type of ligands would be needed to balance the rates of the AP and OA steps in the trifluoroethylation process. During a study of the mechanism for cross-coupling reactions, Amatore and Jutand found that an anionic ligand plays a crucial role in oxidative addition of arylhalides to zero-valent palladium catalysts because the formed anionic palladium complex [Pd(PPh3)2X]-, which is a stronger nucleophile than Pd(PPh3)2, serves as the key catalyst.12 Guided by this knowledge, we speculated that use of an anionic ligand would facilitate OA between CF3CH2I and a palladacylce complex. Consequently, a balance between the AP and OA steps might be achieved, enabling smooth C-H bond trifluoroethylation of indoles. Results and Discussion In order to test the proposal described above, an initial investigation of the reaction of CF3CH2I with a palladacycle complex was conducted. For this purpose, the well-known palladacycle complex int.II-Phen (Phen = phenanthroline) was synthesized and treated with CF3CH2I in the presence of excess amounts of anionic ligands (Scheme 2a). When chloride, acetate, phenoxide and trifluoroacetate are used as anionic ligands, the reaction fails to produce the desired coupling product 5a. However, when Kacac [(H-acac) = acetylacetone] is utilized as
an anionic ligand source, 5a is generated in 10% yield, which is further increased to 15% by increasing the Kacac loading to 50 equivalents. We reasoned that the low yield of this process is a result of strong coordination of Phen to Pd, which causes ligand exchange between palladacycle complex int.II-Phen and Kacac forming int.II-acac to be disfavored. To circumvent this problem, Bach's procedure was employed to prepare palladacycle int.II from a stoichiometric amount of Pd(OAc)2.9b Addition of the extraneous ligand acetylacetone (H-acac) produces the anionic palladium complex int.II-acac, as demonstrated by using 1HNMR spectroscopy and ESI-mass spectrometry (path a, Scheme 2b). Moreover, palladacycle int.II-acac can also be formed by using stoichiometric reaction of Pd(acac)2 (path b). As proposed, reaction of anionic palladacyle int.II-acac with CF3CH2I proceeds smoothly to form the target 5a in high yield (86% through path a; 78% through path b). Notably, as expected treatment of palladacylce int.II with CF3CH2I in the absence of acac forms only a trace amount of 5a (Scheme 2b, top).13 These results demonstrate that the anionic palladacycle [int.II-acac]- is indeed a stronger nucleophile in oxidative addition of CF3CH2I than is the neutral int.II.
Scheme 2. The trifluoroethylation of palladacycle complexes. Encouraged by these findings, we explored the catalytic trifluoroethylation reaction of indole 4a using Pd(acac)2 as the catalyst. The reaction generated the desired product 5a in 60% yield (entry 1, Table 1). In contrast, reactions promoted by other palladium catalysts, such as Pd(CH3CN)2Cl2 and Pd(OAc)2, take place in lower respective yields of 13% and 10% (entries 2-3). Moreover, a variety of phosphine ligands employed previously to promote Catellani reactions and a variety of nitrogen-containing ligands also failed to induce trifluoroethylation of 4a (for details, see SI). Other β-diketones were employed as anionic ligands to enhance the efficiency of the reaction by altering the equilibrium to more greatly favor the anionic palladacycle intermediate. Among those probed ligands, dibenzoylmethane (dbm) was found to be the most effective ligand in that it promoted formation of 5a in 72% yield (entries 4-10). In addition, an increase in the loading
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ACS Catalysis of Pd(acac)2 (15 mol%) led to an improved 80% yield (entry 11). Finally, utilizing CF3CH2OTs and KI in place of CF3CH2I as the trifluoroethyl source enhanced the rate of the reaction but with a lower yield of 5a (54%, entry 12).
