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Application of Microwaves in Organic Synthesis: Speeding up the Process of Drug

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 Review Article

Application of Microwaves in Organic

Synthesis: Speeding up the Process of
Drug Discovery
Harish Rajak1,*, Deepak K. Jain1, Pramod K. Dewangan1, Vijay Patel1
and Navneet Agrawal2
1
Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University)
Bilaspur-495 009 (CG), India
2
Lachoo Memorial College of Science & Technology, Pharmacy Wing, Jodhpur-342 003 (Rajasthan), India

ABSTRACT
One of the main aims of drug discovery process is to generate novel therapeutic agents against the vast number of
potential drug targets and this demands the acceleration of the drug discovery process. It is important to look not
only at the staggering cost of discovering a new drug but also at the development time. Microwave assisted organic
synthesis enhances the drug discovery process by increase in synthetic yields, consistently shorter reaction time
and single step synthesis of many conventional multi-step synthetic procedures. In the present article, an attempt
has been made to outline the importance of microwave assisted organic synthesis in drug discovery process.
Keywords: Microwave, synthesis, drug discovery.

INTRODUCTION equipment such as oil baths or heating man-

Drug discovery in the post genomic era tles. These techniques are rather slow and
is characterized by the ability to efficiently create a temperature gradient within the
develop drugs against the vast number of sample. Moreover, the hot surface of the
Received Date :
potential drug targets. To maintain profitability reaction vessel may result in localized heat- Revised Date :

in this highly competitive and tightly regulated ing to produce decomposition products. Accepted Date :

environment drug companies have to generate In contrast, in microwave heating energy DOI: 10.5530/rjps.2013.1.3

leads efficiently, minimize failure rate of com- is introduced to the chemical reactor Address for
correspondence
pounds in clinical trials by identifying strong remotely and there is no direct contact Harish Rajak
candidates early and move drugs into market- between the energy source and the reac- Institute of Pharmaceutical

ing pipeline quickly. Recently introduced to tion mixture. Microwave radiation passes Sciences,
Guru Ghasidas
the drug development process, Microwave through the walls of the vessel heating the Vishwavidyalaya
Assisted Organic Synthesis (MAOS) increased contact directly by taking advantage of the (A Central University)
Bilaspur-495 009 (C.G),
the throughput by speeding up the synthe- ability of some liquids and solids to trans- India
sis process. The short reaction time and the form electromagnetic radiation into heat. Tel: +919827911824;
Fax: +917752260140
expanded reaction range offered by the micro- A properly designed vessel will not heat E-mail:
wave assisted organic synthesis are well suited under microwave radiation and the energy [email protected]

to the increased demand in the industry.1–4 will be transformed directly to the reaction
mixture, leading to a very rapid temperature
increase throughout the sample that may
MICROWAVE ASSISTED ORGANIC lead to less decomposition products.5
SYNTHESIS: MODE OF ACTION Microwave is a collective term for elec-
Most organic reactions requiring heat have tromagnetic radiation with frequencies in
been heated using conventional heat ­transfer the range of 0.3–300 GHz. Most of the www.rjps.in

14 RGUHS J Pharm Sci | Vol 3 | Issue 1 | Jan–Mar, 2013

 Harish Rajak, et al.: Application of Microwaves in Organic Synthesis: Speeding up the Process of Drug Discovery

