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

Abstract

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.

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. Optimization of reaction conditions ^a.

Entry	Additive	Solvent	Temp.	Yield b
1	AgOAc	EtOH	60	86
2	AgOAc	EtOH	50	86
3	AgOAc	EtOH	40	84
4	AgOAc	EtOH	25	70
5	AgO2CCF3	EtOH	50	85
6	AgSbF6	EtOH	50	92
7	AgF	EtOH	50	82
8	Ag2O	EtOH	50	56
9	AgOTf	EtOH	50	75
10	-	EtOH	50	36
11	AgSbF6	MeOH	50	90
12	AgSbF6	i-PrOH	50	83
13	AgSbF6	t-AmOH	50	80
14	AgSbF6	CH3CN	50	42
15	AgSbF6	DCE	50	54
16	AgSbF6	THF	50	21
17 c	AgSbF6	EtOH	50	0
18 d	AgSbF6	EtOH	50	90

^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.

, 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. Indole scope ^a.

Entry	R1	R2	3	Yield (%) b
1	4-Me	H	3b	93
2	4-OBn	H	3c	92
3	4-CO2Me	H	3d	91
4	4-Cl	H	3e	87
5	5-Me	H	3f	86
6	5-OMe	H	3g	90
7	5-OBn	H	3h	94
8	5-Br	H	3i	93
9	5-Cl	H	3j	92
10	6-Me	H	3k	90
11	6-CO2Me	H	3l	90
12	6-F	H	3m	89
13	6-Cl	H	3n	89
14	H	Me	3o	87
15	H	Br	3p	88

^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.

, 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.