Organic chemistry

Latvian Journal of Chemistry, No 3, 2012, 257–263 DOI: 10.2478/v10161-012-0009-8

Organic chemistry SYNTHESIS OF 3-UNSUBSTITUTED 4-ARYL-4,7DIHYDROTHIENO[2,3-b]PYRIDINE-2,5-DICARBOXYLATES I. Adlere, A. Krauze, G. Duburs Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Rīga, LV-1006 e-mail: [email protected]

Novel 3-unsubstituted 4,7-dihydrothieno[2,3-b]pyridines were prepared by heterocyclization of methyl acetoacetate, an aromatic aldehyde and Meldrum’s acid in the presence of ammonium acetate in glacial acetic acid, followed by treatment of formed intermediates – pyridones with Wilsmeier–Haack reagent and with ethyl mercaptoacetate in the presence of sodium ethoxide in dry ethanol. Key words: 6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylates, 4-aryl6-chloro-5-formyl-1,4-dihydropyridine-3-carboxylates, 3-unsubstituted 4,7-dihydrothieno[2,3-b]pyridines.

INTRODUCTION

Thienopyridines are attractive heterocyclic systems due to their biological activity. They are useful for multiple pharmacological applications and indicate theoretical interest as fused heterocycles due to π-electron rich thiophene and πelectron deficient pyridine ring [1–3]. Clopidogrel (trade name Plavix) – (+)-(S)-methyl-2-(2-chlorophenyl)-2(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl) acetate is an oral antiplatelet agent [4–8]. Methyl 4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2,3-b]pyridine- 5-carboxylate (S-312) is widely investigated as a calcium channel blocking agent, potential cardiovascular [9–15] and anticonvulsant drug [16, 17]. 3-Amino-4,7-dihydrothieno[2,3-b]pyridines have revealed cardiovascular activity [18–21]. Contrary to 3-alkyl-4,7-dihydrothieno[2,3-b]pyridines, which are obtained by hetetocyclization of thiophene derivatives, 3-amino-4-aryl-4,7dihydrothieno[2,3-b]pyridines have been mostly obtained by Thorpe– Ziegler’s cyclization of 6-carbofunction containing 6-alkylsulfanyl-1,4dihydropyridines [22–29]. New 4,7-dihydrothieno[2,3-b]pyridines 1 were synthesized in order to clarify the role of amino group in position 3, which could be responsible for antihypertensive activity (binding with receptors). By searching new biological activities which are not connected with calcium channel blocking activities, 3-unsubstituted 4,7-dihydrothieno[2,3-b]pyridines could be interesting. In addition, electronic parameters of target thienopyridines 1 were differentiated by introducing electron acceptor or electron donating substituent in position 4. 257

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EXPERIMENTAL

All reagents were purchased from Aldrich or Acros and used without further purification. Melting points were determined on Optimelt MPA100 apparatus and were uncorrected. Elemental analyses were performed on an EA 1106 (Carlo Erba Instruments) IR spectra were recorded on a IR Prestige-21 (Shimadzu) spectrometer (in nujol) and peak positions νmax were expressed in cm–1. 1 H NMR spectra were recorded on a Varian Mercury-400 (400 MHz) spectrometer using CDCl3 and DMSO-d6 as solvents. Chemical shifts are expressed in δ (ppm downfield from HMDSO) and coupling constants (J) in Hz, multiplicities are abbreviated as: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The course of the reactions and the individuality of substances were monitored by TLC on Kieselgel 60 F Merck plates with benzene – methanol (4:1) and dichloromethane – hexane – acetone (2:1:1) as eluents. Ar O O

