Regioselective Reaction of 2-Indolylmethanols with Enamides

A highly regioselective reaction of 2-indolylmethanols with enamides has been developed at room temperature by using AlCl3 as a catalyst. A wide range of hybrids (40 examples) of indoles and enamides were obtained in moderate to good yields (up to 98% yield). This transformation represents the efficient way to introduce biologically important indoles and enamides skeleton into structurally complex hybrids.


Results
Initially, the reaction of cyclic enamide 1a and 2-indolylmethanol 2a was employed as a model reaction to testify the feasibility of this reaction under the catalysis of a chiral phosphoric acid (CPA) at room temperature in toluene (Table 1, entry 1). The anticipated product could be obtained in 35% yield albeit with no atroposelectivity. The product was unambiguously determined by X-ray crystallographic analysis (CCDC 2224916). To improve the atroposelectivity of the reaction, a series of CPAs were screened. Unfortunately, further screening of CPAs did not give improved atroposelectivity for the reaction. Then, we turned to the racemic version of this transformation. No reaction occurred under other Brønsted acids, such as trifluoroacetic acid, AcOH, even at elevated temperatures (Table 1, entries  2-3). Therefore, the stronger acids were examined and found that TsOH catalyzed the C3 alkylation reaction smoothly and generated the product in 38% yield (Table 1, entry 4). Then, a variety of Lewis acids were screened to improve the reaction efficiency. However, Sc(OTf) 3 and Cu(OTf) 2 did not work at all. No desired product was detected, and the starting material was decomposed (Table 1, entries 5-6). Gratifyingly, AlCl 3 gave the product in 40% yield within 2 h (Table 1, entry 7). AlCl 3 was then selected as the optimal catalyst for further evaluation of the solvents (entries [8][9][10][11][12], which disclosed that DCM was most suitable in terms of yield and time, giving product 3a in 88% yield within 2 h. Nitrogen-containing heterocyclic compounds constitute important building blocks in biologically active compounds [47][48][49]. Enamides are versatile synthons in cycloadditions [50][51][52][53][54][55] and various functionalization reactions [56][57][58][59][60][61][62][63] to construct nitrogen-containing compounds. Because of our continual research interest in biologically important nitrogencontaining heterocycles synthesis and enamides chemistry [50][51][52][53][54][55], we envisioned that the hybrids of indoles and enamides would be obtained because of the nucleophilicity of enamides and the electrophilicity of 2-indolylmethanols under acidic conditions. Shi et al. reported the Brønsted acid-catalyzed reaction of 2-indolylmethanols with cyclic enaminones for the synthesis of 3-functionalized indole derivatives under elevated temperature [64,65]. Han developed the chiral phosphoramide-catalyzed asymmetric C2 alkylation of 2-indolylmethanols with acyclic enamides [65]. Herein, we report the highly regioselective C3 alkylation reaction of 2-indolylmethanols with cyclic enamides for the construction of hybrids of indoles and cyclic enamides under mild reaction conditions.

