INTRODUCTION:

One-pot multi-component reactions (MCRs) have drawn the attention of organic chemists¹. β -Acetamido ketones are considered as versatile intermediates for the syntheses of a number of biologically or pharmacologically important compounds ^2,3. These compounds are potential precursors for the generation of β-amino alcohols⁴units in natural nucleoside antibiotics such as Nikkomycins or Neopolyoxins⁵. MCRs have proved to be remarkably successful in generating highly complex structure in a single synthetic operation⁶. Synthetic strategies, based upon one-pot multi-component reactions, are considered as powerful tools in the modern drug discovery process and allow fast, automated, and high throughput generation of organic compounds⁷.

The MCRs consist of two or more synthetic steps, which are performed without isolation of any intermediates, thus reduce time and save both energy and raw materials⁷. So one can consider, MCRs as an environment friendly process⁷. Due to their simple experimental procedures and their one-pot character they are perfectly suitable for automated synthesis. Thus MCRs have attracted considerable interest owing to their exceptional synthetic efficiency⁸. Furthermore, the synthesis of many useful synthetic building blocks have been accomplished via MCRs^9-11. Therefore, the discovery of novel MCRs is of prime importance.

The best known route for the synthesis of this class of compounds is the Dakin-West reaction¹², which is basically condensation of an α-amino acid with acetic anhydride in the presence of a base to yield α-acetamido ketones via an azolactone intermediate¹³.

Recently, other synthetic methods have been used for the formation of β-acetamido ketones through the multi-component condensation of aryl aldehydes, acetophenone and acetyl chloride in presence of a Lewis or Bronsted acid catalysts such as sulfuric acid absorbed on silica gel^14,15, BiOCl¹⁶, ZrOCl₂.8H₂O¹⁷, iodine¹⁸, CoCl₂^19,20, CeCl₃.7H₂O²¹, Nafion-H²², Sc(OTf)₃²³, hetero polyacids^24-27, NaHSO₄.H₂O²⁸, FeCl₃.6H₂O²⁹ and sulfated zirconia³⁰.

The synthesis of β-acetamido ketones have also been reported by the condensation of an aryl aldehyde, acetophenone and acetyl chloride in acetonitrile in the presence of montmorillonite K-10 clay³¹, Cerium(IV) sulphate³² and Silica supported perchloric acid³³. Although, the reported methods are valuable, the time for the completion of this transformation is unusually long. Therefore, the introduction of a new, cheap and efficient catalyst to affect this multi-component reaction is still a desired goal.

A perusal of the literature reveals that Cu(II) chloride has been widely used for the additition reaction of bicyclic olefins³⁴, Knoevenagel Condensations of aldehydes and ketones³⁵, Friedel-Craft’s alkylation³⁶, organic oxidative reactions³⁷, animation reactions of aryl halides³⁸, Enantioselective Hetero-Diels–Alder Reactions³⁹ and as a Lewis Acid^40,41. Prompted by these reports, we herein report an efficient and convenient procedure for the synthesis of β-acetamido ketones using Copper (II) chloride as a catalyst.

MATERIALS AND METHODS:

All melting points were determined by Open Capillary Method and are uncorrected. IR spectra were recorded on Perkin-Elmer FTIR-2000 spectrometer (KBr pallet). The ¹H NMR spectra were recorded on a Bruker DRX-300 MHz spectrometer in CDCl₃ using TMS as an internal standard from CDRI, Lucknow. Chemical shifts are expressed in δ (ppm) values with respect to TMS. All chemicals were purchased from Merck (India) Limited and used as received.

General Procedure for the preparation of β-Acetamido ketones:

A solution of aryl aldehyde (4 mmol), acetophenone (4 mmol), acetyl chloride (1.2 mL), acetonitrile (6 mL) and copper chloride dihydrate (68 mg, 10 mol %,) was heated at 80-85^oC under reflux. The progress of the reaction was periodically monitored by TLC. After completion of the reaction, the mixture was filtered and the filterate poured in 50 mL ice-water and recrystallized from ethylacetate/n-hexane to give the pure producst as off white to pale yellow solids. The product so obtained was further purified by Column Chromatograohy to obtain analytically pure products. The purity of products was confirmed by TLC, NMR, and IR spectral analysis. The data are reported below and almost matches with that of reported values.

