Synthesis and characterization of unsaturated diacyl and alkyl-acyl piperazine derivatives

The aim of this study is to obtain new unsaturated piperazine compounds by the reactions of piperazine(1a) and piperazine derivatives (1b–1d) with acylation reactive groups (2a–2j). Methacryloyl piperazine (1b) wassynthesized from the reaction of methacrylic anhydride with piperazine (1a). Acyl chlorides (2b–2d) were prepared from the reaction of thionyl chloride with carboxylic acids (3a–3c) obtained as a result of the reaction with malonic acid and suitable aldehyde (5-methylfuran-2-carbaldehyde for 3a, cinnamaldehyde for 3b, and thiophene-2-carbaldehyde for 3c), respectively, by literature methods. Acyl chlorides 2e and 2f were obtained from the reaction of commercially purchased carboxylic acids 3d and 3e with thionyl chloride. Acyl chlorides (2g–2j) were synthesized from the reaction of thionyl chloride with carboxylic acids (3d–3g) transformed from hydrolyzation of esters (4a–4d) obtained as a result of the reaction of triethyl phosphonoacetate with a suitable ketone (acetophenone for 4a, benzophenone for 4b, 1- (5-methylfuran-2-yl)ethan-1-one for 4c, and 1-(thiophen-2-yl)ethan-1-one for 4d), respectively, by literature methods. Unsaturated piperazine derivatives 5a and 5b were obtained from the reaction of 1b with 2b and 2e, respectively.In addition, from the reaction of 1b and acyl chlorides (2b–2j), unsaturated piperazines (5c–5k) were synthesized in medium to good yields (63%–84%). Also, 5l–5g and 5r–5w were obtained from the reaction of allyl piperazine (2c) and cinnamyl piperazine (2d) with acyl chlorides (2a–2f).

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1. Dua R, Shrivastava S, Sonwane SK, Shrivastava SK. Pharmacological significance of synthetic heterocycles scaffold: a review. Advances in Biological Research 2011; 5: 120-144.
2. Rachakonda V, Alla M, Kotipalli SS, Ummani R. Design, diversity-oriented synthesis and structure activity relationship studies of quinolinyl heterocycles as antimycobacterial agents. European Journal of Medicincal Chemistry 2013; 70: 536-547.
3. Cordell GA, Quinn-Beattie ML, Farnsworth NR. The potential of alkaloids in drug discovery. Pytotheraphy Research 2001; 15 (3): 183-205.
4. Khan I, Ibrar N, Abbas N, Saeed A. Recent advances in the structural library of functionalized quinazoline and quinazolinone scaffolds: synthetic approaches and multifarious applications. European Journal of Medicinal Chemistry 2014; 76: 193-244.
5. Yang SM, Malaviya R, Wilson LJ, Argentieri R, Chen X et al. Simplified staurosporine analogs as potent JAK3 inhibitors. Bioorganic & Medicinal Chemistry Letters 2007; 17: 326-331.
6. Nicolaou KC, Pfefferkorn AJ, Roecker GQ, Cao SB, Mitchell HJ. Natural product-like combinatorial libraries based on privileged structures. 1. General principles and solid-phase synthesis of benzopyrans. Journal of American Chemical Society 2000; 122: 9939-9953.
7. Stegmeier F, Warmuth M, Sellers WR, Dorsch M. Targeted cancer therapies in the twenty-first century: lessons from imatinib. Clinical Pharmacology & Therapeutics 2010; 87: 543-552.
8. Lue TF. Erectile dysfunction. New England Journal of Medicine 2000; 342: 1802-1813.
9. Vacca JP, Dorsey BD, Schleif WA, Levin RB, McDaniel SL et al. L-735,524: An orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proceedings of the National Academy of Sciences of the USA 1994; 91: 4096-4100.
10. Burka JM, Bower KS, Vanroekel RC, Stutzman RD, Kuzmowych CP et al. The effect of fourth-generation fluoroquinolones gatifloxacin and moxifloxacin on epithelial healing following photorefractive keratectomy. American Journal of Ophthalmology 2005; 140: 83-87.
11. Harish KP, Mohana KN, Mallesha L, Kumar BNP. Synthesis of novel 1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2- yl]-piperazine derivatives and evaluation of their in vivo anticonvulsant activity. European Journal of Medicinal Chemistry 2013; 65: 276-283.
12. Chaudhary P, Kumar R, Verma AK, Singh D, Yadav V et al. Synthesis and antimicrobial activity of N -alkyl and N -aryl piperazine derivatives. Bioorganic & Medicinal Chemistry 2006; 14: 1819-1826.
13. Patel KN, Telvekar VN. Design, synthesis and antitubercular evaluation of novel series of N -[4-(piperazin-1- yl)phenyl]cinnamamide derivatives. European Journal of Medicinal Chemistry 2014; 75: 43-56.
14. Wang T, Kadow JF, Zhang Z, Yin Z, Gao Q et al. Inhibitors of HIV-1 attachment. Part 4: A study of the effect of piperazine substitution patterns on antiviral potency in the context of indole-based derivatives. Bioorganic & Medicinal Chemistry Letters 2009; 19: 5140-5145.
15. Duan YC, Ma YC, Zhang E, Shi XJ, Wang MM et al. Design and synthesis of novel 1,2,3-triazole-dithiocarbamate hybrids as potential anticancer agents. European Journal of Medicinal Chemistry 2013; 62: 11-19.
16. Pretorius SI, Breytenbach WJ, de Kock C, Smith PJ, N’Da DD. Synthesis, characterization and antimalarial activity of quinoline–pyrimidine hybrids. Bioorganic & Medicinal Chemistry 2013; 21: 269-277.
