Ultrasound improves the synthesis of 5-hydroxymethyl-2-mercapto-1-benzylimidazole as a base compound of some pharmaceutical products

Article abstract of DOI:10.1016/j.ejmech.2008.02.006

Application of ultrasound in synthesis appears to be a promising alternative for high-value chemicals and pharmaceuticals. This work describes the results of investigations carried out towards the synthesis of 5-hydroxymethyl-2-mercapto-1-benzylimidazole (HMMBI) in the presence of ultrasound (sono-synthetic) and in the absence of ultrasound (control method). Instead of mixing for long time in control method, the mixture was sonicated indirectly with 500 kHz and directly with 20 kHz apparatus. In some experiments the yield of the reaction was optimized by suitable manipulation of conditions such as temperature, vapor pressure of the solvent, ultrasonic intensity, and contact time. In control method, the yield of the reaction was increased by increasing the temperature but in sono-synthetic method, the thermal dependency was different in the range of temperature studied (7-25 °C). Kinetic results at 7 °C indicate that the yield of the reaction was reached to 90% after half an hour sonication but in control method it was reached to 70% after 72 h under the same conditions. Therefore, it is possible to reach a high yield of product under proper conditions of sonication.

Full text of DOI:10.1016/j.ejmech.2008.02.006

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European Journal of Medicinal Chemistry 43 (2008) 2835e2839
http://www.elsevier.com/locate/ejmech
Original article
Ultrasound improves the synthesis of 5-hydroxymethyl-2-mercapto-1-
benzylimidazole as a base compound of some
pharmaceutical products
*
Mohammad H. Entezari , Azam Asghari
Department of Chemistry, Ferdowsi University of Mashhad, 91775 Mashhad, Iran
Received 8 November 2007; received in revised form 7 February 2008; accepted 7 February 2008
Available online 4 March 2008
Abstract
Application of ultrasound in synthesis appears to be a promising alternative for high-value chemicals and pharmaceuticals. This work
describes the results of investigations carried out towards the synthesis of 5-hydroxymethyl-2-mercapto-1-benzylimidazole (HMMBI) in the
presence of ultrasound (sono-synthetic) and in the absence of ultrasound (control method). Instead of mixing for long time in control method,
the mixture was sonicated indirectly with 500 kHz and directly with 20 kHz apparatus. In some experiments the yield of the reaction was
optimized by suitable manipulation of conditions such as temperature, vapor pressure of the solvent, ultrasonic intensity, and contact time.
In control method, the yield of the reaction was increased by increasing the temperature but in sono-synthetic method, the thermal dependency
was different in the range of temperature studied (7e25 ꢀC). Kinetic results at 7 ꢀC indicate that the yield of the reaction was reached to 90%
after half an hour sonication but in control method it was reached to 70% after 72 h under the same conditions. Therefore, it is possible to reach
a high yield of product under proper conditions of sonication.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Sono-synthesis; 5-Hydroxymethyl-2-mercapto-1-benzylimidazole; Cavitation; Sonication
1. Introduction
cavitational collapse [9]. These extreme conditions lead to a di-
verse set of applications of ultrasound such as maximizing rate
of the reaction, changing the reaction pathway, increasing re-
activity of materials in organic synthesis, and so on.
Ultrasound as an efficient means of activation in synthetic
chemistry has been employed for decades with varied success
[1e6]. This method not only enhances the mechanical effects
in heterogeneous processes, but it also induces new reactivities
which leading to the formation of unexpected chemical spe-
cies. What makes sonochemistry unique is the remarkable
phenomenon of cavitation. The cavitation process consists of
the creation, growth and implosive collapse of cavity. The bub-
ble collapse in liquid results in an enormous concentration of
energy from the conversion of kinetic energy of liquid motion
into heating of contents of the bubble [7,8]. Extreme temper-
atures and pressures occur within the bubbles during
HMMBI and its derivatives are the base compounds for
the synthesis of a wide range of drugs which have an important
role in medicinal chemistry [10e12]. For example 1,4-dihy-
dro-2,6-dimethyl-4-(2-alkylthio-1-benzyl-5-imidazolyl)-3,
5-pyridine-dicarboxylic acid esters are evaluated as calcium
antagonists on guinea-pig ileal smooth muscle [13e15] and
9-[1-benzyl-5-(alkylsulfonyl)-1H-2-imidazolyl]perhydro-1,
8-acridinediones has been found as possible effective activa-
tors at the ATP sensitive Kþ channel [16e19]. There is an-
other new drug in the epilepsies therapy which is 2-(2-
alkylthio-1-benzyl-5-imidazolyl)1-2,3,4-threehydro-5-imino-
1,3,4-thiadiazole [20]. There are many different structures in
diverse pharmacological activity that can be prepared from
the compound selected for this work. One of the classical
* Corresponding author. Tel.: þ98 511 8797928x304; fax: þ98 511
8795560.
E-mail address: moh_entezari@yahoo.com (M.H. Entezari).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.02.006

