A convenient access to 2,4-disubstituted quinazolines via one-pot three-component reaction under mild conditions?

Article abstract of DOI:10.1080/00397911.2020.1744014

A new and practical method has been developed for the synthesis of 2,4-disubstituted quinolines via one-pot three-component reaction of o-amino arylketones, aldehydes and ammonium acetate in high yields by using DDQ in CH₃CN under mild conditio

Full text of DOI:10.1080/00397911.2020.1744014

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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A convenient access to 2,4-disubstituted
quinazolines via one-pot three-component
reaction under mild conditions†
D. Subhas Bose & Nukala Ramesh
To cite this article: D. Subhas Bose & Nukala Ramesh (2020): A convenient access to 2,4-
disubstituted quinazolines via one-pot three-component reaction under mild conditions†, Synthetic
Communications, DOI: 10.1080/00397911.2020.1744014
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1744014
A convenient access to 2,4-disubstituted quinazolines via
one-pot three-component reaction under mild conditions†
ꢀ
D. Subhas Bose and Nukala Ramesh
Organic and Biomolecular Chemistry Division, Department of Energy and Environmental Engineering,
Fine Chemicals Lab, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
ABSTRACT
ARTICLE HISTORY
Received 31 August 2019
A new and practical method has been developed for the synthesis
of 2,4-disubstituted quinolines via one-pot three-component reaction
of o-amino arylketones, aldehydes and ammonium acetate in high
yields by using DDQ in CH3CN under mild conditions. Neutral condi-
tions, atom economy, easy work-up procedures and compatible with
different functional groups are the salient features of this protocol.
KEYWORDS
o-Aminobenzophenone; aro-
matic aldehydes;
ammonium acetate; DDQ;
one-pot; multicompo-
nent reaction
GRAPHICAL ABSTRACT
Ph
4
Ph
CHO
DDQ (25 mol%)
N
2
3
O
NH OAc
4
1
N
CH3CN, reflux, 55 oC
NH
R
R
2
R'
R'
1a
2a
4a
3a
14 examples
isolated yields 82-95%
Introduction
Over the past decade, the importance of heterocycles in biological systems has stimu-
lated interest in designing of new drug scaffolds via iterative manipulation of functional
groups around the basic skeletal systems. Among the nitrogen heterocycles, quinazoline
ring system, in particular, constitute a privileged structural motif widely found in a var-
iety of pharmacologically significant compounds, bioactive natural products,[1] microor-
ganisms[2] functional materials,[3] and in particular life saving drugs such as erlotinib
(Tarceva),[4] gefitinib (Iressa)[5] and linagliptin (Tradjenta)[6] (Figure 1). Some of the
modified quinazoline derivatives possess potent antiviral,[7] antibacterial,[8] anticancer[9]
and antitubercular activities.[5] In addition, quinazoline derivatives have also known to
act as selective inhibitors of the tyrosine-kinase activity of the epidermal growth factor
(EGF) receptor,[10] ligands for c-aminobutyric acid (GABA),[11] benzodiazepine recep-
tors[12] in the central nervous system (CNS), CCR4 antagonists[13] or as
DNA binders.[14]
CONTACT D. Subhas Bose
boseiict@gmail.com
Organic and Biomolecular Chemistry Division, Department of
Energy and Environmental Engineering, Fine Chemicals Lab, CSIR-Indian Institute of Chemical Technology, Tarnaka,
Hyderabad 500 007, India.
†IICT manuscript communication no. IICT/Pubs./2019/301.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
D. SUBHAS BOSE AND N. RAMESH
F
Cl
CH3
O
HN
Cl
O
HN
NH2
N
O
N
Cl
N
N
N
N
N
N
N
N
H3CO
N
O
N
N
N
CH3
CH3
N
N
Gefitinib
H
CCR4 antagonist
Linagliptin
O
Figure 1. Structures of some pharmacologically important quinazolines.
Results and discussion
In view of the considerable interest of this class of heterocyclic compounds, an effort
has been drawn to develop new and efficient synthetic methods to substituted quinazo-
lines in both synthetic organic and medicinal chemistry. o-nitrobenzoic acids, anthra-
nilic acids, o-halophenyl precursors, o-aminobenzonitriles as well as N-arylbenzamides
are the most commonly used starting materials among those protocols.[15] These meth-
ods, however, suffer from limitations such as less availability of these starting materials.
The Bischler cyclization is a venerable reaction, it is one of the most simple, and
straightforward methods used to produce quinazolines. Classically, the process involves
cyclization of an amide derived from 2-aminophenone in the presence of ammonia at
high temperature,[16] Niementowski quinazoline reaction,[17] and the reaction of
diamines with dicarbonyl compounds.[15] Moreover, synthesis of 2,4-disubstituted
quinazolines have been investigated starting from substituted anthranilic acids or o-fluo-
robenzoyl derivatives.[18] However, all of these approaches suffer from one or the other
drawbacks such as availability of starting materials, toxic and expensive metal catalysts,
harsh reaction conditions, hazardous, volatile solvents, tedious work-up procedures,
multistep sequence, which has limited the applicability of these methods in high
throughput synthesis[19] Taddei et al[20] have reported 2,4-disubstituted quinazolines
synthesis starting from anilides under microwave conditions heating at 100 ꢁC for 3-
6 min at 150 psi, which has limited substrate scope with few examples. Wang et al have
reported[21] quinazoline synthesis from (i) o-aminocarbonyl compounds and benzyl
amines using CuO nanoparticles supported on kaolin (ii) I2/TBHP catalytic system at
90 ꢁC for 12 h.[22] Prajapati and coworkers reported a quinazoline synthesis using urea/
NH4OAc as nitrogen source under microwave conditions.[23] Evenhough this method is
novel and it lacks selectivity toward quinazoline derivatives. Therefore, a new alternative
protocol needs to be explored having significant practical value for the synthesis of 2,4-
disubstituted quinazolines. In order to overcome these limitations, herein, we report a
new, practical route for the synthesis of substituted quinazolines via one-pot three-
component reaction of o-amino arylketones, aldehydes and ammonium acetate in high
yields by using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in CH3CN under mild
conditions in the absence of ligands or additives (Scheme 1). Recently, DDQ has
emerged as a powerful oxidizing agent to accomplish various organic transformations[24]
including the cleavage of linker molecules from solid supports, the introduction of
unsaturation, deprotection of functional groups, and potential applications for the for-
mation of carbon–carbon and carbon–heteroatom bonds.

