Synthesis of Pyrido-Fused Quinazolinone Derivatives via Copper-Catalyzed Domino Reaction

Article abstract of DOI:10.1021/acs.orglett.6b00113

A simple and efficient synthesis of 11H-pyrido[2,1-b]quinazolin-11-ones by Cu(OAc)₂·H₂O-catalyzed reaction of easily available substituted isatins and 2-bromopyridine derivatives has been developed. The reaction involves C-N/C-C bond cleavage and two C-N bond formations in a one-pot operation. This methodology is complementary to previously reported synthetic procedures, and two plausible reaction mechanisms are discussed. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.6b00113

Letter
pubs.acs.org/OrgLett
Synthesis of Pyrido-Fused Quinazolinone Derivatives via Copper-
Catalyzed Domino Reaction
Meilin Liu, Miaomiao Shu, Chaochao Yao, Guodong Yin,* Dunjia Wang, and Jinkun Huang*
Hubei Collaborative Innovation Center for Rare Metal Chemistry, Hubei Key Laboratory of Pollutant Analysis and Reuse
Technology, Hubei Normal University, Huangshi 435002, People’s Republic of China
S
* Supporting Information
ABSTRACT: A simple and efficient synthesis of 11H-
pyrido[2,1-b]quinazolin-11-ones by Cu(OAc)2·H2O-catalyzed
reaction of easily available substituted isatins and 2-
bromopyridine derivatives has been developed. The reaction
involves C−N/C−C bond cleavage and two C−N bond
formations in a one-pot operation. This methodology is
complementary to previously reported synthetic procedures,
and two plausible reaction mechanisms are discussed.
11-ones via a palladium-catalyzed C−H carbonylation of N-aryl-
s an important class of nitrogen-containing heterocycles,
Aquinazolinone is one of the ubiquitous structural motifs that 2-aminopyridines by using carbon monoxide as the carbonyl
source in the presence of oxidant K2S2O8 (Scheme 1, path b).11
occur in natural products and pharmaceutically active mole-
cules.1−3 Numerous attractive methods have been reported for
DMF could also be used as carbon monoxide surrogate in this
reaction.12 Alper demonstrated that 11H-pyrido[2,1-b]-
quinazolin-11-ones could be prepared by palladium-catalyzed
dearomatizing carbonylation from N-(2-bromophenyl)pyridine-
2-amines (Scheme 1, path c).13 Xu found that the tricyclic or
tetracyclic fused quinazolinones could be synthesized by a
copper-catalyzed domino reaction from arylacetamides involving
an aerobic benzylic oxidation/cyclization/decarbonylation proc-
ess (Scheme 1, path d).14 Despite the significant progress made
in this field, the existing methods often require the use of
expensive metal catalysts or starting materials that are not readily
available. Moreover, most of these methods have difficulty in
accessing valuable halo-substituted products due to undesired
metal-catalyzed dehalogenation reactions. Accordingly, novel
synthetic approaches to the pyrido-fused quinazolinones, with
enhanced reaction efficiency as well as improved availability of
starting materials, are still highly desirable. In a continuation of
our efforts to develop new synthetic protocols for building
valuable heterocyclic frameworks,15 herein we report an efficient
copper-catalyzed domino synthesis of 11H-pyrido[2,1-b]-
quinazolin-11-one derivatives from 2-bromopyridines and read-
ily accessible isatins,16 a type of starting material that has been
widely employed in organic, medicinal, and material synthesis
(Scheme 1, path e).17−19
the preparation of functionalized quinazolinones.4,5
Fused quinzolinones, especially pyrido-fused quizolinones, are
of pariticular pharmaceutical value. For example, 7,8-dehydror-
utaecarpine, 1-hydroxy-7,8-dehydrorutaecarpine, euxylophori-
