Microwave-assisted heterocyclic synthesis ‡

Recent applications of microwave technology in well-known cyclization reactions for heterocyclic ring formation and in other important reactions such as nucleophilic substitution, hetero-Diels − Alder reactions, 1,3-dipolar cycloaddition etc. have been discussed. A comparison with the conventional methods demonstrates the advantages of microwaves in synthetic heterocyclic chemistry.


Introduction
Microwave heating has emerged as a powerful technique to promote a variety of chemical reactions. 1Microwave reactions under solvent-free conditions are attractive in offering reduced pollution and offer low cost together with simplicity in processing and handling. 2The recent introduction of single-mode technology 3 assures safe and reproducible experimental procedures and microwave synthesis has gained acceptance and popularity among the synthetic chemist community.The growing number of publications in microwave-assisted synthesis includes virtually all types of chemical reactions such as additions, cycloadditions, substitutions, eliminations, fragmentations etc. 3 In the present short review, we are trying to highlight some of the applications of microwave methodology in heterocyclic chemistry.The graphic enhancements in the speed of reactions and in yields are striking.Undoubtedly, microwaves are going to be highly important in future synthesis of heterocycles.Bearing in mind that most biologically active compounds are heterocyclic and the importance in combinatorial chemistry to identify leads and to optimize structures, we believe that the number of applications of microwaves will only increase in the future.The present review is organized to emphasize some of the most important areas that have so far been identified.Microwave: 2 min.Conventional: Lewis acid activation, 12h.

Scheme 1 1.1.2. Pyrazoles
Another recent application of microwaves in cyclization is the preparation of pyrazoles from hydrazones using the Vilsmeier cyclization method by treatment with POCl 3 and DMF. 5 As shown in Scheme 2, once again the reaction is speeded-up by factors of several 100-fold.Microwave: 35-50 sec., 45-78% Conventional: 4-5 h, 41-76% Scheme 2

Imidazoles
An important classical preparation of imidazoles is from an α-diketone, an aldehyde and ammonia.Here again, excellent yields can be obtained in reaction times of a few minutes as shown in Scheme 3. 6

Isoxazolines and pyrazolines
The acceleration of 1,3-dipolar cycloaddition reactions to give isoxazolines and pyrazolines by the addition of activated olefins to nitrile oxides or nitrile imides, respectively, is illustrated in Scheme 8; the resulting compounds are obtained in far high yield than under conventional conditions. 10 Cl N XH

Scheme 17
Until now we have concentrated on reactions in which heterocyclic rings are formed.However, microwave assistance can also be extremely valuable in many other types of reactions in heterocyclic chemistry.

Heterocyclic C-alkylations
Nucleophilic substitution reactions can be speeded-up very considerably as is illustrated in Scheme 18 for a chloro-naphthyridine derivative. 3

Intermolecular reactions
Scheme 23 shows two impressive examples of rate enhancement for intermolecular hetero-Diels−Alder reactions. 22In the first example on the top of Scheme 23 the initial reaction is followed by elimination thus involving the conversion of a pyrazine derivative into a pyridine.Perhaps more impressive is the lower example in Scheme 23 where an autoclave is required under conventional conditions but which can be dispensed with when microwave acceleration is utilized.

. Synthesis of C-carbamoyl-1,2,3-triazoles
We now turn to some of our own recent work which has involved microwave induced 1,3dipolar cycloaddition of organic azides to acetylenic amides.As shown in Scheme 24 we were able to achieve these reactions under microwave conditions in a reasonable time at temperatures of around 70±15 o C. 23 Under conventional conditions the times were roughly 100 times as long and the temperature had to be taken up to 120 o C. 24 O N 3   In Scheme 27 we were able to make bis-triazoles from di-azide and monoamidopropiolates. 25 This should be appropriate for the preparation of polymers utilizing bistriazoles and bis-amidopropiolates.

N-Chlorination of amides
Very recently, we have been able to show that N-chlorination can be carried out under very mild conditions and in high yields utilizing 1-chlorobenzotriazole (Scheme 28). 25 Conventional methods for N-chlorination generally involve reaction with tert-butyl hypochlorite in methanol for 2 h.

Scheme 28
In conclusion, we have summarized the recent applications of microwave activation in the synthesis and reactions of heterocycles.In comparison to conventional methods, microwave heating offers advantages such as reduced reaction times and temperatures, better yields, selectivity and reproducibility especially due to the advent of single-mode technology.
for very helpful discussions and the CEM Corporation for providing the Discover ® microwave synthesizer.

Scheme 15 1.4. Polycyclic six-membered rings 1.4.1. Quinolines The
17der reaction between aza-olefins and aza-dicarboxylic ester to give tetrazines is speeded-up by a factor of 1000 by microwave enhancement as shown in Scheme 15.16Skraup synthesis has a bad reputation as it involves very messy conditions and gives only low yields of quinolines when carried out conventionally.Recently, it has been reported that microwave enhancement reduces the reaction time to a few minutes and allows high yields to be isolated (Scheme 16).17 18]pyrimidines are prepared from dihydroaminopyrimidines and chromone-3aldehydes as is shown in Scheme 17.18Although the conventional reaction must proceed in refluxing ethanol, reactions are much faster and better yields have been obtained with microwaves.
20 Scheme 20, the results presented indicate that selectivity is achieved in the N-alkylation of 1,2,4-triazole under microwave conditions where only the N 1 -alkyl derivative was formed in contradistinction to the conventional conditions which give a considerable amount of the di-1,4substituted compound.20