Divergent Synthesis of Quinazolines Using Organocatalytic Domino Strategies under Aerobic Conditions

Article abstract of DOI:10.1002/ejoc.201800746

An easy and efficient organocatalytic approach to the synthesis of 2-substituted quinazolines is described based on the reaction between 2-aminobenzylamines and aldehydes or alcohols or amines. Three organocatalytic platforms were investigated, using 3-nitropyridine, pyridine N-oxide, and vitamin B₃. Having established the new catalytic systems, the tandem transformations of 2-aminobenzylamines to give substituted quinazolines were achieved in excellent yields and with a broad substrate scope, with no formation of toxic side-products. The investigated conditions are not restricted to the use of aldehydes; the protocol also works well with alcohols or amines as substrates. These are oxidized in situ to the corresponding aldehydes to achieve the successful transformation. A mechanistic proposal has been drawn up based on control experiments. We found that under aerobic conditions, catalytic amounts of H₂O₂ can be generated; this plays a key role in the efficacy of the described approach. The green chemistry metrics of the developed method are also presented. The E factor of 8.18 mg/1 mg demonstrates that the reported method is an excellent complement to previous protocols.

Full text of DOI:10.1002/ejoc.201800746

A Journal of
Accepted Article
Title: Divergent Synthesis of Quinazolines using Organocatalytic
Domino Strategies under Aerobic Conditions
Authors: Chandi C Malakar, Raghuram Gujjarappa, Suvik K. Maity,
Chinmoy K. Hazra, Nagaraju Vodnala, Shiv Dhiman, Anil
Kumar, and Uwe Beifuss
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800746
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10.1002/ejoc.201800746
European Journal of Organic Chemistry
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Divergent Synthesis of Quinazolines using Organocatalytic
Domino Strategies under Aerobic Conditions
Raghuram Gujjarappa,[a]† Suvik K. Maity,[a]† Chinmoy K. Hazra,[b] Nagaraju Vodnala,[a] Shiv Dhiman,[c]
Anil Kumar,[c] Uwe Beifuss,[d] Chandi C. Malakar*[a]
Abstract: Efficient organocatalytic platforms are described to
accomplish the easy transformation towards 2-substituted
quinazolines using the reaction between 2-aminobenzylamines and
aldehydes or alcohols or amines. Three distinct organocatalytic
platforms are investigated those rely on the use of 3-nitropyridine,
pyridine-N-oxide and vitamin-B3. Having established the novel
catalytic systems, the tandem transformations of 2-
aminobenzylamines to the substituted quinazolines are achieved
with excellent yields and broad substrate scope that avoids the
formation of toxic side-products. The investigated conditions are
not only restricted to the use of aldehydes, rather the scope of the
protocol can be extended to alcohols or amines as substrates
which was in-situ oxidized to the corresponding aldehydes to
realize the successful transformation. A mechanistic proposal has
been drawn and based upon the control experiments. It was
demonstrated that under the influence of aerobic conditions the
catalytic amounts of H2O2 can be generated which plays a pivotal
role towards efficacy of the described approach. The green
chemistry merits of the developed method have been represented
with the E-factor of 8.18 mg/1 mg, which shows the revealed
method is an excellent complement to the previous protocols.
new organocatalytic system still remains challenging in
multidisciplinary fields of research. Here we report three
independent organocatalytic systems based on 3-nitropyridine,
Figure 1. Selected quinazoline embodied FDA approved marketed drugs.
pyridine-N-oxide and vitamin-B3. Under the aerobic conditions
the described organocatalysts are found efficient to drive the
Introduction
Organocatalytic transformations for the elaboration of complex
molecules have revised organic synthesis and during recent
years the field has remarkably driven the effective synthesis of
biologically active small molcules.[1] The area has been
copiously documented and well-exercised in both academic as
well as industrial sectors.[2,3] Recently, the well-recognized
advantages in the reactivity and intellectual property positions of
organocatalysis have lead many scientists to favor their
application in the field of drug-discovery and medicinal
chemistry.[4] In addition, the concept of organocatalysis has
provided a surrogate and sustainable platform towards varieties
of novel oxidative transformations.[5] Hence, the investigation of
[a]
R. Gujjarappa, S. K. Maity, N. Vodnala, Dr. C. C. Malakar
Department of Chemistry, National Institute of Technology Manipur,
Langol, Imphal - 795004, Manipur.
E-mail: cmalakar@nitmanipur.ac.in
[b]
[c]
[d]
Dr. C. K. Hazra
Department of Chemistry, Korea Advanced Institute of Science &
Technology (KAIST), Daejeon 305 - 701, South Korea.
Shiv Dhiman, Prof. Anil Kumar
Department of Chemistry, BITS Pilani, Pilani Campus, Pilani,
Rajasthan 333031, India.
Scheme 1. Approaches for the synthesis of 2-substituted quinazolines.
Prof. Dr. U. Beifuss
Institut für Chemie, Universität Hohenheim, Garbenstr. 30, D-70599
Stuttgart, Germany.
† R.G. and S.K.M. contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
oxidative transformations for the synthesis of 2-substituted
quinazolines.
N-heterocyclic skeletons are often realized as the core structural
units in both biologically and industrially due to their wide
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10.1002/ejoc.201800746
European Journal of Organic Chemistry
FULL PAPER
occurrence in natural products and valuable medicinal
compounds (Figure 1).[6] Among the N-heterocyclic scaffolds,
wide varieties of quinazoline embodied molecules are of
immense biological relevance. These molecules witnessed for
the pharmacological utilities like antiviral, antibacterial,
anticancer, antitubercular, anticonvulsant, sedative, hypotensive,
antidiabetic, and antitussive activities.[7-11]
as one of the major topics of research in the synthesis of six-
membered heterocycles.[6c] In this regards, a large number of
transition metal-catalyzed transformations using Cu, Rh, Pt, Ir,
and Zn have been devoted in recent years for the synthesis of
these scaffolds (Scheme 1a).[28] Consequently, to serve the
synthesis of these molecules, several strong as well as toxic
organic and inorganic reagents were introduced to oxidize the
derived intermediate from the reaction between 2-aminobenzyl
alcohols or 2-aminobenzylamines and aldehydes (Scheme
1b).[29] The use of large excess of non-renewable, hazardous
and toxic oxidants may restrict the novelty of these protocols.
Table 1. Screening of the conditions for the reaction between 1a and 2a.[a]
Table 2. Optimization of organocatalytic conditions for the reaction of 1a with
2a.[a]
b]
S.N
1
Catalyst (mol%)
TBAI (30)
Conditions
TBHP (1.5
% Yield 3a [
equiv.),
80
DMSO, air, 120 °C, 16 h
TBHP (1.5 equiv.), H2O,
air, 120 °C, 16 h
S.N.
Catalyst (mol%)
Conditions
% Yield 3a
2
TBAI (30)
N.R
85
b]
[
TBHP
(1.5
equiv.),
3
-
1
2
3
4
5
6
7
8
vitamin-B3 (30)
MeCN, air, 110 °C, 16 h
MeCN, air, 110 °C, 16 h
MeCN, air, 110 °C, 16 h
MeCN, air, 110 °C, 16 h
MeCN, air, 110 °C, 16 h
H2O, air, 110 °C, 16 h
THF, air, 110 °C, 16 h
89
DMSO, 120 °C, 9 h
2-picolinic acid (30)
3-nitropyridine (30)
pyridine-N-oxide (30)
isonicotinic acid (30)
vitamin-B3 (30)
86
K2S2O8
(1.5
equiv.),
4
-
71
DMSO, 120 °C, 7 h
95
H2O2
(1.5
equiv.),
5
-
83
91
DMSO, 120 °C, 10 h
85
NIS
(1.0
equiv.),
6 [c]
Ph2Se2 (10)
PhI (10)
I2 (30)
0[d]
54
THF/HFIP, 50 °C, 12 h
N.R
<5[c]
<5[c]
mCPBA (1.5 equiv.),
THF, 50 °C, 10 h
7
vitamin-B3 (30)
vitamin-B3 (30)
Toluene, air, 110 °C, 16
h
mCPBA (1.5 equiv.),
THF, 50 °C, 15 h
8
47
9
vitamin-B3 (30)
vitamin-B3 (30)
vitamin-B3 (30)
vitamin-B3 (15)
-
DMF, air, 110 °C, 16 h
DMSO, air, 110 °C, 16 h
MeCN, N2, 110 °C, 16 h
MeCN, air, 110 °C, 16 h
MeCN, air, 120 °C, 16 h
DMSO, air, 120 °C, 16 h
MeCN, air, 80 °C, 16 h
DMSO, air, 110 °C, 10 h
77
[a] All reactions were performed using 1.0 mmol 1 and 1.0 mmol 2a. [b]
Isolated yields. [c] THF/HFIP (3:1) was used as solvent. [d] Mixture of
unidentified compounds was formed; desired product was not observed.