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3
Previous approaches:
R
R
N
1
1
R3COCl, Et3N, HCO2NH4
MW, 150 oC, 100psi
O
N
ref 20
NH
R
R
2
3
R
2
2
R
O
1
CAN (10 mol%), TBHP (7.0 mmol)
CH3CN, N2atm, 7-7.5h
R
R
R
2
2
3
N
R
NH
2
ref 19d
NH
R
N
2
3
R
4
Ph
N
Ph
maltose-DMU-NHCl
N
O
4
R
R1- CHO
CHO
NH OAc
4
Air, 90 oC
ref 19f
NH
R
2
This work:
Ph
R
1
Ph
N
DDQ (25 mol%)
N
O
NH OAc
4
CH3CN, reflux, 55 oC
R
NH
R
2
R'
R'
4a
1a
2a
3a
Scheme 1. Various reported strategies for the synthesis of 2,4-disubstituted quinazolines.
We embarked upon our study by examining the conditions for the one-pot three
component condensation reaction was performed by the treatment of o-amino benzo-
phenone (1a), aldehyde (2a) with ammonium acetate in the presence of a catalytic
amount of DDQ (25 mol%) leads to the formation of 2-(4-methoxyphenyl)ꢂ4-phenyl-
quinazoline (4a). We first examined the reaction in different solvents including EDC,
CH3CN, THF, CH3NO2, H2O and solvent-free conditions under mild refluxing condi-
tions. It is remarkable to note that the reaction proceeds efficiently in high yields at
55 ꢁC in CH3CN with low catalyst concentration (25 mol%) in 95% yield after stirring
for 5 h (Table 1, entry 8). The role of DDQ catalyst was confirmed when the model
reaction between o-aminobenzophenone (1a), p-methoxybenzaldehyde (2a), ammonium
acetate (3a) was carried out in the absence of catalyst; no product was obtained under
solvent-free conditions even with a long reaction time. As seen from the entries 5 and 6
of Table 1, among the N source, NH4Cl was found to be the suitable for this reaction.
To our knowledge, DDQ catalyst has not yet been exploited for the synthesis of substi-
tuted quinazolines.
To demonstrate the versatility of this protocol, we next investigated the scope of this
reaction under the optimized conditions and the results are presented in Table 2.
Similarly, a variety of substituted aldehydes possessing electron-donating and electron-
withdrawing functional groups, aliphatic aldehydes reacted with o-aminoaryl ketones to
afford the corresponding 2,4-disubstituted quinazolines 4a–4n in 65–95% yield without
any side products. In order to improve the yields, we have carried out reactions using
different quantities of reagents. The optimum results were obtained with a 1:1:0.25 ratio
of o-aminoaryl ketone, aldehyde, and DDQ respectively. Higher amounts of catalyst did
not improve the result to a greater extent (Table 1, entry 14).

