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Rh(III)-Catalyzed, Highly Selectively Direct C–H Alkylation of Indoles with Diazo Compounds

Key Laboratory of Optoelectronic Chemical Materials and Devices, Ministry of Education, School of Chemical and Environmental Engineering, Jianghan University, Wuhan 430056, China
College of Chemistry and Materials Science, Hubei Engineering University, Xiaogan 432000, China
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Catalysts 2016, 6(6), 89;
Submission received: 12 January 2016 / Revised: 16 May 2016 / Accepted: 17 May 2016 / Published: 18 June 2016
(This article belongs to the Special Issue Catalytic Functionalization of C‒H Bonds)


Rh(III)-catalyzed regioselective alkylation of indoles with diazo compounds as a highly efficient and atom-economic protocol for the synthesis of alkyl substituted indoles has been developed. The reaction could proceed under mild conditions and afford a series of desired products in good to excellent yields.

Graphical Abstract

1. Introduction

A major goal for the advancement of modern organic chemistry is the development of highly efficient and atom economical synthetic strategies that allow the rapid construction of structurally complex and functionally diverse molecular architectures [1,2]. Indoles are an important heterocyclic motif and widely found in numerous natural products, pharmacophores, and synthetic building blocks [3,4]. Therefore, direct functionalization of indoles has attracted much attention from synthetic chemists. With the development of transition-metal-catalyzed C–H bond activation, it has become the most straightforward approach for functionalization of indoles in a step- and atom-economical fashion [5,6,7,8,9,10,11,12]. Nevertheless, compared with C3–H functionalization, the methods that allow for the C2–H functionalization of indoles are still rare due to the weak reactivity of the C–H bond at the C2-position of an indole [13,14]. In this context, some excellent studies on selective arylation [15], alkenylation [16], alkynylation [17], cyanation [18], and acylation [19] of the C2–H bond of indoles have been conducted. However, the methods that allow for direct C2–H alkylation of indoles are still rare. In 2011, the group of Bach documented a Pd(II)-catalyzed direct C2-alkylation reaction of free (N–H)-indoles and primary alkyl bromides [20,21]. This reaction relied on a norbornene-mediated cascade process. Shortly after, Shibata developed a cationic iridium-catalyzed C2-alkylation for efficient synthesis of C2-alkyl substituted indoles with various alkenes [22]. Later, Glorius described a Rh(III)-catalyzed C–H alkylation of indoles with allylic alcohols with an excess amount of Cu(OAc)2 as an oxidant, while stoichiometric amounts of salt waste are generated as a byproduct [23,24]. Very recently, Li reported the Rh(III)-catalyzed direct alkylation of indoles using commercially available alkyltrifluoroborates in the presence of 2.8 equiv of AgF at 100 °C [25]. Despite these advances, there are still some limitations, such as high catalyst loading, excess metal oxidant, high temperature, and toxic medium.
Recently, diazo compounds have been widely employed as a class of versatile alkylation reagents in metal catalyzed C–H alkylation [26,27,28,29]. In 2010, Yu reported a highly regioselective approach for C2 alkylation of free (N–H)-indoles and aryldiazoesters catalyzed by Ruthenium catalyst [30]. In 2014, Yi and coworkers disclosed a Rh(III)-catalyzed C2-selective carbenoid functionalization with diazotized Meldrum’s acid, while the catalyst loading of 5 mol % was required for high catalytic efficiency [31]. As part of an ongoing research program on the C–H functionalization of indoles [32,33,34,35], we describe herein a facile and mild Rh(III)-catalyzed highly selectively direct C–H alkylation of indoles with diazo compounds. During the preparation of this manuscript, a similar work was published by Wang and coworkers [36].

