Acetylenic Ester Promoted Tandem Ring Opening of Dienyl Thiazolidin-4-ones and Cyclizations: A Facile and Chemoselective Synthesis of Functionalized Pyridine-2-carboxylates

Abstract

Acetylenic ester promoted ring opening of dienyl-thiazolidin-4-ones and subsequent electrocyclization affords 5-phenyl-6-aryl pyridine-2-carboxylates in good to excellent yields.

Functionalized pyridines having ester substituents at their 2-position i.e., pyridine-2-carboxylates, are prominent in biologically active molecules.[1] [2] [3] Functionalized pyridine-2-carboxylates have been identified as cholecystokinin (CCK1) receptors, cannabinoid receptor type 1 (CB1), and telomerase inhibitors.[4] Similarly, 5,6-diaryl-2-pyridine-­carboxamides have been used as urotensin II receptor anta­gonists and sphingosine-1-phosphate (S1P) receptor agonists.[5] [6]

Traditionally, [4+2] cycloadditions of acyclic 2-azadienes have been used as a versatile method for the formation of functionalized pyridines, dihydropyridines, and tetra­hydropyridines.[7] [8] [9] [10] [11] Barluenga et al. have explored the synthesis of functionalized pyridines utilizing ethoxycarbonyl 2-aza-1,3-butadienes as starting materials.[12] Meurer et al. have reported the synthesis of different 5,6-diarylpyridine carboxylates and carboxamides via cycloaddition of azadiene phosphazene moieties and subsequently studied their human CB1 inverse agonist activity.[13] However, most 2-azadienes are found to be quite unstable and their synthesis requires cumbersome experimental procedures. Moreover, synthesis and cycloadditions of conjugated 2-azadienes have been little explored.

Thiazolidin-4-ones represent an important class of hetero­cyclic compounds due to their diverse biological activities.[14] Thiazolidin-4-ones have activity profiles, acting as inhibitors of COX-1,[15] HIV-RT,[16] aldose reductase,[17] [18] bacterial enzyme MurB and YycG histidine kinase,[19,20] as well as having antidiabetic activity,[21] antitubercular, antifungal, and antihelmintic activities.[21] Thiazolidin-4-ones have also been explored as useful organic synthons of different hetero­cycles.[22]

There are numerous reports on the acetylenic ester-­mediated synthesis of thiazolidin-4-ones using a variety of thioamides and thioureas.[22] However, there are few reports exploring acetylenic ester mediated ring opening/transformations of 4-thiazolidinones. The present manuscript demonstrates acetylenic ester mediated synthetic transformations of dienyl-thiazolidinones[23] leading to a facile synthesis of functionalized pyridine-2-carboxylates. In this transformation, the dienyl-thiazolidinones 1a–h behave as masked conjugated 2-azadienes and afford a facile and chemo­selective formation of pyridine-2-carboxylates mediated by acetylenic esters in good to excellent yields.

The dienyl thiazolidin-4-ones 1a–h were prepared by amidiolytic ring opening of 2-azetidinones-3-thiazolidin-4-ones with sodium alkoxide in the corresponding alcohols (Scheme [1]).[23] Crystallography data for 1a established the trans conformation of the dienyl thiazolidin-4-one moiety.[23]

We started our investigations by attempting Diels–Alder reactions of dienyl thiazolidin-4-one 1a with electron-deficient dienophiles (such as methyl acrylate, methyl vinyl ­ketone, maleic anhydride, N-phenyl maleimides) as well as electron-rich dienophiles (such as ethyl vinyl ether, tetrahydropyram, enamines etc.) in different solvents at different temperatures (rt to 180 °C). However, all attempts to achieve the desired reaction proved unsuccessful. Attempts to use activated acetylenes with dienyl thiazolidin-4-one 1a were also unsuccessful and resulted in the recovery of starting material, even at elevated temperatures (up to 130 °C; Scheme [2]). However, reaction of dienyl thiazolidin-4-one 1a with different acetylenic esters at high temperature (170 °C and above) resulted in the formation of 6-(2,5-dimethylphenyl)-5-phenylpyridine-2-carboxylate (3a) in good yield (Scheme [3], Table [1]; entry 3).

