A simple and efficient large-scale synthesis of 3-hydroxyphthalans via oxa-Pictet-Spengler reaction catalyzed by nanosilica sulfuric acid

Article abstract of DOI:10.1016/j.tetlet.2011.01.037

Nanosilica sulfuric acid is found to be a new, powerful and reusable heterogeneous catalyst for the rapid synthesis of 3-hydroxyphthalans via condensation of aromatic aldehydes and 3-hydroxybenzyl alcohols under conventional heating and microwave irradiat

Full text of DOI:10.1016/j.tetlet.2011.01.037

Tetrahedron Letters 52 (2011) 1213–1216
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple and efficient large-scale synthesis of 3-hydroxyphthalans via
oxa-Pictet–Spengler reaction catalyzed by nanosilica sulfuric acid
⇑
⇑
Zahra Khorsandi, Ahmad Reza Khosropour , Valiollah Mirkhani , Iraj Mohammadpoor-Baltork,
Majid Moghadam, Shahram Tangestaninejad
Catalysis Division, Department of Chemistry, Faculty of Science, University of Isfahan, Isfahan 81746-7344, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Nanosilica sulfuric acid is found to be a new, powerful and reusable heterogeneous catalyst for the rapid
synthesis of 3-hydroxyphthalans via condensation of aromatic aldehydes and 3-hydroxybenzyl alcohols
under conventional heating and microwave irradiation. Scale-up preparation of these heterocycles is also
carried out.
Received 10 September 2010
Revised 27 November 2010
Accepted 10 January 2011
Available online 18 January 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
Phthalans
3-Hydroxybenzyl alcohol
Aryl aldehyde
Oxa-Pictet–Spengler reaction
Nanosilica sulfuric acid
Microwave irradiation
Phthalans (1,3-dihydroisobenzofurans), especially their 3-hy-
droxy derivatives, constitute an important class of building block
because such moieties are found in a wide range of biologically ac-
tive compounds.1 An example of such heterocycles is pestacin,
which is isolated from the microorganism Pestalotiopsis microspora
and exhibits a plethora of biological activities.2 Compound I is an-
other example and shows potential antitumor activity.3 Kim and
co-workers isolated hydroxylated 1,3-dihydroisobenzofuran II,
from Aspergillus flavipes as an inhibitor of peptide deformylase
( Fig. 1).4 In addition, some of these derivatives have attracted
attention due to their potential as anti-influenza agents.5 Phtha-
lans are utilized in the agricultural industry and other uses include
perfumes and colorants.6
An important route to the synthesis of phthalans involves the
Lewis acid assisted intramolecular cyclization, which is also known
as the oxa-Pictet–Spengler reaction.7 However, a large excess of a
strong Brønsted acid is required and the number of reactants is
limited. Recently, Marra and co-workers reported a modified pro-
cedure catalyzed by chloroacetic acid or p-toluenesulfonic acid in
anhydrous methanol under an argon atmosphere,8 but this method
requires long reaction times (48 h) and the products were obtained
in low to moderate yields. Therefore, to overcome these problems,
more convenient methods for the synthesis of phthalans are
required.
The utilization of silica as a solid catalyst has received consider-
able attention.9 Modifications of its activity include immobilization
of various Brønsted or Lewis acids on this solid support.10 Silica
sulfuric acid is a successful candidate for sulfuric acid replacement
in organic synthesis and tolerates acid-sensitive functional
groups.11 Moreover, recent examination of functionalized nanosil-
ica and its applications in organic synthesis has shown unusual
behaviors.12 To achieve an effective and new solid acid catalytic
system for heterocyclic synthesis, we decided to concentrate our
attention on nanosilica sulfuric acid (NSSA) as a solid Brønsted acid
which was prepared easily by adding chlorosulfonic acid to nano-
SiO2 at room temperature. This procedure yielded a white solid
which could be stored at room temperature for several months
in a desiccator without loss of activity (Scheme 1).
HO
CH3
O
HO
Br
HO
O
Br
H3CO
Br
OCH3
OH
HO
HO
I
II
⇑
Corresponding authors. Tel./fax: +98 311 668 9732.
E-mail address: khosropour@chem.ui.ac.ir (A.R. Khosropour).
Figure 1. Examples of 3-hydroxyphthalans with antitumor I and peptide defor-
mylase inhibition II activities.
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.01.037