10
11[d]
12
13
14
15
16
84
<5[c]
49
Those molecules include the FDA approved active marketed
drugs such as erlotinib,[12] afatinib,[13] gefitinib[14] and icotinib[15]
for the treatment of lung cancer; lapatinib[16] as orally active drug
used for the treatment of breast cancer and other solid tumors.
Among the other pharmaceuticals, prazosin[17] a α-adrenergic
blocker is valued for the treatment of anxiety, high blood
pressure and panic disorder; etifoxine[18] used as GABA
receptor inhibitor for the treatment of anxiolytic and
anticonvulsant and cetilistat[19] as pancreatic lipase inhibitor to
treat obesity. Additionally, some reported quinazoline containing
alkaloids have immense importance in medicinal chemistry.[20-27]
The well-known alkaloids of these type include Luotonin A,[20]
tryptanthrin,[21] febrifugine,[22] peganidine,[23] (+)-anisotine,[24] (-)-
vasicinone[25] and vasicine.[26] Another important quinazoline
based alkaloid rutaecarpine[27] is actively used for the treatment
of gastrointestinal disorders, antiinflammatory, headaches, and
postpar tum haemorrhage. Therefore, the investigation of
convenient approaches for the substituted quinazolines remain
7[c]
11[c]
49
-
vitamin-B3 (30)
vitamin-B3 (30)
61
[a] All reactions were performed using 1.0 mmol 1 and 1.0 mmol 2a. [b]
Isolated yields. [c] Starting material was recovered. [d] Reaction was carried
out under nitrogen atmosphere.
More recently, the organocatalytic platforms are recognized for
their
azabicyclo[3.3.1]nonan-N-oxyl, TEMPO and rose Bengal as
green organocatalytic systems.[30] Although, the mentioned
previous methods[28-30] and some other reported methods[31] are
useful, and have found extensive application in the synthesis;
synthesis.[30]
These
approaches
rely
on
9-
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10.1002/ejoc.201800746
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the development of more general and practical organocatalytic
Results and
Discussion
With the ideas in
mind
towards
developing facile
organocatalyzed
aerobic oxidation
protocol for the
synthesis
quinazolines, we
carried out
of
several screening
reactions between
2-aminobenzyl
amine 1a and
benzaldehyde 2a,
(Table 1) and
observed that the
2-
phenylquinazoline
3a was obtained
in 80% yield in the
presence of 30
mol% TBAI and
1.5
TBHP, when the
reaction was
equiv.
of
carried out in
DMSO as solvent
(Entry
1).
However,
the
formation of the
product
inhibited
DMSO
was
when
was
replaced
with
water as solvent
(Entry 2). It was
also
observed
that TBAI has no
Scheme 2. Scope towards the synthesis of quinazolines using novel organocatalysts A, B and C under
influence
on
aerobic conditions.
successful
completion of the
reaction (Entry 3).
platforms are highly desirable. As part of our on-going research
Next, we have attempted to check the feasibility for the
formation of desired product 3a using equivalent amounts of
alternative oxidants such as K2S2O8, and H2O2 (Entries 4-5). It
was found that among the oxidants screened, using 1.5 equiv. of
TBHP the reaction between 1a and 2a delivered the highest
yield of the expected product 3a (Entry 3). Moreover, when the
reaction between 1a and 2a was realized in the presence of 10
mol% Ph2Se2 and 1.5 equiv. NIS as oxidant using DMSO as
solvent, desired product 3a was not identified (Entry 6).
Additionally, the desired product 3a was obtained in moderate
yields, when iodine sources as catalyst and mCPBA as oxidant
were used for the reaction between 1a and 2a (Entries 7-8).
program on developing novel catalytic approaches constraining
the use of excess amounts of reagents, we aimed to investigate
a surrogate protocol for the synthesis of these scaffolds using
easy-to-operate synthetic tools. Hence, we describe that 3-
nitropyridine, pyridine-N-oxide and vitamin-B3 can be exclusively
employed as independent organocatalyst in the reaction
between 2-aminobenzylamines and aldehydes to furnish the
corresponding 2-substituted quinazolines in excellent yields
(Scheme 1, reactions (d)). The developed protocol has been
extended to benzylalcohols and benzylamines as the easy-
available substrates.
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Albeit, under multiple screening conditions the formation of
desired product 3a was observed with high yields (Entries 1, 3-
5); however, our aim still remains towards the optimization of the
conditions that rely on identifying the new organocatalyst for the
conversion of 1a and 2a into 3a. To test the desired possibilities
a series of test reactions were carried out (Table 2). In this
regards, the screening reactions between 1a and 2a were
attempted in presence of catalytic amounts of pyridine
derivatives such as vitamin-B3, 2-picolinic acid, 3-nitropyridine,
pyridine N-oxide and
further scope of the developed methods, the reactivity of a range
of non-aromatic aldehydes such as cinnamaldehydes 2v-w,
formaldehyde 2x and butanal 2y were investigated under the
optimal conditions to obtain the desired quinazolines 3v-y in
high yields.
After having realized the successful application of a diverse
range of aldehydes, we then envisioned to describe the scope of
isonicotinic acid using MeCN as solvent under aerobic
conditions at 110 °C for 16 hours (Entries 1-5). It was found that
among the attempted pyridine derivatives, using 30 mol% of 3-
nitropyridine as catalyst showed the highest efficiency (Entry 3).
However, similar yields of the product 3a were also observed
when 30 mol% of vitamin-B3 (Entry 1), 30 mol% of 2-picolinic
acid (Entry 2), 30 mol% of pyridine N-oxide (Entry 4) and 30
mol% of isonicotinic acid (Entry 5), were used as catalysts. It
was further observed that H2O, THF and toluene as solvents
were inactive to accomplish the transformation (Entries 6-8),
while performing the reaction in DMF and DMSO as solvents
obtain the high yields of the product 3a (Entries 9-10).
Interestingly, when the reaction was performed under nitrogen
atmosphere, formation of the desired product 3a was not
observed (Entry 11). Moreover, the yield of product 3a was
decreased dramatically in the presence of low catalyst loading
(Entry 12). Albeit in low yields, the product 3a was formed in 7%
and 11% respectively, when the reactions between 1a and 2a
were carried out in absence of catalyst under the influence of
MeCN and DMSO (Entries 13-14). Additionally, it was found that
decreasing the reaction temperature and time resulted
insufficient yields of the product 3a (Entries 15-16). Having
performed an extensive optimization of the reaction conditions, it
was realized that the maximum yield of product 3a was obtained
when the reaction between 1 mmol of 1 and 1 mmol of 2a was
conducted in presence of 30 mol% 3-nitropyridine as catalyst
using MeCN as solvent under aerobic conditions at 110 °C for
16 hours (Table 2, Entry 3). These conditions were then
employed to execute the scope of the reaction (Conditions A).
Additionally, the scope of the reactions has also been verified
using 30 mol% pyridine N-oxide (conditions B: Table 2, Entry 4)
or 30 mol% vitamin-B3 (Conditions C: Table 2, Entry 1) as
catalyst in MeCN as solvent under aerobic conditions at 110 °C
for 16 hours.
Scheme 3. Substrate scope for the synthesis of 2-substituted quinazolines.
2-aminobenzylamines
1
under the optimized conditions
(Scheme 3). It was identified that 2-aminobenzylamines 1b-d
containing both electron-rich and electron-poor substituent were
capable for the reaction with aromatic aldehydes 2 to afford the
desired quinazolines 3 in high isolated yields.
Having three independent optimized conditions in hand, further
the reactivity of a broad range of aromatic, heteroaromatic and
aliphatic aldehydes 2a-y containing both electron donating
groups and electron withdrawing groups were tested (Scheme 2).
It has been described that electron donating groups such as
hydroxy, methoxy and methyl residue on aromatic ring, as well
as electron withdrawing substituents such as bromo, chloro,
nitro, fluoro, trifluoromethyl and ester functionalities were well
tolerated under the influence of developed organocatalytic
conditions to furnish the desired products 3a-p with good to
excellent isolated yields. Interestingly, heteroaromatic aldehydes
2q-r and polycyclic aromatic aldehydes 2s-u also delivered the
corresponding quinazolines 3q-u in high yields. To extend the
Scheme 4. Plausible mechanism for 3-nitropyridine catalyzed synthesis of
2-substituted quinazolines under aerobic conditions.
