A One-Pot Multicomponent 1,3-Dipolar Cycloaddition Strategy

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Research Article pubs.acs.org/acscombsci

A One-Pot Multicomponent 1,3-Dipolar Cycloaddition Strategy: Combinatorial Synthesis of Dihydrothiophenone-Engrafted Dispiro Hybrid Heterocycles Mani Anusha Rani,† Sundaravel Vivek Kumar,† Karuppiah Malathi,† Muthumani Muthu,† Abdulrahman I. Almansour,‡ Raju Suresh Kumar,‡ and Raju Ranjith Kumar*,† †

Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai-625021, Tamil Nadu, India Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia

‡

S Supporting Information *

ABSTRACT: The combinatorial syntheses of a library of novel dihydrothiophenone-engrafted dispiro oxindole/indenoquinoxaline−pyrrolidine/pyrrolothiazole/indolizine hybrid heterocycles have been realized through a chemo-, regio-, and stereoselective multicomponent 1,3-dipolar cycloaddition strategy. KEYWORDS: 1,3-dipolar cycloaddition, azomethine ylide, dihydrothiophen-3(2H)-ones, dispiro heterocycles, multicomponent reaction

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INTRODUCTION Spiro heterocycles are prevalent in nature and possess pronounced biological activities.1 In particular, spirooxindolopyrrolidines/indolizines are found in many natural products and pharmaceutically active compounds.2 For instance, horsfiline, elacomine, gelsemine, formosanine, spirotryprotatins A and B, strychnofoline, rhynchophylline, and vincatine3 (Figure 1) are known for their wide range of biological activities. Apart from those of natural origin, many of the synthetic spiro oxindole−pyrrolidine hybrids have been reported to display anticancer,4 antimicrobial,5 antimycobacterial,6 anti-inflammatory, analgesic,7 local anesthetic,8 and acetylcholinesterase (AChE) inhibition activities.9 In addition spiro oxindole− pyrrolothiazole hybrids exhibit antitubercular,10 hepatoprotective,11 antidiabetic,12 anticonvulsant,13 antibiotic,14 and AChE inhibition activities,15 whereas spiro oxindole−indolizine hybrids are known for their antimicrobial,16 anti-HIV, antimycobacterial, anticancer, and AChE inhibition activities.17 The foregoing biological significances of spiro oxindole hybrids encouraged us to explore the feasibility of constructing hybrid heterocycles comprising a dispiro oxindole−pyrrolidine/ pyrrolothiazole/indolizine−dihydrothiophenone system. Incidentally, dihydrothiophene hybrids are known to display antimycobacterial,18 anticancer,19 antimalarial20 and porcupine inhibition21 activities. In spite of their significance, syntheses of spiro dihydrothiophenone derivatives have received little attention. We recently reported the assembly of novel 2thiaspiro[4.5]deca-6,8-dienes via an atom-efficient tandem protocol.22 In continuation, herein we report an easy access to novel dispiro dihydrothiophenone−oxindole hybrids 4−6 via a one-pot multicomponent 1,3-dipolar cycloaddition strategy (Scheme 1).23 To the best of our knowledge, this is the first © 2017 American Chemical Society

report of the synthesis of dispiro dihydrothiophenone hybrid heterocycles 4−6.

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RESULTS AND DISCUSSION

Initially, the essential dipolarophiles, (2Z,4Z)-2,4-bis(arylidene)dihydrothiophen-3(2H)-ones 1{1−11}, were prepared by the base-catalyzed condensation of dihydrothiophen3(2H)-one with aromatic aldehydes following our earlier report.24 Our study commenced with a pilot experiment i n vo l vi n g r e fl u x in g a m i x t u r e o f 2 , 4 - b is ( ( Z ) - 4 chlorobenzylidene)dihydrothiophen-3(2H)-one (1{1}), isatin (2), and sarcosine (3{1}) in methanol, which led to the isolation of (Z)-5″-(4-chlorobenzylidene)-4′-(4-chlorophenyl)1′-methyl-2″H-dispiro[indoline-3,2′-pyrrolidine-3′,3″-thiophene]-2,4″(5″H)-dione (4{1,1}) as a single diastereoisomer in 71% yield after 7 h. The pilot reaction was also examined with solvents like EtOH, 1,4-dioxane, CH3CN, toluene, and MeOH/ 1,4-dioxane (4:1 v/v) under reflux (Table 1). From Table 1, MeOH/1,4-dioxane was found to be the optimum solvent mixture for this transformation, wherein an 81% yield of 4{1,1} was realized. With the optimized condition in hand, we then explored the scope of this cycloaddition with substituted dipolarophiles 1{1−11}, isatin 2, and α-amino acids 3{1−3} (Figure 2). All of these reactions occurred smoothly, affording single diasteroisomers of the dihydrothiophenone-engrafted dispiro heterocyclic hybrids 4−6 in 72−86% yield (Scheme 2 and Table 2). A total of 21 dispiro dihydrothiophenone−oxindole hybrids 4−6 Received: December 15, 2016 Revised: March 30, 2017 Published: April 3, 2017 308

