Skip to main content

Bismuth nitrate-induced microwave-assisted expeditious synthesis of vanillin from curcumin



Curcumin and vanillin are the two useful compounds in food and medicine. Bismuth nitrate pentahydrate is an economical and ecofriendly reagent.


Bismuth nitrate pentahydrate impregnated montmorillonite KSF clay and curcumin were subjected to microwave irradiation.


Microwave-induced bismuth nitrate-promoted synthesis of vanillin from curcumin has been accomplished in good yield under solvent-free condition. Twenty-five different reaction conditions have been studied to optimize the process.


The present procedure for the synthesis of vanillin may find useful application in the area of industrial process development.


Curcumin, a polyphenol derived from Curcuma longa (commonly known as turmeric) is an ancient spice and therapeutic used in India for centuries to induce color in food and to treat a wide array of diseases. It has been demonstrated that curcumin has many beneficial pharmacological effects, including anti-inflammatory [1], antioxidant [2], antiviral [3], antiangiogenic [4] effects. Most importantly, curcumin possesses immense antitumorigenic effect. It prevents tumor formation in a number of animal models, including models of skin, colon, liver, esophageal, stomach, and breast cancer [58]. Curcumin has also demonstrated the ability to improve patient outcomes in Phase I clinical trials [9]. The potential application of curcumin as a chemopreventive agent in both animal and human studies has been demonstrated [10]. Very recently, curcumin has been reported [11] as a protectant against neurodegenerative diseases through chelation with iron. On the other hand, vanillin (4-hydroxy-3-methoxybenzaldehyde) is an important guaiacol derivative which is extremely selective inhibitor of aldehyde oxidase. It has been found that it acts as a substrate of this enzyme, and is metabolized by aldehyde dehydrogenase [12]. Because of the exceptionally widespread utilization of vanillin in the food, cosmetic, pharmaceutical, nutraceutical and fine chemical industries makes this compound as one of the most important aromas. As a result of these crucial properties, considerable attention has been devoted to the improvement of the production processes of vanillin [13]. We report herein an easy and extremely rapid one-step method for the preparation of vanillin from naturally occurring curcumin in the presence of bismuth nitrate under microwave irradiation (Figure 1).

Figure 1

Bismuth nitrate pentahydrate-induced simple synthesis of vanillin from curcumin under microwave irradiation.


FT-IR spectra were registered on a Bruker IFS 55 Equinox FTIR spectrophotometer as KBr discs. 1 H NMR (300 MHz) and 13 C NMR (75 MHz) spectra were obtained at room temperature with JEOL-300 equipment using d6-DMSO as solvent. Analytical grade chemicals (Sigma-Aldrich Corporation, Milwaukee, USA) were used throughout the project. Deionized water was used for the preparation of all aqueous solutions.

Results and discussion

In continuation of our research on environmentally benign reactions, we have been working on methodology development using microwave irradiation for many years. Using microwave irradiation technique, we have successfully developed several new organic methodologies which include stereoselective synthesis of β-lactams [1416], synthesis of pyrroles [1720], aza-Michael addition [21], and synthesis of quinoxalines [22]. On the other hand, we have demonstrated the catalytic activity of trivalent bismuth nitrate pentahydrate in a number of occasions. These experiments resulted in various methods that include nitration of aromatic systems [2325], Michael reaction [26], protection of carbonyl compounds [27], deprotection of oximes and hydrazones [28], Paal-Knorr synthesis of pyrroles [29], hydrolysis of amide [30], electrophilic substitution of indoles [31, 32], synthesis of α-aminophosphonates [33], and Biginelli condensation [34]. Our success in the bismuth nitrate-induced reaction has confirmed that this reagent acts as a Lewis acid. Bismuth nitrate pentahydrate is proved to be an effective reagent for the preparation of vanillin. However, Zn(NO3)2, Ca(NO3)2, LaNO3, NaNO3, ceric ammonium nitrate, and Cu(NO3)2 were also studied but without any success. Dry conditions and solvent-free methods along with commercial solvents without any purification were investigated in order to identify the best conditions for this reaction (Table 1). Reactions were performed at high temperature using Dean-Stark water separator, traditional reflux, and conventional kitchen microwave-induced methods. Solid surfaces such as florisil, silica gel, molecular sieves, montmorillonite KSF clay, and neutral alumina were used as solid support in the reaction. It has been found that montmorillonite KSF clay is the best solid surface (entries 4, 9, and 19) among all others.

