Pseudo four-component synthesis of benzopyranopyrimidines

Article abstract of DOI:10.1016/j.tetlet.2010.06.014

An efficient and simple method for the synthesis of new benzopyranopyrimidines via a pseudo four-component reaction of salicylic aldehydes, malononitrile and various amines in the presence of a catalytic amount of LiClO₄ is reported. The advantages of this procedure are mild reaction conditions, high yields of products and operational simplicity.

Full text of DOI:10.1016/j.tetlet.2010.06.014

Tetrahedron Letters 51 (2010) 4202–4204
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pseudo four-component synthesis of benzopyranopyrimidines
Ramin Ghahremanzadeh a, Tayebeh Amanpour b, Ayoob Bazgir b,
*
a Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
b Department of Chemistry, Shahid Beheshti University, G.C., PO Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and simple method for the synthesis of new benzopyranopyrimidines via a pseudo four-com-
ponent reaction of salicylic aldehydes, malononitrile and various amines in the presence of a catalytic
amount of LiClO4 is reported. The advantages of this procedure are mild reaction conditions, high yields
of products and operational simplicity.
Received 10 March 2010
Revised 19 May 2010
Accepted 4 June 2010
Available online 9 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent
Malononitrile
Benzopyranopyrimidine
Salicylaldehyde
Multicomponent reactions (MCRs) in which several reactions are
combined into one synthetic operation have been used extensively
to form carbon–carbon bonds.1–4 Such reactions offer a wide range
of possibilities for the efficient construction of highly complex mol-
ecules in a single step, thus avoiding complicated purification oper-
ations and allowing savings of both solvents and reagents. There has
been tremendous development in multicomponent reactions, and
significant efforts continue to be made to develop new MCRs.5–8 In
this context, benzopyranopyrimidines show interesting features
which make them attractive targets for the synthesis via MCRs.
Benzopyranopyrimidines demonstrate antiinflammatory, anal-
gesic and, importantly, in vitro anti-aggregating activities.9–13 Sev-
eral benzopyrano[2,3-d]pyrimidines were tested for their cytotoxic
activity against a panel of cancer cell lines, and a number were
shown to cause significant perturbation in cell cycle kinetics.14
Therefore, numerous methods have been reported for the prepara-
tion of benzopyranopyrimidine derivatives.9–13,15–17
As part of our research aimed at developing new methods for
the preparation of heterocyclic compounds,18–37 we report herein
an efficient and simple synthesis of new benzopyranopyrimidines
in high yields via a one-pot, pseudo four-component reaction of
salicylic aldehydes 1a–f, malononitrile (2) and amines 3a–c in
the presence of LiClO4 as a catalyst, in EtOH at room temperature
(Scheme 1).38
To achieve suitable conditions for the synthesis of the benzo-
pyranopyrimidines 4, various Lewis and protic acid catalysts,
namely, ZnCl2, FeCl3, SnCl2, Bi(NO3)2, NH2SO3H, p-TSA, HOAc and
LiClO4 and different solvents were investigated in the model reac-
tion of 2-hydroxybenzaldehyde (1a), malononitrile (2) and dimeth-
ylamine (3a). The best overall yield (93%) was obtained using
NR2
X
X
CHO
N
OH
EtOH/r.t.
NC
CN
+
R2NH
+
OH
LiClO4 (20 mol%)
24 h
O
N
X
1a-f
2
3a-c
4a-n
Scheme 1.
E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.014

