Regioselective Palladium-Catalyzed C-H Bond Trifluoroethylation of

Wissniowski, T.; Di Fazio, P.; Montalbano, R.; Ficker, J. H.; Ocker, M.;. Quint, K. Int. J. Oncology 2015, 47, 963–970. (3) (a) Filler, R.; Kobayash...
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Research Article Cite This: ACS Catal. 2018, 8, 2173−2180

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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,† Yin-Long 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 S Supporting Information *

ABSTRACT: A selective palladium-catalyzed trifluoroethylation reaction of indoles has been developed. The C-H 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 late-stage 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 palladiumcatalyzed 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. KEYWORDS: C-H activation, trifluoroethylation, indoles, palladacycle, Catellani reaction

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metal-catalyzed C-H functionalization of indoles.8 On the basis of this precedence, we envisioned that direct trifluoroethylation reactions of indoles would be a highly competitive strategy for the synthesis of 2-CF3CH2-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 libraries. Herein, we reported a novel palladium-catalyzed direct trifluoroethylation of the C-H bond of indoles using CF3CH2I as a trifluoroethyl source (Scheme 1c). Recently, Bach and co-workers reported an elegant study of a ligand free palladium-catalyzed C-H bond alkylation of indoles,9 which takes place through a modified Catellani pathway.10 This finding suggested that replacement of normal alkyl halides by CF3CH2I in the Bach’s process would enable the generation of 2-C-H trifluoroethylation of indoles (Scheme 1d). In contemplating this proposal, some important issues need to be considered. First, 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 aryl-halides. Second, in a manner that is different from the Catellani reaction, which is initiated by

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 2-methylindole moiety (Scheme 1a).2 Owing to the unique properties bestowed by the fluorine atom and fluorinecontaining 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, 2-trifluoroethylindoles, in which the CF3 group is appended to the 2-methyl group of 2methylindoles, 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 multistep 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 attractive methods developed to date for the preparation of indoles involves highly regioselective transition© 2018 American Chemical Society

Received: September 20, 2017 Revised: January 19, 2018 Published: January 29, 2018 2173

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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 zerovalent 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.

Scheme 1. Direct C-H Trifluoroethylation of Indoles

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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, Scheme 2. Trifluoroethylation of Palladacycle Complexes

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 the palladacycle complex is much slower than that of normal alkyl halide and that, 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 ligand would be needed to balance the rates of the AP and OA steps in the trifluoroethylation process.

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 equiv. We reasoned that the low yield of this process is a result of strong coordination of Phen to Pd, which causes the 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 2174

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ACS Catalysis Table 2. Indole Substrate Scopea

of Pd(acac)2 (path b). As proposed, the 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 the 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. 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 Table 1. Optimization of the Reaction Conditionsa

a

Reactions were run on a 0.2 mmol scale. bOn a 7.0 mmol scale.

the aryl ring also exhibit high reactivities under these conditions. For example, the reactions of halogen-substituted 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, 5-cyanoindole also fails to undergo the trifluoroethylation reaction. Notably, the reaction can be conducted on a gram scale. For example, product 5i is obtained in 71% yield on a 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 show, melatonin, a substance that has antidiabetic activity, is directly converted to its 2-CF3CH2 analogue 5s in 58% yield using the optimized conditions. Also, indoles containing 3-cyclo(L-Pro-L-Trp) and 3-cyclo(LVal-L-Trp) groups, which are cytotoxic and are inhibitors of cell death, undergo trifluoroethylation to form the respective products 5t and 5u, albeit in slightly lower yields (38% and 33%, respectively). Furthermore, the N-tert-butyloxycarbonylprotected L-tryptophan methyl ester participates in a reaction that forms the trifluoroethyl-substituted product 5v in 56% yield without accompanying racemization. Finally, a cholester-

a

All right reactions were run on a 0.2 mmol scale in DMF (1 mL) with a scaled bottle. bYields are determinated by 1H NMR with CF3-DMA as an internal standard. cLigand (40 mol %) was added. dPd(acac)2 (15 mol %) was added. eCF3CH2I was replaced by CF3CH2OTs/KI.

