An Efficient Three-component, One-pot Synthesis of Quinazolines under Solvent-free and Catalyst-free Condition

Article abstract of DOI:10.1002/jhet.2220

An efficient green protocol for the synthesis of quinazolines in the absence of solvent and catalyst has been developed. 2,4-Disubstituted quinazolines have been synthesized from three-component one-pot reactions of 2-aminoaryl ketones, orthoesters, and ammonium acetate. The present method has advantages of operational simplicity, substrate generality, clean reaction, high yields (76-94%), and moderate reaction time. The plausible mechanism of the reaction has been proposed based on the spectral characterization and single crystal X-ray analysis of isolated intermediate.

Full text of DOI:10.1002/jhet.2220

Month 2014
An Efficient Three-component, One-pot Synthesis of Quinazolines under
Solvent-free and Catalyst-free Condition
Subrahmanya Ishwar Bhat, U. K. Das, and Darshak R. Trivedi
a
b
a
*
aDepartment of Chemistry, National Institute of Technology Karnataka, Srinivasanagar, Surathkal, Mangalore, 575025,
Karnataka, India
bDepartment of Organic Chemistry, Indian Association for the Cultivation of Science, 2A&2B, Raja S. C. Mullick Road,
Jadavpur, Kolkata, 700032, West Bengal, India
*
E-mail: darshak_rtrivedi@yahoo.co.in
Received November 12, 2013
DOI 10.1002/jhet.2220
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
An efficient green protocol for the synthesis of quinazolines in the absence of solvent and catalyst has
been developed. 2,4-Disubstituted quinazolines have been synthesized from three-component one-pot
reactions of 2-aminoaryl ketones, orthoesters, and ammonium acetate. The present method has advantages
of operational simplicity, substrate generality, clean reaction, high yields (76–94%), and moderate reaction
time. The plausible mechanism of the reaction has been proposed based on the spectral characterization
and single crystal X-ray analysis of isolated intermediate.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
requirement of additives and much effort to recycle the
materials. Moghadam et al. [39] reported one-pot, three-
component synthesis of 4-aminoquinazolines under
microwave condition; however, it suffers from limitation
of substrate generality. The group of Mahajan [40] reported
the synthesis of quinazolines under solvent-free and
catalyst-free conditions using conventional microwave
oven. However, this method requires tedious synthesis of
starting materials. Recently, Bandaru et al. [41] synthe-
sized 2,4-disubstituted quinazolines in aqueous medium
using 2-aminocarbonyl compounds, aldehydes, and ammo-
nium acetate; however, this method has limitations such as
its low product yield, the requirement of excess ammonium
acetate (10 equiv), and failure to yield the required product
with aliphatic aldehydes. The three-component synthesis
of quinazolines using molecular iodine catalyst under
neat/EtOH condition [42] and copper-catalyzed traditional
solvent-assisted synthesis [43] were reported during the
course of the present work. Owing to their widespread
applications, the quest for new, simple, and efficient
method for the synthesis of quinazolines from readily
available precursors under green reaction condition is of
continuing interest among the chemists.
The concept of green chemistry and its principles [1]
spread worldwide with the aim to develop environmental
consciousness in chemical synthesis. As a result, the
mindset of researchers has been diverted from the tradi-
tional chemistry processes, and scientists are adopting
green chemistry, which not only is advantageous to the
environment but also makes economic sense for the indus-
try and academia [2]. The reduction of waste, lowering of
energy costs, and avoidance of toxic organic solvents and
other auxiliaries in chemical transformations have become
the major concerns in industry and academia to develop an
environmentally benign synthetic protocol.
Quinazoline is one of the most important nitrogen-
containing fused heterocycles present in a wide variety of
natural products and synthetic pharmaceutical ingredients
[3–6]. They are known to show diverse biological and
therapeutic properties [7–22]. Several drugs have been
developed based on quinazoline motif and marketed by
various pharmaceutical companies [23]. In addition,
quinazoline scaffolds have also been found important in
other relevant fields such as material science [24], agro-
chemicals [25–27], and explosives [28].
