Cu-Catalyzed Direct Diversification of 2-(2-Bromophenyl)quinazolin-4(3 H)-ones through Orthogonal Reactivity Modulation

Article abstract of DOI:10.1021/acs.orglett.9b03428

A modular strategy to obtain three different products from a single substrate was developed. The present methodology unveils new step-economical and cost-efficient routes to access diverse fused quinazolinoquinazolinone derivatives which are not prevalent

Full text of DOI:10.1021/acs.orglett.9b03428

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cu-Catalyzed Direct Diversification of 2‑(2-Bromophenyl)quinazolin-
4(3H)‑ones through Orthogonal Reactivity Modulation
Satadru Chatterjee,∥,† Ravuri Srinath,∥,‡ Suvankar Bera,† Krishnendu Khamaru,† Afifa Rahman,‡
and Biswadip Banerji*,†,§
†Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, Raja S. C. Mullick Road, Kolkata-700032,
India
‡National Institute of Pharmaceutical Education and Research (NIPER-Kolkata), Chunilal Bhawan, Maniktala, Kolkata-700054,
India
§Academy of Scientific and Innovative Research (AcSIR), (CSIR-IICB), 4 Raja S. C. Mullick Road, Kolkata-700032, India
S
* Supporting Information
ABSTRACT: A modular strategy to obtain three different products from a single substrate was developed. The present
methodology unveils new step-economical and cost-efficient routes to access diverse fused quinazolinoquinazolinone derivatives
which are not prevalent in literature. Owing to the importance of quinazolinones in therapeutics, quick access to the arena of
these scaffolds could be a valuable addition to the scientific domain of heterocyclic chemistry.
uinazolinones belong to a privileged class of N-
In the past few decades, transition metal catalyzed direct C−
H bond functionalization has emerged as a powerful tool to
construct new carbon−carbon (C−C) and C−heteroatom
(C−X) bonds for the synthesis of structurally complex natural
or unnatural compounds.2 This C−H functionalization
strategy provides direct access and delivers more atom-
economical routes in the synthesis of complex structures as
compared to the traditional synthetic protocols, and this
technique also opens up the scope for the late stage
derivatization of bioactive molecules.3 Hence, use of different
transition metal catalysts in C−H functionalization reactions
received the spotlight over the past few years. However, the
majority of the C−H bond functionalization strategies depend
on the use of different noble metals, for example, palladium,4
rhodium,5 etc. However, the scope is still limited due to the
expensive scale-up procedure of these techniques. In contrast
to these highly expensive metal catalysts, cheap copper
catalysts may be widely utilized to functionalize specific C−
H bonds in large scale and thus copper catalyzed C−H
functionalization reactions have gained much focus with
critical progression.6
Q heterocycles due to their great abundance in several
natural products and pharmaceuticals which exhibit a wide
range of biological activities, including anti-inflammatory,
antitubercular, antiviral, and anticancer activities, etc. (Figure
1).1 Due to the extensive biological significance of the
Figure 1. Some quinazolinone-based drugs and natural products.
In spite of the fact that a number of methodologies involving
synthesis of quinazoline fused structures have been accom-
plished,7 most of these methods suffer from the major
drawback of using expensive metal catalysts. Thus, a
straightforward, efficient strategy for the synthesis of
quinazolinone fused polyheterocycles is still a challenging
quinazolinone moiety, the development of new synthetic
methods for the construction of quinazolinone based
molecular scaffolds draws considerable attention. Furthermore,
synthesis of a new molecular scaffold containing a
quinazolinone nucleus by a short and efficient synthetic
route is in high demand for various kinds of interests, especially
for the therapeutic targets in the pharmaceutical sectors
worldwide.
