Copper-catalyzed domino reaction involving C-C bond cleavage to construct 2-aryl quinazolinones

Article abstract of DOI:10.1002/ejoc.201400108

A copper-catalyzed approach for the synthesis of 2-aryl-quinazolinones through a domino reaction involving C-C bond cleavage is described. This protocol involves intramolecular C-C bond cleavage to construct 2-aryl-quinazolinones, which may offer an alternative method to prepare medically important quinazolinone derivatives and a new strategy for C-C bond cleavage. Besides C-C bond cleavage, this domino reaction includes N-arylation and benzylic C-H amidation. A copper-catalyzed approach for the synthesis of 2-aryl-quinazolinones through a domino reaction involving C-C bond cleavage is described. This transformation offers an alternative method to prepare medically important quinazolinone derivatives and a new strategy for C-C bond cleavage. Copyright

Full text of DOI:10.1002/ejoc.201400108

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201400108
Copper-Catalyzed Domino Reaction Involving C–C Bond Cleavage To
Construct 2-Aryl Quinazolinones
Li-Xia Wang,[a] Jun-Feng Xiang,[a] and Ya-Lin Tang*[a]
Keywords: Synthetic methods / Domino reactions / Cleavage reactions / Nitrogen heterocycles / Copper
A copper-catalyzed approach for the synthesis of 2-aryl-quin-
azolinones through a domino reaction involving C–C bond
cleavage is described. This protocol involves intramolecular
C–C bond cleavage to construct 2-aryl-quinazolinones,
which may offer an alternative method to prepare medically
important quinazolinone derivatives and a new strategy for
C–C bond cleavage. Besides C–C bond cleavage, this domino
reaction includes N-arylation and benzylic C–H amidation.
Introduction
The quinazolinone skeleton is an important pharmaco-
phore, and it has been assigned as a privileged structure in
drug development, because of the diverse range of pharma-
cological activities and biological properties displayed by
compounds consisting of this structural motif.[1] In view of
the importance of quinazolinones and their derivatives,
many classical synthesis methods have been reported.[2] The
main synthetic routes to quinazolinone compounds utilize
2-aminobenzoic acid or its derivatives, 2-aminobenzamide,
2-aminobenzonitrile, isatoic anhydride, 2-methoxycarb-
onylphenyl isocyanate, N-arylnitrilium salts, and 4H-3,1-
benzoxazinones as suitable precursors. Recently, Fu et al.
used substituted 2-halobenzamides and (aryl)methanam-
ines as starting materials for CuBr-catalyzed cascade
Ullmann-type coupling and aerobic oxidative C–H amid-
ation reactions in air to give 2-substituted quinazolinones
in good yields (Scheme 1).[3] In our research, by using α-
substituted arylmethanamines as starting materials, we ob-
Scheme 1. Methods for the synthesis of 2-aryl-substituted quin-
azolinone derivatives.
age can be achieved by noble metals, but only a limited
number of strategies have been reported with the use of
cheap metals such as Cu and Fe.[5] Herein, we describe a
copper-catalyzed approach for the synthesis of 2-aryl-quin-
azolinones through a domino reaction involving C–C bond
cleavage.
Results and Discussion
Our initial studies focused on identifying the optimal
tained 2-aryl-quinazolinones as the major products, which conditions (Table 1). 2-Iodobenzamide (1a) and α-methyl-
were surprisingly related to C–C bond cleavage. To the best benzylamine (2a) were smoothly converted into 2-phenyl-
of our knowledge, no examples of the construction of N- quinazolin-4(3H)-one (3a) in 72% yield with CuBr (10 mol-
heterocycles through domino reactions involving C–C bond %) as the catalyst, K2CO3 (3 equiv.) as the base, and di-
cleavage have been previously reported.
