Electrochemical Synthesis of Bisindolylmethanes from Indoles and

Letter Cite This: Org. Lett. 2018, 20, 2911−2915

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Electrochemical Synthesis of Bisindolylmethanes from Indoles and Ethers Ke-Si Du and Jing-Mei Huang* Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, Guangdong 510640, China S Supporting Information *

ABSTRACT: An electrochemical bisindolylation of ethers was developed. Carried out under ambient conditions and in the absence of any chemical oxidants, this reaction exhibits a broad substrate scope and good functional group compatibility.

3,3′-Bis(indolyl)methanes (BIMs) are present in a large variety of natural products, and their derivatives exhibit diverse biological activitites.1 BIM derivatives have also been used in materials chemistry.2 As a consequence, various methods for the preparation of BIMs have been developed over the past few decades. Synthesis of bis(indolyl)alkane derivatives has been effected through the reaction of indoles with aldehydes,3 ketones,3 olefin derivatives,4 alkynes/allenes,5 amines,6 and amides7 as the alkyl sources. In 2009, Li’s group8 developed a new method for the synthesis of BIMs from ethers promoted by a DTBP/FeCl2 system (Figure 1). Very recently, an efficient photochemical alkylation of indoles with ethers has been achieved by Loh’s group (Figure 1).9 Although these protocols serve as powerful methods for the synthesis of BIMs, they suffer from one or more disadvantages, such as utilization of an

external chemical oxidant, elevated temperature, use of an expensive catalyst, and a stoichiometric amount of a singleelectron-transfer reagent. Therefore, environmentally friendly methods for the synthesis of BIMs using inexpensive and readily available reagents are still highly desirable. The electroorganic synthesis is considered to be an environmentally friendly methodology since dangerous and toxic redox reagents can be replaced by an electrical current or generated in situ in the course of electrolysis. Over the past decade, organic electrochemistry has experienced a renaissance in the field of organic synthesis.10 In continuation of our interest in the application of electrochemical methods to organic synthesis,11 herein, we report an efficient synthesis of BIMs from indoles and ethers through an electrochemical method with the catalysis of LaCl3 (Figure 1). We began our study by optimizing the electrolysis conditions for the synthesis of BIMs from N-methylindole 1a and THF 2a. The reaction was conducted at a constant current in an undivided cell equipped with a Pt wire anode and a Pt foil cathode. 1a and 2a reacted efficiently in the presence of 10 mol % LaCl3 to afford the desired product 3a in 92% yield at 5 mA (Table 1, entry 1). The electrolysis at higher or lower current density blunted the product formation (Table 1, entries 2−3). No reaction took place without electricity (Table 1, entry 4). Other La3+ salts, for instance, La(NO3)3·6H2O, La(OAc)3 and La(OTf)3, were shown to be inferior to LaCl3 in terms of yields (Table 1, entries 5−8). The influence of the electrolyte was also studied. When other electrolytes, such as NaClO4, NH4ClO4, and NaBF4, were used instead of LiClO4, the yields of the desired products decreased (Table 1, entries 9−11). A reaction

Figure 1. Synthesis of BIMs by ethers and indoles.

Received: March 26, 2018 Published: May 2, 2018

© 2018 American Chemical Society

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DOI: 10.1021/acs.orglett.8b00968 Org. Lett. 2018, 20, 2911−2915

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

Scheme 1. Substrate Scopea,b

entry

variation from the standard conditions

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13

none 3 mA instead of 5 mA 8 mA instead of 5 mA no electric current in the absence of LaCl3 La(NO3)3·6H2O instead of LaCl3 La(OAc)3 instead of LaCl3 La(OTf)3 instead of LaCl3 NaClO4 instead of LiClO4 NaBF4 instead of LiClO4 NH4ClO4 instead of LiClO4 under N2 under O2

92 37 56 0 47 60 25 67 22 trace trace 89 73

a

Unless otherwise noted, the mixture of 1a (0.8 mmol), LaCl3 (0.08 mmol) in solvent (THF/MeCN = 2:1, v/v, 5 mL) with 0.2 M LiClO4 as supporting electrolyte was electrolyzed at constant current (5 mA) in an undivided cell at room temperature for 6.5 h, anode: Pt wire (diameter: 0.5 mm, height: 1.5 cm), cathode: Pt foil (1.0 × 1.5 cm2). b Yield determined by 1H NMR with nitrobenzene as the internal standard

was carried out under nitrogen producing a comparable yield (89%, Table 1, entry 12). However, the yield decreased to 73% under an oxygen atmosphere (Table 1, entry 13). In addition, more Lewis acids (Table S1) and solvent systems (Table S2) were suveyed and it was found that LaCl3 displayed the highest catalytic effeciency and THF/MeCN (2:1, v/v) was superior to other solvents. With the optimized conditions in hand, we then examined the substrate scope (Scheme 1). First, the reactivity of Nmethylindoles with substituents on the benzene ring was studied. In general, both electron-donating and -withdrawing groups were tolerated in this reaction. Substrates with methyl or methoxyl groups provided the desired products in good yields (3b, 85%; 3c, 73%); N-methylindoles bearing electronwithdrawing groups, such as CN, COOMe, and NO2, could also be transformed to the corresponding products in moderate to excellent yields (3g, 90%; 3h, 76%; 3i, 66%). Notably, halide substituents remained intact in the reaction (3d, 73%; 3e, 75%; 3f, 63%), which provide the opportunity for further derivatization. Next, the C-2 substituted N-methylindoles, with increased steric hindrance, were explored, and it was found that these substrates were compatible with this transformation (3l, 71%; 3m, 57%). The influence of the Nsubstitution of indoles was then probed. Replacing the Nmethyl group with n-butyl, -benzyl, and -phenyl had little influence on the reaction, and the corresponding indoles worked smoothly in this process to furnish the desired products in good yields (3n, 85%; 3o, 88%; 3p, 87%). Replacement of the N-methyl group of indoles with electron-withdrawing groups, such as N,N-dimethylcarbamoyl and N-tosyl, led to attenuated efficiency (3q, 29%; 3r, 0%). To our delight, N-H indoles could be transformed to the desired products (3s, 51%; 3t, 56%; 3u, 54%) successfully, albeit with moderate yields. Finally, we turned our attention to the scope of corresponding ether sources. When 2-methyltetrahydrofuran