DOI: 10.1021/acscombsci.6b00186 ACS Comb. Sci. 2017, 19, 308−314

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Figure 1. Some biologically active spirooxindolopyrrolidine/indolizine derivatives.

Scheme 1. Synthesis of Dispiro Dihydrothiophenone−Oxindole Hybrids 4−6

were synthesized, with the aryl ring comprising electronreleasing or -withdrawing groups. The structures of 4−6 were elucidated using 1H, 13C, and 2D NMR spectroscopic techniques, as illustrated for a representative example. In the 1H NMR spectrum of 4{3,1} (Figure 3), the H-5″ benzylidene proton appeared as a singlet at 7.25 ppm and showed a heteronuclear multiple-bond correlation (HMBC) with the carbonyl C-4″ at 201.0 ppm. The H-4′ proton appeared as doublets of doublets at 4.46 ppm (J = 10.2, 7.8 Hz). The diastereotopic 5′-CH2 protons appeared as a triplet and multiplet at 3.96 ppm (J = 9.6 Hz) and 3.44−3.53 ppm, respectively, and showed HMBCs with C-3 at 76.6 ppm and C-3′ at 65.3 ppm. The 2″-CH2 protons appeared as a doublet and multiplet at 2.47 ppm (J = 12.6 Hz) and 3.44−3.53 ppm, respectively. The singlets at 2.17, 2.30, and 2.31 ppm were due to the N-CH3 and methyl protons of the aryl rings, respectively. The NH proton gave a broad singlet at 7.68 ppm. The 1H and 13C NMR chemical shifts of 4{3,1} are shown in Figure 3. Similarly, the structures of all the dispiro

Table 1. Optimization of the Reaction Conditions for the Synthesis of 4{1,1}

entry

solvent

reaction time (h)

yield of 4{1,1} (%)a

1 2 3 4 5 6

MeOH EtOH 1,4-dioxane CH3CN toluene MeOH/1,4-dioxane (4:1 v/v)

7 7 8 10 8 6

71 64 68 46 38 81

a

Isolated yields after purification by column chromatography.

Figure 2. Substrate diversity. 309

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5{7,2}, the structure was further confirmed by single-crystal Xray studies (Figure 4).25

Scheme 2. Synthesis of Dispiro Dihydrothiophenone− Oxindole Hybrids 4−6

Table 2. Yields and Melting Points of Dispiro Dihydrothiophenone−Oxindole Hybrids 4−6

a

Figure 4. ORTEP diagram of 5{7,2}.

entry

compd

yield (%)a

mp (°C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

4{1,1} 4{2,1} 4{3,1} 4{5,1} 4{6,1} 4{7,1} 4{9,1} 5{1,2} 5{2,2} 5{3,2} 5{5,2} 5{6,2} 5{7,2} 5{9,2} 6{1,3} 6{2,3} 6{3,3} 6{5,3} 6{6,3} 6{7,3} 6{9,3}

81 78 80 75 80 73 82 75 72 82 79 84 76 80 82 80 85 80 86 79 80

165−167 160−162 173−175 205−207 215−217 199−201 154−156 121−123 125−127 132−134 138−140 225−227 172−174 125−127 245−247 204−206 232−234 228−230 244−246 203−205 109−111