methyl sulfoxide (DMSO) as the solvent under an air atmo-
Selective C–C bond cleavage by transition-metal com- sphere at 120 °C over 24 h (Table 1, entry 1). Performing
plexes has recently emerged as an active research topic in the reaction under an argon atmosphere led only to a small
organic chemistry, along with C–H bond cleavage.[4] In amount of 3a in 24 h (Table 1, entry 2), but the yield could
comparison, C–C bond cleavage is more challenging owing be increased to 38% in 72 h (Table 1, entry 3), which sug-
to the inertness of this bond. As is known, C–C bond cleav- gested the absence of air could decelerate the transforma-
tion. Thus, we began to screen other catalysts in air
(Table 1, entries 4–6), and we found that CuBr provided the
highest yield. The base had a significant effect on the yield;
bases such as Cs2CO3 (Table 1, entry 7) and Na2CO3
(Table 1, entry 8) were tested, and neither of them gave a
better result. Using other solvents such as DMF (Table 1,
entry 9) and dimethylacetamide (DMA; Table 1, entry 10)
instead of DMSO gave the products in lower yields. The
[a] Beijing National Laboratory for Molecular Sciences (BNLMS),
Center for Molecular Sciences, State Key Laboratory for Struc-
tural Chemistry of Unstable and Stable Species, Institute of
Chemistry, Chinese Academy of Sciences,
Beijing 100190, P. R. China
E-mail: tangyl@iccas.ac.cn
www.iccas.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400108.
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L.-X. Wang, J.-F. Xiang, Y.-L. Tang
SHORT COMMUNICATION
effect of temperatures was also investigated, and 120 °C was Arylation product 4a was placed under the above-optimized
the best choice (Table 1, compare entries 1, 11, 12).
conditions and further converted into final product 2-phen-
ylquinazolin-4(3H)-one (3a) in 87% yield (see Scheme 2, b).
We purposely prepared 5 according to the reported
method,[6] and it was transformed into final product 3a ef-
ficiently under the established conditions (see Scheme 2, c).
Without the involvement of CuBr, the transformation from
5 into 3a was also realized, but it took 3 days, and the yield
of the isolated product was 81%, which revealed the impor-
tant role of CuBr as the catalyst (see the Supporting Infor-
mation).
Table 1. Optimization of the conditions for the copper-catalyzed
domino reaction of 2-iodobenzamide with α-methylbenzylamine to
form 2-phenylquinazolin-4(3H)-one in air.[a]
Entry Cat.
Base
Solvent
t
[h]
T
[°C]
Yield[b]
[%]
1
2
3
4
5
6
7
8
CuBr
CuBr
CuBr
CuBr2
CuCl2
CuI
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
K2CO3 DMSO
K2CO3 DMSO
K2CO3 DMSO
K2CO3 DMSO
K2CO3 DMSO
K2CO3 DMSO
Cs2CO3 DMSO
Na2CO3 DMSO
K2CO3 DMF
K2CO3 DMA
K2CO3 DMSO
K2CO3 DMSO
24
24
72
24
24
24
24
24
24
24
24
24
120
120
120
120
120
120
120
120
120
120
140
100
72
13[c]
38[c]
48
70
23
16
trace
58
63
61
9
10
11
12
52
[a] Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst
(0.05 mmol), base (1.5 mmol), and solvent (5 mL) under an air at-
mosphere. [b] Yield of isolated product. [c] Under an argon atmo-
sphere.
Scheme 2. CuBr-catalyzed (a) Ullmann-type coupling of 1a with 2a
Under the established conditions [CuBr (10 mol-%) as under an argon atmosphere, (b) domino reaction of 4a in air, and
the catalyst, K2CO3 (3 equiv.) as the base (relative to the
(c) transformation from 5 into 3a in air.
amount of 1a)], the domino reactions between substituted
2-halobenzamides 1 and α-substituted arylmethanamines 2
were performed. As shown in Table 2, most of the sub-
strates examined provided the corresponding products in
21–73% yield. For substituted 2-halobenzamides, the aryl
iodide showed higher reactivity than the corresponding
bromide and chloride (Table 2, entries 1, 10, 11), and 2-
bromo-5-methoxybenzamide gave a better result than 2-
On the basis of the above results, we proposed a possible
mechanism, as shown in Scheme 3. Ullmann-type coupling
product I is first prepared starting from a substituted 2-
halobenzamide and an α-substituted arylmethanamine, and
the results showed an ortho-substituent effect of the amide
group in I during N-arylation.[7] Then, N-arylation product
I is transformed into imine II, which was verified indirectly
from the isolation of the ketone as a byproduct (see the
Supporting Information). Then, intramolecular nucleo-
chloro-4-nitrobenzamide (Table 2, entries 12–15, 16). For
the starting α-substituted arylmethanamines, if the R2
group was a methyl (Table 2, entry 1), allyl (Table 2, en-
try 2), benzyl (Table 2, entry 3), or phenyl group (Table 2,
entry 4) and the Ar group was a phenyl group, product 3a
was obtained in all cases in 62–73% yield. The reaction also
tolerated Ar groups with varied electronic properties, in-
cluding electron-neutral (e.g., phenyl: Table 2, entries 1 and
12), electron-rich (e.g., p-methylphenyl: Table 2, entries 5
and 13; p-methoxyphenyl: Table 2, entries 6 and 14), and
electron-poor (e.g., p-chlorophenyl: Table 2, entries 7 and
15), in addition to a pyridine ring (Table 2, entry 8) and a
naphthalene ring (Table 2, entry 9), all of which gave corre-
sponding products 3a–k in 49–73% yield.
