Oxidant- and metal-free synthesis of 4(3H)-quinazolinones from 2-amino-N-methoxybenzamides and aldehydes via acid-promoted cyclocondensation and elimination

Article abstract of DOI:10.1039/c4ra04331f

A series of biologically important 4(3H)-quinazolinones were readily synthesized in good to excellent yields from 2-amino-N-methoxybenzamides and aldehydes via a cascade reaction consisting of AcOH-promoted cyclocondensation and elimination. The current m

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COMMUNICATION
Oxidant- and Metal-Free Synthesis of 4(3H)-Quinazolinones from 2-
Amino-N-methoxybenzamides and Aldehydes via Acid-Promoted
Cyclocondensation and Elimination†
Ran Cheng,a Linlin Tang,a Tianjian Guo, a Daisy Zhang-Negrerie,a Yunfei Du*,a,b and Kang Zhao*,a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
of quinazolinones through a oneꢀpot oxidative cyclization of
primary alcohols with oꢀaminobenzamides as well as through a
domino process of Nꢀarylation followed by condensative
A series of biologically important 4(3H)-quinazolinones were
readily synthesized in good to excellent yields from 2-amino-
N-methoxybenzamides and aldehydes via a cascade reaction
45 cyclization. Another extensively studied strategy was
sometimes metalꢀfree, oneꢀpot protocol which involves
a
a
10 consisting of AcOH-promoted cyclocondensation and
elimination. The current method sets itself apart from the
conventional approach utilizing anthranilamide derivatives
and aldehydes as building blocks, by its unique features,
other than the high yields and one-pot procedure, including
15 the absence of an oxidant, the obviation of a heavy-metal
catalyst, and the formation of a non-toxic ester byproduct.
cyclocondensation of anthranilamides with aldehydes followed
by a subsequent oxidantꢀmediated dehydrogenation process
(Scheme 1, eq 1).19 Various nonꢀmetal oxidants such as DDQ,19a
50 I2,19f O220 as well as metal ones such as CuCl2,19c KMnO4,19e have
been applied to realize the second oxidative step. Although this
last strategy has some practical advantages and potential
applications, many of the existing methods have the
disadvantages such as harsh conditions, unsatisfactory yields and
55 most seriously, the use of the stoichiometric oxidants or heavyꢀ
metal reagents. To the best of our knowledge, there are few
reports, if any, describing the dehydrogenation step that does not
require the participation of an oxidantor a heavyꢀmetal catalyst.21
In this communication, we report a novel green protocol for the
60 synthesis of 4(3H)ꢀquinazolinone compounds 3, that is free of
oxidant or catalyst and was carried out in a convenient oneꢀpot
reaction between 2ꢀaminoꢀNꢀmethoxybenzamides 1 and various
aldehydes 2, going through an intermediate of 3ꢀmethoxyꢀ2,3ꢀ
dihydroquinazolinꢀ4(1H)ꢀone A (Scheme 1, eq 2). It is worthy to
65 note that the generated MeOH was converted to a nontoxic ester
as a byproduct in this approach.22
Quinazolinones are an important class of nitrogenꢀcontaining
heterocycles (azaheterocycles) which exhibit a range of biological
and pharmaceutical properties,1 including but not limited to
20 antihypertensive,2 anticancer,3 anti‐inflammatory,4 antimalarial5
and antimicrobial6 activities. In addition to their occurrence in
natural products, they also frequently appear in pharmaceutical
agents for their applications as potent antagonistic receptors.7 For
example, Pegamine, isolated from Peganum harmala, has been
25 found to possess cytotoxic activity,8 and NPS 53574, a new
calcilytic template for blocking calcium receptor (CaR) activity,
is proven to be capable of treating osteoporosis (Figure 1).9 Both
of these two biologically active compounds possess the common
quinazolinone skeleton in their respective structure.
30
Fig. 1 Representative quinazolinones in natural products and
pharmaceutical agents.