With this encouraging outcome, we concentrated on finding optimal reaction conditions. Several acetylenes were found to be ineffective or less effective for tandem ring opening and electrocyclization reaction leading to low yields of pyridine ester 3 (Table [1], entries 6–8). Starting ­material 1a did not afford any functionalized pyridine 3a using unactivated acetylenes such as butyne-1,4-diol and propargyl alcohol (entries 9–12). The reaction of dienyl thiazolidin-4-one 1a with methyl propiolate 2b was also not successful (entry 5). However, the reaction of dienyl thiazolidin-4-one 1a with activated acetylenes such as DMAD, ethyl but-2-enoate, or ethyl-2-pentenoate resulted in the formation of 5,6-diaryl pyridine-2-carboxylate 3a in fair to good yields (entries 3–8). Best results in terms of yield for the synthesis of 5,6-diaryl pyridine-2-carboxylate 3a were observed with the use of DMAD as the activated acetylene in xylene (entries 3 and 4). The reaction gave poor yields at low temperature or with the use of other solvents such as dioxane, 1,2-dichloroethane (DCE) etc. (entries 13 and 14).

The synthesis of 5,6-diaryl pyridine-2-carboxylate (3a) is proposed to involve a ring opening of the functionalized dienyl thiazolidin-4-one, resulting in generation of the functionalized conjugated 2-azadeine in situ, which undergoes subsequent electrocyclization to yield final product 3a at high temperature. The possible by-product of this reaction, the acetylenic ester thioglycolic complex, was never isolated, probably due to its unstable nature at elevated temperature.

After optimization of the reaction conditions, these tandem ring opening and electrocyclizations were further explored by employing dienyl-thiazolidin-4-ones with different substituents such as 4-methoxyphenyl, phenyl, 2-furyl and 2 pyridyl at C-5 using DMAD and xylene as solvent at 170 °C (Scheme [4]).[24] All the reactions resulted in the formation of pyridine-2-carboxylates 3a–h in good yields (Table [2]). The acetylenic ester promoted tandem ring opening and electrocyclization was found to be well tolerated by a variety of substituents on the dienyl thiazolidin-4-one. The ­reaction of 2-[2-(2,5-dimethylphenyl)-4-oxo-thiazolidin-3-yl]-5-phenyl-penta-2,4-dienoic acid methyl ester (1a) gave the best yield of pyridine-2-carboxylate 3a (entry 1). 2-[(Furyl/pyridyl)-4-oxo-thiazolidin-3-yl]-5-phenyl-penta-2,4-dienoic acid methyl and ethyl esters 1d/1h on reaction with DMAD afforded 6-furan-2-yl-5-phenyl-pyridine-2-carboxylic acid alkyl ester (3d) and 3-phenyl[2,2′]bipyridinyl-6-carboxylic acid alkyl ester (3h), respectively, in good yields (entries 4 and 8).

The functionalized 5,6-disubstituted pyridine-2-carboxylates 3a–h, thus obtained were characterized on the basis of spectroscopic analysis. For example, 6-(2,5-dimethylphenyl)-5-phenylpyridine-2-carboxylate (3a), showed a molecular ion at m/z 318 in its mass spectrum.[25] The ¹H NMR (300 MHz) spectrum of 3a showed two characteristic doublets (J = 7.8 Hz) at δ = 7.88 and 8.19 ppm corresponding to H3 and H4 of the pyridine ring. A singlet at δ = 4.00 ppm corresponded to the methyl ester, and two ­singlets at δ = 2.25 and 1.83 ppm where assigned to the methyl protons of the 2,5-dimethylphenyl group. ¹³C NMR analysis demonstrated the presence of a carbonyl carbon at δ = 166.0 ppm (CO of ester) and three aromatic carbons at δ = 140.1, 146.2, and 158.6 ppm corresponding to C-4, C-2 and C-5 of the pyridine ring, respectively, as well as resonances corresponding to the methyl ester at δ = 52.9 ppm and two methyl carbons at δ = 19.1 and 20.8 ppm corresponding to the 2,5-dimethylphenyl group (Figure [1]).[24] [25] [26]

A plausible mechanism for the formation of alkyl 5,6-disubstituted pyridine-2-carboxylates 3a–h is proposed to involve an initial thia-Michael addition of sulfur from the thiazolidin-4-one ring onto the acetylenic ester to provide a dipolar complex 4. This is followed by an intramolecular amidolytic ring opening of the thiazolidinone ring by nucleo­philic attack of the carbanion generated by initial thia-Michael addition reaction and then a rearrangement to yield the corresponding conjugated 2-azadiene 5. The conjugated 2-azadiene 5 subsequently undergoes electrocyclic ring closure reaction at high temperature to yield pyridines-2-ester 3 (Scheme [5]).

