Green synthesis of 5-aryl-(1H,3H,5H,10H)-pyrimido[4,5-b]quinoline-2,4- diones catalysed by 1,4-diazabicyclo[2.2.2]octane in water

Article abstract of DOI:10.3184/174751914X13917105358323

A green and efficient synthesis of 13 of the title compounds, three of which are novel, has been achieved via a one-pot, threecomponent reaction of anilines, aldehydes and barbituric acids, catalysed by 1,4-diaza-bicyclo[2.2.2] octane (DABCO) in water at reflux. Using microwave heating, reaction times were shortened from 12 h to under a minute and yields were generally higher.

Full text of DOI:10.3184/174751914X13917105358323

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 MARCH, 169–171
RESEARCH PAPER 169
Green synthesis of 5‑aryl‑(1H,3H,5H,10H)‑pyrimido[4,5‑b]quinoline‑2,4‑
diones catalysed by 1,4‑diazabicyclo[2.2.2]octane in water
Mohammad Hossein Mosslemina*, Elham Zarenezhada, Nasim Shamsa, Mohammad Navid
Soltani Radb, Hossein Anaraki‑Ardakanic and Rassol Fayazipoora
aDepartment of Chemistry, Yazd Branch, Islamic Azad University, PO Box 89195-155, Yazd, Iran
bDepartment of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran
cDepartment of Chemistry, College of Chemistry, Mahshahr Branch, Islamic Azad University, Mahshahr, Iran
A green and efficient synthesis of 13 of the title compounds, three of which are novel, has been achieved via a one-pot, three-
component reaction of anilines, aldehydes and barbituric acids, catalysed by 1,4-diaza-bicyclo[2.2.2]octane (DABCO) in water
at reflux. Using microwave heating, reaction times were shortened from 12 h to under a minute and yields were generally higher.
Keywords: green synthesis, 1,4-diaza-bicyclo[2.2.2]octane, microwave irradiation, multi-component reactions
Recently, considerable attention has been paid to multi-
component reactions (MCRs) for the synthesis of heterocycles.1
Many such procedures, for example, have been developed for the
quinoline compounds,2 which show a wide range of biological
activities including antimalarial, antitumor, anthelmintic,
antibacterial, antiasthmatic, and antiplatelet properties.3–5
It has very recently been reported that a one-pot three-
component reaction between aldehydes, anilines and barbituric
acids in water at reflux using proline as a catalyst produces
5-aryl-(1H,3H,5H,10H)-pyrimido[4,5-b]quinoline-2,4-diones
in moderate to good yields.6 We have now found that the
reaction can be carried out much more rapidly and in good to
excellent yields using 1,4-diazabicyclo[2.2.2]octane (DABCO)
as a catalyst.
DABCO has been used in many organic preparations as a
good solid catalyst,7 and has received considerable attention as
an inexpensive, eco-friendly, highly reactive, easy to handle
and nontoxic basic catalyst for various organic transformations,
affording the corresponding products in excellent yields with
high selectivity. The reactions are environmentally friendly
and the catalyst can be recycled in some cases.8
Results and discussion
A mixture of an aniline 1, an aromatic or heterocyclic aldehyde
2 and (thio)barbituric acid 3 in water (10 mL) in the presence of
a catalytic amount of DABCO at 100 °C for 12 h (Scheme 1),
afforded 5-aryl-pyrimido[4,5b]quinoline-2,4-diones 4a–m
in good yields (Table 1). Then the reaction was repeated with
less water (2 mL), using microwave irradiation in order to
decrease the reaction time and to improve the yield of 5-aryl-
pyrimido[4,5-b]quinoline-2,4-diones. The results are compared
with conventional heating in Table 1. As can be seen, yields
using microwave heating are generally higher than conventional
heating and, importantly, reaction times are reduced from 12 h
to 30s.
