Microwave-assisted synthesis of 1,3-benzodioxole derivatives from catechol and ketones or aldehydes

Article abstract of DOI:10.1016/j.tetlet.2011.03.063

An efficient synthetic procedure for the preparation of a diverse library of 1,3-benzodioxoles was developed by applying controlled microwave heating in comparison with currently available conventional heating. Reactions were completed in less than 3 h. The isolation of product is simple, the isolated yields are good to excellent, and this method is applicable to large scale production.

Full text of DOI:10.1016/j.tetlet.2011.03.063

Tetrahedron Letters 52 (2011) 4371–4374
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Tetrahedron Letters
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Microwave-assisted synthesis of 1,3-benzodioxole derivatives from catechol
and ketones or aldehydes
Subramanya R. K. Pingali a, Branko S. Jursic a,b,
⇑
a Department of Chemistry, University of New Orleans, New Orleans, LA 70148, United States
b Stepharm, PO Box 24220, New Orleans, LA 70184, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic procedure for the preparation of a diverse library of 1,3-benzodioxoles was devel-
oped by applying controlled microwave heating in comparison with currently available conventional
heating. Reactions were completed in less than 3 h. The isolation of product is simple, the isolated yields
are good to excellent, and this method is applicable to large scale production.
Received 8 February 2011
Revised 9 March 2011
Accepted 10 March 2011
Available online 21 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Benzodioxoles
Microwave-assisted reactions
Catechol protection
Carbonyl protection
1. Introduction
chloride.25 Clearly, there is a demand for simple and highly effi-
cient synthetic procedures for the preparation of these valuable
In many instances, protection groups that are commonly used
in synthetic organic chemistry are also present in nature for com-
pletely different purposes.1 This is certainly the case with 1,3-ben-
zodioxoles.2–5 Probably the most commonly known and widely
used natural products with 1,3-benzodioxole moieties are safrole,6
myristicin,7,8 and piperin.9 Derivatives of these natural products
are used as inhibitors of mono-oxygenase enzymes,10 pesticides
or pesticide intermediates,11 herbicides,12 antioxidants,13 antimi-
crobials,14 and medicines.15–17 Therefore, it should not be a
surprise that there is a substantial demand for a simple and very
effective method for the preparation of a wide variety of the 1,3-
benzodioxole derivatives.
There are several synthetic approaches for the preparation of
these important compounds. One of the most common approaches
is through condensation of carbonyl compounds with catechol in
the presence of an acid catalyst.18 The applicability of this syn-
thetic approach strongly depends on the efficiency of the acidic
catalyst.19 In particular 1,3-benzodioxoles have been prepared
from the corresponding carbonyl compounds and catechol with
catalysts, such as p-toluenesulfunic acid,20 copper p-toluenesulfo-
nate,21 pyridinium p-toluenesulfonate,22 and KSF or K-1023 to
name a few. There are also methods that utilize aggressive Lewis
acid catalysts, such as phosphorus pentoxide24 or phosphorus tri-
compounds.
Recently, we designed a microwave organic synthetic reactor26
that allows the synthetic organic chemist to carry out organic reac-
tions together with magnetic stirring, stable microwave power
control, temperature control, and solvent refluxing.27 This reactor
design adds an advantage in performing a number of very efficient
reactions over conventional synthetic methods.28–30 Microwave-
assisted reactions are particularly effective when small polar mol-
ecules are part of the reaction transformation.31–33 One can also
speculate that microwave heating should be especially effective
for chemical transformations in which water is one of the reaction
products. In conventional approaches, to drive the reaction to com-
pletion, the addition of water-consuming and aggressive reagents,
such as phosphorus pentoxide and phosphorus trichloride, are
used. We believe that the combination of simple and safe catalysts,
such as acidic polymers (dowex), acidic clay (K-10), and p-toluene-
sulphonic acid, in combination with microwave heating will be a
prevailing alternative approach for preparing a wide variety of
1,3-benzodioxole derivatives.
To test the validity of this assumption, we subsequently
selected four different carbonyl compounds (both aliphatic and
aromatic ketones and aldehydes) that have the capability of
producing four different derivatives of 1,3-benzodioxoles
presented in Scheme 1. Three acid catalysts (amberlite, clay K-10,
and p-toluenesulfonic acid) and three solvents (benzene, toluene,
and xylene) were selected for a comparison of the differences in
conventional and microwave assisted preparation of the
⇑
Corresponding author. Tel.: +1 504 858 0515; fax: +1 504 280 7090.
E-mail address: bsjstepharm@ymail.com (B.S. Jursic).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.063