cine B, euxylophoricine E, and euxylophoricine F are important
biologically active natural alkaloids bearing a 11H-pyrido[2,1-
b]quinazolin-11-one fragment isolated from the plants (see
Supporting Information).6,7 The general method for the
synthesis of tricyclic pyrido-fused quinazolinones8 involves the
lactamization of 2-(pyridin-2-ylamino)benzoic acid, which is
prepared by the reaction of 2-chlorobenzoic acid and 2-
aminopyridine.9 Recently, Beller and Wu reported a base-
controlled selective synthesis of liner and angular pyrido-fused
quinazolinones by palladium-catalyzed carbonylation/nucleo-
philic aromatic substitution sequence (Scheme 1, path a).10 Zhu
illustrated an efficient synthesis of 11H-pyrido[2,1-b]quinazolin-
Scheme 1. Pathways for the Synthesis of Pyrido-Fused
Quinazolinones
At the start of our study, the model reaction of isatin (1a) and
2-bromopyridine (2a) was conducted in the presence of CuO
(2.0 equiv) in DMF at 150 °C in an effort to synthesize N-
pyridinyl-substituted isatin 1-(pyridin-2-yl)indoline-2,3-dione.20
However, no desired product was observed, and the yellow solid
precipitated, which was isolated to give the unexpected 11H-
Received: January 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00113
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Organic Letters
Letter
pyrido[2,1-b]quinazolin-11-one (3a) in 76% yield (Table 1,
entry 1). Then, we attempted to reduce the loading of copper salt
nonpolar and lower boiling point solvents (entries 17−19). 3a
was not formed in the absence of Cu(OAc)2·H2O (entry 20), and
the reaction gave 3a in 38% yield even without additional base
probably due to the weak basic nature of 2-bromopyridine and
the product (entry 21).
a
Table 1. Optimization of the Reaction Conditions
With the aforementioned optimized reaction conditions in
hand (Table 1, entry 8), reactions between a variety of
substituted isatins (1) and 2-halopyridines (2) were investigated,
and good substrate scope was observed (Scheme 2). Specifically,
b
base
temp
yield
(%)
entry
catalyst (equiv)
(equiv)
solvent
(°C)
a
Scheme 2. Scope of Isatins
c
1
2
3
4
5
6
7
8
CuO (2.0)
CuO (0.2)
Cu2O (0.2)
CuI (0.2)
none
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
150
120
120
120
120
120
120
120
76
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
35
87
89
84
90
82
93
CuBr (0.2)
CuCl (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2·H2O
(0.2)
9
Cu(OAc)2·H2O
Na2CO3
K2CO3
DMF
120
91
(0.2)
10
11
12
13
14
15
16
17
18
19
Cu(OAc)2·H2O
(0.2)
DMF
120
90
Cu(OAc)2·H2O
(0.2)
NEt3
DMF
120
62
Cu(OAc)2·H2O
(0.3)
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
DMF
120
93
Cu(OAc)2·H2O
(0.1)
DMF
120
85
Cu(OAc)2·H2O
(0.2)
DMF
90
52
a
Unless otherwise specified, all of the reactions were carried out using
Cu(OAc)2·H2O
(0.2)
DMSO
n-PrOH
toluene
dioxane
t-BuOH
120
88
substituted isatins (1, 1.0 mmol), 2-bromopyridine (2a, 1.2 mmol),
Cu(OAc)2·H2O (0.2 mmol), and NaHCO3 (2.0 mmol) in DMF (5
Cu(OAc)2·H2O
(0.2)
reflux
reflux
reflux
reflux
70
b
mL). Isolated yield. Using 2-chloropyridine (2b, 1.2 mmol) at 150 °C
for 14 h.
Cu(OAc)2·H2O
(0.2)
trace
trace
0
Cu(OAc)2·H2O
(0.2)
the reaction of relatively less active 2-chloropyridine with isatin at
150 °C gave 3a in 75% yield. Isatins bearing electron-donating
(-Me and -OMe) or electron-withdrawing groups (-F, -Cl, -Br,
-CF3, and -NO2) on the phenyl ring was reacted smoothly with 2-
bromopyridine to deliver the corresponding 11H-pyrido[2,1-
b]quinazolin-11-one derivatives 3b−j in good to excellent yields
(75−94%). The structure of 3i was confirmed by X-ray single-
crystal diffraction analysis (Figure 1).