In conclusion, we have demonstrated the acetylenic ester promoted tandem ring opening and electrocyclization of dienyl-thiazolidin-4-ones for the synthesis of pyridine-2-carboxylates in good to excellent yields. The present methodology represents a facile, chemoselective and metal-free synthesis of substituted pyridines

• References and Notes

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• 6b Richard BL. John D. Haiqing Y. Xiaoxia L. WO2008/030843A1, 2008
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• 18 Ottana A. Maccari R. Giglio M. Corso AD. Cappiello M. Mura U. Cosconati S. Marinelli M. Novellino E. Sartini S. La-Motta C. Settimo FD. Eur. J. Med. Chem. 2011; 46: 2797
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• 23 Kuila B. Kumar Y. Mahajan D. Singh P. Kumar K. Bhargava G. RSC Adv. 2016; 6: 57485
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• 24 General procedure for the preparation of alkyl 6-(aryl)-5-phenylpyridine-2-carboxylate (3a–h): To a solution of compound 1 (0.1 g, 0.2544 mmol, 1 equiv) in xylene (10 mL), DMAD (3 equiv) was added and the reaction mixture was heated to 170 °C for 16 h. Progress of the reaction was monitored by TLC taking 1 as the limiting reactant. After completion of reaction, the solvent was removed under reduced pressure. The crude product was purified by column chromatography, using a 20–25% mixture of ethyl acetate in hexane as eluent to obtain 3 as the pure product.
• 25 Methyl 6-(2,5-dimethylphenyl)-5-phenylpyridine-2-carboxylate (3a): White solid; ¹H NMR (300 MHz, CDCl₃): δ = 1.83 (s, 3 H), 2.25 (s, 3 H), 4.00 (s, 3 H), 6.91 (d, J = 7.8 Hz, 1 H), 6.98 (dd, J = 7.8, 1.2 Hz, 1 H), 7.04 (s, 1 H), 7.10–7.15 (m, 2 H), 7.20–7.23 (m, 3 H), 7.88 (d, J = 7.8 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H); ¹³C NMR (CDCl₃): δ = 19.1, 20.8, 52.9, 123.7, 127.7, 128.1, 128.9, 129.1, 129.9, 130.9, 132.6, 134.9, 138.4, 139.0, 140.1, 146.2, 158.6, 166.0; LRMS: m/z = 318.2 [M+1]; HRMS: m/z calcd for C₂₁H₂₀NO₂ [MH⁺]: 318.1494; found: 318.1490.
• 26 Ethyl 6-(2,5-dimethylphenyl)-5-phenylpyridine-2-carboxylate (3e): Yellow solid; ¹H NMR (300 MHz, CDCl₃): δ = 1.25 (t, J = 7.8 Hz, 3 H), 1.85 (s, 3 H), 2.22 (s, 3 H), 4.23 (q, J = 7.8 Hz, 2 H), 6.94–7.05 (m, 3 H), 7.13–7.25 (m, 5 H), 7.89 (d, J = 7.5 Hz, 1 H), 8.16 (d, J = 7.5 Hz, 1 H); ¹³C NMR (CDCl₃): δ = 15.5, 18.9, 20.8, 60.5, 123.7, 127.8, 128.3, 128.7, 129.9, 130.4, 131.0, 132.6, 135.2, 138.4, 139.1, 139.9, 146.2, 158.4, 165.7; LRMS: m/z = 332 [M+1]; HRMS: m/z calcd for C₂₂H₂₂NO₂ [MH⁺]: 332.1651; found: 332.1655.