Among various chemical approaches, multicomponent
reactions [44] have gained significant importance because
of their highly flexible, (chemo)selective, convergent, and
atom-efficient nature [45–48] and hence become current
area of interest in organic, medicinal, and combinatorial
chemistry research [49–51]. Being one-pot reactions,
multicomponent reactions are practically single-step con-
versions, and they are easier to carry out than classical
A variety of conventional procedures have been reported
for the synthesis of quinazolines [29–36], but most of them
suffer from multistep synthesis, lower yield, harsh condi-
tions, and use of toxic solvents, expensive catalyst, and
additives. Quite recently, practical protocols in the absence
of solvents [37] and catalysts [38] have been reported.
However, these methods suffer from drawbacks such as
© 2014 HeteroCorporation

S. I. Bhat, U. K. Das, and D. R. Trivedi
Vol 000
RESULTS AND DISCUSSION
multistep approach to synthesize complex organic mole-
cules. If such reactions with near quantitative yield could
be carried out under solvent-free and catalyst-free conditions
from readily available starting materials, they would comply
with most of the green chemistry principles [1] and closely
approach the concept of ideal synthesis [52].
As a part of our ongoing research program on the develop-
ment of efficient and green approaches in organic synthesis
[53,54], herein we report a one-pot three-component proto-
col for the synthesis of quinazolines. This method involves
the reaction of 2-aminoarylketones, orthoesters, and ammo-
nium acetate under solvent-free and catalyst-free conditions
in one pot (Scheme 1). The present protocol has several
advantages such as it involves neat reaction condition, uses
readily available starting materials that are well known in
several green transformations, achieves high yield, and has
moderate reaction time and hence can be considered as green
or sustainable synthetic protocol.
Initially, the three-component reaction of 2-amino-
benzophenone (1a) with 1 equiv of triethyl orthoformate
(2a) and 1 equiv of ammonium acetate were investigated
under solvent-free and catalyst-free conditions at 110°C.
The reaction was monitored with TLC (petroleum ether/
ethyl acetate, 9:1). Partial conversion was observed after
1 h, but the complete conversion was not observed even
after prolonged reaction time (Table 1, entry 1). However,
quinazoline (4a) was isolated in 52% yield, and
unconsumed starting material 1a was recovered. These
results encouraged us to optimize the reaction conditions,
and hence, excess amounts of triethyl orthoformate and
ammonium acetate have been used in order to improve
the product yield (Table 1, entries 2–4). The optimized
ratio of 1a/2a/NH4OAc 1:1.5:1.5 was determined to be
the more suitable combination for better conversion and
to obtain the desired product with good yield, without
Scheme 1. Synthesis of quinazolines under solvent-free and catalyst-free conditions.
R
R
solvent and catalyst free
O
110 oC
N
CR2(OR3)3
2
NH4OAc
3
N
4
R2
R1
Yield: 76-94%
NH2
R1
1
Table 1
Optimization of the one-pot three-component synthesis of quinazolines.
Entry
Ammonia source
Molar ratio 1a:2a:3
Time (min)a
Yield (%)b
1
2
3
4
5
6
7
8
1:1:1
240
240
240
120
180
180
180
180
180
180
180
180
52
66
70
93
32
1:1.2:1.2
1:1.2:1.5
1:1.5:1.5
1: 1.5:1.5
1: 1.5:1.5
1: 1.5:1.5
1: 1.5:1.5
1: 1.5:1.5
1: 1.5:1.5
1: 1.5:1.5
1: 1.5:1.5
Ammonium acetate
Urea
Ammonium sulfate
Ammonium chloride
Ammonium fluoride
Ammonium phosphate
Ammonium oxalate
Ammonium hydroxide
Ammonium carbonate
46
trace
trace
67
43
52
9
10
11
12
81
aThe reactions were monitored by TLC.
bIsolated yield.
To highlight the optimized conditions.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
An Efficient Three-component, One-pot Synthesis of Quinazolines under Solvent-
free and Catalyst-free Condition
any impurity formation, and in moderate reaction time
(Table 1, entry 4). Further, decrease of temperature to
90°C resulted in poor reactant conversion even after
prolonged reaction time. Subsequently, a series of solvent-
free reaction of 2-aminobenzophenone and triethyl ortho-
formate have been carried out with various other ammonia
sources under identical conditions in order to compare the
efficiency (Table 1, entries 5–12) of the current green
protocol. Decreased yields, a small amount of unidentified
impurities along with unconsumed starting materials were ob-
served when urea, ammonium chloride, ammonium fluoride,
ammonium phosphate, ammonium oxalate, ammonium
hydroxide, and ammonium sulfate were used as ammonia
source. Comparative conversion was observed when
ammonium carbonate was used as ammonia source; however,
it requires longer reaction time. Hence, ammonium acetate
was found to be the most efficient ammonia source for the
present three-component synthesis, and further reactions were
carried out using ammonium acetate as a source of ammonia.
