Microwave-accelerated synthesis of benzyl 3,5-dimethyl-pyrrole-2- carboxylate

Article abstract of DOI:10.1002/jhet.5570430645

Benzyl 3,5-dimethyl-pyrrole-2-carboxylate, a very useful pyrrole in porphyrin and dipyrromethene synthesis, can be synthesized via the Knorr-type reaction, but in low yield. Alternative routes to benzyl 3,5-dimethyl-pyrrole-2- carboxylate have been develo

Full text of DOI:10.1002/jhet.5570430645

Nov-Dec 2006 Microwave-accelerated Synthesis of Benzyl 3,5-Dimethyl-pyrrole-2-carboxylate
1709
Jasmine Regourd, Ian M. Comeau, Cory S. Beshara and Alison Thompson*
Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, B3H 4J3, CANADA
Received February 2, 2006
O
Ethylene glycol,
BnOH, NaO Me
p-TS A
O
O
O
N
H
microwave ener gy
microwave ener gy
N
H
N
H
O
O
O
Benzyl 3,5-dimethyl-pyrrole-2-carboxylate, a very useful pyrrole in porphyrin and dipyrromethene
synthesis, can be synthesized via the Knorr-type reaction, but in low yield. Alternative routes to benzyl 3,5-
dimethyl-pyrrole-2-carboxylate have been developed involving the trans-esterification of ethyl 3,5-
dimethyl-pyrrole-2-carboxylate and the de-acetylation of benzyl 4-acetyl-3,5-dimethyl-2-carboxylate, both
precursors being easily obtained using the Knorr reaction. These traditional methods involve treatment of
the known products with a strong basic solution or heating for extended periods which often lead to
decomposition. The use of microwave energy to promote these two reactions proves to be an extremely
efficient way to obtain benzyl 3,5-dimethyl-pyrrole-2-carboxylate quickly, in high yield, and in excellent
purity with no need for recrystallization. Of particular note is the use of catalytic sodium methoxide in
benzyl alcohol, rather than stoichiometric amounts of sodium benzoxide, to effect benzylation.
J. Heterocyclic Chem., 43, 1709 (2006).
Introduction.
pentanedione (Scheme 1) but the yields are typically low
[5,6] (our group obtained 22 % of 1 on a 20 g, 0.07 mol
scale of dibenzyl malonate).
The chemistry of substituted pyrroles is a challenging
field that often relies on traditional reactions using harsh
conditions, e.g. very high temperatures for extended
periods of time, or highly acidic/caustic conditions. Many
reactions for the synthesis (or functional group intercon-
version) of pyrroles were first introduced several decades
ago, with little refinement having been reported since
then. Benzyl 3,5-dimethyl-pyrrole-2-carboxylate 1 is a
very useful precursor in the synthesis of functionalized
pyrroles, dipyrromethenes and other multi-pyrrolic
systems [1-3]. The ꢀ-free position allows for further sub-
stitution of the pyrrole. As well, porphyrins and dipyrro-
methenes made using this pyrrole can be substituted at
this position. Pyrrole 1 can be synthesized via the Knorr-
type reaction [4] by reacting dibenzyl malonate with 2,4-
Alternative syntheses for benzyl 3,5-dimethyl-pyrrole-
2-carboxylate 1 are also available, both involving trans-
formations of other Knorr-type pyrroles: the trans-
esterification of pyrrole 2 (Path B, Scheme 1) and the de-
acetylation of benzyl 4-acetyl-3,5-dimethyl-pyrrole-2-
carboxylate 3 (Path C, Scheme 1). Unlike for pyrrole 1,
the Knorr synthesis of ethyl 3,5-dimethyl-pyrrole-2-
carboxylate 2 [7] and 4-acetyl-3,5-dimethyl-pyrrole-2-
carboxylate 3 [8] gives good yields. Dibenzyl malonate, a
precursor in the Knorr synthesis of 1 is around 70 times
more expensive than diethyl malonate (a precursor in the
Knorr synthesis of 2) and around 10 times more expensive
than benzyl acetoacetate (a precursor in the Knorr
synthesis of 3).
Scheme I
O
O
O
O
+
O
O
Knorr Reaction
A
O
B
C
O
O
O
N
N
H
N
O
H
O
H
O
2
1
3
Synthetic (A) and retrosynthetic (B & C) pathways for 1

1710
J. Regourd, I. M. Comeau, C. S. Beshara and A. Thompson
Vol 43
Although highly successful, both the trans-esterification
methodology for the trans-esterification of 2 is
modeled after the traditional method for trans-
esterification of pyrrole-2-carboxylate esters [9]
previously described and the trans-esterification of
ethyl esters to benzyl esters using microwave energy
in open systems, reported by Loupy et al. [11]. Their
procedure for the trans-esterification of methyl
esters is essentially solvent-free, using two
equivalents of the alcohol corresponding to the
desired ester functionality, and varying the
equivalents of acid or base catalysts.
