Microwave-promoted efficient synthesis of dihydroquinazolines

Article abstract of DOI:10.1039/c0gc00838a

A solvent- and catalyst-free synthesis of dihydroquinazolines is described. 2,4-Disubstituted-1,2-dihydroquinazolines can be readily obtained from 2-aminobenzophenone and aldehydes under microwave irradiation using urea as an environmentally benign source

Full text of DOI:10.1039/c0gc00838a

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PAPER
Microwave-promoted efficient synthesis of dihydroquinazolines†
Rupam Sarma and Dipak Prajapati*
Received 22nd November 2010, Accepted 16th December 2010
DOI: 10.1039/c0gc00838a
A solvent- and catalyst-free synthesis of dihydroquinazolines is described.
2,4-Disubstituted-1,2-dihydroquinazolines can be readily obtained from 2-aminobenzophenone
and aldehydes under microwave irradiation using urea as an environmentally benign source of
ammonia, with a small amount of the corresponding quinazolines as the minor product. The
reaction is simple, clean and excellent yields are obtained within minutes.
development of mild and rapid approaches to quinazolines,
especially under solvent-free conditions, is still desired because
of their biological significance.
Introduction
Over the last decade, design of the quinazoline scaffold has
caught the attention of synthetic chemists because of their im-
mense biological and pharmacological potency. The importance
of quinazoline derivatives has been well documented. It is the
building block for many naturally occurring alkaloids found
across the plant and animal kingdoms and various microorgan-
isms such as Bouchardatia Neurococca,1 Peganum nigellastrum,2
Bacillus cereus3 and Dichroa febrifuga.4 Quinazoline derivatives
are known to act as selective inhibitors of the tyrosine kinase
activity of the epidermal growth factor receptor (EGFR).5 They
have also shown remarkable activity as anticancer, antitubercu-
lar, antibacterial, and antiviral agents.6 In a recent report, 3,4-
dihydroquinazoline derivatives have been found to have excellent
T-type calcium channel blocking activity.7 Development of the
quinazoline-based drugs such as gefitinib (Iressa) and erlotinib
(Tarceva) has renewed the interest in developing new synthetic
strategies for synthesis of quinazoline derivatives.
Although a number of methods for the synthesis of quinazo-
line derivatives have been reported,8 most of them suffer from
one or more disadvantages like preparation of starting materials
via multistep synthesis, use of catalyst, ligand or additives,
requirement of inert atmosphere and stringent reaction condi-
tions. Vanelle et al.8d reported a microwave-mediated process for
synthesis of quinazolinones in aqueous medium, but suffered
from the drawback of preparation of the starting compound
using organic solvent. In a recent report, Fu and his coworkers8c
have synthesised quinazolines from 2-bromobenzaldehydes.
However, their method required use of ligand, base, catalyst and
inert atmosphere for the transformation to take place. As such,
The most fundamental obstacles in developing technolo-
gies are to minimise the energy consumption and to elimi-
nate/minimise the use of hazardous solvents. In this scenario,
use of microwave energy to bring about chemical transforma-
tions is a suitable alternative, as it takes care of two very essential
criteria of synthesis: minimise energy consumption required
for heating and time required for the reaction.9 Moreover,
solventless synthesis results in reaction rate enhancements along
with differed selectivity compared to conventional conditions.10
Thus microwave heating coupled with dry reaction media
presents a green protocol to carry out organic reactions.
Conventional synthetic approaches towards 1,2-dihydro-
quinazolines are based on reaction of 2-aminobenzonitriles
with Grignard reagents, followed by condensation with an
aldehyde.11a,b The yield of the reaction was very poor under such
conditions due to competitive side reactions. Moreover, inert
atmosphere and long reaction time is necessary. In another re-
port, 2-carboxylic acid derivatives of 1,2-dihydroquinazoline11c
were synthesized from hydroxyglycine and aminobenzophenone
wherein the stability of the products were compromised as they
tend to decompose in solution.