2. Results and Discussion

We began our initial exploration by using N-pyrimidyl indole 1a and diazo compound 2a as starting materials, and the reaction was carried out in EtOH at 60 °C in the presence of [RhCpCl2]2 (2 mol %). To our delight, the reaction proceeded smoothly to afford product 3a with an 86% yield. Encouraged by this preliminary result, the effect of temperature on this catalytic system was investigated. We observed that there was no change in yield even when the temperature was decreased from 60 °C to 50 °C (Table 1, Entries 1 and 2). When the C–H alkyaltion process was carried out at room temperature, a lower yield was obtained, even with a longer reaction time (Table 1, Entry 4). Next, a variety of additives, such as AgO2CCF3, AgSbF6, AgF, AgOTf, and Ag2O were tested to improve the yield of product (Table 1, Entries 5–9). Gratifyingly, AgSbF6 was proved to be the most effective, and the desired product was obtained with the highest yield at 92% (Table 1, Entry 6). When the C–H alkylation was performed without additives, the desired product could be obtained with a 36% yield (Table 1, Entry 10). Afterward, we studied different media, such as MeOH, i-PrOH, t-AmOH, CH3CN, DCE, and THF (Table 1, Entries 11–16). It was noted that the reaction proceeded in all solvents with different degrees of conversion, and the results showed that EtOH was still the best choice. The control experiment confirmed that this transformation would not occur in the absence of [RhCp*Cl2]2 (Table 1, Entry 17). Finally, we were pleased to find that the reaction could also be performed on a 6.0 mmol scale under the optimized conditions without a significant decrease in efficiency (Table 1, Entry 18).
Having established the optimal reaction conditions, the scope of the indoles was explored. As shown in Table 2, indoles containing electron-donating and electron-withdrawing groups (Me, OMe, CO2Me, F, Br, Cl), regardless of substituent position on the aromatic ring, were found to be favored in the C–H alkylation reaction to afford the corresponding products in high to excellent yields. The reaction showed good functional group compatibility. For instance, the ester group on the aryl ring was compatible with this catalytic process, and the desired alkylated products were obtained in an excellent yield (Table 2, Entries 3 and 11). Perhaps more importantly, this protocol could also be successfully applied to the substrates with a methyl or bromo group on the pyrimidine ring to provide the corresponding products with 87% and 88% yields, respectively (Table 2, Entries 14 and 15).
To further evaluate the substrate scope of this reaction, a broad range of symmetric and non-symmetric diazo compounds was examined to couple with 1a. As shown in Scheme 1, diazomalonates bearing substituents such as methyl, i-propyl, and benzyl were all suitable for the reaction and gave the desired products (3q–t) in excellent yields. Notably, this catalytic process proceeded well with α-diazo acetylacetone to afford the desired product 3u with an 85% yield. Additionally, high efficiency was also obtained when one of the ester groups was replaced with a diethyl phosphonate group (3v). To our disappointment, the reaction did not provide the corresponding products when using diazoacetate or methyl phenyldiazoacetate as coupling partners (Scheme 1).
To gain an understanding of more details on the reaction, the competitive reaction between differently substituted indoles was carried out under the standard conditions. As shown in Scheme 2, a mixture of 3f and 3j in a ratio of 6.8:1.0 was obtained, which indicated that the more electron-rich indoles are kinetically favored in this catalytic system (Scheme 2).
On the basis of these observations and literature precedents, we propose a possible mechanism as illustrated in Scheme 3. Firstly, the [RhCp*Cl2]2 could be activated by AgSbF6 to generate the active cationic [Cp*Rh(III)] species. Subsequently, the C2–H bond of 1a is cleaved directly by [Cp*Rh(III)] species to afford the five-member rhodacyclic intermediate A. The coordination of intermediate A with the diazo compound 2a provides the diazonium intermediate B, followed by the formation of the cyclic Rh(III) carbene species C through the emission of N2. Rh(III) carbene C undergoes intramolecular migratory insertion, leading to rhodacyclic complex D. Finally, protonolysis of D provides the desired product 3a with regeneration of the active Rh(III) catalyst (Scheme 3).