Results
Initially, the reaction of cyclic enamide 1a and 2-indolylmethanol 2a was employed as a model reaction to testify the feasibility of this reaction under the catalysis of a chiral phosphoric acid (CPA) at room temperature in toluene (Table 1, entry 1). The anticipated product could be obtained in 35% yield albeit with no atroposelectivity. The product was unambiguously determined by X-ray crystallographic analysis (CCDC 2224916). To improve the atroposelectivity of the reaction, a series of CPAs were screened. Unfortunately, further screening of CPAs did not give improved atroposelectivity for the reaction. Then, we turned to the racemic version of this transformation. No reaction occurred under other Brønsted acids, such as trifluoroacetic acid, AcOH, even at elevated temperatures ( Table  1, entries 2-3). Therefore, the stronger acids were examined and found that TsOH catalyzed the C3 alkylation reaction smoothly and generated the product in 38% yield ( Table  1, entry 4). Then, a variety of Lewis acids were screened to improve the reaction efficiency. However, Sc(OTf)3 and Cu(OTf)2 did not work at all. No desired product was detected, and the starting material was decomposed ( Table 1, entries 5-6). Gratifyingly, AlCl3 gave the product in 40% yield within 2 h (Table 1, entry 7). AlCl3 was then selected as the optimal catalyst for further evaluation of the solvents (entries [8][9][10][11][12], which disclosed that DCM was most suitable in terms of yield and time, giving product 3a in 88% yield within 2 h. Having established the optimal reaction conditions, we thereby examined the substrate scope of this protocol by employing a variety of enamides 1, and the results are summarized in Figure 2. Various cyclic enamides tested could smoothly furnish the corresponding C3 alkylation product in good to excellent yields (68-98%) under the optimal reaction conditions ( Figure 2, 3ba-3pa). The alkylation can be extended to a variety of fivemembered ( Figure 2, 3ba-3ka) and six-membered enamides (Figure 2, 3la-3pa) bearing either electron-rich ( Figure 2, 3ca-3fa, 3la-3na) or electron-deficient ( Figure 2, 3ga-3ka, 3oa-3pa) substituents on the phenyl ring, giving the corresponding C3 alkylation products in good yields. It is worth noting that when changing the acyl group with a benzoyl group on enamines, no reaction was observed probably due to the hindrance and the electron-deficient effect.
Having established the optimal reaction conditions, we thereby examined the s strate scope of this protocol by employing a variety of enamides 1, and the results summarized in Figure 2. Various cyclic enamides tested could smoothly furnish the c responding C3 alkylation product in good to excellent yields (68-98%) under the optim reaction conditions (Figure 2, 3ba-3pa). The alkylation can be extended to a variety five-membered ( Figure 2, 3ba-3ka) and six-membered enamides (Figure 2, 3la-3pa) be ing either electron-rich ( Figure 2, 3ca-3fa, 3la-3na) or electron-deficient ( Figure 2, 3g 3ka, 3oa-3pa) substituents on the phenyl ring, giving the corresponding C3 alkylat products in good yields. It is worth noting that when changing the acyl group with a b zoyl group on enamines, no reaction was observed probably due to the hindrance and electron-deficient effect. To further examine the generality of the reaction, we next investigated the scope different 2-indolylmethanols with six-membered enamides under the established con tions. First, the substituent effect on the indole ring was examined. The electronic eff on the indole ring seems to have no obvious effect on the reaction efficiency ( Figure 3, 3 and 3ac vs. 3ad-3af). Then, 2-indolylmethanols derived from different Grignard reage were applied in this reaction. The substrates with electron-donating groups such as m thyl and methoxyl at the meta-and para-position of the benzene resulted in relativ lower yields compared to the electron-withdrawing ones ( Figure 3, 3ah, 3ai, 3ao and 3 vs. 3aj, 3ak, 3al, 3am and 3an). These results showed that electron-donating substitue on the phenyl ring may reduce the electrophilicity of the in-site formed cation. It is wo noting that the ortho-position-substituted substrate was also compatible and afforded 3aq in 87% yield. To further examine the generality of the reaction, we next investigated the scope of different 2-indolylmethanols with six-membered enamides under the established conditions. First, the substituent effect on the indole ring was examined. The electronic effect on the indole ring seems to have no obvious effect on the reaction efficiency ( Figure 3, 3ab and 3ac vs. 3ad-3af). Then, 2-indolylmethanols derived from different Grignard reagents were applied in this reaction. The substrates with electron-donating groups such as methyl and methoxyl at the meta-and para-position of the benzene resulted in relatively lower yields compared to the electron-withdrawing ones ( Figure 3, 3ah, 3ai, 3ao and 3ap vs. 3aj, 3ak, 3al, 3am and 3an). These results showed that electron-donating substituents on the phenyl ring may reduce the electrophilicity of the in-site formed cation. It is worth noting that the ortho-position-substituted substrate was also compatible and afforded the 3aq in 87% yield. To obtain the structure-diverse indole-containing compounds and further expand the scope of this reaction, acyclic enamides were used to couple with the 2-indolylmethanols. As shown in Figure 4, a series of highly functionalized enamides-containing indoles were obtained in 52-87% yield. To obtain the structure-diverse indole-containing compounds and further expand the scope of this reaction, acyclic enamides were used to couple with the 2-indolylmethanols. As shown in Figure 4, a series of highly functionalized enamides-containing indoles were obtained in 52-87% yield.
To demonstrate the practical utility of this reaction, a gram-scale synthesis of 3aa was performed with 3.2 mmol of 1a with 3.2 mmol of 2a, affording 1.01 g of 3aa in 68% yield, without significant losses of yield compared with the small-scale reaction (Scheme 1).
Based on the literature information [6][7][8][9], a plausible mechanism was proposed. As depicted in Scheme 2. Cations A and B were generated in the presence of Lewis acid. Next, enamide attacked the C3 position of the indole unit. The subsequent isomerization processes of the imine and indole gave the final product 3aa.  To demonstrate the practical utility of this reaction, a gram-scale synthesis of 3aa wa performed with 3.2 mmol of 1a with 3.2 mmol of 2a, affording 1.01 g of 3aa in 68% yield without significant losses of yield compared with the small-scale reaction (Scheme 1).