A plausible reaction pathway for the formation of dispiro dihydrothiophenone−oxindole hybrids 4−6 is depicted in Scheme 3. Initially, condensation of isatin and the α-amino acid forms spiro intermediate 7, which upon decarboxylation generates azomethine ylide 8 in situ. The subsequent reaction of 8 with dipolarophile 1 may occur via route A or B to afford the dispiro dihydrothiophenone−oxindole hybrid 4−6 or 9, respectively (Scheme 3). However, the exclusive formation of 4−6 in the cycloaddition reactions reveals that route A is preferred over route B. This selectivity may presumably be correlated to the electrostatic repulsion exerted between the carbonyls present in the same face during the approach of dipole 8 over dipolarophile 1 via route B. Moreover, the approach of 8 over 1 via route A places the carbonyls in the opposite face and hence overcomes the electrostatic repulsion. The above discussion is evidenced from the single-crystal X-ray studies of a representative product, 5{7,2} (Figure 4). The cycloadditions occurred chemoselectively on one of the two exocyclic CC bonds of 1 to furnish exclusively the dispiro dihydrothiophenone−oxindole hybrids 4−6. This is ascribable to the steric hindrance posed by these cycloadducts 4−6 for the second cycloaddition. In addition, the sulfur in thiophenes 1 in conjugation with the adjacent CC at C-2 may alter the polarity of the α,β-unsaturated CC bond, making it less reactive toward cycloaddition. Furthermore, the above cycloadditions were found to be regioselective, and the regioisomers of hybrids 4−6 were not observed in the reaction (Scheme 3). This may be rationalized from the fact that the electron-rich carbon of dipole 8 adds to the more electrondeficient β-carbon of α,β-unsaturated 1. The regiochemistry was apparent from the 1H NMR data for these cycloadducts 4− 6. Also the above cycloadditions create up to four new contiguous stereocenters in the products in a single transformation. However, all of the reactions proceeded diastereoselectively, leading to the formation of a single diastereoisomer of the product 4−6. With the intention to further explore the utility of (2Z,4Z)2,4-bis(arylidene)dihydrothiophen-3(2H)-ones 1{1−11} as dipolarophiles, the four-component reaction of 1, 3, ninhydrin (10) and o-phenylenediamines 11 was investigated. The

Isolated yields after column chromatography purification.

Figure 3. 1H and 13C NMR chemical shifts of 4{3,1}.

dihydrothiophenone−oxindole hybrids 4−6 were assigned using NMR spectroscopy. For one representative compound, 310

DOI: 10.1021/acscombsci.6b00186 ACS Comb. Sci. 2017, 19, 308−314

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ACS Combinatorial Science Scheme 3. Plausible Reaction Pathway for the Formation of 4−6

reaction under the previously optimized conditions (Table 1) led to the formation of novel dispiro dihydrothiophenone− indenoquinoxaline−pyrrolidine or pyrrolothiazole hybrids 12 or 13, respectively (Scheme 4). The cycloadditions were

Table 3. Yields and Melting Points of 12 and 13

Scheme 4. Synthesis of Dispiro Dihydrothiophenone− Indenoquinoxaline−Pyrrolidine or Pyrrolothiazole Hybrids 12 and 13

effected by refluxing the reactants in a 4:1 methanol/dioxane mixture for 3 h. In each case, after the completion of the reaction as evidenced by TLC, the reaction mixture was poured into water to get pure 12 or 13 as a yellow solid. All of the reactions proceeded well, affording near-quantitative yields of the products, notably without the need of any purification methods such as crystallization or column chromatography (Table 3). However, the reaction failed to occur in the case of pipecolic acid (3{3}). The structures of all of the cycloadducts 12 and 13 were elucidated with the help of 1H, 13C, and 2D NMR spectroscopic studies, as detailed for 13{3,2,1} as a representative example (see the Supporting Information). Similar to the previous case (Scheme 3), all of these cycloadditions proceeded chemo-, regio-, and stereoselectively, affording single isomers of the products 12 and 13 in excellent yields. The complete stereochemical assignments of 12 and 13 were made on the basis of our earlier report.26 A plausible reaction pathway for the formation of cycloadducts 12 and 13 is proposed in Scheme 5. Initially the reaction of ninhydrin 10 and o-phenylenediamine 11 may presumably form intermediate ketone 14 or 14A.