SPECTRAL DATA ON PRODUCTS:

β- Acetamido- β-(phenyl)propiophenone (Entry 1, Table 3)

IR data (cm^-1, KBr):

3284, 3090, 1688, 1646, 1556, 1446, 1362, 1301, 1198, 990, 752, 697, 620.

¹H NMR data (CDCl₃, 300 MHz):

δ_H: 2.03(s, 3H,CH₃), 3.46(dd, 1H, CH₂), 3.75(dd, 1H, CH₂), 5.52-5.59(m, 1H, methylene H), 6.85( brd, 1H, NH), 7.21-7.88(m, 8H, ArH), 7.90(d, 2H, ArH)

β- acetamido- β-(3-nitrophenyl)propiophenone (Entry 2, Table 3):

IR data (cm^-1, KBr):

3290, 3073, 1690, 1650, 1527, 1351, 1298, 753, 688, 622.

¹H NMR data (CDCl₃, 300 MHz):

δ_H: 2.06(s, 3H,CH₃), 3.83(dd, 1H, CH₂), 3.75(dd, 1H, CH₂), 5.63-5.67(m, 1H, methylene H), 7.07( brd, 1H, NH), 7.43-7.50(m, 3H, ArH), 7.61(t, 1H, ArH), 7.72(d, 1H, ArH), 7.90(d, 1H, ArH), 8.09(d, 1H, ArH), 8.22(s, 1H, ArH).

Spectroscopic data for rest of the compounds were identical with the literature values^{17, 22, 29, 31}

RESULT AND DISCUSSION:

The MCRs for the preparation of β-acetamido ketones were carried out under reflux at 80-85^oC as shown in Scheme 1.

Scheme 1

In order to discern the catalytic activity of Copper(II) chloride, the reaction of 4-chloro benzaldehyde (4 mmol), acetophenone (4 mmol), acetyl chloride (1.2 mL) and acetonitrile (6 mL) was choosen as model reaction. Various reactions were carried out with different amount of catalyst in order to optimize the reaction conditions (Table 1). It is clear from Table 1 that the best result was obtained with 10 mol% of the catalyst (Entry 5b) under reflux conditions.

Table 1: Effect of Catalyst loading and Temperature for the synthesis of β-Acetamido- β-(4-chlorophenyl)Propiophenone

Entry	Temperature Condition	Catalyst	Time (h)	Yield (%)^a
1a.	Room Temperature	NIL	24	10
1b	Reflux	NIL	24	15
2a	Room Temperature	1 mol% CuCl₂.2H₂O	20	22
2b	Reflux	1 mol% CuCl₂.2H₂O	20	30
3a.	Room Temperature	2 mol% CuCl₂.2H₂O	12	30
3b	Reflux	2 mol% CuCl₂.2H₂O	12	40
4a	Room Temperature	5 mol% CuCl₂.2H₂O	5	43
4b	Reflux	5 mol% CuCl₂.2H₂O	5	60
5a	Room Temperature	10 mol% CuCl₂.2H₂O	3	65
5b	Reflux	10 mol% CuCl₂.2H₂O	3	90
6a	Room Temperature	15 mol% CuCl₂.2H₂O	3	74
6b	Reflux	15 mol% CuCl₂.2H₂O	3	90

^aisolated yields after work up.

Table 2: Study of Solvent effects for the synthesis of β-Acetamido-β-(4-chlorophenyl)-Propiophenone

Entry	Solvent	Temperature Condition	Time (h)	Yield (%)^b
1.	THF	Reflux	3	35
2.	CHCl₃	Reflux	3	54
3.	EtOH	Reflux	3	74
4.	CH₃CN	Reflux	3	90
5.	MeOH	Reflux	3	63

^bisolated yields.

Table 3. Synthesis of β-Acetamido Ketones catalyzed by Copper(II) chloride dihydrate

Entry

Aldehyde

Acetophenone

Product

Time

(hr)

Yeild^c,d

(%)

M.p(^oC) Found^e

(Rep.)

101-103

(102-104)²²

132-135

(130-132)²⁸

144-146

(147-149)²²

3.5

146-149

(148-149)³¹

2.5

113-115

(114-115)¹⁷

147-149

(148-150)²⁹

110-112

(112)¹⁷

108-111

(110-112)¹⁷

^cIsolated yields after work up.

^dAryl aldehyde (4 mmol), acetophenone (4 mmol), acetyl chloride (1.2 mL) and acetonitrile (6 mL) at 80-85^oC.

^eAll melting pointss were determined in sealed capillary.

CONCLUSION:

In summary, we have shown that Copper(II) chloride dihydrate is an inexpensive, efficient, and environmental friendly catalyst for the synthesis of various β-acetamido ketones in high yields compared to other catalysts as it takes less time. The products obtained are clean and devoid of any undesired impurities. The cheapness and common abundance of the catalyst make it a versatile method for the syntheses of β-acetamido ketones. The catalyst is justified from environmental point of view since it produces little waste.

ACKNOWLEDGEMENT:

Mr Amiya Shekhar thanks the Director, ISM, Dhanbad for the award of Senior Research Fellowship. Mr Rajat S. Pathak is grateful to Head, Department of Applied Chemistry, ISM, Dhanbad for permitting to carry out this work in the department.

REFERENCES:

1. (a) Terret, N. K., Gardner, M., Gordon, D.W., Kobylecki, R. J. and Steele, J. Tetrahedron 1995; 51: 8135, (b) Armstrong, R.W., Combs, A. P., Tempest, P. A., Brown, S. D. and Keating, T. A. Acc. Chem. Res. 29; 1996: 123, (c) Thomson, L. A. and Ellman, J. A. Chem. Rev. 96; 1996: 555, (d) Tietze, L. F. and Lieb, M. E. Curr. Opin. Chem. Biol. 2; 1998: 363, (e) Domling, A. and Ugi, I. Angew. Chem. Int. Edn. 39; 2000: 3168.

2. Casimir, J. R., Turetta, C., Ettouati, L. and Paris, J. Tetrahedron Lett., 36; 1995 : 4797.

3. Godfrey, A. G., Brooks, D. A., Hay, L. A., Peters, M. J., McCarthy, R. and Mitchell, D. J. Org. Chem., 68; 2003 : 2623.

4. (a) Barluenga, J., Viado, A. L., Aguilar, E. Fustero, S. and Olano, B. J. Org. Chem. 58; 1993: 5972–5975, (b) Enders, D., Moser, M., Geibel, G. and Laufer, M. C. Synthesis. 2004: 2040–2046.

5. (a) Da-hn, U., Hagenmaier, H., Ho¨ hne, H., Ko¨nig, W. A., Wolf, G., Za¨hner, H. Arch. Microbiol. 107; 1976: 249–256, (b) Kobinata, K., Uramoto, M., Nishii, M., Kusakabe, H., Nakamura, G.,Isono, K. Agric. Biol. Chem. 44; 1980: 1709–1711.

6. (a) Elibracht, P. and Schimdt, A. Chem. Rev. 99; 1999: 3329, (b) Ugi, I. Pure Appl. Chem. 77; 2001: 187, (c) Bagley, M. C., Cale, J. W. and Bower, J. Chem. Commun. 2002: 1682, (d) Dallinger, D., Gorobets, N. Y., Kappe, C. O. Org. Lett. 5; 2003: 1205,.(e) Bora, U., Saikia, A. and Boruah, R. C. Org. Lett. 5; 2003: 435.

