SYNTHESIS OF A FEW OXYGEN HETEROCYCLES

Heterocyclic compounds are widely distributed in nature and are crucial for our survival. Nature always prefers heterocycles. The very reason for the Natures selection of heterocycles is due to the fact that they are chemically more flexible. The ability of many heterocycles to produce stable metallohetrocycles has got immense biochemical significance (for e.g., Hemoglobin, Chlorophyll, Vitamins, Enzymes, etc.). The introduction of hetero atoms into a carbocyclic compound makes a spectacular change in its chemistry and transforms it to synthetically much more attractive molecule.1 Heterocyclic compounds have a wide range of applications: they are predominant among the types of compounds used as pharmaceuticals, agrochemicals, and veterinary products. They are used as optical brightening agents, antioxidants, corrosion inhibitors, and additives with a variety of other functions. Many dyestuffs and pigments have heterocyclic structures. Heterocyclic compounds are also finding increasing use as intermediates in organic synthesis.2,3 Natures selection of heterocycles as well as their synthetic potential has created a significant interest in the synthesis and transformations of heterocycles. 1,3-Dipolar cycloaddition reaction, where two organic molecules, a 1,3-dipole 1 and a dipolarophile 2 combines to give a 5-membered heterocycle 3 (Scheme 1), is one of the typical reactions in synthetic organic chemistry.4
b a c d e 3

b 1

d e 2

Scheme 1
1

The use of the 1,3-dipolar cycloaddition reaction for the construction of heterocyclic compounds has been extensively utilized in recent years and has proven valuable for the preparation of complex ring systems.5 The ease of the cycloaddition, the rapid accumulation of polyfunctionality in a relatively small molecular framework, the high stereochemical control of the cycloaddition, and the fair predictability of its regiochemistry have contributed to the popularity of the reaction in organic synthesis.6,7 The complex heterocyclic compounds or adducts thus obtained can be readily transformed into a variety of other cyclic as well as acyclic functionalized organic molecules. 1,3-Dipolar cycloaddition reactions are therefore generally described as the single most important method for the construction of five membered heterocyclic rings in synthetic organic chemistry. The mechanism of 1,3-dipolar cycloaddition has been extensively investigated. The first mechanistic study was proposed by Huisgen in 1963. According to him, 1,3dipolar cycloadditions are concerted.8 At the same time Firestone proposed a Whether the mechanism of the different mechanism a diradical mechanism.9

cycloaddition is a stepwise diradical mechanism or a concerted mechanism sparked considerable debate. At the end, it was concluded that the mechanism may be an asynchronous concerted reaction mechanism (concerted but not synchronous!).10 In 1986, Huisgen reported the first two step 1,3-dipolar cycloaddition reaction.11,12 He found that when a highly electron-rich thiocarbonyl ylide dipole added to an electron-deficient dipolarophile, such as a dicyano-substituted alkene, there is a scrambling of stereochemistry in the products. The E-alkene dipolarophile gave rise to both cis- and trans- products. (Scheme 2) Huisgen concluded that, by making the dipole electron deficient and the dipolarophile electron rich (or vice versa) and thereby making a large difference in the HOMO-LUMO energies of the reaction partners as well as a pronounced steric hindrance at one terminus of the 1,3-dipole the bond formation in the concerted

reaction will become asynchronous. When this is taken to the extreme, the bond formation becomes so asynchronous that a zwitterionic intermediate is formed which results in nonstereospecific 1,3-dipolar cycloadditions.
S R2C H3CO2C R2C S CH2 NC CN CO2CH3 S R2C NC H3CO2C cis + CO2CH3 CN CO2CH3 CO2CH3 CN CN

trans

Scheme 2 Recently, advanced theoretical studies carried out on different systems also lead to the conclusion that 1.3-dipolar additions follow both concerted and stepwise paths and they may be in close competition.13-15 From the literature analysis, it is obvious that there are different opinions about the mechanism of 1,3-dipolar cycloaddition reactions. Together with this issue, our continued interest in the area of the synthesis and transformations of nitrogen and oxygen heterocycles prompted us to explore the dipolar cycloaddition reactions to synthesis such heterocycles and study the mechanism involved in such reactions.16,17 For our present study we synthesised a few nitrones (Fig. 1) and azomethine imines (Fig. 2) as dipoles and dibenzoylacetylene as the dipolarophile.

Nitrones 1 and 2 are ketonitrones and nitrone 3 is an aldonitrone. Here we changed the substituents on the -C of the nitrones to study how the substituents on -C affect the course of reaction. Interestingly we found that the reaction between
3

these nitrones and DBA lead to the formation of a mixture of products. Also we found that there is a slight difference in the product distribution on moving from nitrone 1 (Scheme 3) to nitrone 2 (Scheme 4). The difference is much more pronounced in the case of the reaction between nitrone 3 and DBA (scheme 5). The identity of the products was confirmed by spectral and analytical data including XRD analysis and chemical transformations. Compounds 7 and 10, for example could be converted to highly substituted quinoloine derivatives such as D under mild conditions. None of the products obtained in the above reactions are likely to be formed via a concerted process. In addition to this the observed dipole moment values of nitrones, for example, the dipole moment of N-methyl-C-phenyl nitrone, = 3.55 D, shows a dominance of the azomethine N-oxide structure. In other words, the terminal oxygen bears a larger portion of the negative charge than the carbon atom.18 That is the nitrone has got a nucleophilic character. We found that a stepwise mechanism is more suitable to explain the formation of products. We also developed an efficient method for the synthesis of highly substituted quinolins using a product derived from the reaction between nitrones and DBA. Scheme 6 represents the synthetic loop for a typical quinoline.

As we have seen from the above reactions, the reaction between nitrones and DBA resulted in the formation of highly interesting molecules. Besides this, it provides an opportunity for us to examine the course of the reaction. To generalize our findings we did some preliminary investigations with N-cyanoazomethine imine and DBA. The broad range of applications of pyrazolines and their derivatives is another reason for the selection of such a system. In contrast to the reaction between nitrones and DBA, the reaction between azomethine imines and DBA exclusively lead

to the formation of 3-pyrazolines. Since pyrazolines are known to be stable, probably the polar intermediate formed by the reaction between azomethine imines and DBA (an intermediate similar to the one formed in the reaction between nitrones and DBA) undergo cyclisation to the corresponding pyrazolines (Scheme 7 and 8). In this case other possible reaction pathways may not be competitive.

We found that the 3-pyrazolines 12a-c and 13a-c were readily undergoing decyanation on the surface of silica gel and gets rearranged to the corresponding 2-pyrazolines (Scheme 9 and 10). Even though the 2-pyrazolines 14a-c as well as 15a-c contains keto carbonyl groups, which are known to be a fluorescent quencher by facilitating a fast inter system crossing, they are found to be highly fluorescent. In an attempt to change this functional group to get an even more fluorescent material we did the reaction between azomethine imine 4a with DMAD. compound 16 on the surface of silica gel. The reaction leads to the formation of corresponding 3-pyrazoline 16 (Scheme 11). We found there is no decyanation for