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Next, our observation towards similar yields using catalysts A, B
and C inspired us to question about the plausible mechanistic
pathways for the formation of desired quinazolines 3. In order to
identify the plausible mechanism, we paid our attention towards
conditions via the stepwise formation of superoxide ion and
dioxygen dianion. Next, the catalytic amounts of 3-nitropyridine-
N-hydroxide A1 can be formed in-situ by the reaction between 3-
nitropyridine A and H2O2 which can be further converted to A2 in
the optimizations for the reaction between 1a and 2a (Table 1, 2). presence of aerial oxygen and 3-nitropyridine A. The
In this regards some screening reactions have been identified to
conclude the plausible mechanism; these conditions are (i) the
reaction delivered the desired product 3a when peroxides have
been used as oxidants (Table 1, Entries 1-3 and 5), (ii) formation
of the desired product 3a was reduced drastically when the
intermediates 5, 6 and 7 are formed via successive hydrogen
abstraction by A2 which can be generated by re-oxidation of
intermediate A1. Finally, the interaction between intermediate 7
and A2 leading to the formation of the product 3a and A1. The
proposed mechanism has been supported by the experiment
performed in presence of nitrogen atmosphere that failed to
deliver the product 3a (Table 2, Entry 11). However, in absence
of catalyst only catalytic amounts of H2O2 can be generated
using aerial oxygen which could afford the minor amounts of
product 3a (Table 2, Entries 13-14) and the formation of the
Scheme 6. Oxidation of benzylalcohols and benzylamines using developed
organocatalytic conditions under aerobic conditions.
product 3a can be accelerated using external peroxide as
oxidant (Table 1, Entries 1-3 and 5). These observations align
with the fair involvement of aerial oxygen with which the
generation of H2O2 might be possible under aerobic conditions.
Scheme 5. Scope of benzylalcohols and benzylamines under developed
conditions.
reaction was performed under nitrogen atmosphere (Table 2,
Entry 11), while a minor amounts of the product 3a was formed
when the reactions were carried out under aerobic conditions in
absence of catalyst using MeCN and DMSO as solvent (Table 2,
Entries 13-14), (iii) reaction delivered the desired product 3a in
presence of all pyridine derivatives those used as catalysts
under the aerobic conditions (Table 2, Entries 1-5). On the basis
of our experimental observations and literature evidence,[30b,32]
a
plausible mechanism has been drawn in scheme 4. It is
expected that the intermediate 4, can be formed by the
condensation reaction between 1a and 2a. On the other hand,
the catalytic amounts of H2O2 might be generated under aerobic
Scheme 7. Evaluation of green chemistry metrics for the synthesis.
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10.1002/ejoc.201800746
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on a Brucker spectrometer using CDCl3 and DMSO-d6 as a solvent. The
1H and 13C chemical shifts were referenced to residual solvent signals at
Moreover, the yield of product 3a was diminished when the
reaction was carried out in the presence of 60 mol% of TEMPO
as radical scavenger that indicates the radical nature of the
reaction pathways for the formation of the desired product 3a
(Scheme 4).
H/C 7.26 /77.28 (CDCl3) and H/C 2.51 /39.50 (DMSO-d6) relative to TMS
as internal standards. Coupling constants J [Hz] were directly taken from
the spectra and are not averaged. Splitting patterns are designated as s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), overlapped and
br (broad).
To extend the further scope of the developed transformation, the
reactivity of a broad spectrum of alcohols 8a-o and amines 9a-k
have been examined under the optimized conditions (Scheme 5).
It was identified that the developed conditions can effectively
induce the reaction between 1a and 8a-o or 9a-k to obtain the
desired quinazolines 3 in high yields. These results guided to
assume that using the organocatalytic conditions A, B or C the
corresponding alcohols 8a-o and amines 9a-k can be in-situ
oxidized to the corresponding aldehydes 2 under aerobic
conditions to accomplish the transformation. To confirm the
hypothesis, selected alcohols 8f,p and amines 9a,f were reacted
under the optimized conditions that delivered the corresponding
aldehydes 2a,d,j in high yields (Scheme 6).
After the successful development and operation of the depicted
approaches for the synthesis of the targeted N-heterocycles, we
intended to verify the green chemistry merits of the described
protocol (Scheme 7). It was found that the established method
reveals the E-factor of 8.18 mg/1 mg with high atom-economy
(90.34%), atom-efficiency (85.82%), carbon-efficiency (100%)
and reaction mass-efficiency (85.96%).
General experimental procedure for the synthesis of quinazolines
(3a-y or 3ba-dj) using aldehydes (2a-y): A 25 mL pressure tube was
charged with
a mixture of 2-aminobenzylamines 1a-d (1.0 mmol),
aldehydes 2a-y (1.0 mmol), MeCN (2 mL) and 30 mol% catalyst A (37.2
mg) or B (28.5 mg) or C (37 mg). The pressure tube was then sealed and
heated at 110 °C for 16 h. After completion of the reaction (progress was
monitored by TLC; SiO2, Hexane/EtOAc = 4:1), the mixture was diluted
with hot ethyl acetate (15 mL) and water (25 mL) and extracted with ethyl
acetate (3 × 10 mL). The combined organic layer was washed with brine
(3 × 10 mL) and dried over anhydrous Na2SO4. Solvent was removed
under reduced pressure and the remaining residue was purified by
column chromatography over silica gel using hexane / ethyl acetate = 4:1
(v/v) as an eluent to obtain the desired products 3a-y or 3ba-dj in high
yields.
General experimental procedure for the synthesis of quinazolines
(3a-t) using benzylalcohols (8a-o) or benzylamines (9a-k): A 25 mL
pressure tube was charged with a mixture of 2-aminobenzylamine 1a
(1.0 mmol, 122 mg), benzyl alcohols 8a-o (1.0 mmol) or benzylamines
9a-k (1.0 mmol), MeCN (2 mL) and 30 mol% catalyst A (37.2 mg) or B
(28.5 mg) or C (37 mg). The pressure tube was then sealed and heated
at 110 °C for 16 h. After completion of the reaction (progress was
monitored by TLC; SiO2, Hexane/EtOAc = 4:1), the mixture was diluted
with hot ethyl acetate (15 mL) and water (25 mL) and extracted with ethyl
acetate (3 × 10 mL). The combined organic layer was washed with brine
(3 × 10 mL) and dried over anhydrous Na2SO4. Solvent was removed
under reduced pressure and the remaining residue was purified by
column chromatography over silica gel using hexane / ethyl acetate = 4:1
(v/v) as an eluent to obtain the desired products 3a-t in high yields.
Conclusions
In summary, we have studied in depth the novel organocatalytic
synthesis of 2-substituted quinazolines under aerobic conditions
using 2-aminobenzyl amines and aldehydes as substrates. The
reactivity of a broad spectrum of alcohols and amines were also
investigated under established conditions to introduce the
surrogate of aldehydes as substrates. The proposed reaction
mechanism has been verified by several control experiments.
Considering the immense impact of 2-functionalized
quinazolines, these facile and convenient organocatalytic
approaches could be the excellent complements of current
methods which represent a low E-factor, and high atom-
economy, atom-efficiency, carbon-efficiency, and reaction mass-
efficiency.
2-Phenylquinazoline (3a)[30b] (Table 1-2, Scheme 2,5): Yellow solid, Rf
= 0.60 (SiO2, Hexane/EtOAc = 4:1); m.p = 100 - 102 °C (Lit[30b] 100 -
101 °C); 1H NMR (400 MHz, DMSO-d6): δ = 9.71 (s, 1H; 4-H), 8.57 (d, 3J
= 9 Hz, 2H; 12-H), 8.18 (d, 3J = 7.96 Hz, 1H; 8-H), 8.08 – 8.02 (m, 2H; 5-
H and 7-H), 7.75 (t, 3J = 7.5 Hz, 1H; 6-H), 7.56 – 7.57 (m, 3H; 13-H, and
14-H) ppm; 13C NMR (101 MHz, CDCl3) δ = 161.08 (C-2), 160.50 (C-4),
150.79 (C-9), 138.06 (C-11), 134.10 (C-7), 130.61 (C-14), 128.67 (C-8),
128.64 (C-13), 128.59 (C-12), 127.27 (C-6), 127.12 (C-5), 123.62 (C-10)
ppm; HRMS (EI, [M + H]+): calculated for C14H11N2: 207.0922; found:
207.0917.
