Thiamine hydrochloride (VB1) as an efficient promoter for the one-pot synthesis of 2,3-dihydroquinazolin-4(1H)-ones

Article abstract of DOI:10.1016/j.tetlet.2012.08.090

A facile, efficient, and environmentally friendly procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones from isatoic anhydride, aldehyde, and ammonium acetate in the presence of thiamine hydrochloride (VB₁) in EtOH is described. The p

Full text of DOI:10.1016/j.tetlet.2012.08.090

Tetrahedron Letters 53 (2012) 5923–5925
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Tetrahedron Letters
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Thiamine hydrochloride (VB1) as an efficient promoter for the one-pot
synthesis of 2,3-dihydroquinazolin-4(1H)-ones
Yijia Chen a, Weiguang Shan a, Min Lei b, , Lihong Hu a,b,
⇑
⇑
a College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, PR China
b Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile, efficient, and environmentally friendly procedure for the synthesis of 2,3-dihydroquinazolin-
4(1H)-ones from isatoic anhydride, aldehyde, and ammonium acetate in the presence of thiamine hydro-
chloride (VB1) in EtOH is described. The protocol proves to be efficient and environmentally benign in
terms of high yields, ease of recovery, and reusability of catalyst.
Received 2 May 2012
Revised 20 August 2012
Accepted 23 August 2012
Available online 30 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Thiamine hydrochloride (VB1)
Isatoic anhydride
Aldehyde
Dihydroquinazolin-4(1H)-one
Green chemistry
2,3-Dihydroquinazolin-4(1H)-ones are an important class of
heterocyclic compounds with a broad spectrum of pharmacologi-
cal and biological activities, such as antibacterial, antifertility, anti-
fungal, antitumor, and mono amine oxidase inhibitory activity.1
Moreover, the quinazolinone core scaffold has been extensively
utilized as a drug-like template in medicinal chemistry.2 Therefore,
much considerable attention has been devoted toward these het-
erocyclic compounds.
In the past few years, several methods for the synthesis of 2,3-
dihydroquinazolin-4(1H)-ones have been reported, which include:
(i) the condensation reaction of anthranilamide with aldehyde or
ketone using p-toluenesulfonic acids as a catalyst;3 (ii) the reduc-
tive cyclization of o-nitrobenzamide or o-azidobenzamide with
aldehydes or ketones using metallic samarium in the presence of
iodine or SmI2;4 (iii) the condensation of isatoic anhydride, alde-
hydes, and ammonium acetate or primary amine in the presence
of SnCl2,5 p-toluenesulfonic acid,6 gallium(III) triflate,7 montmoril-
lonite K-10,8 molecular iodine,9 silica sulfuric acid,10 Zn(PFO)2,11
ceric ammonium nitrate,12 and MCM-41-SO3H.13
salts as catalysts. Hence, the development of efficient and conve-
nient approach to construct this type of heterocyclic compounds
is necessary.
It is well known that thiamine hydrochloride (VB1) is a non-
flammable, inexpensive, stable, and non-toxic reagent. The struc-
ture of VB1 contains a pyrimidine ring and a thiazole ring linked
by a methylene bridge (Fig. 1). VB1 is an essential nutrient for all
the animals which must be obtained from their diet. In mammals,
the deficiency of VB1 results in Korsakoff’s syndrome, optic neurop-
athy, and a disease called beriberi that affects the peripheral ner-
vous and/or cardiovascular system. VB1 analogs as powerful
catalysts have been applied in various organic transformations.14
Recently, we have reported several VB1-catalyzed reactions for
the synthesis of heterocyclic compounds, such as pyrimidinones,15
dihydropyridines,16
1,2-dihydro-naphth[1,2-e][1,3]oxazine-3-
one,17 and benzo[4,5]imidazo[1,2-a]pyrimidine.18
In continuation of our investigations on the applications of VB1
in organic synthesis, herein we wish to report a facile, efficient,
and environmentally friendly procedure for the synthesis of
2,3-dihydroquinazolin-4(1H)-ones via one-pot three-component
Although, several modified methods under improved conditions
have been reported, most of them are so far associated with one or
more drawbacks, such as harsh reaction conditions, prolonged
reaction times, high reaction temperature, poor isolated yields,
the use of toxic organic solvents, and the use of expensive metal
Cl NH3
Cl
N
N
S
H3C
N
H3C
⇑
Corresponding authors. Tel.: +86 021 2023 1000; fax: +86 021 2023 1965 (M.L.);
tel./fax: +86 021 2023 1965 (L.H.).
OH
Figure 1. The structure of thiamine hydrochloride (VB1).