f­requencies in this band are dedicated to radar equip- technology of vessel design is improving and a range
ment and telecommunication. To avoid interferences of vessels are now available for carrying out reactions
between different applications it has been agreed that under pressure.9
appliances for heating purposes will operate at 2.45 GHz
corresponding to a wavelength of 12.2 cm. MICROWAVE EQUIPMENT
Energy in the form of microwaves can be transferred to When microwaves enter a cavity, they are reflected by
substances that are present in the beam line of micro- the walls. The reflections of the waves eventually gener-
wave radiation. Absorption of energy occurs when ate a three dimensional stationary pattern of standing
dipolar molecules rotate to align themselves with the waves within the cavity, called modes. In a microwave
fluctuating electric field component of the radiation or oven radiation is generated by a magnetron, the micro-
when ions move back and forth by the same phenom- waves are guided into the cavity by a wave-guide and
enon. Essentially the ability of a substance to heat in a reflected by the walls of cavity. If the microwaves are
microwave field is dependent upon two factors. Firstly, not absorbed they may be reflected back down the
the efficiency with which substance absorbs the micro- wave-guide and damage the magnetron. Thus it is essen-
wave energy and secondly the efficiency with which the tial to have a microwave active “dummy load”, which
absorbed energy can be converted to heat.6 will absorb excess microwaves and avoid such damage.10
To date, the majority of microwave-promoted organic
SOLVENTS IN MICROWAVE ASSISTED synthesis has been performed in multi-mode domes-
ORGANIC SYNTHESIS tic ovens. In these ovens, the power levels commonly
Using microwave heating, boiling points of solvents can fluctuate as a result of the pattern of switching of on-
be raised up to 26°C above their conventional values; off cycles.11,12 Multimode ovens have several drawbacks
this phenomenon is known as superheating effect. This (i) The microwaves are heterogeneously distributed
higher boiling point can be maintained in pure solvents within the cavity and consequently less-defined regions
for as long as the microwave radiation is applied.7 of high and low energy intensity are produced. (ii) The
temperature can not be simply and accurately mea-
All types of solvents can be used in MAOS. Polar sol- sured. (iii) The power is not tunable and is fact the
vents such as DMF and ethanol are good microwave sample is always subjected to maximum power levels
absorbers and will heat efficiently. On the other hand, for varying periods of time. (iv) The reproducibility of
less polar or non polar solvents are more or less trans- experiments is very poor especially with small amounts
parent to the microwave radiation and will not heat in of products.13
the pure form. However most chemical reactions contain
enough polar or ionic substances to efficiently absorb These drawbacks led to the development of Monomode
microwave energy and generate heat. However, when the microwave oven which focuses the electromagnetic
dielectric properties of the sample are too poor to allow waves in an accurately dimensioned wave-guide. They
for efficient heating by microwave radiation, the addition allow a homogeneous distribution of the electric field
of small amount of polar or ionic additives, can signifi- and can be used with a low entitled power with a high
cantly overcome this problem. Energy transfer between energetic yield.14 Monomode reactors offer increased
the polar molecules that couple with the microwave radi- efficiencies and reliabilities. They lead to considerable
ation and the non polar solvent bulk is rapid and often improvements in yields of organic synthesis by preserv-
provides an efficient means of using non polar solvents ing thermal stabilities of products with real low emitted
for synthesis using non polar solvents.8 power and good homogeneity in temperature.15
Most of today’s commercially available microwave reac-
tors feature built-in magnetic stirrers, direct temperature
VESSELS IN MICROWAVE ASSISTED control of the reaction mixture with the aid of fiber-
ORGANIC SYNTHESIS optic probes, shielded thermocouples or IR sensors,
The reaction vessels are made of material that is and software that enables on-line temperature/pressure
­virtually transparent to microwaves at the operating control by regulation of microwave power output. In
­frequency. Borosilicate glass or poly tetrafluoroethylene single-mode cavities, only one mode is present and the
(Teflon, which is resistant to strong bases and hydro- electromagnetic irradiation is focused directly through
gen fluoride) are most commonly used. However, if an accurately designed wave-guide onto the reaction
reactions are to be carried out under pressure in sealed vessels mounted at a fixed distance from the radiation
systems the major concern is the ability of the vessel source. One drawback of single-mode cavities is that
to withstand the changes in pressure and temperature reaction size is more or less fixed at a relatively small
associated with the particular transformation. The volume.
RGUHS J Pharm Sci | Vol 3 | Issue 1 | Jan–Mar, 2013 15
 Harish Rajak, et al.: Application of Microwaves in Organic Synthesis: Speeding up the Process of Drug Discovery