4
D. SUBHAS BOSE AND N. RAMESH
Table 1. Optimization of the reaction conditions.a
Ph
4
Ph
CHO
Reagent (mol%)
N
O
3
NH OAc
+
+
4
2
1
CH3CN, ref lux, 55 oC
N
NH2
2a
1a
3a
4a
OCH3
OCH3
__________________________________________________________________________
Yield (%)b
Entry
Reagent (mol %)
Solvent
Time (h)
N source
__________________________________________________________________________
c
ClCH2CH2Cl
CH3CN
NH4Cl
8
12
1
2
3
4
5
6
7
8
9
10
11
12
BQ (25)
Trace
BQ (50)
NH4OAc
NH4Cl
8
12
15
25
20
45
89
95d
90
74
42
ClCH2CH2Cl
CH3CN
ClCH2CH2Cl
CH3CN
ClCH2CH2Cl
CH3CN
CH3NO2
Chloranil (25)
NH4OAc
NH4Cl
NH4OAc
NH4OAC
NH4OAc
NH4OAc
Chloranil (50)
DDQ (10)
DDQ (10)
DDQ (25)
DDQ (25)
10
5
5
5
DDQ (25)
5
5
10
10
20
5
NH4OAc
aq NH3
NH4OAc
NH4OAc
NH4OAc
NH4OAc
DDQ (25)
DDQ (25)
DDQ (25)
DDQ (25)
DDQ (50)
THF
CH3CN
H2O
solvent-free
CH3CN
solvent-free
37
41
13
14
15
93
no reactione
>24
__________________________________________________________________________
aReaction conditions: o-aminoarylketone (1a, 10 mmol), aldehyde (2a, 10 mmol), N source (2.5mmol), BQ =
1,4-benzoquinone, Chloranil (tetrachloro 1,4-benzoquinone, DDQ (25 mol %). bIsolated and unoptimized
yields. cNo reaction. dOptimum reaction conditions. eRecovered sarting materials.
Interestingly, when aldehyde with an electron-donating group, such as 2-hydroxyben-
zaldehyde, was used as substrate, the corresponding product failed to generate, even after
prolonged reaction time. This may be due to the hydrogen bonding interaction to the aldi-
mine group which provides stability via chelation to the intermediate (B) in Scheme 2,
and orientation of phenyl ring prevents cyclization process. In addition, an analogous
quinine oxidants 1,4-benzoquinone (BQ), and chloranil was studied for this three compo-
nent reaction. The results indicate that the reaction was relatively sluggish, and the yields
were very poor. Obviously, these reagents are not efficient as DDQ for this condensation
reaction (Table 1, entries 1–4). After the reaction was complete as monitored by TLC, the
product was isolated by simple filtration. In the absence of catalyst, the reaction did not
yield any product even after longer reaction times (>24 h, Table 1, entry 15). All the prod-
1
ucts were characterized by IR, H NMR, 13C NMR, and mass spectroscopy and also by
comparison with authentic samples. In general, the reaction is very clean, involves a simple
work-up procedure[19,20] and free from side reactions such as self-condensation of car-
bonyl compounds which normally take place under basic conditions. Unlike previous
reports, the current protocol does not require high temperatures, use of strong acids or
bases or the use of toxic solvents to produce quinazoline derivatives.
Based on our observations and the literature precedents, a proposed mechanistic
pathway for the quinazoline synthesis is illustrated in Scheme 2. First, the aniline