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Z. Khorsandi et al. / Tetrahedron Letters 52 (2011) 1213–1216
Herein we describe an efficient and facile synthesis of 3-hydrox-
r.t.
OSO3H
+ ClSO3H
OH
yphthalans catalyzed by nanosilica sulfuric acid under thermal and
microwave conditions (Scheme 2).13
The experimental procedure for the reaction is remarkably sim-
ple and does not require the use of toxic or expensive organic sol-
vents or reagents. First, in order to optimize the conditions, the
reaction of 3-hydroxybenzyl alcohol and 4-chlorobenzaldehyde
was chosen as a model system under thermal conditions (Table 1).
The results listed in Table 1 showed that the conversions were
sensitive to the catalyst. Nanosilica sulfuric acid proved to be the
best catalyst affording the highest yield (Table 1, entry 4). In order
to evaluate the effect of the catalyst particle size on the catalytic
activity, the results were compared with those obtained using
silica sulfuric acid (SSA). Utilizing NSSA increased the yield from
42% to 95% (Table 1, entries 4 and 5). One reason for this behavior
may be related to the number of available active sites which in
turn increases the catalytic activity. No activity was observed in
the presence of pure nanosilica (NS) (Table 1, entry 6). The reaction
was clean and fairly rapid. No side products were detected in these
reactions. Only 0.15 g of NSSA was required to convert 1 mmol of
the aldehyde into the corresponding product and higher amounts
of the catalyst did not increase the yields significantly. Reaction
with 0.1 g of the catalyst required a longer reaction time while
the reaction with 0.08 g of NSSA produced only a 69% yield of
the product after 60 min under thermal conditions (Table 1). More-
over, increasing the amount of ethanol led to lower yields (Table 1,
entries 8–10).
Using microwave irradiation decreased remarkably the reaction
times. So, to further optimize the reaction conditions, the temper-
ature and the MW power were also optimized and the best results
were obtained using 0.15 g of NSSA in 0.1 ml of EtOH at 400 W.14 In
both methods, 80 °C was the optimum temperature. No increase in
yield was observed at higher temperatures, while lowering the
temperature below 80 °C reduced the reaction rate.
Using the optimized reaction conditions, we explored the gen-
erality of this method with different aldehydes to prepare a series
of 3-hydroxyphthalans (Table 2). In most cases, the reactions pro-
ceeded cleanly. The results obtained by the two different tech-
niques: conventional heating (method A) and MW irradiation
(method B), were compared. As shown in Table 2, the micro-
wave-assisted NSSA-catalyzed reactions were superior to those
using conventional heating. It was observed that under conven-
tional heating (method A), sterically hindered or electron-deficient
aryl aldehydes gave lower yields of products (Table 2, entries 4, 8
nano-SiO2
=
Scheme 1. Conversion of nano-SiO2 into nanosilica sulfuric acid (NSSA).
HO
HO
OSO3H
C2H5OH
OH
O
ArCHO
+
Ar
Δ or MW
R
R
2
1
3
R=H or OH
Scheme 2. Synthesis of 3-hydroxyphthalans catalyzed by NSSA under conventional
heating and microwave irradiation.
Table 1
Optimization of the oxa-Pictet–Spengler reaction catalyzed by NSSA under thermal
conditionsa,b
O
HO
OSO3H
EtOH
OH
+
4-ClC6H4CHO
Cl
HO
Entry
Catalyst (g)
EtOH (ml)
Yieldc (%)
1
2
3
4
5
6
7
8
9
NSSA (0.08 g)
NSSA (0.1 g)
NSSA (0.15 g)
NSSA (0.2 g)
SSAe (0.15 g)
NSf
p-TSA (0.1)
NSSA (0.1 g)
NSSA (0.1 g)
NSSA (0.1 g)
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.5
1
69d
81d
94
95
42
—
28
92
83
77
10
a
Synthesis of 1-(4000chlorophenyl)-1,3-dihydroisobenzofuran-5-ol via reaction of
4-chlorobenzaldehyde (1 mmol) and 3-hydroxybenzyl alcohol (1 mmol) at 80 °C
over 30 min.
b
NSSA prepared from 0.2 mmol of chlorosulfonic acid and 60 mg of nano-SiO2.
c
Isolated yield.
After 60 min.
d
e
Silica sulfuric acid.
f
Nano-SiO2.
Table 2
Synthesis of 3-hydroxyphthalans catalyzed by nanosilica sulfuric acid
Entry
R
Ar
Product
Method A
Time (min)
Method B
Time (s)
Yielda (%)
Marra method8
Time (h)
Yielda (%)
Yielda (%)
95
O
1
2
H
H
C6H5
20
30
120
90
96
93
48
48
60
56
HO
HO
O
4-CH3OC6H4
96
92
95
OCH3
OCH3
O
3
4
H
H
3,4-(CH3O)2C6H3
30
20
90
90
94
97
48
48
55
55
HO
HO
OCH3
OCH3
O
4-HO-3-CH3OC6H3
OH