R. Ghahremanzadeh et al. / Tetrahedron Letters 51 (2010) 4202–4204
4203
X
CHO
X
X
R2NH
3
CN
CN
NH
+
NC
CN
OH
CN
OH
O
1
2
5
6
NR2
NR2
H
X
X
NH
NH
1
N
OH
proton shift
4
O
O
N
H
7
X
Scheme 2.
zopyrano[2,3-d]pyrimidin-2-yl)phenols 4. The results are shown
in Table 1. These reactions proceeded very cleanly under mild con-
ditions at room temperature, and no side reactions were observed.
To the best of our knowledge, this new procedure provides the first
example of an efficient and pseudo four-component reaction for
the synthesis of (5H-benzopyrano[2,3-d]pyrimidin-2-yl)phenols.
The work-up involved filtration and washing with EtOH to pro-
vide the products in high purity. The nature of these compounds as
2:1:1 adducts was apparent from their mass spectra, which dis-
played, in each case, a molecular ion peak at the appropriate m/z
value. Compounds 4a–n are stable solids whose structures were
established by IR, 1H and 13C NMR spectroscopy and by elemental
analysis.
It is reasonable to assume that products 4 result from initial
Knoevenagel condensation of salicylic aldehyde (1) and malonont-
rile (2) followed by subsequent Pinner reaction (5?6). Next, the
cyano group of intermediate 6 can be attacked by the amine 3 to
produce intermediate 7. Finally, amine 7 reacts with another mol-
ecule of salicylic aldehyde 1 followed by proton transfer to afford
the product 4 (Scheme 2).
Table 1
Synthesis of benzopyrano[2,3-d]pyrimidines 4
Aldehyde
Amine
Product
Yield (%)
93
CHO
OH
Me
Me
N
H
4a
3a
1a
1a
4b
4c
84
95
N
H
3b
3c
O
1a
N
H
OMe
CHO
OH
3b
4d
96
1b
1b
3c
3a
4e
4f
91
70
Br
CHO
In conclusion, we have developed a new, simple, pseudo four-
component method for the synthesis of (5H-benzopyrano[2,3-
d]pyrimidin-2-yl)phenols via the reaction of salicylic aldehydes,
malononitrile and amines at room temperature. We believe that
this method will find useful applications in the growth of benzo-
pyranopyrimidine chemistry.
OH
1c
1c
1c
3b
3c
4g
4h
80
88
CHO
OH
3b
4i
82
Acknowledgements
1d
OH
We are grateful for the financial support from the Research
Council of Shahid Beheshti, University.
1d
3c
3a
4j
79
73
CHO
4k
References and notes
OH
1e
MeO
1e
3b
3c
4l
4m
80
81
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hydroxybenzaldehyde (1a) (2 mmol), malononitrile (2) (1 mmol),
dimethylamine (3a) (1 mmol) and LiClO4 (20 mol %) in EtOH (5 ml) was
stirred at rt for 24 h (the progress of the reaction was monitored by TLC). After
completion, the reaction mixture was filtered and the precipitate washed with
H2O (5 ml) and EtOH (5 ml) to afford pure 4a. White powder (93%); mp: 177–
179 °C. IR (KBr) (m H
max/cmÀ1): 3427, 3048, 1608. MS (EI, 70 eV) m/z: 319 (M+). 1
NMR (300 MHz, DMSO-d6): dH (ppm) 3.18 (6H, s, N(CH3)2), 4.15 (2H, s, CH2),
6.88 (2H, br s, H-Ar), 7.12 (2H, br s, H-Ar), 7.27 (3H, br s, H-Ar), 8.22 (1H, br s,
H-Ar), 13.36 (1H, s, OH). Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16.
Found: C, 71.57; H, 5.29; N, 13.05. (Due to the very low solubility of product 4a,
we were unable to obtain the 13C NMR spectrum). 2-{4-(Piperidin-1-yl)-5H-
benzopyrano[2,3-d]pyrimidin-2-yl)phenol} (4b): white powder (84%); mp: 168–
170 °C. IR (KBr) (m
max/cmÀ1): 3416, 3064, 2933, 1608. MS (EI, 70 eV) m/z: 359
(M+). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 1.69 (6H, s, 3CH2), 3.48 (4H, s,
2CH2), 3.99 (2H, s, CH2), 6.89–6.95 (2H, m, H-Ar), 7.13–7.20 (2H, m, H-Ar),
7.26–7.39 (3H, m, H-Ar), 8.26 (1H, d, 3JHH = 6.0 Hz, H-Ar), 13.28 (1H, s, OH). 13
C
NMR (75 MHz, DMSO-d6): dC (ppm) 24.3, 25.3, 26.0, 49.2, 97.8, 116.8, 117.8,
118.6, 119.3, 120.6, 125.0, 128.6, 129.1, 129.5, 133.3, 150.4, 160.3, 161.0, 163.8,
146.8. Anal. Calcd for C22H21N3O2: C, 73.52; H, 5.89; N, 11.69. Found: C, 73.43;
H, 5.81; N, 11.76. 4-Bromo-2-{7-bromo-4-(dimethylamino)-5H-benzopyrano[2,3-
d]pyrimidin-2-yl)phenol} (4f): white powder (70%); mp: 196–198 °C. IR (KBr)
(m
max/cmÀ1): 3453, 2917, 1596. MS (EI, 70 eV) m/z: 477 (M++2), 475 (M+). 1H
NMR (300 MHz, DMSO-d6): dH (ppm) 3.16 (6H, s, 2CH3), 4.12 (2H, s, CH2), 6.80–
7.08 (2H, m, H-Ar), 7.40–7.50 (3H, m, H-Ar), 8.20–8.27 (1H, br s, H-Ar), 13.30
(1H, s, OH). Anal. Calcd for C19H15Br2N3O2: C, 47.83; H, 3.17; N, 8.81. Found: C,
47.71; H, 3.11; N, 8.72. (Due to the very low solubility of product 4f, we were
unable to obtain the 13C NMR spectrum). 2-Methoxy-6-{9-methoxy-4-
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2010, 12, 191.
(piperidin-1-yl)-5H-benzopyrano[2,3-d]pyrimidin-2-yl}phenol
(4n):
white
powder (92%); mp: 181–183 °C. IR (KBr) (
m
max/cmÀ1): 3442 2933, 1572. MS
(EI, 70 eV) m/z: 419 (M+). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 1.66 (6H, s,
3CH2), 3.43 (4H, s, 2CH2), 3.78 (3H, s, CH3), 3.84 (3H, s, CH3), 3.91 (2H, s, CH2),
6.80–6.85 (2H, m, H-Ar), 6.92–6.99 (1H, m, H-Ar), 7.01–7.03 (2H, m, H-Ar), 7.82
3
(1H, d, JHH = 6.0 Hz, H-Ar), 13.47 (1H, s, OH). Anal. Calcd for C24H25N3O4: C,
36. Ahadi, S.; Ghahremanzadeh, R.; Mirzaei, P.; Bazgir, A. Tetrahedron 2009, 65,
9316.
68.72; H, 6.01; N, 10.02. Found: C, 68.81; H, 5.93; N, 10.10. (Due to the very low
solubility of product 4n, we were unable to obtain the 13C NMR spectrum).