• References and Notes

• 1a Dzierszinski F. Coppin A. Mortuaire M. Dewally E. Slomianny C. Ameisen J.-C. Debels F. Tomavo S. Antimicrob. Agents Chemother. 2002; 46: 3197
  CrossrefPubMedSearch in Google Scholar
• 1b Kletsas D. Li W. Han Z. Papadopoulos V. Biochem. Pharmacol. 2004; 67: 1927
  CrossrefPubMedSearch in Google Scholar
• 2a Mach UR. Hackling AE. Perachon S. Ferry S. Wermuth CG. Schwartz J.-C. Sokoloff P. Stark H. ChemBioChem 2004; 5: 508
  CrossrefPubMedSearch in Google Scholar
• 2b Muscarella DE. Brian KA. Lemley AT. Bloom SE. Toxicol. Sci. 2003; 74: 66
  CrossrefPubMedSearch in Google Scholar
• 3a Rover S. Andjelkovic M. Nardeau AB. Chaput E. Guba W. Hebeisen P. Mohr S. Nettekoven M. Obst U. Richter WF. Ullmer C. Waldmeier P. Wright MB. J. Med. Chem. 2013; 56: 9874
  CrossrefPubMedSearch in Google Scholar
• 3b Jew SS. Park BS. Lim DY. Kim MG. Chung IK. Kim JH. Hong CI. Kim JK. Park HJ. Lee JH. Park HG. Bioorg. Med. Chem. Lett. 2003; 13: 609
  CrossrefSearch in Google Scholar
• 4 Liping W. James AH. Susan JL. Jie P. Su Q. Marc LR. Alison MS. Drew TW. Douglas JM. Ann EW. Scott DE. Bioorg. Med. Chem. Lett. 2011; 21: 2911
  CrossrefSearch in Google Scholar
• 5 Chengde W. Eric AC. Huong B. Daxin G. Jamal K. Wen L. Junmei W. Robert MV. WO2004073634 A2, 2004
• 6a Janet TA. Ling L. Xiaoxia L. WO 2011/143332 Al, 2011
• 6b Richard BL. John D. Haiqing Y. Xiaoxia L. WO2008/030843A1, 2008
• 7a Komatsu M. Takamatsu S. Uesaka M. Yamamoto S. Ohshiro Y. Agawa T. J. Org. Chem. 1984; 49: 2691
  CrossrefSearch in Google Scholar
• 7b Komatsu M. Ohgishi H. Takamatsu S. Ohshiro Y. Agawa T. Angew. Chem., Int. Ed. Engl. 1982; 21: 213
  CrossrefSearch in Google Scholar
• 8 Villacampa M. Phrez JM. Avendaho C. Mencdez JC. Tetrahedron 1994; 50: 10047
  CrossrefSearch in Google Scholar
• 9a Behforouz M. Ahmadian M. Tetrahedron 2000; 56: 5259
  CrossrefSearch in Google Scholar
• 9b Buonora P. Olsen J.-C. Oh T. Tetrahedron 2001; 57: 6099
  CrossrefSearch in Google Scholar
• 9c Jayakumar S. Ishara MP. S. Mahajan MP. Tetrahedron 2002; 58: 379
  CrossrefSearch in Google Scholar
• 10 Robin A. Julienne K. Meslin JC. Deniaud D. Tetrahedron Lett. 2004; 45: 9557
  CrossrefSearch in Google Scholar
• 11 Stephen PS. Brian T. Michael DW. Tetrahedron 2004; 60: 8893
  CrossrefSearch in Google Scholar
• 12 Barluenga J. Ferrero M. Palacios F. J. Chem. Soc., Perkin Trans. 1 1990; 2193
• 13 Meurer LC. Finke PE. Mills SG. Walsh TF. Toupence RB. Debenham JS. Goulet MT. Wang J. Tong X. Fong TM. Lao J. Schaeffer M.-T. Chen J. Shen C.-P. Stribling DS. Shearman LP. Strack AM. Van der Ploeg LH. T. Bioorg. Med. Chem. Lett. 2005; 15: 645
  CrossrefSearch in Google Scholar
• 14a Barreca ML. Balzsarini J. Chimirri A. Clercq ED. Luca LD. Holtje HD. Holtje M. Monforte AM. Monforte P. Pannecouque C. Rao A. Zapalla M. J. Med. Chem. 2002; 45: 5410
  CrossrefSearch in Google Scholar
• 14b Rao A. Balzarini J. Carbone A. Chimirri A. Clercq ED. Monforte AM. Monforte P. Pannecouque C. Zapallà M. Antiviral Res. 2004; 63: 79
  CrossrefPubMedSearch in Google Scholar
• 14c Rawal RK. Tripathi R. Katti SB. Pannecouque C. Clercq ED. Bioorg. Med. Chem. 2007; 15: 3134
  CrossrefPubMedSearch in Google Scholar
• 14d Desai KG. Desai KR. J. Sulfur Chem. 2006; 27: 315
