Cadmium chloride: a simple and efficient catalyst for the synthesis of 1,4-dihydropyridine (Hantzsch pyridines)

1,4-Dihydropyridine synthesis has been carried out using cadmium chloride as a catalyst. This protocol is applicable to a variety of aldehydes with β-ketoester and ammonium acetate to afford the corresponding Hantzsch pyridines in excellent yields. This multicomponent condensation took place very smoothly in acetonitrile reflux.

Multicomponent condensation strategies offer significant advantages over conventional linear-type synthesis in providing products with the diversity needed for the discovery of new lead compounds or lead optimization employing combinatorial chemistry [1-6]. In 1882, Arthur Rudolf Hantzsch, a German chemist, reported a cyclocondensation between ethyl acetoacetate, aldehyde and aqueous ammonium hydroxide to afford a heterocyclic system of 1,4-dihydropyridine; since then, it became familiar as the Hantzsch reaction [7,8].

The dihydropyridine derivatives exhibit a large range of biological activities such as anticonvulsant, antitumor, antianxiety, vasodilator, bronchodilator, antidepressant,analgesic, hypnotic, anti-inflammatory and neuroprotectants as well as platelet antiaggregatory agents [9-12]. Dihydropyridines are commercially used as calcium channel blockers for the treatment of cardiovascular diseases (Figure 1). The tremendous biological activity of Hantzsch pyridines attracted many researchers and academicians. Hence, several attempts have been made to synthesize 1,4-dihydropyridine derivatives using various catalysts and reaction conditions such as triphenyl phosphine [13], CAN [14], heteropoly acids [15], Zn complex [16], phenylboronic acid [17], magnesium perchlorate [18], cyanuric chloride [19], Yb(OTf)₃[20], ionic liquid [21], organocatalyst [22], L-proline [23], molecular iodine [24], tetrabutylammonium hydrogen sulfate [25] and glycerine-CeClO₂.7H₂O [26,27]. But many of the methods are suffering from some drawbacks such as long reaction time, low yields, tedious workup procedures and the use of expensive catalysts. Therefore, the development of efficient protocol is still in demand. As part of our research program in developing new methodologies [28-31], we report herein a simple and efficient procedure for the synthesis of 1,4-dihydropyridine derivatives using cadmium chloride as a catalyst. Cadmium chloride is a nonhygroscopic white solid that is highly soluble in water, a mild Lewis acid and a catalyst known for various organic transformations in the literature [32-34].

In a model reaction, benzaldehyde, β-ketoester and ammonium acetate were reacted in the presence of a catalytic amount (10 mol%) of CdCl₂ at acetonitrile reflux. The reaction was completed within 3 h to afford the corresponding product, diethyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (compound 3a), in excellent yields as shown in Scheme 1.

Encouraged by the result obtained with benzaldehyde, we had applied this methodology to a variety of aldehydes such as aromatic, heteroaromatic and aliphatic aldehydes successfully. The condensation reaction proceeded smoothly with β-ketoester and ammonium acetate in the presence of a catalytic amount of cadmium chloride at acetonitrile reflux to give the corresponding 1,4-dihydropyridine derivatives in very good yields. The acid sensitive aldehydes such as cinnamaldehyde (compound 1e), pyridine-2-aldehyde (compound 1 h) and 2-furfuraldehyde (compound 1i) worked well under these reaction conditions. The aromatic aldehydes having electron-withdrawing group react a little slower than aromatic aldehydes, and the aromatic aldehydes having electron-donating group react a little faster than aromatic aldehydes. In a similar manner, the aromatic aldehydes reacted comparatively faster than aliphatic aldehydes. This protocol is successfully applicable to both electron-rich as well as electron-deficient aldehydes. In general, all the reactions were completed within 3 to 5 h at 80°C to 85°C, and the products of 1,4-dihydropyridine derivatives were obtained in 75% to 93% yields. All the products were confirmed by their proton nuclear magnetic resonance (¹ H NMR), infrared (IR) and mass spectroscopy data.

