Microwave-Assisted Regioselective Synthesis of 3-Functionalized

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Microwave-Assisted Regioselective Synthesis of 3-Functionalized Indole Derivatives via Three-Component Domino Reaction Wei Lin, Yong-Xiang Zheng, Zhan Xun, Zhi-Bin Huang, and Da-Qing Shi ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.7b00126 • Publication Date (Web): 06 Oct 2017 Downloaded from http://pubs.acs.org on October 7, 2017

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ACS Combinatorial Science

Microwave-Assisted

Regioselective

Synthesis

of

3-Functionalized

Indole

Derivatives via Three-Component Domino Reaction

Wei Lin a,b, Yong-Xiang Zhenga, Zhan Xuna, Zhi-Bin Huang*,a and Da-Qing Shi*,a a

College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou

215123, P. R. China b

School of Chemistry and Environmental Engineering, Jiangsu University of Technology, Changzhou

213001, P. R. China

ABSTRACT: A microwave-assisted regioselective synthesis of 3-functionalized indole derivatives via a three-component domino reaction of anilines, arylglyoxal monohydrates and cyclic 1,3-dicarbonyl compounds is described. The main advantages of this protocol are short reaction times, practical simplicity, being metal-free, availability of starting materials, green solvents, and high regioselectivity. KEYWORDS: indole, three-component reaction, microwave-assisted

INTRODUCTION Indole motifs are present in many natural products and biologically active compounds.1 Tryptophan is a significant indole derivative, while serotonin and melatonin are biochemically active indole molecules. Many indole derivatives have important biological activities, including anti-cancer,2 antioxidant,3 antirheumatoidal,4 anti-HIV,5 antiproliferactive,6 anti-neoplastic and antiestrogenic activities.7 In addition, various 3-substituted indoles have been used as starting materials for the synthesis of a number of alkaloids, pharmaceuticals, and agrochemicals. Over the last hundred years, many powerful approaches have been developed for the construction of the indole

moiety,8

including

the

classical

Fischer

indole

synthesis.9

Recently,

transition-metal-catalyzed cross-dehydrogenative coupling reactions,10 directing-group-assisted inter-molecular C-H annolation,11 and other methods have been emerging as powerful tools for the synthesis of this versatile molecule. 12 However, there is an enormous need to develop new and efficient methods for the synthesis of indoles and their functionalized derivatives using readily

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available starting materials. The development of environmentally friendly synthetic methods is a challenge in modern organic synthesis. Multicomponent reactions (MCRs) are promising powerful tools in organic, 13 combinatorial, and medical chemistry, on account of their atom economy, high complexity and diversity of products, multi bond formation efficiency, and environmental friendliness.14 These processes avoid the isolation and purification of intermediates, maximize the yield of the final product, minimize solvent waste, and enhance the greenness of the transformations. Consequently, MCRs have been significantly used for the construction of complex heterocycles and natural products.15 Recently, our group has developed a series of new MCRs that offer convenient and efficient access to some heterocycles of chemical and pharmaceutical interest using arylglyoxals as a reaction partner.16 In this study, we found that when anilines (1), arylglyoxal monohydrates (2) and cyclic 1,3-dicarbonyl compounds (3) in the mixture of ethanol and water were under microwave irradiation (MWI), the reaction underwent a regioselective three-component domino reaction to give the functionalized indole derivatives (4) without observation of hydroquinolines (5) (Scheme 1). 17 Herein, we would like to report these useful transformations. Scheme 1. Synthesis of Functionalized Indoles under Microwave Irradiation

RESULTS AND DISCUSSION We initially selected the three-component domino reaction of 4-chloroanline 1{1}, phenylglyoxal monohydrate 2{1}, and 4-hydroxy-6-methyl-2H-pyran-2-one 3{1} as the model reaction for optimizing the reaction conditions. The reaction was conducted using a 1:1:1 mixture of 1{1}, 2{1}, and 3{1} under microwave irradiation and different conditions. Table 1 summarized the