Our method for the trans-esterification of 2 using
microwave energy involves stirring pyrrole 2 in benzyl
alcohol in the presence of catalytic sodium methoxide
in a round bottom flask linked to a condenser in the
microwave (MARS 5, CEM) open to air (under
atmospheric pressure). CAUTION: All chemical
reactions utilizing microwave energy should be
performed in a commercial unit designed for that
purpose and incorporating temperature and pressure
monitoring facilities. For this trans-esterification, the
microwave unit is programmed at 600 W to reach 215
°C but the reaction mixture never attains this
temperature because of the constant condensation of
ethanol in the reaction flask. After 30 minutes (on a 1
g, 0.006 mol scale reaction) to 45 minutes (on a 15 g,
and the de-acetylation routes involve harsh conditions and
often produce colored crude products [9,10].
Recrystallization of the crude materials gives clean
products, but we wished to avoid using the harsh
conditions that render this step essential. Recent reports
on the use of microwave energy for the trans-
esterification of ethyl esters [11] and the synthesis of
pyrroles (via palladium-assisted transfer hydrogenation
followed by the Paal-Knorr reaction or by reacting diones
with primary amines) [12-14] led us to attempt the trans-
esterification and de-acetylation pathways for the
synthesis of benzyl 3,5-dimethyl-pyrrole-2-carboxylate 1
using microwave energy in order to improve conditions,
yields and the purity of the crude products.
Results and Discussion.
Trans-esterification. In the traditional trans-
esterification [9] of 2 (Path B, Scheme 1), the pyrrole is
dissolved in benzyl alcohol at reflux (bp = 205 °C) and
a solution of sodium benzoxide, prepared from sodium
and benzyl alcohol, is slowly added thereby producing
ethanol vapor which lowers the temperature of the
reaction mixture (Scheme 2). When the production of
ethanol ceases, the temperature returns to 205 °C,
announcing the completion of the reaction.
Scheme II
a/ BnONa, BnOH, reflux, ~ 1 h
O
O
b/ NaOMe, BnOH, 215 oC, 30-45 min
microwave energy
N
N
H
O
H
O
2
1
Trans-esterificcation of pyrrole 2: a/traditional method; b/ microwave method
0.090 mol scale reaction), crystallization of the product
is performed by the addition of ethanol/water or
methanol/water.
In practice, these temperatures are often difficult
to monitor, and so an excess of sodium benzoxide is
often used. Crystallization from methanol/water
gives pyrrole 1, but due to the solubility of benzyl
alcohol in water and the solubility of pyrrole 1 in
benzyl alcohol, low isolated yields of the desired
product are often obtained. If the pyrrole-2-
carboxylate ester is left in refluxing benzyl alcohol
for too long the yields are further reduced,
presumably due to decomposition. It has been
reported that, for many reactions, the use of
microwave energy to obtain high reaction
temperatures is an excellent alternative to
conventional heating methods [15]. Our new
The results of the two methods are compared in
Table 1 and the yields prove to be very similar.
However the traditional method [16] afforded product 1
as a coloured compound that turned red-brown over
time. The microwave method proved to be easier as
there is no need to prepare sodium benzoxide, no slow
addition procedure, no handling of sodium metal and
the reaction does not need to reach high temperatures
which can take up to several hours using a heating
bath, depending on the scale. The work-up and
purification methods are the same for both procedures.

Nov-Dec 2006
Synthesis of pyrroles using microwave energy
1711
Table 2
To summarize, microwave-accelerated trans-esteri-
fication uses cheap easily prepared ethyl 3,5-dimethyl-
pyrrole-2-carboxylate (2), and is a quick, easy and
clean method to produce pyrrole 1 in good yields. The
method does not require the preparation of sodium
benzoxide and instead uses catalytic sodium methoxide
which is commercially available as a powder.
Initial conditions and yields of the de-acetylation of 3 performed in
the microwave.