In order to evaluate the scope and limitations of the
present protocol, the reaction was further performed using
various substituted 2-aminoaryl ketones and trialkyl
orthoesters, and the results are summarized in Table 2.
To evaluate the generality of the reaction, the reaction
was performed with both 2-aminobenzophenones and 2′-
aminoacetophenones. The reaction with 2′-aminoaceto-
phenones proceeds faster than 2-aminobenzophenones to
yield corresponding quinazolines. This may be attributed
Table 2
Three-component synthesis of quinazolines under solvent-free and catalyst-free conditions.
Entry
2-Aminoarylketone
Trialkyl orthoester
Time (min)
Producta
Yield (%)b
Lit. ref.c
1
2
3
4
5
H–C(OC2H5)3
120
120
120
120
150
4a
4b
4c
4d
4e
93
89
90
86
90
59,60
59,60
59
H3C–C(OC2H5)3
H5C2–C(OC2H5)3
H9C4–C(OCH3)3
H5C6–C(OCH3)3
59
6
7
8
9
H–C(OC2H5)3
120
120
120
150
4f
4g
4h
4i
94
88
88
87
60,61
62
59
H3C–C(OC2H5)3
H5C2–C(OC2H5)3
H5C6–C(OCH3)3
10
11
12
H–C(OC2H5)3
H3C–C(OC2H5)3
H5C6–C(OCH3)3
120
120
150
4j
4k
4 l
93
86
84
63
36
13
14
15
16
H–C(OC2H5)3
120
120
120
150
4m
4n
4o
88
76
79
H5C2–C(OC2H5)3
H9C4–C(OCH3)3
H5C6–C(OCH3)3
4p
Trace
17
18
19
H–C(OC2H5)3
H3C–C(OC2H5)3
H5C6–C(OCH3)3
90
120
120
4q
4r
4s
88
79
81
64,65
59
20
21
22
H–C(OC2H5)3
H3C–C(OC2H5)3
H5C6–C(OCH3)3
90
120
120
4t
4u
4v
Trace
82
84
41
aReaction conditions: 2-aminoaryl ketone (1 mmol), trialkyl orthoester (1.5 mmol), and ammonium acetate (1.5 mmol) at 110°C.
bIsolated yield.
cThe spectral data are consistent with reported literature.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. I. Bhat, U. K. Das, and D. R. Trivedi
Vol 000
to the steric factor induced by the aryl substitution, which
reduces the reactivity of carbonyl group. The reaction
worked well with both electron-withdrawing and electron-
donating substituents on the aniline ring of 2-amino-
benzophenones. However, poor conversion was observed
with strong electron-donating group on the aniline ring of
2′-aminoacetophenone, and unexpectedly, only trace amount
of product was observed when 2-amino-4′,5′-dimethoxy-
acetophenone reacted with triethyl orthoformate, even after
prolonged reaction time as shown in Table 2, entry 20.
Furthermore, the reaction feasibility was also exam-
ined with different substituted trialkyl orthoesters. The
reactivity of aliphatic orthoesters was found to be better
than orthobenzoate, and their order of reactivity is
orthoformate > orthoalkylate (orthoacetate ≈ orthopropio-
nate ≈ orthovalerate) > orthobenzoate. This may be attri-
buted to the steric effect induced by the substituent on the
orthoester functionality. It was found that there was no
remarkable effect of chain length of orthoalkylates on
the present reaction. For instance, the reaction of
2-aminobenzophenone with orthoacetate, orthopropionate,
and orthovalerate underwent smoothly to obtain corres-
ponding quinazolines in good yields. The reactions of
2-aminobenzophenones with trimethyl orthobenzoate found
to be very slow and took longer time to complete. This
may be attributed to the formation of stabilized imidate inter-
mediate (I, scheme 2) as a result of the presence of phenyl
group at 2-position, and this phenomenon helps us to isolate
the intermediate in order to predict the mechanistic pathway.
