An efficient method for Synthesis of flavanone

Nikunj Patadiya¹*, Vipul Vaghela²

¹Research Scholar, Department of Pharmaceutical Chemistry,

A.R College of Pharmacy and G.H Patel Institute of Pharmacy, Vallabh Vidhyanagar, Anand, Gujarat, India.

²Professor, Department of Pharmaceutical Chemistry,

A.R College of Pharmacy and G.H Patel Institute of Pharmacy, Vallabh Vidhyanagar, Anand, Gujarat, India.

*Corresponding Author E-mail: nikunj20899@gmail.com

ABSTRACT:

The main aim of present work is to develop efficient method for synthesis of flavanone. For the synthesis of flavanone acid and based catalyzed methods were tried in which base catalyzed methods proved ineffective. No reaction was take place upon using HCl, H₂SO_4, glacial acetic acid and p-TSA as catalyst. In presence of methane sulphonic acid as catalyst, flavanone was formed in lower yield. Mixture of sulfuric acid and glacial acetic acid proved better catalyst than previous ones and leads to 65% yield. The reaction condition parameters effects on product yield were carried out. Ratio of sulfuric acid and glacial acetic acid in (4:1) proved highly beneficial. In methanol product yield was higher compare to other selected solvents. Solvent quantity effect on yield was also screened which proved that 50ml solvent necessary for 0.004mol of reactant.  From which 90˚C temperature was highly favorable to reaction that takes minimum 6hr to complete the reaction. So, in this study we developed new efficient method for synthesis of flavanone.

KEYWORDS: 2’ hydroxyl chalcone, Flavanone, Acid catalyzed cyclisation.

INTRODUCTION:

Flavanones are the group of compounds which widely distributed in nature. Flavanone and its derivatives are well-known for variety of biological activities with high potency and lower toxicity. Flavanone also known as 2-phenyl chroman-4-one. Flavanone is an isomer of 2’hydroxy chalcone. Flavanone contains 3 rings in the structure.

2’hydroxy chalcone is synthesized by Claisen–Schmidt condensation between o-hydroxy acetophenone and benzaldehyde.^1-18 Most widely flavanone synthesized from 2’-hydroxy chalcone by acid, based and inorganic salt catalyst or microwave assisted techniques. Methane sulfonic acid¹⁹, glacial acetic acid²⁰, phosphoric acid²¹ and hydrochloric acid²² generally used as acid catalyst in synthesis of flavanone.  triethyl amine²², aniline²³ and KOH²⁴ generally used as base catalyst. Sodium acetate widely used as catalyst in synthesis of flavanone from 2’hydroxy chalcone¹⁸. Conversation of flavanone from 2’hydroxy chalcone in presence of variety of solid support catalyst like MgO²⁵, ZnO²⁵, CoIII (L1) (OH)²² and H[bimBF4]²² also reported. Microwave assisted reaction also reported for flavanone synthesis. Flavanone used as procuresses for 3-benzylidene-2-phenylchroman-4-one.^26-27

CHEMISTRY:

The synthesis of flavanone was carried out from 2’hydroxy chalcone by using acid and base catalyzed mechanism.  Variety of acids like hydrochloric acid, sulfuric acid, orthophosphoric acid, glacial acetic acid, methane sulfuric acid and mixture of sulfuric acid and glacial acetic acid was used as catalyst. NaOH and KOH was used as base catalyst for synthesis of flavanone. Methods which give higher yield selected for optimization. In optimization step, study of various factors on yield like temperature, amount of catalyst, reaction time etc. were carried out.

Table 1. Methods were tried for the synthesis of Flavanone

Sr No.	Catalyst	Solvent	Reaction time (hr)	Temperature (˚C)	%yield
1	HCl	Methanol	24	90	No Reaction
2	H2SO4	Methanol	24	90	No Reaction
3	Ortho phosphoric acid	Methanol	24	90	*
4	Glacial acetic acid	Methanol	24	90	No Reaction
5	Methane sulfonic acid	Methanol	12	90	40
6	p-TSA	Methanol	72	90	No Reaction
6	KOH	Methanol	72	28	No Reaction
7	NaOH	Methanol	72	28	No Reaction
8	H2SO4 + Glacial Acetic acid	Methanol	12	90	65

*By product formation

Table 2. Effect of catalysts amount, solvent, amount of solvent, temperature and reflux time on product (flavanone) yield.