a

entry

compd

yield (%)a

mp (°C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

12{1,1,1} 12{2,1,1} 12{3,1,1} 12{4,1,1} 12{5,1,1} 12{8,1,1} 12{10,1,1} 12{11,1,1} 12{2,1,2} 12{8,1,2} 12{6,1,3} 13{1,2,1} 13{2,2,1} 13{3,2,1} 13{4,2,1} 13{5,2,1} 13{8,2,1} 13{10,2,1} 13{11,2,1} 13{2,2,2} 13{8,2,2} 13{6,2,3}

93 94 95 94 90 92 88 91 88 90 86 94 93 95 90 88 92 93 90 94 90 91

126−128 123−125 118−120 150−152 117−119 127−129 130−132 135−137 120−122 135−137 144−145 125−127 180−182 130−132 140−142 122−124 208−210 156−158 202−204 132−134 137−139 129−130

Isolated yields after filtration.

However, on the basis of literature reports, the formation of intermediate 14A in this reaction is ruled out.27 Intermediate ketone 14 reacts with α-amino acid 3 to generate azomethine ylide 15 via decarboxylative condensation. Subsequently, the electron-rich carbon of dipole 15 adds to the electron-deficient β-carbon of the α,β-unsaturated dipolarophile 1 to afford the product 12 or 13. The regiochemistry was also confirmed from the 1H NMR spectrum of the products 12 and 13.

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CONCLUSIONS We have successfully synthesized novel dihydrothiophenonetethered dispiro oxindole/indenoquinoxaline−pyrrolidine/pyrrolothiazole/indolizine hybrid heterocycles for the first time through a multicomponent 1,3-dipolar cycloaddition strategy. 311

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Scheme 5. Possible Mechanism for the Formation of Dispiro Dihydrothiophenone−Indenoquinoxaline−Pyrrolidine or Pyrrolothiazole Hybrids 12 and 13

(viz., sarcosine or 1,3-thiazolone-4-carboxylic acid) (1 mmol), and (2Z,4Z)-2,4-bis(arylidene)dihydrothiophen-3(2H)-one 1 (1 mmol) was dissolved in methanol/1,4-dioxane (4:1 v/v) and subjected to reflux on a boiling water bath for 3 h. After completion of the reaction as evidenced by TLC, the mixture was poured into water, and the residue was filtered and dried under vacuum to obtain pure dispiro dihydrothiophenone− indenoquinoxaline−pyrrolidine or pyrrolothiazole hybrid 12 or 13. Characterization data for a representative compound follow; for the full set of data, see the Supporting Information. (Z)-5″-(4-Chlorobenzylidene)-4′-(4-chlorophenyl)-1′methyl-2″H-dispiro[indeno[1,2-b]quinoxaline-11,2′-pyrrolidine-3′,3″-thiophen]-4″(5″H)-one (12{1,1,1}). Yellow solid. Yield: 93%. Mp: 126−128 °C. IR (neat) υmax: 2939, 1705, 1490, 1092, 1012 cm−1. 1H NMR (300 MHz, CDCl3) δH: 1.94 (s, 3H), 2.28 (d, J = 12.3 Hz, 1H), 3.07 (d, J = 12.3 Hz, 1H), 3.68−3.73 (m, 1H), 4.29 (t, J = 9.6 Hz, 1H), 4.68−4.74 (m, 1H), 7.06−7.09 (m, 3H), 7.20 (d, J = 8.7 Hz, 2H), 7.29−7.40 (m, 4H), 7.46 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.80−7.85 (m, 2H), 7.96 (d, J = 7.5 Hz, 1H), 8.15−8.18 (m, 1H), 8.26−8.29 (m, 1H). 13C NMR (75 MHz, CDCl3) δC: 34.4 (−CH2), 35.2 (−NCH3), 48.0 (−CH2), 60.1 (−C), 66.8 (−CH2), 76.8 (−C), 121.6 (−CH), 127.4 (−CH), 127.9 (−CH), 128.7 (−CH), 128.8 (−CH), 129.1 (−CH), 129.2 (−CH), 129.6 (−CH), 130.1 (−CH), 130.7 (−CH), 131.0 (−CH), 131.2 (−CH), 131.5 (−C), 131.9 (−C), 133.2 (−C), 134.5 (−C), 137.2 (−C), 138.1 (−C), 140.3 (−C), 142.1 (−C), 145.5 (−C), 155.1 (−C), 161.2 (−C), 200.7 (−CO). ESI-MS: m/z calcd, 605.11; found, 606.21 [M + 1]+. Anal. Calcd for C35H25Cl2N3OS: C, 69.31; H, 4.15; N, 6.93. Found: C, 69.35; H, 4.21; N, 6.89.