To elucidate the reaction mechanism, the reaction of 2-
aminobenzophenone with ammonium acetate and trime-
thylorthobenzoate was quenched after 60 min. It was found
that the reaction was incomplete and methyl N-2-
benzoylphenylbenzimidate (4ei) was formed as a major
product with trace amount of aromatized quinazoline 4e.
Further, a similar observation was found when the three-
component reaction was performed using (2-amino-5-
chlorophenyl)(phenyl)methanone and (2-amino-5-chlorophenyl)
(2-fluorophenyl)methanone. The isolated intermediates
4ei, 4ii, and 4li were confirmed by spectral analysis, and
in addition, N-2-benzoyl-4-chlorophenylbenzimidate (4ii)
was confirmed by single crystal X-ray diffraction analysis
(CCDC no. 912138) (Figure 1).
Figure 1. ORTEP (50% probability) diagram of the crystal structure of N-
2-benzoyl-4-chlorophenylbenzimidate (4ii). [Color figure can be viewed in
the online issue, which is available at www.interscience.wiley.com].
Based on our studies and literature references, two plausible
mechanistic pathways are proposed as shown in Scheme 2. It
Scheme 2. Proposed mechanism for the formation of quinazolines 4 in the current protocol.
R2
R2
O
O
O
R2
R1
I
II
III
R
N
R
N
path A
NH3
R
R
O
O
NH
N
O
O
R1
R2
N
H
NH2
2 R2OH
H2O
R2
R2
R1
R1
O
1
NH3
R2OH
R2OH
path B
R
R
N
O
N
R1
N
H2O
R1
IV
NH2
4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
An Efficient Three-component, One-pot Synthesis of Quinazolines under Solvent-
free and Catalyst-free Condition
(1.5 mmol), and ammonium acetate 3 (1.5 mmol) were charged
into a 10-mL round-bottom flask, and the mixture was heated to
110°C using conventional oil bath. The reaction mixture was
stirred for 90–150 min until the starting material 1 was consumed
to maximum extent. The mixture was diluted with EtOAc
(10 mL × 2) and quenched with water (10 mL). The organic layer
was separated and directly column chromatographed using 1:9
ethyl acetate/petroleum ether (boiling range 60–80°C) as the
eluent to obtain pure quinazoline 4. The structures of the products
were unequivocally confirmed by spectral data and elemental
analysis. All spectra of previously reported compounds were
consistent with literature [36,41,59–65].
2,4-Diphenylquinazoline (4e). White solid; yield: 90%; mp:
119–121°C (lit. 118–120°C) [56]; IR (neat, cmÀ1): 3056, 1610,
1562, 1535, 1482, 1380, 1336, 1165, 1073; 1H-NMR
(500 MHz, CDCl3) δ: 7.48–7.55 (m, 4H), 7.59–7.62 (m, 3H),
7.87–7.90 (m, 3H), 8.13(d, 1H, J = 8.5Hz), 8.16 (d, 1H,
J = 8.5Hz), 8.7 (dd, 2H, J1 = 8 Hz, J2 = 1.5 Hz); 13C-NMR
(100.6 MHz, CDCl3) δ: 121.7, 126.9, 128.4, 128.6, 128.7, 129.2,
129.9, 130.2, 130.5, 133.5, 137.7, 138.2, 152.0, 160.3, 168.3; ESI
MS (m/z) = 283.1 (M+ H)+; Anal. Calcd for C20H14N2: C, 85.08;
H, 5.00; N, 9.92, Found: C, 84.94; H, 5.14; N, 9.82.
6-Chloro-2,4-diphenylquinazoline (4i). White solid; yield:
87%; mp: 196–198°C (lit. 190–192°C) [57]; IR (neat, cmÀ1):
3051, 1556, 1530, 1473, 1381, 1301, 1157, 1071; 1H-NMR
(500 MHz, CDCl3) δ: 7.49–7.55 (m, 3H), 7.60–7.64 (m,
3H), 7.81(dd, 1H, J1 = 2 Hz, J2 = 9 Hz), 7.85–7.88 (m, 2H),
8.09–8.11 (m, 2H), 8.66–8.68 (m, 2H); 13C-NMR
(100.6 MHz, CDCl3) δ: 122.2, 125.8, 128.6, 128.7, 128.8,
130.1, 130.2, 130.8, 130.9, 132.6, 134.5, 137.1, 137.8,
150.5, 160.5, 167.6; ESI MS (m/z) = 317.1 (M + H)+; Anal.