Cu(OAc)2·H2O
(0.2)
20
21
none
NaHCO3
none
DMF
DMF
120
120
0
Cu(OAc)2·H2O
(0.2)
38
a
Unless otherwise specified, all of the reactions were carried out using
isatin (1a, 1.0 mmol), 2-bromopyridine (2a, 1.2 mmol), and base (2.0
mmol) in solvent (5 mL) for 10 h in the presence of catalyst. Isolated
yield. The reaction was carried out for 2 h.
b
c
and lower the reaction temperature, and it was found that in the
presence of NaHCO3 (2.0 equiv) and 0.2 equiv of CuO at 120
°C, the reaction could furnish 3a in 35% yield (entry 2). After
screening other typically used copper salts, such as Cu2O, CuI,
CuBr, CuCl, Cu(OAc)2, and Cu(OAc)2·H2O (0.2 equiv), the
reaction gave 3a in best yield (93%) when Cu(OAc)2·H2O was
used as the catalyst (entries 3−8). Inorganic bases such as
Na2CO3 and K2CO3 were also effective for this reaction,
affording 3a in 91% and 90% yield, respectively (entries 9, 10),
while the organic base Et3N gave the product in moderate yield
(entry 11). Increasing the loading of catalyst led to less significant
improvement, but the reaction gave a slightly lower yield when
reducing the amount of catalyst to 0.1 equiv (entries 12 and 13).
Decreasing the reaction temperature to 90 °C resulted in a lower
yield (entry 14). Other polar solvents such as DMSO and n-
PrOH also delivered the product in 88% and 70% yield,
respectively (entries 15 and 16). Nearly no reaction occurred in
Figure 1. X-ray structure of compound 3i.
Encouraged by the results achieved above, the substrate scope
was further examined, as shown in Scheme 3. It was found that 3-,
4-, and 5-position methyl substituted 2-bromopyridines were
tolerated in this transformation to furnish the corresponding 4a−
c in good yields. The slightly lower yield of 4d was possibly
attributed to the steric hindrance of the 2-bromo-6-methylpyr-
idine. Substrates with methoxy, halogen (-F, -Cl, and -Br), and
CF3 substituents on the pyridine ring were smoothly converted
into the corresponding 4e−i in 75−91% yields. These results are
B
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Letter
a
Scheme 3. Scope of 2-Bromopyridine Derivatives
Scheme 4. Controlled Experiments
synthesis of 3a as an example (Scheme 5). Initially, a copper-
catalyzed Ullmann-type coupling reaction22 of isatin and 2-
Scheme 5. Possible Reaction Mechanism
a
Unless otherwise specified, all of the reactions were carried out using
substituted isatins (1, 1.0 mmol), 2-bromopyridine derivatives (2, 1.2
mmol), Cu(OAc)2·H2O (0.2 mmol), and NaHCO3 (2.0 mmol) in
DMF (5 mL). Isolated yield.
particularly worth noting as halo-substituted 11H-pyrido[2,1-
b]quinazolin-11-ones, which could be transformed to other
functionalized molecules by C−C or C−N cross-coupling
reactions, have been problematic substrates for the previous
reported methods due to the undesired dehalogenation
reactions.10,13,14 The presence of nitriles appeared to partially
inhibit the reaction, evidenced by the modest yield (48%)
obtained for 4j. 2-Bromoquinoline, 2-bromothiazole, and 2-
bromobenzo[d]thiazole were also suitable substrates for the
reaction, affording the products 4k−m in 80−93% yields.
Demonstrating the structural diversity of target molecules, some
representative disubstituted 11H-pyrido[2,1-b]quinazolin-11-
ones 4n−t were also obtained in good results under the standard
reaction conditions.
Importantly, an attempted direct reaction of 2-amino-5-
methylbenzoic acid (5) with 2-bromopyridine under the above
standard conditions only led to the product 3b in <5% yield,
highlighting the importance of isatin in this novel reaction
(Scheme 4a). When the mixture of DMF/H2O (5:1, v/v) was
used as the solvent, 3a was obtained in 68% yield within 2 h.
Meanwhile, the natural alkaloid indolo[2,1-b]quinazoline-6,12-
dione (6, tryptanthrin) was isolated in 12% yield, which was
likely to undergo the self-condensation of isatin and its hydrolysis
product 2-(2-aminophenyl)-2-oxoacetic acid (Scheme 4b; see
Supporting Information).21 Apparently, the C−N bond cleavage
occurred in the presence of water and sodium bicarbonate.