2836
M.H. Entezari, A. Asghari / European Journal of Medicinal Chemistry 43 (2008) 2835e2839
methods for the synthesis of HMMBI is stirring of benzyl-
amine hydrochloride with 1, 3-dihydroxyacetone dimmer
and potassium thiocyanate for 72 h. In this study for decreas-
ing the contact time and increasing the yield, we investigated
the sono-synthesis of HMMBI as a new method for this com-
pound and compared the results with control method.
2. Experimental
2.1. Apparatus
The irradiation of solution was carried out by two ultra-
sonic equipments working at 20 kHz and 500 kHz separately.
Schemes 1 and 2 demonstrate the set up used in this work. The
melting points were determined in open capillary tubes by an
Electrothermal IA 9000 melting point apparatus. The H NMR
spectra were recorded on a Bruker 100-MHz instruments using
tetramethylsilan (TMS) as an internal standard. The mass
spectra were determined with Shimadzu GCMS-QD 1000
EX instrument (70 eV).
Scheme 2. Experimental setup for 500 kHz apparatus.
demonstrates the preparation of the mentioned compound
by the formula.
2.2. Procedure
3. Results and discussion
In control method the reaction was proceed by adding 1, 3-
dihydroxyacetone dimmer 4.6 mmol (0.42 g) (99%, Merck),
potassium thiocyanate 6.9 mmol (0.68 g) (99%, Merck) and
benzylamine hydrochloride 6.5 mmol (0.94 g) (salt of benzyl-
amine reaction with concentrated chloric acid in butanol sol-
vent) to a mixture of glacial acetic acid (1 ml) (98%, Merck)
and 1-butanol 6.5 ml (99%, Merck) as a solvent. The pro-
duced white suspension was stirred for 72 h. Then by adding
water-de-ionized (1 ml), the mixture was filtered and the solid
phase washed with water-de-ionized (3 ml) and ether (3 ml),
respectively [10]. The product was HMMBI as a pure com-
pound. In sono-synthetic method instead of stirring, the mix-
ture was sonicated for different length of times. The resulting
solid was filtered, washed with water-de-ionized (4 ml) and
then ether (3 ml), respectively. The structure of this com-
3.1. Same product with two different methods
The compound of HMMBI produced by control and sono-
synthetic methods was analyzed with different methods. The
H NMR and the Mass spectrum of the final product was the
same in both methods. In addition, the melting point and
the TLC were also confirmed the similarity of the mentioned
compound produced by the two different methods.
3.2. Synthesis under control and indirect sonication
(500 kHz)
In control method, the synthesis was normally carried out at
different temperatures to give HMMBI. In sono-synthesis the
solution was sonicated indirectly by 500 kHz apparatus at dif-
ferent temperatures. The synthesis of this compound was stud-
ied at temperatures 7, 13, and 25 ꢀC. The sono-synthetic
method was behaved differently than control method by
changing the temperature. Fig. 1 shows the different effects
of temperature on the yield of HMMBI in both methods. In
control method with increasing the temperature, the yield
was also increased. This is attributed to the higher collisions
of reactants at higher temperature which lead to the higher
yield. In contrast, in the presence of ultrasound (sono-synthetic
pound was studied by different methods. Scheme
3
Scheme 3. Formula for the synthesis of 5-hydroxymethyl-2-mercapto-1-
benzylimidazole.
Scheme 1. Experimental setup for 20 kHz apparatus.