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results. When the reaction was carried out in ethanol at 100 °C for 30 min under microwave irradiation and catalyst-free conditions, the desired product 3-(6-chloro-2-phenyl-1H-indol-3-yl)4-hydroxy-6-methyl-2H-pyran-2-one 4{1,1,1} was obtained in 44 % yield without observation of hydroquinolines 5{1,1,1} (Table 1, entry 1). Various solvents were evaluated to determine the impact of the solvent on the yield. Of all the solvents tested―ethanol, acetonitrile, dimethyl sulphoxide (DMSO), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), toluene, acetic acid, and water―ethanol gave the best result (Table 1, entries 1-8). Water is a greener solvent; therefore, we evaluated the effect on the yield of mixing ethanol and water in different ratios. Screening experiments showed that a 1:1 (v/v) mixture of ethanol and water was the best solvent for this particular transformation (Table 1, entries 9–11). To improve the yield, several catalysts were evaluated: sodium carbonate, ferric chloride, acetic acid, trifluoroacetic acid (TFA), p-toluenesulfonic acid (p-TSA) (Table 1, entries 12-17), and L-proline. The results revealed that the catalytic efficiency of TFA was the highest. The reaction was then conducted at different temperatures, such as: 60, 70, 80, 90, 100, and 110 °C, to determine the optimum temperature for the transformation. All of these experiments were conducted in ethanol-water (1:1 v/v) under microwave irradiation and catalyzed by TFA; and the desired product 4{1,1,1} was obtained in yields of 27 %, 37 %, 48 %, 69 %, 66 %, and 65 %, respectively (Table 1, entries 15 and 18-22). Accordingly, the best temperature for this transformation was 90 °C. Finally, the reaction was performed at different reaction times to determine the optimum reaction time. The results showed that the best reaction time was 40 min (Table 1, entries 15 and 23-26). Based on all of these experiments, the optimum reaction conditions were identified as ethanol and water (1:1, v/v) at 90 °C for 40 min under microwave irradiation catalyzed by TFA. Table 1. Optimization of Reaction Conditions for the Synthesis of Compound 4{1,1,1}a

entry

solvent

catalyst (20 mol%)

T (°C)

time (min)

yield (%)b

1

EtOH

―

100

30

44



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2 CH3CN ― 100 30 32 3 DMSO ― 100 30 12 4 DMF ― 100 30 trace 5 THF ― 100 30 14 6 toluene ― 100 30 30 7 HOAc ― 100 30 43 ― 100 30 19 8 H2O 9 EtOH/H2O(1:1) ― 100 30 47 ― 100 30 44 10 EtOH/H2O(2:1) 11 EtOH/H2O(1:2) ― 100 30 41 12 EtOH/H2O(1:1) Na2CO3 100 30 33 13 EtOH/H2O(1:1) FeCl3 100 30 39 14 EtOH/H2O(1:1) HOAc 100 30 62 15 EtOH/H2O(1:1) TFA 100 30 66 p-TSA 100 30 42 16 EtOH/H2O(1:1) 17 EtOH/H2O(1:1) L-proline 100 30 47 18 EtOH/H2O(1:1) TFA 60 30 27 19 EtOH/H2O(1:1) TFA 70 30 37 20 EtOH/H2O(1:1) TFA 80 30 48 21 EtOH/H2O(1:1) TFA 90 30 69 22 EtOH/H2O(1:1) TFA 110 30 65 23 EtOH/H2O(1:1) TFA 90 10 56 24 EtOH/H2O(1:1) TFA 90 20 66 25 EtOH/H2O(1:1) TFA 90 40 74 26 EtOH/H2O(1:1) TFA 90 50 70 a Reaction conditions: 1{1} (1 mmol), 2{1} (1 mmol), 3{1} ( 1 mmol) and solvent (4 mL). b Yields was determined by HPLC-MS.

With the optimal reaction conditions in hand, the substrate scope of the transformation was then evaluated using sixteen substituted anilines (1), five arylglyoxal monohydrates (2) and four cyclic 1,3-dicarbonyl

compounds

(4-hydroxy-6-methyl-2H-pyran-2-one,

tetronic

acid,

4-hydroxycoumarin and dimedione) (3) (Figure 1). The corresponding functionalized indoles (4) were obtained with the results being summarized in Table 2. As displayed in Table 2, the anilines and arylglyoxal bearing either electron-withdrawing or electron-donating groups were tolerated under the reaction conditions, leading to the final products in satisfactory yields. However, when the 2-substituted anilines (Table 2, 4{12,1,1} and 4{13,1,1}) were used, the yields of the products were very low (27 % and 38 %, respectively). This fact indicated that the steric hindrance of the anilines can affect the yields in this transformation. Recently, Bhuyan’s group reported the synthesis of 3-aryl substituted indoles via a three-component reaction of arylamine, arylglyoxal