3

H O

O

+

O

O 2

Ar

O

O

O

O 5

4

NH 4OAc

N H

O

1) DM F + POCl3 2) NaOAc/H 2O

O

Ar O

O N H 1

O

HS

S

O

O NaOEt

Ar

O

O H

O

a) Ar = 2-F-C6H4; b) Ar = 3,4,5-(OMe)3-C6H2

N H

Cl

6

Methyl 4-(2-fluorophenyl)-2-methyl-6-oxo1,4,5,6-tetrahydropyridine-3-carboxylate (5a) A mixture of methyl acetoacetate (2) (3.48 g, 30 mmol), 2-fluorobenzaldehyde (3a) (3.78 g, 30 mmol), Meldrum’s acid (4) (4.32 g, 30 mmol) and ammonium acetate (2.46 g, 32 mmol) in glacial acetic acid (30 ml) was refluxed for 7 h (monitored by TLC) and then poured into ice-water. The precipitated solid was collected by filtration and recrystallized from ethanol to give 3.63 g (46%) of 4-(2-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine 5a as colourless powder; m.p. 184–185 oC. IR spectrum, ν, cm–1: 1694, 1709 (C=O); 3230 (NH). 1H NMR spectrum (CDCl3, δ, ppm): 2.38 (3H, s, 6-Me); 2.68, 2.87 and 2.92 (2H, d, J = 16.4 Hz, d and d, J = 8.2 Hz, 5-HAHB); 3.60 (3H, s, 3-COOMe); 4.56 (1H, d, J = 8.2 Hz, 4-H). 6.94–7.17 (4H, m, 4-C6H4F); 7.97 (1H, br s, NH). Found, %: C 63.83, H 5.23, N 5.19. Calculated for C14H14FNO3, %: C 63.87, H 5.36, N 5.32. In similar manner (10 h reflux) 5.23 g (52%) of methyl 2-methyl-6-oxo-4(3,4,5-trimethoxyphenyl)-1,4,5,6-tetrahydropyridine-3-carboxylate (5b) has 258