Received: September 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03428
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Organic Letters
Letter
a b c
, ,
Table 1. Optimization of Reaction Conditions
d
entry
catalyst
ligand
base
oxidant/inert atm.
solvent
compound/yield (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
1,10-Phen
Bipy
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
N2
N2
N2
AgNO3
O2
O2
O2
−
−
−
N2
O2
−
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
−
−
−
−
L-HP
L-HP
L-HP
−
1,10-Phen
−
−
−
−
−
−
3a/60%
3a /88%
4a /89%
4a/40%
4a/60%
4a/0%
5a/92%
5a/90%
a
b
9
10
11
12
13
14
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
1,10-Phen
−
c
−
5a / 92%
a
Optimized reaction conditions: 1 (0.1 mmol), benzylamine (0.15 mmol), CuI (20 mol %), K2CO3(0.3 mmol), O2 atmosphere, DMSO (1
b
c
mL),120 °C, 12 h. 1 (0.1 mmol), benzylamine (0.15 mmol), CuI (20 mol %), K2CO3 (0.3 mmol), DMSO (1 mL), 120 °C, 12 h. 1 (0.1 mmol),
Cu(OAc)2. H2O (20 mol %), K2CO3 (0.3 mmol), DMSO (1 mL), 120 °C, 12 h. Yields of isolated products.
d
task in the synthetic community. These facts inspired us to
develop an efficient synthetic route for the construction of
quinazolinone fused polyheterocycles through copper cata-
lyzed C−H functionalization. In an ongoing project in our
laboratory toward the synthesis of quinazolinonefused N-
heterocycles and the study of their photophysical properties,7f
we were interested in constructing quinazolinoquinazolines via
C−H functionalization. We expected these new heterocycles to
be highly fluorescent active because of their extended
conjugation. Interestingly during the course of study, we
observed a single substrate of this reaction produced diverse
quinazolinone fused scaffolds depending on the presence of an
oxygen atmosphere. To the best of our knowledge, we are the
first group to report copper catalysis in such a diversity
oriented synthesis of the quinazolinone moiety using a single
substrate, 2-(2-bromophenyl)quinazolin-4(3H)-one.
Initially, 2- (2-bromophenyl)quinazolin-4(3H)-one and
benzylamine were used as model substrates to optimize
reaction conditions including catalysts, ligands, bases, solvents,
and oxidants. As shown in the Table 1, it was found that, under
the catalysis of CuI (20 mol %) with different ligands such as
1,10-phenanthroline (1,10-Phen), 2,2′-bipyridine (2,2′-bipy),
and L-hydroxyproline (L-HP) in DMSO under N2 at 120 °C
after 12 h, no product formation was observed (entries 1−3).
By keeping the ligand same, i.e., L-HP, and using oxidants such
as silver nitrate (AgNO3) or oxygen, no product formation was
observed (entries 4−5). After changing the ligand from L-HP
to 1,10-Phen under the positive pressure of oxygen under the
same condition delivered the product (3a) in 60% yield (entry
6). However, the product yield improved further without any
ligand to about 88% (3a) (entry 7). The same reaction
conditions were utilized without the use of oxygen.
Surprisingly, it afforded a new product (4a) with a better
yield of about 89% (entry 8). Changing the solvent from
DMSO to DMF decreased the reaction yields (entry 9).
Changing the base from K2CO3 to Cs2CO3 slightly decreased
the product formation (entry 10). Under the nitrogen
atmosphere the same reaction conditions yield 0% product
(entry 11). Afterward, we changed the catalyst from CuI to Cu
(OAc)2·H2O, which was found to produce compound 5a with
92% yield. It was surprising to observe benzylamine served no
role under these reaction conditions. Moreover, the presence
or absence of oxygen/ligand did not affect the yield of
compound 5a (entries 12−14).
After obtaining the optimized conditions, we next studied
the substrate scope in the presence of oxygen (Scheme 1).We
synthesized a small set of these compounds to show the
generality and scope of the above conditions. Different types of
benzylamines were found to be well tolerated and provided the
desired products in moderate to good yields (3a−3i). The
structural ambiguity is confirmed by ROESY spectra (see SI, p
S29). Benzylamines with an electron-donating group (−Me,
−OMe, etc.) on the benzene ring produced a slightly lesser
yield than in the case of an electron-withdrawing group (−CF3,
−OCF3, etc.). Interestingly, compounds in this series showed
solid state fluorescence in the green-orange region (Scheme 1).