Z. Khorsandi et al. / Tetrahedron Letters 52 (2011) 1213–1216
1215
Table 2 (continued)
Entry
R
Ar
Product
Method A
Method B
Time (s)
Yielda (%)
Marra method8
Time (h)
Yielda (%)
Time (min)
Yielda (%)
O
O
OCH3
5
6
7
8
H
H
H
H
3-CH3OC6H4
4-PhCH2OC6H4
2-Naphthyl
4-ClC6H4
20
90
90
120
300
120
91
82
84
97
—
HO
HO
90
90
30
55
65
92
—
Ph
OCH2
O
—
HO
HO
O
48
56
Cl
Br
F
O
O
O
9
H
H
4-BrC6H4
4-FC6H4
30
30
94
68
120
180
95
90
—
—
HO
HO
HO
10
11
12
13
H
H
H
4-O2NC6H4
3-O2NC6H4
4-NCC6H4
40
40
30
60
88
63
90
210
120
85
93
80
48
48
—
61
61
NO2
NO2
O
HO
HO
O
CN
O
14
15
16
17
18
HO
HO
HO
HO
HO
4-CH3OC6H4
4-HOC6H4
4-ClC6H4
55
50
30
40
45
88
82
93
85
90
240
240
120
180
150
92
86
94
84
88
48
48
48
48
48
48
29
57
61
61
HO
HO
OCH3
OH
O
OH
OH
O
HO
HO
HO
Cl
OH
O
4-O2NC6H4
3-O2NC6H4
NO2
NO2
OH
O
OH
a
Yields refer to isolated pure products characterized by 1H NMR, 13C NMR and IR spectroscopy and CHN analysis.
and 12). With method B, the type of substituent on the aryl alde-
hyde had little impact on the product yields.
alcohol required more than 48 h to produce the phthalan in only
56% yield, but, with methods A and B, the corresponding product
was obtained in 92% and 97% yields after 30 min and 120 s, respec-
tively (Table 2, entry 8). Moreover, the use of 3,5-dihydroxybenzyl
alcohol under the optimized conditions also afforded the corre-
sponding products in very short reaction times (Table 2, entries
14–18). All the products were characterized by NMR, IR and mass
spectroscopy, and also by comparison with authentic samples.
For example, 4-nitrobenzaldehyde was converted into the cor-
responding product in 60% yield after 40 min under conventional
conditions, while the yield was 85% in less than 90 s under MW
irradiation (Table 2, entry 11). Also, surprising results were ob-
tained when compared to those of Marra.8 In the previous meth-
od,8 reaction of 4-chlorobenzaldehyde with 3-hydroxybenzyl