3. Experimental Section

3.1. General Information

All chemicals were purchased from commercial suppliers and used without further purification. All solvents were treated prior to use according to the standard methods. Flash column chromatography was performed using 200–300 mesh silica gel. 1H NMR spectra were recorded on 400 MHz spectrophotometers. Chemical shifts (δ) are reported in ppm from the solvent resonance as the internal standard (CDCl3: 7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet), coupling constants (Hz), and integration. 13C NMR spectra were recorded on 100-MHz spectrophotometers with complete proton decoupling spectrophotometers (CDCl3: 77.0 ppm). High-resolution mass spectral analysis (HRMS) was performed with a Bruker micrOTOF-QII. Melting points were measured with a Melting Point apparatus WPS-2. IR spectra were measured with a Bruker Tensor 27 FT-IR spectrometer. NMR spectra can be viewed in the supporting material.

3.2. Representative Procedure for the C–H Alkylation Reaction

A mixture of N-pyrimidyl indole 1a (0.20 mmol, 1.0 equiv.), diazo compounds 2a (0.24 mmol, 1.2 equiv), [RhCp*Cl2]2 (2.5 mg, 2 mol %), and AgSbF6 (6.8 mg, 10 mol %) were combined in EtOH (2.0 mL) in a dried 10-mL Schlenk tube. The mixture was stirred at 50 °C for 6–18 h and monitored by TLC. After the reaction was finished, the volatiles were removed under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate) to afford the desired product 3a with a 92% yield.

4. Conclusions

In conclusion, we have developed a highly efficient and atom-economic Rh(III)-catalyzed regioselective C2–H alkylation of indoles with diazo compounds. A wide range of alkyl group substituted indoles was smoothly obtained in good to excellent yields under the optimized conditions. Beside N2 as the single byproduct, the remarkable features of this reaction included mild conditions, simple operation, high efficiency, and broad functional group tolerance.

Supplementary Materials

The following are available online at Figures S1–S60 are the NMR spectra and HRMS of compounds of 3a–v.


We are grateful to the National Science Foundation of China (No. 21302064) and Scientific Research Project of Hubei Provincial Department of Education (No. B2015231) for support of this research.