2-(Quinazolin-2-yl)phenol (3b)[29d] (Scheme 2,5): Pale yellow solid, Rf =
0.60 (SiO2, Hexane/EtOAc = 4:1); m.p = 136 - 137 °C (Lit[29d] 135 -
136 °C); 1H NMR (400 MHz, CDCl3) δ = 13.72 (s, 1H; 17-H), 9.47 (s, 1H;
Experimental Section
General Method: All starting materials were purchased from commercial
suppliers (Sigma-Aldrich, Alfa-Aesar, SD fine chemicals, Merck, HI
Media) and were used without further purification unless otherwise
indicated. All reactions were carried out under aerobic condition in oven-
dried glassware with magnetic stirring. The reactions were performed in
pressure tube purchased from Sigma-Aldrich glassware. Solvents used
in extraction and purification were distilled prior to use. Thin-layer
chromatography (TLC) was performed on TLC plates purchase from
Merck. Compounds were visualized with UV light (λ = 254 nm) and/or by
immersion in KMnO4 staining solution followed by heating. Products were
purified by column chromatography on silica gel, 100 - 200 mesh. 1H
(13C) NMR spectra were recorded at 600 (150) MHz and 400 (100) MHz
3
4-H), 8.65 (d, 3J = 8.4 Hz, 1H; 8-H), 8.01 (d, J = 8.0 Hz, 1H; 16-H), 7.94
- 7.92 (overlapped, 2H; 5-H and 7-H), 7.64 (t, 3J = 8.0 Hz, 1H; 6-H), 7.43
(t, 3J = 7.2 Hz, 1H; 14-H), 7.07 (d, 3J = 8.0 Hz, 1H; 13-H), 7.00 (t, 3J = 8.0
Hz, 1H; 15-H) ppm; 13C NMR (101 MHz, CDCl3) δ = 161.83 (C-2), 160.89
(C-4), 160.51 (C-2, 148.16 (C-9), 134.98 (C-16), 133.24 (C-7), 129.71 (C-
14), 127.56 (C-8), 127.43 (C-5), 127.1 (C-6), 123.05 (C-10), 119.2 (C-15),
119.08 (C-11) 117.88 (C-13) ppm; MS (APCI): [M + 1]+ = 223.1 (85.2%);
HRMS (EI, [M + H]+): calculated for C14H11N2O : 223.0871; found:
223.0869.
3,5-Di-tert-butyl-2-(quinazolin-2-yl)phenol (3c) (Scheme 2): Pale
yellow solid, Rf = 0.62 (SiO2, Hexane/EtOAc = 4:1); m.p = 120 - 121 °C;
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800746
European Journal of Organic Chemistry
FULL PAPER
IR (KBr) ν = 3315 (br, OH), 2917(s), 1572 (m C=N), 1348 (s), 1014 (s, C-
O), 796 (m), 725 (m) cm-1; 1H NMR (599 MHz, CDCl3) δ = 9.47 (s, 1H; 4-
H), 8.62 (s, 1H; 16-H), 8.02 (d, 3J = 8.4 Hz, 1H; 8-H), 7.93 – 7.90
(overlapped, 2H; 5-H and 7-H), 7.61 (t, 3J = 8.0 Hz, 1H; 6-H), 7.51 (s, 1H;
14-H), 1.53 (s, 9H; 21-H), 1.40 (s, 9H; 19-H) ppm; 13C NMR (151 MHz,
CDCl3) δ = 178.42 (C-2), 162.70 (C-4), 160.41 (C-12), 158.23 (C-9),
147.73 (C-14), 140.06 (C-15), 134.77 (C-7), 128.18 (C-8), 127.35 (C-6),
127.22 (C-5), 126.86 (C-16), 123.99 (C-10), 122.72 (C-11), 117.99 (C-
13), 35.25 (C-20), 34.44 (C-18), 31.62 (C-21), 29.65 (C-19) ppm; HRMS
(EI, [M + H]+): calculated for C22H27N2O: 335.2123; found: 335.2119.
15), 128.08 (C-8), 127.48 (C-6), 127.16 (C-5), 123.30 (C-10), 121.94 (C-
12) ppm; MS (APCI): [M + 1]+ = 285.00 (99.78%); HRMS (EI, [M + H]+):
calculated for C14H10BrN2 : 285.0027; found: 285.0020.
2-(2-Chlorophenyl)quinazoline (3i)[29f] (Scheme 2,5): Yellow solid, Rf =
0.64 (SiO2, Hexane/EtOAc = 4:1); m.p = 67 - 68 °C (Lit[29f] 68 - 70 °C); 1H
NMR (400 MHz, DMSO-d6) δ = 9.74 (s, 1H; 4-H), 8.23 (d, 3J = 8 Hz, 1H;
8-H), 8.07 (s, 2H; 5-H and 7-H ), 7.81 (overlapped, 2H; 13-H and 16-H),
7.62 (d, 3J = 7 Hz, 1H; 6-H), 7.52 (t, 3J = 5.36 Hz, 2H; 14-H and 15-H)
ppm; 13C NMR (101 MHz, CDCl3) δ = 161.97 (C-2), 160.24 (C-4), 150.36
(C-9), 138.29 (C-11), 134.39 (C-7), 132.92 (C-12), 131.81 (C-14), 130.55
(C-13), 130.33 (C-16), 128.64 (C-8), 128.06 (C-6), 127.15 (C-5), 126.89
(C-15), 123.28 (C-10) ppm; HRMS (EI, [M + H]+): calculated for
C14H10ClN2: 241.0532; found: 241.0528.
2-(4-Methoxyphenyl)quinazoline (3d)[29c] (Scheme 2): Pale yellow solid,
Rf = 0.63 (SiO2, Hexane/EtOAc = 4:1); m.p = 89 - 91 °C (Lit[29d] 90 -
91 °C); 1H NMR (300 MHz, CDCl3) δ = 9.42 (s, 1H; 4-H), 8.58 (d, 3J = 8.0
Hz, 2H; 12-H), 8.04 (d, 3J = 8.6 Hz, 1H; 8-H), 7.91 – 7.85 (m, 2H; 5-Hand
3
7-H), 7.58 (d, 3J = 8.0 Hz, 1H; 6-H), 7.04 (d, J = 8.0 Hz, 2H; 13-H), 3.90
2-(4-Chlorophenyl)quinazoline (3j)[29c] (Scheme 2,5): Pale yellow solid,
(s, 3H; 15-H) ppm; 13C NMR (75 MHz, CDCl3) δ = 161.81 (C-2), 160.84
(C-4), 160.36 (C-14), 150.80 (C-9), 134.0 (C-11), 130.68 (C-7), 130.18
(C-12), 128.38 (C-8), 127.10 (C-6), 126.76 (C-5), 123.30 (C-10), 113.95
(C-13), 55.37 (C-15); HRMS (EI, [M + H]+): calculated for C15H13N2O:
237.1027; found: 237.1017.
Rf = 0.62 (SiO2, Hexane/EtOAc = 4:1); m.p = 130 - 132 °C (Lit[29d] 130 -
1
131 °C); H NMR (300 MHz, CDCl3) δ = 9.46 (s, 1H; 4-H), 8.58 (td, 3J =
8.0 Hz, 2H; 12-H), 8.08 (d, 3J = 8.0 Hz, 1H; 8-H), 7.95 - 7.89 (overlapped,
2H; 5-H and 7-H), 7.63 (dt, 3J = 8.0 Hz, 1H; 6-H), 7.50 (td, 3J = 8.0 Hz,
2H; 13-H) ppm; 13C NMR (75 MHz, CDCl3) δ = 160.50 (C-2), 160.03 (C-
4), 150.67 (C-9), 136.83 (C-14), 136.48 (C-11), 134.25 (C-7), 129.88 (C-
13), 128.80 (C-12), 128.58 (C-8), 127.45 (C-6), 127.13 (C-5), 123.61 (C-
10) ppm; HRMS (EI, [M + H]+): calculated for C14H10ClN2 : 241.0532;
found: 241.0526.
2-(2,6-Dimethoxyphenyl)quinazoline (3e) (Scheme 2,5): Light yellow
solid, Rf = 0.60 (SiO2, Hexane/EtOAc = 4:1); m.p = 58 - 59 °C; IR (KBr) ν
= 2921 (m), 1590 (s, C=N), 1149 (s), 1038 (s, C-O), 802 (s), 725 (s) cm-1;
1H NMR (400 MHz, DMSO-d6) δ = 9.70 (s, 1H; 4-H), 8.17 (d, 3J = 7.8 Hz,
1H; 8-H), 8.06 (overlapped, 2H; 5-H and 7-H), 7.75 (3H), 6.69 (1H), 3.86
(s, 6H; 15H) ppm; 13C NMR (101 MHz, CDCl3) δ = 161.09 (C-2), 160.69
(C-4), 160.37 (C-12), 150.71 (C-9), 140.14 (C-7), 134.09 (C-14), 128.71
(C-8), 127.35 (C-6), 127.10 (C-5), 123.72 (C-10), 106.24 (C-13), 103.84
2-(4-Fluorophenyl)quinazoline (3k)[30b] (Scheme 2): White solid, Rf =
0.60 (SiO2, Hexane/EtOAc = 4:1); m.p = 130 - 132 °C (Lit[30b] 132 -
133 °C); 1H NMR (400 MHz, CDCl3) δ = 9.44 (s, 1H; 4-H), 8.94 (d, 3J =
8.0 Hz, 2H; 12-H), 8.09 (d, 3J = 8.0 Hz, 1H; 8-H), 7.75 (d, 3J = 8.0 Hz,
1H), 7.70 (t, 3J = 8.0 Hz, 2H), 7.21 (d, 3J = 8.0 Hz, 2H; 13-H) ppm; HRMS
(EI, [M + H]+): calculated for C14H10FN2: 225.0828; found: 225.0818.