M.H. Entezari, A. Asghari / European Journal of Medicinal Chemistry 43 (2008) 2835e2839
2837
3.3. Synthesis under direct sonication (20 kHz)
The frequency of ultrasound has a significant effect on the
sonochemical reactions [21,22]. This effect is related to the
cavitation process which influences the critical size of the cav-
itation bubble and the collapse time. At very high frequencies,
the cavitational effects are reduced.
There was a possibility to sonicate directly the solution for
synthesis of HMMBI by 20 kHz apparatus. In indirect sonica-
tion (500 kHz), the acoustic power deliver to the solution was
lower than the direct sonication (20 kHz) and in addition, the
reflection and absorption of acoustic wave by the wall of the
reactor immersed into the liquid medium reduces the acoustic
intensity. Fig. 3 shows the yield of the reaction versus contact
time at different temperatures under direct sonication of solu-
tion by 20 kHz. The yield was higher in direct sonication than
indirect one, especially at lower temperature (7 ꢀC). This
could be related to the higher intensity and the harsher condi-
tions produced during the cavitation process in lower fre-
quency. In addition, the most pertinent effects of ultrasound
on liquidesolid systems are mechanical which are attributed
to the asymmetric cavitation. Shock waves are produced dur-
ing the cavitation process and lead to microscopic turbulences
within interfacial films surrounding nearby solid particles, also
referred to as microstreaming [23]. This phenomenon in-
creases the mass-transfer of the film, thus increasing the intrin-
sic mass-transfer coefficient, as well as possibly thinning the
film. Hagenson and Doraiswamy [24] obtained evidence of
a twofold increase in the intrinsic mass-transfer coefficient
when modeling experimental data obtained for the synthesis
of dibenzyl sulfide in the presence and absence ultrasound.
The shock waves produced by the cavitation increase the mo-
mentum of solid powders in solution, causing them to collide
with great force. Then, the particles are fractured upon colli-
sion, leading to an overall decrease in the average particle
size. Suslick et al. [25] have also estimated the speed of the
microjets to be 100 m/s in aqueous solution; and this lead to
Fig. 1. The yield of 5-hydroxymethyl-2-mercapto-1-benzylimidazole versus
contact time at different temperatures in classic and indirect sonication
(500 kHz).
method) by increasing the temperature the yield of the reaction
was decreased. Contrary to the chemical reactions in general,
in some cases an increase in the ambient reaction temperature
results in an overall decrease in the sonochemical effect. This
behavior could be explained by the cavitation process. As the
reaction temperature is raised, the equilibrium vapor pressure
of the system is also increased. This leads to the reduction of
critical conditions produced during the cavitation process and
therefore the sonochemical effects are reduced at higher tem-
peratures. For each system there is an optimum temperature
which the effect of cavitation process is higher than the other
temperatures. For this system, the highest difference of the
yield between control and sonicated method was achieved at
about 7 ꢀC (Fig. 2).
Fig. 3. The yield of 5-hydroxymethyl-2-mercapto-1-benzylimidazole versus
contact time at different temperatures in classic and in direct sonication
(20 kHz).
Fig. 2. The yield of 5-hydroxymethyl-2-mercapto-1-benzylimidazole versus
temperature in classic and indirect sonication (500 kHz) for 30 min.