Next, we explored the substrate scope for the products formed
in absence of oxygen (Scheme 2). Under the optimized
B
DOI: 10.1021/acs.orglett.9b03428
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Organic Letters
Letter
Scheme 1. Synthesis of 11-Hydroxy-6-phenyl-11b,12-
dihydro-13H Quinazolino[3,4-a]quinazolin-13-ones
Scheme 2. Synthesis of 6-Phenyl-5,6-dihydro-8H-
a b
a b
,
,
quinazolino[4,3b]quinazolin-8-ones
a
Conditions: 1 (0.1 mmol, 1 equiv), benzyl amine (0.15 mmol, 1.2
equiv), CuI (20 mol %), K2CO3 (3 equiv), DMSO (1 mL), 120 °C,
b
O2, 18 h. Isolated yields. (A) Solid state fluorescence of compound 3
series (under long UV, 365 nm).
condition, this catalytic system with different types of
benzylamines yielded the desired products from moderate to
good yields (4a−4l). Benzylamines with electron-donating
groups (−Me, −OMe, etc.) produced better yields than in the
case of electron-withdrawing groups (like −CF3, OCF3, etc.).
The structures of compounds 4a and 4f were established by
single crystal X-ray diffraction studies (see SI, pp S17−S19).
Surprisingly, all the compounds of this series showed bright
blue fluorescence in solution state (Scheme 2).
Further, we studied the substrate scope for copper catalyzed
hydroxylation8 (Scheme 3) and synthesized three different
derivatives by varying the substituent on 2-aminobenzamide
and 2-bromobenzaldehyde moieties. Various electron-donating
as well as electron-withdrawing substituents on the benzene
ring were found to be equally compatible in this case, smoothly
giving the desired products with good yields (5a−5c).
Interestingly, all the compounds in the 5 series showed bright
green fluorescence in the solid state which may be due to the
Excited State Internal Proton Transfer (ESIPT) process
operating inside the molecule.8c The structure of compound
5a was further confirmed by single crystal X-ray diffraction
analysis (see SI, p S20).
a
Conditions: 1 (0.1 mmol, 1 equiv), Amine (0.15 mmol, 1.2 equiv),
b
CuI (20 mol %), K2CO3 (3 equiv), DMSO, 120 °C, 12 h. Isolated
yields. (A) Solution Phase fluorescence of a few selected compound 4
series in CH2Cl2. (B) Spectra of compound 4 series (10 mM in
CH2Cl2, λEx = 340−384 nm, λEm = 420−450 nm).
Scheme 3. Synthesis of 2-(2-Hydroxyphenyl)quinazolin-
4(3H)-ones
a b
,
The unexpected and unprecedented results found in the
present study encouraged us to perform a control set of
experiments (Scheme 4). These studies were focused toward
determining the reaction mechanism behind hydroxylation as
well as cyclization under variable conditions. A few test
reactions were performed to establish the mechanistic pathway.
Herein, we found that the reaction failed to produce the
desired product 5a under an O2 environment in the absence of
Cu(OAc)2·H2O (reaction 1). The same was also observed in
the case of reaction 2, where the substrate was changed from 2-
(2-bromophenyl)quinazolin-4(3H)-one to 2-phenylquinazolin-
4(3H)-one, to establish the necessity of the −Br group for
hydroxylation for series 5. In the case of reaction 3, where N-
methyl quinazolinone was used as a substrate, 0% conversion
of the product resulted hence proving the directed
hydroxylation of the quinazolinone moiety. The same reaction
conditions in the presence of TEMPO almost gave a
a
Conditions: 1 (0.1 mmol, 1 equiv), Cu(OAc)2.H2O (20 mol %),
b
K2CO3 (3 equiv), DMSO, 120 °C, 12 h. Isolated yields. (a) Normal
light (left) and solid state fluorescence of compound 5a captured by
irradiation at 365 nm (right)
C
DOI: 10.1021/acs.orglett.9b03428
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Organic Letters
Letter
characterized (see SI, pp S11−S12, S54−S55)) followed by
imine formation in the presence DMSO, finally producing the
cyclized compound, 4f. In the next reaction, the presence the
radical quencher TEMPO yielded 0% of product 4a, indicating
that it involves the free radical mechanism (reaction 9). Next,
we performed a reaction where DDQ was introduced with
compound 4a to check whether any aromatization takes place.
