Base-catalyzed synthesis of quinazolines in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2019.151186

An alternative green protocol and step economy for the synthesis of quinazoline has been developed. The reaction of readily available 2-aminobenzonitriles with various organometallic reagents led to ortho-aminoaryl N[sbnd]H ketimine species. The subsequen

Full text of DOI:10.1016/j.tetlet.2019.151186

Tetrahedron Letters 60 (2019) 151186
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Tetrahedron Letters
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Base-catalyzed synthesis of quinazolines in aqueous medium
⇑
Nagesh Jatangi, Radha Krishna Palakodety
Organic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2019
Revised 17 September 2019
Accepted 19 September 2019
Available online 19 September 2019
An alternative green protocol and step economy for the synthesis of quinazoline has been developed. The
reaction of readily available 2-aminobenzonitriles with various organometallic reagents led to
ortho-aminoaryl NAH ketimine species. The subsequent base catalysed NAC bond formation with various
isothiocyanates afforded quinazoline scaffolds in aqueous medium. The salient features of this protocol
are use of readily available inexpensive precursors, water as a green environmentally benign solvent,
short reaction time, operational simplicity, easy workup procedure and good functional group tolerance.
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Quinazoline
Isothiocyanate
Water
Base
Significant attention has been attached to the study and devel-
opment of organic transformations in aqueous media in last two
decades [1]. A reaction is considered ideal if it proceeds in a green
reaction medium in the presence of benign reagents without the
use of hazardous organic solvents, metal complexes. Furthermore
the development of environmentally friendly catalytic processes
is currently one of the greatest challenges for the chemists [2]. In
this regard, development of a green methodology utilizing water
as a green, non-toxic and non-flammable solvent has become one
of the prime goals in sustainable chemistry, hence large number
of environmentally friendly novel protocols have been developed
over the past two decades [1].
Quinazolines are privileged N-heterocyclic structure motifs that
are well-known for their wide range of utility in life-saving syn-
thetic pharmaceutical [3], these scaffolds are associated with anti-
cancer activity for example Gefitinib is a tyrosine kinase inhibitor
drug, like gefitinib, Erlotinib also receptor tyrosine kinase inhibitor
which act on the (EGRF), while Lapatinib (1) is an U.S. FDA
approved drug used for the treatment of breast cancer and other
solid tumours. Alfuzosin (2) is used for the treatment of benign
prostatic hyperplasia and Doxazosin (3) is used for the treatment
of prostate enlargement and high blood pressure, and also this
scaffold is associated with anti-hypertensive, anti-malarial, anti-
bacterial anti-inflammatory, anti-tuberculosis properties (Fig. 1)
[3].
drawn towards their synthesis and consequently various synthetic
methods were also reported for their preparation [4]. Few
approaches reported for the construction of substituted 2-amino-
quinazolines are: for example Mahajan et al. reported the synthesis
of 2-sec-amines quinazolines [5] from condensation reaction of
guanidines with aldehydes, Zhao et al. obtained the same from 2-
bromobenzaldehyde and guanidines as the starting materials and
copper(I) iodide as a catalyst [6] and very recently Zhu co-workers
disclosed the formation of quinazoline by palladium-catalyzed
intramolecular CAH amidination [7] with isonitriles and N-ary-
lamidines and, Neuville and his group also developed a method
for the construction of 2-aminoquinazolines scaffolds from boronic
acids, amines and cyanamides as a starting precursors [8]. The
above maintained synthetic protocols are among the few fruitful
strategies. However, large number of existing protocols encounter
several disadvantages, like risky starting materials, expensive tran-
sition metal complexes, additives, oxidants, multistep synthesis,
ligands and toxic solvents. Hence development of economical
and green strategies is needed for the construction of substituted
quinazolines derivatives.