Sr No.	H2SO4 (ml)	Glacial Acetic acid (ml)	Solvent	Amount of Solvent (ml)	Temperature (˚C)	Reflux time (hr)	%yield
1	5	1	Methanol	50	90	12	No Reaction
2	6	1	Methanol	50	90	12	No Reaction
3	7	1	Methanol	50	90	12	25.12
4	8	1	Methanol	50	90	12	30.70
5	9	1	Methanol	50	90	12	*
6	10	1	Methanol	50	90	12	*
7	5	2	Methanol	50	90	12	No Reaction
8	6	2	Methanol	50	90	12	No Reaction
9	7	2	Methanol	50	90	12	50.12
10	8	2	Methanol	50	90	12	75.9
11	9	2	Methanol	50	90	12	*
12	10	2	Methanol	50	90	12	*
13	5	3	Methanol	50	90	12	No Reaction
14	6	3	Methanol	50	90	12	No Reaction
15	7	3	Methanol	50	90	12	60.45
16	8	3	Methanol	50	90	12	64.41
17	9	3	Methanol	50	90	12	*
18	10	3	Methanol	50	90	12	*
19	8	2	Ethanol	50	90	12	67.2
20	8	2	IPA	50	90	12	No Reaction
21	8	2	THF	50	90	12	No Reaction
22	8	2	DCM	50	90	12	No Reaction
23	8	2	ACN	50	90	12	No Reaction
24	8	2	Methanol	10	90	12	1.23
25	8	2	Methanol	20	90	12	13.78
26	8	2	Methanol	30	90	12	40.12
27	8	2	Methanol	40	90	12	67.54
28	8	2	Methanol	60	90	12	75.12
29	8	2	Methanol	70	90	12	75.16
30	8	2	Methanol	50	70	12	40.25
31	8	2	Methanol	50	85	12	58.74
32	8	2	Methanol	50	95	12	68.25
33	8	2	Methanol	50	100	12	58.12
34	8	2	Methanol	50	105	12	54.57
35	8	2	Methanol	50	110	12	50.56
36	8	2	Methanol	50	90	3	5.23
37	8	2	Methanol	50	90	4	20.12
38	8	2	Methanol	50	90	5	62.45
39	8	2	Methanol	50	90	6	76.8
40	8	2	Methanol	50	90	7	76.8
41	8	2	Methanol	50	90	8	76.8

*By product formation; Amt. of 2’hydroxy chalcone: 0.04 mol

Acid catalyzed cyclisation of 2’hydroxy chalcone was carried out using concentrated sulfuric acid and glacial acetic acid in appropriate concentration. Other acids show no effect and byproduct formed upon using orthophosphoric acid. Base catalyzed cyclisation was not effective for synthesis of flavanone. The ratio of concentrated sulfuric acid and glacial acetic acid (4:1) was given best results. Methanol proved beneficial solvent compare to ethanol, ACN, DCM, IPA and THF. The amount of solvent highly affects the yield of product. 90˚C was proved as most suitable temperature for conversation of 2’hydroxy chalcone. For the completion of reaction minimum 6h was required, further heating was not effective.

Scheme 1. Synthesis of flavanone from 2’hydroxy chalcone.

CONCLUSION:

Varieties of methods were tried for synthesis of flavanone. Based catalyst methods proved ineffective. Varieties of acids catalyst were screened for synthesis of flavanone. Hydrochloric acid, sulfuric acid, p-TSA and glacial acetic acid proved ineffective. Upon using methane sulfonic acid as catalyst, formation of flavanone occurred in lower yield. Presence of orthophosphoric acid as catalyst, byproduct was formed. The mixture of concentrated sulfuric acid and glacial acetic acid proved excellent catalyst. Ratio of sulfuric acid and glacial acetic acid (4:1) proves beneficially for synthesis. At 90˚C, best results were obtained. Upon using methanol as solvent, higher yield obtained. Amount of solvent also affects the product yield. Minimum 6h was required to complete reaction. So optimized method developed which was efficient to synthesized flavanone in high amount and extra purity.

EXPERIMENTAL:

Chemistry:

General:

All purchased chemicals were of analytical grade and used without further purification. The synthesis of flavanone was carried out as per the procedure detailed in Scheme 1. The progress of the reactions was monitored by thin‐layer chromatography analysis (Silica gel G60 F254; Merck). Melting points of the synthesized compounds were determined in open capillary tubes using Veego Melting Point Apparatus model VMP-D. Infrared spectra were recorded on Perkin Elmer spectrum GX FTIR spectrophotometer using KBr discs. 1H-NMR was recorded on Bruker Advance–II NMR-400MHz instrument using DMSO as a solvent and tetra methyl silane (TMS) as internal standard. Mass spectra were recorded on LCQ Fleet and TSQ quantum surveyor plus HPLC system spectrophotometer.