Author Contributions

Kang Wan and Zhan Li performed the experiments and analyzed the data. Xing Qu contributed to the experimental design. Kang Wan wrote the first draft of the manuscript that was then improved by Feng Wang and Liang Wang.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Trost, B.M. On inventing reactions for atom economy. Acc. Chem. Res. 2002, 35, 695–705. [Google Scholar] [CrossRef] [PubMed]
  2. Nicolaou, K.C.; Hale, C.R.; Nilewski, C.; Ioannidou, H.A. Constructing molecular complexity and diversity: Total synthesis of natural products of biological and medicinal importance. Chem. Soc. Rev. 2012, 41, 5185–5238. [Google Scholar] [CrossRef] [PubMed]
  3. Kochanowska-Karamyan, A.J.; Hamann, M.T. Marine indole alkaloids: Potential new drug leads for the control of depression and anxiety. Chem. Rev. 2010, 110, 4489–4497. [Google Scholar] [CrossRef] [PubMed]
  4. Cacchi, S.; Fabrizi, G. Synthesis and functionalization of indoles through palladium-catalyzed reactions. Chem. Rev. 2005, 105, 2873–2920. [Google Scholar] [CrossRef] [PubMed]
  5. Giri, R.; Shi, B.F.; Engle, K.M.; Maugel, N.; Yu, J.-Q. Transition metal-catalyzed C–H activation reactions: Diastereoselectivity and enantioselectivity. Chem. Soc. Rev. 2009, 38, 3242–3272. [Google Scholar] [CrossRef] [PubMed]
  6. Lyons, T.W.; Sanford, M.S. Palladium-catalyzed ligand-directed C–H functionalization reactions. Chem. Rev. 2010, 110, 1147–1169. [Google Scholar] [CrossRef] [PubMed]
  7. Cho, S.H.; Kim, J.Y.; Kwak, J.; Chang, S. Recent advances in the transition metal-catalyzed twofold oxidative C–H bond activation strategy for C–C and C–N bond formation. Chem. Soc. Rev. 2011, 40, 5068–5083. [Google Scholar] [CrossRef] [PubMed]
  8. Wencel-Delord, J.; Dröge, T.; Liu, F.; Glorius, F. Towards mild metal-catalyzed C–H bond activation. Chem. Soc. Rev. 2011, 40, 4740–4761. [Google Scholar] [CrossRef] [PubMed]
  9. Song, G.; Wang, F.; Li, X. C–C, C–O and C–N bond formation via rhodium(III)-catalyzed oxidative C–H activation. Chem. Soc. Rev. 2012, 41, 3651–3678. [Google Scholar] [CrossRef] [PubMed]
  10. Kakiuchi, F.; Murai, S. Catalytic C−H/olefin coupling. Acc. Chem. Res. 2002, 35, 826–834. [Google Scholar] [CrossRef] [PubMed]
  11. Zhang, Y.; Jie, X.; Zhao, H.; Li, G.; Su, W. Recent advances in directed C–H functionalizations using monodentate nitrogen-based directing groups. Org. Chem. Front. 2014, 1, 843–893. [Google Scholar] [CrossRef]
  12. Ackermann, L. Carboxylate-assisted ruthenium-catalyzed alkyne annulations by C–H/het–H bond functionalizations. Acc. Chem. Res. 2014, 47, 281–295. [Google Scholar] [CrossRef] [PubMed]
  13. Olah, G.A.; Khrishnamurti, R.; Prakash, G.K.S. Comprehensive Organic Synthesis, 1st ed.; Trost, B.M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Volume 3, pp. 293–335. [Google Scholar]
  14. Bandini, M.; Eichholzer, A. Catalytic functionalization of indoles in a new dimension. Angew. Chem. Int. Ed. 2009, 48, 9608–9644. [Google Scholar] [CrossRef] [PubMed]
  15. Deprez, N.R.; Kalyani, D.; Krause, A.; Sanford, M.S. Room temperature palladium-catalyzed 2-arylation of indoles. J. Am. Chem. Soc. 2006, 128, 4972–4973. [Google Scholar] [CrossRef] [PubMed]