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5
Table 2. DDQ-catalyzed synthesisof 2,4-disubstituted quinazolines under mild conditions.a
Yield (%)b
Time (h) Quinazoline (4)
m.p. oC(lit)
Aldehyde (2)
Entry
1
o-Aminobenzophenone ( )
______________________________________________________________________________________
Ph
CHO
Ph
O
157-159(159-162)19d
N
1.
2.
3.
5
5
8
95
91
93
NH2
Ph
2a
OCH3
CHO
N
1a
1b
1c
4a
OCH3
Ph
O
N
165-168(167-170)19d
NH2
Ph
N
2b
CH3
CHO
4b
CH3
Ph
O
N
173-175
OCH3
OH
NH2
2c
OCH3
N 4c
OH
CHO
Ph
O
Ph
N
4.
8
133-136
82
NH
2
1d
1e
2d
N
4d
N
CH3
H3C
CH3
CHO
N
Ph
O
Ph
N
CH3
141-143(140-145)19d
157-160(159-161)19d
5.
6.
5
8
85
89
NH2
2e
N
4e
Br
Br
Ph
O
Ph
N
CHO
NO2
NO2
NH2
Ph
1f
2f
N
4f
CHO
Ph
O
N
193-195(195)25
7.
8.
5
5
91
93
2g
NO2
NH
2
N
1g
4g
Ph
Ph
NO2
CHO
S
144-146(146-147)19f
O
N
S
2h
1h NH2
N
4h
Ph
CHO
CHO
OCH3
Ph
Cl
Cl
Cl
O
9.
184-186(185)19b
114-116
N
8
5
87
92
NH2
Ph
2i
2j
1i
1j
N
4i
Ph
OCH3
Cl
O
N
10.
N
NH2
4j
H3CO
Ph
OCH3
Ph
CHO
Cl
Cl
O
N
158-160(159-161)26
8
86
11.
NH2
1k
N
2k
4k
N
CH3
H3C
CH3
N
Ph
Ph
CH3
Cl
Cl
Cl
N
O
10
8
89-90
65
88
12.
13.
CHO
NH2
2l
N
1l
4l
Ph
Ph
CHO
Cl
187-190(185-187)19d
N
O
N
NH
Ph
1m
2m
Cl
2
4m
Cl
Ph
CHO
Cl
Cl
127-130(128)19d
NO2
N
NO2
O
8
82
14.
NH2
N
1n
4n
2n
aReaction conditions: o-aminoarylketone (1a, 10 mmol), aldehyde (2a, 10 mmol), N source (2.5 mmol), BQ ¼ 1,4-benzo-
quinone, Chloranil (tetrachloro 1,4-benzoquinone, DDQ (25 mol %). bIsolated and unoptimized yields. cNo reaction.
e
dOptimum reaction conditions. Recovered sarting materials.

