Solvent-free synthesis and oxidative aromatization of diethyl-2 , 6-dimethyl-4-( 1-phenyl-3-aryl-1 H-pyrazol-4-yl )-1 , 4-dihydropyridine-3 , 5-dicarboxylates using hypervalent iodine ( III ) reagents

Article history: Received June 28, 2013 Received in Revised form December 10, 2013 Accepted 30 January 2014 Available online 30 January 2014 In this article, an efficient, environmentally benign, solvent-free synthesis of diethyl-2,6dimethyl-4-(1-phenyl-3-aryl-1H-pyrazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylates and their simple oxidative aromatization in presence of selected hypervalent iodine (III) reagents under solvent-free condition at room temperature is demonstrated. All reactions were carried out by grinding the reactant pyrazole substituted Hantzch-1,4-dihydropyridines and hypervalent iodine (III) reagent in a mortar with pestle. [Hydroxy(tosyloxy)iodo]benzene act as an more efficient oxidizing reagent in comparison to phenyliodine bistrifluoroacetate and iodobenzene diacetate in terms of reaction time and yields. The advantages of present protocol are the environment friendly, short reaction time, mild reaction conditions, and high yields of the products. © 2014 Growing Science Ltd. All rights reserved.


Introduction
The exploration of privileged structures in drug discovery is rapidly emerging theme in medicinal chemistry 1 .Pyrazoles and their derivatives are important class of compounds in organic and medicinal chemistry due to their biological properties 2 including anti-inflammatory, antimicrobial, analgesic, hypoglycaemic and non-nucleoside HIV-1 reverse transcriptase inhibitor properties.Pyridine and its derivatives are an important part of organic compounds that have significant place in medicinal chemistry 3 .Thus, the synthesis of highly substituted pyridines has attracted much attention, and a number of procedures have been developed 4 .Out of these trials, we selected the oxidative aromatization of 1,4-dihydropyridines (1,4-DHP's).The 1,4-DHP's and their oxidized derivatives belong to such immensely important class of heterocyclic systems, owing to their potent antihypertensive activity 5 and other biological utilities 6 .These compounds generally undergo oxidative metabolism in the liver by the action of cytochrome p-450 to form the corresponding pyridine derivatives 7 .Due to the relevance of this oxidative event to the biological NADH redox process [4][5][6][7] , this transformation has attracted the attention of several research groups  .
Out of these numerous oxidative protocols, we selected the aromatization of pyrazole substituted-1,4-DHP with hypervalent iodine (III) reagents under solvent-free condition.Recently hypervalent iodine (III) reagents have gained much importance as an oxidizing reagent due to their environmentally benign properties and replacing the use of toxic transition metals involved in such processes [43][44][45][46] .Hypervalent iodine (III) reagents are sparingly soluble in common organic solvents and therefore solvent free reactions are developed 47 .Solvent free reactions are of great importance in order to minimize pollution and toxic waste [48][49][50] .Literature survey shows that many exothermic reactions can be accomplished in high yields by just grinding solids together using mortar and pestle, a technique known as 'Grindstone Chemistry' 51 .Reactions are initiated by grinding, with the transfer of very small amount of energy through friction.It is not only advantageous from the environmental point of view but also offers rate enhancement, less waste products and higher yields 51 .

Fig.1. The hydrogen assignment in 1 H-NMR spectra of 2b and 3b
In 1 H-NMR spectra of 2b the two separate multiplets appears at δ 3.746-3.853and 3.965-4.072for methylene protons but in 1 H-NMR spectra of 3b these multiplets changes into a single multiplet at δ 3.900-4.079.Appearance of two multiplets in 1 H-NMR spectra of 2b clearly indicates that both of the methylene groups are in different environment.This is further confirmed by finding most stable conformation of 2b with ChemBio 3D ultra 11.0 (Chem Bio Office 2008) and by using MM2 force field method of energy minimization (Fig. 2.).

Fig. 2 Most stable conformation of 2b
The total energy of the resulting conformation found for 2b is 24.2179 kcal/mol.Appearance of one multiplet in 1 H-NMR spectra of 3b shows that both of the methylene group are in similar environment (Fig. 3.).In 1 H-NMR spectra of 3b, the protons of methyl group, pyrazolyl proton, and aromatic proton of N-phenyl ring resonate at down field in comparison to 2b which evidently prove the electron withdrawing effect of sp 2 hybridized nitrogen i.e. pyridine nitrogen.However, three types of proton (six protons of methyl group of ester, ortho and meta protons of p-nitrophenyl ring) resonate at high field.

Conclusions
In conclusion, in the present experiment, oxidation of 1,4-dihydropyridines with hypervalent iodine (III) reagents were performed efficiently.The hydroxy(tosyloxy)iodo]benzene (HTIB) was found more efficient reagent in comparison of IBD or PIFA.Literature survey 30 and our present protocol also illustrate that efficiency of hypervalent iodine (III) reagents in studied oxidative aromatization of 1,4-DHP's is rose following HTIB > PIFA> IBD.
All chemicals used in this study were of the highest purity available and purchased from local vendors.Melting points were determined on a Buchi oil heated melting apparatus and are uncorrected. 1H-NMR spectra were recorded in CDCl 3 on a Bruker-300 MHz spectrometer using TMS as an internal standard (chemical shift in δ).IR spectra were taken on a Perkin Elmer FTIR spectrophotometer using KBr pellets and peaks are reported in cm -1 .

General procedure for the oxidation of 1,4-dihydropyridines (2a-g) with HTIB
A mixture of 1,4-dihydropyridine (2a-g) (2 mmol) and HTIB (2.2 mmol) was blended thoroughly in a mortar by pestle.The resulting homogeneous mixture was ground at room temperature for 5-10 min.The completion of reaction was indicated by wetting of the reaction mixture.Progress of reaction was monitored by TLC.After completion of reaction, saturated solution of aq.sodium bicarbonate (20 mL) was added to quench the reaction and filtered the product.The resulting crude product was purified by silica gel column chromatography (using different ratios of ethyl acetate and n-hexane as eluent according to different products).

General procedure for the oxidation of 1,4-dihydropyridines (2a-g) with IBD or PIFA
1,4-Dihdropydine was taken in mortar and heated in an oven by maintain the temperature of oven at 80-90°C.After heating, mortar was taken off from the oven and IBD was added to it.Then the reaction mass was blended with pestle till the completion of reaction.Progress of reaction was monitored on TLC.If starting compound was observed on TLC then again the reaction mass was kept in oven for 2-3 min.After completion of reaction, saturated solution of aq.sodium bicarbonate (20 mL) was added to quench the reaction and filtered the product.The resulting crude product was purified by silica gel column chromatography (using different ratios of ethyl acetate and n-hexane as eluent according to different products).
The same procedure was adopted for oxidative aromatization of 1,4-DHP with PIFA except the temperature of oven which was kept 50-60 ºC.