7. Weber, L., Curr. Med. Chem. 9; 2002: 1241.

8. Fayol, A., and Zhu, J. Org. Lett. 7; 2005: 239.

9. Ugi, I., Werner, B. and Domling, A. Molecules 8; 2003: 53.

10. Domling, A. Curr. Opin. Chem. Biol. 4; 2000: 318.

11. Weber, L., Drug Discovery Today. 7; 2002: 143.

12. Dakin, H. D. and West, R. J. Biol. Chem. 78; 1928: 745.

13. Buchanam, G. L. Chem. Soc. Rev. 17; 1988: 91.

14. Khodaei, M. M., Khosropour A. R. and Fattahpour, P. Tetrahedron Lett. 46; 2005: 2105.

15. Yakaiah, T., Venkat Reddy, G., Lingaiah, B. V. P., Narsaiah, B., and Shanthan Rao, P. Synth. Commun. 35; 2005: 1307.

16. Ghosh, R., Maity, S. and Chakraborty, A. Synlett. 2005: 115.

17. Ghosh, R., Maity, S., Chakraborty, A., Chakraborty, S., Mukherjee, A. K. Tetrahedron, 62; 2006: 4059.

18. Das, B., Reddy, K. R., Ramu, R., Thirupathi, P. and Ravikanth, B. Synlett. 11; 2006: 1756.

19. Bhatia, B., Reddy, M. M. and Iqbal, J. J. Chem. Soc. Chem. Commun. 1994: 713.

20. Mukhopadhyay, M., Bhatia, B. and Iqbal, J. Tetrahedron Lett. 38; 1997: 1083.

21. Khan, A. K., Choudhury, L. H., Parvin, T. and Asif Ali, M. Tetrahedron Lett. 47; 2006: 8137.

22. Yakaiah, T., Venkat Reddy, G., Lingaiah, B. V. P., Narsaiah, B., and Shanthan Rao, P. ARKIVOK. (xiii); 2007: 227.

23. Pandey, G., Singh, R. P., Garg, A. and Singh, V. K. Tetrahedron Lett. 46; 2005: 2137.

24. Nagarapu, L., Kantevari, S., Cheemalapati, V. N., Apuri, S. N. and Kumari, V. J. Mol. Cat. A: Chem. 264 ; 2007 : 22.

25. Rafiee, E., Torka, F. and Joshaghani, M. Bioorg. Med. Chem. Lett. 16; 2006: 1221.

26. Rafiee, E., Shahbazi, F., Torka, F. and Joshaghani, M. J. Mol. Catal. A: Chem. 242; 2005: 129.

27. Heravi, M. M., Ranjbar, L., Derikvand, F., Bamoharram, F. F. Catal. Commun. 8; 2007: 289.

28. Hassankhani, M., Maghsoodlou, M. T., Khorassani, S. M. H., Mahdiabad, H. H. and Marandi G. ARKIVOK (ii); 2008: 134.

29. Khan, A. T., Parvin, T. and Choudhury, L. H. Tetrahedron, 63; 2007: 5593.

30. Das, B., Krishnaiah, M., Lxminarayana, K., and Reddy, K. R. J. Mol. Catal. A: Chem. 270; 2007: 284.

31. Bahulayan, D. Das, S. K. and Iqbal J. J. Org. Chem. 68; 2003: 5735.

32. Selvam, N. P. and Perumal, P. T. ARKIVOK 10; 2009: 265.

33. Masoud, N. E., Morteza, M. and Tahere, G. Chin. J. Chem. 29; 2011: 123.

34. Adderley, C. J.R., Nebzydosky, J. W., Battiste, M. A., Baker, R. and Halliday, D. E. Tetrahedron Lett. 12; 1971: 3545.

35. Attanasi, O., Fillippone, P. and Mei, A. Synth. Commun. 13; 1983: 1203.

36. Kanwar, D., Rani, R.., Agarwal, J. and Peddinti, R. K. Ind. J. Chem. 49(B); 2010: 1290.

37. Puzari, A. and Jubaraj, B. J. Mol. Catal. A: Chem. 187; 2002: 189.

38. Gajare, A. S., Toyota, K. and Yoshifuji, M. Chem Commun(Camb). 7; 2004: 1994.

39. Evans, D. A., Johnson, J. S. and Janey, J. M. Angew. Chem. Int. Edn. 37; 1998: 3372.

40. Evans, D. A., Rovis, T. and Johnson, J. S. Pure Appl. Chem. 71; 1999: 1407.

41. Cooke, M., Clark, J. and Breeden, S. J. Mol. Catal. A: Chem. 303; 2009: 132.

Received on 15.06.2011 Modified on 10.07.2011

Asian J. Research Chem. 4(12): Dec., 2011; Page 1930-1934