6
D. SUBHAS BOSE AND N. RAMESH
Ph
Ph
N
Ph
O
DDQ
-H2O
O
NH4OAc
R1
NH
R1
O
R1
H
NH2
R2
R2
R2
N
B
C
Ph
Ph
Aromatization
via oxidation
N
N
N
R1
R1
N
R2
R2
D
H
Scheme 2. A Plausible reaction mechanism for the synthesis of quinazolines.
reacted with a carbonyl species of aldehyde, yielding an Schiff’s base intermediate (B),
which underwent cyclization (C) followed by DDQ mediated aromatization via oxida-
tion to obtain the quinazoline. Here, the rate-limiting step is the formation of the aldi-
mine intermediate (B) is kinetically more favorable than the ketimine (C).
In summary, we have developed a DDQ-catalyzed one-pot, three-component synthe-
sis of a highly substituted quinazolines starting from readily available o-aminoarylke-
tones, aldehydes and nitrogen source NH4OAc in high yields. This method offers a high
degree of flexibility to the functional groups that can be incorporated on various posi-
tions of the quinazolne moiety, which in turn generates scaffolds for hit discovery. It is
a valuable addition to the existing protocols available for the synthesis of substituted
quinazolines.
Experimental
Reagents and chemicals were obtained from commercial sources and used as received
without further purification. Melting points were determined in open capillaries with a
precision digital melting point Veego VMP-DS apparatus and are uncorrected. IR spec-
1
tra were recorded on a thermo Nicolet Nexus 670 FT-IR spectrophotometer. H and 13C
NMR spectra were recorded on either a Bruker Avance 300 (300.132 MHz for 1H,
75.473 for 13C) or Varian FT-200MHz (Gemini) spectrometer in CDCl3. The chemicals
shifts (d) and coupling constants (J) quoted in Hz are reported in parts per million
1
(ppm) relative to tetramethylsilane (TMS; d ¼ 0.00 ppm) (for H) as an internal stand-
ard. The resonances of residual proton and those of carbons in deuterated solvents
CDCl3 (dH ¼ 7.26 ppm, dc ¼ 77.0 ppm), DMSO-d6 (dH ¼ 2.50 ppm, dc ¼ 39.52 ppm) were
used as internal standards. Elemental analyses were performed on a Elementar Vario EL
microanalyzer. Low-resolution mass spectra (ESI-MS) and HRMS were recorded on
Quattro LC, Micromass, and Q STAR XL, Applied Biosystems respectively. Column
chromatography was performed using silica gel (Acme’s 60–120 mesh). Solvents for
chromatography (n-hexane, acetonitrile, cyclohexane, EtOAc) were distilled prior to use.
For analytical TLC, Merck pre-coated silica gel 60 F-254 plates were used; the plates
were visualized using UV light (254 nm) or iodine vapor or by dipping the plates in

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SYNTHETIC COMMUNICATIONSV
7
phosphomolybdic acid ceric(IV)sulphate-sulphuric acid (PMA) solution and heating the
plates at 100 ꢁC.
2-(4-Methoxyphenyl)-4-phenylquinazoline (4a) (typical procedure)
A solution of o-aminobenzophenone (1a, 10 mmol), p-methoxybenzaldehyde (2a,
10 mmol), and ammonium acetate (3, 25 mmol) in CH3CN (5 mL) was heated under
reflux in the presence of DDQ (0.25 mmol) for 5 h until starting material could no lon-
ger be detected by TLC (Petroleum ether:EtOAc, 9:1). After completion of the reaction,
the reaction mixture was extracted with ethyl acetate (30 mL) and washed with water
(15 mL), saturated brine solution, dried over anhydrous Na2SO4 and evaporated under
reduced pressure. The residue was purified by silica gel column chromatography (10%
ethyl acetate in hexane) to afford the pure product 4a as a brown solid (2.97 g, 95%). Rf
(Petroleum ether/EtOAc 9:1 v/v): 0.85. mp 157–159 ꢁC (lit.17i mp 159–162 ꢁC); IR
1
(KBr): 3062, 2924, 2852, 1604, 1536, 1451, 1249, 1219, 1021, 772, 699 cmꢂ1. H NMR
(300 MHz, CDCl3), d: 3.89 (s, 3H, OCH3), 7.05 (d, J ¼ 8.5, Hz, 2H), 7.55 (t, J ¼ 7.5 Hz,
1H), 7.59–7.62 (m, 3H), 7.83–7.91 (m, 3H), 8.12 (t, J ¼ 8.0 Hz, 2H), 8.66 (d, J ¼ 8.5, Hz,
2H) ppm; 13C NMR (CDCl3) d: 55.3, 113.8, 121.3, 126.5, 126.9, 128.4, 128.8, 129.8,
130.1, 130.2, 130.8, 133.4, 137.7, 152.0, 159.9, 161.7, 168.0 ppm; [ESI]þ: [M þ H]þ
HRMS Calcd: For C21 H16 N2 O 313.1336, Found: 313.1339. C21H16N2O.; Anal. Calcd
for C21H16N2O: C, 80.75, H, 5.16; N, 8.97. Found: C, 80.57; H, 5.22; N, 9.05.
Supplemental data associated with this article (Full experimental details and charac-
1
teristics for all new compounds and copies of H NMR, 13C NMR, and Mass spectral
data) can be accessed on the publisher’s website.
Acknowledgments
One of the authors (N.R.) thanks Council of Scientific and Industrial Research (CSIR), New
Delhi, for financial support.
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