been obtained as colourless powder; m.p. 188–189 oC. IR spectrum, ν, cm–1: 1695, 1703 (C=O); 3226 (NH). 1H NMR spectrum (CDCl3, δ, ppm): 2.35 (3H, s, 6-Me); 2.70, 2.86 and 2.90 (2H, d, J = 16.4 Hz, d and d, J = 8.2 Hz, 5-HAHB); 3.67 (3H, s, 3-COOMe); 3.74 (9H, s, 4-C6H2(OMe)3; 4.19 (1H, d, J = 7.0 Hz, 4-H); 6.33 (2H, s, 4-C6H2(OMe)3); 7.97 (1H, br s, NH). Found, %: C 59.58, H 6.34, N 3.86. Calculated for C17H21NO6, %: C 60.89, H 6.31, N 4.18. Methyl 6-chloro-4-(2-fluorophenyl)-5-formyl-2-methyl1,4-dihydropyridine-3-carboxylate (6a) Solution of anhydrous N,N-dimethylformamide (DMF) (2.48 ml, 32 mmol) and dry dichloromethane (8 ml) was added dropwise to stirred solution of phosphorus oxychloride (POCl3) (3.0 ml, 32 mmol) at room temperature. After 30 min solution of 6-oxo-1,4,5,6-tetrahydropyridine 5a (2.10 g, 8 mmol) in 32 ml of dry dichloromethane was added. After 23 h stirring at room temperature, solution of sodium acetate (32 g NaOAc in 48 ml of water) was slowly added. After 1 h the reaction mixture was partionated between water and dichloromethane and the aqueous phase was extracted with ethyl acetate. The organic solvent was removed in vacuo and the solid was recrystallized from ethanol to give 2.12 g (68%) of 6-chloro-4-(2-fluorophenyl)-5-formyl-1,4-dihydropyridine 6a as light yellow powder; mp 197–199 °C. IR spectrum, ν, cm–1: 1641, 1703 (C=O); 3255 (NH). 1H NMR spectrum (DMSO-d6, δ, ppm): 2.22 (3H, s, 6-Me); 3.46 (3H, s, 3-COOMe); 5.05 (1H, s, 4-H); 6.94–7.18 (4H, m, 4-C6H4F); 9.59 (1H, s, HCO); 10.30 (1H, s, NH). Found, %: C 57.93, H 4.09, N 4.39. Calculated for C15H13ClFNO3, %: C 58.17, H 4.23, N 4.52. In similar manner 0.52 g (17%) of methyl 6-chloro-5-formyl-2-methyl-4(3,4,5-trimethoxyphenyl)-1,4-dihydropyridine-3-carboxylate (6b) has been obtained as light yellow powder; mp. 173–174 °C. IR spectrum, ν, cm–1: 1634; 1703 (C=O); 3251 (NH); 1H NMR spectrum (DMSO-d6; δ, ppm): 2.28 (3H, s, 6-Me); 3.53 (3H, s, 3-COOMe); 3.54 and 3.63 (6H and 3H, s and s, 4C6H2(OMe)3), 4.86 (1H, s, 4-H); 6.33 (2H, s, C6H2(OMe)3); 9.66 (1H, s, HCO); 10.30 (1H, s, NH). Found, %: C 56.32, H 5.27, N 3.49. Calculated for C18H20ClNO6, %: C 56.62, H 5.28, N 3.67. 2-Ethyl 5-methyl 4-(2-fluorophenyl)-6-methyl4,7-dihydrothieno[2,3-b]pyridine-2,5-dicarboxylate (1a) Mixture of 1,4-dihydropyridine 6a (0.31g, 1.0 mmol), ethyl 2-mercaptoacetate (0.17 g, 1.4 mmol) and sodium ethoxide (1.4 ml of 1N NaOEt) in 5 ml of dry ethanol was refluxed for 3 h. The reaction mixture was evaporated to dryness under reduced pressure. The residue was triturated with water (10 ml) and the solid was recrystallized from methanol to give 0.21 g (57%) of 4-(2-fluorophenyl)-4,7-dihydrothieno[2,3-b]pyridine 6a as light yellow powder; mp 212–213 °C. IR (ν/cm): 1672, 1700 (C=O); 3301 (NH). 1H NMR spectrum (DMSO-d6; δ, ppm): 1.16 and 4.10 (5H, t and q, J = 7.04 Hz, 2-COOEt); 2.20 (3H, s, 6-Me); 3.38 (3H, s, 5-COOMe); 5.38 (1H, s, 4-H); 7.02–7.16 (5H, m, 3-H and C6H4F); 10.04 (1H, s, NH). Found, %: C 60.76, H 4.63 N 3.62. Calculated for C19H18FNO4S, %: C 60.79, H 4.83, N 3.73. In similar manner, 0.27 g (61%) of 2-ethyl 5-methyl 6-methyl-4-(3,4,5trimethoxyphenyl)-4,7-dihydrothieno[2,3-b]pyridine-2,5-dicarboxylate (1b) has been obtained as light yellow powder; Mp 186–188 °C. IR spectrum, ν, cm–1: 259


1653, 1700 (C=O); 3309 (NH). 1H NMR spectrum (DMSO-d6; δ, ppm): 1.16 and 4.10 (5H, t and q, J = 7.04 Hz, 2-COOEt); 2.30 (3H, s, 6-Me); 3.44 (3H, s, 5-COOMe); 3.54 and 3.65 (6H and 3H, s and s, 4-C6H2(OMe)3); 5.03 (1H, s, 4-H); 6.42 (2H, s, C6H2(OMe)3); 7.35 (1H, s, 3-H); 9.95 (1H, s, NH). Found, %: C 58.67, H 5.66 N 3.00. Calculated for C22H25NO7S, %: C 59.05, H 5.63, N 3.13. RESULTS AND DISCUSSION

