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ChemistrySelect doi.org/10.1002/slct.202100534

z Organic & Supramolecular Chemistry

Catalyst-Free One-Pot Multi-Component Synthesis of

2-Substituted Quinazolin-4-carboxamides from
2-Aminophenyl-2-oxoacetamides, Aldehydes, and
Ammonium Acetate
Seung-Hwan Shim+,[a] Hyejun Park+,[a] Neeraj Kumar Mishra,[b] In Su Kim,[b] Jae Kyun Lee,[c]
Kiho Lee,[d] Hitesh B. Jalani,*[e] and Yongseok Choi*[a]

Herein, we report a simple and straightforward catalyst-free
one-pot multi-component synthesis of quinazolin-4-carboxa-
mides using 2-(2-aminophenyl)-N,N-dialkyl-2-oxoacetamide, al-
dehydes and ammonium acetate. As compared to the conven-
tional approached for quinazolin-4-carboxamides synthesis, this
transformation demonstrates very good reactivity by tolerating
a large number of functional groups, and proceeds with good
to moderate yields under mild conditions. Notably, the
synthesized 6-bromoquinazolin-4-carboxamide was subjected
to Suzuki-Miyaura cross-coupling and Buchwald-Hartwig C N
bond forming reactions providing a straightforward method to
obtain structurally diverse and valuable quinazoline scaffolds.
Furthermore, the reaction could be easily scaled up to gram
scale.

Introduction
have been known to constitute an active class of drugs[13] and
Quinazoline and its derivatives are an important class of other materials,[14] while on the other hand, the 4-carbonyl
nitrogen containing heterocyclic scaffolds which are found in a derivatives of quinazoline such as quinazolin-4-carboxamides
variety of natural products, pharmaceutical substances, materi- have not explored well so far despite exhibiting variety of
als and agrochemicals. A majority of substituted quinazoline biological properties such as potent inhibitor of AAKl, acetyl
derivatives are known for their broad-spectrum biological CoA carboxylase inhibitor, anti-disorders, adenosine receptors,
activities including anticancer (tyrosine kinase inhibitors), anti-neurodegenerative, and anticancer have been described
antiviral, anti-inflammatory, antiprotozoan, antifungal, antibac- (Figure 1).[15–20]
terial, diuretics, antimalarial, antidepressant, muscle relaxants, In the past few decades, the catalytic one-pot multi-
antitubercular, anticonvulsant and many more.[1–12] Among the component reactions has become a powerful tool for the
4-substituted quinazolines, 4-amino and 4-phenoxy derivatives synthesis of N-containing biologically active heterocycles.[21–27]
Recent efforts towards the synthesis of quinazolin-4-carboxa-
mide derivatives are summarized in Scheme 2. For example,
[a] S.-H. Shim,+ H. Park,+ Prof. Y. Choi
School of Life Sciences and Biotechnology Dervis and some other groups independently reported the C N
Korea University bond formation reactions for the direct transformation of
Seoul 02841, Republic of Korea quinazolin-4-carboxylic acids with various amines, providing
E-mail: ychoi@korea.ac.kr
the corresponding amide products (Scheme 1, eq. 1a).[15,16,18–21]
[b] Dr. N. K. Mishra, Prof. I. S. Kim
School of Pharmacy
Sungkyunkwan University
Suwon 16419, Republic of Korea
[c] Dr. J. K. Lee
Center for Neuromedicine
Korea Institute of science and Technology
Seoul 02792, Republic of Korea
[d] Prof. K. Lee
College of Pharmacy, Korea University
Seoul, 2511, Republic of Korea
E-mail: sejong-ro
[e] Dr. H. B. Jalani
Smart BioPharm 310-Pilotplant,
Incheon Techno-Park, 12-Gaetbeol-ro,
Yeonsu-gu, Incheon 21999, South Korea
E-mail: hbjalani@gmail.com
[+] S.-H.S. and H.P. equally contributed.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/slct.202100534 Figure 1. Selected Bioactive Quinazolin-4-carboxamides.