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 the formation of 5a in 72% yield (entries 4−10). In addition, an increase in the loading 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). 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 electron-withdrawing groups on 2175

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nitrile 13 using a palladium-catalyzed cyanation reaction. This sequence serves as a formal synthesis of the target because conversion of 13 to 1 has been accomplished in an earlier study.5b 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 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

Table 3. Late-Stage Trifluoroethylation of Complex Moleculesa

a

Reactions were run on a 0.2 mmol scale; isolated yields are shown.

ol-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 develop potential drug leads. In the final phase of this effort, the new trifluoroethylation process was applied to the synthesis of the CF3CH2-containing bioactive indoles 1 and 3 (Scheme 1b). As shown in Scheme 3,

C−H activation pathway is involved in the catalytic cycle. Second, the observation that the process is attended by a small kinetic isotopic effect (KIE) (kH/kD = 1.1 using 4a/4a-d1) reveals that C-H bond activation is not the rate-determining 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 palladacycle int.II cannot 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

Scheme 3. Synthetic Application

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 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

Figure 1. Kinetic data for the individual substances involved in the trifluoroethylation reaction. 2176

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ACS Catalysis 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−D). Consequently, it is highly reasonable to propose that both the palladium catalyst and indole substrate are involved in the RDS, while norbornene is incorporated after the RDS (Scheme 1d). Thus, the RDS should occur prior to C-H activation, which is consistent with the measured KIE number in eq 1. 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 that 4a is recovered in 68% yield.17 However, the key palladacycle intermediate int.II-acac cannot 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 the 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).

The above analysis is consistent with the plausible mechanism for the catalytic trifluoroethylation reaction displayed in Scheme 4. The reaction is initiated by the Scheme 4. Proposed Reaction Mechanism

formation of palladium complex int.V through deprotonation of the indole-Pd complex by a weak base. Coordination of norbornene followed by fast cis-aminopalladation 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.IIdk, 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 the palladacycle, which enables successful oxidative addition of CF3CH2I. Finally, the presence of excess dbm enhances the 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, which differs from the experimental results (Figure 1B). We reasoned that, the observation might be explained by the fact that the coordination of norbornene to palladium center in int.VIII is much weaker than that of indoles in int.IX, which is confirmed by density functional theory (DFT) calculations (see Figure 3; there is 25 kcal/mol difference between int.VIII amd int.IX). DFT Calculation. 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

Figure 2. (a) 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 °C for 2 h. (b) Negative ion mode ESI-MS spectrum of a mixture containing 5a (28%) and the recovered 4a (68%), obtained by the catalytic reaction of 4a (0.2 mmol), without dbm, at 100 °C for 2 h.

This observation is significantly different from one made by using in situ ESI-MS analysis of a 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 intIX 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 RDS of the trifluoroethylation reaction. To gain evidence to support this proposal, the N-H/N-D KIE was determined (eq 2). The significantly large KIE value (kH/kD = 2.3) strongly supports this suggestion. 2177

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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 the M11-L method in DMF solvent. 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.)

intermediate int.VII. 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 int.IX releasing a large amount of energy as high as 25 kcal/mol, which could be well addressed by the kinetic behavior on the zeroth-dependence of the concentration of norbornene. The following proton transfer generates the isomer int.XII of active catalyst int.V and releases α-trifluoroethylindole product 5a, thereby completing the catalytic cycle. The theoretical calculations show that the barrier of this step is 29.5 kcal/mol, which corresponds to the RDS 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, has relative free energies that are 3.1 kcal/mol higher than that of TS6.

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 Pd−N 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 the 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

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CONCLUSION

In the study described above, we developed a selective palladium-catalyzed C-H trifluoroethylation reaction of indoles, which utilizes commercially available CF3 CH 2I as the trifluoroethyl source. The reaction, which displays a wide 2178

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substrate scope and excellent functional group compatibility, serves as a straightforward and practical method to synthesize a variety of 2-trifluoroethylindoles. Importantly, the β-diketone ligand plays an important role in determining the efficiency of this transformation through its ability to promote oxidative addition of the palladacycle to CF3CH2I. Interestingly, βdiketones have less effect on aminopalladation of norbornene, a finding that may open avenues to developing more strategies for indole functionalization.

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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/acscatal.7b03220. Synthetic procedures, characterization, additional data, and DFT calculation (PDF) NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*(H.-Y.W.) E-mail: [email protected]. *(Y.L.) E-mail: [email protected]. *(G.L.) E-mail: [email protected]. ORCID

Yu Lan: 0000-0002-2328-0020 Guosheng Liu: 0000-0003-0572-9370 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the 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/Techn ology 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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REFERENCES

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