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Thursday, May 14, 2009

MICROWAVE ASSISTED HETEROCYCLIC SYNTHESIS – A BOON OVER CONVENTIONAL METHODS


MICROWAVE ASSISTED HETEROCYCLIC SYNTHESIS – A BOON OVER CONVENTIONAL METHODS

Jaya Thomas, Toji Tom, Vimal Mathew
National College of Pharmacy, Manassery, Calicut

Cite this: Jaya Thomas, Toji Tom, Vimal Mathew "MICROWAVE ASSISTED HETEROCYCLIC SYNTHESIS – A BOON OVER CONVENTIONAL METHODS", B. Pharm Projects and Review Articles, Vol. 1, pp. 463-512, 2006. (http://farmacists.blogspot.in/)
 
1. INTRODUCTION TO MICROWAVE TECHNOLOGY
The enchanting art of 'Microwave Mediated Organic Synthesis' which makes use of dielectric heating instead of conventional heating has emerged as a magic wand which is able to convert 0% yield to close to 90% under same experimental conditions.

 
This section provides a basic idea about microwaves, fundamentals of microwave heating mechanism, apparatus used, principles governing its usage in organic synthesis, types of reactions catalyzed by the technique, its benefits and limitations. Also enumerates some of the examples were microwave heating is employed.

 

1.1 Microwaves

Microwaves lie in the electromagnetic spectrum between infrared and radio waves. They have wavelengths between 0.01 and 1m and operate in a frequency range between 0.3-30GHz. However for their use in laboratory reaction, a frequency of 2.45 GHz is preferred.

 
1.2 Fundamentals of Microwave Technology
The fundamental mechanism of microwave heating involves agitation of polar molecules or ions that oscillate under the effect of an oscillating electric and magnetic field. In the presence of an oscillating field, particles try to orient themselves or be in phase with the field. However, the motion of these particles is restricted by resisting forces (inter particle interaction and electric resistance) which restrict the motion of particles and generate random motion, producing heat.

 
Only materials that absorb microwave radiation are relevant to microwave chemistry. These materials can be categorized according to the three main mechanisms of heating, namely
1. Dipolar polarization
2. Conduction mechanism
3. Interfacial polarization

 

1.2.1 Dipolar polarization
Dipolar polarization is a process by which heat is generated in polar molecules. On exposure to an oscillating electromagnetic field of appropriate frequency, polar molecules try to follow the field and align themselves in phase with the field .However, owing to inter molecular forces, polar molecules experience inertia and this random interaction generates heat. Dipolar polarization can generate heat by either on or both the following mechanisms.

 
  • Interaction between polar solvent molecules such as water, methanol and ethanol.
  • Interaction between polar solute molecules such as ammonia and formic acid
The key requirement for dipolar polarisation is that the frequency range of the oscillating field should be appropriate to enable adequate inter-particle interaction.
.
1.2.2 Conduction mechanism
The conduction mechanism generates heat through resistance to an electric current. The oscillating electromagnetic field generates an oscillation of electrons or ions in a conductor, resulting in an electric current. This current faces the external resistance, which heats the conductor.

 
The main limitation of this method is that it is not applicable for materials that have high conductivity, since such materials reflect most of the energy falls on them.
1.2.3 Interfacial polarization
The interfacial polarization method can be considered as a combination of the conduction and dipolar polarization methods. It is important for heating systems that comprise a conducting material dispersed in a non conducting material1.
1.3 Microwave Chemistry Apparatus
Many of the early microwave assisted reactions were carried out in sealed Teflon or glass vessels using unmodified domestic household ovens. Domestic microwave ovens use a magnetron to generate microwaves with wavelength around 12.2cm.

 
This domestic microwave oven had many drawbacks. Due to the nature of microwave dielectric heating, accurate temperature determination during the irradiation process was not possible with this. These ovens cannot be expected to contain explosions and are incompatible with corrosive and inflammable compounds. Also flux densities within the microwave cavity can vary considerably. As domestic microwave ovens operate on duty cycles, intermittent bursts of power lead to poor temperature control. So it is suggested that domestic microwave ovens should never be used in the lab-even if it is modified- for performing organic reactions at reflux(open system) or under pressure.

