An efficient and green synthesis of phthalide-fused pyrazole and pyrimidine derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.02.101

An efficient and green method for the synthesis of phthalide [isobenzofuran-1(3H)-one] fused pyrazoles via the catalyst-free condensation reaction of 2-formylbenzoic acid, hydrazine hydrate, and acetylenic esters in water is reported. Reaction of 2-formylbenzoic acid with 6-amino-uracils or cyclic 1,3-diketones resulted in the formation of phthalide-fused pyrimidine or cyclic 1,3-diketone derivatives.

Full text of DOI:10.1016/j.tetlet.2014.02.101

Tetrahedron Letters 55 (2014) 2366–2368
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient and green synthesis of phthalide-fused pyrazole
and pyrimidine derivatives
⇑
Anahita Motamedi, Elahe Sattari, Peiman Mirzaei, Mahsa Armaghan, Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University G.C., Tehran 1983963113, 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 green method for the synthesis of phthalide [isobenzofuran-1(3H)-one] fused pyrazoles
via the catalyst-free condensation reaction of 2-formylbenzoic acid, hydrazine hydrate, and acetylenic
esters in water is reported. Reaction of 2-formylbenzoic acid with 6-amino-uracils or cyclic 1,3-diketones
resulted in the formation of phthalide-fused pyrimidine or cyclic 1,3-diketone derivatives.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 22 October 2013
Revised 18 December 2013
Accepted 25 February 2014
Available online 3 March 2014
Keywords:
Uracil
Phthalide
Pyrimidine
Pyrazole
Green chemistry
The development of new, clean, and environmentally benign
synthetic methods in organic synthesis has gained significant
attention. Notably the use of water as a solvent has attracted much
interest.1–5 Indeed the use of water has many advantages because
it is a cheap, readily available, non-toxic, and non-flammable
solvent, thus being very attractive from both an economical and
an environmental point of view. It is well established that the
unique structure and physicochemical properties of water lead to
particular interactions such as polarity, hydrogen bonding,
hydrophobic effects, and trans-phase interactions that might
greatly influence the course of a reaction.6
Phthalide is a useful building block in many natural products
with remarkable biological activities.7–13 Examples of phthalides,
functionalized at C-3, have shown good biological activity. For
example, isopestacin (I) is used as an antifungal,14 compounds
II15 and III16 are anti-platelet and anticonvulsant agents, respec-
tively. The phytotoxic IV17 and cytotoxic V18 compounds are other
examples of bioactive phthalides (Fig. 1).
O
OH
O
O
Br
O
O
O
HO
OH
HO
III
II
I
OH
HO
O
OMe
O
O
O
HO
OH
C13H27
V
O
IV
COOH
Figure 1. Representative examples of important phthalides.
They have been reported as antibacterial, antiviral, and antitumor
agents.23 A number of heterocyclic compounds fused with pyrimi-
dines are known for their varied biological activities.24–27
There has been significant interest in the combination of two
pharmacophores on the same scaffold leading to hybrid molecules
or conjugates. These hybrids combine two active moieties in a
single molecule with the goal of creating a chemical entity that is
medically more effective than its individual components.28–32
As a result, phthalide-fused pyrazoles or pyrimidines, which
combine two biologically active heterocyclic cores, are expected
to be of pharmacological interest.
Heterocycles containing the pyrazole ring are important targets
in synthetic and medicinal chemistry because this fragment is a
key moiety in numerous biologically active compounds,19–21
among them are prominent drugs such as celecoxib, and pyrazofu-
rine. They have also emerged as potential atypical antipsychotics.22
Similarly, pyrimidine and its derivatives have been studied for over
a century due to their wide chemical and biological significance.
⇑
Corresponding author. Tel.: +98 21 29903104; fax: +98 21 22431661.
E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
http://dx.doi.org/10.1016/j.tetlet.2014.02.101
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