Ten of the synthesised products 4d–m were known compounds
and their identity was confirmed by a comparison of their
melting point (Table 1) and their spectral properties with
literature data.1
Three products 4a–c were new, and they were characterised
1
by their IR, H NMR and 13C NMR spectral data and their
elemental analyses.
We propose the following mechanism for the reaction
(Scheme 2). Activation of the aldehyde is achieved by DABCO.
Simultaneously, DABCO as Brønsted acid/base assists the
enolisation of the barbituric acid where barbituric acid in the
enol form is then reacted with adduct I to form intermediate II.
Intermediate II can lose a water molecule and so barbiturate
III as an unsaturated carbonyl compound is generated. On
the other hand, DABCO can activate the adduct III to form
intermediate IV, to undergo reaction with aniline, resulting
in the production of the adduct V. DABCO could function
Microwave assisted organic synthesis has become an
increasingly popular technique in academic and industrial
research laboratories due to certain advantages, particularly
shorter reaction times and rapid optimisation of chemical
reactions.9,10
We here describe our results in which we have synthesised all
of the 5-aryl-(1H,3H,5H,10H)-pyrimido[4,5-b]quinoline-2,4-
diones reported previously6 and three new ones, and we have
compared yields by both conventional and microwave heating
in water (Scheme 1).
Ar
O
O
NH2
DABCO
NH
CHO
Ar
NH
H2O
+
+
N
H
N
H
X
Reflux / MW
O
N
H
X
R
R
4
1
2
3
X = O,S
Scheme 1
* Correspondent. E-mail: mhmosslemin@gmail.com

170 JOURNAL OF CHEMICAL RESEARCH 2014
Table 1 Comparison between classical and microwave heating for synthesis of 5-aryl-pyrimido[4,5-b]quinoline-diones
M.p./oC
Classical heating
Time/h Yield/%
Microwave irradiation
Entry
R
Ar
X
Product
Found Reported21
Time/s
Yield/%
Br
1
H
H
O
4a
196–198
268–270
249–252
12
95
30
97
H
C
3
2
O
4b
12
96
30
98
Br
3
4
5
4-CH3
4-OMe
4-Br
O
O
S
4c
4d
4e
12
12
12
96
85
86
30
30
30
97
94
93
185–191
183–190
N
O2
H
O
336–340
335–339
6
7
4-OMe
H
S
O
O
S
O
4f
4g
4h
4i
Decompose>370
12
12
12
12
12
90
90
86
85
86
30
30
30
30
30
92
95
92
92
90
225–230
225–230
N
O2
185–190
185–190
8
2,5-Di-OMe
2-OMe
4-OMe
310–312
310–312
9
S
187–194
188–195
10
4j
l
C
l
C
Cl
298–304
300–305
11
3-NO2
O
4k
12
83
30
91
N
285–290
285–289
12
13
3-OH
O
O
4l
12
12
83
78
30
30
92
89
260–265
260–265
4-OMe
4m
O
Table 2 Optimisation of the one-pot synthesis of 4c via reaction between
4-methylaniline, 4-bromobenzaldehyde, and barbituric acid (Scheme 1;
R=4-Me, Ar=4-Br-C6H4, X=O)
as nucleophilic catalyst and react with adduct V to generate
intermediate VI. Intermediate VI subsequently undergoes an
intramolecular reaction to give compound VII, DABCO can
assist compound VII to lose a water molecule and afford the
corresponding products 4a–m.
In order to establish optimised reaction conditions, the effect
of varying the solvent and temperatures of reaction and using
different catalysts, on the model reaction of 4-methylaniline,
4-bromobenzaldehyde and barbituric acid in the presence of
DABCO were evaluated. The results are depicted in Table 2 and
as the data indicate, the use of EtOH, MeOH, CH2Cl2 and MeCN
as solvents at reflux, (entries 1–4) gave only moderate yields of
product. Among the examined solvents H2O at reflux (entry 5)
afforded the best result. The use of 1,3,5,7-tetraazaadamantane
as catalyst gave no product, even after 24 h (entries 7 and 8) Thus
15 mol% DABCO was the preferred catalyst for this reaction.