Considering the significance of this class of compounds, many
efforts have been devoted to explore the methodologies for the
35 construction
representative
of
4(3H)ꢀquinazolinone
skeletons.
of
The
oꢀ
methods
involve cyclization
acylaminobenzamide,10 amination of benzoxazinꢀ4ꢀone,11
multicomponent reactions (MCRs) among isatoic anhydride,
amine with aldehyde,12 benzyl halide13 or orthoester.14 In
40 addition, transition metal catalysts such as copper,15 ruthenium,16
iridium17 and palladium18 have also been applied to the synthesis
Scheme 1 Strategies of synthesis of 4(3H)-quinazolinones.
70
In our previous work,23 we found that the reaction of 2ꢀaminoꢀ
Nꢀmethoxybenzamides 1 with aldehydes 2 conveniently afforded
3ꢀmethoxyꢀ2,3ꢀdihydroquinazolinꢀ4(1H)ꢀones A in the presence
of catalytic amount of TsOH. We envisaged that the treatment of
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3ꢀmethoxyꢀ2,3ꢀdihydroquinazolinꢀ4(1H)ꢀone A with a suitable
acid might trigger an acidꢀpromoted demethanolization and
thereafter give 4(1H)ꢀquinazolinone B, which should quickly
although the reaction time was further shortened to 1 h (Table 1,
entry 9). Study on the concentration of the reactant 1a showed
neither higher nor lower concentration was beneficial to the
isomerize into 4(3H)ꢀquinazolinone 3 (Scheme 2). To our 35 reaction as negative consequences such as more byproducts
5
pleasant surprise, we found that by heating the isolated 3ꢀ
methoxyꢀ2,3ꢀdihydroquinazolinꢀ4(1H)ꢀone A1 in refluxed TFA
for 55 minutes, the desired 4(3H)ꢀquinazolinone 3a was obtained
in 84% yield (Scheme 3).
(therefore less desired product) or lengthened reaction time were
observed, respectively (Table 1, entries 10ꢀ11).
With the optimal reaction conditions in hand, the scope and
generality of this new oneꢀpot protocol was investigated, the
40 results of which are summarized in Table 2. By reacting 2ꢀaminoꢀ
Nꢀmethoxybenzamides 1b-e with substituted aldehydes 2b-e,
bearing electronꢀwithdrawing groups, the desired products 3b-e
were conveniently achieved in satisfactory to excellent yields
(Table 2, entries 2ꢀ5) in each case. One slight exception was the
45 reaction between 1e and 2e, which was completed in a much
longer 4.5 h and afforded the desired product 3e in relatively
lower yield. This was obviously due to the steric hindrance
brought by the oꢀsubstituted bulky trifluoromethyl group in
aldehyde 2e (Table 2, entry 5). The method was equally well
50 applicable to the benzaldehydes bearing electronꢀrich substituent
(Table 2, entries 6ꢀ8). In the case of diꢀsubstituted benzaldehydes,
bearing either electronꢀwithdrawing or electronꢀdonating group,
the desired products were obtained in even better yields (Table 2,
entries 9ꢀ10). Each of the substrates, containing either an
55 electronꢀdeficient or electronꢀrich substituent on the benzene ring
of 2ꢀaminoꢀNꢀalkoxybenzamide, was converted to the
corresponding 4(3H)ꢀquinazolinone products 3kꢀm in good to
excellent yields (Table 2, entries 11ꢀ13). Further study revealed
10 Scheme 2 Proposed route to access 4(3H)-quinazolinones.
Scheme 3 Conversion of A1 into 3a through acid-promoted
elimination of MeOH.
Considering the fact the formation of 3ꢀmethoxyꢀ2,3ꢀ
15 dihydroquinazolinꢀ4(3H)ꢀone A was also realized under acidic
conditions, we next focused on designing a cascade reaction
which entails developing a oneꢀpot protocol for the synthesis of 3
from 1 and 2. We selected 2ꢀaminoꢀNꢀmethoxybenzamide 1a and
benzaldehyde 2a as model substrates. To our delight, after
20 heating the two starting materials in TFA for 1 h, the reaction
afforded the desired product 3a in 81% yield (Table 1, entry 1).