Entry
Scale
(g)a
0.8
1.0
4.9
1.0
1.0
15.0
Time
Temperature
(°C)
Ratiob
Yield
1
2
3
2 x 1 min
6 min
6 min
6 min
17 h
160
160
174
160
140
160
140
1.2:1
1.2:1
1:0
1:6
1:6
80 %
78 %
0 %c
89 %
79 %
84 %
87 %
4
Table 1
5d
6
Comparison of traditional synthesis of 1 with synthesis using
microwave energy
1:5.5
1:5.5
6 min
26 h
7d
15.0
aamount of pyrrole 3 used; bratio of volume of ethylene
glycol:toluene. cdue to polymerization; dtraditional method.
Entry
Scale (g)a
Microwave method
Traditional method
yieldb
70 %
68 %
yieldb
75 %
69 %
1
2
1.0
15.0
temperature (Entry 3) in the absence of toluene
promoted polymerization and no benzyl 3,5-dimethyl-
pyrrole-2-carboxylate (1) was recovered. However,
changing the ratio of ethylene glycol and toluene from
1.2:1 to 1:6 (Entry 4) improved the yields. The
traditional method [16] and the method that uses
microwave energy were compared on different scales
(1 g scale: Entry 4 and 5; and 15 g scale: Entry 6 and 7
Table 2) and even though the yields are very similar,
the reaction time (traditional ~ 17-26 hours) was
reduced to a few minutes by using microwave energy,
with excellent isolated yields (Entry 4, 89 %).
aamount of pyrrole 2. bafter crystallization
De-acetylation The traditional manner to de-
acetylate benzyl 4-acetyl-3,5-dimethyl-2-carboxylate 3
(Path B, Scheme 1) involves heating the pyrrole in a
mixture of ethylene glycol and toluene with a catalytic
amount of para-toluene sulfonic acid [10] (Scheme 3).
The reaction is typically heated to reflux overnight
(depending on the scale it can require several days)
followed by a methanol/water recrystallization. Given
our success with using microwave energy for the trans-
esterification of 2 and the ready availability of pyrrole
3, we decided to use microwave energy for the de-
acetylation reaction, thus enabling us to perhaps
perform the same reaction in a reduced time.
Solvent-free de-acetylation. We had previously
noticed that the exposure of benzyl 3,5-dimethyl-
pyrrole-2-carboxylate (1) to high temperature when
evaporating the toluene under reduced pressure over an
Scheme III
O
a/ p-TSA, ethylene glycol, toluene, reflux, ~17 h
O
O
b/ p-TSA, ethylene glycol, toluene, 160-174 oC,
N
N
H
O
H
2-6 min, microwave energy
O
3
1
De-acylation of pyrrole 3: a/traditional method; b/ microwave method
The initial de-acetylation of 3 using microwave
energy was modeled after the literature methods
for de-acetylation of the same pyrrole using
traditional heating methods [10]. The reactions
were performed in a sealed 100 mL, Quartz, QXP,
vessel with different ratios of ethylene glycol and
toluene (Table 2).
It was shown that by increasing the reaction time
(Entries 1 and 2, Table 2) the yields were not
significantly enhanced. In the pressurized vessel, and
under more concentrated conditions, exposure to high
extended period of time in a water bath (heating bath)
lead to decomposition of the product. Consequently,
the traditional method was performed without toluene
(Scheme 4, a). The results of the solvent-free de-
acetylation were successful: 15 min for 1 g scale (69 %
yield), and 30 min for 10 g scale (75 % yield) and the
product was easily crystallized upon cooling and
addition of water. This idea led us to perform the
reaction without toluene using microwave energy, with
the power, temperature and reaction time being varied
(Table 3 and Scheme 4, b). This time the reaction was

1712
J. Regourd, I. M. Comeau, C. S. Beshara and A. Thompson
Vol 43
conducted using a round bottom flask and a condenser
at atmospheric pressure. The reactions were monitored
by TLC and the product was recrystallized using
methanol/water.