General procedure for the synthesis of 1,4-dihydropyridines

To a stirred mixture of aldehyde (212 mg, 2 mmol) and ethyl acetoacetate (572 mg, 4.4 mmol) in acetonitrile (10 mL) was added ammonium acetate (170 mg, 2.2 mmol) and cadmium chloride (36.6 mg, 0.2 mmol). The resulting reaction mixture was refluxed for a specified period (Table 1). After completion of the reaction, as indicated by TLC, the solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to obtain the crude products, which were purified by column chromatography using silica gel 60 to 120 mesh and eluted with ethyl acetate-hexane mixture in 3:7 ratio. All the products were confirmed by their spectral data and compared with literature reports.

Spectral data for all the compounds

Diethyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (3a)

Solid, Melting point (Mp) 155°C to 156°C. IR (KBr): υ 3,342, 3,061, 2,978, 2,931, 1,690, 1,651, 1,489, 1,453, 1,375, 1,300, 1,248, 1,212, 1,121, 1,091, 1,024, 825, 767 and 701 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 1.25 (t, 6 H, J = 6.0 Hz), 2.35 (s, 6 H), 4.10 (q, 4 H, J = 6.0 Hz), 4.90 (s, 1 H), 5.52 (brs, 1 H, NH) and 7.08 to 7.25 (m, 5 H); ¹³ C NMR (75 MHz, CDCl₃): δ 168.3, 146.1, 143.9, 136.1, 129.2, 126.8, 103.9, 60.1, 40.0, 20.5 and 14.3; EIMS m/z (%): 328 (m⁺ 95), 284 (100), 256 (25), 252 (35), 225 (15), 219 (10), 195 (10), 181 (12), 173 (25), 131 (15) and 107 (20).

Diethyl-2,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylate (3b)

IR (KBr): υ 3,357, 2,928, 2,853, 1,696, 1,636, 1,593, 1,497, 1,460, 1,378, 1,317, 1,273, 1,205, 1,127, 1,092, 1,001, 864, 803, 748 and 627 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 1.28 (t, 6 H, J = 6.0 Hz), 2.35 (s, 6 H), 3.78 (s, 6 H), 3.80 (s, 3 H), 4.12 (q, 4 H, J = 6.0 Hz), 4.90 (s, 1 H), 5.52 (brs, 1 H, NH) and 6.45 (s, 2 H); EIMS m/z (%): 420 (m⁺¹ 30), 374 (25), 346 (20), 328 (10), 252 (100), 227 (10), 170 (10) and 121 (10).

Diethyl-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (3c)

Solid, Mp 130°C to 131°C. IR (KBr): υ 3,341, 3,084, 2,979, 2,927, 2,855, 1,683, 1,518, 1,484, 1,344, 1,301, 1,213, 1,101, 1,020, 828, 754 and 706 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 1.25 (t, 6 H, J = 6.0 Hz), 2.35 (s, 6 H), 4.10 (q, 4 H, J = 6.0 Hz), 5.05 (s, 1 H), 5.70 (brs, 1 H, NH), 7.41 (d, 2 H, J = 6.5 Hz) and 8.06 (d, 2 H, J = 6.5 Hz); ¹³ C NMR (75 MHz, CDCl₃): δ 166.9, 156.0, 145.9, 144.7, 128.3, 123.5, 103.4, 60.1, 40.2, 20.3 and 14.2; EIMS m/z (%): 375 (m⁺¹ 45), 348 (10), 329 (100), 320 (10), 301 (25) and 102 (10).

Diethyl-2,6-dimethyl-4-(3-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (3d)

Solid, Mp 130 to 131°C. IR (KBr): υ 3,323, 3,246, 3,098, 2,979, 2,925, 1,705, 1,649, 1,488, 1,375, 1,333, 1,299, 1,214, 1,119, 1,022, 869, 788, 751 and 694 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 1.23 (t, 6 H, J = 6.0 Hz), 2.36 (s, 6 H), 4.10 (q, 4 H, J = 6.0 Hz), 4.90 (s, 1 H), 5.58 (brs, 1 H, NH), 7.05 to 7.20 (m, 4 H); ¹³ C NMR (75 MHz, CDCl₃): δ 167.9, 150.1, 144.1, 143.5, 132.6, 128.0, 127.6, 126.0, 103.6, 60.1, 40.2, 19.3 and 14.8; EIMS m/z (%): 386 (m⁺¹ 65), 364 (40), 318 (100), 292 (10), 251 (20), 201 (10) and 171 (25).