a

Unless otherwise noted, the reaction were carried out at room temperature under air using 1 (0.8 mmol), 10 mol % LaCl3, 0.2 M LiClO4, THF/MeCN (2:1, v/v, 5 mL) in an undivided cell for 6.5 h. Anode: Pt wire (diameter: 0.5 mm, height: 1.5 cm), cathode: Pt foil (1.0 × 1.5 cm2). bYield determined by 1H NMR with nitrobenzene as the internal standard. c2-Methyl tetrahydrofuran; reaction time: 2 h. d 1,4-Dioxane. eDiethyl ether/MeCN = 5:2. fIsochroman/MeCN = 4:1; reaction time: 2 h.

was employed instead of THF, the homologous product 3v was isolated in 58% yield. 1,4-Dioxane and diethyl ether could also participate in the reaction to afford the desired products in moderate yields (3w, 61%; 3x, 55%). When isochroman was 2912

DOI: 10.1021/acs.orglett.8b00968 Org. Lett. 2018, 20, 2911−2915

Letter

Organic Letters used as the ether source, two products were detected (3y, 59%; 3z, 13%). To gain an understanding of the reaction mechanism, more studies were conducted. Only a trace amount of product 3a was observed when the reaction was carried out in the presence of butylated hydroxytoluene (BHT) or 1,1-diphen-ylethylene (Scheme 2a). It suggested that the reaction might go through

Scheme 3. Control Experiments

Scheme 2. Radical Experiments

a radical mechanism. Hence, radical-trapping experiments were further explored. As shown in Scheme 2b, when an excess amount of triethyl phosphite was added to the reaction mixture, the indole-phosphorylation product 5a was obtained in 71% yield, implying the involvement of indole radicals during the reaction.12 Furthermore, the cyclic voltammetry (CV) studies showed an oxidative peak of 1a at 1.46 V vs SCE and an oxidative peak of THF at 1.78 V vs SCE, which suggested the possibility of the anodic oxidation of 1a to produce indole radicals (Figure 2). utilized, the high current density on the anode could promote the oxidation of THF to produce alkyoxycarbienium ion, as the concentration of THF was very high in the reaction system.15 Second, 2,3-dihydrofuran 6 was found to be an unproductive reaction partner, which revealed that 6 was not involved in this reaction (Scheme 3c).8,16 As a trace of monoindolylated THF 7 could be detected in the mixture of the standard reaction, 7 was then prepared and subjected to the standard conditions, and 3a was obtained in 97% yield which suggested the intermediacy of 7 in the present process (Scheme 3d). Finally, the effects of LaCl3 and electricity on the transformation of 7 to 3a were studied. It was found that LaCl3 worked as a Lewis acid to catalyze the reaction of 7 with the second N-methylindole (Scheme 3d, 3e, and 3f). However, the electricity was not necessary for this step (Scheme 3d and 3f). On the basis of the above results and the literature reports,8,9,12,13,17 a tentative mechanism was proposed, as shown in Scheme 4. First, the N-methylindole radical cation b was formed by the anode oxidant through single electron transfer. Then radical cation b reacted with 2a to give the THF radical c, which was trapped by 1a to generate the monoindolylated product 7 (path A). 7 might also be obtained through the reaction of 1a with the alkoxycarbenium ion e, which was produced by the anodic oxidation of THF (path B). Subsequently, Friedel−Craft alkylation of 7 afforded the crosscoupling product 3a. Meanwhile, cathodic reduction of protonhydrogen led to the formation of hydrogen gas. In summary, an electrochemical synthesis of BIMs from a broad range of indoles and ethers has been developed. Carried

Figure 2. Cyclic voltammogram of 0.2 M LiClO4 solution in THF/ MeCN (2:1, v/v) at room temperature: (a) none, (b) MeCN instead of THF/MeCN (2:1, v/v), (c) 1a (0.008 M). The voltammogram was obtained with a Pt wire as an auxiliary electrode and a saturated calomel electrode (SCE) as a reference electrode. The scan rate was 0.1 V/s on a platinum disk electrode (d = 2 mm).

To gain more insight into the reaction, diverse control reactions were undertaken (Scheme 3). First, the “cation pool method” was performed.10b,13 THF was electrolyzed for 4.5 h,14 followed by the addition of 1a in the absence of current. After the resulting mixture stirred for 1 h, the stepwise reactions gave 3a in a yield of 55% (Scheme 3a). This result showed that the alkyoxycarbienium ion might have been generated during the reaction.13 Moreover, when the Pt wire was replaced by the Pt foil (1.0 × 1.5 cm2) as an anode, the yield decreased to 79% (Scheme 3b). It indicated that when a Pt wire anode was 2913

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Organic Letters

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Scheme 4. Proposed Mechanism

out at ambient conditions, this new approach obviates the use of chemical oxidants and expensive reagents and provides a straightforward and environmentally friendly means for the synthesis of BIMs. Further investigation to determine the mechanism of this reaction and to expand its scope is underway in our laboratory.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00968. Experimental procedures and spectroscopic data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jing-Mei Huang: 0000-0003-2861-3856 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Grant Nos. 21672074 and 21372089) for financial support.

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