 
Today a variety of dedicated apparatus for organic reactions are made available with the help of developments in microwave equipment technology. These apparatus have got built in magnetic stirring, direct temperature control of reaction mixture with the aid of flouroptic probes shielded thermocouples or IR sensors and software that enables online temperature/pressure control by regulation of microwave output power.

 
Commercial microwave apparatus
The microwave chemistry apparatus can be categorized to two as follows.
  • Single-mode apparatus
  • Multi-mode apparatus

 

1.3.1 Single-mode apparatus
The differentiating feature of a single mode apparatus is its ability to create a standing wave pattern, which is generated by the interference of fields that have the same amplitude but different oscillating directions. This interference generates an array of nodes where microwave energy intensity is zero, and an array of antinodes where the magnitude of microwave energy is at its highest. The apparatus should be designed in such a way to ensure that the sample is placed at the antinodes of standing electromagnetic wave pattern.

 

One of the limitations of single mode apparatus is that only one vessel can be irradiated at the time. However, after the completion of reaction period, the reaction mixture can be rapidly cooled by using compressed air-a built in cooling feature of apparatus which makes it more user friendly. The main advantage of apparatus is their high rate of heating.

 

1.3.2 Multimode apparatus

An essential feature of multimode apparatus is the deliberate avoidance of generating a standing wave pattern inside it so as to generate as much as chaos as possible inside the apparatus. As result multimode microwave heating apparatus can accommodate a number of samples simultaneously for heating. A major limitation of multimode apparatus is that even with radiation disturbed around them, samples cannot be controlled effectively.

 
1.4 Microwaves in Organic Synthesis
Microwave radiation was discovered as a method of heating as early as1946 and commercial domestic microwave oven was also introduced. It was used in chemistry since 1970s and it was introduced to organic synthesis only in 1980's. Since then, the terms like MAOS(Microwave Assisted Organic Synthesis) and MORE(Microwave induced Organic Reaction Enhancements) came in to usage.

 
Organic synthesis in the preparation of a desired organic compound from available starting materials. Microwave assisted organic synthesis has been the foremost and one of the most researched applications of Microwaves in chemical reactions.The earliest of such reactions are conducted by Richard Gedge and his colleagues, in the hydrolysis of benzamide to benzoic acid under acidic conditions. Since then, chemists have successfully conducted a large range of organic reactions. These include the following
  • The Diels-Alder reaction
  • Racemisation of large organic molecules thorough Diels-Alder cyclo-reversions
  • The Ene reaction
  • Heck reaction
  • Suzuki reaction
  • Mannich reaction
  • Hydrogenation of [beta]-lactams
  • Hydrolysis
  • Dehydration
  • Esterification
  • Cycloaddition reaction
  • Epoxidation
  • Reductions
  • Condensations
  • Protection and deprotection
  • Cyclisation reactions, etc.
Based on reaction conditions, organic synthesis can be conducted in the following ways
  • Organic synthesis at atmospheric pressure
  • Organic synthesis at elevated pressure
  • Organic synthesis in dry medium

 


 

1.4.1 Organic synthesis at atmospheric pressure

Microwave assisted organic reactions can be conveniently conducted at atmospheric pressure in reflex conditions. A good example of microwave assisted organic synthesis at atmospheric pressure is the Diels-Alder reaction of maleic anhydride with anthracene. In the presence of diglyme (boiling point-162*C), under microwave conditions can be completed in a minute with 90% yield. However the conventional synthetic route, which uses benzene, requires 90 minutes.

 
Diels Alder reaction under microwave conditions

 

1.4.2 Organic synthesis at elevated pressure

    
    Microwaves can be used to directly heat the solvent in sealed microwave transparent containers. The sealed container helps in increase the pressure in rotor which facilitates the reaction that will take place at higher temperature. This results in a substantial increase in the reaction rate of microwave assisted organic synthesis. However increase in reaction rate depends on volume of vessel, the solvent to space ratio and the solvent boiling point.

