Molecular iodine-catalyzed one-pot synthesis of some new Hantzsch 1,4-dihydropyridines at ambient temperature

An efficient and simple one-pot synthesis of some new symmetrical, unsymmetrical and N-substituted Hantzsch 1,4-dihydropyridines using molecular iodine as catalyst from an aldehyde, a 1,3-dicarbonyl compound and ammonium acetate / aromatic amine in ethanol is described. This new method has the advantage of good to excellent yields (80-95%) and short reaction times (2.5-5 h) at ambient temperature.


Introduction
Hantzsch 1,4-dihydropyridines (1,4-DHPs) and their derivatives have gained great importance in the field of organic and medicinal chemistry since they display a fascinating array of pharmacological properties. 1,5The dihydropyridine skeleton is common in many drugs such as nifedipine, nicardipine, amlodipine and others, which are effective as cardiovascular agents and which are also used for the treatment of hypertension. 6,71][12][13] They even possess neuroprotective platet antiaggregation activity. 14The tremendous drug activity of these compounds has attracted many chemists to synthesize these molecules.More than 100 years ago the first 1,4-DHPs were synthesized by Hantzsch and Liebigs. 15The classical method involves a one-pot condensation of an aldehyde with 1,3-dicarbonyl compounds and ammonia either in acetic acid or in an refluxing alcohol for a longer time. 16Due to some disadvantages of this method, there are several efficient methods developed for the synthesis of 1,4-DHPs, which comprise the use of microwave, [17][18] ionic liquid, [20][21] high temperature in refluxing solvents, [22][23][24][25] TMSCl-NaI 26 and metal triflates. 27However, the use of high temperatures, expensive metal precursors and longer reaction times limits these methods.Due to these problems, the development of an efficient and versatile method for the synthesis of 1,4-DHPs is an active research area and there is room for further improvement towards mild reaction conditions and to improve the yields of the reaction.Molecular iodine [28][29][30][31] has attracted attention as an inexpensive, non toxic, readily available catalyst for various organic transformations to afford the corresponding products in excellent yields with high selectivity.It has been used as a mild Lewis acid in the dehydration of tertiary alcohols to alkenes, in the formation of ethers, as well as β-keto enol ethers, [32][33][34] for esterification, 35 transesterification, 36 acetylation 29 and benzothiophene 37 formation, but there are only a few reports about its use for the synthesis of 1,4-DHPs. 38,39Therefore, we decided to synthesize some new symmetrical, unsymmetrical and N-substituted 1,4-DHPs promoted by a catalytic amount of iodine under ambient conditions with good to excellent yields. 38

Results and Discussion
In the present work, based on a literature survey, 38 30 mol% of catalyst was used throughout the experiments.One equiv. of different aromatic aldehydes 1 and ammonium acetate 3 with two equiv. of a 1,3-dicarbonyl compound 2 were stirred at room temperature in the presence of molecular iodine in a little amount of ethanol afforded the corresponding 1,4-DHPs 4a-f in 88-95% yield at room temperature (Scheme1).In a similar fashion, reaction of various aldehydes 1 reacted smoothly with 1,3-dicarbonyl compounds 2, methyl acetoacetate 5 and ammonium acetate 3 under these reaction conditions to give the corresponding unsymmetrical 1,4-DHPs derivatives 6a-f in 88-94% yield under ambient conditions (Scheme 2).No statistical mixture of symmetrical and unsymmetrical products has been obtained.Next, we investigated the effect of iodine in the synthesis of N-substituted 1,4-DHPs.Aromatic aldehydes 1, such as 3-nitrobenzaldehyde, reacts with isopropyl acetoacetate 7 and aromatic amines 8 such as 4-methoxyaniline in the presence of iodine to afford the products 9a-d in moderate yields (81-84%) as compared to 4a-f and 6a-f (Scheme 3).All the products were fully characterized by IR, 1 H NMR and mass spectral analysis.
Table 1.Synthesis of symmetrical, unsymmetrical, and N-substituted 1,4-DHPs using 0.3 mmol iodine as a catalyst through out the experiment at ambient temperature In conclusion, in this article an efficient and convenient process has been used to prepare various symmetrical, unsymmetrical and N-substituted Hantzsch 1,4-dihydropyridines from the reaction of different araldehydes, 1,3-dicarbonyl compounds, and ammonium acetate / aryl amines in the presence of a catalytic amount of iodine at ambient temperature.The present methodology offers very attractive features such as shorter reaction times, milder conditions, simplicity of the reaction, good to excellent product yields and commercially available iodine as a powerful catalyst for the synthesis of 1,4-DHPs.

Experimental Section
General Procedures.Melting points were estimated in open capillaries and are uncorrected.IR spectra were recorded on KBr discs, using FTIR-8400 spectrophotometer.

,6-diisopropyl-4-(4-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4c).
GCMS-QP2010 mass spectrometer (Shimadzu).Elemental analyses were performed on a Carlo Erba EA 1108 elemental analyzer at SAIF, CDRI Lucknow.Reactions were monitored on Merck aluminium thin layer chromatography (TLC, UV 254nm ) plates.Visualization was accomplished either on UV chamber or in iodine vapour.Column chromatography was carried out on silica gel (60-120 mesh, Merck chemicals). ) and iodine (0.38 g, 1.5 mmol) was charged in a 25 ml round bottom flask containing 2 ml of ethanol.The reaction mixture was then stirred at room temperature until the reaction was completed (2.5-4 hr monitored by TLC).The reaction mixture was treated with aq Na 2 S 2 O 3 solution, extracted into ethyl acetate (2 × 20 ml).The solvent was removed in vacuo and the resulting crude product (88-95%) was recrystallized from ethanol to give the pure compounds 4a-f.The reaction time and yields are depicted in Table1.