microwave energy: this results in a significant decrease
in the reaction times and cleaner products are obtained,
compared to conventional heating methods. The trans-
esterification of pyrrole 2 and the de-acetylation of 3
Scheme IV
O
a/ p-TSA, ethylene glycol, reflux
O
O
b/ p-TSA, ethylene glycol,
N
N
H
microwave energy
O
H
O
3
1
Optimization of the solvent-free de-acetylation of pyrrole 3 in the micowave
Table 3
Our initial attempt evidently utilized a higher power
than necessary since, despite the set temperature of 100
°C, the temperature overshot to >200 °C. It was
observed that exposure to such high temperature (Entry
1, Table 3) gives slightly lower yields than de-
acetylation in toluene. In order to avoid excess
temperature jumps, it is recommended that the
optimization process begins by using a low power,
increasing it as necessary to achieve completion of the
reaction. The power was decreased (Entry 2) leading to
increased yields. As the maximum temperature reached
was still very high (150 °C) the set temperature was
lowered to 80 °C (Entry 3). This change resulted in an
increased reaction time of four minutes and so the
temperature was fixed at 100 °C for the following
experiments. The power was decreased to 225 W
(Entry 4), which resulted in a slight increase of the
yield compared to Entry 2. The power was finally set to
150 W (Entry 5), which led to a maximum temperature
closer to 100 °C and our best yield recorded 91 % for
the 1 g scale de-acetylation reaction. The reaction was
also performed on scales of 30 g and 50 g (Entry 8 and
9, respectively, Table 3). The results were excellent
with reaction times not exceeding eight minutes and
yields close to 100 %. It was not necessary to further
purify the crystals by recrystallization as high quality
platelets are formed originally.
Optimization of solvent-free de-acetylation of 3 in the microwave
Entry
Scale
(g)a
Power
(W)
Set
temp.
(°C)
100
100
80
100
100
100
100
100
100
Temp.
reached
(°C)
>200
150
95
130
115
100
Time
(min)
Yield
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
15.0
15.0
30.0
50.0
600
300
300
225
150
300
360
360
360
2
2
4
2
2
12
6
8
76 %
83 %
87 %
84 %
91 %
93 %
96 %
99 %
98 %
100
100
100
8
aamount of pyrrole 3 used
use readily available reagents, and require no special
equipment save the microwave unit itself. Either of
these routes can produce a significant quantity of
benzyl 3,5-dimethyl-pyrrole-2-carboxylate (1) quickly
and cleanly. The mechanism(s) for the enhanced
reactivity and product purity are under investigation.
EXPERIMENTAL
General method. All reagents were used as supplied unless
otherwise stated. Dichloromethane was distilled prior to use.
Pyrroles 2 and 3 were prepared and purified according to literature
procedure [7,8]. The results obtained following the traditional
methods were performed using the Macdonald and Lide method
for the trans-esterification [9] and the Smith method for the de-
acetylation [10]. Thin layer chromatography was performed with
ultra pure silica gel pre-coated aluminum plates (0.25 mm thick)
with a 3:7 ethyl acetate: hexanes solution as eluent with
The color of the product was one of the reasons we
tried to improve our methodology and by varying the
power and temperature we observed that the lower the
power, the longer the reaction time but the more white
the crystals (e.g. Entry 1 gives grey crystals and Entry
6 gives white crystals).
visualization by UV light (254 nm) and stain (vanillin). 1H and 13
C
NMR, the chemical shifts are reported in part per million (ppm)
and J values are quoted in Hertz. Melting points were determined
using a Fisher-Johns melting point apparatus. General microwave
information: All the microwave reactions were conducted in a
CEM brand MARS 5® industrial microwave. Microwave
Conclusions.
We have improved the two major ways of obtaining
benzyl 3,5-dimethyl-pyrrole-2-carboxylate (1) by using

Nov-Dec 2006
Synthesis of pyrroles using microwave energy
1713
reactions for the trans-esterification and the optimized de-
acetylation were performed in an open glass round bottom flask
connected to a condenser and equipped with a RTP-300 Plus
temperature probe. Microwave reactions for the initial de-
acetylation were performed in a 100 mL, QXP, quartz-lined vessel
sealed with a bolt, perpendicular to the cap, tightened to a torque
of 50 Nm. It was equipped with a RTP-300 Plus temperature
probe and an ESP-1500 Plus pressure probe. CAUTION: All
chemical reactions utilizing microwave energy should be
performed in a commercial unit designed for that purpose and
incorporating temperature and pressure monitoring facilities.
poured into a round bottomed flask equipped with a stirrer bar,
a condenser and the temperature probe. The reaction mixture
was exposed to 150 W for 2 minutes reaching a maximum
temperature of 115 °C (set target temperature of the program:
100 °C). The reaction mixture was then allowed to cool (~10
minutes) and water was then added resulting in the formation
of sticky flat crystals. They were dissolved, as they were very
hard to collect, and the two phases were separated. The
aqueous phase was extracted with DCM (3 x 30 mL) and the
combined organics were dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure. Hot
methanol was added (20 mL) to dissolve the resulting solid
then water was added until the pyrrole crystallized (~ 5 mL).