Calcd for C20H13ClN2: C, 75.83; H, 4.14; N, 8.84, Found: C,
75.67; H, 4.28; N, 8.71.
6-Chloro-4-(2-fluorophenyl)-2-methylquinazoline (4k). White
solid; yield: 86%; mp: 139–141°C; IR (neat, cmÀ1): 3059,
2913, 1614, 1548, 1484, 1385, 1215; 1H-NMR (500 MHz,
CDCl3) δ: 2.95 (s, 3H), 7.27–7.31 (m, 1H), 7.38 (td, 1H,
J1 = 1 Hz, J2 = 7.5 Hz); 7.56–7.59 (m, 2H), 7.72 (t, 1H,
J = 2.5 Hz), 7.81 (dd, 1H, J1 = 2.5 Hz, J2 = 9 Hz), 7.96 (d, 1H,
J = 9 Hz); 13C-NMR(100.6 MHz, CDCl3) δ: 26.5, 116.2,
116.4, 124.9, 125.6, 129.9, 131.5, 132.0, 132.1, 132.7,
135.0, 149.5, 161.0, 163.9; ESI MS (m/z) = 273.1 (M + H)+;
Anal. Calcd for C15H10ClFN2: C, 66.06; H, 3.70; N, 10.27,
Found: C, 65.90; H, 3.81; N, 10.13.
was unambiguously confirmed that the initial reaction of 2-
aminoketone and orthoester leads to the formation of imidate
intermediate [I] with the elimination of alcohol. The imidate
intermediate [I] can undergo two different pathways to
obtain the final quinazoline (4). According to Panja et al.,
the ketone group can form a ketimine [II] by condensation
with the ammonia generated [42], which on simultaneous
intramolecular cyclization and aromatization with the elimi-
nation of alcohol yields quinazoline (4). Alternatively, the
imidate can react with ammonia generated to form
vinylamidine intermediate [IV] [55], which can lead to for-
mation of the final quinazoline (4) product through intramo-
lecular cyclization with the elimination of water.
CONCLUSION
In conclusion, herein we report a three-component, one-pot
synthesis of quinazolines using 2-aminoaryl ketones,
orthoesters, and ammonium acetate as building blocks under
solvent-free and catalyst-free conditions. The mechanism has
been investigated scientifically with the confirmation of the
intermediate using spectral and single crystal X-ray analysis.
It was clearly found that the first step of the reaction involves
the formation of imidate intermediate. Notably, this single
flask protocol offers easier method to synthesize both aliphatic
and aromatic substitutions at 2-position and 4- position of
quinazolines. The current protocol circumvents some of the
problems and limitations associated with the earlier proce-
dures, is advantageous in terms of operational simplicity,
ready availability of starting materials, simple work up proce-
dure, and high product yield, and it is conceivable that it offers
a facile and environmental friendly approach toward the
development of biologically potent quinazolines.
EXPERIMENTAL
General methods.
Melting points were determined with
Stuart SMP3 (Stuart Scientific, UK) melting point apparatus and
are uncorrected. IR spectra were recorded on a Thermo
scientific Nicolet Avatar 330 (Thermo Scientific, USA) FT-IR
spectrometer as neat sample. NMR spectra were recorded as a
solution in CDCl3/DMSO-d6 500 MHz (1H) and 400 MHz (13C)
instrument. Chemical shifts (δ) are reported in parts per million
(ppm) with TMS as an internal standard. NMR raw data were
analyzed with the program MestReNova (Mestrelab Research)
7.0.0-8331. Mass spectra were performed on Waters Micromass
Q-Tof mass spectrometer with an ESI source. Elemental
analysis was performed using Perkin Elmer, Series II, 2400
(Perkin Elmer, USA) analyzer. The X-ray single-crystal
diffraction was performed on the Bruker AXS APEX II system
(Bruker, Germany). All experiments were monitored by TLC,
performed on pre-coated silica gel 60 F254 plates (Merck).
