Metal-free synthesis of quinazolinones without any additives in water

Article abstract of DOI:10.1039/c6ra05777b

Here we report that an excess amount of aldehyde, in particular, aliphatic aldehyde, without any additives, efficiently facilitates the oxidation of aminal intermediates to quinazolinones in pure water.

Full text of DOI:10.1039/c6ra05777b

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Metal-free synthesis of quinazolinones without any additives in
water
Received 00th January 20xx,
Accepted 00th January 20xx
Ben-Quan Hu,a,b Jie Cui,c Li-Xia Wang,b,* Ya-Lin Tangb,* and Luo Yanga,*
DOI: 10.1039/x0xx00000x
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Here we reported the excess amount of aldehyde especially In this communication, we report our initial results that
aliphatic aldehyde, without any additives, efficiently facilitates the indicate the excess amount of aldehydes especially aliphatic
oxidation of aminal intermediates to quinazolinones in pure aldehydes, without any additives, efficiently facilitates the
water.
oxidation of aminal intermediates to quinazolinones in pure
water.
In the last decade, there is an increasing focus on developing
green chemical processes for synthetic organic chemists.
Developing atom economical reactions, minimizing use of toxic
reagents1 and adopting environmentally benign solvents2 in an
effort to achieve ideal chemical transformations have begun to
rise to the green challenge.3 Quinazolinones represent a class
of privileged scaffolds that occur in approximately 150
naturally occuring alkaloids, some of which exhibit a wide
range of biological and pharmacological activities, such as
rutaecarpine, luotonin A, luotonin F, sildenafil, bouchardatine
and raltitrexed.4 Although numerous methods have been
developed,5 the previously reported conditions required to
effect the synthesis include metal catalysts, organic solvents
and/or specific oxidants.
Recently, we found C-C (or C-H) bonds at the 2-position of
2,2-disubstituted-1,2,3,4-tetrahydroquinazolinone could be
selectively cleaved by the Cu/air catalytic system, and the C-H
bond was the most easily cleaved.8 As our ongoing research,
we detected the excess amount of aldehyde by accident in the
reaction system could favor the synthesis of quinazolinone
(Table 1). The condensation between o-aminobenzamide 1a
and 3-phenylpropanal 2a (1 equiv., relative to the amount of
1a) could provide the cyclic aminal intermediate 3a easily with
the yield of 92% and just a little trace amount of quinazolinone
4a was detected (entry 1 ), and the water was chosen as the
solvent. While increasing the amount of 3-phenylpropanal 2a
to 1.5 equiv. or even to 2.0 equiv. (relative to the amount of
1a), the yield of quinazolinone 4a was increased to 58% (entry
2 ) and 73% (entry 3 ), respectively, and of course the
The most classical and general protocols for the synthesis of
quinazolinones are still through the condensation between o-
aminobenzamides and aldehydes followed by the oxidation of
the resulting aminal intermediates.6 However, these
procedures suffer from the use of stoichiometric or excess
amounts of toxic and/or hazardous oxidants, such as KMnO4,6a
MnO2,6b CuCl,6c DDQ,6d I2,6e t-BuOOH6f and PhI(OAc)2,6g and the
generation of a large amount of harmful by-products.7 In
addition, the above procedures were generally performed in
organic solvents, which might cause environmental pollution.
Table 1 Optimization of conditions for the condensation
reaction
between
o-aminobenzamide
1a
and
3-
phenylpropanal 2a a
.
O
O
O
H
O
NH
NH
NH2
120-130 o
C
+
+
N
H
N
NH2
H2O, 24 h
Ph
4a
2a
3a
1a
Ph
Ph
yieldb [%]
Solvent
Entry
2a(equiv.)
3a
4a
trace
58
a.Key Laboratory for Environmental Friendly Chemistry and Application,
Department of Chemistry, Xiangtan University, Hunan 411105, PR China.
.yangluo@xtu.edu.cn
1
2
1.0
1.5
2.0
2.0
2.0
2.0
2.0
H2O
H2O
H2O
H2O
H2O
92
34
11
29
0
b.Beijing National Laboratory for Molecular Sciences (BNLMS), Center for Molecular
Sciences, State KeyLaboratory for Structural Chemistry of Unstable and Stable
Species, Institute of Chemistry, ChineseAcademy of Sciences, Beijing 100190, PR
China. wlx8825@iccas.ac.cn; tangyl@iccas.ac.cn.