The starting substances 6-oxo-1,4,5,6-tetrahydropyridines 5 were prepared employing a four-component reaction according to synthesis protocol mentioned in literature [30, 31]. Reaction involves heterocyclization of Meldrum’s acid 4 with the β-ketoester and an aromatic aldehyde 3 in the presence of ammonium acetate in glacial acetic acid as solvent. Thus, using methyl acetoacetate 2 and refluxing for 7–10 h, reaction mixture was poured in ice-water and yellow solid was recrystallized from ethanol giving 3,4-dihydropyridone-5-carboxylates 4 in moderate yields (46 and 52%). Original 6-chloro-1,4-dihydropyridines 6 as stable yellow crystalline solids were prepared in 17–68 % yield by treatment of pyridones 5 with Wilsmeier– Haack reagent (POCl3, N,N-dimethylformamide). According to literature data [32], enolic form of pyridone 5 is involved in the reaction with in situ generated Wilsmeier–Haack reagent. The following basic hydrolysis of formed intermediate, iminium salt, gave products 6. 1,4-Dihydropyridines 6 proved to be an excellent candidates for further heterocyclizations yielding bicyclic systems [33]. Here, we employed condensation of 6-chloro-5-formyl-1,4-dihydropyridine-3-carboxylate 6 with ethyl mercaptoacetate in the presence of sodium ethoxide in dry ethanol. The reaction takes place by nucleophilic attack of the anion of mercaptoacetate at the electrophilic carbon atom at the position 6, followed by cyclization and dehydration to afford compounds 1a and 1b in good yields (57 and 61%). The structures of the intermediates 5 and 6 and reaction products 1 were confirmed by their spectral (1H NMR, IR) and elemental analysis data. The NH stretching vibration in the IR spectrum appears at 3230–3255 cm–1 for compounds 5 and 6, and at ca. 3300 cm–1 for 4,7-dihydrothieno[2,3-b]pyridines 1. Absorption bands (1634–1672 cm–1) of νC=O of compounds 1 and 6 are in agreement with the β-aminovinylcarbonyl-type conjugation of C=O groups. In the 1H NMR spectrum the characteristic C-4 proton signals for 1,4-dihydropyridines 6b,a appears as a singlet at 4.87 and 5.05 ppm and at 5.03 and 5.38 ppm for 4,7-dihydrothieno[2,3-b]pyridines 1b,a, respectively. For compounds 1a and 6a, bearing electron acceptor fluorine in aryl ring, 4-H proton signals were shifted downfield due to electron deficient aromatic-1,4-dihydropyridine system, while influence of electron donating methoxy groups in the compounds 1b and 6b results in upfield shifting of 4-H proton signals. CONCLUSIONS

Novel 3-unsubstituted 4,7-dihydrothieno[2,3-b]pyridines were prepared by heterocyclization of methyl acetoacetate, an aromatic aldehyde and Meldrum’s acid in the presence of ammonium acetate in glacial acetic acid, folloved by treatment of formed intermediates – pyridones with Wilsmeier–Haack reagent 260


and with ethyl mercaptoacetate in the presence of sodium ethoxide in dry ethanol. Acknowledgement This work was supported by European Regional Development Fund (ERDF) project 2010/0227/2DP/2.1.1.1.0/10/APIA/VIAA/072. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.

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3-NEAIZVIETOTU 4-ARIL-4,7-DIHIDROTIĒNO[2,3-b]PIRIDĪN2,5-DIKARBONSKĀBES ESTERU SINTĒZE I. Adlere, A. Krauze, G. Duburs KOPSAVILKUMS

Jauni 3-neaizvietotie 4,7-dihidrotieno[2,3-b]piridīni iegūti acetetiķskābes metilestera, aromātiskā aldehīda un meldrumskābes heterociklizācijā amonija acetāta klātbūtnē ledus etiķskābes vidē un izveidojušos starpproduktu – hidrēto piridonu –apstrādē ar Vilsmeijera–Hāka reaģentu un tad ar merkaptoetiķskābes esteri nātrija metoksīda klātbūtnē. Received 24.10.2012

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