Results and discussion
In our continued effort towards development of microwave-
assisted synthetic methodologies,12 we describe in this paper
an efficient catalyst- and solvent-free protocol for the synthesis
of 1,2-dihydroquinazolines under one-pot conditions. Initially,
reaction of 2-aminobenzophenone with one equivalent of an
aldehyde and 1.5 equivalents of urea were investigated. For-
mation of 1,2-dihydroquinazolines were observed in excellent
yields as the major product with little amount of the aromatic
counterpart as the minor product when the reactants were
irradiated under MW at 540 W and 130 ◦C for 4 min. The
feasibility of the reaction scheme was tested by using various
Medicinal Chemistry Division, CSIR-North-East Institute of Science &
Technology, Jorhat, Assam, India 785006.
E-mail: dr_dprajapati2003@yahoo.co.uk; Fax: +91 376 2370011
† Electronic supplementary information (ESI) available: Detailed exper-
imental procedure, compound characterization data and NMR spectra.
See DOI: 10.1039/c0gc00838a
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Table 1 Reaction of different aldehydes with 2-aminobenzophenone
Table 2 Reaction of different 2-aminobenzophenones with benzalde-
and ureaa
hyde and ureaa
Entry Aldehyde
Product Product ratio Yield (%)b
Entry 2-Aminobenzophenone Product Product ratio Yield (%)b
1
2
3
4
5
6
7
C6H5–CHO (2a)
3aa/4aa 85 : 15
82
79
85
85
90
88
90
90
85
80
82
83
4-CH3–C6H5–CHO (2b) 3ab/4ab 84 : 16
1
2
3
3aa/4aa 85 : 15
3ba/4ba 88 : 12
3ca/4ca 85 : 15
82
80
85
4-F–C6H5– (2c)
3ac/4ac 87 : 13
3ad/4ad 85 : 15
3ae/4ae 100 : 0
3af/4af 99 : trace
3ag/4ag 99 : trace
3ah/4ah 99 : trace
3ai/4ai 99 : trace
3aj/4aj 90 : 10
3ak/4ak 80 : 20
3al/4al 80 : 20
3-Br–C6H5–CHO (2d)
2-Cl–C6H5–CHO (2e)
CH3–CHO (2f)
(CH3)2CH–CHO (2g)
CH3(CH2)4–CHO (2h)
CH3(CH2)2–CHO (2i)
C6H5CHCHCHO (2j)
C4H3O–CHO (2k)
C4H3S–CHO (2l)
8
9
10
11
12
a Reaction conditions: 1a (1 mmol), 2 (1 mmol) and urea (1.5 mmol) were
irradiated at 540 W for 4 min in absence of any solvent in a microwave
reactor. b Isolated yield.
4
5
3da/4da 90 : 15
3ea/4ea 87 : 13
85
78
aromatic, aliphatic, heteroaromatic and conjugated aldehydes
and the results are summarised in Table 1.
It was observed that the nature of the substituent present
in aromatic aldehydes has an impact over the yield of the
reaction. The presence of an electron-donating substituent
resulted in lowering of the overall yield (Table 1, entry 2),
whereas electron-withdrawing substituent increased the yield
(Table 1, entry 3–5), relative to benzaldehyde. This may be
due to the inductive effect exerted by the substituents on the
aldehyde functionality. A positive inductive effect by electron-
donating groups lowers the reactivity of the carbonyl carbon of
the aldehyde towards nucleophilic attack by the N atom of 2-
aminobenzophenone, thereby lowering the rate of the reaction.
Electron-withdrawing substituents impart a negative inductive
effect, which subsequently increases the reaction rate. However,
the nature of the substituent on aromatic aldehydes seems to
have no impact on the ratios of the products formed. Quite
interestingly, though, the reaction with o-chlorobenzaldehyde
yielded the dihydroquinazoline as the only product (Table 1,
entry 5). Aliphatic aldehydes were reluctant to undergo aroma-
tisation and the dihydro product was formed almost exclusively
(Table 1, entry 6–9). This methodology worked equally well with
heteroaromatic and conjugated aldehydes and excellent yields
were observed (Table 1, entry 10–12).