E-mail addresses: mlei@mail.shcnc.ac.cn (M. Lei), simmhulh@mail.shcnc.ac.cn (L.
Hu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.090

5924
Y. Chen et al. / Tetrahedron Letters 53 (2012) 5923–5925
Table 2
condensation reaction of isatoic anhydride, aldehydes, and ammo-
nium acetate in excellent yields using VB1 as a reusable catalyst in
EtOH (Scheme 1).
a
Synthesis of 2,3-dihydroquinazolin-4(1H)-ones 4 catalyzed by VB1
O
O
X
VB1
X
Initially, we studied the three-component condensation reac-
tion of isatoic anhydride 1a (5 mmol), benzaldehyde 2a
(5.5 mmol), and ammonium acetate 3 (7.5 mmol) in 5 mL EtOH
in the absence of VB1 under reflux temperature for 6 h (Table 1, en-
try 1). However, only 20% yield of the corresponding product 4a
was obtained (Table 1, entry 1). Then, we carried out the reaction
under similar conditions in the presence of 3 mol % of VB1. To
our delight, the product 4a was obtained in 90% yield for 3 h
(Table 1, entry 3). These results indicated that VB1 could be used
as an efficient catalyst for the condensation of isatoic anhydride
1, benzaldehyde 2a, and ammonium acetate 3 to synthesise 2-
phenyl-2,3-dihydroquinazolin-4(1H)-one 4a. Further investigation
revealed that 3 mol % VB1 was sufficient to catalyze this reaction.
The excess amount of VB1 could not increase the yields of the reac-
tion significantly.
O
R1 CHO
NH4OAc
NH
R1
+
+
EtOH
N
H
O
N
H
2
3
1
4
Entry
X
R1
Time (h)
Product 4
Yield of 4 (%)b
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
Cl
Cl
C6H5 2a
3
3
4
6
3
3
5
3
2
3
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
90
85
80
75
90
90
84
94
80
88
85
4-ClC6H4 2b
3-ClC6H4 2c
2-ClC6H4 2d
4-MeOC6H4 2e
4-MeC6H4 2f
3-MeO-4-OHC6H3 2g
3,4-(MeO)2C6H3 2h
4-MeOOCC6H4 2i
C6H5 2a
10
11
4m
4n
4-MeOC6H4 2e
The activity of the recycled VB1 was also examined according to
the typical experiment conditions. After the reaction was com-
pleted as indicated by TLC, the target product 4a was collected
by simple filtration and washed with ethanol after cooled to the
room temperature. Then, the filtered solution containing the cata-
lyst was further treated with the reactants. It was shown that the
catalyst could be used for three runs without significant drop in
the product yields (Table 1, entry 3). Hence, this result demon-
strated that VB1 could be effectively used as a reusable catalyst
for this multi-component condensation without any treatment.
In order to study the generality of this condensation reaction, a
series of 2,3-dihydroquinazolin-4(1H)-ones were synthesized from
isatoic anhydride 1, aldehydes 2, and ammonium acetate 3 in the
presence of 3 mol % VB1 in EtOH at reflux temperature (Table 2).19
As shown in Table 1, this three-component condensation could
proceed in the presence of 3 mol % VB1 to obtain the 2,3-dihydro-
quinazolin-4(1H)-ones 4 in good yields (80–94%). The aromatic
aldehydes bearing substitutions at ortho-, meta-, and para-
positions participated well in this reaction (Table 2).
a
Conditions: isatoic anhydride 1 (5 mmol), aldehyde 2 (5.5 mmol), ammonium
acetate 3 (7.5 mmol), VB1 (0.15 mmol, 3 mol %), and EtOH (5 mL), reflux.
b
Isolated yields.
Table 3
a
Synthesis of quinazolin-4(3H)-ones 5 catalyzed by VB1
O
VB1
NH
R1
EtOH
N
H
O
4j-4l
O
+ R1 CHO
+
NH4OAc
N
H
O
O
1a
2j-2l
3
VB1
NH
R1
EtOH
N
5j-5l
O
O
X
VB1
X
Entry
R1
Time (h)
Product 5
Yield of 5b (%)
O
R1 CHO
NH4OAc
NH
R1
+
+
EtOH
1
2
3
3,4,5-(MeO)3C6H2 2j
4-NO2C6H4 2k
3-CNC6H4 2l
4
3
4
5j
5k
5l
80
82
92
N
H
O
N
H
2
3
1
4
a
Conditions: isatoic anhydride 1a (5 mmol), aldehyde 2 (5.5 mmol), ammonium
Scheme 1. VB1-catalyzed synthesis of 2,3-dihydroquinazolin-4(1H)-ones 4.
acetate 3 (7.5 mmol), VB1 (0.15 mmol, 3 mol %), and EtOH (5 mL), reflux.
b
Isolated yields.