2-Ethyl-6-nitro-4-phenylquinazoline (4n).
Pale yellow
solid; yield: 76%; mp: 127–129°C; IR (neat, cmÀ1): 3090,
2975, 2917, 2850, 1611, 1578, 1542, 1474, 1326, 1079;
1H-NMR (500 MHz, DMSO-d6) δ: 1.43 (t, 3H, J = 7.5 Hz),
3.16 (q, 2H, J = 7.5 Hz), 7.68–7.73 (m, 3H), 7.88 (dt, 2H,
J1 = 2 Hz, J2 = 5.5 Hz), 8.22 (d, 1H, J = 9 Hz), 8.68 (dd, 1H,
J1 = 2 Hz, J2 = 9 Hz), 8.82 (d, 1H, J = 2.5 Hz); 13C-NMR
(100.6 MHz, CDCl3) δ: 12.1, 32.9, 119.6, 123.7, 126.3,
128.6, 129.5, 129.9, 130.4, 135.6, 144.9, 153.5, 170.0,
170.9; ESI MS (m/z) = 280.2 (M + H)+; Anal. Calcd for
C16H13N3O2: C, 68.81; H, 4.69; N, 15.05, Found: C,
68.94; H, 4.78; N, 14.91.
2-Butyl-6-nitro-4-phenylquinazoline (4o).
White solid;
yield: 79%; mp: 104–107°C; IR (neat, cmÀ1): 3059, 2953,
2925, 2860, 1615, 1543, 1491, 1336, 1251, 1086; 1H-
NMR (500 MHz, DMSO-d6) δ: 0.95 (t, 3H, J = 7.5 Hz),
1.39–1.46 (sextet, J = 7.5 Hz, 2H), 1.86–1.92 (m, 2H), 3.13
(t, 2H, J = 7.5 Hz), 7.68–7.73 (m, 3H), 7.86–7.88 (m, 2H),
Column chromatography was performed on silica gel
(
60–120 mesh, Merck) using ethyl acetate/petroleum ether
(boiling range 60–80°C) as eluent.
General procedure for the synthesis of quinazoline
derivatives.
2-Aminoaryl ketone 1 (1 mmol), orthoester 2
Journal of Heterocyclic Chemistry
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S. I. Bhat, U. K. Das, and D. R. Trivedi
Vol 000
8.21 (d, 1H, J = 9.5 Hz), 8.67 (dd, 1H, J1 = 2.5 Hz, J2 = 9.5 Hz),
8.81 (d, 1H, J = 2.5 Hz); 13C-NMR (100.6 MHz, CDCl3) δ:
13.9, 22.7, 30.8, 40.0, 120.1, 124.2, 126.9, 129.1, 130.1,
130.4, 130.9, 136.2, 145.4, 153.9, 170.5, 170.8; ESI MS
(m/z) = 308.2 (M + H)+; Anal. Calcd for C18H17N3O2: C,
70.34; H, 5.58; N, 13.67, Found: C, 70.50; H, 5.41; N,
13.49.
Acknowledgments. D. R. T. and S. I. B. acknowledge the director
and the HOD of the Department of Chemistry, NITK, Surathkal,
for providing the research infrastructure. S. I. B. is thankful to
NITK for the research fellowship. D. R. T. and S. I. B. are also
thankful to CSMCRI Bhavnagar, IISc Bangalore, and SAIF
Panjab University, for providing analytical support.
4-Methyl-2-phenylquinazoline (4s).
White solid; yield:
81%; mp: 71–74°C (lit. 72–76°C) [58]; IR (neat, cmÀ1): 3058,
3007, 2920, 1611, 1540, 1489, 1432, 1387, 1335, 1226, 1023;
1H-NMR (500 MHz, CDCl3) δ: 3.03 (s, 3H), 7.49–7.55 (m,
3H), 7.57–7.60 (m, 1H), 7.85–7.88 (m, 1H), 8.07–8.11 (m, 2H),
8.61–8.63 (m, 2H); 13C-NMR (100.6 MHz, CDCl3) δ: 22.03,
123.05, 125.0, 126.9, 128.6, 129.3, 130.4, 133.5, 138.4, 150.5,
160.2, 168.2; ESI MS (m/z) = 221.1 (M + H)+; Anal. Calcd for
C15H12N2: C, 81.79; H, 5.49; N, 12.72, Found: C, 81.90; H,
5.33; N, 12.65.