Various acids were used as solvent to further screen for the more
favorable reaction conditions (Table 1, entries 2ꢀ7). Judging by
the yield of the desired product, acetic acid was concluded as the
25 best solvent (Table 1, entry 7). By increasing the reaction
Table
2 Synthesis of 4(3H)ꢀquinazolinones via AcOHꢀpromoted
60 cyclocondensation and eliminationa
o
o
temperature from 80 C to 100 C, the reaction time was cut
down by half, from 3 h to 1.5 h, and the yield was slightly
increased (Table 1, entry 8). However, operating the reaction at
entry
1
R1
2
R2
product time yield
3
(h)
1.5
1
(%)b
93
95
95
82
81
87
73
92
95
98
93
80
98
79
75
95
80
82
Table 1 Optimization of reaction conditionsa
1
H
H
H
H
H
H
H
H
H
H
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
Ph
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
2
pꢀBrꢀPh
pꢀFꢀPh
O
O
3
0.5
0.3
4.5
1
OMe
N
solvent
NH
Ph
Ph-CHO
+
4
mꢀClꢀPh
oꢀCF3ꢀPh
pꢀMeꢀPh
pꢀMeOꢀPh
pꢀOHꢀPh
H
NH2
N
5
1a
2a
3a
30
6
entry
solvent
TFA
T (oC)
time (h)
yield (%)b
7
2g
2h
2i
3g
3h
3i
1
1
reflux
80
1
81
0
8
2
2
PivOH
8
9
2,6ꢀdiClꢀPh
3,4ꢀdiMeOꢀPh
Ph
2
3
Cl2COOH
TfOH
80
1.5
12
3
70
ND
12
34
88
93
89
82
92
10
11
12
13
14
15
16c
17c
2j
3j
1
4
80
5ꢀBr 1b
3ꢀMe 1c
4ꢀMeO 1d
2a
2a
2a
2k
2k
2l
3k
3l
0.3
0.5
0.5
1
5
HCl
80
Ph
6
HCO2H
AcOH
AcOH
AcOH
AcOH
AcOH
80
12
3
Ph
3m
3n
3o
3p
3q
3r
7
80
H
1a
6ꢀCl 1e
4ꢀF 1f
4ꢀMeO 1d
1a
nꢀpropyl
nꢀpropyl
Me
8
100
110
100
100
1.5
1
1
9
5
10c
1.5
4
iꢀpropyl
2m
3
11d
18
H
(E)ꢀPhꢀCH=C(Me) 2n
3
a
Reaction conditions: substrate 1a (1.0 mmol) and aldehyde 2a (1.1
a
Reaction conditions: substrate 1a (1.0 mmol) and aldehyde 2a (1.1
b
c
mmol) in solvent (4 mL). Isolated yields. The concentration of the
reaction was 0.5 mol·Lꢀ1, based on substrate 1a. d The concentration of the
reaction was 0.20 mol·Lꢀ1, based on substrate 1a.
mmol) in solvent (4 mL). b Isolated yields. c 3 equiv of aldehyde was used.
even higher temperature did not improve the product yield,
that the aromatic aldehydes could also be replaced with aliphatic
2
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aldehydes, rendering the method applicable to the synthesis of 2ꢀ
substrates and to afford the desired 4(3H)ꢀquinazolinone in
alkyl 4(3H)ꢀquinazolinones 3nꢀq in good to excellent yields 45 satisfactory to excellent yields. The numerous attractive
(Table 2, entries 14ꢀ17). Furthermore, we were pleased to find
that (E)ꢀ2ꢀ(1ꢀphenylpropꢀ1ꢀenꢀ2ꢀyl)quinazolinꢀ4(3H)ꢀone 3r
could also be obtained in good yield, which indicated that this
method was also compatible with the aldehydes bearing an α,βꢀ
unsaturated double bond (Table 2, entry 18).
properties such as the oxidantꢀfree and environmental benignancy
characteristics, the oneꢀpot protocol, and simple setup and workꢀ
up procedure, altogether promise this method many potentially
useful applications in organic synthesis.