Table 1
Optimization of the reaction conditionsa
Furthermore, we also used 3,4,5-trimethoxybenzaldehyde 2j,
4-nitrobenzaldehyde 2k, and 4-cyanobenzaldehyde 2l as the
substrates to synthesise 2,3-dihydroquinazolin-4(1H)-ones 4j–4l.
To our surprise, the products quinazolin-4(3H)-ones 5j–5l, shown
in Table 3 and confirmed by NMR measurements, were obtained,
while in contrast, the desired product 2,3-dihydroquinazolin-
4(1H)-ones 4j–4l were not obtained. The probable reason for these
results is that 2,3-dihydroquinazolin-4(1H)-ones 4j–4l are easy to
be oxidized by air to form quinazolin-4(3H)-ones 5j–5l.20
As shown in Scheme 2, the condensation of isatoic anhydride
1a, triethyl orthoformate 6, and ammonium acetate 3 was studied
in the presence of 3 mol % VB1. The reaction could proceed
smoothly to obtained the quinazolin-4(3H)-one 7 in 85% yield.21
In summary, the present method discloses a facile, efficient, and
environmentally friendly procedure for the synthesis of 2,3-dihy-
droquinazolin-4(1H)-ones via one-pot three-component condensa-
tion of isatoic anhydride 1, aldehydes 2, and ammonium acetate 3
O
O
O
NH
Ph
NH4OAc
+
+
Ph CHO
N
H
O
N
H
1a
2a
3
4a
Entry
Cat. (mol %)
Time (h)
Yield of 4ab (%)
1
2
3c
4
5
6
None
6
6
3
3
3
3
20
60
VB1 (1)
VB1 (3)
VB1 (5)
VB1 (8)
VB1 (10)
90, 88, 86
90
88
91
a
Conditions: isatoic anhydride 1a (5 mmol), benzaldehyde 2a (5.5 mmol),
ammonium acetate 3 (7.5 mmol), EtOH (5 mL), reflux.
b
Isolated yields.
Catalyst was reused for three times.
c

Y. Chen et al. / Tetrahedron Letters 53 (2012) 5923–5925
5925
10. (a) Dabiri, M.; Salehi, P.; Baghbanzadeh, M.; Zolfigol, M. A.; Agheb, M.; Heydari,
S. Catal. Commun. 2008, 9, 785; (b) Salehi, P.; Dabiri, M.; Zolfigol, M. A.;
Baghbanzadeh, M. Synlett 2005, 1155.
11. Wang, L. M.; Hu, L.; Shao, J. H.; Yu, J. J.; Zhang, L. J. Fluorine Chem. 2008, 129,
1139.
O
O
N
VB1 3 mol %
EtOH
O
CH(OCH2CH3)3
NH4OAc
+
+
NH
N
H
O
12. Baghbanzadeh, M.; Dabiri, M.; Salehi, P. Heterocycles 2008, 75, 2809.
13. Rostamizadeh, S.; Amani, A. M.; Mahdavinia, G. H.; Sepe-hrian, H.; Ebrahimi, S.
Synthesis 2010, 1356.
1a
6
3
7
85% yield
14. (a) Noonan, C.; Baragwanath, L.; Connon, S. J. Tetrahedron Lett. 2008, 49, 4003;
(b) Dünkelmann, P.; Jung, D. K.; Nitsche, A.; Demir, A. S.; Siegert, P.; Lingen, B.;
Baumann, M.; Pohl, M.; Müller, M. J. Am. Chem. Soc. 2002, 124, 12084; (c)
Orlandi, S.; Caporale, M.; Benaglia, M.; Annunziata, R. Tetrahedron: Asymmetry
2003, 14, 3827.
15. Lei, M.; Ma, L.; Hu, L. Monatsh Chem. 2010, 141, 1005.
16. Lei, M.; Ma, L.; Hu, L. Synth. Commun. 2011, 41, 1969.
17. Lei, M.; Ma, L.; Hu, L. Synth. Commun. 2011, 41, 3424.
18. Liu, J.; Lei, M.; Hu, L. Green Chem. 2012, 14, 840.
Scheme 2. VB1-catalyzed synthesis of quinazolin-4(3H)-one 7.
in the presence of 3 mol % VB1 in EtOH. Furthermore, quinazolin-
4(3H)-one 5 is obtained when 3,4,5-trimethoxybenzaldehyde 2j,
4-nitrobenzaldehyde 2k, 4-cyanobenzaldehyde 2l, and triethyl
orthoformate 6 are used as the substrates. The mild reaction con-
ditions, high yields of the products, ease of work-up, and the eco-
logically clean procedure, will make the present method a useful
and important addition to the present methodologies.