Solvent
temperature
Entry
Catalyst/mol%
Time/h
Yield/%b
1
2
3
4
5
6
7
8
DABCO (15)
DABCO (15)
DABCO (15)
DABCO (15)
DABCO (15)
DABCO(15)
EtOH R.t
12
12
12
12
12
12
24
24
50
60
52
59
90
40
0
MeOH Reflux
CH2Cl2 Reflux
MeCN Reflux
H2O Reflux
H2O r.t
Hexamine (15)c H2O r.t
Hexamine (15)c H2O Reflux
0
aReaction conditions: 4-Me-aniline (1 mmol), 4-Br-benzaldehyde (1 mmol),
barbituric acid (1 mmol) and solvent (10 mL).
bYield of isolated products.
cHexamine=1,3,5,7-tetraazaadamantane.

JOURNAL OF CHEMICAL RESEARCH 2014 171
OH
O
HN
O
N
H
HN
HN
Ar
OH
HN
HN
Ar
N
O
X
N
H
N
-H2O
N
N+
O
Ar
+
O
O
N
H
Ar
O
O
OH
H
II
III
I
NH2
O
Ar
O
O
Ar
N
NH
NH
HN
HN
NH
Ar
N
X
O
X
R
R
R
OH
NH
NH2
OH
N+
NH2
OH
N+
N
V
N
IV
VI
H
N+
N
O
Ar
Ar
O
N
N
NH
R
NH
R
X
N
H
N
H
OH
N
H
N
H
X
VII
4
Scheme 2 Suggested mechanism for the synthesis of 5-aryl-pyrimido[4,5-b] quinoline-diones using DABCO as catalyst.
p‑Tolyl‑(1H,3H,5H,10H)‑pyrimido [4,5‑b] quinoline‑2,4‑dione (4b):
Yield 95%; white powder, m.p. 268–270°C; IR (νmax): 3210, 3410, 3560,
Experimental
Melting points were measured on the Electrothermal 9100 apparatus
and are uncorrected. Elemental analyses were performed using a
Heracus CHN-O-Rapid analyser. IR spectra were determined as KBr
discs on a Shimadzu IR-460 spectrophotometer. NMR spectra were
obtained on a Bruker Avance DRX-300 MHz spectrometer (1H NMR
at 400 Hz, 13C NMR at 100 Hz) in DMSO-d6 using TMS as internal
standard. Mass spectra were recorded on a Hewlett-Packard 5973 mass
spectrometer operating at an ionisation potential of 70 eV. Microwave
reactions were carried out in a microwave oven (2500 W power; Micro-
Synth, Milestone). The chemicals used in this work purchased from
Fluka (Buchs, Switzerland) and were used without further purification.
1
3095, 1701, 1656 cm–1; H NMR 3.65 (3H, s, CH3), 5.91 (1H, s, CH),
6.60–7.14 (8H, m, Aromatic), 9.96 (1H, s, NH), 11.13 (2H, s, NH); 13
C
NMR: 20.9, 42.9, 79.2, 108.7, 119.5, 126.7, 127.5, 127.8, 129.2, 130.3,
137.0, 142.5, 144.4, 152.8, 164.5, 165.6. Anal. calcd for C18H15N3O2: C,
70.81; H, 4.95; N, 13.76; found: C, 70.72; H, 5.07; N, 13.57%.