All of the cycloadditions occurred chemo-, regio-, and stereoselectively to yield single isomers of the products. In addition, the generation of up to four new contiguous stereocenters and the formation of two C−C bonds and one C−N bond in a single transformation were observed. The relatively simple protocol offers a facile entry to these biologically relevant classes of hybrid heterocycles in good to excellent yields.

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EXPERIMENTAL PROCEDURES Synthesis of Dispiro Dihydrothiophenone−Oxindole Hybrids 4−6. An equimolar mixture of (2Z,4Z)-2,4-bis(arylidene)dihydrothiophen-3(2H)-one 1 (1 mmol), isatin (2) (1 mmol), and α-amino acid 3 (viz., sarcosine, 1,3thiazolane-4-carboxylic acid, or pipecolic acid) (1 mmol) in methanol/1,4-dioxane (4:1 v/v) was refluxed on a boiling water bath for 6 h. After the completion of the reaction (TLC), the solvent was removed under reduced pressure, and the crude product was purified by column chromatography using petroleum ether/ethyl acetate (90:10 v/v) to obtain dispiro dihydrothiophenone−oxindole hybrids 4−6. Characterization data for a representative compound follow; for the full set of data, see the Supporting Information. (Z)-5″-(4-Chlorobenzylidene)-4′-(4-chlorophenyl)-1′methyl-2″H-dispiro[indoline-3,2′-pyrrolidine-3′,3″-thiophene]-2,4″(5″H)-dione (4{1,1}). White solid. Yield: 81%. Mp: 165−167 °C. IR (neat) υmax: 3249, 2940, 2861, 1700, 1583, 1486, 1466, 1218, 1183, 1157, 1089 cm−1. 1H NMR (300 MHz, CDCl3) δH: 2.15 (s, 3H), 2.45 (d, J = 12.9 Hz, 1H), 3.43−3.55 (m, 2H), 3.92 (t, J = 9.6 Hz, 1H), 4.45 (dd, J = 7.8, 9.9 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 6.8 Hz, 2H), 7.20−7.31 (m, 7H), 7.41 (d, J = 8.1 Hz, 2H), 7.92 (s, 1H). 13C NMR (75 MHz, CDCl3) δC: 34.3 (−CH2), 34.7 (N−CH3), 48.3 (−CH2), 58.9 (−CH), 65.1 (−C), 109.5 (−CH), 122.5 (−CH), 125.8 (−CH), 126.2 (−C), 127.2 (−CH), 128.7 (−CH), 128.8 (−CH), 129.5 (−CH), 130.9 (−CH), 131.2 (−CH), 131.8 (−C), 133.2 (−C), 133.3 (−C), 134.6 (−C), 136.9 (−C), 141.5 (−C), 177.6 (−CO), 200.5 (−CO). ESI-MS: m/z calcd, 520.08; found, 519.04 [M − 1]−. Anal. Calcd for C28H22Cl2N2O2S: C, 64.49; H, 4.25; N, 5.37. Found: C, 64.60; H, 4.20; N, 5.33. Synthesis of Dispiro Dihydrothiophenone−Indenoquinoxaline Hybrids 12 and 13. An equimolar mixture of ninhydrin (10) (1 mmol), o-phenylenediamine 11 (1 mmol), 3

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscombsci.6b00186. Details on the experimental methods, isolation procedures, spectral data, and copies of 1H and 13C NMR and spectra for all compounds (PDF) Crystallographic data for 5{7,2} (CIF) 312

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +919655591445. ORCID

Raju Ranjith Kumar: 0000-0002-9926-7770 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS R.R.K. thanks the University Grants Commission, New Delhi, for funds through Major Research Project F. No. 42-242/2013 (SR) and the Department of Science and Technology, New Delhi, for funds under the IRHPA Program for the highresolution NMR facility and the PURSE Programme. The authors acknowledge the Deanship of Scientific Research at King Saud University for Research Grant No. RGP-026.

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ABBREVIATIONS AChE, acetylcholinesterase; HIV, human immunodeficiency virus; HMBC, heteronuclear multiple-bond correlation; TLC, thin-layer chromatography

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REFERENCES

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