Previously our group developed a metal free synthesis of
N,4-disubstituted quinazoline as shown in (Scheme 1 Eq. (1)),
these synthesis rely on the reaction of isothiocyanates with
2-amino-benzophenone and ammonium acetate to furnish the
corresponding product catalysed by iodine [9]. In general
2-amino-arylphenones were prepared from starting precursors
2-aminobenzonitriles and organometallic reagents initially led to
the formation of ortho-aminoketimine, followed by acid hydrolysis
of this intermediate [9,10], where as it requires an additional
ammonium source for the quinazoline ring formation in our previ-
Due to diverse range of pharmacological activities of the substi-
tuted 2-aminoquinazoline derivatives, considerable attention was
⇑
Corresponding author.
E-mail address: prkgenius@iict.res.in (R.K. Palakodety).
https://doi.org/10.1016/j.tetlet.2019.151186
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
N. Jatangi, R.K. Palakodety / Tetrahedron Letters 60 (2019) 151186
Table 1
Optimization of the reaction conditions.a,b
Entry
Solvent
Base (equiv)
Temp
Time
Yieldb (%)
1
2
3
4
5
6
7
8
DMSO
DMSO
CH3CN
Dioxane
DMF
H2O
H2O
H2O
H2O
H2O
NaOH (2.0)
NaOH (2.0)
NaOH (2.0)
NaOH (2.0)
NaOH (2.0)
NaOH (2.0)
NaOH (2.0)
KOH (2.0)
K2CO3 (2.0)
Cs2CO3 (2.0)
NaOH (3.0)
NaOH (4.0)
rt
12 h
8 h
9 h
8 h
3 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
31
52
39
42
61
71
82
69
42
39
91
91
60
60
60
60
60
80
80
80
80
80
80
9
10
11
12
H2O
H2O
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), catalyst (x equiv.) and sol-
vent (3 mL) at 80 °C for 2 h.
b
Isolated yield.
Fig. 1. Quinazolines as medicinal agents.
raised to 60 °C, the reaction was completed within 8 h, however
moderate yield (52%) was observed. To improve the yields, various
solvents such as CH3CN, DMF and dioxane were screened, among
all DMF provide better yields within 3 h under same reaction con-
ditions (Table 1, entries 2–5). Interestingly the reaction proceeds
efficiently under the polar solvent. Considering the sustainable
chemistry we invoked water as a solvent and to our delight the
reaction was proceeded quickly and reaction yield was observed
71%, (Table 1 entry 6). Based on the solvent screening H2O was rec-
ognized as a better solvent in terms of yields and reaction time
[12]. Subsequently we increased the temperature to 80 °C the reac-
tion was completed within 2 h with 82% of yield (Table 1 entry 7).
Then we investigated different bases and their influence on the
reaction. Thus various bases like K2CO3, Cs2CO3 and KOH were
tested among all NaOH was observed to be more effective (Table 1,
entries 8–10). The equivalent of NaOH was also studied, raising the
quantity of NaOH from 2.0 equiv to 3.0 equiv. provided the product
3a in 91% of yield (Tabel 1, entry 11), however further raising the
NaOH equivalent 3.0–4.0 did not improve the yields [12]. Thus
the optimized reaction conditions for this reaction are ortho-
aminoketimine (1.0 mmol), isothiocyanate (1.0 mmol) and NaOH
(3.0 equiv) in water at 80 °C in 1–2 h, and hence chosen for the
synthesis of N,4-disubstituted quinazolines.
With suitable reaction conditions in hand (Table 1, entry 11),
the scope and the electronic nature and their positions on the
phenylisothiocyanate was investigated, and the results are sum-
marized in Scheme 2. A series of para-substituted electronic-with-
drawing and electronic-donating phenylisothiocyanates like
methyl, methoxy, chloro, fluoro and nitro groups were well toler-
ated and gave the corresponding N,4-disubstituted quinazoline
(3a-3f) in good to excelent yields, subsequently meta-substituted
phenylisothiocyanate like methyl, methoxy and chloro were also
examined, when the reaction proceed smoothly and offered the
corresponding products (3g-3i) in good to excellent yields. The dis-
ubstituted isothiocyanate also well tolerated under the reaction
conditions and provided corresponding product 3j in good yields,
demonstrating that substituents on phenylisothiocyanates do not
influence the outcome of the reaction.