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and cyclic 1,3-dicarbonyl compound catalyzed by PTSA.18 This method provided an efficient and regioselective synthesis of 2-aryl substituted indoles. Substituted anilines 1: NH2

NH2

NH2

NH2

CH3

NH2

Cl

CH3

OCH3

C(CH3)3

Br

F

CH(CH3)2

1{3}

1{4}

1{5}

1{6}

1{7}

1{1}

1{2}

NH2

NH2

NH2

NH2

NH2

NH2

NH2

CH3

CO2CH3 CH3

CH(CH3)2

1{8}

1{9}

NH2

NH2

1{12}

1{11}

1{10}

1{13}

NH2

Cl

Cl

CH3

Br

Cl

F

CH3

1{14}

1{15}

O O 1{16}

Arylglyoxal monohydrates 2: O

O

O OH OH

O OH

OH

OH

OH

H3CO

2{1}

2{2}

Br

2{4}

O

O O O 3{1}

O

O

O

3{2}

3{3}

O

O

OH

Cl

2{3}

OH

OH

OH

H3C

Cyclic 1,3-dicarbonyl compounds 3: OH

O OH

3{4}

Figure 1. Substrates used in the synthesis of compounds 4. Table 2. Synthesis of Functionalized Indole Derivatives 4


2{5}


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entry

products

isolated yield (%)

mp (°C)

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4{1,1,1} 4{2,1,1} 4{3,1,1} 4{4,1,1} 4{5,1,1} 4{6,1,1} 4{8,1,1} 4{9,1,1} 4{10,1,1} 4{11,1,1} 4{12,1,1} 4{13,1,1} 4{14,1,1} 4{15,1,1} 4{16,1,1} 4{1,2,1} 4{2,2,1} 4{3,2,1} 4{4,2,1} 4{5,2,1} 4{6,2,1} 4{7,2,1} 4{9,2,1} 4{14,2,1} 4{15,2,1} 4{3,3,1} 4{4,3,1} 4{5,3,1} 4{7,3,1} 4{1,4,1} 4{3,4,1} 4{4,4,1} 4{5,4,1} 4{6,4,1} 4{7,4,1} 4{4,5,1} 4{5,5,1} 4{2,1,2} 4{4,1,2} 4{5,1,2} 4{16,1,2} 4{4,2,2} 4{5,2,2}

72 60 51 72 81 76 57 64 66 72 27 38 80 71 69 81 62 58 76 84 72 73 66 89 86 64 65 72 62 73 62 71 74 67 71 66 72 57 71 65 72 69 64

275―277 261―263 276―278 259―261 218―220 210―212 236―238 > 300 275―277 285―287 214―216 210―212 288―290 276―278 247―249 293―295 266―268 256―258 248―250 > 300 272―274 227―229 280―282 290―292 281―283 218―220 228―230 > 300 231―233 > 300 266―268 234―236 > 300 282―284 234―236 278―280 > 300 276―278 250―252 280―282 244―246 268―270 266―268


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44 45 46 47 48 49 50 51

4{16,2,2} 4{1,1,3} 4{4,1,3} 4{3,2,3} 4{1,4,3} 4{14,4,3} 4{2,1,4} 4{4,1,4}

78 57 75 65 74 74 72 67

280―282 235―236 174―175 249―250 > 300 265―266 225―227 214―216

The structures of the products synthesized in the current study were identified using IR, 1H NMR, and 13C NMR spectroscopies, as well as HRMS analysis. The structure of compound 4{1,1,1} was confirmed using single-crystal X-ray diffraction analysis (Figure 2).