(E)-Diethyl-2,6-dimethyl-4-styryl-1,4-dihydropyridine-3,5-dicarboxylate (3e)

Solid, Mp 148° to 150°C. IR (KBr): υ 3,334, 3,095, 2,924, 1,690, 1,644, 1,490, 1,375, 1,326, 1,296, 1,219, 1,161, 1,116, 1,025, 783, 755 and 715 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 1.22 (t, 3 H, J = 6.0 Hz), 2.38 (s, 6 H), 3.92 (s, 3 H), 4.18 (q, 2 H, J = 6.0 Hz), 5.14 (d, 1 H, J = 4.5 Hz), 5.6.0 (brs, 1 H), 6.15 (dd, 1 H, J = 4.5 & 14.8 Hz), 7.18 (d, 1 H, J = 14.8 Hz) and 7.22 to 7.34 (m, 5 H); EIMS m/z (%): 341 (m⁺¹ 20), 327 (10), 297 (100), 269 (10), 211 (15), 183 (20), 104 (18), 81 (25), 76 (35) and 51 (22).

Diethyl-4-decyl-2,6-dimethyl-1,4-dihydropyrimidine-3,5-dicarboxylate (3f)

IR (neat): υ 3,377, 2,926, 2,855, 1,728, 1,567, 1,461, 1,376, 1,282, 1,233, 1,104, 1,041, 860 and 772 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 0.90 (t, 3 H, J = 6.0 Hz), 1.20 to 1.36 (m, 24 H), 2.29 (s, 6 H), 3.85 (t, 1 H, J = 6.0 Hz), 4.20 (q, 4 H, J = 6.0 Hz) and 5.48 (brs, 1 H, NH); EIMS m/z (%): 393 (m⁻¹ 100), 335 (10) and 320 (10).

Diethyl-4-benzyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (3g)

IR (neat): υ 2,978, 2,927, 1,719, 1,592, 1,443, 1,369, 1,289, 1,252, 1,222, 1,105, 1,043, 863, 769 and 699 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 1.26 (t, 6 H, J = 6.0 Hz), 2.15 (s, 6 H), 2.55 (d, 2 H, J = 5.0 Hz), 4.05 (q, 4 H, J = 6.0 Hz), 4.97 (s, 1 H), 5.45 (brs, 1 H, NH), 6.98 (d, 2 H, J = 7.0 Hz) and 7.10 to 7.20 (m, 3 H); EIMS m/z (%): 344 (m⁺¹ 20), 342 (10), 318 (10), 250 (10), 298 (25), 252 (100) and 224 (10).

Diethyl-2,6-dimethyl-4-(pyridin-2-yl)-1,4-dihydropyridine-3,5-dicarboxylate (3h)

IR (KBr): υ 3,273, 3,172, 3,054, 2,925, 1,676, 1,593, 1,508, 1,437, 1,371, 1,304, 1,256, 1,212, 1,116, 1,018, 751 and 677 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 1.20 (t, 6 H, J = 6.0 Hz), 2.25 (s, 6 H), 4.05 (q, 4 H, J = 6.0 Hz), 5.12 (s, 1 H), 7.08 to 7.12 (m, 1 H), 7.32 to 7.38 (m, 1 H), 7.51 to 7.58 (m, 1 H), 8.05 (brs, 1 H) and 8.48 (d, 1 H, J = 6.0 Hz); EIMS m/z (%): 331 (m⁺¹ 100), 308 (10), 286 (55), 292 (10) and 262 (10).

Diethyl-4-(furan-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate(3i)

Solid, Mp 158°C to 160°C. IR (KBr): υ 3,346, 2,981, 1,702, 1,650, 1,487, 1,373, 1,331, 1,298, 1,262, 1,209, 1,119, 1,095, 1,047, 1,013, 807, 731 and 687 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 1.28 (t, 6 H, J = 6.0 Hz), 2.32 (s, 6 H), 4.10 to 4.22 (m, 4 H), 5.12 (s, 1 H), 5.61 (brs, 1 H), 5.90 (s, 1 H), 6.20 (s, 1 H) and 7.18 (s, 1 H); ¹³ C NMR (75 MHz, CDCl₃): δ 168.1, 159.0, 145.5, 141.2, 109.8, 104.9, 99.8, 60.2, 33.5, 20.1 and 14.5; EIMS m/z (%): 320 (m⁺¹ 45), 318 (25), 304 (40), 274 (10), 261 (10), 252 (100) and 214 (15).