(C-11), 55.60 (C-15) ppm; HRMS (EI, [M
C16H15N2O2: 267.1134; found: 267.1130.
+
H]+): calculated for
2-(4-(Trifluoromethyl)phenyl)quinazoline (3l)[29f] (Scheme 2,5): Pale
yellow solid, Rf = 0.64 (SiO2, Hexane/EtOAc = 4:1); m.p = 136 - 137 °C
(Lit[29f] 135 - 137 °C); 1H NMR (400 MHz, CDCl3) δ = 9.36 (s, 1H; 4-H),
8.75 (d, 3J = 8.0 Hz, 2H; 12-H), 8.50 (d, 3J = 8.0 Hz, 1H; 8-H), 7.83 (d, 3J
= 8.0 Hz, 2H; 13-H), 7.74 (overlapped, 2H; 5-H and 7-H), 7.62 (d, 3J = 8.0
Hz, 1H; 6-H) ppm; 13C NMR (101 MHz, CDCl3) δ = 160.61 (C-2), 159.60
(C-4), 150.65 (C-9), 141.31 (C-11), 134.37 (C-7), 132.27 (q, C-14),
128.82 (C-8), 128.77 (C-6), 127.86 (C-5), 127.16 (C-12), 125.57 (C-10),
125.52 (q, C-13), 123.84 (C-15) ppm; HRMS (EI, [M + H]+): calculated for
C15H10F3N2: 275.0796; found: 275.0786.
2-(2-Bromo-4-methylphenyl)quinazoline (3f) (Scheme 2): Yellow solid,
Rf = 0.65 (SiO2, Hexane/EtOAc = 4:1); m.p = 49 - 50 °C; IR (KBr) ν =
2930 (m), 1563 (s, C=N), 1287 (m), 799 (s), 769 (s), 729 (s) cm-1; 1H
NMR (400 MHz, CDCl3) δ = 9.52 (s, 1H; 4-H), 8.13 (d, 3J = 7.2 Hz, 1H; 8-
H), 8.00 – 7.93 (overlapped, 2H; 5-H and 7-H), 7.71 – 7.66 (overlapped,
2H; 6-H and 16-H), 7.57 (s, 1H; 13-H), 7.26 (d, 3J = 7.9 Hz, 1H; 15-H),
2.41 (s, 3H; 17-H) ppm; 13C NMR (101 MHz, CDCl3) δ = 162.79 (C-2),
160.15 (C-4), 150.32 (C-9), 140.86 (C-11), 137.26 (C-14), 134.32 (C-13),
134.21 (C-7), 131.57 (C-16), 128.62 (C-15), 128.29 (C-8), 127.92 (C-6),
127.14 (C-5), 123.23 (C-10), 121.69 (C-12), 20.97 (C-17) ppm; HRMS
(EI, [M + H]+): calculated for C15H12BrN2: 299.0183; found: 299.0179.
Methyl 4-(quinazolin-2-yl)benzoate (3m) (Scheme 2,5): Light brown
solid, Rf = 0.62 (SiO2, Hexane/EtOAc = 4:1); m.p = 120 - 121 °C; IR (KBr)
ν = 2918 (m), 1719 (s, C=O), 1547 (m, C=N), 1281 (s), 1014 (m, C-O),
768 (s), 710(s) cm-1; 1H NMR (400 MHz, CDCl3) δ = 9.50 (s, 1H; 4-H),
8.70 (d, 3J = 8.0 Hz, 2H; 13-H), 8.21 (d, 3J = 8.0 Hz, 2H; 12-H), 8.12 (d,
3J = 8.0 Hz, 1H; 8-H), 7.98 – 7.93 (overlapped; 2H, 5-H and 7-H), 7.67 (t,
3J = 8.0 Hz, 1H; 6-H), 3.97 (s, 3H; 15-H) ppm; 13C NMR (101 MHz,
CDCl3) δ = 166.96 (C-15), 160.57 (C-2), 160.01 (C-4), 150.68 (C-9),
142.13 (C-11), 134.34 (C-7), 131.70 (C-14), 129.85 (C-12), 128.77 (C-8),
128.49 (C-13), 127.81 (C-6), 127.16 (C-5), 123.76 (C-10) 52.23 (C-16)
ppm; HRMS (EI, [M + H]+): calculated for C16H13N2O2 : 265.0977; found:
265.0971.
2-(4-Methylphenyl)quinazoline (3g)[30b] (Scheme 2): Pale yellow solid,
Rf = 0.65 (SiO2, Hexane/EtOAc = 4:1); m.p = 105 - 107 °C (Lit[30b] 104 -
1
106 °C); H NMR (300 MHz, CDCl3) δ = 9.45 (s, 1H; 4-H), 8.52 (td, 3J =
8.0 Hz, 2H; 12-H), 8.09 (d, 3J = 8.6 Hz, 1H; 8-H), 7.94 – 7.87 (m, 2H; 5-H
and 7-H), 7.60 (dt, 3J = 8.0 Hz, 1H; 6-H), 7.34 (d, 3J = 8.0 Hz, 2H; 13-H),
2.45 (s, 3H; 15-H) ppm; 13C NMR (75 MHz, CDCl3) δ = 161.10 (C-2),
160.40 (C-4), 150.76 (C-9), 140.86 (C-11)135.25 (C-7), 134.02 (C-14),
129.38 (C-8), 128.52 (C-13), 128.50 (C-12), 127.09 (C-6), 127.01 (C-5),
123.49 (C-10), 21.49 (C-15) ppm; HRMS (EI, [M + H]+): calculated for
C15H13N2: 221.1079; found: 221.1074.
2-(2-Bromophenyl)quinazoline (3h)[29f] (Scheme 2,5): Yellow solid, Rf =
0.64 (SiO2, Hexane/EtOAc = 4:1); m.p = 71 - 72 °C (Lit[29f] 72 - 74 °C); 1H
NMR (400 MHz, CDCl3) δ = 9.53 (s, 1H; 4-H), 8.14 (d, 3J = 8.4 Hz, 1H; 8-
H), 8.02 - 7.95 (overlapped, 2H; 5-Hand 7- H), 7.79 (dd, 4J = 9.6 Hz, 1H;
13H), 7.78 – 7.70 (overlapped, 2H; 6-H and 16-H), 7.46 (t, 3J = 7.6 Hz,
1H; 14-H), 7.32 (t, 3J = 8.0 Hz, 1H; 15-H) ppm; 13C NMR (101 MHz,
CDCl3) δ = 162.80 (C-2), 160.24 (C-4), 150.27 (C-9), 140.19 (C-11),
134.42 (C-14), 133.71 (C-13), 131.69 (C-7), 130.41 (C-16), 128.62 (C-
2-(2-Nitrophenyl)quinazoline (3n)[29f] (Scheme 2,5): Yellow solid, Rf =
0.60 (SiO2, Hexane/EtOAc = 4:1); m.p = 95 - 96 °C (Lit[29f] 93 - 95 °C); 1H
NMR (599 MHz, CDCl3) δ = 9.42 (s, 1H; 4-H), 8.11 (dd, 3J = 7.7, 4J = 1.4
Hz, 1H; 8-H), 8.05 (d, 3J = 8.4 Hz, 1H; 16-H), 7.95 – 7.91 (overlapped,
2H; 13-H and 15-H), 7.87 (d, 3J = 8.0 Hz, 1H; 14-H), 7.72 – 7.66
(overlapped, 2H; 5-H and 7-H), 7.58 (td, 3J = 7.8, 4J = 1.4 Hz, 1H; 6-H)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800746
European Journal of Organic Chemistry
FULL PAPER
ppm; 13C NMR (151 MHz, CDCl3) δ = 160.47 (C-2), 159.63 (C-4), 150.38
(C-12), 149.98 (C-9), 134.53 (C-15), 133.61 (C-16), 132.21 (C-7), 131.80
(C-14), 130.11 (C-8), 128.58 (C-6), 128.27 (C-5), 127.20 (C-11), 124.09
(C-10), 123.44 (C-13) ppm; HRMS (EI, [M + H]+): calculated for
C14H10N3O2: 252.0773; found: 252.0765.