Table 2. Indole Substrate Scope.a Pd(acac)2 (15 mol%) dbm (40 mol%) norbornene (2 equiv)
R2 R1
+ N H
CF3CH2I (3 equiv)
R1
KHCO3 (2 equiv), 100 oC
Me
5
MeO
CH2CF3
BnO CH2CF3
CH2CF3
N H
N H
5a 78%
5b 76%
N H
5c 82%
5d 75%
Cl
CH2CF3
Br
CH2CF3
CH2CF3
CH2CF3
N H
N H
N H
N H
5e 74%
5f 78%
5g 80%
5h 66%
Cl
R
MeO2C CH2CF3
N H 5i 80% (71%, 1.16g)b
CH2CF3 N H 5j 74%
CH2CF3 N H 5m 80%
CH2CF3 N H 5n 58%
CO2Me
5q 58%
5l 13%
CH2CF3 N H 5r 56%
CO2Me
CH2CF3
CH2CF3
N H
N H
5o 66%
5p 76%
inactive substrates
O
CO2Me
O N H
Me
N H
CN
O
CH2CF3 iPr
CH2CF3
CH2CF3 N H R = CH2NHBoc 5k 63%
OH
The indole scope of the trifluoroethylation reaction, using the optimal conditions described above, was probed. The results (Table 2) show that indoles with electron-donating groups (Me 4b and 4e, OMe 4c, and OBn 4d) on the aryl ring undergo reactions that form the corresponding 2-CF3CH2 substituted products 5b-5e in high yields (74-82%). Furthermore, indoles bearing electronwithdrawing groups on the aryl ring also exhibit high reactivities under these conditions. For example, the reactions of halogensubstituted indoles 4f-4i proceed smoothly to generate the corresponding products 5f-5i, in which the halide atom is retained. Indole 4j, containing a carboxylic ester moiety, reacts to form 5j in 74% yield, and indole 4k bearing a Boc protected benzylamine group also serves as a substrate in the trifluoroethylation reaction that produces 5k in high yield. Notably, 7-methylindole reacts very inefficiently to give product 5l in only a 13% yield under the optimized conditions. In contrast, indoles possessing 3-alkyl substituents, including those that contain ester, nitrile, hydroxyl and amide groups, react smoothly to generate the corresponding products 5m-5r in high yields. However, when electronwithdrawing groups like an ester, cyanide and ketone are present at the 3-position, the indoles are unreactive. In addition, owing to the strong electron-withdrawing property of the cyanide group, 5cyanoindole also fails to undergo the trifluoroethylation reaction. Notably, the reaction can be conducted in gram scale. For example, product 5i is obtained in 71% yield in 7 mmol sale. The versatility of the newly developed protocol was demonstrated by its successful application to late-stage trifluoroethylation of bioactive and complex substances. As the results in Table 3, melatonin, a substance that has antidiabetic activity, is directly converted to its 2-CF3CH2 analog 5s in 58% yield using the optimized conditions. Also, indoles containing 3cyclo(L-Pro-L-Trp) and 3-cyclo(L-Val-L-Trp) groups, which are
CH2CF3
N H
F
a
CH2CF3 N H
DMF, Ar, 24 h
4
Table 1. Optimization of the Reaction Condition.a
R2
CN
N H
N H
N H NC N H
Reactions were run on 0.2 mmol scale, isolated yield. b On 7.0 mmol scale.