General procedure for the synthesis of 2-phenyl chroaman-4-one (flavanone) 2

Dissolve 2’ hydroxy Chalcone (0.04 mol, 8.96gm) in 50 ml methanol add 2 ml of glacial acetic acid dropwise. Add 8ml of concentrated sulfuric acid 8ml in solution drop wise with care and reflux solution for 6hr at 90˚C. Put solution overnight and add water into it. Filter the solution and collect precipitate of crude flavanone. Recrystallized product using methanol. Colorless solid; %yield 76.8%(6.88gm); mp 77-79˚C; IR (KBr, cm^-1 ) vmax: 3062.42 (Aromatic C-H), 2896.50 (Aliphatic C-H), 1689.51 (C=O), 1480.66 (C=C), 1227.80 (C-O); ¹H NMR (400 MHz, DMSOd₆) δ ppm: 2.814-2.863 (dd, 1H), 3.244-3.285 (ds, 1H), 5.666-5.705 (dd, 1H), 7.374-7.790(m, 9H, Aromatic CH); MS (ESI+): m/z 223[M^-], 224[M⁺], 225[M⁺¹].

REFERENCES:

1. Bhagyesh Baviskar, Sureshbhi Patel, Bhushan Baviskar, SS Khadabadi, Mahendra Shiradkar. Design and Synthesis of Some Novel Chalcones as Potent Antimicrobial Agent. Asian J. Research Chem. 2008; 1(2): 67-69.

2. Bhaskar S. Dawane, Baseer M Shaikh, Namdev T. Khandare, Gajanan G. Mandawad, Santosh S. Chobe, Shankaraiah G. Konda. Synthesis of Some Novel Substituted Pyrazole Based Chalcones and Their In-Vitro Antimicrobial Activity. Asian J. Research Chem. 2010; 3(1): 90-93.

3. H.V. Shahare, G.R. Pawar, S.S. Patil, P.D. Patil. Synthesis and Biological Evaluation of New Chalcone Analogs. Asian J. Research Chem. 2011; 4(2): 237-240.

4. Gopi C., Dhanaraju M. D. Synthesis, Characterization and Anti-Microbial Evaluation of Derivative of Chalcone. Asian J. Research Chem. 2011; 4(2): 181-182.

5. Gondu Eswara Rao, S.A. Rahaman, A. Prameela Rani, Ch. M.M. Prasada Rao. Synthesis, Characterization and Antimicrobial Activity of Novel Chalcones from 1-[4-(1H-imidazol-1-yl) Phenyl] Ethanone. Asian J. Research Chem. 2013; 6(7): 687-689.

6. Pushkar Pratap Singh, B. Jayalakshmi, N. Senthil Kumar. Synthesis, Characterization and Antimicrobial Evaluation of Some New Chalcones. Asian J. Research Chem. 2013; 6(12): 1133-1136.

7. Suha K. Al-Mosawi, Hanan A. Al-Hazam, Abbas F. Abbas. Synthesis, Characterization and Biological Study of Some Chalcones derived from Terphthaldehyde. Asian J. of Research Chem. 2019; 12(3): 153-156. DOI: 10.5958/0974-4150.2019.00031.2

8. Yeonjoong Y, Hwang SA and Yoon H. 1H and 13C NMR spectral assignments of 2-hydroxychalcones. Magn. Reson. Chem. 2013; 51: 364–370.

9. Laxmi Lal Dangi, Mangal S. Dulawat, Parul Tiwari, Shiv Singh Dulawat. New substituted m-Phenoxy chalcones; their synthesis by microwave irradiation and antifungal activity. Asian J. Research Chem. 2013; 6(5): 461-463.

10. Sharma N and Joshi YC. Synthesis of substituted chalcones under solvent–free microwave irradiation conditions and their antimicrobial evaluation. International Journal of Pharmacy and Pharmaceutical Sciences. 2012; 4(4): 436-439.

11. Shima H. M. E. Ketabforoosh et al. Synthesis and Anti-Cancer Activity Evaluation of New Dimethoxylated Chalcone and Flavanone Analogs. Arch. Pharm. Chem. Life Sci. 2014; 347: 1–8.