2-(Anthracen-9-yl)quinazoline (3t) (Scheme 2,5): Yellow solid, Rf =
0.65 (SiO2, Hexane/EtOAc = 4:1); m.p = 112 - 114 °C; IR (KBr) ν = 2920
(w), 1664 (s), 1550 (m, C=N), 1253 (m), 725 (s), 698 (s) cm-1; 1H NMR
(599 MHz, CDCl3) δ = 9.69 (s, 1H), 8.99 (d, 3J = 9.0 Hz, 1H; 8-H), 8.59 (s,
1H; 18-H), 8.19 (d, 3J = 8.5 Hz, 1H; 5-H), 8.12 (d, 3J = 8.2 Hz, 1H; 7-H),
8.07 (d, 3J = 8.6 Hz, 2H; 13-H), 7.80 (t, 3J = 7.5 Hz, 1H; 6-H), 7.59 (d, 3J
= 9.0 Hz, 2H; 16-H), 7.45 (t, J = 7.6 Hz, 2H; 15-H), 7.36 (t, J = 7.6 Hz,
2H; 14-H) ppm; 13C NMR (101 MHz, CDCl3) δ = 160.68 (C-2 and C-4),
150.60 (C-9), 134.63 (C-11), 134.12 (C-17), 131.48 (C-7), 129.99 (C-12),
129.15 (C-18), 128.80 (C-6), 128.60 (C-16), 128.30 (C-5), 127.29 (C-8),
126.48 (C-15), 125.71 (C-10), 125.61 (C-14), 125.14 (C-13), ppm; HRMS
(EI, [M + H]+): calculated for C22H15N2: 307.1235; found: 307.1152.
3
3
2-(3-Nitrophenyl)quinazoline (3o)[28m] (Scheme 2): Pale yellow solid, Rf
= 0.64 (SiO2, Hexane/EtOAc = 4:1); m.p = 101 - 102 °C (Lit[28m] 103 -
103 °C); 1H NMR (300 MHz, CDCl3) δ = 9.52 – 9.50 (overlapped, 2H; 4-H
and 12-H), 8.99 (dt, 3J = 7.8, 4J = 1.4 Hz, 1H; 16-H), 8.36 (ddd, 3J = 8.2,
2.4, 1.1 Hz 1H; 14-H), 8.14 (d, 3J = 8.0 Hz, 1H; 8-H), 8.00 – 7.95
(overlapped, 2H; 5-H and 15-H), 7.74 – 7.67 (overlapped, 2H; 6-H and 7-
H) ppm; 13C NMR (75 MHz, CDCl3) δ = 160.72 (C-2), 158.68 (C-4),
150.60 (C-9), 148.84 (C-13), 139.87 (C-16), 134.55 (C-7), 134.19 (C-11),
129.50 (C-15), 128.75 (C-8), 128.06 (C-6), 127.20 (C-5), 124.99 (C-10),
123.94 (C-14), 123.59 (C-12) ppm; HRMS (EI, [M + H]+): calculated for
C14H10N3O2: 252.0773; found: 252.0764.
2-(Pyren-1-yl)quinazoline (3u) (Scheme 2,5): Yellow solid, Rf = 0.65
(SiO2, Hexane/EtOAc = 4:1); m.p = 145 - 147 °C; IR (KBr) ν = 3016 (w),
1624 (s, C=N), 1375 (m), 839 (s), 765 (s), 702 (s) cm-1; 1H NMR (599
3
MHz, CDCl3) δ = 9.68 (s, 1H; 4-H), 9.08 (d, J = 9.3 Hz, 1H; 13-H), 8.73
(d, 3J = 8.0 Hz, 1H; 18-H), 8.33 (d, 3J = 7.9 Hz, 1H; 12-H), 8.26 – 8.22 (m,
3H; 8-H, 15-H and 16-H), 8.19 – 8.13 (m, 3H; 19-H, 20-H and 22-H), 8.07
– 8.00 (m, 3H; 5-H, 7-H and 23-H), 7.73 (t, J = 8.1 Hz, 6.7 Hz, 1H; 6-H)
ppm; 13C NMR (151 MHz, CDCl3) δ = 163.65 (C-2), 160.44 (C-4), 150.61
(C-9), 134.52 (C-11), 133.03 (C-14), 132.49 (C-17), 131.30 (C-7), 130.84
(C-13), 129.52 (C-8), 129.06 (C-18), 128.61 (C-6), 128.47 (C-5), 127.85
(C-15 and C-16), 127.43 (C-19), 127.21 (C-22), 126.00 (C-20), 125.58
(C-25), 125.32 (C-21), 125.25 (C-10), 125.18 (C-26), 124.88 (C-12),
124.72 (C-23), 122.93 (C-24) ppm; HRMS (EI, [M + H]+): calculated for
C24H15N2 : 331.1235; found: 331.1228.
2-([1,1'-Biphenyl]-4-yl)quinazoline (3p)[28k] (Scheme 2,5): White solid,
3
Rf = 0.62 (SiO2, Hexane/EtOAc = 4:1); m.p = 116 - 117 °C; 1H NMR (400
3
MHz, CDCl3) δ = 9.49 (s, 1H; 4-H), 8.70 (d, J = 8.0 Hz, 2H; 12-H), 8.11
(d, 3J = 8.0 Hz, 1H; 8-H), 7.96 – 7.91 (overlapped, 2H; 5-H and 7-H), 7.79
(d, 3J = 8.0 Hz, 2H; 16-H), 7.71 (d, 3J = 8.0 Hz, 2H; 13-H), 7.63 (t, 3J =
8.0 Hz, 1H; 6-H), 7.49 (t, 3J = 8.0 Hz, 2H; 17-H), 7.39 (t, 3J = 8.0 Hz, 1H;
18-H) ppm; 13C NMR (101 MHz, CDCl3) δ = 160.85 (C-2), 160.50 (C-4),
150.85 (C-9), 143.27 (C-14), 140.64 (C-15), 137.00 (C-11), 134.14 (C-7),
129.04 (C-17), 128.83 (C-12), 128.66 (C-8), 127.67 (C-6), 127.35 (C-16),
127.25 (C-18), 127.20 (C-13), 127.16 (C-5), 123.64 (C-10) ppm; HRMS
(EI, [M + H]+): calculated for C20H15N2: 283.1235; found: 283.1231.
(E)-2-Styrylquinazoline (3v)[29c] (Scheme 2,5): White solid, Rf = 0.59
(SiO2, Hexane/EtOAc = 4:1); m.p = 122 - 123 °C (Lit[29c] 120 - 121 °C); 1H
NMR (599 MHz, CDCl3) δ = 9.27 (s, 1H 4-H), 8.06 (d, 3J = 15.9 Hz, 1H;
11-H), 7.89 (d, 3J = 8.5 Hz, 1H; 8-H), 7.78 (d, 3J = 7.5, 1.3 Hz, 2H; 5-H
and 7-H), 7.58 (d, 3J = 7.6 Hz, 2H; 14-H), 7.48 (td, 3J = 7.5, 4J = 1.3 Hz,
1H; 6-H), 7.35 – 7.28 (m, 3H; 12-H and 15-H), 7.24 (t, 3J = 7.3 Hz, 1H;
16-H) ppm; 13C NMR (151 MHz, CDCl3) δ = 161.25 (C-2), 160.22 (C-4),
150.52 (C-9), 138.58 (C-13), 136.17 (C-12), 134.21 (C-7), 129.04 (C-15),
128.78 (C-14), 128.08 (C-8), 127.85 (C-16), 127.66 (C-6), 127.20 (C-5),
127.13 (C-10), 123.34 (C-11) ppm; HRMS (EI, [M + H]+): calculated for
C16H13N2: 233.1078; found: 233.1070.
2-(Pyridin-4-yl)quinazoline (3q)[29f] (Scheme 2,5): Pale yellow solid, Rf =
0.60 (SiO2, Hexane/EtOAc = 4:1); m.p = 125 - 127 °C (Lit[29f] 124 -
1
126 °C); H NMR (400 MHz, CDCl3) δ = 9.53 (s, 1H; 4-H), 8.81 (d, J = 4
Hz, 2H; 13-H), 8.47 (d, J = 4 Hz, 2H; 12-H), 8.15 (d, 3J = 8 Hz, 1H; 8-H),
8.01 - 7.96 (m, 2H; 5-H and 7-H), 7.75 - 7.69 (m, 1H; 6-H) ppm; 13C NMR
(101 MHz, CDCl3) δ = 160.77 (C-2), 158.94 (C-4), 150.91 (C-13), 150.39
(C-9), 145.40 (C-11), 134.55 (C-7), 128.91 (C-8), 128.34 (C-6), 127.21
(C-5), 124.20 (C-10), 122.40 (C-12) ppm; HRMS (EI, [M + H]+):
calculated for C13H10N3: 208.0874; found: 208.0864.