Table 1 Bismuth nitrate pentahydrate-induced simple synthesis of vanillin from curcumin following Figure 1


Curcumin (1 mmol), bismuth nitrate pentahydrate (0.75 equivalent), and solid support (500 mg) were mixed in dichloromethane (4 mL) and the solvent was evaporated by rotavapor. The mixture was irradiated in kitchen microwave and the reaction was monitored by TLC. After completion of the reaction (Table 1), the reaction mixture was extracted with dichloromethane and basified with saturated aqueous sodium bicarbonate solution. The organic layer was then washed with brine and water successively, dried with anhydrous sodium sulfate. The pure product (77%) was isolated by flash chromatography over silica gel.

4-hydroxy-3-methoxybenzaldehyde (vanillin)

Light yellow crystals; Mp: 82-83°C, IR (KBr disk, cm-1): 3176, 1679, 1597, 1512, 1426, 1385, 1112, 814, 710; 1 H NMR (d6-DMSO, 300 MHz) δ: 9.86 (s, 1 H), 8.09 (m, 2 H), 7.57 (s, 1 H), 3.96 (s, 1 H). 13 C NMR (d6-DMSO, 75 MHz) δ: 190.98, 151.33, 148.08, 137.57, 128.28, 121.47, 113.05, and 57.34.


In summary, a new and simple method for the synthesis of vanillin from naturally occurring curcumin has successfully been investigated. Trivalent bismuth nitrate-induced synthesis of vanillin has successfully been carried out under various conditions and the formation of a single product (4-hydroxy-3-methoxybenzaldehyde) has been observed in variable yields. The exploratory results described herein confirm that bismuth nitrate pentahydrate is the reagent of choice for the oxidative cleavage of curcumin to vanillin in the absence of any solvent under microwave-irradiation condition (entry 19). Importantly, no aromatic nitration and rearrangement of curcumin or vanillin has been observed with bismuth nitrate. A selective oxidation of the alkene bond of curcumin to vanillin has taken place. Considering the structure of vanillin and the conditions of the experiments, one can expect further oxidation of the aromatic aldehyde group or nitration of the aromatic system might be other possibilities. However, it is interesting to note that such reactions although feasible, but vanillin is the only isolated product. On the basis of these important and selective observations, this method will find very useful applications in industrial chemistry.


  1. 1.

    Srivastava R, Srimal RC: Modification of certain inflammationinduced biochemical changes by curcumin. Ind J Med Res 1985, 81: 215–223.

    CAS  Google Scholar 

  2. 2.

    Ruby AJ, Kuttan G, Babu KD, Rajasekharan KN, Kuttan R: Anti-tumour and antioxidant activity of natural curcuminoids. Cancer Lett 1995, 94: 79–83. 10.1016/0304-3835(95)03827-J

    CAS  Article  Google Scholar 

  3. 3.

    Li CJ, Zhang LJ, Dezube BJ, Crumpacker CS, Pardee AB: Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication. Proc Natl Acad Sci USA 1993, 90: 1839–1842. 10.1073/pnas.90.5.1839

    CAS  Article  Google Scholar 

  4. 4.

    Aggarwal BB, Kumar A, Bharti AC: Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 2003, 23: 363–398.

    CAS  Google Scholar 

  5. 5.

    Chuang SE, Kuo ML, Hsu CH, Chen CR, Lin JK, Lai GM, Hsieh CY, Cheng AL: Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis. Carcinogenesis 2000, 21: 331–335. 10.1093/carcin/21.2.331

    CAS  Article  Google Scholar 

  6. 6.

    Ushida J, Sugie S, Kawabata K, Pham QV, Tanaka T, Fujii K, Takeuchi H, Ito Y, Mori H: Chemopreventive effect of curcumin on N -nitrosomethylbenzylamine-induced esophageal carcinogenesis in rats. Jpn J Cancer Res 2000, 91: 893–898. 10.1111/j.1349-7006.2000.tb01031.x

    CAS  Article  Google Scholar 

  7. 7.

    Kawamori T, Lubet R, Steele VE, Kelloff GJ, Kaskey RB, Rao CV, Reddy BS: Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res 1999, 59: 597–601.

    CAS  Google Scholar 

  8. 8.