4‑Bromophenyl‑7‑methyl‑(1H,3H,5H,10H)‑pyrimido[4,5‑b]
quinoline‑2,4‑dione (4c): Yield 96%; white powder, m.p. 249–252°C;
IR (νmax): 3195, 3425, 3620, 2990, 1694, 658 cm–1; 1H NMR: 3.47 (3H, s,
CH3), 5.91 (1H, s, CH), 6.69–7.34 (7H, m, Aromatic), 10.17 (2H, s, NH),
11.14 (1H, s, NH); 13C NMR: 21.2, 42.6, 80.1, 109.7, 121.2, 127.5, 128.6,
129.7, 130.3, 131.4, 133.4, 139.7, 147.5, 152.5, 162.2, 163.9. Anal. calcd
for C18H14 Br N3O2: C, 56.27; H, 3.67; N, 10.94; found: C, 56.43; H, 3.48;
N, 11.05%.
Synthesis of 5‑aryl‑pyrimido[4,5‑b]‑quinoline‑diones; general
procedure
(i) Thermal method: In a round-bottomed flask (10 mL), a mixture
of an aromatic amine (1 mmol), barbituric acid (0.13 g, 1 mmol),
an aldehyde (1 mmol) and DABCO (15 mol%) in H2O (10 mL) was
heated to reflux for the time indicated in (Table 2). The progress
of the reaction was monitored by TLC. After cooling to room
temperature, the reaction mixture was poured into cold water,
and washed with H2O (10 mL) and EtOH (5 mL) to afford the pure
product (Table 1).
Received 11 December 2013; accepted 18 January 2014
Paper 1302331 doi: 10.3184/174751914X13917105358323
Published online: 7 March 2014
References
1
J. Hzhu and H. Bienayme, eds, Multicomponent reactions. Wiley-VCH,
(ii) Microwave irradiation method: A mixture of an aromatic amine
(1 mmol), barbituric acid (0.13 g, 1 mmol), an aldehyde (1 mmol)
and DABCO (15 mol%) in H2O (2 mL) was placed in a screw
capped Teflon vessel. Microwave irradiation was applied for 30 s
at 90 °C (400 W). After the completion of reaction (TLC analysis),
the residue was washed with water H2O (10 mL) and EtOH (5 mL)
to give pure product in high yield.
Weinheim, 2005.
2
J.J. Li and E.J. Corey, eds, Name reactions in heterocyclic chemistry.
Wiley Interscience, 2005.
3
4
A.P. Kozikowski, J. Med. Chem., 2009, 52, 2109.
V.K. Hzishiri, M.C. Joshi, R. Hunter, K. Chibale, P.J. Smith, R.L.
Summers, R.E. Martin and T.J. Egan, J. Med. Chem., 2011, 54, 6956.
R. Daoud, J. Desneves, L.W. Deady, L. Tilley, R.J. Scheper, P. Gros and E.
Georges, Biochemistry, 2000, 39, 6094.
A. Khalafi-Nezhad, S. Sarikhani, E.S. Shahidzadeh and F. Panahi, Green
Chem., 2012, 14, 2876.
H. Yang, R. Tian and Y. Li, Front. Chem. China, 2008, 3, 279.
B. Baghernejad, Eur. J. Chem., 2010, 1, 54.
5
6
4‑Bromophenyl‑(1H,3H,5H,10H)‑pyrimido[4,5‑b]quinoline‑2,4‑
dione (4a): Yield 96%; pink powder, m.p. 196–198°C; IR (νmax) 3200,
3470, 3615, 3095, 1698, 1614, 632 cm–1. 1H NMR: 6.49 (1H, s, CH–Ph),
7
8
9
6.51–7.62 (8H, m, aromatic), 11.16 (2H, s, NH), 11.32 (1H, s, NH); 13
C
NMR: 49.7, 79.1, 120.8, 121.1, 127.4, 129.4, 129.7, 130.7, 130.7, 131.4,
141.2, 144.4, 150.4, 166.2, 169.3. Anal. calcd for C17H12 Br N3O2: C,
55.15; H, 3.27; N, 11.35; found: C, 55.37; H, 3.03; N, 11.61%.
C.O. Kappe, Angew. Chem. Int. Ed., 2004, 43, 6250.
10 A. Loupy, ed. Microwaves in organic synthesis. Wiley-VCH, Weinheim,
2002.