However, no reaction of compound 4a occurred in the
presence of DDQ, therefore indicating that compound 4a is
−5.83 kcal/mol more stable than the aromatized compound
4a′ which was further studied by DFT (see SI, p S21).
Scheme 4. Control Experiments
Based on the control experiments, a plausible reaction
mechanism has been proposed and depicted in Scheme 5.
Scheme 5. Plausible Mechanism
Initially, under copper catalysis9 substrate 1 and benzylamine 3
becomes converted to intermediate III. Intermediate III
oxidized to imine intermediate IV in the presence of
DMSO.10 Next, intermediate IV follows two distinct pathways
regarding the presence and absence of O2. In the presence of
O2, the in situ superoxide radical11 is generated by the redox
couple CuI/CuII and this forms the metallocomplex V which
then undergoes concerted hydroxylation and cyclization to
form the intermediate VI. Now, intermediate VI goes through
tautomerization and 1,3-hydride transfer to deliver the final
product 3.12 On the other hand, in the absence of O2
compound 4 was formed from intermediate IV through simple
cyclization.
quantitative yield (reaction 4). Substrate 1 without benzyl-
amine in the presence of O2 under CuI catalysis forms the
compound 5a in quantitative yield (reaction 5). While testing
with a 2,6-disubstituted substrate, however compound 3a was
not formed under the reported conditions (reaction 6). This
study hereby concludes that the cyclization and hydroxylation
in the case of formation of compound 3a follows a concerted
pathway and also C−H hydroxylation occurs only when the
ortho-position is unsusbstituted. In the next reaction, presence
of a radical quencher, TEMPO, yielded 0% of product 3a,
indicating that it involves the free radical mechanism (reaction
7). In reaction 8, we confirmed that the formation the
compound 4 series first involves N-arylation (4f′ isolated and
In conclusion, from a single quinazolinone substrate, three
diverse quinazolinone derivatives were synthesized in high
yields by efficient copper catalyzed modular methodology.
Twenty four such different quinazolinone derivatives were
D
DOI: 10.1021/acs.orglett.9b03428
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Organic Letters
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aspect of this work is C−H hydroxylation (compound 3 series)
which is highly important from a therapeutic point of view, as a
hydroxyl functional group is very much abundant in bioactive
molecules. Another very important feature of these molecules
is solid state fluorescence (3 series) and solution state as well
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derivatives will be explored to make “Biomolecular probes”.
Our laboratory is currently investigating this kind of probes
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03428.
General information, General procedures, X-ray crys-
1
tallography data, DFT studies, and H and 13C NMR
spectra for all synthesized compounds (PDF)
Accession Codes
CCDC 1954063 and 1954068−1954069 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
́
Goetz, A.; Zhang, Y.; Gehrke, S.; Tkach, I.; Holloczki, O.; Das, S. ACS
Catal. 2018, 8 (12), 11679−11687.
(11) (a) Cowley, R. E.; Tian, L.; Solomon, E. I. Proc. Natl. Acad. Sci.
U. S. A. 2016, 113 (43), 12035−12040. (b) Lewis, E. A.; Tolman, W.
B. Chem. Rev. 2004, 104 (2), 1047−1076.
(12) (a) Angle, S. R.; Mattson-Arnaiz, H. L. J. Am. Chem. Soc. 1992,
114 (25), 9782−9786. (b) Kramer, G. M.; McVicker, G. B. Acc. Chem.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: biswadip.banerji@gmail.com; biswadip@iicb.res.in.
ORCID
Biswadip Banerji: 0000-0001-9898-253X
Author Contributions
∥S.C. and R.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank NIPER and CSIR. R.S. thanks DOP,
Ministry of Chemical and Fertilizers, Govt. of India, for
providing a Junior Research Fellowship. The authors also
thank Mr. Sandip Kundu, Technical Officer, CSIR-IICB, for
recording X-ray data; Mr. E. Padmanaban, Senior Technical
Officer, CSIR-IICB; for recording the NMR; and Mr. Santu
Paul, Technical Officer, CSIR-IICB, for recording the ESI HR-
MS spectra.
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