 

1.4.3 Organic synthesis in dry medium
Microwaves has been applied to organic synthesis in dry medium, using solid supports. Microwave radiation based on solid support, has been highly successful in reducing the reaction time for condensation,acetylation and deactivation reactions. Eg:-Deacetylation of protected compounds such as alcoholic acetate held on a support material. The microwave assisted chemical reaction could be completed within three minutes while the conventional oil bath heating at 70C will take about 40 hours.2

 

1.5 Benefits of Microwave Assisted Synthesis
Microwave radiation has proved to be a highly effective heating source in chemical rections.Microwaves can accelerate reaction rate,provides better yield and selective heating,achieve greater reproductibility of reactions and help in developing cleaner and greener synthetic routes.Beneficial effects can be listed as follows.

 

1.5.1 Increased rate of reaction
    Compared to conventional heating,microwave heating enhances the rate of certain reactions by 10 to 1000 times.This is due to its ability to substancially increase the temperature of a reaction
Eg:-
Comparison of reaction duration in minutes
Reaction ConventionalMicrowave
Synthesis of flourescein60035
Condensation of benzoin with urea6030
Biginelli reaction36035
Synthesis of aspirin130 1 

 

At present, there are two main theories that seek to explain the rate of acceleration caused by microwaves.These theories are based on experiments conducted on the following set of reactions .
  1. Liquid phase reactions
  2. Catalytic reactions

 

Liquid phase reactions
    The rate acceleration in liquid phase reactions heated by microwave radiation can be attributed to super heating of solvents.For example water when heated by conventional methods,has a boiling point of 100C.However when a power input of 500 watts is employed for a minute in microwave equipment,the reaction can be performed at a temperature of 110C.It has been observed that the boiling point of water reaches 119C at the reaction conditions mentioned above.This super heating of solvent enables the reaction to be performed at higher temperatute and results in an increase in the rate of reaction.

 
Catalytic reactions
    The rate of acceleration in catalytic reaction,on exposure to microwave radiation,is attributed to high temperature on the surface of the catalyst.The increase in the local surface temperature of the catalyst results in enhancement of catalytic action leading to an enhanced rate of reaction.It has been observed that when the catalyst is introduced in a solid granular form,the yield and the rate of heterogeneous oxidation,esterification and hydrolysis reactions increases with microwave heating,compared to conventional heating under the same conditions.Table shows an increase in yield by 200% for oxidation and 150% for hydrolysis,when the reaction is conducted in the microwave batch reactor.
Table:-comparison of yield under microwave & conventional heating methods
Chemical reaction Temperature (C)Time (Minutes)M.W yield(%) Conventional yield(%) 
Hydrolysis of hexa nitrite 100504025
Oxidation of cyclohexane80662612
Esterification of stearic acid1401209783

 

1.5.2 Efficient source of heating
    Heating by means of microwave radiation is a highly efficient process ad results in significant energy saving.This is primarily because microwaves heat up just the sample and not the apparatus and therefore energy consumption is less.
1.5.3 Higher yields

    In certain chemical chemical reaction,microwave radiation produces higher yields compared to conventional heating methods.For eg:-microwave synthesis results in an increase in the yield of the reaction,from 70%to92%.
Table:-Comparison of yields(in %)
Reaction conventional microwave
Synthesis of flourescein70 80 
Condensation of benzoin with urea70 73 
Biginelli .70 75-
Synthesis of aspirin 85 92 

 

1.5.4 Uniform heating

    Microwave radiation, unlike conventional heating methods, provides uniform heating through out a reaction mixture.

 
    In conventional heating, the walls of the oil bath get heated first, and then the solvent. As a result of this distributed heating in an oil bath, there is always a temperature difference between the walls and the solvent. In the case of microwave heating, only the solvent and the solute particles are excited, which results in uniform heating of the solvent. This feature allows the chemist to place reaction vessels at any location in the cavity of a microwave oven. It also proves vital in processing multiple reactions simultaneously, or in scaling up reactions that require identical heating conditions.