1216
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L.; Heider, E. M.; Grant, D. M. Tetrahedron 2003, 59, 2471; (c) Lee, N. H.; Gloer, J.
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Yielda (%)
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Method A
Method B
1
2
3
4
5
6
92
90
90
90
88
72
97
96
95
93
91
85
a
Isolated yield.
NSSA not only exhibits excellent activity in this condensation
reaction, but also simplifies recycling and reuse of the catalyst.
Recycling results are shown in Table 3.
The catalyst was separated by filtration and washed with etha-
nol. This catalytic system was easily recyclable after activation at
80 °C under reduced pressure. NSSA retained its activity over five
consecutive runs.
Finally, the scale-up synthesis of phthalans was also investi-
gated in the reaction of 3-chlorobenzaldehyde with 3-hydroxyben-
zyl alcohol. We increased the scale of the reaction to 10.0 mmol,
keeping the reaction stoichiometry intact. The reaction was found
to proceed successfully and the corresponding product was ob-
tained in 91% and 94% yields via methods A and B, respectively.
In conclusion, we have demonstrated a convenient, simple, and
efficient method for the synthesis of 3-hydroxyphthalans (3-
hydroxydihydro-isobenzofurans) in the presence of NSSA under
conventional heating and microwave irradiation. Moreover, this
method represents the first application of nanosilica sulfuric acid
as a powerful heterogeneous catalyst in heterocycle synthesis.
11. (a) Mohammadpoor-Baltork, I.; Mirkhani, V.; Moghadam, M.; Tangestaninejad,
S.; Zolfigol, M. A.; Abdollahi-Alibeik, M.; Khosropour, A. R.; Kargar, H.; Hojati, S.
F. Catal. Commun. 2008, 9, 894; (b) Khodaei, M. M.; Khosropour, A. R.;
Fattahpour, P. Tetrahedron Lett. 2005, 46, 2105; (c) Polyakov, A. I.; Eryomina, V.
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T.; Schiestel, T. J. Membr. Sci. 2010, 346, 215.
13. General procedure (Method A): Alcohol 1 (1 mmol) and aldehyde 2 (1.5 mmol)
were taken in a mixture of NSSA (150 mg) and EtOH (0.1 ml) in a round-bottom
flask. The reaction was stirred vigorously at 80 °C. After the reaction was
complete (monitored by TLC) the mixture was filtered and concentrated under
reduced pressure to leave a crude residue which was purified by silica gel
column chromatography (EtOAc/hexane mixtures).
14. General procedure (Method B): In a high pressure Teflon reactor equipped with a
magnetic stir bar and an optical fiber (for controlling the reaction
temperature), a mixture of alcohol 1 (1 mmol), aldehyde 2 (1.5 mmol), NSSA
(150 mg) in EtOH (0.1 ml) was submitted to microwave irradiation at 80 °C
(400 W) using a Micro-SYNTH lab station reactor for 1.5–5 min. The reaction
mixture was cooled to room temperature, filtered and concentrated to give
crude 3, which was purified by silica gel column chromatography (EtOAc /
hexane mixtures).
Acknowledgments
The authors are grateful to the Center of Excellence of Chemis-
try of University of Isfahan (CECUI) and the Research Council of the
University of Isfahan for financial support of this work.
Data for 1,3-dihydro-1-(3,4-dimethoxyphenyl)isobenzofuran-5-ol (Table 2, entry
3): Red oily liquid, 1H NMR (300 MHz, CDCl3): d = 6.7–6.9 (6H, ArH), 6.09 (s,
1H), 5.89 (br s, 1H, OH), 5.25 (d, J = 12.3 Hz, 1H), 5.12 (d, J = 12.3 Hz, 1H), 3.85
(s, 3H, OCH3), 3.90 (s, 3H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): d = 155.4,
141.2, 139.1, 138.6, 134.6, 134.3, 123.2, 119.5, 114.8, 110.9, 110.2, 107.7, 85.8,
References and notes
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72.2, 56.0 and 55.9 ppm. IR (CHCl3):
m = 3300, 2950, 1660, 1520, 1460, 1280,
1130, cmꢀ1 MS: m/z = 271.3 [MꢀH]. Calcd for C16H16O4 (272.30): C, 70.58; H,
5.92. Found: C, 70.22; H, 6.07.
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