l-Proline-Catalysed Unusual Product Formation from the Reaction of 4- Hydroxydithiocoumarin and Aldehydes through a Pseudo-Three-Component Reaction

Abstract

A convenient and highly efficient synthetic protocol is reported for the synthesis of hitherto unreported thiopyrano{2,3-b:6,5-b′}bis(thiochromene)-12,14(13H)-diones by a domino pseudo-three-component reaction utilizing 4-hydroxydithiocoumarin and aldehydes. Single-crystal X-ray crystallographic analysis of the 13-phenyl-12H-thiopyrano[2,3-b:6,5-b′]bis(thiochromene)-12,14(13H)- dione derivative shows a layered structure that is stabilized by the unexpected C–S···π interactions.

Sulfur-containing heterocycles have attracted considerable attention due to their wide range of biological activities,[1] in particular as valuable building blocks for the synthesis of antipsychotic drugs.[2] Thiochromones exhibit antihyperplasia,[3] antibacterial,[4] anti-inflammatory,[5] and anticancer activities.[6] Substituted thiochromone molecules having a thiopyran unit serves as potent inhibitors of deoxyribonucleic acid protein kinase.[7]

However, the preparation of these compounds by conventional methods usually requires multiple synthetic steps and expensive starting materials. Multicomponent reactions (MCR) have manifested themselves as a potent tool for the rapid introduction and expansion of molecular diversity thus providing probable solutions to the above problems and such protocols have provided access to bioactive complex molecules[8] with advantages such as shorter reaction times, lower cost, higher atom-economy, energy efficiency, and avoidance of purification processes.[9]

There are several methods for the synthesis of thiopyrano[2,3-b]thiochromen-5(2H)-one derivatives.[10] Such derivatives have been synthesized from 4-hydroxydithiocoumarin, aldehydes, and dimedone or malononitrile through a domino sequence in water,[11] and sequential Knoevenagel–hetero-Diels–Alder reaction of 4-hydroxydithiocoumarin with terminal alkynes leads to thiochromone-annulated thiopyranocoumarin derivatives.[12] Herein, we report the synthesis of unreported thiopyrano[2,3-b:6,5-b′]bis(thiochromene)-12,14(13H)-dione derivatives through a one-pot, pseudo-three-component domino Knoevenagel–Michael reaction of 4-hydroxydithiocoumarin and aldehydes using l-proline as catalyst as shown in Scheme [1].

Recently, various research groups have exploited the utility of l-proline as catalyst for numerous organic transformations.[13]

4-Hydroxydithiocoumarin is not commercially available and was synthesized following the literature method.[14] Initially, the condensation was performed with two equivalents of 4-hydroxydithiocoumarin (1) and one equivalent of benzaldehyde (2) as model substrates to optimize the reaction conditions for the synthesis of 13-phenyl-12H-thiopyrano[2,3-b:6,5-b′]bis(thiochromene)-12,14(13H)-dione derivative 3a. A control reaction in the absence of catalyst in 2 mL acetonitrile under refluxing conditions gave only 22% yield of product after 12 hours (Table [1], entry 1). The isolated product 3a [15] was characterized by IR, ¹H NMR, ¹³C NMR spectroscopic and elemental analysis. Product 3a showed a singlet at δ = 7.03 ppm in the ¹H NMR spectrum and a resonance at δ = 39.7 ppm in ¹³C NMR spectrum, respectively, corresponding to Ph–CH (19-C and 19-H) and these two signals were correlated to each other through HMQC (see the Supporting Information). In order to optimize the yield, the reaction was performed with a wide range of catalysts such as iodine, ammonium chloride, and PTSA under similar reaction conditions but these modifications led not only lower yields but also longer reaction time (Table [1], entries 2–4). Interestingly, when the same set of conditions was applied out in the presence of 5, 10, and 15 mol% l-proline catalyst the desired product 3a was obtained in good yields (Table [1], entries 5–7).