17. Meena P, Nemaysh V, Khatri M, Manral A, Luthra PM et al. Synthesis, biological evaluation and molecular docking study of novel piperidine and piperazine derivatives as multi-targeted agents to treat Alzheimer’s disease. Bioorganic & Medicinal Chemistry 2015; 23: 1135-1148.
18. Hu C, Sun ZG, Wei CX, Quan ZS. Synthesis and anticonvulsant activity of some cinnamylpiperazine derivatives. Letters in Drug Design & Discovery 2010; 7 (9): 661-664.
19. Kapanda CN, Masquelier J, Labar G, Muccioli GG, Poupaert JH et al. Synthesis and pharmacological evaluation of 2,4-dinitroaryldithiocarbamate derivatives as novel monoacylglycerol lipase inhibitors. Journal of Medicinal Chemistry 2012; 55 (12): 5774-5783.
20. Srikanth RT, Suryakiran N, Narasimhulu M, Ramesh D, Chinni MK et al. Semi-synthesis and bio-evaluation of polybrominated diphenyl ethers from the sponge Dysidea herbacea. Bioorganic & Medicinal Chemistry Letters 2012; 22 (14): 4900-4906.
21. Hatnapure GD, Keche AP, Rodge AH, Birajdar SS, Tale RH et al. Synthesis and biological evaluation of novel piperazine derivatives of flavone as potent anti-inflammatory and antimicrobial agent. Bioorganic & Medicinal Chemistry Letters 2012; 22 (20): 6385-6390.
22. Kakwani MD, Suryavanshi P, Ray M, Rajan MGR, Majee S et al. Design, synthesis and antimycobacterial activity of cinnamide derivatives: a molecular hybridization approach. Bioorganic & Medicinal Chemistry Letters 2011; 21: 1997-1999.
23. Zhong Y, Xu Z, Wang Y, Xu Y, Li P et al. Synthesis, crystal structure and anti-ischaemic activity of (E)- 1-{4-[bis(4-methoxy-phenyl)methyl]piperazin-1-yl}-3-(4-chlorophenyl)-prop-2-en-1-one. South African Journal of Chemistry 2014; 67: 214-217.
24. Saadeh HA, Mosleh IM, Mubarak MS. Synthesis of novel hybrid molecules from precursors with known antiparasitic activity. Molecules 2009; 14: 1483-1494.
25. Schoeffmann A, Wimmer L, Goldmann D, Khom S, Hintersteiner J et al. Efficient modulation of γ -aminobutyric acid type A receptors by piperine derivatives. Journal of Medicinal Chemistry 2014; 57 (13): 5602-5619.
26. Mu LH, Wang B, Ren HY, Liu P, Guo DH et al. Synthesis and inhibitory effect of piperine derivates on monoamine oxidase. Bioorganic & Medicinal Chemistry Letters 2012; 22 (9): 3343-3348.
27. Sangwan PL, Koul JL, Koul S, Reddy MV, Thota N et al. Piperine analogs as potent Staphylococcus aureus NorA efflux pump inhibitors. Bioorganic & Medicinal Chemistry 2008; 16 (22): 9847-9857.
28. Korhonen P. Novel crosslinking agents highly soluble in water, their preparation and use. PCT International Applications, 1995, WO 9501347 A1 19950112.
29. Pontiki E, Hadjipavlou-Litina D, Litinas K, Nicolotti O, Carotti A. Design, synthesis and pharmacobiological evaluation of novel acrylic acid derivatives acting as lipoxygenase and cyclooxygenase-1 inhibitors with antioxidant and anti-inflammatory activities. European Journal of Medicinal Chemistry 2011; 46: 191-200.
30. Dunnavant WR, Hauser CR. Synthesis of β -hydroxy esters from ethyl acetate and ketones or aldehydes by means of lithium amide. Some results with other esters. Journal of Organic Chemistry 1960; 25: 503-507.
31. Xu G, Yang X, Jiang B, Lei P, Liu X et al. Synthesis and bioactivities of novel piperazine-containing 1,5-diphenyl-2- penten-1-one analogues from natural product lead. Bioorganic & Medicinal Chemistry Letters 2016; 26: 1849-1853.
32. Pinna GA, Cignarella G, Ruiu S, Loriga G, Murineddu G et al. Synthesis of novel diazatricyclodecanes (DTDs). Effects of structural variation at the C3’ allyl end and at the phenyl ring of the cinnamyl chain on µ-receptor affinity and opioid antinociception. Bioorganic & Medicinal Chemistry 2003; 11: 4015-4026.
33. Miller ER, Nord FF. Studies on the scope of the Reformatsky reaction. Journal of Organic Chemistry 1951; 16 (5): 728-740.
34. Yan Q, Kong D, Zhao W, Zi G, Hou G. Enantioselective hydrogenation of β ,β -disubstituted unsaturated carboxylic acids under base-free conditions. Journal of Organic Chemistry 2016; 81: 2070-2077.
35. Li J, Chen H, Negrerie DZ, Du Y, Zhao K. Synthesis of coumarins via PIDA/I2-mediated oxidative cyclization of substituted phenylacrylic acids. RSC Advances 2013; 3: 4311-4320.
36. Freeman F, Lilian YC. Permanganate ion oxidations. 17. Kinetics and mechanism of the oxidation of (E)-3- (2-thienyl)-2-propenoates and (E)−3-(3-thienyl)-2-propenoatesin phosphate-buffered solutions. Journal of the American Chemical Society 1986; 108: 4504-4509.