3
73
4c
5d
6
68
60
c. Center for Physcochemical Analysis and Measurement, Institute of Chemistry,
Chinese Academy of Sciences (ICCAS), Beijing 100190, China.
† Footnotes relaꢀng to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
H2O/EtOH (3:1)
14
26
72
H2O/i-PrOH (3:1)
61
7
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a
reaction conditions: 1a (0.3 mmol), H2O: 2 ml, 120-130
℃,
During the synthetic process of quinazolinones investigated
b
24h. isolated yield. degassed before heating and reacted here, the oxidation of the cyclic aminal intermediate was very
under argon. d dioxygen atmosphere.
c
important. To elucidate the transformation process from the
cyclic aminal intermediates to 2-substituted quinazolinones
, some control experiments were tested. As shown in scheme
3
correspondingly decreased yields of the aminal intermediate
4
3a were found. Control experiments under argon and dioxygen 1, cyclohexyl-substituted aminal intermediate 3c could convert
atmosphere both produced the quinazolinone 4a in lower into 2-cyclohexyl-quinazolinone 4c in yield of 76%, just in the
yields (entries 4 and 5), which confirmed the aromatization of presence of additional cyclohexanecarboxaldehyde 2c. These
the cyclic aminal intermediate was promoted by the excess results indicated that the excess amount of aliphatic aldehyde
aldehyde. When the model reactions were conducted in mixed might serve as an oxidant to convert the aminal intermediate
solvents [water/ethanol (entry 6) or water/IPA (entry 7)], into the final product . Aryl-substituted aminal intermediates
slightly lower yields of 4a were obtained compared with pure gave different results, which were shown in Table 2. We
water. As the requirements of green chemistry on solvent, investigated the transformations from 3h and 3g to 4h and 4g
3
4
,
water is chosen as the best solvent for the further study.
respectively, in the presence of cyclohexanecarboxaldehyde
2c, and we found para-nitrophenyl substituted substrate 3h
led to a trace amount of quinazolinone 4h, while para-
methoxylphenyl substituted substrate 3g gave two
quinazolinone products 4g and 4c in yields of 24% and 57%,
respectively. The different reactivity might be attributed to the
increased stability of the para-nitrophenyl substituted aminal
To investigate the quinazolinone synthesis in the presence
of
2 equiv. aldehyde (relative to the amount of 2-
anthraniamide), we found 2-anthraniamide 1a treated with
aliphatic aldehyde 2a-e in water at 120-130 oC, led to 2-
substituted quinazolinones 4a-e as the major products with
the yields in the range of 41% to 73%. Aromatic aldehydes
showed different results, and that benzaldehyde 2f and para-
nitrobenzaldehyde 2h gave the cyclic aminal intermediate 3f in
86% yield and 3h in 63% yield, respectively. However, the
para-methoxylbenzaldehyde 2g and picolinaldehyde 2i
provided the 2-substituted quinazolinones as the major
products, with the isolated yields of 71% and 39%,
intermediate 3h
O
.
O
o
C
NH
(A)
120-130
NH
H2O, 24 h
0%
N
H
N
3c
4c
O
O
N
O
H
o
C
120-130
NH
(B)
NH
+
H2O, 24 h
76%
N
H
respectively. Besides 2-anthraniamide 1a
anthraniamide 1b and 4-nitro-2-anthraniamide 1c reacted with
3-phenylpropanal 2a both led to the 2-substituted
,
4-methyl-2-
3c
4c
2c
,
O
O
o
O
H
C
120-130
NH
quinazolinones as the major products in moderate to good
yields.
NH
(C)
+
H2O, 24 h
trace
N
N
H
NO2
NO2
4h
2c
3h
Table 2 Substrate scope for substituted 2-anthranilamide
treated with aldehyde in water.a
O
O
N
O
O
H
o
C
120-130
NH
O
NH
NH
(D)
O
O
+
+
H2O, 24 h
H
N
o
C
N
H
NH2
NH2
R1
NH
R2
120-130
NH
R2
R2
O
R1
OMe
4g 24%
R1
4c 57%
OMe
2c
3g
H2O, 24h
N
H
N
Scheme 1 Control experiments under the optimized conditions:
transformations of the cyclic aminal intermediate 3c in the
absence (A) or presence (B) of 2c, and transformations of 4-
nitro-substrate 3h and 4-methoxyl-substrate 3g in the
presence of 2c. The amount of cyclohexanecarboxaldehyde 2c
1
2
3
4
1a, 2-anthranilanmide
1b, 4-methyl-2-anthranilanmide
1c, 4-nitro-2-anthranilanmide
Yield (%)b
entry
1
2
(R2)
3
4
was 2 equiv., relative to the amount of 3.