Table 1 Optimization of the Reaction Conditions^a

Entry	Catalyst (mol%)	Solvent	Time (h)	Yield (%)b
1	–	MeCN	12	22
2	I2 (10)	MeCN	12	28
3	NH4Cl (10)	MeCN	8	50
4	PTSA (10)	MeCN	12	22
5	l-proline (5)	MeCN	0.75	75
6	l-proline (10)	MeCN	0.25	85
7	l-proline (15)	MeCN	0.75	82
8	l-proline (10)	EtOH	1.5	65
9	l-proline (10)	THF	12	48
10	l-proline (10)	H2O	12	56

^a All reactions were carried out using 4-hydroxy-2H-thiochromene-2-thione (2 equiv) and aldehyde (1 equiv).

^b Isolated yield.

The reaction was also examined using different solvents such as EtOH, THF, and H₂O under similar reaction conditions (Table [1], entries 8–10) and it was observed that MeCN proved to be the most efficient solvent. Therefore, it was concluded that 10 mol% l-proline in 2 mL acetonitrile under refluxing conditions provided the optimum conditions in terms of yield and reaction time.

Thus, the scope of the reaction was expanded to various aromatic aldehydes having substituents on the aromatic ring such as 4-Me, 4-MeO, 2,4-di-MeO, and 4-O₂N and these reactions were found to afford the desired products 3b–e in 78–88% yields (Table [2], entries 2–5).

The reactions of various aromatic aldehydes were also examined with 4-hydroxydithiocoumarin under identical reaction conditions, and products 3f–i were isolated in 78–82% yields (Table [2], entries 6–9). Furthermore, the reaction of 2-napthaldehyde with 4-hydroxydithiocoumarin gave product 3j in 75% yield (Table [2], entry 10). When the protocol was applied to different hetero aromatic aldehydes, such as 2-furfural, 2-thiophenylcarboxaldehyde and 3-formylindole, this led to formation of products 3k–m (Table [2], entries 11–13).

Finally, the reaction was assessed with a range of aliphatic aldehydes, and the expected products 3n–p were isolated in good yields (Table [2], entries 14–16). All the products were characterized by ¹H NMR and ¹³C NMR spectroscopy and elemental analysis.

Moreover, the structure of the compound 3a was confirmed by single-crystal X-ray crystallographic analysis (Figure [1]); it was shown to have an unexpected infinite layered arrangement via C–S···π interactions. Analysis of the crystal structure of 3a revealed that it forms a dimer through C–S···π interactions involving one molecule of S-2 with C-10 of a second molecule as shown in Figure [2] (A). This interaction leads the molecule to undergo complete assembly in the solid state thereby forming a layered structure shown in Figure [2] (B).

Formation of product 3 may be rationalized by aldehyde 2 reacting with l-proline to form enamine A, followed by reaction of 4-hydroxydithiocoumarin 1 with A to form the Knoevenagel product B that reacts with another 4-hydroxydithiocoumarin to form Michael adduct C. This, on cyclization and elimination of H₂S gas, leads to the final product 3 (Scheme [2]).

In conclusion, we have developed an interesting pseudo-three-component reaction of 4-hydroxydithiocoumarin and aldehydes to generate novel thiopyrano[2,3-b:6,5-b′]bis(thiochromene)-12,14(13H)-dione derivatives in high yield with good substrate scope. The reaction profits from the efficiency of sulfur as a nucleophile as well as a leaving group. The protocol involves a simple workup procedure involving filtration and washing the precipitate with acetonitrile to afford the desired products. Finally, the compound 3a was found to demonstrate C–S···π interactions, leading to assembly into a layered structure.

Acknowledgment

K.M. and P.R.B. acknowledge UGC, New Delhi for Research Fellowships. The authors are grateful to the Department of Science and Technology (DST) for providing the XRD facility under the FIST program to the Department of Chemistry and to the Director, IIT Guwahati for providing general facilities.