4372
S. R. K. Pingali, B. S. Jursic / Tetrahedron Letters 52 (2011) 4371–4374
O
O
O
O
H3C
O
O
O
O
IV
III
II
I
Scheme 1. Structures of selected 1,3-benzodioxoles for optimization of the reaction conditions.
1,3-benzodioxoles. Overall, 72 reactions were performed and the
isolated yields of the corresponding 1,3-benzodioxoles are pre-
sented in Table 1. Microwave magnetron power was adjusted to
generate vigorous solvent refluxing (400 W for benzene, 500 W
for toluene, and 560 W for xylene). There were substantial
differences regarding the nature of substrate, solvent, acid catalyst,
and above all conventional versus microwave-assisted reactions.
There was a clear improvement in using microwave heating over
conventional heating in all of our studied substrates. The reaction
time for microwave-assisted reactions was up to twenty times
shorter than for comparable reactions under conventional heating.
When the reaction time was shortened, thermal decomposition
was also minimized, resulting in higher isolated yields and more
simplified product purification. This was also the case for
microwave-assisted reactions. The choice of the acid catalyst was
also important. p-Toluenesulfonic acid (PTSA) continuously gave
the best results in comparison to amberlite and clay K-10 (Table
1). In many instances, the solvent of choice was benzene, although
comparable results were obtained with toluene as a solvent and
although xylene as a solvent somewhat shortened the reaction
times, the amount of thermal decomposition byproducts increased.
Isolated yields were good to excellent for the aromatic and ali-
phatic ketones as well as aromatic aldehydes. Isolated yields were
slightly lower for aliphatic aldehydes. Under both conventional
Table 1
Comparison of microwave and conventional heating in catechol carbonyl protection
Product
Solvent
Conventional
Time (min)
Microwave
Acidic catalyst
Yield (%)
Time (min)
Yield (%)
Dowex
PTSA
Clay K-10
Dowex
PTSA
Clay K-10
Dowex
PTSA
1300
1440
71
68
120
120
105
105
105
90
90
90
90
78
96
Benzene
Toluene
1620
1270
1440
1160
1220
1200
1500
83
77
87
85
58
72
74
84
72
89
78
66
74
62
O
O
Xylene
Clay K-10
I
Dowex
PTSA
Clay K-10
Dowex
PTSA
Clay K-10
Dowex
PTSA
3600
7440
68
58
240
240
63
59
Benzene
Toluene
2400
3240
7440
1440
3000
7200
1200
69
72
71
73
63
76
69
210
120
120
120
90
66
71
91
82
73
79
84
O
O
CH3
Xylene
90
90
Clay K-10
II
Dowex
PTSA
Clay K-10
Dowex
PTSA
Clay K-10
Dowex
PTSA
1080
4200
900
900
2880
510
720
2400
450
48
58
120
120
62
87
Benzene
Toluene
58
54
80
65
53
68
61
120
120
120
120
90
69
62
84
74
59
72
71
O
O
Xylene
90
90
Clay K-10
III
Dowex
PTSA
Clay K-10
Dowex
PTSA
Clay K-10
Dowex
PTSA
900
1200
34
42
90
90
28
72
Benzene
Toluene
900
780
1080
840
690
900
600
29
31
60
26
22
38
18
90
90
90
90
75
75
75
39
33
72
41
25
49
33
O
O
IV
Xylene
Clay K-10