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6,7-Dimethoxy-2,4-dimethylquinazoline
(4u).
Light
brownish solid; yield: 82%; mp: 87–89°C; IR (neat, cmÀ1):
2944, 2838, 1655, 1614, 1568, 1500, 1461, 1410, 1234,
1014; 1H-NMR (500 MHz, CDCl3) δ: 2.8 (s, 3H), 2.85 (s,
3H), 4.04 (s, 6H), 7.18 (s, 1H), 7.25 (s, 1H); 13C-NMR
(100.6 MHz, CDCl3) δ: 21.7, 26.2, 56.2, 56.3, 102.3, 106.7,
155.7, 164.7; ESI MS (m/z) = 219.1 (M + H)+; Anal. Calcd for
C12H14N2O2: C, 66.04; H, 6.47; N, 12.84, Found: C, 65.93;
H, 6.55; N, 12.77.
Methyl N-2-benzoylphenylbenzimidate (intermediate of 4e)
(4ei).
Pale yellow viscous liquid; IR (neat, cmÀ1): 3059,
2947, 1648, 1594, 1446, 1284, 1109; 1H-NMR (500 MHz,
CDCl3) δ: 3.52 (s, 3H), 6.76 (dd, 1H, J1 = 1.5 Hz, J2 = 8 Hz),
7.05(td, 1H, J1 = 1 Hz, J2 = 7.5 Hz), 7.16–7.23 (m, 4H),
7.28–7.41 (m, 5H), 7.50–7.53 (m, 1H), 7.67–7.69 (m, 2H);
13C-NMR(100.6 MHz, CDCl3) δ: 53.9, 115.5, 117.0, 122.3,
122.5, 128.0, 128.1, 129.1, 129.1, 129.8, 130.1, 131.5,
132.5, 147.3, 159.4, 197.3; ESI MS (m/z) = 338.2 (M + Na)+,
316.2 (M + H)+, 284.2 (M–OMe)+; Anal. Calcd for
C21H17NO2: C, 79.98; H, 5.43; N, 4.44, Found: C, 79.92; H,
5.51; N, 4.38.
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Methyl N-2-benzoyl-4-chlorophenylbenzimidate (intermediate
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of 4i) (4ii).
White solid; mp: 96–98°C; IR (neat, cmÀ1):
3059, 2949, 1651, 1590, 1441, 1396, 1280, 1108; 1H-NMR
(500MHz, CDCl3) δ: 3.50 (s, 3H), 6.70 (d, 1H, J = 8.5 Hz),
7.2 (d, 2H, J = 4 Hz), 7.28–7.33 (m, 4H), 7.40–7.43 (m, 2H),
7.53–7.56 (m, 1H), 7.7 (dd, 2H, J1 = 1 Hz, J2 = 8 Hz);
13C-NMR (100.6 MHz, CDCl3) δ: 54.0, 123.9, 127.8, 128.2,
128.3, 129.0, 129.3, 129.8, 130.4, 130.7, 131.3, 132.6,
132.9, 137.3, 145.8, 160.1, 195.8; ESI MS (m/z) = 372.2
(M + Na)+, 350.2 (M + H)+, 318.2(M–OMe)+; Anal. Calcd for
C21H16ClNO2: C, 72.10; H, 4.61; N, 4.00, Found: C, 71.98;
H, 4.56; N, 4.11.
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Methyl N-4-chloro-2-(2-fluorobenzoyl)phenylbenzimidate
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White solid; mp: 93–96°C; IR
(neat, cmÀ1): 3061, 2933, 2921, 1645, 1597, 1477, 1442,
1278, 1223, 1105; 1H-NMR (500 MHz, CDCl3) δ: 3.43 (s,
3H), 6.60 (d, 1H, J = 9 Hz), 7.06–7.10 (m, 1H), 7.19–7.25 (m,
6H), 7.31–7.34 (m, 1H), 7.46–7.50 (m, 3H); 13C-NMR
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128.2, 129.0, 129.5, 130.4, 130.5, 130.9, 132.2, 133.7, 133.8,
146.1, 159.8, 160.0, 162.3, 192.4; ESI MS (m/z) = 390.2
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