A. Motamedi et al. / Tetrahedron Letters 55 (2014) 2366–2368
2367
O
O
O
CHO
OR1
NH2NH2 . H2O
H2O, reflux
+
+
OH
NH
R2
24 h
CO2H
R2
N
1
2
3
4
O
O
N
O
O
O
O
OH
NH
OH
NH
O
OH
NH
O
Ph
N
MeO
EtO
N
4a (71%)
4b (74%)
4c (65%)
Scheme 1. Synthesis of phthalide-fused pyrazole derivatives 4.
OH
O
1
2
+
O
OH
OH
O
O
O
3
O
OR1
R1OH
O
R2
N
OH
OH
R2
-H2O
OH
NH
R2
O
OH
NHNH2
R2
R2
N
OH
H
N
5
4
N
NH
N
NH
6
Scheme 2. Proposed mechanism for the synthesis of phthalide-fused pyrazoles 4.
Table 1
O
Synthesis of phthalide-fused pyrimidines 10
O
O
H2O, ref lux
12 h
Ph
CHO
O
O
NH2
NPh
NH2
R1
H2O, reflux
5-10 h
CHO
+
N
O
N
Ph
N
CO2H
+
Ph
N
H2N
CO2H
3
7
8
(75%)
R1
X
N
R2
NH2
N
N
R2
10
Scheme 3. Synthesis of 3-(5-amino-1,3-diphenyl-1H-pyrazol-4-yl)isobenzofuran-
one (8).
X
3
9
R1
R2
X
Product
Time (h)
Yielda (%)
Thus, we were interested in investigating how a pyrazol-3-one
intermediate generated in situ from acetylenic esters 1 and hydra-
zine hydrate (2) could be trapped by 2-formylbenzoic acid (3) to
give a phthalide-fused pyrazole product. Initially, we explored
the reaction of acetylenic esters 1 with hydrazine hydrate (2) in
water under reflux conditions, which afforded the expected pyraz-
olone intermediates.33 Next, the sequential addition of 2-formyl-
benzoic acid (3) successfully gave the phthalide-fused pyrazole
derivatives 4 in good isolated yields (Scheme 1).34 Different sol-
vents such as H2O, EtOH, CH3CN, toluene, and THF were screened,
and the results showed that the reaction proceeded with good
yields when water was utilized as the solvent.
A plausible mechanism for the formation of products 4 is de-
picted in Scheme 2. The initial step is the formation of 5-hydrox-
ypyrazole 5 from the reaction of acetylenic ester 1 and hydrazine
hydrate (2).35 Next, the pyrazolone 5 undergoes nucleophilic addi-
tion to 2-formylbenzoic acid (3) followed by enolization affording
intermediate 6. Finally, intramolecular cyclization of 6 gives the
desired product 4.
H2N
NMe
NMe
Me
Me
O
O
O
S
6
92
O
O
O
S
O
O
O
10a
10b
10c
10d
H2N
NH
NH
H
H
H
H
10
7
80
86
74
O
O
O
H2N
NMe
NH
Me
H
O
O
O
H2N
NH
NH
9
O
O
O
O
As expected, the reaction of pyrazol-5-amine 7 and 2-formyl-
benzoic acid (3) afforded 3-(5-amino-1,3-diphenyl-1H-pyrazol-4-
yl)isobenzofuran-one (8) in a good 75% yield (Scheme 3).
Considering the very important biological activities of mole-
cules containing a pyrimidine scaffold,23–27 we hypothesized that
the combination of a pyrimidine moiety with a phthalide may re-
sult in the discovery of novel drug candidates. Accordingly, we
NH
H
—
SMe
5
89
SMe
O
O
N
H2N
10e
a
Isolated yield.