19. General procedure for the preparation of 2,3-dihydroquinazolin-4(1H)-ones 4
using VB1 as a catalyst: A mixture of isatoic anhydride 1 (5 mmol), aldehydes
2a–2i (5.5 mmol), ammonium acetate
3 (7.5 mmol), and VB1 (0.15 mmol,
3 mol %) in EtOH (5 mL) was heated to reflux for 3–6 h. After completion of the
reaction (TLC), the solid was filtered off, washed with EtOH, and recrystallized
from EtOH (5 mL) to yield pure product 4.
4a: 1H NMR (400 MHz, DMSO-d6): d = 5.75 (s, 1H), 6.68 (t, J = 7.6 Hz, 1H), 6.75
(d, J = 8.2 Hz, 1H), 7.12 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.33–7.42 (m, 3H), 7.50
(d, J = 7.2 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 8.30 (s, 1H); MS (ESI): m/z 225
([M+H]+).
Acknowledgments
This work was supported by the National Natural Science Foun-
dation of China (Grants 30925040, 81102329), the Chinese Na-
4e: 1H NMR (400 MHz, DMSO-d6): d = 3.75 (s, 3H), 5.70 (s, 1H), 6.67(t,
J = 7.4 Hz, 1H), 6.74(d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 7.02 (s, 1H), 7.24
(t, J = 7.7 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 7.7 Hz, 1H), 8.19 (s, 1H);
MS (ESI): m/z 255 ([M+H]+).
tional Science
& Technology Major Project ‘‘Key New Drug
Creation and Manufacturing Program’’ (Grant 2011ZX09307-002-
03), and the Science Foundation of Shanghai (Grant 12XD14057).
4i: 1H NMR (400 MHz, DMSO-d6): d = 3.85 (s, 3H), 5.85 (s, 1H), 6.69 (t,
J = 7.6 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.61
(t, J = 8.0 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 8.42 (s, 1H);
13C NMR (100 MHz, DMSO-d6): d = 55.34, 69.04, 117.61, 118.05, 120.44, 130.32,
130.52, 132.31, 132.75, 136.58, 150.12, 150.68, 166.54, 169.09; MS (ESI): m/z
283 ([M+H]+); HRMS (ESI) calcd for C16H15N2O3 [M+H]+ 283.1077, found
283.1071.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
090.
20. General procedure for the preparation of quinazolin-4(3H)-ones 5 using VB1 as
a
catalyst: A mixture of isatoic anhydride 1 (5 mmol), aldehydes 2j–2l
(5.5 mmol), ammonium acetate 3 (7.5 mmol), and VB1 (0.15 mmol, 3 mol %)
in EtOH (5 mL) was heated to reflux for 3–4 h. After completion of the reaction
(TLC), the solid was filtered off, washed with EtOH, and recrystallized from
EtOH (5 mL) to yield pure product 5.
References and notes
5j: 1H NMR (400 MHz, DMSO-d6): d = 3.75 (s, 3H), 3.91 (s, 6H), 7.52 (t,
J = 8.0 Hz, 1H), 7.57 (s, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 8.16
(d, J = 8.0 Hz, 1H), 12.54 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d = 56.59,
60.62, 105.62, 121.30, 126.33, 126.97, 127.96, 128.12, 135.12, 140.66, 149.15,
152.16, 153.34, 162.79; MS (ESI): m/z 313 ([M+H]+); HRMS (ESI) calcd for
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Indian Chem. Soc. 1979, 56, 219.
17H17N2O4 [M+H]+ 313.1183, found 313.1177.
2. Liu, J. F. Curr. Org. Synth. 2007, 4, 223.
C
5k: 1H NMR (400 MHz, DMSO-d6): d = 7.59 (t, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz,
1H), 7.88 (t, J = 8.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.37–8.45 (m, 4H), 12.87 (s,
1H); MS (ESI): m/z 268 ([M+H]+).
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21. General procedure for the preparation of quinazolin-4(3H)-one 7 using VB1 as a
catalyst: A mixture of isatoic anhydride 1 (5 mmol), triethyl orthoformate 6
(6 mmol), ammonium acetate 3 (7.5 mmol), and VB1 (0.15 mmol, 3 mol %) in
EtOH (5 mL) was heated to reflux for 4 h. After completion of the reaction
(TLC), the solid was filtered off, washed with EtOH, and recrystallized from
EtOH (5 mL) to yield pure product 7.
8. Salehi, P.; Dabiri, M.; Baghbanzadeh, M.; Bahramnejad, M. Synth. Commun.
2006, 36, 2287.
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