Diethyl-4-(2-chloro-6-methylquinolin-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-di carboxylate (3j)

IR (neat): υ 3,338, 2,981, 1,725, 1,695, 1,560, 1,495, 1,448, 1,375, 1,301, 1,275, 1,213, 1,171, 1,104, 1,043, 925, 824 and 755 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 1.19 (t, 6 H, J = 6.0 Hz), 2.32 (s, 6 H), 2.50 (s, 3 H), 4.01 to 4.12 (m, 4 H), 5.42 (s, 1 H), 5.65 (brs, 1 H), 7.40 to 7.50 (m, 2 H), 7.82 (d, 1 H, J = 7.0 Hz) and 7.99 (s, 1 H). EIMS m/z (%): 429 (m⁺¹ 100), 393 (35), 251 (10) and 178 (20).

Diethyl-4-(2,6-dimethylhept-5-enyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (3k)

IR (neat): υ 3,373, 2,967, 2,927, 1,728, 1,565, 1,449, 1,377, 1,283, 1,236, 1,106, 1,040, 859 and 775 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 0.88 (s, 3 H), 0.90 (s, 3 H), 0.98 to 1.10 (m, 1 H), 1.20 to 1.35 (m, 10 H), 1.58 (s, 3 H), 1.68 (s, 3 H), 1.80 to 1.95 (m, 2 H), 2.30 (s, 6 H), 4.20 (q, 4 H, J = 6.0 Hz) and 5.48 (brs, 1 H, NH); EIMS m/z (%): 378 (m⁺¹ 40), 376 (50), 332 (20), 306 (10), 274 (15), 252 (100), 197 (10), 161 (10), 116 (10), 81 (10) and 65 (18).

Diethyl-4-[4-(dimethylamino)phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (3l)

IR (KBr): υ 3,319, 3,095, 2,979, 2,923, 2,804, 1,697, 1,674, 1,613, 1,519, 1,492, 1,446, 1,352, 1,302, 1,276, 1,203, 1,128, 1,096, 1,050, 1,021, 945, 818, 785, 747 and 683 cm⁻¹; ¹ H NMR (300 MHz, CDCl₃): δ 1.26 (t, 6 H, J = 6.0 Hz), 2.32 (s, 6 H), 2.90 (s, 6 H), 4.02 to 4.15 (m, 4 H), 4.81 (s, 1 H), 5.50 (brs, 1 H, NH), 6.60 to 6.70 (m, 2 H) and 7.10 (d, 2 H, J = 7.0 Hz); EIMS m/z (%): 373 (m⁺¹ 100), 252 (25), 227 (10), 205 (10), 116 (10), 65 (10) and 55 (10).

Diethyl-4-[4-(benzyloxy)-3-methoxyphenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (3m)

IR (KBr): υ 3,365, 3,063, 2,926, 2,853, 1,693, 1,642, 1,621, 1,511, 1,484, 1,422, 1,380, 1,270, 1,201, 1,161, 1,093, 1,049, 1,007, 862, 812, 748, 703 and 658 cm⁻¹;¹ H NMR (300 MHz, CDCl₃): δ 1.25 (t, 6 H, J = 6.0 Hz), 2.32 (s, 6 H), 3.82 (s, 3 H), 4.06 to 4.15 (m, 4 H), 4.85 (s, 1 H), 5.05 (s, 2 H), 5.42 (brs, 1 H, NH), 6.62 to 6.70 (m, 2 H), 6.82 (s, 1 H) and 7.28 to 7.42 (m, 5 H); EIMS m/z (%): 465 (m⁺ 35), 464 (65), 420 (15), 392 (20), 367 (10), 322 (10), 252 (100), 152 (10), 115 (10), 102 (15) and 75 (10).

In conclusion, we have demonstrated a simple and efficient three-component process for the synthesis of 1,4-dihydropyridines by condensation of aldehyde, β-ketoester and ammonium acetate using cadmium chloride as the catalyst. The notable features of this protocol are mild reaction conditions, simplicity in operation, improved yields, and cleaner reaction profiles.

The authors declare that they have no competing interests.

YV lu caried out‐synthesis of 1,4 dihydropyridine derivatives - SRK participated in the design of the study spectral analysis, PL conceived of thye study and participated in its design and coordination. All authors read and approved the final manmuscript.