  CrossrefSearch in Google Scholar
• 14e Solomon VR. Haq W. Srivastava K. Puri SK. Katti SB. J. Med. Chem. 2007; 50: 394
  CrossrefPubMedSearch in Google Scholar
• 15 Look GC. Schullek JR. Homes CP. Chinn JP. Gordon EM. Gallop MA. Bioorg. Med. Chem. Lett. 1996; 6: 707
  CrossrefSearch in Google Scholar
• 16 Barreca ML. Chimirri A. Luca LD. Monforte A. Monforte P. Rao A. Zappala M. Balzarini J. Clercq ED. Pannecouque C. Witvrouw M. Bioorg. Med. Chem. Lett. 2001; 11: 1793
  CrossrefSearch in Google Scholar
• 17 Maccari R. Corso AD. Giglio M. Moschini R. Mura U. Ottana R. Bioorg. Med. Chem. Lett. 2011; 21: 200
  CrossrefSearch in Google Scholar
• 18 Ottana A. Maccari R. Giglio M. Corso AD. Cappiello M. Mura U. Cosconati S. Marinelli M. Novellino E. Sartini S. La-Motta C. Settimo FD. Eur. J. Med. Chem. 2011; 46: 2797
  CrossrefPubMedSearch in Google Scholar
• 19 Anders CJ. Bronson JJ. D’Andrea SV. Deshpande SM. Falk PJ. Grant-Young KA. Harte WE. Ho H. Misco PF. Robertson JG. Stock D. Sun Y. Walsh AW. Bioorg. Med. Chem. Lett. 2000; 10: 715
  CrossrefSearch in Google Scholar
• 20 Schreiber M. Res J. Matter A. Curr. Opin. Cell Biol. 2009; 21: 325
  CrossrefPubMedSearch in Google Scholar
• 21 Kini D. Ghate M. Eur. J. Chem. 2011; 8: 386
  Search in Google Scholar
• 22a Pujari HK. Adv. Heterocycl. Chem. 1990; 49: 1
  Search in Google Scholar
• 22b Singh SP. Parmar SS. Raman K. Stenberg VI. Chem. Rev. 1981; 81: 175
  CrossrefSearch in Google Scholar
• 23 Kuila B. Kumar Y. Mahajan D. Singh P. Kumar K. Bhargava G. RSC Adv. 2016; 6: 57485
  CrossrefSearch in Google Scholar
• 24 General procedure for the preparation of alkyl 6-(aryl)-5-phenylpyridine-2-carboxylate (3a–h): To a solution of compound 1 (0.1 g, 0.2544 mmol, 1 equiv) in xylene (10 mL), DMAD (3 equiv) was added and the reaction mixture was heated to 170 °C for 16 h. Progress of the reaction was monitored by TLC taking 1 as the limiting reactant. After completion of reaction, the solvent was removed under reduced pressure. The crude product was purified by column chromatography, using a 20–25% mixture of ethyl acetate in hexane as eluent to obtain 3 as the pure product.
• 25 Methyl 6-(2,5-dimethylphenyl)-5-phenylpyridine-2-carboxylate (3a): White solid; ¹H NMR (300 MHz, CDCl₃): δ = 1.83 (s, 3 H), 2.25 (s, 3 H), 4.00 (s, 3 H), 6.91 (d, J = 7.8 Hz, 1 H), 6.98 (dd, J = 7.8, 1.2 Hz, 1 H), 7.04 (s, 1 H), 7.10–7.15 (m, 2 H), 7.20–7.23 (m, 3 H), 7.88 (d, J = 7.8 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H); ¹³C NMR (CDCl₃): δ = 19.1, 20.8, 52.9, 123.7, 127.7, 128.1, 128.9, 129.1, 129.9, 130.9, 132.6, 134.9, 138.4, 139.0, 140.1, 146.2, 158.6, 166.0; LRMS: m/z = 318.2 [M+1]; HRMS: m/z calcd for C₂₁H₂₀NO₂ [MH⁺]: 318.1494; found: 318.1490.
• 26 Ethyl 6-(2,5-dimethylphenyl)-5-phenylpyridine-2-carboxylate (3e): Yellow solid; ¹H NMR (300 MHz, CDCl₃): δ = 1.25 (t, J = 7.8 Hz, 3 H), 1.85 (s, 3 H), 2.22 (s, 3 H), 4.23 (q, J = 7.8 Hz, 2 H), 6.94–7.05 (m, 3 H), 7.13–7.25 (m, 5 H), 7.89 (d, J = 7.5 Hz, 1 H), 8.16 (d, J = 7.5 Hz, 1 H); ¹³C NMR (CDCl₃): δ = 15.5, 18.9, 20.8, 60.5, 123.7, 127.8, 128.3, 128.7, 129.9, 130.4, 131.0, 132.6, 135.2, 138.4, 139.1, 139.9, 146.2, 158.4, 165.7; LRMS: m/z = 332 [M+1]; HRMS: m/z calcd for C₂₂H₂₂NO₂ [MH⁺]: 332.1651; found: 332.1655.

• Supplementary Material