A facile synthesis of sugar-pyrazole derivatives Arasappan Hemamalini, Subbiah Nagarajan, Thangamuthu Mohan Das ⇑ Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India article info Article history: Received 5 May 2011 Received in revised form 15 June 2011 Accepted 16 June 2011 Available online 28 June 2011 Keywords: Pyrazole a,b-Unsaturated ketones Self-oxidation Knoevenagel condensation Sugar-heterocyclics C-b-Glycosides abstract A facile synthesis of sugar-pyrazole derivatives has been accomplished by condensation of sugar-chal- cone with hydrazine hydrate under neutral conditions resulting in yields of 70–85%. The products are characterized by FTIR and NMR spectroscopy and by elemental analysis. The b-anomeric forms for these derivatives were assigned by NMR spectroscopy. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Pyrazole derivatives are important biologically active heterocy- clic compounds. 1–9 These derivatives are the subject of many re- search studies due to their widespread potential biological activities, such as, anti-inflammatory, 1 antipyretic, 2 antimicrobial, 3 antiviral, 4 antitumor, 5 anticonvulsant, 6 antihistaminic, 7 insecti- cidal 8 and fungicidal activities. 9 Pyrazole derivatives represent important building blocks in organic and medicinal chemistry, such as luminophores, dyes, insecto-acaricides, analgesic, antiphlo- gistic, antibacterial, and antidepressant drugs. 10–22 In addition, they are of great interest due to their pharmacological properties. For example, pyrazole-3-carboxylic acid (1) and pyrazolo[1,5- c]quinazoline-2-carboxylates are nicotinic acid receptor agonists 23 and excitatory amino acid antagonists, respectively (Fig. 1). 23,24 Bis(benzo-[g]indazole-3-carboxamide) derivatives exhibit antipro- liferative activity against various cancer cell lines. 25 Ethyl-5- propyl-1H-pyrazole-3-carboxylate is a key intermediate for the synthesis of Viagra Ò . 26 Celecoxib (4-[5-(4-methylphenyl)-3-(tri- fluoromethyl)pyrazol-1-yl]benzenesulfonamide, 2) is the first drug to market amongst a number of selective cyclo-oxygenase-2 (COX- 2) inhibitors that are promising anti-inflammatory and analgesic agents without the undesirable side effects associated with other nonsteroidal anti-inflammatory drugs (Fig. 1). 27,28 Recently, Nico- laou et al. reported that a pyrazole-substituted epothilone deriva- tive that shows strong antitumor activity through the stabilization of microtubules by binding with tubulin. 29 Pyrazoles are obtained by 1,3-dipolar cycloaddition reaction of diazoalkanes with alkynes and related transformations. 30–32 Other syntheses rely on cycliza- tion of 1,3-diketones with hydrazine 33–35 and on Michael addition of hydrazines with a,b-unsaturated ketones. 36,37 Due to the impor- tance of sugars in biological systems, recent research focuses on the studies of sugar-based biomolecules. 38–41 In the present study, we have reported a facile synthesis of novel class of sugar-based pyrazole derivatives. 2. Results and discussion 4,6-O-Butylidene-D-glucopyranose was synthesized from D-glu- cose by adopting the literature procedure. 42,43 C-b-Glycosidic ke- tone 3 was synthesized by the Knoevenagel condensation of 2,4- pentanedione with 4,6-O-butylidene-D-glucopyranose in the pres- ence of sodium bicarbonate using THF–H 2 O as solvent. 44–46 Aldol condensation of C-b-glycosidic ketones 3(a and b) with various substituted aromatic aldehydes 4(a–f) resulted in the formation of the corresponding a,b-unsaturated-C-b-glycosidic ketones 5(a–g) in 70–90% yield (Scheme 1). Acetylation of 5b using Ac 2 O resulted in the formation of the acetylated product (E)-1-(2,3-di- O-acetyl-4,6-O-butylidene-b-D-glucopyranosyl)-4-(4-bromophe- nyl)-but-3-en-2-one (5h) in 90% yield. Reaction of (E)-1-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-4- (4-bromophenyl)-but-3-en-2-one (5a) with hydrazine hydrate under neutral conditions leads to the formation of a pyrazoline intermediate, which undergoes self-oxidation resulting in the for- mation of a sugar-based pyrazole derivative. Under the given reac- tion conditions, formation of the unprotected saccharide has been observed. However, compound 5h reacts with hydrazine hydrate 0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2011.06.019 ⇑ Corresponding author. Tel.: +91 44 22202814; fax: +91 44 22352494. E-mail address: tmdas_72@yahoo.com (T. Mohan Das). Carbohydrate Research 346 (2011) 1814–1819 Contents lists available at ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres