Mildly basic ionic liquid catalyzed pseudo four component synthesis of 7,10-diaryl-7H-benzo[7,8]chromeno[2,3-d]pyrimidin-8-amine derivatives under solvent-free conditions

Article abstract of DOI:10.1039/c4ra11141a

2-Hydroxyethylammonium formate [2-HEAF] as a mildly basic ionic liquid catalyzed the one-pot pseudo four component condensation reaction of aromatic aldehydes, α-naphthol, malononitrile, and ammonium acetate under thermal solvent-free conditions. This convenient and efficient procedure synthesized 7,10-diaryl-7H-benzo[7,8]chromeno[2,3-d]pyrimidin-8-amine derivatives in short reaction times and good yields.

Full text of DOI:10.1039/c4ra11141a

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ARTICLE
Mild basic ionic liquid catalyzed pseudo four
component synthesis of 7,10-diaryl-7H-
Cite this: DOI: 10.1039/x0xx00000x
benzo[7,8]chromeno[2,3-d]pyrimidin-8-amine
derivatives under solvent-free conditions
Received 00th January 2012,
Accepted 00th January 2012
H.R. Shaterian*, S. Noura
DOI: 10.1039/x0xx00000x
2ꢀHydroxyethylammonium formate [2ꢀHEAF] as mild basic ionic liquid catalyzed the oneꢀpot
pseudo four component condensation reaction of aromatic aldehydes, αꢀnaphthol,
malononitrile, and ammonium acetate under thermal solventꢀfree conditions. This convenient
www.rsc.org/
and efficient procedure synthesized 7,10ꢀdiarylꢀ7
Hꢀbenzo[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀ
amine derivatives in short reaction times and good yields.
Introduction
Chromene derivatives are an important class of compounds,
widely present in plants, including edible vegetables and fruits
[1]. Numerous bioactive natural products have been identified,
and the presence of the chromeneꢀbased structure has been
associated with the capacity to prevent disease [2]. Synthetic
analogues have been developed over the years, some of them
displaying remarkable effects as pharmaceuticals activities [3]
such as antiꢀmicrobial [4], antiꢀinflammatory [5], analgesic [6],
antiviral [7], antiproliferative [8], antibacterial [9], anticancer
[10], antioxidants [11], antitumor [12]. Pyrimidine scaffold is
the base of many bioactive molecules such as antimalarial [13],
antibacterial [14], antitumor [15], anticancer [16], antiꢀ
inflammatory and antifungal agent [17]. Thus, synthetic
methodologies for the synthesis of molecules containing
chromene and pyrimidine rings are of particular interests for
organic and medicinal chemists. Recently, antibacterial activity
CHO
OH
R
O
N
CN
CN
1. (2-HEAF = 25mol%)
N
+
+
2
2. NH4OAC
110 °C, Solvent- Free
R
H
R
NH2
a
b
c
d
e
f
4-Cl
4-Br
R
4-Me
4-OMe
2-Cl
HCOO-
NH3
(2-HEAF) =
HO
Scheme 1: The oneꢀpot preparation of 7,10ꢀdiarylꢀ7Hꢀ
benzo[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀamine derivatives
Results and discussion
of
7,10ꢀdiarylꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀ
First, to find optimization conditions, the solventꢀfree reaction
of αꢀnaphthol, malononitrile, benzaldehyde and ammonium
acetate in the presence of [2ꢀHEAF] as a catalyst was selected
as a model. The reaction was carried out with different amount
of the catalyst (15, 20, 25, 30, 40 mol %) and varieties
amine derivatives was studied by researchers [18].
Multiꢀcomponent reactions (MCRs), because of their
productivity, simple procedures, timeꢀsaving manner,
convergence, and facile execution, are one of the best tools in
combinatorial chemistry [19]. Herein, we report the oneꢀpot
o
temperature (80, 90, 100, 110, 120 C) (Table 1). As it was
pseudo four component synthesis of 7,10ꢀdiarylꢀ7Hꢀ
shown from table 1, 25 mol % of [2ꢀHEAF] as catalyst at 110
oC
afforded
7,10ꢀdiphenylꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀ
benzo[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀamine derivatives using
2ꢀhydroxyethylammonium formate [2ꢀHEAF] ionic liquid as
mild basic catalyst by the condensation of aromatic aldehydes,
αꢀnaphthol , malononitrile and ammonium acetate under
solventꢀfree conditions (Scheme 1).
d]pyrimidinꢀ8ꢀamine in 36 min with 92% of yield.
Department of Chemistry, Faculty of Sciences, University of Sistan and
Baluchestan,PO Box 98135ꢀ674, Zahedan, Iran, Tel: 0098ꢀ541ꢀ
2447010, Fax: 0098ꢀ541ꢀ2431067;Eꢀmail:hrshaterian@chem.usb.ac.ir
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DOI: 10.1039/C4RA11141A
Table 1: Optimization conditions for the oneꢀpot synthesis of
7,10ꢀdiphenylꢀ7 ꢀbenzo[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀamine
in the presence of [2ꢀHEAF] under solventꢀfree conditions
Table 2: Synthesis of 7,10ꢀdiarylꢀ7
amine derivatives catalyzed by (2ꢀHEAF)
H
ꢀbenzo[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀ
H
M.P/MP
[ref](oC)
Time (min)
Time (min)
Catalyst
(mol %)
Temp
( C )
Yield
(%)a
Entry
Yield (%)a
Entry Aldehyde
Product
o
Step1
Step2
Step1 Step2
1
2
25
80
10
50
68
76
46
175ꢀ176/
176ꢀ178
[18]
25
90
9
1
5
7
31
38
92
91
43
31
31
44
37
31
28
26
3
4
25
25
25
15
20
25
30
40
100
110
120
110
110
110
110
110
7
5
4
7
6
5
3
2
82
92
93
83
90
92
92
93
Cl
O
N
5
192ꢀ194/
194ꢀ196
[18]
N
2
3
NH2
6
Cl
7
8
232ꢀ234/
234ꢀ236
[18]
6
34
89
9
10
a Yields refer to the isolated pure product. Based on the reaction of
αꢀnaphthol, malononitrile, benzaldehyde and ammonium acetate.
212ꢀ214/
212ꢀ214
[18]
4
5
6
6
8
8
34
42
49
93
91
90
Next, pseudo four component condensation of aromatic
aldehydes, αꢀnaphthol, malononitrile and ammonium acetate
under optimized conditions for preparation of 7,10ꢀdiarylꢀ7Hꢀ
benzo[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀamine derivatives were
investigated (Table 2). The wide ranges of substituted and
structurally diverse aldehydes (aromatic aldehydes carrying
165ꢀ167/
164ꢀ166
[18]
electronꢀdonating or electronꢀwithdrawing
substituent)
synthesize the corresponding products in high to excellent
yields using the mentioned ionic liquid as catalyst (Table 2).
There was no effect in the reaction time and the yield of the
corresponding products when electron donating groups or
electronꢀwithdrawing groups on banzaldehydes were used. Our
observation can be confirmed with only one catalyst which
reported in the literature [18]. We also examined aliphatic
aldehydes such as n‐heptanal and nꢀoctanal instead of
benzaldehydes in the reaction. All the starting materials were intact
and none of the desired products, or byꢀproducts were formed after
24 h.
189ꢀ191/
188ꢀ190
[18]
a Yield refer to the isolated pure product. All known products have been reported
previously in the literature and were characterized by comparison of IR and NMR
spectra with authentic samples [18].
The proposed mechanism for the preparation of 7,10ꢀdiphenylꢀ
7
H
ꢀbenzo[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀamine
from
bezaldehyde, αꢀnaphthol, malononitrile and ammonium acetate
using weak basic ionic liquids as a catalyst is described in
Scheme
2.
According
to
literature
[18],
2ꢀ
benzylidenemalononitrile, containing the electronꢀpoor CꢀC
double bond, is formed by Knoevenagel addition of
malononitrile to benzaldehyde in the presence basic ionic
liquids as catalyst. Then, 2ꢀbenzylidenemalononitrile has been
attacked by αꢀnaphthol in the presence of weak basic ionic
liquids, which leads to the 2ꢀaminoꢀ4
carbonitrile. In the continuation of the catalytic cycle, 2ꢀaminoꢀ
ꢀchromenoꢀ3ꢀcarbonitrile reacts with other benzaldehyde to
Hꢀchromenoꢀ3ꢀ
4
H
give imine 5 as intermediate, which it reacts with ammonium
acetate to form intermediate 6, followed by cyclization and
aromatization to afford the corresponding products.
2 | J. Name., 2012, 00, 1-3
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Scheme 2: Plausible mechanism for the catalytic synthesis of 7,10ꢀ
diphenylꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀd] pyrimidinꢀ8ꢀamine derivatives
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DOI: 10.1039/C4RA11141A
We also investigated the recycling of the ionic liquids under Avance DPX 300 MHz instrument. The spectra were measured
solventꢀfree conditions using a model reaction of αꢀnaphthol, in DMSOꢀd6 relative to TMS (0.00 ppm). IR spectra were
malononitrile, benzaldehyde and ammonium acetate for the recorded on a JASCO FTꢀIR 460 plus spectrophotometer.
preparation of 7,10ꢀdiphenylꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀd] Melting points were determined in open capillaries using a
pyrimidinꢀ8ꢀamine in the presence of [2ꢀHEAF] (Table 2, BUCHI 510 melting point apparatus. Thin layer
Entry 1). After completion of the reaction, water was added and chromatography (TLC) was performed on silica gel Poly
the precipitated mixture was filtered off for separation of crude Gram SIL G/UV 254 plates.
products. After washing the solid products with water
completely, the water containing ionic liquid (IL is soluble in 2.1. Preparation of the ionic liquid [2ꢀHEAF]
water) was evaporated under reduced pressure and ionic liquid 2ꢀAminoethanol (119.8 g, 0.2 mol) was placed in a two necked
was recovered and reused (Fig. 1). The recovered catalysts flask equipped with a reflux condenser and a dropping funnel.
were reused four runs without any loss of its activities.
The flask was mounted in an ice bath. Under vigorous stirring
with a magnetic stirring bar, 76 ml (0.2 mol) formic acid was
added dropwise to the flask in about 45 min. Stirring was
continued for 24 h at room temperature, to obtain a viscous
clear liquid [20].
2-HEAF
95
95
93
92
100
90
80
70
60
50
40
30
20
10
0
2.2. General procedure for the oneꢀpot synthesis of 7,10ꢀdiarylꢀ
7Hꢀbenzo[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀamine derivatives
under solventꢀfree conditions
[2ꢀHEAF] as mild basic ionic liquid (0.25 mmol) was added to
a mixture of αꢀnaphthol (1 mmol), malononitrile (1 mmol), and
aromatic aldehydes (2 mmol) and the reaction mixture was
o
stirred at 110 C in an oil bath. The completion of the reaction
was monitored by TLC (Step1). After completion of the step 1
(single spot on TLC), ammonium acetate (5 mmol) was added
at the same temperature (110 oC) and the reaction was
monitored by TLC for appropriate time (Step 2). After
completion of the reaction, the reaction mixture was cooled to
room temperature and 20 mL of water was added. The solid
separated was filtered, washed with ether, dried and purified by
column chromatography using silica gel (eluent: CHCl3:MeOH
9:1). All of the desired products were characterized by
comparison of their physical data with those of known
compounds.
1
2
Runs
3
4
Figure 1: The Investigation of the reusability of the ionic liquids under
solventꢀfree conditions using model reaction of αꢀnaphthol,
malononitrile, benzaldehyde and ammonium acetate in the presence of
[2ꢀHEAF] as catalyst
a
In order to show the accessibility of the present work (4ꢀCRs)
in comparison with only one catalyst which reported in the
literature. We summarized some of the results for the
Selected spectral data for some known products are given
below:
preparation of 7,10ꢀdiphenylꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀd]
pyrimidinꢀ8ꢀamine in Table 3. The results show that ionic
liquid [2ꢀHEAF] is the most efficient catalyst with respect to
the reaction time and in terms of obtained yield.
7,10ꢀDiphenylꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀ
o
amine: [mp: 175ꢀ176 C]; IR (KBr): 3695, 3475, 3055, 1650,
1
1259 Cmꢀ1; H NMR (300 MHz, DMSOꢀd6): δ 5/42 (s, 1H,
Table 3: Comparison the results of 2ꢀhydroxyethylammonium formate with 1ꢀ
butylꢀ3 methylimidazolium tetrafluoroborate ([bmim]BF4) in the synthesis of
7,10ꢀdiphenylꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀd] pyrimidinꢀ8ꢀamine
pyranꢀ CH), 6.96 (s, 2H, ꢀNH2), 7.18–7.96 (m, 15H, ArꢀH),
8.38 (d, 1H, ArHꢀ1); 13C NMR (75 MHz, DMSOꢀ d6): δ 44.0,
108.2, 118.6, 120.7, 121.8, 126.2, 126.8, 127.1, 127.9, 128.7,
129.2, 129.8, 130.2, 130.9, 131.4, 133.4, 135.2, 144.2, 151.6,
159.3, 167.4, 174.9 .
Amount of
the catalyst
(mol %)
Time
(min)
Yield %
[ref]
Entry
Catalyst
[bmim]BF4
2ꢀHEAF
Conditions
7,10ꢀDiꢀ(4ꢀchlorophenyl)ꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀ
d]pyrimidinꢀ8ꢀamine: [mp: 192ꢀ194 oC]; IR (KBr): 3700, 3390,
1
3065, 1649, 1259 Cmꢀ1 ; H NMR (300 MHz, DMSOꢀ d6): δ
TEA/DMF;
1
2
20
25
90
36
92 [18 ]
5.44 (s, 1H, pyran ꢀCH), 6.94 (s, 2H, ꢀNH2), 7.20–8.02 (m,
13H, ArꢀH), 8.38 (d, 1H, ArHꢀ1); 13C NMR (75 MHz, DMSOꢀ
d6): δ 44.2, 108.3, 118.6, 120.9, 122.0, 126.2, 126.6, 127.2,
128.6, 129.1, 130.1, 130.8, 131.0, 131.9, 132.7, 134.1, 136.3,
143.7, 151.8, 159.5, 167.8, 175.0 .
100℃
92
Solventꢀ
The present
work
Free; 110℃
7,10ꢀDiꢀ(4ꢀbromophenyl)ꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀ
o
1
d]pyrimidinꢀ8ꢀamine: [mp: 232ꢀ234 C]; H NMR (300 MHz,
DMSOꢀ d6): δ 5.48 (s, 1H, pyran ꢀCH), 6.96 (s, 2H, ꢀNH2),
7.20–8.06 (m, 13H, ArꢀH), 8.34 (d, 1H, ArHꢀ1); 13C NMR (75
Experimental
All reagents were purchased from Merck and Aldrich and used MHz, DMSOꢀ d6): δ 44.4, 108.8, 118.9, 120.9, 122.0, 122.8,
without further purification. The weak basic ionic liquid [2ꢀ 125.4, 126.4, 126.9, 127.4, 128.7, 129.3, 130.8, 131.7, 132.2,
HEAF] as a catalyst was prepared according to the reported 134.3, 135.1, 144.5, 151.9, 159.6, 168.0, 175.2 .
procedure [20]. All yields refer to isolated products after 7,10ꢀDiꢀ(4ꢀmethylphenyl)ꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀ
o
1
purification. The NMR spectra were recorded on a Bruker d]pyrimidinꢀ8ꢀamine: [mp: 212ꢀ214 C]; H NMR (300 MHz,
4 | J. Name., 2012, 00, 1-3
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DMSOꢀ d6): δ 2.24 (s, 6H, ꢀCH3), δ 5.38 (s, 1H, pyran ꢀCH), 10 K. Paul , S. Bindal , V. Luxami, Bioorg. Med. Chem. Lett.,
6.88 (s, 2H, ꢀNH2), 7.10–7.86 (m, 13H, ArꢀH), 8.30 (d, 1H, Arꢀ 2013, 23, 3667.
H) ;13C NMR (75 MHz, DMSOꢀ d6): δ 28.2, 43.4, 108.3, 118.4,
120.6, 121.7, 126.1, 126.9, 127.1, 128.4, 129.0, 129.8, 130.2,
131.2, 132.3, 133.6, 137.2, 140.7, 142.4, 151.3, 159.1, 167.3,
174.8 .
11 O.M. Singh, N.S. Devi, D.S. Thokchom , G.J. Sharma, Eur.
J. Med. Chem., 2010, 45,2250.
12 M.M. Kandeel, A.M. Kamal, E.K.A. Abdelall, H.A.H.
Elshemy, Eur. J. Med. Chem., 2013, 59, 183.
13 K. Singh, H. Kaur, K. Chibale, J. Balzarini, Eur. J. Med.
Chem., 2013,66, 314.
7,10ꢀDiꢀ(4ꢀmethoxyphenyl)ꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀ
o
1
d]pyrimidinꢀ8ꢀamine: [mp: 165ꢀ167 C]; H NMR (300 MHz,
DMSOꢀ d6): δ 3.58 (s, 6H, ꢀOCH3), δ 5.40 (s, 1H, pyran ꢀCH),
6.90 (s, 2H, ꢀNH2), 7.12–7.94 (m, 13H, ArꢀH), 8.32 (d, 1H, Arꢀ
H) ;13C NMR (75 MHz, DMSOꢀ d6): δ 44.2, 58.3, 108.4, 116.7,
118.5, 120.7, 121.8, 125.3, 126.2, 126.9, 127.3, 128.7, 129.3,
130.3, 131.4, 134.0, 137.9, 152.3, 159.2, 160.1, 162.3, 168.2,
175.2 .
14
W.M. AlꢀAdiwish
, M.I.M. Tahir, A. SitiꢀNoorꢀ
Adnalizawati, S.F. Hashim, I. N brahim, W.A. Yaacob, Eur. J.
Med. Chem., 2013, 64, 464.
15 S.E. Abbas, N.M. Abdel Gawad, R.F. George, Y.A. Akar,
Eur. J. Med. Chem., 2013, 65, 195.
7,10ꢀDiꢀ(2ꢀchlorophenyl)ꢀ7Hꢀbenzo[7,8]chromeno[2,3ꢀ
o
16 A.E. Kassab, E.M. Gedawy, Eur. J. Med. Chem., 2013, 63
,
d]pyrimidinꢀ8ꢀamine: [mp: 189ꢀ191 C]; IR (KBr): 3690, 3385,
1
224.
3055, 1654, 1269 Cmꢀ1; H NMR (300 MHz, DMSOꢀ d6): δ
17 A.P. Keche, G.D. Hatnapure, R.H. Tale, A.H. Rodge, S.S.
5.42 (s, 1H, pyran ꢀCH), 6.95 (s, 2H, ꢀNH2), 7.15–7.94 (m,
13H, ArꢀH), 8.36 (d, 1H, ArHꢀ1); 13C NMR (75 MHz, DMSOꢀ
d6): δ 38.4, 108.9, 118.7, 120.7, 122.3, 126.2, 126.9, 127.4,
128.5, 129.1, 129.4, 129.8, 130.4, 131.2, 131.8, 132.6, 133.5,
134.4, 135.3, 140.4, 145.2, 151.7, 159.2, 167.8, 174.9 .
Birajdar, V.M. Kamble, Bioorg. Med. Chem. Lett., 2012, 22
,
3445.
18
S. Kanakaraju, B. Prasanna, S. Basavoju, G.V.P.
Chandramouli, J. Mol. Struct., 2012, 1017, 60.
19 N. Isambert, M.D.M. Sanchez Duque, JꢀC. Plaquevent, Y.
Génisson, J. Rodriguez, T. Constantieux, Chem. Soc. Rev.,
2011, 40, 1347.
Conclusions
20 N. Bicak, J. Mol. Liq., 2005, 116, 15.
In this research, the basic ionic liquid [2ꢀHEAF] was used for
oneꢀpot
preparation
of
7,10ꢀdiarylꢀ7Hꢀbenzo
[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀamine derivatives under
thermal solventꢀfree conditions for the first time. The attractive
features of this protocol are efficient procedure, cleaner
reaction, use of inexpensive and reusable ionic liquid as
catalysts. Satisfactory yields of products, as well as a simple
experimental, isolation and purification of the products make it
a useful protocol for the synthesis of this class of compounds.
Acknowledgements
We are thankful to the University of Sistan and Baluchestan
Research Council for the partial support of this research.
Notes and references
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Applications and Mode of Action, John. Wiley & Sons,
Chichester, U.K., 1997.
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http://dx.doi.org/10.1016/j.jare.2013.03.003.
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A. Mondal
Ethnopharmacol., 2013, 147, 525.
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, T. KumarMaity, J.
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Din , N.S. Youssef , H.I. ElꢀDiwani , Eur. J. Med. Chem., 2010,
45, 3035.
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Cao , Z. Zhang , X. Du , L.Q. Tang , X. Mao , Z.P. Liu,
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This journal is © The Royal Society of Chemistry 2012
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Graphical Abstract
Mild basic ionic liquid catalyzed pseudo four component synthesis of 7,10-diaryl-7H-
benzo[7,8]chromeno[2,3-d]pyrimidin-8-amine derivatives under solvent-free conditions
H.R. Shaterian*, S. Noura
2ꢀHydroxyethylammonium formate [2ꢀHEAF] as basic ionic liquid catalyzed the oneꢀpot pseudo four component
condensation reaction of aromatic aldehydes, αꢀnaphthol, malononitrile, and ammonium acetate under thermal
solventꢀfree
conditions.
This
convenient
and
efficient
procedure
synthesized
7,10ꢀdiarylꢀ7Hꢀ
benzo[7,8]chromeno[2,3ꢀd]pyrimidinꢀ8ꢀamine derivatives in short reaction times and good yields.
This procedure is
1. one-pot
2. solvent-free
3. [2-HEAF] as
catalyst
4 short reaction
times
H
C
O
N
Ionic liquid:
[2ꢀHEAF]