5
Unfortunately, when 4ꢀnitrobenzaldehyde 2o and 2ꢀaminoꢀNꢀ
methoxyꢀ4ꢀnitrobenzamide 1g were applied, the reaction only
50 Acknowledgements
We acknowledge the National Natural Science Foundation of China
(#21072148), Foundation (B) for Peiyang ScholarꢀYoung Core Faculty of
Tianjin University (2013XRꢀ0144), the Innovation Foundation of Tianjin
University (2013XJꢀ0005) and, especially, the National Basic Research
55 Project (2014CB932201) for financial support.
10 gave 3ꢀmethoxyꢀ2ꢀ(4ꢀnitrophenyl)ꢀ2,3ꢀdihydroquinazolinꢀ4(1H)ꢀ
one A2 and 3ꢀmethoxyꢀ7ꢀnitroꢀ2ꢀphenylꢀ2,3ꢀdihydroquinazolinꢀ
4(1H)ꢀone A3 as the only products, rather than the expected
4(3H)ꢀquinazolinones even at reflux temperature for 14 hrs. To
our delightful surprise, treating the obtained compound A2 and A3
15 with KOH in DMSO could also trigger the elimination and finally
afforded the desired 4(3H)ꢀquinazolinone products 3s and 3t in
satisfactory yields (Scheme 4).
Notes and references
a Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency,
School of Pharmaceutical Science and Technology, Tianjin University,
Tianjin 300072, China. Fax: +86-22-27404031; Tel: +86-22-27404031;
60 duyunfeier@tju.edu.cn; kangzhao@tju.edu.cn
b Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin), Tianjin 300072, China. Fax: +86-22-27404031; Tel: +86-22-
27404031; duyunfeier@tju.edu.cn
† Electronic Supplementary Information (ESI) available: NMR data. See
65 DOI: 10.1039/b000000x/
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20 Scheme 4 Another way to synthesize nitro-substituted 4(3H)-
quinazolinones.
70
75
To further demonstrate the potential applications of this novel
acidꢀpromoted synthesis of 4(3H)ꢀquinazolinones, we directed
our efforts toward the synthesis of the naturally occurring
25 Pegamine. The required substrate aldehyde 2p can be easily
prepared from butaneꢀ1,4ꢀdiol according to the reported
procedures.24 To our delight, subjecting 1a and 2p to our
optimized reaction conditions afforded the 4(3H)ꢀquinazolinone
3u in a satisfactory 86% yield. After deprotecting the benzyl
30 group of 3u by hydrogenation over Pd/C, the desired natural
product Pegamine was obtained in 88% yield.
80
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Scheme 5 Application of the method to the synthesis of natural
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35 Conclusions
In summary, we have developed an efficient green approach
which allows for rapid construction of the 4(3H)ꢀquinazolinone
skeleton from 2ꢀaminoꢀNꢀmethoxybenzamides 1 and aldehydes 2
through a novel oneꢀpot AcOHꢀpromoted cyclocondensation and
40 elimination process. This is a successful example of synthesizing
the biologically important 4(3H)ꢀquinazolinone compounds
obviating the participation of either an oxidant or a heavyꢀmetal
catalyst. The method has proven to apply to a broad scope of
100
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4
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DOI: 10.1039/C4RA04331F
Graphical Abstract
Oxidant-
and
Metal-Free
Synthesis
of
4(3H)-Quinazolinones
from
2-Amino-N-methoxybenzamides and Aldehydes via Acid-Promoted Cyclocondensation and
Elimination
Abstract: A series of biologically important 4(3H)-quinazolinones were readily synthesized in good to excellent
yields from 2-amino-N-methoxybenzamides and aldehydes via a cascade reaction consisting of AcOH-promoted
cyclocondensation and elimination. The current method sets itself apart from the conventional approach utilizing
anthranilamide derivatives and aldehydes as building blocks, by its unique features, other than the high yields and
one-pot procedure, including the absence of an oxidant, the obviation of a heavy-metal catalyst, and the formation of
a non-toxic ester byproduct.