2-(Furan-2-yl)quinazoline (3r)[30b] (Scheme 2,5): Pale yellow solid, Rf =
0.62 (SiO2, Hexane/EtOAc = 4:1); m.p = 126 - 127 °C (Lit[30b] 127 -
129 °C); 1H NMR (400 MHz, CDCl3) δ = 9.40 (s, 1H; 4-H), 8.11 (d, 3J = 8
Hz, 1H; 8-H), 7.93 - 7.90 (overlapped, 2H; 5-H and 7-H), 7.77 (d, 3J = 12
Hz, 1H; 13-H), 7.61 (t, 3J = 8 Hz, 1H; 6-H), 7.51 (d, 3J = 8 Hz, 1H; 15-H),
6.63 (s, 1H; 14-H) ppm; 13C NMR (101 MHz, CDCl3) δ = 160.74 (C-2),
154.09 (C-4), 152.50 (C-11), 150.43 (C-9), 145.35 (C-13), 134.54 (C-7),
128.38 (C-8), 127.29 (C-6), 127.28 (C-5), 123.28 (C-10), 114.12 (C-14),
112.23 (C-15) ppm; HRMS (EI, M+): calculated for C12H9N2O: 197.0714;
found: 197.0706.
(E)-2-(4-Methoxystyryl)quinazoline (3w) (Scheme 2): White solid, Rf =
0.61 (SiO2, Hexane/EtOAc = 4:1); m.p = 102 - 103 °C; IR (KBr) ν = 2961
(m), 1584 (m, C=N), 1547 (m, C=C), 1256 (s), 1020 (s, C-O), 966 (s),
825(s), 750 (s) cm-1; 1H NMR (599 MHz, CDCl3) δ = 9.34 (s, 1H; 4-H),
8.11 (d, 3J = 12.0 Hz, 1H; 11-H), 7.96 (d, 1H; 8-H), 7.86 (d, 3J = 7.7 Hz,
2H; 6-H and 7-H), 7.61 (d, 2H; 14-H), 7.55 (td, 3J = 7.4 Hz, 4J = 1.1 Hz,
1H; 5-H), 7.28 (d, 3J = 8.0 Hz, 1H; 12-H), 6.93 (d, 3J = 8.0 Hz, 2H; 15-H),
3.78 (s, 3H; 17-H) ppm; 13C NMR (151 MHz, CDCl3) δ = 160.57 (C-2),
159.48 (C-16), 159.19 (C-4), 149.54 (C-9), 137.29 (C-12), 133.17 (C-7),
128.14 (C-14), 127.96 (C-13), 126.94 (C-8), 126.20 (C-6), 125.89 (C-5),
124.57 (C-10), 122.22 (C-11), 113.27 (C-15), 54.33 (C-17) ppm; HRMS
(EI, [M + H]+): calculated for C17H15N2O : 263.1184; found: 263.1177.
2-(Naphthalen-1-yl)quinazoline (3s)[30b] (Scheme 2,5): Pale yellow solid,
Rf = 0.66 (SiO2, Hexane/EtOAc = 4:1); m.p = 123 - 124 °C (Lit[30b] 124 -
125 °C); 1H NMR (599 MHz, CDCl3) δ = 9.58 (s, 1H; 4-H), 8.69 (d, 3J =
8.2 Hz, 1H; 18-H), 8.17 (d, 3J = 7.7 Hz, 2H; 14-H and 15-H), 8.00 – 7.92
(overlapped, 4H; 5-H, 8-H, 12-H and 13-H), 7.68 (t, 3J = 7.5 Hz, 1H; 7-H),
7.62 (t, 3J = 7.6 Hz, 1H; 17-H), 7.56 – 7.51 (m, 2H; 6-H and 16-H) ppm;
13C NMR (151 MHz, CDCl3) δ = 163.42 (C-2), 160.38 (C-4), 150.54 (C-9),
136.23 (C-11), 134.33 (C-20), 134.17 (C-19), 131.20 (C-7), 130.38 (C-8),
129.63 (C-15), 128.64 (C-14), 128.47 (C-5), 127.74 (C-6), 127.13 (C-16),
126.84 (C-17), 125.88 (C-13), 125.28 (C-10), 123.11 (C-12) ppm; HRMS
(EI, [M + H]+): calculated for C18H13N2: 257.1078; found: 257.1071.
Quinazoline (3x)[29f] (Scheme 2): White solid, Rf
= 0.48 (SiO2,
Hexane/EtOAc = 4:1); m.p = 48 - 49 °C (Lit [29g] 45 - 47 °C); 1H NMR (599
MHz, CDCl3) δ = 9.43 (s, 1H; 4-H), 9.353 (s, 1H; 2-H), 8.07 (d, 3J = 8.5
Hz, 1H; 8-H), 7.95 (t, 3J = 7.5 Hz, 2H; 5-H and 7-H), 7.69 (t, J = 7.6 Hz,
3
1H; 6-H) ppm; 13C NMR (151 MHz, CDCl3) δ = 160.21 (C-2), 155.21 (C-
4), 150.00 (C-9), 134.20 (C-7), 128.40 (C-8), 127.95 (C-6), 127.19(C-5),
125.10 (C-10) ppm; HRMS (EI, [M + H]+): calculated for C8H7N2
131.0609; found: 131.0600.
:
2-Propylquinazoline (3y)[30b] (Scheme 2): Pale brown liquid, Rf = 0.58
(SiO2, Hexane/EtOAc = 4:1); b.p = 120 - 122 °C; 1H NMR (599 MHz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800746
European Journal of Organic Chemistry
FULL PAPER
CDCl3) δ = 9.36 (s, 1H; 4-H), 8.00 (d, 3J = 8.4 Hz, 1H; 8-H), 7.91 – 7.90
(m, 2H; 5-H and 7-H), 7.61 (t, 3J = 7.5 Hz, 1H; 6-H), 3.11 (t, 3J = 7.7 Hz,
2H; 11-H), 1.98 – 1.94 (m, 2H; 12-H), 1.05 (t, 3J = 7.4 Hz, 3H; 13-H) ppm;
13C NMR (151 MHz, CDCl3) δ = 167.62 (C-2), 160.39 (C-4), 150.16 (C-9),
134.07 (C-7), 127.78 (C-8), 127.07 (C-6), 126.97 (C-5), 123.04 (C-10),
41.76 (C-11), 22.27 (C-12), 13.96 (C-13) ppm; HRMS (EI, [M + H]+):
calculated for C11H13N2: 173.1078; found: 173.1076.
6,7-Methylenedioxy-2-(4-chlorophenyl)quinazoline (3cj)[28m] (Scheme
3): Colorless solid, Rf = 0.65 (SiO2, Hexane/EtOAc = 4:1); m.p = 223 -
225 °C (Lit[28m] 224 - 226 °C); 1H NMR (300 MHz, CDCl3): δ = 9.14 (s,
1H; 4-H), 8.48 (d, 3J = 9 Hz, 2H; 12-H), 7.47 (d, 3J = 8 Hz, 2H; 13-H),
7.32 (s, 1H; 8-H), 7.11 (s, 1H; 5-H), 6.17 (s, 2H; 15-H) ppm; 13C NMR (75
MHz, CDCl3) δ = 159.29 (C-2), 157.72 (C-4), 154.52 (C-9), 150.50 (C-7),
148.69 (C-6), 136.92 (C-14), 136.61 (C-11), 129.76 (C-13), 128.98 (C-
12), 121.06 (C-10), 105.19 (C-8), 102.51 (C-6), 102.13 (C-15) ppm;
HRMS (EI, [M + H]+): calculated for C15H10ClN2O2: 285.0431; found:
285.0423.
6-Methoxy-2-phenylquinazoline (3ba)[28m] (Scheme 3): Colorless solid,
Rf = 0.63 (SiO2, Hexane/EtOAc = 4:1); m.p = 118 - 119 °C (Lit[28m] 119 -
121 °C); 1H NMR (300 MHz, CDCl3): δ = 9.38 (s, 1H; 4-H), 8.57 (d, 3J = 9
Hz, 2H; 12-H), 8.05 (d, 3J = 7.96 Hz, 1H; 8-H), 7.58 – 7.46 (m, 4H; 7-H,
13-H and 14-H), 7.16 (d, 4J = 2.8 Hz, 1H; 5-H), 3.98 (s, 3H; 15-H) ppm;
13C NMR (75 MHz, CDCl3) δ = 159.37 (C-2), 158.78 (C-4), 158.24 (C-6),
146.98 (C-9), 138.11 (C-11), 130.17 (C-14), 130.11 (C-8), 128.58 (C-13),
128.16 (C-12), 127.19 (C-7), 124.45 (C-10), 103.88 (C-5), 55.72 (C-15)
ppm; HRMS (EI, [M + H]+): calculated for C15H13N2O: 237.1028; found:
237.1021.