S. R. K. Pingali, B. S. Jursic / Tetrahedron Letters 52 (2011) 4371–4374
4373
Table 2
and microwave heating, a considerable amount (10–30%) of the al-
Microwave-assisted preparation of 1,3-benzodioxole from aldehydes
dol condensation product was formed. However, separation of the
aldol byproduct from the corresponding 1,3-benzodioxole was
simple and involved filtration through a short column of silica
gel. Nevertheless, the microwave-assisted preparation of 1,3-ben-
zodioxole from aliphatic aldehydes can be optimized to about
80–85% conversion with more than 75% isolated yield.
Now that the advantage of the microwave versus conventional
heating was demonstrated (Table 1), we would also like to show
the NMR reaction following the preparation of (1f) from benzalde-
hyde and catechol in benzene with PTSA as an acid catalyst
(Fig. 1).34 This reaction was the perfect demonstration of the effi-
ciency and selectivity of the microwave-assisted preparation of
1,3-benzodioxoles. There was no formation of byproducts and
according to 1H NMR, the conversion was almost quantitative, with
the isolated yield reflecting loss during isolation and purification. If
xylene was used instead of benzene as the reaction medium, the
reaction time shortened to 90 min (benzaldehyde is consumed)
and a small amount of decomposition byproduct is formed, reflect-
ing slightly a lower isolated yield (Table 1).
The efficiency of the microwave-assisted preparation of 1,3-
benzodioxole from both aliphatic and aromatic aldehydes was
demonstrated in Table 2. All reactions were performed in benzene
as the reaction medium, p-tolunebenzoic acid (PTSA) as the acid
catalyst, and the microwave heating with magnetron power of
400 W.35 For aromatic aldehydes, the reactions were very clean
but for aliphatic aldehydes the reaction must be carefully moni-
tored because the aldol byproducts are formed. Considering these
problems, benzene was the better solvent choice when using ali-
phatic aldehydes because benzene as a solvent presents lower
amounts of the aldol product formation when compared to xylene.
For aliphatic aldehydes, the optimal reaction time was between 90
and 120 min. The formation of the aldol product with aliphatic
aldehydes was not a problem for 1,3-benzodioxole purification (fil-
tration through short silica gel column) resulting that their isolated
yields are in general ꢀ10% lower than those for aromatic aldehydes
(Table 2). However, aliphatic 1,3-benzodioxoles can be prepared
with this method in 70–80% making it a method of choice for the
preparation of these valuable compounds.
O
1
R
Time (min)
Yield (%)
O
1a: R = n-C3H7
1b: R = n-C4H9
1c: R = n-C7H15
1d: R = n-C9H19
1e: R = n-C11H23
1f: R = C6H5
1g: 2-CH3OC6H4
1h: 3-CH3OC6H5
1i: 3-NO2C6H4
120
120
90
90
90
120
90
90
79
73
72
72
70
87
91
89
79
150
microwave heating is shorter than in comparison with aldehydes.
Contrary to the problem with aldol condensation products forming
as a byproduct in the reactions with aliphatic aldehydes, when
aromatic aldehydes were used, the condensation product was not
present at all or the formed amount is negligible (1–2% at the
most). The reaction with both aliphatic and aromatic ketones with
one aliphatic group was practically quantitative. The lower isolated
yields result from the loss of product during the isolation and the
acid catalyst removal (Table 3). However, we were not able to
prepare 2,2-diphenyl-1,3-benzodioxole from benzophenone and
catechol. This was the case with several other diaromatic ketones.
Aromatic substituents such as nitro, methoxy, hydroxyl, dimethyl-
amino, and amino do not interfere with the reaction; however,
they can either facilitate (electron donating group) or retard (elec-
tron withdrawing group) the reaction. This reaction was very
simple and was applicable to a large-scale preparation of 1,3-ben-
zodioxoles. Hundred gram quantities of these compounds can be
prepared in research laboratories in a matter of hours. For instance,
104 g of 2-methyl-2-phenyl-1,3-benzodioxole was prepared from
acetophenone and catechol in less than 3 h.36
In conclusion it can be stated that microwave-assisted prepara-
tion of 1,3-benzodioxole derivatives from aldehydes and ketones is
superior to currently existing preparation methods. The isolated
yields are generally higher and the required reaction time is signif-
icantly (up to 20 times) shorter in comparison with conventional
heating. Aromatic aldehydes, aromatic-aliphatic ketones, and
Ketones are ideal starting materials for the preparation of 1,3-
benzodioxoles. They are more reactive and, therefore, the required
Figure 1. The NMR microwave-assisted reaction following for preparation of 1f.