On the basis of these results and previously reported work, a
preliminary reaction mechanism was proposed using the
bromopyridine gave the N-substituted intermediate 1-(pyridin-
2-yl)indoline-2,3-dione A. The byproduct hydrogen bromide
(HBr) would be neutralized with sodium bicarbonate to release
water and carbon dioxide. A then could undergo two possible
pathways to give the final product 3a. For pathway I, in the
presence of base, the hydrolysis of A would deliver a keto-acid
intermediate B,21,23 which can be isomerized to form imine B′.24
The ensuing intramolecular addition cyclization reaction would
generate a six-membered ring intermediate C via the Pfitzinger-
type reaction.21b,25 The subsequent decarboxylation/aerobic
oxidation reaction promoted by copper and air would furnish the
conjugated target molecule 3a.26 For pathway II, the direct
intramolecular nucleophilic attack of pyridine nitrogen atom to
ketone would afford a tricyclic zwitterionic intermediate E, which
could be converted to 3a after the extrusion of carbon monoxide,
and a similar mechanism has been proposed by Xu’s group.14 It
was also found that in the absence of base NaHCO3, when 1.1
equiv of Cu(OAc)2·H2O was used, 2-methylbenzo[b][1,8]-
naphthyridin-5(10H)-one (4d′) was isolated as the major
product in 75% yield, and 4d was only obtained in <5% yield
(Scheme 4c), which indicated the possible extrusion of the
carbon monoxide process (see Supporting Information).
In summary, we have described a simple and efficient method
for the synthesis of pyrido-fused quinazolinone derivatives
catalyzed by Cu(OAc)2·H2O from substituted isatins and 2-
bromopyridine derivatives. The C−N/C−C bond cleavage and
two C−N bond formations were observed in a one-pot
operation. Two plausible reaction mechanisms are also
C
DOI: 10.1021/acs.orglett.6b00113
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Organic Letters
Letter
2011, 2011, 1930. (d) Schwender, C. F.; Sunday, B. R.; Herzig, D. J. J.
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proposed. The prominent advantages of this route are the (1)
easily available starting materials; (2) wide scope of substrates
with further functionalization potentials; and (3) low cost
catalyst Cu(OAc)2·H2O with good to excellent yields of desired
products. This methodology is complementary to previous
synthetic procedures. Further investigations on the applications
of this transformation for other functionalized heterocyclic
systems and on the clarification of the mechanism are currently
underway in our laboratory.
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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.orglett.6b00113.
General experimental procedure and characterization data
of the products (PDF)
X-ray data (CIF)
(16) Da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc.
2001, 12, 273.
AUTHOR INFORMATION
■
(17) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104.
(18) Głowacki, E. D.; Voss, G.; Sariciftci, N. S. Adv. Mater. 2013, 25,
6783.
Corresponding Authors
*(G.Y.) E-mail: gdyin_hbnu@163.com.
*(J.H.) E-mail: jxhcm99@qq.com.
(19) Pakravan, P.; Kashanian, S.; Khodaei, M. M.; Harding, F. J.
Pharmacol. Rep. 2013, 65, 313.
Notes
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(b) Coppola, G. M. J. Heterocycl. Chem. 1987, 24, 1249.
(21) (a) Wang, C.; Zhang, L.; Ren, A.; Lu, P.; Wang, Y. Org. Lett. 2013,
15, 2982. (b) Moskovkina, T. V.; Kalinovskii, A. I.; Makhan’kov, V. V.
Russ. J. Org. Chem. 2012, 48, 123.
(22) (a) Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C.
Chem. Soc. Rev. 2014, 43, 3525. (b) Xu, Z. L.; Li, H. X.; Ren, Z. G.; Du,
W. Y.; Xu, W. C.; Lang, J. P. Tetrahedron 2011, 67, 5282. (c) Qiao, J. X.;
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(23) Casey, L. A.; Galt, R.; Page, M. I. J. Chem. Soc., Perkin Trans. 2
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Natural
Science Foundation of China (21542009) and the Educational
Commission of Hubei Province (D20142051).
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