• References and Notes

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• 1c Katritzky AR, Bonlton AJ. Adv. Heterocycl. Chem. 1975; 18: 76
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• 2a Vink P. NL 6411477, 1965 ; Chem. Abstr. 1965, 63: 13265
• 2b El-Subbagh HI, El-Emam AA, El-Ashmawy MB, Shehata IA. Arch. Pharm. Res. 1990; 13: 24 ; and references cited therein
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• 6a Berlin KD, Benbrook DM, Nelson EC. US 6586460, 2003
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• 10a Majumdar KC, Khan AT, Saha S. Synlett 1991; 595
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• 12 Moghaddam FM, Kiamehr M, Khodabakhsh MR, Mirjafary Z, Fathi S, Saeidian H. Tetrahedron 2010; 66: 8615
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• 13a Chandrasekhar S, Reddy NS, Sultana SS, Narsihmulu C, Reddy KV. Tetrahedron 2006; 62: 338
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• 14 Andersonmckay JE, Liepa AJ. Aust. J. Chem. 1987; 40: 1179
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• 15 A mixture of 4-hydroxydithiocoumarin (2 mmol), benzaldehyde (1 mmol), and l-proline (0.012 mg, 10 mol%) was dissolved in MeCN (2 mL) into an oven-dried 25 mL round-bottomed flask and heated to reflux with stirring, progress of reaction being monitored by TLC. The precipitate was filtered off and washed with MeCN to furnish the pure product 3a. Yield 85%, white solid, mp 306–307 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.03 (s, 1 H), 7.12–13 (m, 1 H), 7.16–7.19 (m, 2 H), 7.45 (d, J = 7.8 Hz, 2 H), 7.49–7.53 (m, 4 H), 7.57–7.59 (m, 2 H), 8.53 (d, J = 8.4 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ = 39.7, 125.6, 127.3, 128.2, 128.3, 128.6, 130.1, 131.0, 131.9, 132.5, 135.7, 139.8, 142.3, 176.3. IR (KBr): ν_max = 1146, 1155, 1233, 1277, 1325, 1340, 1435, 1454, 1491, 1547, 1572, 1588, 1616, 2848, 2925, 3059 cm^–1. Anal. Calcd for C₂₅H₁₄O₂S₃: C, 67.85; H, 3.19. Found: C, 67.73; H, 3.10.