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ChemistrySelect doi.org/10.1002/slct.202100534
Figure 2. Postulated mechanism for the synthesis of quinazoline-4-carbox-
amides.
Scheme 1. Synthesis of Quinazolin-4-Carboxamides.
In this context, the synthesis of N,N’-dimethyl-2-phenylquinazo-
lin-4-carboxamide was reported via two steps process. 4-
chloro-2-phenylquinazolines converted into 4-iodo-2-phenyl-
quinazolines which on reaction with dimethyl carbamic
chloride in presence of isopropyl magnesium chloride-lithium
chloride delivered the desired aminated products (Scheme 1,
eq. 1b).[22]
ChemistrySelect 2021, 6, 5446 – 5450
Scheme 2. Scope of Aldehydes Reaction conditions: 1a (1.0 equiv), 2 a–2 t
(1.2 equiv), ammonium acetate (6.0 equiv) and EtOH (5 mL) at 80 °C for
overnight under air. b Yield after flash column chromatography.
Takamura and co-workers developed a palladium catalyzed
protocol for the synthesis of quinazolin-4-carboxamides using
4-chloro-2-arylquinazolines, carbon monoxide and amines
(Scheme 1, eq. 1c).[23] Recently, Lee and co-workers developed a
(NH4)2S2O8 mediated direct C–H acylation and carbamoylation
of quinazolines with oxamic acids (Scheme 1, eq. 1d).[24] In
addition, 4-cyanoquinazoline can also converted to correspond-
ing carboxamide under acidic hydrolysis of cyano
functionality.[26] Due to the rapid evolvement in drug discovery
area, the efficient methods for the construction of quinazolin-4-
carboxamides are still in demand. To the best of our knowl-
edge, the one-pot synthesis of 2-substituted-quinazolin-4-
carboxamides using 2-(2-aminophenyl)-N,N-dimethyl-2-oxoace-
5447 © 2021 Wiley-VCH GmbH
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ChemistrySelect doi.org/10.1002/slct.202100534

tamide with benzaldehyde and ammonium acetate via C N
bond formation and cyclization have not been explored so far.
Encouraged by the work carried out by Bergman and co-
workers on the study of the reactions between isatins and
secondary aliphatic amines, providing 2-(2-aminophenyl)-N,N-
dialkyl-2-oxoamides,[27] we became interested to explore a
metal-free one pot three-component synthesis of 2-aryl
quinazolin-4-carboxamide employing Bergman’s 2-(2-amino-
phenyl)-N,N-dialkyl-2-oxoamides with aldehydes, and
ammonium acetate (Scheme 1, eq. 1e).
Result and discussions
Initially, we examined the reaction of 2-(2-aminophenyl)-N,N-
dimethyl-2-oxoacetamide (1 a) with benzaldehyde (2 a) and
ammonium acetate in ethanol at 80 °C. As expected, the
desired product 2-phenylquinazolin-4-carboxamide (3 a) was
obtained in 55 %.
After getting the initial result of desired product 3 a, we
have screened the substrate scope of this condensation
reaction. A range of electron-donating and electron-withdraw-
ing groups containing aldehydes 2 a–2 t, regardless of the
electronic nature of substituents, were employed to couple
with 2-(2-aminophenyl)-N,N-dimethyl-2-oxoacetamide 1 a and
ammonium acetate under the optimal reaction condition
(Scheme 2). Electron rich para-substituted aryldehydes such as
methyl (Me), ethyl (Et) and methoxy (OMe) 2 b–2 d, were found
to react smoothly with 1 a and ammonium acetate to afford
the corresponding products 3 b–3 d in satisfactory yields. It is
worthy to mention that aldehydes bearing halogens 2 e–2 h
and 2 k (aryl C F, C Cl, C Br, C I) are also compatible in this
reaction, which may allow further construction of complex
molecules by coupling reactions. In addition, para-fluoro and
3,3’-di chloro substituted aldehydes 2 e and 2 k shows less
reactivity. Likewise, the aldehyde 2 i and 2 j with highly
electron-deficient group (OH and NO2), which is often problem-
atic in the coupling reactions, resulted in the formation of
desired products 3 i and 3 j in 39 % and 60 % yields,
respectively. Interestingly, acetanilide functionality present in
the aldehyde core has provided the quinazoline 3 l in 83 %
yield. Bulky biphenyl aldehyde also underwent the reaction
smoothly and provided the hanging biphenyl ring containing
quinazoline (3 m) in moderate yield.
This protocol was not limited to aromatic aldehydes but it
has also worked well with aliphatic aldehydes such as propional
(2 n), pivalic aldehyde (2 o) and cyclohexyl carboxaldehyde
(2 p), thus furnishing 3 n–3 p in good to excellent yield. More-
over, aldehydes containing heteroaryl functionality such as
furan (2 q), thiophene (2 r), indole (2 s) and pyridine (2 t) were
efficiently participated in this three component reaction to
furnish the corresponding quinazolin-4-carboxamide deriva-
tives 3 q–3 t. These results reveal that the developed method-
ology is facile for all kind of aldehydes, aromatic, heterocyclic
as well as aliphatic under otherwise identical reaction con-
ditions.
Next, we sought to expand the substrate scopes with a
range of 2-(2-aminophenyl)-N,N-dialkyl-2-oxoamides bearing
different substitution patterns (Scheme 3). Relatively, far less
reactivity were observed when different substituted 2-(2-
aminophenyl)-N,N-dimethyl-2-oxoacetamide (1 b–1 i) treated
with aldehydes 2 a and 2 d and ammonium acetate. Interest-
ingly, the reaction between N,N-diethyl containing oxoaceta-
mide 1 e, 4-methoxybenzaldehyde 2 d and ammonium acetate
displayed high reactivity to afford our desired quinazolinyl
butanone product 4 d in 62 % yield. However, morpholine (1 f),
piperazine (1 g) and ester (1 h) groups protected oxoacetamide
were found to be less effective in the one-pot three component
reaction (4 e–4 g). The obtained 2-anisylquinazolin-4-carboxylic
ester compound 4 g, which is previously synthesized by Dervis
via three step process compared to our two step protocol, we
further hydrolyzed the ester group at the C4-position of
quinazoline 4 g under basic hydrolysis delivered the corre-
sponding quinazoline-4-carboxylic acid 4 h in good yield.[21]
Since the 2-arylquinazolin-4-carboxamides are very impor-
tant scaffolds in medicinal chemistry, to highlight the synthetic
applicability of our methodology, further post synthetic trans-
formation was useful in order to generate more structurally
decorated molecules (Scheme 4). 6-Bromo-N,N-dimethyl-2-phe-
nylquinazoline-4-carboxamide 4 c was first employed for the
Suzuki-Miyaura cross-coupling reaction under the reported
reaction condition,[28] 4 c was smoothly reacted with phenyl-
boronic acid in the presence of palladium catalyst provided 6-
arylated product 2,6-diphenyl substituted quinazolin-4-carbox-
amide 5 a with 76 % yield. Next, the Buchwald-Hartwig C–N
bond forming reaction was investigated between the 6-bromo-
2-phenylquinazolin-4-N,N’-dimethylcarboxamide 4 c and aniline
in presence of palladium catalyst,[29] which provided 2-phenyl-
6-anilino-quinazolin-4-carboxamide 5 b with 76 % yield. Addio-
nally, a gram scale synthesis using 1 a and 2 g was performed
Scheme 3. Scope of 2-(2-Aminophenyl)-2-Oxoamides Reaction conditions:
1 b–1 i (1.0 equiv), 2 a and 2 d (1.2 equiv), ammonium acetate (6.0 equiv) and
EtOH (5 mL) at 80 °C for overnight under air. b Yield after flash column
chromatography.