cytotoxic and inhibitors of cell death, undergo trifluoroethylation to form the respective produts 5t and 5u, albelt in slightly lower yields (38% and 33% respectively). Furthermore, the N-tertbutyloxycarbonyl-protected L-tryptophan methyl ester participates in a reaction that forms the trifluoroethyl-substituted product 5v in 56% yield without accompanying racemization. Finally, a cholesterol-linked indole serves as an acceptable substrate for this reaction that generates the fluorinated product 5w in high yield. These observations suggest that the newly developed trifluoroethylation process will be a key late-stage step in routes to prepare targets used to explore the effects of fluorine on biological activities and to develope potential drug leads. Table 3. Late-stage trifluoroethylation of complex molecules.a
In the final phase of this effort, the new trifluoroethylation process was applied in the synthesis of the CF3CH2-containing bioactive indoles 1 and 3 (Scheme 1b). As shown in Scheme 3, late-stage trifluoroethylation of isoxazole-indole 8, which is derived from commercially available 5-aminomethylindole 6 and the isoxazolecarboxylic acid 7, serves as the key step in an
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efficient route for synthesis of 3 in 68% yield. The bioactive oxadiazole-substituted indole 1, was prepared earlier in low yield using a cumbersome route from 4-chloro-3-(trifluoromethyl)aniline.5b In contrast, this target can now be generated efficiently using the concise sequence shown in Scheme 3 that features two fluoroakylation reactions. In the pathway, carbamate 10, produced from 5-hydroxylindole 9 using a literature procedure,14 undergoes trifluoromethylation reaction with the Togni-I reagent in the presence of a copper catalyst.15 Removal of the Boc group gives the free indole 11 that then undergoes trifluoroethylation to form the key intermediate 12 in high yield (70%). Treatment of 12 with Cp2ZrHCl14a and Tf2O, produces the corresponding triflate, which is converted to nitrile 13 using a palladium-catalyzed cyanation reaction. This sequence serves as a formal synthesis of target because conversion of 13 to 1 have been accomplished in an earlier study.5b N O H2 N
N O
O
HBTU/7, Et3N DMF, 78%
HN
Standard condition
N H
OH
HO
Boc N
O
ref. 14 N H
Et2N
9
O 10
N O
NC
BPin
H N
NC
1) CuTc/1,10-Phen Togni-I [CF3+] O 66% yield Et2N O 2) CF3CO2H 80% yield
H N
1
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0
0
CF3
11
0
0.2
0.4
0.6
CH2CF3 1) Cp ZrHCl, 2 Tf2O/Et 3N
CF3
2) Pd2(dba) 3/dppf Zn(CN)2
13
0.8
1
0
1.2
0.2
H N
CH2CF3
0.4
0.6
0.8
1
1.2
1.4
[Norbornene] (M)
[CF CH I] (M) 3
2
C
D 1
0.6
0.8
0.5 0.4
O
52% yield (two steps) 1
1
F3C
Standard condition 70% yield
CH2CF3 ref. 5b
CF3
N H
3
CF3
N N
N H
8
N O 7
palladacycle int.II can not be detected as an intermediate in the catalytic trifluoroethylation reaction using in situ 1H NMR and ESI-MS methods (see below). The results of additional kinetic studies revealed that the reaction rate is not dependent on the concentration of CF3CH2I (Figure 1A). The combined observations suggest that the oxidative addition of CF3CH2I to anionic palladacycle [int.II-dk]- (dk = diketone, such as acac or dbm) does not contribute to the rate-determining step of the trifluoroethylation process. In addition, the rate of this reaction displays a zeroth order dependence on the concentration of norbornene, first order dependence on the concentration of Pd(acac)2 and a saturation dependence on the concentration of indole 4a16 (Figure 1B-1D). Consequently, it is highly reasonable to propose that both palladium catalyst and indole substrate are involved in the RDS, while norbornene is incorporated after RDS (Scheme 1d). Thus, the rate-determining step should occur prior to C-H activation, which is consistent with the measured KIE number in eq 1. A B
HN
CF3CH2I 68% yield
O 6
O
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Et2N
O
0.6
CF3 12
0.3 0.4
Scheme 3. Synthetic application.
0.2 0.2
0.1
Mechanism Observations made in the study of oxidative addition of CF3CH2 to palladacyle int.II-acac (see above) and those made by Bach show that the nature of the ligand utilized has a significantly different impact on the trifluoroethylation reaction than it does on the analogous alkylation reaction. This finding stimulated our interest in conducting studies designed to gain preliminary information about the mechanism of the trifluoroethylation process. In the first experiment, partial reaction of the 2-deuterio substituted indole 4a-d1 under the standard reaction conditions for 2 h was found to produce adduct 5a along with recovered 4a-d1, which fully retained the deuterium label (eq 1). This result indicates that an irreversible C-H activation pathway is involved in the catalytic cycle. Secondly, the observation that the process is attended by a small kinetic isotopic effect (kH/kD = 1.1 using 4a/4a-d1) reveals that C-H bond activation is not the ratedetermining step (RDS) in the process.