Department of Chemistry, University College for women noti asmania University, Hydevabac 500095,India YV Lu and SRK are research scholars and PL is a Proffesor.

The authors are thankful to the direct IICT for providing working space and chemicals.

1. Eynde JJV, Mayence A (2003) Molecules. 8:381 Publisher Full Text

2. Syamala M (2009) Org Prep Proc Int. 41:1 Publisher Full Text

3. Saini A, Kumar S, Sandhu JS (2008) J Sci Ind Res 67:95

4. Hopes PA, Parker AJ, Patel I (2006) Org Pro Res Dev. 10:808 Publisher Full Text

5. Domling A, Ugi I (2000) Angew Chem Int Ed. 39:3168 Publisher Full Text

6. He R, Toy PH, Lam Y (2008) Adv Syn Catal. 350:54 Publisher Full Text

7. Hantzsch A (1881) Ber 14:1637

8. Hantzsch A (1882) Jusfus Liebigs Ann Chem. 215:1 Publisher Full Text

9. Cosconati S, Marinelli L, Lavecchia A, Novellino E (2007) J Med Chem. 50:1504 PubMed Abstract | Publisher Full Text

10. Mannhold R, Jablonka B, Voigdt W, Schoenafinger K, Schravan K (1992) Eur J Med Chem 229

11. Miri R, Javidnia K, Sarkarzadeh H, Hemmateenejad B (2006) Bioorg Med Chem Lett. 14:4842 Publisher Full Text

12. Boer R, Gekeler V (1995) Drugs Future 20:499

13. Debache A, Ghalem W, Boulcina R, Belfaitah A, Rhouati S, Carboni B (2009) Tetrahedron Lett. 50:5248 Publisher Full Text

14. Sridharan V, Perumal PT, Avendano C, Manendez JC (2007) Tetrahedron. 63:4407 Publisher Full Text

15. Heravi MM, Bakhtiari K, Javadi NM, Bamoharram FF, Saeedi M, Oskooie HA (2007) J Mol Catal A. 264:50 Publisher Full Text

16. Murugan VS, Kumar RS, Chamy MP, Murugesan V (2005) J Heterocyclic Chem. 42:969 Publisher Full Text

17. Debache A, Boulcina R, Belfaitah A, Rhouati S, Carboni B (2008) Synlett 509

18. Bartoli G, Babiuch K, Bosco M, Carlone A, Galzerano P, Melchiorre P, Sambri L (2007) Synlett 2897

19. Sharma GVM, Reddy KL, Lakshmi PS, Krishna PR (2006) Synthesis 55

20. Wang LM, Sheng J, Zhang L, Han JW, Fan ZY, Tian H, Qian CT (2005) Tetrahedron. 61:1539 Publisher Full Text

21. Yadav JS, Reddy BVS, Basak AK, Narsaiah AV (2003) Green Chem. 5:60 Publisher Full Text

22. Kumar A, Maurya RM (2008) Tetrahedron. 64:3477 Publisher Full Text

23. Karade NN, Budhewari VH, Shinde SV, Jadav WN (2007) Lett Org Chem. 4:16 Publisher Full Text

24. Akbari JD, Tala SD, Daduk MF, Joshi HS (2008) Arkivoc XII:126

25. Tewari N, Dwivedi N, Tripathi RP (2004) Tetrahedron Lett. 45:9011 Publisher Full Text

26. Narsaiah AV, Nagaiah B (2010) Asian J Chem 22:8099

27. Shen L, Cao S, Wu J, Zhang J, Li H, Liu N, Qian X (2009) Green Chem. 11:1414 Publisher Full Text

28. Kumar SR, Leelavathi P (2005) J Mol Catal A 240:99

29. Kumar SR, Leelavathi P (2007) J Mol Catal A. 266:65 Publisher Full Text

30. Kumar SR, Leelavathi P (2007) Can J Chem. 85:37 Publisher Full Text

31. Venkateswarlu Y, Leelavathi P (2010) Lett Org Chem. 7:208 Publisher Full Text

32. Narsaiah AV, Basak AK, Nagaiah K (2004) Synthesis 1253

33. Baruah B, Baruah A, Prajapati D, Sandhu JS (1996) Tetrahedron Lett. 37:9087 Publisher Full Text

34. Vijender M, Kishore P, Satyanarayana B (2007) Synth Commun 37:591