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ChemistrySelect doi.org/10.1002/slct.202100534
Scheme 4. Synthetic Transformations of 4 c.
which provided quinazoline 3 g with almost 70% yield showing
that the present method can be suitable for industrial scale.
Based on previous literatures and our observations, follow-
ing reaction mechanism can be postulated for the synthesis of
quinazoline-4-caboxamides.[30] Initially, the ammonium acetate
being salt of ammonia adds to the aldehyde carbonyl to give
imine A, which is further reacts with the protonated form of 1 a
to form the hemi-aminal B, which upon addition of second
molecule of ammonia to form C, which is then losing one water
molecule to become an amidine D. This amidine can be
protonated by acetic acid present in the reaction media to E,
which loses ammonia molecule due to the attack of anilinic
amino group to provide the six membered cyclized intermedi-
ate F. This cyclized product then undergoes deprotonation to G
which then on air oxidation aromatize to the desired quinazo-
line compound 3 a.
Alternative pathway is possible wherein the aldehyde 2a
reacts with 1a to provide anilinic imine compound, which
further follows the similar path as described from B to the final
product. Another possibility is the oxo-carbonyl being electro-
philic so susceptible towards the attack of ammonia via SN2
mechanism therefore addition of ammonia to the 1a to provide
imino-carboxamide which can attack to the aldehyde carbonyl
to give an intermediate similar to D, but without NH2 group on
benzylic carbon and then follow the similar pathway towards
the G and thus 3a.
Conclusion
In summary, we have developed a mild and efficient catalyst-
free one-pot multi-component reaction of 2-(2-aminophenyl)-
N,N-dialkyl-2-oxoamides, aldehydes and ammonium acetate for
the synthesis of 2-arylquinazolin-4-carboxamide derivatives.
The broad functional group tolerance and its suitability for
further transformations into biologically relevant nitrogen-
containing diversely substituted quinazoline are the potential
features of this methodology; hence this protocol could be
ChemistrySelect 2021, 6, 5446 – 5450
useful in drug discovery programs as well as for the large scale
synthesis. Further, work on the development of various
heterocyclic systems and their carboxamide formation is
currently underway in our laboratory. Experimental Section
Deposition numbers 2042323 (for 3c), 2042324 (for 3 g),
2042326 (for 3 h) and 2042328 (for 4e) contain the supplemen-
tary crystallographic data for this paper. These data are
provided free of charge by the joint Cambridge Crystallo-
graphic Data Centre and Fachinformationszentrum Karlsruhe
Access Structures service www.ccdc.cam.ac.uk/structures.
Acknowledgments
This work was supported by korea University Grant [K2102821]
and the Institute of Life Science and Natural Resources Grant,
Korea University.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Carboxamide · Catalyst-Free · N-Heterocycles ·
Multicomponent Reaction · One-Pot Synthesis · Quinazoline
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