• References and Notes

• 1a Ingall AH In Comprehensive Heterocyclic Chemistry II . Vol. 5. Boulton AS, McKkillop A. Pergamon Press; Oxford: 1996: 501
  CrossrefSearch in Google Scholar
• 1b Schneller SW. Adv. Heterocycl. Chem. 1975; 18: 59
  Search in Google Scholar
• 1c Katritzky AR, Bonlton AJ. Adv. Heterocycl. Chem. 1975; 18: 76
  Search in Google Scholar
• 2a Vink P. NL 6411477, 1965 ; Chem. Abstr. 1965, 63: 13265
• 2b El-Subbagh HI, El-Emam AA, El-Ashmawy MB, Shehata IA. Arch. Pharm. Res. 1990; 13: 24 ; and references cited therein
  CrossrefSearch in Google Scholar
• 3 Quaglia W, Pigini M, Piergentili A, Giannella M, Gentili F, Marucci G, Carrieri A, Carotti A, Poggesi E, Leonardi A, Melchiorre C. J. Med. Chem. 2002; 45: 1633
  CrossrefSearch in Google Scholar
• 4 Brown MJ, Carter PS, Fenwick AE, Fosberry AP. Hamprecht D. W, Hibbs MJ, Jarvest RL, Mensah L, Milner PH, O’Hanlon PJ, Pope AJ, Richardson CM, West A, Witty DR. Bioorg. Med. Chem. Lett. 2002; 12: 3171
  CrossrefPubMedSearch in Google Scholar
• 5 Rogier DJ. Jr, Carter JS, Talley JJ. WO 2001049675, 2001
• 6a Berlin KD, Benbrook DM, Nelson EC. US 6586460, 2003
• 6b Sugita Y, Hosoya H, Terasawa K, Yokoe I, Fujisawa S, Sakagami H. Anticancer Res. 2001; 21: 2629
  Search in Google Scholar
• 7 Hollick JJ, Golding BT, Hardcastle IR, Martin N, Richardson C, Rigoreau LJ, Smith GC, Griffin RJ. Bioorg. Med. Chem. Lett. 2003; 13: 3083
  CrossrefSearch in Google Scholar
• 8 Zhu J, Bienaymé H. Multicomponent Reactions . Wiley-VCH; Weinheim: 2005. 1st ed
  CrossrefSearch in Google Scholar
• 9a Dömling A. Chem. Rev. 2006; 106: 17
  CrossrefPubMedSearch in Google Scholar
• 9b Ramón DJ, Yus M. Angew. Chem. Int. Ed. 2005; 44: 1602 ; Angew. Chem. 2005, 117, 1628
  CrossrefPubMedSearch in Google Scholar
• 9c Zhu J. Eur. J. Org. Chem. 2003; 1133
• 9d Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168
  CrossrefPubMedSearch in Google Scholar
• 10a Majumdar KC, Khan AT, Saha S. Synlett 1991; 595
  Thieme Connect
• 10b Majumdar KC, Bandyopadhyay A, Ghosh SK. Synth. Commun. 2004; 34: 2159
  CrossrefSearch in Google Scholar
• 10c Majumdar KC, Bandyopadhyay A. Monatsh. Chem 2004; 135: 581
  CrossrefSearch in Google Scholar
• 10d Majumdar KC, Saha S, Khan AT. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1994; 33: 216
  Search in Google Scholar
• 10e Majumdar KC, Taher A, Ponra S. Tetrahedron Lett. 2010; 51: 2297
  CrossrefSearch in Google Scholar
• 11 Majumdar KC, Ponra S, Ghosh T. RSC Adv. 2012; 2: 1144
  CrossrefSearch in Google Scholar
• 12 Moghaddam FM, Kiamehr M, Khodabakhsh MR, Mirjafary Z, Fathi S, Saeidian H. Tetrahedron 2010; 66: 8615
  CrossrefSearch in Google Scholar
• 13a Chandrasekhar S, Reddy NS, Sultana SS, Narsihmulu C, Reddy KV. Tetrahedron 2006; 62: 338
  CrossrefSearch in Google Scholar
• 13b Li H, Wang B, Deng L. J. Am. Chem. Soc. 2006; 128: 732
  CrossrefPubMedSearch in Google Scholar
• 13c Gunasekaran P, Prasanna P, Perumal S. Tetrahedron Lett. 2014; 55: 329 ; and references cited therein
  CrossrefSearch in Google Scholar
• 14 Andersonmckay JE, Liepa AJ. Aust. J. Chem. 1987; 40: 1179
  CrossrefSearch in Google Scholar
• 15 A mixture of 4-hydroxydithiocoumarin (2 mmol), benzaldehyde (1 mmol), and l-proline (0.012 mg, 10 mol%) was dissolved in MeCN (2 mL) into an oven-dried 25 mL round-bottomed flask and heated to reflux with stirring, progress of reaction being monitored by TLC. The precipitate was filtered off and washed with MeCN to furnish the pure product 3a. Yield 85%, white solid, mp 306–307 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.03 (s, 1 H), 7.12–13 (m, 1 H), 7.16–7.19 (m, 2 H), 7.45 (d, J = 7.8 Hz, 2 H), 7.49–7.53 (m, 4 H), 7.57–7.59 (m, 2 H), 8.53 (d, J = 8.4 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ = 39.7, 125.6, 127.3, 128.2, 128.3, 128.6, 130.1, 131.0, 131.9, 132.5, 135.7, 139.8, 142.3, 176.3. IR (KBr): ν_max = 1146, 1155, 1233, 1277, 1325, 1340, 1435, 1454, 1491, 1547, 1572, 1588, 1616, 2848, 2925, 3059 cm^–1. Anal. Calcd for C₂₅H₁₄O₂S₃: C, 67.85; H, 3.19. Found: C, 67.73; H, 3.10.

• Supplementary Material