  16. García-Rubia, A.; Arrayás, R.G.; Carretero, J.C. Palladium(II)-catalyzed regioselective direct C2 alkenylation of indoles and pyrroles assisted by the N-(2-pyridyl)sulfonyl protecting group. Angew. Chem. Int. Ed. 2009, 48, 6511–6515. [Google Scholar] [CrossRef] [PubMed]
  17. Xie, F.; Qi, Z.; Yu, S.; Li, X. Rh(III)- and Ir(III)-catalyzed C–H alkynylation of arenes under chelation assistance. J. Am. Chem. Soc. 2014, 136, 4780–4787. [Google Scholar] [CrossRef] [PubMed]
  18. Kou, X.; Zhao, M.; Qiao, X.; Zhu, Y.; Tong, X.; Shen, Z. Copper-catalyzed aromatic C–H bond cyanation by C-CN bond cleavage of inert acetonitrile. Chem. Eur. J. 2013, 19, 16880–16886. [Google Scholar] [CrossRef] [PubMed]
  19. Pan, C.; Jin, H.; Liu, X.; Cheng, Y.; Zhu, C. Palladium-catalyzed decarboxylative C2-acylation of indoles with α-oxocarboxylic acids. Chem. Commun. 2013, 49, 2933–2935. [Google Scholar] [CrossRef] [PubMed]
  20. Jiao, L.; Bach, T. Palladium-catalyzed direct 2-alkylation of indoles by norbornene-mediated regioselective cascade C–H activation. J. Am. Chem. Soc. 2011, 133, 12990–12993. [Google Scholar] [CrossRef] [PubMed]
  21. Jiao, L.; Herdtweck, E.; Bach, T. Pd(II)-catalyzed regioselective 2-alkylation of indoles via a norbornene-mediated C–H activation: Mechanism and applications. J. Am. Chem. Soc. 2012, 134, 14563–14572. [Google Scholar] [CrossRef] [PubMed]
  22. Pan, S.; Ryu, N.; Shibata, T. Ir(I)-catalyzed C–H bond alkylation of C2-position of indole with alkenes: Selective synthesis of linear or branched 2-alkylindoles. J. Am. Chem. Soc. 2012, 134, 17474–17477. [Google Scholar] [CrossRef] [PubMed]
  23. Shi, Z.; Boultadakis-Arapinis, M.; Glorius, F. Rh(III)-catalyzed dehydrogenative alkylation of (hetero)arenes with allylic alcohols, allowing aldol condensation to indenes. Chem. Commun. 2013, 49, 6489–6491. [Google Scholar] [CrossRef] [PubMed]
  24. Wang, H.; Schröder, N.; Glorius, F. Mild rhodium(III)-catalyzed direct C–H allylation of arenes with allyl carbonates. Angew. Chem. Int. Ed. 2013, 52, 5386–5389. [Google Scholar] [CrossRef] [PubMed]
  25. Wang, H.; Yu, S.; Qi, Z.; Li, X. Rh(III)-catalyzed C–H alkylation of arenes using alkylboron reagents. Org. Lett. 2015, 17, 2812–2815. [Google Scholar] [CrossRef] [PubMed]
  26. Xiao, Q.; Zhang, Y.; Wang, J. Diazo compounds and N-tosylhydrazones: Novel cross-coupling partners in transition-metal-catalyzed reactions. Acc. Chem. Res. 2013, 46, 236–247. [Google Scholar] [CrossRef] [PubMed]
  27. Chan, W.-W.; Lo, S.-F.; Zhou, Z.; Yu, W.-Y. Rh-catalyzed intermolecular carbenoid functionalization of aromatic C–H bonds by α-diazomalonates. J. Am. Chem. Soc. 2012, 134, 13565–12568. [Google Scholar] [CrossRef] [PubMed]
  28. Hyster, T.K.; Ruhl, K.E.; Rovis, T. A Coupling of benzamides and donor/acceptor diazo compounds to form γ-lactams via Rh(III)-catalyzed C–H activation. J. Am. Chem. Soc. 2013, 135, 5364–5367. [Google Scholar] [CrossRef] [PubMed]
  29. Shi, Z.; Koester, D.C.; Boultadakis-Arapinis, M.; Glorius, F. Rh(III)-catalyzed synthesis of multisubstituted isoquinoline and pyridine N-oxides from oximes and diazo compounds. J. Am. Chem. Soc. 2013, 135, 12204–12207. [Google Scholar] [CrossRef] [PubMed]