To explore the reaction mechanism, we chose α-methyl-
benzylamine (2a) as the model substrate and launched the
control experiments shown in Scheme 2. If 2-iodobenz-
amide (1a) was treated with 2a under an argon atmosphere
(1 atm, with extrusion of air) for 4 h, Ullmann-coupling
Scheme 3. Possible mechanism for the CuBr-catalyzed domino syn-
product 4a was obtained in 69% yield (see Scheme 2, a). N- thesis of 2-aryl-substituted quinazolinones in air.
2
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Copper-Catalyzed Domino Reaction Involving C–C Bond Cleavage
Table 2. Substrate scope for the CuBr-catalyzed domino synthesis of 2-aryl-substituted quinazolinones.[a]
[a] Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), CuBr (0.05 mmol), K2CO3 (1.5 mmol), and DMSO (5 mL) under an air atmosphere.
[b] Yield of isolated product.
philic addition of the amide to the C=N bond provides aryl-quinazolinone 3 is formed through carbon–carbon
benzylic C–H amidation product III.[8] In the end, target 2- bond cleavage. A thorough mechanistic study of the C–C
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L.-X. Wang, J.-F. Xiang, Y.-L. Tang
SHORT COMMUNICATION
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bond cleavage reaction is needed to unravel the mechanistic
intricacies of this process.
Conclusions
[2]
In summary, we demonstrated a copper-catalyzed ap-
proach for the construction of 2-aryl-quinazolinones
through a domino reaction involving C–C bond cleavage by
using air as the accelerant. Besides C–C bond cleavage, the
domino reactions also included N-arylation and benzylic
C–H amidation. This reaction not only provides an efficient
method for constructing medically important quinazoli-
nones but also offers a new strategy for C–C bond cleavage.
Experimental Section
General Information: Reactions were monitored by analytical thin-
layer chromatography (TLC) by using ultraviolet light. Purification
of the products was accomplished by flash chromatography on sil-
ica gel (100–200 mesh), and the purified compounds showed a sin-
gle spot by analytical TLC. Chemical shifts are in ppm versus tet-
ramethylsilane with either tetramethylsilane or the residual solvent
resonance used as the internal standard. Melting points are uncor-
rected.
[3]
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General Procedure for Synthesis of Quinazolinone Derivatives 3a–k:
A mixture of substituted 2-halobenzamide 1 (0.5 mmol), α-substi-
tuted benzylamine 2 (1.0 mmol), K2CO3 (1.5 mmol, 207 mg), and
CuBr (0.05 mmol, 7.1 mg) in DMSO (5 mL) was allowed to stir at
120 °C for 24 h. Upon completion of the reaction, the resulting
solution was cooled to room temperature and filtered, and the sol-
vent of the filtrate was removed under reduced pressure. The resi-
due was purified by column chromatography on silica gel (petro-
leum ether/ethyl acetate) to provide desired product 3.
[5]
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Supporting Information (see footnote on the first page of this arti-
cle): Detailed description of the experimental procedures and ana-
lytical data for all compounds.
Acknowledgments
The authors wish to thank the National Natural Science Founda-
tion of China (NSFC) (grant numbers 21302188, 81072576,
91027033) and the Chinese Academy of Sciences (grant numbers
KJCX2-EW-N06-01 and XDA09030307) for financial support.
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Received: January 22, 2014
Published Online: ᭿
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Copper-Catalyzed Domino Reaction Involving C–C Bond Cleavage
Domino Reactions
L.-X. Wang, J.-F. Xiang,
Y.-L. Tang* ....................................... 1–5
Copper-Catalyzed Domino Reaction In-
volving C–C Bond Cleavage To Construct
2-Aryl Quinazolinones
A copper-catalyzed approach for the syn-
thesis of 2-aryl-quinazolinones through a
domino reaction involving C–C bond
cleavage is described. This transformation
offers an alternative method to prepare
medically important quinazolinone deriva-
tives and a new strategy for C–C bond
cleavage.
Keywords: Synthetic methods / Domino re-
actions / Cleavage reactions / Nitrogen het-
erocycles / Copper
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