The flask was kept in the freezer for 24 hours and the resulting
white crystals were filtered, rinsed with water and dried in a
vacuum oven at room temperature overnight to produce
pyrrole 1 as flat white crystals (0.77 g, 91 %). The large-scale
reactions (15, 30 and 50 g) did not require an aqueous work-
up: when water was added to the reaction mixture, the product
crystallized out. Filtration followed by rinsing of the crystals
with water and then drying in a vacuum oven at room
temperature overnight gave the isolated pure pyrrole 1. Further
re-crystallization was possible following the small scale
procedure in order to obtain flatter and shinier crystals. Data
mp: 102 °C (Lit. 102-103 °C)17; Rf 0.80 (1:1 ethyl acetate:
hexanes); ꢀH (250 MHz; CDCl3)18 8.67 (1H, bs, NH), 7.42-
7.30 (5H, m, ArH), 5.80 (1H, d, J = 2.8 Hz, CH=), 5.29 (2H, s,
CH2OCO), 2.32 (3H, s, CH3), 2.23 (3H, s, CH3); ꢀC (126
MHz; CDCl3) 161.3 (C), 136.6 (C), 132.7 (C), 127.7 (C),
128.6 (CH= x 2), 128.1 (CH= x 3), 117.4 (C), 111.6 (CH=),
65.5 (CH2), 13.1 (CH3), 12.9 (CH3); m/z [EI+] 229.1 (M+,
100 %).
Benzyl 3,5-dimethyl-pyrrole-2-carboxylate (1) via trans-
esterification of Ethyl 3,5-dimethyl-pyrrole-2-carboxylate (2)
(Entry 1, Table 1).
Sodium methoxide (0.48 g, 8.97 mmol) was added to a
solution of pyrrole 2 (1 g, 5.98 mmol) in benzyl alcohol (7.5
mL, 71.8 mmol) and the flask was equipped with a stirrer bar,
a condenser and the temperature probe. The reaction mixture
was exposed to 600 W for 30 minutes reaching a final
temperature of 200 °C (set temperature of the program: 215
°C), allowed to cool for about 10 minutes and water added to
dissolve the excess sodium methoxide. The aqueous phase was
extracted with DCM (3 x 30 mL) and the combined extracts
were washed with brine (30 mL), dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. Methanol was added (15 mL), followed by a 50/50
water/methanol mixture (30 mL). Water was then slowly
added until the pyrrole crystallized (~ 8 mL). The flask was
kept in the freezer for 24 hours and the resulting white crystals
were filtered, rinsed with water and dried in a vacuum oven at
room temperature over night to give pyrrole 1 as flat white
crystals (0.96 g, 70 %).
Acknowledgements.
Benzyl 3,5-dimethyl-pyrrole-2-carboxylate (1) via Initial De-
acetylation of Ethyl 3,5-dimethyl-pyrrole-2-carboxylate (3)
(Entry 3, Table 2).
This research was supported by the Canadian Breast Cancer
Foundation Atlantic Chapter, the Canadian Institutes of Health
Research and the Nova Scotia Health Research Foundation.
We are grateful to the Canada Foundation for Innovation and
the Nova Scotia Research and Innovation Trust for research
infrastructure, and C. S. B. thanks the Sumner Foundation for
financial support. We thank Yousef Alattar (Dalhousie
University) for performing preliminary experiments.
Pyrrole 3 (1.07 g, 3.93 mmol) and para-toluene sulfonic
acid (49 mg, 0.26 mmol) were weighed in a QXP vessel to
which was added ethylene glycol (2.5 mL, 44.8 mmol) and
toluene (15.5 mL). The vessel was then equipped with a stirrer
bar, the temperature probe and the pressure probe of the
microwave and exposed to 600 W for 6 minutes at 160 °C. The
reaction mixture was then allowed to cool to room
temperature, cautiously unsealed and water (20 mL) added.
The aqueous phase was extracted with DCM (3 x 30 mL) and
the combined organics were dried over anhydrous magnesium
sulfate, filtered and the solvent removed in vacuo. Water (40
mL) was added to the crude product in benzyl alcohol (15 mL)
and the mixture was heated to approximately 60 °C to dissolve
the pyrrole after which ethanol (40 mL) was added. The flask
was set aside to cool, resulting in the crystallization of the
product which was filtered, rinsed with water and left to air-
dry to afford pyrrole 1 as white flaky crystals (0.80 g, 89 %).
REFERENCES AND NOTES
* Corresponding author. Alison Thompson; E-mail: alison.thompson@
dal.ca; Fax: (1) 902 494 1310; Tel: (1) 902 494 3305.
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(Entry 5, Table 4).
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J. Regourd, I. M. Comeau, C. S. Beshara and A. Thompson
Vol 43
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