2368
A. Motamedi et al. / Tetrahedron Letters 55 (2014) 2366–2368
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O
H2O, reflux
2-6 h
CHO
OH
+
O
O
O
CO2H
3
11
12
O
O
O
O
O
O
OH
OH
OH
O
O
O
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O
12c
O
O
12b
12a
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(5 h, 85%)
O
(2 h, 84%)
O
(4 h, 75%)
O
O
O
O
OH
OH
NMe
OH
NH
O
O
O
MeN
12e
HN
12f
O
12d
O
(6 h, 68%)
(2 h, 75%)
(2 h, 80%)
Scheme 4. Synthesis of phthalide-fused diketones 12.
investigated the reaction of 2-formylbenzoic acid (3) and uracils 9
under the same reaction conditions, and obtained the desired
phthalide-fused pyrimidines 10 in good isolated yields after 7–
10 h (Table 1).36
To further explore the potential of this protocol for the synthe-
sis of phthalide derivatives, we investigated the reactions of 2-
formylbenzoic acid (3) and cyclic 1,3-diketones 11, and obtained
phthalide-fused cyclic 1,3-diketone derivatives 12 in good isolated
yields (Scheme 4).
In conclusion, an efficient and catalyst-free method for the
preparation of various phthalide derivatives has been reported.
The work-up of these clean reactions required only filtration and
washing with ethanol. The present synthesis shows attractive
characteristics such as the use of water as a green solvent, easy
work-up/purification and reduced waste production without using
any catalyst or additive.
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34. Typical procedure for the preparation of phthalide-fused pyrazoles 4: A solution of
acetylenic ester 1 (1 mmol) and hydrazine hydrate (2) (96%, 1 mmol) was
stirred for 4 h in H2O (4 mL) under reflux conditions. Next, 2-formylbenzoic
acid (3) (1 mmol) was added and the mixture was stirred for 20 h. After
completion of the reaction (TLC), the mixture was filtered and the residue
washed with EtOH (5 mL) to afford the pure product 4. Methyl 5-hydroxy-4-(3-
oxo-1,3-dihydroisobenzofuran-1-yl)-1H-pyrazole-3-carboxylate
(4a).
White
powder (0.19 g, yield 71%), mp 182–184 °C. IR (KBr) (
m
max/cmÀ1): 3305, 3078,
Acknowledgement
1771, 1719. 1H NMR (300 MHz, DMSO-d6): dH (ppm) 3.73 (3H, s, OCH3), 6.87
(1H, s, CH), 7.36 (1H, d, J = 7.5 Hz, H–Ar), 7.54–7.72 (2H, m, H–Ar), 7.84 (1H, d,
J = 7.5 Hz, H–Ar), 10.27 (1H, s, NH), 13.14 (1H, s, OH). 13C NMR (100 MHz,
DMSO-d6): dC (ppm) 52.0, 73.5, 101.7, 122.5, 124.3, 125.9, 126.0, 128.9, 130.7,
134.0, 149.1, 160.2, 170.2. MS (EI, 70 eV) m/z: 274 (M+). Anal. Calcd for
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
C13H10N2O5: C, 56.94; H, 3.68; N, 10.22. Found: C, 56.87; H, 3.72; N, 10.15.
35. Tu, X.-C.; Feng, H.; Tu, M.-S.; Jiang, B.; Wang, S.-L.; Tu, S.-J. Tetrahedron Lett.
2012, 53, 3169.
Supplementary data
36. Typical procedure for the preparation of phthalide-fused pyrimidines 10 and
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
02.101.
phthalide-fused cyclic diketones 12.
A mixture of 2-formylbenzoic acid (3)
(1 mmol) and the appropriate uracil (1 mmol) or cyclic diketone (1 mmol) was
stirred at reflux in H2O (4 mL) for the required amount of time (see Table 1 and
Scheme 4). After completion of the reaction, the mixture was filtered and the
precipitate washed with EtOH (4 mL) to afford the pure product. 6-Amino-1,3-
dimethyl-5-(3-oxo-1,3-dihydroisobenzofuran-1-yl)pyrimidine-2,4(1H,3H)-dione
References and notes
(10a): White powder (0.26 g, 92%). Mp 220–222 °C; IR (KBr) (m
max/cmÀ1):
3373, 3219, 1765, 1702, 1659. 1H NMR (300 MHz, DMSO-d6): dH 2.92 (3H, s,
Me), 3.34 (3H, s, Me), 6.68 (1H, s, CH), 7.28 (2H, br s, NH2), 7.28–7.78 (4H, m,
Ar-H). 13C NMR (75 MHz, DMSO-d6): dC 26.9, 30.0, 77.0, 80.3, 121.5, 124.2,
126.7, 128.1, 133.6, 150.4, 150.8, 154.4, 159.8, 170.5. MS (EI, 70 eV) m/z: 287
(M+). Anal. Calcd for C14H13N3O4: C, 58.53; H, 4.56; N, 14.63. Found: C, 58.45; H,
4.51; N, 14.71.
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