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
phenylethyl, 2a
H, 2b
3a 11
---e
4a 73
4b 68
4c 62
4d 52
4e 41
4f <5
4g 71
---e
Based on these results above, we tried to provide a
reasonable mechanism to elaborate the role of the excess
amount of aldehyde, especially aliphatic aldehyde. As is known
3
cyclohexyl, 2c
ethyl, 2d
3c 34
4c
5d
6
3d 21
---e
n-hexyl, 2e
phenyl, 2f
in scheme 2, the cyclic aminal intermediates
3 was easily to be
3f 86
3g 27
3h 63
---e
prepared from the condensation between o-aminobenzamide
7
p-methoxyphenyl, 2g
and aldehydes. Then as shown in Scheme 2, there will be a
8
p-nitrophenyl, 2h
balance between the aminal intermediate
i and imine
9
2-pyridyl, 2i
4i 39
4j 57
4k 78
intermediate ii. In the presence of an additional aliphatic
aldehyde, aromatic imine intermediate ii will be transformed
to aliphatic imine intermediates iii to a certain extent, which
would form the cyclic alkyl-substituted aminal intermediate iv
readily. Subsequently, the nucleophilic addition of this aminal
10
2a
2a
---e
11
3k 22
a
reaction conditions:
1 (0.3 mmol), 2 (0.6 mmol); H2O: 2 ml,
d
e
120-130
℃
, 24h. b isolated yield. c 2d (1.2 mmol ). 48 h. not
detected.
intermediate iv to the excess aliphatic aldehyde generates
v,
which further dehydrate to produce an exo imine cation vi
.
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Then, a [1,3] hydride shift takes place to transform this exo In conclusion, the excess amount of aldehyde during the
imine cation into the endo imine cation vii 9
The final condensation reaction between 2-anthraniamide and
hydrolysis of the endo imine cation vii would afford the aldehyde, especially aliphatic aldehyde, efficiently facilitates
.
quinazolinone product.
the oxidation of aminal intermediate to quinazolinone in pure
water. This protocol was simple and avoided the use of any
additional oxidants and additives. To the best of our
knowledge, the work reported herein provides the first
example of the excess amount of the aldehyde as an oxidant.
Acknowledgements
The authors wish to thank the National Natural Science
Foundation of China (Grant No. 21302188, 91027033) and
Chinese Academy of Sciences (Grant No. KJCX2-EW-N06-01
and XDA09030307) for financial support.
Scheme 2. Possible mechanism for the balance between the
aminal intermediate and the imine intermediate, and the
further transformation to the quinazolinone product, in the
presence of the excess aliphatic aldehyde.
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2
Besides the mechanism described above, there is another
one possibility that the new formed acid from the oxidation of
aldehyde in this reaction system, facilitated the transformation
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amount of aldehyde doesn't play the role of an oxidant. In
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5
cyclohexanecarboxaldehyde
2c,
2-cyclohexyl-substituted
aminal intermediate 3c could convert into 2-cyclohexyl-
quinazolinone 4c in yield of 49%, the value of which is
obviously lower than the result of cyclohexanecarboxaldehyde
2c. Moreover, the addition of 2.0 equiv. amount of organic
base triethylamine wouldn't inhibit the transformation process
from the aminal intermediate 3c to quinazolinone 4c aided by
cyclohexanecarboxaldehyde 2c. Besides, cyclohexanemethanol
as a by-product was detected by GC-MS (Figure S1), indicating
that the excess amount of aldehyde served as an oxidant
possibly in this reaction.
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O
o
O
OH
C
Cui, Org. Chem. Front., 2015, 2, 366–368.
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H2O, 24 h
49%
NH
NH
+
(A)
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N
H
N
4c
3c
O
O
NEt3 (2eq.)
O
H
o
C
NH
120-130
H2O, 24 h
73%
NH
(B)
+
N
H
N
4c
3c
2c
Scheme 3 Control experiments under the optimized conditions:
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presence of 2 equiv. 2c and triethylamine (B).
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7
8
2
Conclusions
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For recent reports on [1,3] hydride shift: (a) M. Tang, L. Tong,
Journal Name
9
L. Ju, W. Zhai, Y. Hu and X. Yu, Org. Lett. 2015, 17, 5180–
5183; (b) W. Chenand, D. Seidel, Org. Lett., 2014, 16, 3158–
3161; and references cited therein.
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