 

1.5.5 Selective heating
    Selective heating is based on the principle that different materials respond differently to microwaves. Some materials are transparent whereas others absorb microwaves. Therefore, microwaves can be used to heat a combination of such materials.

 
1.5.6 Environmentally-friendly Chemistry
    Reactions conducted through microwaves are cleaner and more environmentally friendly than conventional heating methods. Microwaves heat the compounds directly; therefore, usage of solvents in the chemical reaction can be reduced or eliminated, for example, Hamelin developed an approach to carry out a solvent-free chemical reaction on a sponge-like material with the help of microwave heating. The reaction is conducted by heating a spongy material such as alumina. The chemical reactants are adsorbed to alumina, and on exposure to microwaves, react at a faster rate than conventional heating. The use of microwaves has also reduced the amount of purification required for the end products of chemical reactions involving toxic reagents.

 
1.5.7 Greater reproducibility of Chemical Reactions
    Reactions with microwave heating are more reproducible compared to conventional heating because of uniform heating and better control of process parameters. The temperature of chemical reactions can also be easily monitored. This is of particular relevance in the lead optimization phase of the drug development process in pharmaceutical companies3.

 
1.6 Limitations of Microwave Chemistry
    The limitations of microwave chemistry are linked to its scalability, limited application, and the hazards involved in its use.

 
1.6.1 Lack of Scalability
    The yield obtained by using microwave apparatus available in the market is limited to a few grams. Although there have been developments in the recent past, relating to the scalability15 of microwave equipment, there is still a gap that needs to be spanned to make the technology scalable. This is particularly true for reactions at the industrial production level and for solid-state reactions.

 
1.6.2 Limited applicability
    The use of microwaves as a source of heating has limited applicability for materials that absorb them.Microwaves cannot heat materials such as sulphur, which are transparent to their radiation. In addition, although microwave heating increases the rate of reaction in certain reactions, it also results in yield reduction compared toconventional heating methods.

 
1.6.3 Safety hazards relating to the use of Microwave-heating apparatus
    Although manufacturers of microwave-heating apparatus have directed their research to make microwaves a safe source of heating, uncontrolled reaction conditions may result in undesirable results, for example, chemical reactions involving volatile reactants under super heated conditions may result in explosive conditions. Moreover, improper use of microwave heating for rate enhancement of chemical reactions involving radioisotopes may result in uncontrolled radioactive.
decay.

 
    Certain problems, with dangerous end results, have also been observed while conducting polar acid-based reactions, for example, microwave irradiation of a reaction involving concentrated sulphuric acid may damage the polymer vessel used for heating. This is because sulphuric acid is a strong coupler of microwave energy and raises the reaction temperature to 300C within a very short time. As a result, the polymer microwave-heating container may melt, with hazardous 17 consequences.Conducting microwave reactions at high-pressure conditions may also result in uncontrolled reactions and cause explosions.

 
1.6.4 Health hazards relating to the use of Microwave-heating apparatus
    Health hazards related to microwaves are caused by the penetration of microwaves. Microwaves operating at a low-frequency range are only able to penetrate the human skin, higher frequency-range microwaves can reach body organs. Research has proven that on prolonged exposure microwaves may result in the complete degeneration of body tissues and cells. It has also been established that constant exposure of DNA to high-frequency microwaves during a biochemical reaction may result in complete degeneration of the DNA strand.Research has been carried out to understand this phenomenon, and two schools of thought have evolved. The first is based on the thermal degeneration of DNA by microwave radiation, and believe that microwaves have enough energy to disrupt the covalent bond of a DNA strand. The other school of thought is emphatic about the existence of a 'non-thermal microwave effect'. Kakita et al have proved that in identical temperature conditions, microwave-irradiated DNA strands were different from those heated under conventional heating methods. Microwave-irradiated DNA strands were usually destroyed, which does not occur in conventional heating. This discovery has restricted the use of microwave heating to only abiological reactions.3

 

2. APPLICATIONS OF MICROWAVES IN HETEROCYCLIC SYNTHESIS


2.1
Heterocyclic Ring Formation


2.1.1 Five-Membered Heterocyclic Rings


2.1.1.a Pyrroles


    The classical Paal-Knorr cyclization of 1, 4-diketones to give pyrroles is dramatically speeded- up under microwave irradiation and high yields are obtained as shown in Scheme 14.