4374
S. R. K. Pingali, B. S. Jursic / Tetrahedron Letters 52 (2011) 4371–4374
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Microwave-assisted preparation of 1,3-benzodioxole from ketones
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R1
R2
O
2
Time (min)
Yield (%)
O
2a: R1 = R2 = CH3
120
60
120
90
60
60
120
75
75
120
120
120
120
82
98
96
93
92
91
96
86
89
96
87
97
89
2b: R1 = CH3; R2 = C(CH3)3
2c: R1 = CH3, R2 = CH2CH3
2d: R1 = R2 = CH2CH3
2e: R1 = CH3; R2 = n-C6H13
2f: R1–R2 = –(CH2)4–
26. Jursic, B. S. Microwave Reactor for Laboratory and Industrial Organic Reactions,
U.S. Patent in preparation.
2g: R1–R2 = –(CH2)5–
2h: R1 = CH3; R2 = CH2COCH3
2i: R1 = CH3; R2 = CH2CH2COCH3
2j: R1 = CH3; R2 = C6H5
27. The laboratory version of our microwave has a cavity size of 21.6 cm in height,
17.30 cm wide, and 25.4 cm deep with two 2.54 cm hole on the top of the
microwave for the condenser and thermometer. The magnetron (700 W) was
directly wired to variable electronic autotransformer for control of the
magnetron power. ECM meter (10 A) was wired to the magnetron
transformer to control the microwave power. The magnetic stirrer was
installed beneath the cavity for stirring the reaction mixture. The reaction
temperature was measured directly with a thermometer inserted into the
reaction mixture through a condenser and/or by infrared reading. For chemical
reactions, a conventional microwave is not applicable due to the fact that the
magnetron power cannot be controlled and, therefore, reaction mixtures are
burned after several minutes of microwave irradiation. Additionally, reaction
mixtures cannot be stirred and neither a condenser nor a thermometer can be
added to the reaction container. For these reasons conventional as well as
currently available commercial microwave laboratory reactors cannot be used
effectively in organic synthetic labs. However, conventional microwaves can be
used for few short reactions (maximum a few minutes) where reaction media
overheating and solvent evaporation are acceptable.
2k: R1 = CH3; R2 = 4-ClC6H4
2l: R1 = CH3; R2 = 3,5-(CH3)2C6H4
2m: R1 = CH3; R2 = CH2CO2C2H5
aliphatic ketones are excellent starting materials; however, reac-
tion with aliphatic aldehydes must be carefully monitored to max-
imize the isolated yield of the product due to formation aldol
byproduct. Even in this case, isolated yield of corresponding 1,3-
benzodioxole is higher than 70%. Due to its simplicity the method
is applicable to a large-scale preparation of benzodioxoles.
28. Upadhyay, S. K.; Subramanya, P. R. K.; Jursic, B. S. Tetrahedron Lett. 2010, 51,
2215–2217.
Acknowledgment
29. Upadhyay, S. K.; Jursic, B. S. Synth. Commun., in press.
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c0gc00794c.
31. Nagariya, A. K.; Meena, A. K.; Yadav, A. K.; Niranjan, U. S.; Pathak, A. K.; Singh,
B.; Rao, M. M. J. Pharm. Research 2010, 3, 575–580.
32. Kappe, C. O.; Dallinger, D.; Murphree, S. S. Practical Microwave Synthesis for
Organic Chemists; Wiley-VCH: Weinheim, 2009.
We thank the National Science Foundation for financial support
(CHE-0611902).
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taken from reaction mixture at the time described in Figure 1 and the solvent
was immediately removed under nitrogen flow. The solid residue was slurred
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was refluxed under microwave heating (magnetron power of 400 W). After 2 h
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