Catalyst-free Multicomponent Synthesis of Novel Chromene Carbonitriles from Pyrazole Aldehydes using Ethanol

A catalyst-free synthetic strategy to chromene carbonitriles by Multi-Component reaction of pyrazole aldehydes, 5,5-dimethylcyclohexane-1,3-dione and malononitrile with ethanol, at room temperature is reported. Screening of solvents and purification of the compounds were also performed. The newly synthesized novel compound’s (4H-chromene-3-carbonitriles) structures were authenticated by the spectral techniques viz. ( 1 H , 13 C) Nuclear Magnetic Resonance, FT-IR, and LC-MS analysis


INTRODUCTION
Multi-drug resistant varieties of many pathogens threaten health as well as economy. Ugi-Multicomponent Reaction has played a vital part in pharmaceutical chemistry. Traditional Ugi-MCRs provide one-step synthesis of molecules with peptide core. Ugi-MCRs with a number of modifications were made available which enabled medicinal chemists to design diverse molecular scaffolds and have enlarged its application in modern drug evolution tremendously. The multicomponent reaction's applications in drug design like molecules were notable 1-3 . MCRs also play a vital role in agrochemical industries. Several studies have revealed the importance of innovative synthetic organic methods via one-pot multi-component reactions (MCRs) 4 . Simple protocols, environmentally friendly principles, usage of readily available low-cost reactants and greater product yields were the advantages of one-pot synthesis compared to conventional multistep synthesis 5 . These reactions enable the production of variety of heterocyclic compounds without the necessity for isolation of intermedeiates 6 . Reduced reaction time, simple workup method, greater selectivity, high atom economy and the ability to employ green solvents are all the added advantages of MCRs 7 .
T h e v a s t m a j o r i t y o f m a r k e t e d pharmaceuticals contain heterocycles as common fragments and hence heterocycles play essential role in modern drug synthesis. They played a crucial influence in the contemporary organic synthesis development. Heterocycles were largest diverse class of synthesized compounds with notable biomedical, commercial and chemical uses. Large number of natural products, diverse drugs and biologically active substances contain heterocycles in their structures. Considering the importance of heterocycles, substantial attentions were paid to strategize various eminent methods for their synthesis. Heterocyclic chemistry has its origin in organic synthesis and medicinal chemistry 8 .
Chromenes were a group of heterocycles containing oxygen atom, bicyclic, formed by fusion of a pyran ring with that of a benzene ring. They were most common types of naturally occurring heterocyclic compounds with diverse spectrum of biological activities. They were found in plants, bacteria, fungi and animals. Chromenes were important cores in medicinal chemistry, since they exhibit a myriad of biological activities like β-secretase inhibition, anti-dyslipidemic and antineoplastic behaviour. Chemotherapeutic chromenes such as EPC2407, LY290181 and LY290191 are well known for their anticancer activities 9 .
The lack of literatures with synthesis of chromene cores imbibing pyrazole aldehydes have been the driving force for the synthesis of these compounds. In our aim to build a novel library of biologically active targets, we discuss the catalystfree, one-step, three-component synthesis of functionalized chromene carbonitriles process in RT.

Chemicals and reagents
The chemicals involved in the reaction were bought from Sigma-Aldrich (U.S.A).
Pre-coated aluminium sheets of silica gel [CCM Gel de silica 60 F254-0.2mm thickness (Merck, Germany)] was utilized to perform analytical T.L Chromatography. Silica gel of 230-400 mesh size (Merck, India) was used for performing column chromatography.

Analytical equipment
FT-IR spectra were recorded with a Lambda spectrophotometer. Using DMSO, NMR spectra ( 1 H and 13 C) of the compounds were acquired at 400MHz and 100MHz respectively with spectrometer of BRUKER Company with TMS as standard. QTRAP system (4000) [LC/MS/MS (UPLC)-hybrid triple quadruple/Linear Ion trap] was used for recording the mass spectra.

RESULTS AND DISCUSSION
Using water, methanol and ethanol, solvent screening was carried out. It was found that, poor yield was obtained in water; better results were obtained while using methanol and excellent yield were seen with ethanol. The obtained results were given in Table 1. The proton NMR spectrum of product-4e shows a 6 protons singlet in 1.36ppm must be due to the presence of two methyl(-CH 3 ) group. 2 protons singlet at 2.94ppm was due protons at C-8 position and two protons singlet at 3.40ppm was assigned to C-6 position. 1 proton singlet in 5.11ppm was attributed for chromene [pyran]ring proton C-4 position. The ten protons multiplet at 7.47-7.94ppm was attributed to aromatic protons. The singlet 8.21ppm was assigned to proton of pyrazole ring. Two protons singlet in 9.22ppm assigned to presence of amine (-NH 2 ).

CONCLUSION
In summary, we have presented an unique, catalyst-free three component reaction which provides a simple methodology for synthesising chromene derivatives using pyrazole aldehydes, malononitrile and dimedone using various solvents. Regarding solvents, ethanol was found to be the most suitable solvent. The current method is advantageous for it's milder cum quicker reaction procedure, high desired compounds yield, eco-friendly, simple experimental and purification procedures, making it an efficient synthetic scenario to the 4H-chromene-3-carbonitriles. Our future perspective is to carry out single-crystal XRD and evaluate various pharmaceutical activities for 4H-chromene-3-carbonitrile derivatives.