 

 

2.1.1.b Pyrazoles


    Another recent application of microwaves in cyclization is the preparation of pyrazoles from hydrazones using the Vilsmeier cyclization method by treatment with POCl3 and DMF5.
As shown in Scheme 2, once again the reaction is speeded-up by factors of several 100-fold.

Scheme 2



 
2.1.1.c 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

 

Scheme 3



 

 

2.1.1.d Oxazolines


    The example of Scheme 4, the preparation of oxazolines shows that partially saturated five-membered rings can also be prepared advantageously using microwaves7.

Scheme 4



 
2.1.1.e Triazoles and Tetrazoles
    Schemes 5 and 6 continue the overview of five-membered rings with illustrations of the advantageous preparation of 1,2,4–triazoles (Scheme 5)8 and tetrazoles (Scheme 6)9 using microwaves. Notice that in Scheme 6 the starting aryl cyanides are also made by a Pd-catalyzed but microwave-enhanced replacement of aryl bromides using zinc cyanide.

 
Scheme 5

 

 
Scheme 6
.
2.1.1.f Oxadiazoles
    The dehydration of unsymmetrical diacylhydrazines (themselves prepared by a conventional Mitsunobu reaction) using Burgess's reagent is shown in Scheme 7 to give 1,3,4-oxadiazoles rapidly under microwave irradiation.3

Scheme 7

 
2.1.1.g 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

 
Scheme 8

 

2.1.2 Benzo-Derivatives of Five-Membered Rings


2.1.2.a Benz-imidazoles, -oxazoles, and -thiazoles


    Ring closure reactions of appropriate o-substituted anilines to give benzimidazoles, benzoxazoles, and benzthiazoles takes place much faster and in significantly high yield under microwave conditions11a than conventionally11b as shown in Scheme 9.

 

Scheme 9



 

 
2.1.2.b Indoles
    The classical Fischer-indole synthesis from an aryl hydrazine and a ketone is speeded-up by several 100-fold as documented in Scheme 10.12

 

Scheme 10



 

 
2.1.2.c γ-Carbolines
    The Graebe-Ullmann synthesis which converts 1-arylbenzotriazoles into carbazoles or their heterocyclic analogs is also accelerated under microwave conditions as shown in Scheme 11 where the 1-(4-pyridyl)benzotriazole is converted into a γ-carboline.13

 

Scheme 11



 
2.1.3 Six-Membered Rings

2.1.3.a Dihydropyridines


    The Hantzsch dihydropyridine synthesis remains one of the most important routes to pyridine ring systems. Under conventional conditions long periods of heating are required and yields are poor to moderate. Microwaves dramatically reduce the heating times and also significantly increase the yields as shown in Scheme 1214.

Scheme 12



 

2.1.3.b Dihydropyridopyrimidinones


    Dihydropyridopyrimidinones have been produced by ring annulations of aminopyrimidinones. Once again the reaction time is dramatically reduced and yields are much better with the solvent-free microwave conditions (Scheme 13)15.


 

Scheme 13



 
2.1.3.c Dihydropyrimidines
    The Biginelli reaction is important for the preparation of dihydropyrimidine derivatives and excellent results are found for reactions carried out with microwave enhancement (Scheme 14)3.


 

Scheme 14



 
2.1.3.d Tetrazines
    The Diels-Alder 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 1516.

Scheme 15



 

2.1.4 Polycyclic Six-Membered Rings


2.1.4.a Quinolines
    The Skraup 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.

Scheme 16



 
2.1.4.b Pyrimido[1,2-a]pyrimidines
    Pyrimido[1,2-a]pyrimidines are prepared from dihydroaminopyrimidines and chromone-3- aldehydes as is shown in Scheme 1718.
Although the conventional reaction must proceed in refluxing ethanol, reactions are much faster and better yields have been obtained with microwaves.