IMPACT OF MAOS ON RESEARCH 50% completion, however use of microwave irradiation

AND DEVELOPMENT enables conversion to 3 : 1 (exo:endo) ratio in favour of
MAOS can have a significant impact on drug research desired exo-isomer.
and development if its strengths namely speed and sim- In the search for new CNS-active drugs, Olsson et al.,23
plicity are capitalized on.16 extended the procedure developed by Varma and
Speed: The main benefit of MAOS is shortening of Kumar24 for thioamide synthesis that relies on
reaction times through an increase in reaction tempera- Lawesson’s reagent and produced a library of 25 thio-
ture. The short reaction time provided by MAOS makes amides from the corresponding amides by a solvent-
it perfect for rapid reaction optimization, allowing one free parallel synthesis (Figure 1c). After extraction of
to ensue very rapidly, resulting in more decisions per solid-phase, products with adequate purity for use in
unit time. high throughput screening were obtained.
Simplicity: Simplicity is one of the assets of modern Generally lead optimization is limited by speed of ortho-
microwave equipments. Reactions are performed in dox organic synthesis. Use of microwaves in this con-
glass vials sealed with crimp caps. The vials are subse- cern accelerates the analogue synthesis and thus plays
quently heated in the microwave at constant tempera- an important role in drug discovery. Selway and Terrett
ture for a set period of time. With the availability of employed microwave irradiation to achieve quick and
proper analytical techniques, the time from the genesis convenient alkylation of 60 piperidines and piperazines
of an idea to result can be a matter of minutes, allowing to generate a library using parallel synthesis (Figure 1d).
the chemist to test the viability of novel synthetic route The library was screened in a herpes simplex virus
very rapidly.17 (HSV-1) helicase ATPase assay and confirmed hits were
Productivity: Productivity is related to the speed and identified.25
simplicity of a synthetic procedure. In MAOS, the pro- A novel method for the synthesis of a library of
ductivity is much higher than conventional methods substituted prolines utilizing microwave-assisted
of synthesis. A productivity increase of 200–400% has synthesis was described by Wilson and coworkers.26
been reported by various scientists.18 The process involves rapid microwave irradiation
of a-aminoesters and aldehydes to generate imines
­followed by the addition of a dipolarophile and subse-
EFFECTS IN LEAD GENERATION quent irradiation to produce the [3+2] cycloadducts.
AND LEAD OPTIMIZATION The decrease in reaction time afforded by micro-
MAOS because of its speed, is perfectly suited for the wave irradiation allowed for the production of an
development and production of focused and small 800-membered solution-phase library in twofold less
diverse libraries. The first application of microwave time than by traditional thermal methods (Figure 1e).
assisted combinatorial synthesis was in the production These products were purified by solid-supported
of libraries of diverse pyridines using a 96 well micro reagent scavenging to furnish the desired products in
titer plate.19 Since then MAOS has been used for the high yields and purity.
high speed parallel synthesis of libraries and building Wilson et al., prepared a library of 2-aminoquinolines
blocks. While most examples in the literature show that utilizing microwave-assisted synthesis.27 The heterocy-
MAOS has been used for single phase transformations clic quinoline scaffold and derivatives occur in a large
using solution phase or solid phase synthesis, the tech- number of natural products and drug-like compounds.
nique has also been used in making libraries requiring The process involves rapid microwave irradiation of
two step sequences in a fully automated manner.20 secondary amines and aldehydes to form enamines
Kappe and Verma synthesized 4-aryl-3, 4-dihydropyr- ­followed by the addition of 2-azidobenzophenones with
idinones using a Biginelli multi-component Biginelli ­subsequent irradiation to produce the 2-aminoquinoline
condensation reaction.21 Mixture of aryl aldehydes, derivatives. In this method, the initially formed triazo-
b-ketoesters and urea derivatives, in the presence of line intermediates undergo a thermal rearrangement
polyphosphate ester as the reaction mediator subjected and ­intermolecular base-catalyzed cyclocondensation to
to microwaves for 1.5 min, resulted in moderate to high produce a quinoline based pharmacophore combinato-
yields (Figure 1a). rial library (Figure 1f). Conventional heating methods
Habermann et al., employed microwave irradiation can be used to synthesize 2-aminoquinolines, but only
in sealed vessel to epimerize the a-pyridyl proton of low to moderate yields are obtained even after pro-
endo-epibatidine to the more thermodynamically sta- longed heating.
ble exoisomer of epibatidine22 (Figure 1b). Potassium A series of dihydropyrimidines utilizing the Biginelli
tert-butoxide, 30 h could not drive this process beyond multi-component reaction was reported by Stadler and
16 RGUHS J Pharm Sci | Vol 3 | Issue 1 | Jan–Mar, 2013
 Harish Rajak, et al.: Application of Microwaves in Organic Synthesis: Speeding up the Process of Drug Discovery

Figure 1: Applications of microwaves in organic synthesis.