Thus, the trifluoroethylation reaction differs from Bach's alkylation process, in which the oxidative addition step is ratedetermining. Consistent with this finding is the observation that
0 0
0.01
0.02
0.03
0.04
[Pd(acac)2] (M)
0.05
0.06
0 0
0.1
0.2
0.3
0.4
0.5
[indole 4a] (M)
Figure 1. Kinetic Data for the individual substances involved in the trifluoroethylation reaction. As mentioned above, 1H NMR monitoring of the catalytic reaction of 4a in d7-DMF not containing dbm for 2 h showed that product 5a is formed in 28% yield and 4a is recovered in 68% yield.17 However, the key palladacycle intermediate int.II-acac can not be detected in the solution after partial reaction. Moreover, the ESI-MS arising from in situ monitoring of the partial reaction mixture contained only one signal in the negative ion mode at m/z 519, which corresponds to loss of a proton from palladium complex int-IX. Importantly, signals associated with palladacycle int.II bound to other ligands were not present in the negative ion mass spectrum (Figure 2b). This observation is significantly different from one made by using in situ ESI-MS analysis of simple mixture of 4a and 5a (70:30 ratio), Pd(acac)2 and KHCO3 in DMF. In this case, signals arising from intermediates formed by random coordination of indoles to the palladium center are observed (Figure 2a). As a result, we surmise that palladium complex int-IX exists in a steady state in the catalytic cycle. In accord with the kinetic observations, we believe that proton transfer between indoles 4a and 5a in complex int.IX is the likely rate-determining step of the trifluoroethylation reaction. To gain evidence to support this proposal, the N-H/N-D
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ACS Catalysis kinetic isotopic effect was determined (eq 2). The significantly large KIE value (kH/kD = 2.3) strongly supports this suggestion.
Scheme 4. The proposed reaction mechanism.
Figure 2. (a) The negative ion mode ESI-MS spectrum of a solution of indole 4a (70%) and product 5a (30%), containing Pd(acac)2 (15 mol %) and KHCO3 (2 equiv.) at 100 oC for 2 h. (b) The negative ion mode ESI-MS spectrum of a mixture containing 5a (28%) and the recovered 4a (68%), obtained by catalytic reaction of 4a (0.2 mmol),without dbm, at 100 oC for 2 h.
The above analysis is consistent with the plausible mechanism for the catalytic trifluoroethylation reaction displayed in Scheme 4. The reaction is initiated by formation of palladium complex int.V through deprotonation of indole-Pd complex by a weak base. Coordination of norbornene (NBE) followed by fast cisaminopalladation leads to the formation of complex int.I-dk. C-H activation in int.I-dk then occurs to form the key anionic palladacycle intermediate int.II-dk, which undergoes oxidative addition with CF3CH2I and sequential reductive elimination to generate int.VII accompanied by C-C bond formation. Cleavage of the C-N bond generates palladium complex int.VIII, which reacts with the indole substrate via ligand exchange to yield the steady state complex int.IX. The final, rate-determining, proton transfer step produces product 5 and regenerates complex int.V. In the catalytic cycle, the diketone ligand plays the important role of enhancing the nucleophilicity of palladacycle, which enables successful oxidative addition of CF3CH2I. Finally, the presence of excess dbm enhances formation of palladacycle int.II-dk. Analysis of this catalytic cycle suggests that the reaction rate should be inversely proportional to the concentration of norbornene (NBE), which differs from the experimental results (Figure 1B). We reasoned that, the observation might be explained by the fact: the coordination of NBE to palladium center in int.VIII is much weaker than indoles in int.IX, which is confirmed by DFT calculation (see Figure 3, 25 kcal/mol difference between int.VIII amd int.IX).