12. M. Safavi et al. Halogenated flavanones as potential apoptosis-inducing agents: Synthesis and biological activity evaluation. European Journal of Medicinal Chemistry. 2012; 58: 573-580.

13. Y. Murti and P. Mishra. Synthesis and Evaluation of Flavanones as Anticancer Agents. Indian Journal of Pharmaceutical Sciences. 2014; 76(2): 163-166.

14. Cabrera M., Simoens M., Falchi G. and Lavaggi M.L. Synthetic chalcones, flavanones, and flavones as antitumoral agents: Biological evaluation and structure activity relationships. Bioorganic and Medicinal Chemistry. 2007; 15: 3356–3367.

15. Albogami A.S., Karama U., Amousa A.A, Khan M., Al-Mazroa S.A and Alkhathlan A.Z. Simple and Efficient One Step Synthesis of Functionalized Flavanones and Chalcones. Orient. J. Chem. 2012; 28(2): 619-626.

16. Borse SL. PhD. Thesis. Microwave Assisted Synthesis of Substituted Flavonoids and Pharmacological Evaluation.” Shri Jagdish Prasad Jhabarmal Tibrewala University, 2010.

17. Thornton M.T. PhD. Thesis. Synthesis of flavonoids and flavonoid-based designed multiple ligands for hypertension. Deakin University January, 2013, 32-33.

18. K. Ishwar Bhat, Ranee Kumari, Abhishek Kumar, Pankaj Kumar. Synthesis of Some Novel Flavanones and Evaluation of Antioxidant Activities. Research J. Pharm. and Tech. 2019; 12(5): 2141-2144 DOI: 10.5958/0974-360X.2019.00355.X

19. Pramod Kulkarni, Pradip Wagh and Pudukulathan Zubaidha. An Improved and Eco-Friendly Method for the Synthesis of Flavanone by the Cyclization of 2’-Hydroxy Chalcone using Methane Sulphonic Acid as Catalyst. Chemistry Journal. 2012; 2(3): 106-110.

20. Preet Anand and Baldev Singh. Synthesis and evaluation of novel carbamate-substituted flavanone derivatives as potent acetylcholinesterase inhibitors and anti-amnestic agents. Med Chem Res. 2013; 22: 1648–1659. doi 10.1007/s00044-012-0162-3.

21. Yuh-Meei Lin, Yasheen Zhou, Michael T. Flavin, Li-Ming Zhou, Weiguo Niea and Ching Chen. Chalcones and Flavonoids as Anti-Tuberculosis Agents”, Bioorganic & Medicinal Chemistry. 2002; 10: 2795–2802.

22. Yogesh Murti and Pradeep Mishra. Flavanone: A Versatile Heterocyclic Nucleus. International Journal of ChemTech Research. 2014; 6(5): 3160-3178.

23. Srinivasu V. N. Vuppalapati, Likai Xia, Naushad Edayadulla, Yong Rok Lee. Mild and Efficient One-Pot Synthesis of Diverse Flavanone Derivatives via an Organocatalyzed Mannich-Type Reaction. Synthesis. 2014; 46: 465–474.

24. Moorthy N.S.H.N, Singh R.J, Singh H.P, and Gupta S.D. Synthesis, Biological Evaluation and In Silico Metabolic and Toxicity Prediction of Some Flavanone Derivatives. Chem. Pharm. Bull. 2006; 54(10): 1384-1390.

25. S. Saravanamurugan, M. Palanichamy, Banumathi Arabindoo, V. Murugesan. Solvent free synthesis of chalcone and flavanone over zinc oxide supported metal oxide catalysts. Catalysis Communications. 2005; 6: 399-403.

26. Elzbieta Budzisz et al. Biological Evaluation of 3-Benzylidenechromanones and Their Spiropyrazolines-Based Analogues. Molecules. 2020; 25: 1613.

27. Lincy Joseph, Mathew George. Analgesic and Anti-Oxidant Activities of Certain (E)-3 Arylidene Flavanones Synthesized by One Pot Method. Asian Journal of Research in Chemistry. 2009; 2(3): 318-321.

Received on 29.01.2022                    Modified on 07.04.2022

Accepted on 24.05.2022                   ©AJRC All right reserved

Asian J. Research Chem. 2022; 15(3):221-224.

DOI: 10.52711/0974-4150.2022.00039