6-Fluoro-2-phenylquinazoline (3da)[28m] (Scheme 3): (Scheme 3)
Colorless solid, Rf = 0.66 (SiO2, Hexane/EtOAc = 4:1); m.p = 138 -
[28m]
140 °C (Lit
140 - 141 °C); 1H NMR (300 MHz, CDCl3): δ = 9.44 (s,
1H; 4-H), 8.59 (dd, 3J = 9 Hz, 2H; 12-H), 8.11 (dd, 3J = 9.3, 5.0 Hz, 1H; 8-
H), 7.68 (td, 3J = 8.8, 2.8 Hz, 1H; 7-H), 7.57 – 7.50 (m, 4H; 5-H, 13-H and
14-H) ppm; 13C NMR (75 MHz, CDCl3) δ = 162.35 (C-4), 160.08 (d, J =
250 Hz, C-6), 159.01 (C-4), 148.21 (C-9), 137.97 (C-11), 131.71 (d, J =
35 Hz, C-8), 130.95 (C-14), 128.93 (C-13), 128.71 (C-12), 124.96 (d, J =
104.2 Hz, C-7), 124.24 (d, J = 38.2 Hz, C-10), 110.25 (d, J = 88 Hz, C-5)
ppm; HRMS (EI, [M + H]+): calculated for C14H10FN2: 225.0828; found:
225.0819.
6-Methoxy-2-(p-tolyl)quinazoline (3bg)[28m] (Scheme 3): Colorless solid,
Rf = 0.62 (SiO2, Hexane/EtOAc = 4:1); m.p = 140 - 142 °C (Lit[28m] 142 -
143 °C); 1H NMR (300 MHz, CDCl3): δ = 9.35 (s, 1H; 4-H), 8.47 (d, 3J = 8
Hz, 2H; 12-H), 7.98 (d, 3J = 7.96 Hz, 1H; 8-H), 7.54 (dd, 3J = 7.96 Hz, 1H;
7-H), 7.33 (d, 3J = 8 Hz, 2H; 13-H), 7.15 (d, 4J = 2.8 Hz, 1H; 5-H), 3.97 (s,
3H; 15-H), 2.44 (s, 3H; 16-H) ppm; 13C NMR (75 MHz, CDCl3) δ = 159.47
(C-2), 158.74 (C-4), 158.07 (C-6), 146.99 (C-9), 140.35 (C-11), 135.38
(C-14), 130.02 (C-8), 129.34 (C-13), 128.10 (C-12), 127.09 (C-7), 124.31
(C-10), 103.91 (C-5), 55.70 (C-15), 21.45 (C-16) ppm; HRMS (EI, [M +
H]+): calculated for C16H15N2O: 251.1184; found: 251.1180.
2-(4-chlorophenyl)-6-fluoroquinazoline
(3dj)[28m]
(Scheme
3):
Colorless solid, Rf = 0.64 (SiO2, Hexane/EtOAc = 4:1); m.p = 187 -
188 °C (Lit[28m] 185 - 187 °C); 1H NMR (300 MHz, CDCl3): δ = 9.44 (s,
1H; 4-H), 8.57 (dd, 3J = 9 Hz, 2H; 12-H), 8.11 (dd, 3J = 9.3, 5.0 Hz, 1H; 8-
H), 7.68 (td, 3J = 8.8, 2.8 Hz, 1H; 7-H), 7.59 – 7.50 (overlapped, 3H; 5-H
and 13-H) ppm; 13C NMR (75 MHz, CDCl3) δ = 162.43 (C-4), 160.11 (d, J
= 250 Hz, C-6), 159.1 (C-4), 148.11 (C-9), 137.18 (C-11), 136.45 (C-14),
131.67 (d, J = 34 Hz, C-8), 128.93 (C-13), 128.71 (C-12), 125.11 (d, J =
103.4 Hz, C-7), 124.27 (d, J = 37.8 Hz, C-10), 110.59 (d, J = 87 Hz, C-5)
ppm; HRMS (EI, [M + H]+): calculated for C14H9ClFN2: 259.0438; found:
259.0433.
2-(4-chlorophenyl)-6-methoxyquinazoline (3bj)[28m] (Scheme 3):
Colorless solid, Rf = 0.65 (SiO2, Hexane/EtOAc = 4:1); m.p = 172 –
173 °C (Lit[28m] 173 - 175 °C); 1H NMR (300 MHz, CDCl3): δ = 9.30 (s,
1H; 4-H), 8.50 (d, 3J = 8 Hz, 2H; 12-H), 7.94 (d, 3J = 7.96 Hz, 1H; 8-H),
7.53 (dd, 3J = 9.2, 2.7 Hz, 1H; 7-H), 7.46 (d, 3J = 8 Hz, 2H; 13-H), 7.15 (d,
4J = 2.8 Hz, 1H; 5-H), 3.94 (s, 3H; 15-H) ppm; 13C NMR (75 MHz, CDCl3)
δ = 159.02 (C-2), 158.61 (C-4), 158.55 (C-6), 147.12 (C-9), 136.91 (C-
14), 136.56 (C-11), 130.30 (C-8), 129.74 (C-13), 128.99 (C-12), 127.56
(C-7), 124.74 (C-10), 104.14 (C-5), 55.98 (C-15) ppm; HRMS (EI, [M +
H]+): calculated for C15H12ClN2O: 271.0638; found: 271.0630.
Acknowledgements
CCM appreciate Science and Engineering Research Board
(SERB), New Delhi and NIT Manipur for financial support in the
form of research grant (ECR/2016/000337). We acknowledge Mr.
M. Wolf (Institut für Chemie, Universität Hohenheim) and the
central instrumentation fecilities Indian Institute of Technology,
Guwahati for recording NMR and Mass spectra. We sincerely
thank Prof. T. Punniyamurthy, V. Satheesh and R. Bag from
Department of Chemistry, Indian Institute of Technology,
Guwahati for sample analysis and research support. RG and NV
grateful to Ministry of Human Resource and Development
(MHRD), New Delhi for fellowship support.
6,7-Methylenedioxy-2-phenylquinazoline (3ca)[28m] (Scheme 3):
Colorless solid, Rf = 0.61 (SiO2, Hexane/EtOAc = 4:1); m.p = 172 -
173 °C (Lit[28m] 173 - 175 °C); 1H NMR (300 MHz, CDCl3): δ = 9.15 (s,
1H; 4-H), 8.53 (d, 3J = 9 Hz, 2H; 12-H), 7.54 – 7.44 (m, 3H; 13-H and 14-
H), 7.33 (s, 1H; 8-H), 7.09 (s, 1H; 5-H), 6.13 (s, 2H; 15-H) ppm; 13C NMR
(75 MHz, CDCl3) δ = 160.28 (C-2), 157.71 (C-4), 154.38 (C-9), 150.53
(C-7), 148.51 (C-6), 138.41 (C-11), 130.44 (C-14), 128.81 (C-13), 128.43
(C-12), 120.98 (C-10), 105.23 (C-8), 102.43 (C-6), 102.09 (C-15) ppm;
HRMS (EI, [M + H]+): calculated for C15H11N2O2: 251.0821; found:
251.0815.
6,7-Methylenedioxy-2-(4-methylphenyl)quinazoline
(3cg)[28m]
Keywords: Organocatalysis • Domino reaction • C-N bond
formation • Quinazolines • Aerobic oxidation
(Scheme 3): Colorless solid, Rf = 0.64 (SiO2, Hexane/EtOAc = 4:1); m.p
= 187 - 188 °C (Lit[28m] 187 - 189 °C); 1H NMR (300 MHz, CDCl3): δ =
9.12 (s, 1H; 4-H), 8.42 (d, 3J = 9 Hz, 2H; 12-H), 7.32 – 7.30 (overlapped,
3H; 13-H and 8-H), 7.06 (s, 1H; 5-H), 6.11 (s, 2H; 15-H), 2.43 (s, 2H; 16-
H) ppm; 13C NMR (75 MHz, CDCl3) δ = 160.36 (C-2), 157.66 (C-4),
154.29 (C-9), 150.53 (C-7), 148.32 (C-6), 140.60 (C-11), 135.69 (C-14),
129.57 (C-13), 128.37 (C-12), 120.82 (C-10), 105.16 (C-8), 102.38 (C-6),
102.10 (C-15), 21.74 (C-16) ppm; HRMS (EI, [M + H]+): calculated for
C16H13N2O2: 265.0927; found: 265.0923.
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Entry for the Table of Contents
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N-Heterocycles*
Raghuram Gujjarappa, Suvik K. Maity,
Chinmoy K. Hazra, Nagaraju Vodnala,
Shiv Dhiman, Anil Kumar, Uwe Beifuss,
Chandi C. Malakar*
Page No. – Page No.
A convenient approach towards synthesis of 2-substituted quinazolines is described
using organocatalytic domino reaction. Under the developed conditions a broad
range of substrates were explored to afford the desired products in high yields.
Divergent Synthesis of Quinazolines
using Organocatalytic Domino
Strategies under Aerobic Conditions
*Organocatalysis, Domino cyclization
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