In the next step we tried to generalise the reaction by varying
the 2-aminobenzophenone molecule and the results obtained
are summarised in Table 2. The yield of the reaction was found
to be excellent in all the cases (Table 2, entry 1–5). Further, the
product ratios were also found to be similar with the dihydro
compound being the major product. We were delighted to note
that 2-aminobenzophenone with substituents on either one or
both the phenyl rings underwent the reaction smoothly. The
scope and generality of the reaction was studied by reacting 2-
aminobenzophenones 1a–e with a range of aryl aldehydes and
the results are summarised in Table 3.
a Reaction conditions: 1a (1 mmol), 2 (1 mmol) and urea (1.5 mmol) were
irradiated at 540 W for 4 min in absence of any solvent in a microwave
reactor. b Isolated yield.
Mechanistically, there are two possible pathways by which the
reactants can come together to form the observed products. The
ketone group of 2-aminobenzophenone can form an imine [A]
with the ammonia generated from urea under MW conditions.
The free NH2 group of [A] can then react with the aldehyde to
give intermediate [C], which after cyclisation generates dihydro-
quinazoline 3. Aromatisation of 3 yields quinazoline 4 as the
minor product (path (a), Scheme 1). Alternatively, the aldehyde
can form an imine [B] by reacting with ammonia liberated from
urea under MW conditions, which, after simultaneous addition-
cyclisation reactions, forms 3 (path (b), Scheme 1).
As ammonium acetate is also a good source of ammonia,
we tried our methodology by employing ammonium acetate in
place of urea under identical reaction conditions. Accordingly,
when 2-aminobenzophenone was reacted with benzaldehyde
and ammonium acetate in a microwave reactor under neat
conditions in absence of any catalyst, we were happy to note that
a mixture of dihydroquinazoline and quinazoline were obtained
with yield and product ratios comparable to the reaction with
urea (Scheme 2). The only difference in the two processes was
that in case of urea the reaction took slightly more time (4 min,
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Table 3 Synthesis of 2,4-disubstituted 1,2-dihydroquinazolines 3 and quinazolines 4a
entry
2-Aminobenzophenone
Aldehyde (Ar)
Products
Product Ratio
Yield(%)b
1
2
3
4
4-CH3–C6H4– (2b)
4-F–C6H4– (2c)
3bb
3bc
3be
3bf
4bb
4bc
4be
4bf
85 : 15
87 : 13
90 : 10
85 : 15
82
88
90
84
2-Cl–C6H4– (2e
4-CH3O–C6H4– (2f)
5
6
7
8
4-CH3–C6H4– (2b)
4-F–C6H4– (2c)
2-Cl–C6H4– (2e)
4-CH3O–C6H4– (2f)
3cb
3cc
3ce
3cf
4cb
4cc
4ce
4cf
85 : 15
82 : 18
99 : 1c
80
90
90
85
100 : 0d
9
4-CH3–C6H4– (2b)
4-F–C6H4– (2c)
3-Br–C6H4– (2g)
C4H3S– (2l)
3db
3dc
3dg
3dl
4db
4dc
4dg
4dl
80 : 20
90 : 10
90 : 10
80 : 20
87
91
90
70
10
11
12
13
14
15
4-CH3–C6H4– (2b)
2-Cl—C6H4– (2e)
4-CH3O–C6H4– (2f)
3eb
3ee
3ef
4eb
4ee
4ef
78 : 22
99 : 1c
82 : 18
82
90
83
a Reaction conditions: 1a (1 mmol), 2 (1 mmol) and urea (1.5 mmol) were irradiated at 540 W for 4 min in absence of any solvent in a microwave
reactor. b Isolated yields. c Trace amount of quinazoline detected in NMR. d No quinazoline product detected in NMR.
Table 1) than that required in case of ammonium acetate (3 min,
Scheme 2).
the reaction is promoted by microwave radiation, but also it
prevents formation of unwanted side products. This makes our
methodology a very clean and green one.