DFT Calculation Density functional theory (DFT) calculations were carried out to gain a more detailed understanding of the trifluoroethylation process. As shown in Figure 3, the active intermediate int.V (R = Me), generated from indole 4a and Pd(acac)2 followed by deprotonation, is set as the zero energy point in the free energy profiles constructed by using the calculations. Because of entropy release, coordination of norbornene with int.V to generate intermediate int.VI is endergonic by 6.1 kcal/mol. Norbornene then inserts into the PdN bond via transition state TS1 with an overall activation free energy of 19.7 kcal/mol to yield intermediate int.I-dk in a reversible manner. Coordination of the indole group to palladium in intermediate int.I-dk activates the α-hydrogen, enabling deprotonation by bicarbonate via low energy (1.2 kcal/mol) transition state TS2 to form the palladate complex int.II-dk irreversibly with concomitant release of carbon dioxide and water. Because of the existence of a formal negative charge on palladium, complex int.II-dk participates as a nucleophile in a substitution reaction with CF3CH2I, which takes place via transition state TS3 with a barrier of 21.4 kcal/mol. After release of iodide, the neutral Pd(IV) complex int.IV-dk is formed. Analysis of the calculated structure of transition state TS3 (Figure 3) shows that it has a Pd-C-I bond angle of 148.1°, which indicates that it corresponds to an SN2 type process. DFT calculations were also performed on species involved in the oxidative addition pathway (Figure 3, blue lines). The results show that the dissociation energy of acetylacetone is 20.4 kcal/mol and that the overall barrier created by a three-membered ring type oxidative addition transition state TS7 is as high as 41 kcal/mol. Therefore, this pathway should be unfavorable. Reductive elimination in int.IV-dk via transition state TS4 generates a new C-C bond at the α-position of indole in intermediate int.II. Reversible β-nitrogen elimination via transition state TS5 yields the norbornene-coordinated indolylpalladium intermediate int.VIII. Subsequent ligand exchange between the indole reactant and norbornene forms intermediate
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Figure 3. Free energy profile for palladium-catalyzed direct C-H bond trifluoroethylation of indoles. The values given by kcal/mol are the relative free energies calculated by M11-L method in DMF solvent. Density functional theory (DFT) calculations are used to further study the mechanism of this palladium-catalyzed C-H bond trifluoroethylation reaction (for the structure of intermediates, see Scheme 4).
int.IX releasing a large energy as high as 25 kcal/mol, which could be well addressed the kinetic behavior on the zerothdependence of the concentration of norbornene. The followed proton transfer generates the isomer int.XII of active catalyst int.V and release α-trifluoroethylindole product 5a, thereby complete the catalytic cycle. The theoretical calculations show that the barrier of this step is 29.5 kcal/mol, which corresponds to the rate-determining step in the whole catalytic cycle. The calculated geometry of transition state TS6 is shown in Figure 3. When proton transfer between two nitrogen atoms takes place, palladium is coordinated through π bonds of two indoles. Indeed, consideration of the protonation of indolyl-palladium indicates that it could take place via transition state TS8, in which an N-Pd bond exists. The DFT calculation results showed that proton transfer, occurring via transition state TS8 or another type taking place through transition state TS9, have relative free energies that are 3.1 kcal/mol higher than that of TS6. Conclusion In the study described above, we developed a selective palladium-catalyzed C-H trifluoroethylation reaction of indoles, which utilizes commercial available CF3CH2I as the trifluoroethyl source. The reaction, which displays a wide substrate scope and excellent functional group compatibility, serves as a straightforward and practical method to synthesize a variety of 2trifluoroethylindoles. Importantly, β-diketones ligand plays an important role in determining the efficiency of this transformation
through their ability to promote oxidative addition of palladacycle to CF3CH2I. Interestingly, β-diketones have less effect on aminopalladation of norbornene, a finding that which may open windows to developing more strategies for indole functionalization. Corresponding Author Email:
[email protected];
[email protected];
[email protected]; Supporting Information Synthetic procedures, characterization, additional data and density functional theory (DFT) calculation. This material is available free of charge via the Internet at http://pubs.acs.org. ACKNOWLEDGMENT We are grateful for financial support from the National Nature Science Foundation of China (Nos. 21532009, 21472219, 21761142010 and 21790330), the National Basic Research Program of China (973-2015CB856600), Program of Shanghai Academic/Technology Research Leader (17XD1404500 and 17JC1401200), the strategic Priority Research Program (No. XDB20000000) and the Key Research Program of Frontier Science (QYZDJSSW-SLH055) of the Chinese Academy of Sciences. This research was partially supported by the Key Laboratory of Functional Molecular Engineering of Guangdong Province (2016kf02, South China University of Technology).
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