  30. Chan, W.-W.; Yeung, S.-H.; Zhou, Z.; Chan, A.S.C.; Yu, W.-Y. Ruthenium catalyzed directing group-Free C2-selective carbenoid functionalization of indoles by α-Aryldiazoesters. Org. Lett. 2010, 12, 604–607. [Google Scholar] [CrossRef] [PubMed]
  31. Shi, J.; Yan, Y.; Li, Q.; Xu, H.E.; Yi, W. Rhodium(III)-catalyzed C2-selective carbenoid functionalization and subsequent C7-alkenylation of indoles. Chem. Commun. 2014, 50, 6483–6486. [Google Scholar] [CrossRef] [PubMed]
  32. Wang, L.; Qu, X.; Li, Z.; Peng, W.-M. Rhodium-catalyzed regioselective direct C–H arylation of indoles with aryl boronic acids. Tetrahedron Lett. 2015, 56, 3754–3757. [Google Scholar] [CrossRef]
  33. Wang, L.; Li, Z.; Qu, X.; Peng, W.-M. Highly efficient synthesis of arylpyrrole derivatives via Rh(III)-catalyzed direct C–H arylation with aryl boronic acids. Chin. J. Chem. 2015, 33, 1015–1018. [Google Scholar] [CrossRef]
  34. Wang, L.; Qu, X.; Li, Z.; Peng, W.-M. Rhodium(III)-catalyzed C–H activation/cylization of indole-2-amides derivatives and terminal alkynes. Chin. J. Org. Chem. 2015, 35, 688–697. [Google Scholar] [CrossRef]
  35. Wang, L.; Li, Z.; Qu, X.; Peng, W.-M.; Hu, S.-Q.; Wang, H.-B. Sequential one-pot Rh(III)-catalyzed direct C2 and C7 alkylation of (hetero)aromatic C–H bonds of indoles. Tetrahedron Lett. 2015, 56, 6214–6218. [Google Scholar] [CrossRef]
  36. Liu, X.-G.; Zhang, S.-S.; Wu, J.-Q.; Li, Q.; Wang, H. Cp*Co(III)-catalyzed direct functionalization of aromatic C–H bonds with a-diazomalonates. Tetrahedron Lett. 2015, 56, 4093–4095. [Google Scholar] [CrossRef]
Scheme 1. Diazo compound scope a. a Conditions: 1a (0.2 mmol), 2 (0.24 mmol), [RhCp*Cl2]2 (2.0 mol %), AgSbF6 (10.0 mol%), EtOH (2.0 mL), 50 °C.
Scheme 1. Diazo compound scope a. a Conditions: 1a (0.2 mmol), 2 (0.24 mmol), [RhCp*Cl2]2 (2.0 mol %), AgSbF6 (10.0 mol%), EtOH (2.0 mL), 50 °C.
Catalysts 06 00089 sch001
Scheme 2. Intermolecular competition experiment.
Scheme 2. Intermolecular competition experiment.
Catalysts 06 00089 sch002
Scheme 3. The proposed mechanism.
Scheme 3. The proposed mechanism.
Catalysts 06 00089 sch003
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Catalysts 06 00089 i001
EntryAdditiveSolventTemp.Yield b
17 cAgSbF6EtOH500
18 dAgSbF6EtOH5090
a Conditions: 1a (0.2 mmol), 2a (0.24 mmol), [RhCp*Cl2]2 (2.0 mol %), Ag(I) additive (10.0 mol %), solvent (2.0 mL), 12 h; b Isolated yields; c without [RhCp*Cl2]2; d Performed on a 6.0 mmol scale.
Table 2. Indole scope a.
Table 2. Indole scope a.
Catalysts 06 00089 i002
EntryR1R23Yield (%) b
a Conditions: 1 (0.2 mmol), 2a (0.24 mmol), [RhCp*Cl2]2 (2.0 mol %), AgSbF6 (10.0 mol %), EtOH (2.0 mL), 50 °C, 6–18 h; b Isolated yields.

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MDPI and ACS Style

Wan, K.; Li, Z.; Qu, X.; Wang, F.; Wang, L. Rh(III)-Catalyzed, Highly Selectively Direct C–H Alkylation of Indoles with Diazo Compounds. Catalysts 2016, 6, 89.

AMA Style

Wan K, Li Z, Qu X, Wang F, Wang L. Rh(III)-Catalyzed, Highly Selectively Direct C–H Alkylation of Indoles with Diazo Compounds. Catalysts. 2016; 6(6):89.

Chicago/Turabian Style

Wan, Kang, Zhan Li, Xing Qu, Feng Wang, and Liang Wang. 2016. "Rh(III)-Catalyzed, Highly Selectively Direct C–H Alkylation of Indoles with Diazo Compounds" Catalysts 6, no. 6: 89.

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