2838
M.H. Entezari, A. Asghari / European Journal of Medicinal Chemistry 43 (2008) 2835e2839
Table 1
Comparison of the yields of 5-hydroxymethyl-2-mercapto-1-benzylimidazole
for the classic and indirect sonication (500 kHz)
Temperature (ꢀC)
Ultrasound (500 kHz)
indirect (30 min) (%)
Classic (30 min) (%)
7
86
81
48
9
18
19
13
25
3.5. Synthesis with different solvents
The reaction was carried out with four different solvents
(ethanol, n-butanol, n-cyclohexanol, and 2-octanol with boil-
ing point of 78, 116, 160, 170 ꢀC, respectively) under the
same conditions. The results indicated that the yield of the re-
action was also dependent on the kind of the solvent. As it was
shown in Fig. 5, the yield of the reaction was increased by in-
creasing the boiling point of the solvent. In general, the cavi-
ties are more readily formed when using a solvent with a high
vapor pressure or low boiling point. In contrary, the cavitation
process produces harsher conditions when using a solvent with
a high boiling point. According to the results, it could be con-
cluded that the harsher conditions produced in solvents with
higher boiling point is preferred than the more readily forma-
tion of the cavity. In addition, Fig. 5 also confirms that higher
power applied to the solvent with higher boiling points is more
favorable to reach the higher yield.
Fig. 4. The yield of 5-hydroxymethyl-2-mercapto-1-benzylimidazole versus
intensity for 30 min direct sonication (20 kHz) at different temperatures in
n-butanol as a solvent.
pitting and erosion of the surface, in addition to the well-
known cleaning effects associated with ultrasound. These be-
haviors of ultrasound in heterogeneous systems could be very
effective in enhancement of the mentioned reaction.
3.4. Synthesis under different acoustic powers
According to Fig. 4, the effect of acoustic power and tem-
perature on the synthesis of this compound was studied in the
range of 20e75 (W) acoustic power. The length of sonication
for all the samples was 30 min. The yield was negligible in the
range of 20e40 W. This is due to the low power which is less
than the threshold power for this process. There is a sharp
increase in the yield in the range of 40e60 W which is above
the threshold power. The acoustic power over 60 W has a neg-
ligible effect on the yield of the reaction. The best result was
obtained in low temperature and high acoustic power.
3.6. Comparison of the results
Synthesis of HMMB was carried out under different condi-
tions. Tables 1 and 2 summarize the yield of the reaction in
control and sono-synthetic method with indirect sonication
(500 kHz) and direct sonication (20 kHz) for 30 min. In indi-
rect sonication (500 kHz), the yield was enhanced by approx-
imately 9.4 times at 7 ꢀC and 2.6 times at 25 ꢀC with respect to
the control method. Under the same conditions with direct
sonication (20 kHz), the best results were obtained at lower
temperature (7 ꢀC) which ultrasound enhanced the yield to
about 9.7 times. At higher temperature (25 ꢀC) the yield en-
hanced to about 3.8 times in the presence of ultrasound.
4. Conclusion
The synthesis of HMMBI was carried out by control and
sono-synthetic methods under different conditions. The most
important point is that with sonication under proper
Table 2
Comparison of the yields of 5-hydroxymethyl-2-mercapto-1-benzylimidazole
for the classic and direct sonication (20 kHz)
Temperature (ꢀC)
Ultrasound (20 kHz)
direct (30 min) (%)
Classic (30 min) (%)
7
90
88
70
9
18
18
Fig. 5. The yield of 5-hydroxymethyl-2-mercapto-1-benzylimidazole versus
boiling point of different solvents for 30 min direct sonication (20 kHz) at
13 ꢀC.
13
25

M.H. Entezari, A. Asghari / European Journal of Medicinal Chemistry 43 (2008) 2835e2839
2839
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The authors gratefully acknowledge the assistance of the
Department of Medical Chemistry of Mashhad University
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