Scheme 1. Gram-scale experiment for the synthesis of 3aa.
Based on the literature information [6][7][8][9], a plausible mechanism was proposed. A depicted in Scheme 2. Cations A and B were generated in the presence of Lewis acid. Next enamide attacked the C3 position of the indole unit. The subsequent isomerization pro cesses of the imine and indole gave the final product 3aa. Scheme 2. Proposed mechanism.

General Procedures
Unless otherwise specified, all reactions were carried out under nitrogen atmosphere  Based on the literature information [6][7][8][9], a plausible mechanism was proposed depicted in Scheme 2. Cations A and B were generated in the presence of Lewis acid. N enamide attacked the C3 position of the indole unit. The subsequent isomerization cesses of the imine and indole gave the final product 3aa. Scheme 2. Proposed mechanism.

General Procedures
Unless otherwise specified, all reactions were carried out under nitrogen atmosp in anhydrous conditions. All chemicals that are commercially available were used wit  Based on the literature information [6][7][8][9], a plausible mechanism was proposed depicted in Scheme 2. Cations A and B were generated in the presence of Lewis acid. N enamide attacked the C3 position of the indole unit. The subsequent isomerization cesses of the imine and indole gave the final product 3aa. Scheme 2. Proposed mechanism.

General Procedures
Unless otherwise specified, all reactions were carried out under nitrogen atmosp in anhydrous conditions. All chemicals that are commercially available were used wit Scheme 2. Proposed mechanism.

General Procedures
Unless otherwise specified, all reactions were carried out under nitrogen atmosphere in anhydrous conditions. All chemicals that are commercially available were used without further purification unless otherwise noted. All the solvents were purified according to the standard procedures. Analytical thin-layer chromatography (TLC) was performed on silica gel plates (GF-254) using UV light (254 and 365 nm). Flash chromatography was conducted on silica gel (200-300 mesh). NMR spectra were recorded at ambient temperature in CDCl3 and DMSO on a Bruker AMX 500 (1H NMR at 500 MHz and 13C NMR at 125 MHz) or on an AVANCE III (1H NMR at 400 MHz and 13C NMR at 100 MHz) spectrometer. Chemical shifts were reported in parts per million (ppm) downfield from an internal standard, tetramethylsilane (0 ppm). High-resolution mass spectra were obtained on an Agilent 6200 Q-TOF MS and Waters G2-S QTOF.

Conclusions
In summary, we have developed the regioselective C3 alkylation of 2-indolylmethanols with cyclic and acyclic enamides under mild reaction conditions. A variety of hybrids of indoles and enamides (40 examples) were obtained in good to excellent yields (up to 98%) with excellent regioselectivities. This protocol represents the first example of C3 alkylation of 2-indolylmethanols with enamides. The potential application of these compounds is under investigation in our laboratory.

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Data Availability Statement:
The details of the data supporting the report results in this research were included in the paper and Supplementary Materials.

Conflicts of Interest:
The authors declare no conflict of interest.