Scheme 1. Synthesis of quinazolines.
ous method. It was also observed that meta and ortho substituted
2-aminoaryl ketones did not tolerate the reaction conditions due
to steric effect [9]. To overcome this limitation and taking into
account the step and atom economy, we envisioned that a direct
synthesis of quinazoline from the ortho-aminoketimine species
should be a viable and attractive approach to this important class
of compounds, further more we discovered that such transforma-
tions could be facilitated via a transition metal-free catalyzed, base
promoted and using water as a environmentally benign solvent in
our strategy. Therefore the present protocol relies on generation of
ortho-aminoketimine species and its subsequent usage in the for-
mation of quinazolines. In continuation with previous work, herein
we report a novel, step economy and environmentally benign pro-
tocol by using sodium hydroxide as a base in water for the con-
struction of N,4-disubstituted quinazolines (Scheme 1).
ortho-Aminoketimine was prepared from the reaction of 2-
aminobenzonitrile with aryl magnesium bromide [10,11]. Then
the reaction of ortho-aminoketimine (1a) and phenylisothio-
cyanate (2a) with NaOH (2.0 equiv) in DMSO stirred at room tem-
perature for 12 h, provided the desired product quinazoline 3a in
31% yield (Table 1, entry 1). When the reaction temperature was
To further examine the different types of ortho-aminoketimines
(1), ortho, meta and para substituents present on the phenyl ring, it

N. Jatangi, R.K. Palakodety / Tetrahedron Letters 60 (2019) 151186
3
Scheme 4. Proposed reaction mechanism.
As described in Scheme 4, firstly, ortho-aminoketimine 1a reacts
with phenylisothiocyanate 2a to offer the thiourea intermediate A,
subsequently intramolecular nucleophilic attack of the amine or
imine group on the thiocarbonyl carbon gave the cyclised product
B via NAC bond formation. The intermediate B on aromatization
offered 3a with subsequently generation of S and H2O.
In conclusion, we have successfully developed a step economy
and sustainable synthetic methodology for the construction of
highly valuable substituted quinazolines by using starting precur-
sor 2-aminobenzonitrile, Grignard reagent, phenylisothiocyanate,
NaOH and H2O as a solvent at 80 °C. This methodology possess sev-
eral advantages like transition-metal free protocol, use of readily
available and inexpensive sodium hydroxide as a base, use of water
as a green and renewable solvent with step economy. We strongly
believe that this methodology will useful for the construction of
highly valuable quinazolines in an economical and sustainable
manner.
Scheme 2. Synthesis of substituted quinazolines.a,b aReaction conditions: 1a
(1.0 mmol), 2a (1.0 mmol), catalyst (3 equiv.) and solvent (3 mL) at 80 °C for 2 h.
bIsolated yield.
Acknowledgment
J. N thanks the University Grants Commission, New Delhi,
was found that they were well tolerated under the standard condi-
tions and led to the formation of corresponding products in good to
excellent yields (3k-3n). The reaction also tolerated chloro and flu-
oro substituents on ortho-aminoketimines (1) with different sub-
stituted phenylisothiocyanates to afford the corresponding
products (3o-3r) in excellent yields. However, alkyl isothiocyanate
and ortho-aminoalkylketamine were not tolerated under the stan-
dard conditions (3s-3t). Also, both 2-(imino(phenyl)methyl)-4-
methylaniline and 4-methoxy bearing substrate failed to yield
the corresponding products (3u-3v).
India for research fellowship. CSIR-IICT Commun. No.
ICT/pubs./2019/239.
I
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151186.
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the reaction (Scheme 3).
Based on the above results and from the previous literature data
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mechanism for the formation of quinazoline as outlined below
Scheme 4.
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