    Huang MT, Newmark HL, Frenkel K: Inhibitory effects of curcumin on tumorigenesis in mice. J Cell Biochem Suppl 1997, 27: 26–34.

    CAS  Article  Google Scholar 

  9. 9.

    Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, Ko JY, Lin JT, Lin BR, Ming-Shiang W, Yu HS, Jee SH, Chen GS, Chen TM, Chen CA, Lai MK, Pu YS, Pan MH, Wang YJ, Tsai CC, Hsieh CY: Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001, 21: 2895–2900.

    CAS  Google Scholar 

  10. 10.

    Jiao Y, Wilkinson J, Pietsch EC, Buss JL, Wang W, Planalp R, Torti FM, Torti SV: Iron chelation in the biological activity of curcumin. Free Rad Biol Med 2006, 40: 1152–1160. 10.1016/j.freeradbiomed.2005.11.003

    CAS  Article  Google Scholar 

  11. 11.

    Minear S, O'Donnell AF, Ballew A, Giaever G, Nislow C, Stearns T, Cyert MS: Curcumin inhibits growth of Saccharomyces cerevisiae through iron chelation. Eukaryot Cell 2011, 10: 1574–1581. 10.1128/EC.05163-11

    CAS  Article  Google Scholar 

  12. 12.

    Panoutsopoulos G, Beedham C: Enzymatic oxidation of vanillin, isovanillin and protocatechuic aldehyde with freshly prepared guinea pig liver slices. Cell Physiol Biochem 2005, 15: 89–98. 10.1159/000083641

    CAS  Article  Google Scholar 

  13. 13.

    Korthou H, Verpoorte R: Vanilla, flavours and fragrances, chap 9. Springer, Berlin; 2007:203–217.

    Google Scholar 

  14. 14.

    Bandyopadhyay D, Banik BK: Microwave-induced stereoselectivity of β-lactam formation with dihydrophenanthrenyl imines via Staudinger cycloaddition. Helv Chim Acta 2010, 93: 298–301. 10.1002/hlca.200900212

    CAS  Article  Google Scholar 

  15. 15.

    Bandyopadhyay D, Yanez M, Banik BK: Microwave-induced stereoselectivity of β-lactam formation: effects of solvents. Heterocycl Lett 2011,1(special issue, July):65–67.

    Google Scholar 

  16. 16.

    Bandyopadhyay D, Rivera G, Salinas I, Aguilar H, Banik BK: Iodine-catalyzed remarkable synthesis of novel N -polyaromatic β-lactams bearing pyrroles. Molecules 2010, 15: 1082–1088. 10.3390/molecules15021082

    CAS  Article  Google Scholar 

  17. 17.

    Bandyopadhyay D, Mukherjee S, Banik BK: An expeditious synthesis of N -substituted pyrroles via microwave-induced iodine-catalyzed reaction under solventless conditions. Molecules 2010, 15: 2520–2525. 10.3390/molecules15042520

    CAS  Article  Google Scholar 

  18. 18.

    Andoh-Baidoo R, Danso R, Mukherjee S, Bandyopadhyay D, Banik BK: Microwave-induced N -bromosuccinimide-mediated novel synthesis of pyrroles via Paal-Knorr reaction. Heterocycl Lett 2011,1(special issue, July):107–109.

    Google Scholar 

  19. 19.

    Bandyopadhyay D, Banik A, Bhatta S, Banik BK: Microwave-assisted ruthenium trichloride catalyzed synthesis of pyrroles fused with indole systems. Heterocycl Commun 2009, 15: 121–122.

    CAS  Google Scholar 

  20. 20.

    Abrego D, Bandyopadhyay D, Banik BK: Microwave-induced indium-catalyzed synthesis of pyrrole fused with indolinone in water. Heterocycl Lett 2011, 1: 94–95.

    Google Scholar 

  21. 21.

    Kall A, Bandyopadhyay D, Banik BK: Microwave-induced aza-Michael reaction in water: a remarkable simple procedure. Synth Commun 2010, 42: 1730–1735.

    Article  Google Scholar 

  22. 22.

    Bandyopadhyay D, Mukherjee S, Rodriguez RR, Banik BK: An effective microwave-induced iodine-catalyzed method for the synthesis of quinoxalines via condensation of 1,2-dicarbonyl compounds. Molecules 2010, 15: 4207–4212. 10.3390/molecules15064207

    CAS  Article  Google Scholar 

  23. 23.