Figure 2. Crystal structure of compound 4{1,1,1} On the basis of our results, we proposed the reaction mechanism shown in Scheme 2 for this novel three-component reaction. Intermediate A is obtained through the Knoevenagel condensation of arylglyoxal (2) with 4-hydroxy-6-methyl-2H-pyran-2-one (3) catalyzed by TFA. The subsequent Michael addition of anilines (1) to A gives intermediate B, which undergoes an intramolecular nucleophilic addition reaction, followed by a loss of water to form the products 4. Scheme 2. Proposed Reaction Mechanism for the Formation of Compound 4



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CONCLUSION In summary, we have developed a clean and efficient protocol for the construction of functionalized indole derivatives via a novel three-component domino reaction using aniline, arylglyoxal monohydrates and cyclic 1,3-dicarbonyl compounds as starting materials. This protocol has the advantages of mild reaction conditions, short reaction times, convenient operation, metal-free, cheat and green solvents, high regioselectivity and environmental friendliness.

EXPERIMENTAL PROCEDURES Melting points were measured using a XT-5 micro melting point apparatus and were uncorrected. IR spectra were recorded with a Varian F-1000 spectrometer using KBr disks; absorptions are reported as cm-1. 1H NMR and

13

C NMR spectra were obtained in DMSO-d6 solution, using a

Varian Inova 400 MHz or 300 MHz spectrometer. J values are reported in hertz and chemical shifts are expressed in parts per million downfield from TMS as the internal standard. HRMS analyses were carried out using a Bruker micrOTOF-QII instrument. General Procedure for the Synthesis of Functionalized Indole Derivatives 4. Anilines 1 (1 mmol), arylglyoxal monohydrates 2 (1 mmol), cyclic 1,3-dicarbonyl compounds 3 (1 mmol) and CF3CO2H (0.2 mmol) were placed in a 10 mL initiator reactor vial, followed by ethanol (2 mL) and water (2 mL). The reaction vial was then sealed and prestirred for 10 s before being irradiated in the microwave (time, 40 min; temperature, 90 °C; absorption leave, high; fixed hold time) until TLC (3:1 mixture of petroleum ether and ethyl acetate) revealed the complete consumption of the


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starting materials. The reaction mixture was then cooled to room temperature. The solvent was evaporated under reduced pressure and the compound was purified by column chromatography using petroleum ether and ethyl acetate as eluent, which gave pure compounds 4. 3-(6-Chloro-2-phenyl-1H-indol-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one

4{1,1,1}:

White

solid; IR (KBr, ν, cm–1) 3292, 3063, 2921, 1667, 1624, 1571, 1446, 1238, 1217, 992, 921, 786, 692; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.62 (s, 1H, NH), 11.10 (s, 1H, OH), 7.58 (d, J = 7.6 Hz, 2H, ArH), 7.44―7.40 (m, 3H, ArH), 7.30 (t, J = 7.2 Hz, 1H, ArH), 7.16 (d, J = 8.4 Hz, 1H, ArH), 7.00―6.97 (m, 1H, ArH), 6.12 (s, 1H, ArH), 2.25 (s, 3H, CH3);

13

C NMR (75 MHz,

DMSO-d6) δ (ppm) 167.2, 163.7, 161.6, 136.5, 136.4, 132.8, 128.6, 127.8, 127.5, 126.5, 125.9, 120.6, 119.2, 110.6, 103.6, 100.1, 95.2, 19.5; HRMS (ESI) calcd for C20H15ClNO3 [M+H]+ 352.0740, found 352.0749. 4-Hydroxy-3-(5-methyl-2-phenyl-1H-indol-3-yl)furan-2(5H)-one 4{2,1,2}: White solid; IR (KBr, ν, cm–1) 3418, 1719, 1610, 1479, 1453, 1431, 1076, 1052, 1029, 800, 774, 739, 696; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.95 (s, 1H, OH), 11.39 (s, 1H, NH), 7.65 (d, J = 7.6 Hz, 2H, ArH), 7.42 (t, J = 7.6Hz, 2H, ArH), 7.30 (t, J = 8.4 Hz, 2H, ArH), 7.09 (s, 1H, ArH), 6.96 (d, J = 8.4 Hz, 1H, ArH), 4.85 (s, 2H, CH2), 2.37 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 175.3, 173.6, 135.7, 134.4, 133.0, 129.2, 128.5, 127.5, 127.2, 126.6, 123.4, 118.9, 110.9, 99.9, 94.9, 67.0, 21.3; HRMS (ESI) calcd for C19H15NaNO3 [M+Na]+ 328.0950, found 328.0940. 3-(5-Chloro-2-phenyl-1H-indol-3-yl)-2-hydroxy-4H-chromen-4-one 4{1,1,3}: Yellow solid; IR(KBr, ν, cm–1) 3440, 3424, 3283, 1689, 1618, 1495, 1469, 1457, 1414, 1251, 1230, 1155, 1132, 969, 799, 753, 695; 1H NMR(400 MHz, DMSO-d6) δ (ppm) 11.83 (s, 1H, OH), 11.03 (s, 1H, NH), 7.91 (d, J = 8.0 Hz, 1H, ArH), 7.67 (t, J = 7.2 Hz, 1H, ArH), 7.61 (d, J = 7.6 Hz, 2H, ArH), 7.48―7.36 (m, 5H, ArH), 7.32―7.26 (m, 2H, ArH), 7.16―7.14 (m, 1H, ArH);