(a) Pharmacologically important dihydropyrimidinones synthesized by a microwave – promoted, solvent free modified Biginelli reaction.
(b) Synthesis of potent analgesic compound (+/–) epibatidine assisted by microwave energy.
(c) Microwave accelerated solvent – free parallel synthesis of thioamides.
(d) Library of antiherpes aminothiazoles prepared using microwave power.
(e) Synthesis of substituted proline library using microwave irradiation.
(f) Synthesis of 2-aminoquinolines library using microwave energy.
(g) Formation of multifunctionalized dihydro-pyrimidines (Biginelli multi-component reaction) using microwave energy.
(h) Generation of imidazo–annulated pyridines, pyrazines and pyrimidines using microwave heating.

RGUHS J Pharm Sci | Vol 3 | Issue 1 | Jan–Mar, 2013 17

 Harish Rajak, et al.: Application of Microwaves in Organic Synthesis: Speeding up the Process of Drug Discovery

Kappe.28 A diverse set of 17 CH-acidic carbonyl com- i­midazo-annulated pyridines, pyrazines and pyrimi-
pounds, 25 aldehydes and 8 urea/thioureas was used in dines. 29 These Ugi reaction, using clay as inorganic
the preparation of a dihydropyrimidine library. Out of support are suitable for high speed parallel synthesis
full set of 3400 possible dihydropyrimidine derivatives, and library generation (Figure 1h).
a representative subset of 48 analogs was prepared Kidwai et al.,30 employed microwave heating in the
using automated addition of building blocks and sub- synthesis of Cephalosporin’s and quinolones. The
sequent sequential microwave irradiation of each pro- synthesis of anti-carcinogenic soyabean isoflavones,31
cess vial (Figure 1g). Empolying 10 min of microwave the antileukemic alkaloid convolutamydine,32 potential
flash heating at 120°C leads to average yield of 52% of HIV-1 protease inhibitors and well known commer-
dihydropyrimidines with more than 90% purity. cial drug sildenafil have been reported using MAOS.33
Varma employed solvent free conditions for multi-­ These are only few of the practical applications of
component reactions that leads to generation of MAOS.

Figure 2: Recent applications of microwave-assisted synthesis of biologically active compounds.

(a) Microwave synthesis of novel chalcone based 6-carbethoxy-2-cyclohexen-1-one and 2H-indazol-3-ol derivatives.
(b) Rapid microwave-enhanced synthesis of C5-alkynyl pyranonucleosides as novel cytotoxic antitumor agents.
(c) One of critical step involved in the synthesis of bioisosteres of trimethadione, N-derivative-1,2,3-oxathiazolidine-4-one-2,2-dioxides.
(d) Microwave assisted synthesis of sulfones by reaction of sulfinate salts with 4-chloromethyl-2-methyl-5-nitro-1,3-thiazole.
(e) Microwave assisted synthesis of novel steroidal chalcones for antimicrobial activity.

18 RGUHS J Pharm Sci | Vol 3 | Issue 1 | Jan–Mar, 2013

 Harish Rajak, et al.: Application of Microwaves in Organic Synthesis: Speeding up the Process of Drug Discovery

RECENT ADVANCEMENTS IN MICROWAVE application of microwave as non-conventional energy

SYNTHESIS source. Although the cost of microwave reactors is high
A diverse range of biologically active compounds has but this technique has gained massive acceptance due to
recently been synthesized using various merits of micro- the reason that most of the medicinal chemists claims
wave technology. that almost all reaction takes place in shorter time under
microwave with respect to the same under conventional
Shakil et al.,34 reported synthesis of novel chalcone based heating. Other benefits of using this technique includes
6-carbethoxy-2-cyclohexen-1-one and 2H-indazol- higher yield, more purity and environmental friendly reac-
3-ol derivatives for anti-fungal, anti-bacterial and anti- tions with more energy saving. The microwave assisted
oxidant activity. These compounds were synthesized synthesis of medicinal compounds has shown promising
using microwave radiation and non-microwave method impact upon lead generation, hit-to-lead efforts and lead
to study the advantageous effect of microwaves. It was optimization processes of drug discovery.
found that use of microwave results in reduction in
reaction time and increased yield with high purity of
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