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.

 

2.2 Nucleophilic Substitutions


2.2.1 Heterocyclic C-Alkylations

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

Scheme 18



 
2.2.2 Heterocyclic N-Alkylations

    Another class of nucleophilic substitution is involved in heterocyclic N-alkylation which we have illustrated in Scheme 19. This shows that nucleophilic substitution on the nitrogen atom of saccharin is significantly speeded-up by microwave irradiation.19

Scheme 19



 
2.2.3 Selective-Alkylation

    In 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 N1-alkyl derivative was formed in contradistinction to the conventional conditions which give a considerable amount of the di-1,4-substituted compound.20

Scheme 20



 
2.2.4 Transition Metal Cross-Coupling

    An important type of nucleophilic substitution reactions which are recently much exploited are comprised of transition metal cross-coupling. A Suzuki coupling is shown at the top of Scheme 21 to give significantly better yield in the presence of microwave irradiation.21a At the bottom of Scheme 21 another Suzuki coupling is speeded-up by a factor of 100.21b

 
Scheme 21

 

 
2.3 Hetero-DielsAlder Reactions
2.3.1 Intramolecular Reactions

    We have already seen one example of a hetero-Diels−Alder reaction involving acyclic components. Hetero-Diels−Alder reactions involving cyclic components which lead to polycyclic ring systems are of great importance. An intramolecular example shown in Scheme 22 indicates that the reaction was accelerated by a factor of around 1000 by microwave irradiation.22

 
Scheme 22

 


 

 
2.3.2 Intermolecular Reactions

    Scheme 23 shows two impressive examples of rate enhancement for intermolecular hetero-Diels−Alder reactions.22 In 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.

 
Scheme 23

 
2.4 1, 3-Dipolar Cycloaddition Reactions
2.4.1 Synthesis of C-Carbamoyl-1, 2, 3-triazoles

    We now turn to some of our own recent work which has involved microwave induced 1,3- dipolar 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 oC.23 Under conventional conditions the times were roughly 100 times as long and the temperature had to be taken up to 120 oC.24

 
Scheme 24

 


 

 

 
2.4.2 Synthesis of Substituted Mono-Triazoles

    Scheme 25 shows some similar results of rate enhancements of formation of mono-triazoles from alkoxycarbonyl-activated acetylenes and azides25.

 
Scheme 25

 


 

 
2.4.3 Synthesis of Substituted Bis-Triazoles
    In Scheme 26 examples are shown of the preparation of bis-triazoles from mono-azides and bis-amidopropiolates. In Scheme 27 we were able to make bis-triazoles from di-azide and mono-amidopropiolates25.
This should be appropriate for the preparation of polymers utilizing bis-triazoles and bis-amidopropiolates.

Scheme 26



 

Scheme 27



 

 
2.5 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).
Conventional methods for N-chlorination generally involve reaction with tert-butyl hypochlorite in methanol for 2 h.26

Scheme 28



 


 

3. CONCLUSION

 
    As the graphic enhancements in the speed of reactions and in yields shown by the microwave assisted methods compared to conventional methods are striking, undoubtedly, microwaves are going to be highly important in future synthesis of heterocycles. Also heterocyclic compounds being the most biologically active and are highly important in combinatorial chemistry to identify leads and to optimize structures, the applications of microwaves will only increase in future.

 
    Moreover, the microwave assisted methods especially reactions under solvent free conditions being attractive in offering reduced pollution and offer low cost together with simplicity in processing and handling, it opens new horizons for the synthetic chemist community.    

 

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Cite this: Jaya Thomas, Toji Tom, Vimal Mathew "MICROWAVE ASSISTED HETEROCYCLIC SYNTHESIS – A BOON OVER CONVENTIONAL METHODS", B. Pharm Projects and Review Articles, Vol. 1, pp. 463-512, 2006. (http://farmacists.blogspot.in/)
 

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