13

C NMR (100

MHz, DMSO-d6) δ (ppm) 162.2, 161.8, 152.8, 138.4, 134.8, 132.4, 132.2, 130.4, 128.7, 127.8, 126.8, 123.9, 123.8, 123.7, 121.5, 116.3, 102.1, 98.6; HRMS (ESI) calcd for C23H14ClNNaO3 [M+Na]+ 410.0547, found 410.0560. 3-Hydroxy-5,5-dimethyl-2-(5-methyl-2-phenyl-1H-indol-3-yl)cyclohex-2-enone

4{2,1,4}:

White solid; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.13 (s, 1H, OH), 10.00 (s, 1H, NH), 7.57 (d, J = 7.5 Hz, 2H, ArH), 7.36 (t, J = 7.7 Hz, 2H, ArH), 7.24 ( t, J = 7.7 Hz, 2H, ArH), 6.93―6.82 (m, 2H, ArH), 2.33 (s, 7H, CH3 + 2 × CH2), 1.17 (s, 3H, CH3), 1.12 (s, 3H, CH3); 13C NMR (100



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MHz, DMSO-d6) δ (ppm) 135.2, 134.6, 133.6, 129.9, 128.2, 126.7, 126.5, 122.7, 118.8, 110.7, 108.8, 104.6, 31.6, 28.4, 28.0, 21.3; HRMS (ESI) calcd for C23H23NO2 [M+H]+ 346.1807, found 346.1809. ASSOCIATED CONTENT Supporting Information Experimental details and spectroscopic characterization for compound 4. This material is available free of charge via the Internet at http://pubs.acs.org/. AUTHRS INFORMATION Corresponding Author *E-mail: [email protected] ORCID Da-Qing Shi: 0000-0003-2262-8491 Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS We are grateful for the financial support from the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (No. 15KJA150006), a project fund from the Priority Academic Project Development of the Jiangsu Higher Education Institutions, and the Key Laboratory of Organic Synthesis of Jiangsu Province (No. JSK1210). REFERENCES (1) (a) Houlihan, W. J.; Remers, W. A.; Brown, R. K. Indoles: Part I; Wiley: New York, 1992. (b) Sundberg, R. J. The Chemistry of Indoles; Academic: New York, 1996. (c) Somei, M.; Yamada, F. Simple indole alkaloids and those with a nonrearranged monoterpenoid. Nat. Prod. Rep. 2004, 21, 278―311. (2) Chen, I.; Safe, S.; Bjeldanes, L. Indole-3-carbinol and diindolymethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer. Biochem. Pharm. 1996, 51, 1069―1076. (3) Suzen, S.; Buyukbingol, E. Anti-cancer activity studies of indolalthiohydantoin (PIT) on


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Microwave-Assisted

Regioselective

Synthesis

of

3-Functionalized

Derivatives via Three-Component Domino Reaction Wei Lin, Yong-Xiang Zheng, Zhan Xun, Zhi-Bin Huang* and Da-Qing Shi*

R

+ Ar NH2

EtOH/H2O CF3CO2H

O

O

OH + OH

O

MWI,90oC R 40 min.

Atom economic, One-pot, Green


HO O N Ar H 51 examples up to 89% yield

Indole

Microwave-Assisted Regioselective Synthesis of 3-Functionalized

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