    Canales L, Bandyopadhyay D, Banik BK: Bismuth nitrate pentahydrate-induced novel nitration of Eugenol. Org Med Chem Lett 2011, 1: 9. 10.1186/2191-2858-1-9

    Article  Google Scholar 

  24. 24.

    Banik BK, Samajdar S, Banik I, Ng S, Hann J: Montmorillonite impregnated with bismuth nitrate: microwave-assisted facile nitration of β-lactams. Heterocycles 2003, 61: 97–100. 10.3987/COM-03-S62

    CAS  Article  Google Scholar 

  25. 25.

    Bose A, Sanjoto WP, Villarreal S, Aguilar H, Banik BK: Novel nitration of estrone by metal nitrates. Tetrahedron Lett 2007, 48: 3945–3947. 10.1016/j.tetlet.2007.04.050

    CAS  Article  Google Scholar 

  26. 26.

    Srivastava N, Banik BK: Bismuth nitrate-catalyzed versatile Michael reactions. J Org Chem 2003, 68: 2109–2114. 10.1021/jo026550s

    CAS  Article  Google Scholar 

  27. 27.

    Srivastava N, Dasgupta SK, Banik BK: A remarkable bismuth nitrate-catalyzed protection of carbonyl compounds. Tetrahedron Lett 2003, 44: 1191–1193. 10.1016/S0040-4039(02)02821-6

    CAS  Article  Google Scholar 

  28. 28.

    Banik BK, Adler D, Nguyen P, Srivastava N: A new bismuth nitrate-induced stereospecific glycosylation of alcohols. Heterocycles 2003, 61: 101–104. 10.3987/COM-03-S63

    CAS  Article  Google Scholar 

  29. 29.

    Rivera S, Bandyopadhyay D, Banik BK: Facile synthesis of N -substituted pyrroles via microwave-induced bismuth nitrate-catalyzed reaction under solventless conditions. Tetrahedron Lett 2009, 50: 5445–5448. 10.1016/j.tetlet.2009.06.002

    CAS  Article  Google Scholar 

  30. 30.

    Bandyopadhyay D, Fonseca RS, Banik BK: Microwave-induced bismuth nitrate-mediated selective hydrolysis of amide. Heterocycl Lett 2011,1(special issue, July):75–77.

    Google Scholar 

  31. 31.

    Iglesias L, Aguilar C, Bandyopadhyay D, Banik BK: A new bismuth nitrate-catalyzed electrophilic substitution of indoles with carbonyl compounds under solventless conditions. Synth Commun 2010, 40: 3678–3682. 10.1080/00397910903531631

    CAS  Article  Google Scholar 

  32. 32.

    Rivera S, Bandyopadhyay D, Banik BK: Microwave-induced bismuth nitrate-catalyzed electrophilic substitution of 7-aza indole with activated carbonyl compound under solvent-free conditions. Heterocycl Lett 2011,1(special issue, July):43–46.

    Google Scholar 

  33. 33.

    Banik A, Bhatta S, Bandyopadhyay D, Banik BK: A highly efficient bismuth salts-catalyzed route for the synthesis of α-aminophosphonates. Molecules 2010, 15: 8205–8213. 10.3390/molecules15118205

    CAS  Article  Google Scholar 

  34. 34.

    Banik BK, Reddy AT, Datta A, Mukhopadhyay C: Microwave-induced bismuth nitrate-catalyzed synthesis of dihydropyrimidones via Biginelli condensation under solventless conditions. Tetrahedron Lett 2007, 48: 7392–7394. 10.1016/j.tetlet.2007.08.007

    CAS  Article  Google Scholar 

Download references


We gratefully acknowledge the funding support from the NIH-SCORE (Grant # 2S06M008038-37).

Author information



Corresponding author

Correspondence to Bimal K Banik.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

DB performed the reactions and structure elucidation of the product. All authors read and approved the final manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Bandyopadhyay, D., Banik, B.K. Bismuth nitrate-induced microwave-assisted expeditious synthesis of vanillin from curcumin. Org Med Chem Lett 2, 15 (2012).

Download citation


  • Curcumin
  • Vanillin
  • Microwave
  • Bismuth nitrate
  • Fragrance