We also carried out the reaction under classical condi-
tions and compared the results with those obtained under
microwave conditions. Thus, a mixture of ammonium acetate, 2-
aminobenzophenone and benzaldehyde when refluxed in acetic
acid for 10 h, yielded dihydroquinazoline and quinazoline in a
combined yield of 50% (Scheme 3). Further increase in reaction
time resulted in decomposition of products thereby leading
to lower yields. This observation made it clear that not only
Conclusions
In summary, a range of substituted 2-aminobenzophenones
and aldehydes have been shown to undergo a microwave
promoted three component, one pot reaction with urea to gen-
erate a library of 2,4-disubstituted-1,2-dihydroquinazolines and
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Microwave instrumentation
All MW reactions were carried out in a Synthos 3000 (Anton
Paar) microwave reactor. The multitude microwave has a
twin magnetron (2.45 GHz) with maximum output power of
1400 W. The output power can be controlled in unpulsed control
mode over whole power range which is adjustable in 1 W
increments. A Motorola 68xxx series microprocessor system
control is used to measure temperature, pressure, time and
power during the reaction. The temperature and pressure were
monitored throughout the reaction by an infrared detector. The
temperature can be measured from 0 to 280 ◦C with uncertainty
1%. The pressure can be measured from 0 to 86 bar with
uncertainty 0.2 bar.
General procedure for synthesis of quinazolines
Scheme 1 Proposed mechanism for formation of quinazolines 3 and 4.
(a) Under MW irradiation using urea. 2-Aminoben-
zophenone 1 (1 mmol), an aldehyde 2 (1 mmol) and urea
(1.5 mmol) were irradiated in a closed vessel in absence of
any solvent in a Synthos 3000 microwave reactor at 540 W,
140 ◦C and 10.9 bar for 4 min. The crude product mixture was
dissolved in ethyl acetate and directly column chromatographed
using 2 : 8 ethyl acetate–hexane as the eluent to get pure 1,2-
dihydroquinazoline 3 and quinazoline 4.
Scheme 2 Reaction of 2-aminobenzophenone and benzaldehyde with
ammonium acetate.
(b) Under MW irradiation using ammonium acetate. 2-
Aminobenzophenone 1 (1 mmol), an aldehyde 2 (1 mmol) and
ammonium acetate (1.5 mmol) were irradiated in a closed vessel
for 2 min in absence of any solvent in a Synthos 3000 microwave
reactor at 540 Watt, 130 ◦C and 15 bar pressure. The crude
product mixture was dissolved in ethyl acetate and directly
column chromatographed using 2 : 8 ethyl acetate–hexane as the
eluent to get pure 1,4-dihydroquinazoline 3 and quinazoline 4.
Scheme 3 Three component reaction of 2-aminobenzophenone, ben-
zaldehyde and ammonium acetate under classical conditions.
(c) Under classical conditions using ammonium acetate. 2-
Aminobenzophenone 1 (1 mmol), an aldehyde 2 (1 mmol) and
ammonium acetate (1.5 mmol) were refluxed in acetic acid
under air for 10 h. The reaction mixture was poured in water,
neutralised with potassium bicarbonate solution and extracted
with ethyl acetate and dried over anhydrous sodium sulfate.
It was filtered and purified by column chromatography using
2 : 8 ethyl acetate–hexane as the eluent to get the products 1,4-
dihydroquinazoline 3 and quinazoline 4.
2,4-disubstituted quinazolines under catalyst- and solvent-free
conditions. This methodology works equally well when ammo-
nium acetate is employed as the source of ammonia instead
of urea. This approach offers an environmentally friendly and
‘green’ alternative towards removing organic solvents from
organic synthesis.
Experimental
General experimental
Acknowledgements
Melting points were measured with a Buchi B-540 melting
point apparatus and are uncorrected. IR spectra were recorded
on a SHIMADZU FTIR-8400. NMR spectra were recorded
on Advance DPX 300 MHz FT-NMR spectrometer using
tetramethylsilane (TMS) as an internal standard. Mass spectra
were recorded on ESQUIRE 3000 Mass spectrometer. All the
commercially available regents were used as received. All exper-
iments were monitored by thin layer chromatography (TLC).
TLC was performed on pre-coated silica gel plates (Merck).
After elution, plate was visualized under UV illumination at
254 nm for UV active materials. Further visualization was
achieved by staining KMnO4 and warming in a hot air oven.
Column chromatography was performed on silica gel (100—
200 mesh, Merck) using ethyl acetate–hexane as eluent.
One of us (RS) thanks Council of Scientific and Industrial
Research (CSIR), New Delhi, for the award of a research fellow-
ship. We are grateful to Department of Science & Technology
(DST), New Delhi for financial support to this work. We also
thank the Director, NEIST, Jorhat for his keen interest and
encouragement.
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