Improved catalyst-free synthesis of pyrrole derivatives in aqueous media

Article abstract of DOI:10.1055/s-0033-1339294

An improved catalyst-free, three-component reaction of ammonium acetate, 1,3-dicarbonyl compounds, and aromatic α-hydroxycarbonyl compounds has been carried out in water-ethanol (50:50) under reflux conditions. The improvement of yield in this aqueous med

Full text of DOI:10.1055/s-0033-1339294

LETTER
▌1791
lIemtterproved Catalyst-Free Synthesis of Pyrrole Derivatives in Aqueous Media
Catalyst-Free Synthesis of Pyrroles in Aqueous Media
Fatemeh Tamaddon,* Farideh Amirpoor
Department of Chemistry, Faculty of Science, Yazd University, Yazd 89195-741, Iran
Fax +98(351)8210664; E-mail: ftamaddon@yazduni.ac.ir
Received: 16.04.2013; Accepted after revision: 29.05.2013
alyst-free extension of our strategy for the synthesis of
Abstract: An improved catalyst-free, three-component reaction of
substituted pyrroles in refluxing aqueous ethanol.14
ammonium acetate, 1,3-dicarbonyl compounds, and aromatic α-hy-
droxycarbonyl compounds has been carried out in water–ethanol
(50:50) under reflux conditions. The improvement of yield in this
aqueous medium is attributed to a combination of increased associ-
ation of the reactants by hydrophobic interactions and precipitation
of the product during the reaction. This operationally simple proce-
dure is less laborious and provides a better scope and chemoselec-
tivity than previously reported procedures.
Due to the lack of in the synthesis of highly substituted
pyrroles from electron-rich benzoins in our previously re-
ported acid-catalyzed method,14 a model study was initi-
ated with anisoin (1a), acetylacetone, and ammonium
salts under various catalyst-free conditions (Table 1).
Table 1 Screening Conditions for the Model Reaction
Key words: catalyst-free, multicomponent reaction, aqueous medi-
um, pyrrole derivatives, α-hydroxycarbonyl compounds
MeO
COMe
Me
Me
Me
O
O
anisoin
1a
+
+
ammonium
salt
Replacement of hazardous procedures with safe alternates
is one of the main goals of modern organic synthesis, and
catalyst-free, water-based transformations are environ-
mentally friendly chemical processes.1–4 Organic reac-
tions in aqueous media are influenced by the low
hydrophilicity of organic materials resulting in increased
association, leading to higher reaction rates or yields, and
permitting simple isolation of the water-insoluble prod-
ucts by filtration.
N
H
2a
MeO
Entry Solvent
Temp
Ammonium Time Isolated
salt (h) yield (%)
1
2
EtOH
EtOH
H2O
60–70 °C NH4OAc
7
5
78
80
reflux
reflux
reflux
NH4OAc
The unique properties and broad applications of pyrrole
derivatives in biology, pharmacology, chemistry, and
materials science make them among the most important
heterocyclic compounds.5–8 The pyrrole nucleus is a con-
stituent of molecules such as hemoglobin, chlorophyll,
cytochromes, vitamins, myoglubin,9 and a wide range of
pharmaceuticals.10
3
(NH4)2CO3 10 trace
NH4OAc 10 20
4
H2O
5
H2O–EtOH
H2O–EtOH
60–70 °C (NH4)2CO3
60–70 °C NH4OAc
7
7
4
9
65
85
96
78
6
7
H2O–EtOH (50:50) reflux
H2O–EtOH (50:50) reflux
H2O–EtOH (50:50) reflux
H2O–EtOH (50:50) reflux
H2O–EtOH (40:60) reflux
H2O–EtOH (30:70) reflux
H2O–EtOH (60:40) reflux
H2O–EtOH (70:30) reflux
NH4OAc
(NH4)2CO3
NH4Cl
Although pyrroles can be prepared by a variety of meth-
ods, one-pot multicomponent reactions (MCR) provide an
option to design substituted pyrroles by altering the initial
components.11–18 Recently, we have reported a new
[2+2+1] strategy for the synthesis of 2,3,4,5-tetrasubsti-
tuted pyrroles via a solid-acid-catalyzed, three-compo-
nent reaction.14 In this protocol, silica sulfuric acid (SSA)
and molybdate sulfuric acid (MSA) have been used as het-
erogeneous catalysts and the pyrrole products isolated by
extraction with organic solvents. However, electron-rich
benzoins such as anisoin failed to give the desired pyrrole
products.
8
9
12 55
10
11
12
13
14
15
NH4OCHO
NH4OAc
NH4OAc
NH4OAc
NH4OAc
8
5
5
6
8
75
87
85
68
55
MeCN
toluene
dioxane
CHCl3
EtOAC
80–90 °C NH4OAc
10 30
10 22
10 38
10 32
10 35
Following of our interest in water-based organic 16
reflux
reflux
reflux
reflux
NH4OAc
NH4OAc
NH4OAc
NH4OAc
reactions19–22 and to overcome the limited scope and prob-
lems associated with the isolation of pyrrole products with
our catalyzed protocol, we report herein a successful cat-
17
18
19
SYNLETT 2013, 24, 1791–1794
Advanced online publication: 24.07.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339294; Art ID: ST-2013-D0320-L
© Georg Thieme Verlag Stuttgart · New York

1792
F. Tamaddon, F. Amirpoor
LETTER
The results showed that by performing the reaction with excellent yields under these catalyst-free conditions (Ta-
NH4OAc in refluxing EtOH–H2O (50:50) (Table 1, entry ble 2, entries 2 and 3). While the yields of products were
7) the yield of 2a was dramatically improved to 98%, consistently high, electron-deficient benzoins led to high-
while 2a was formed in lower yields using other ammoni- er yields with shorter reaction times (Table 2, entries 4, 6,
um salts such as the carbonate or chloride. Further EtOH– and 7). Comparison between entries 1 vs. 8 and 4 vs. 7
H2O mixtures (Table 1, entries 8–14) and non-hydrogen- show the greater influence of steric hindrance over elec-
bonding solvents such as EtOAc, MeCN, toluene, diox- trophilicity of the carbonyl groups in 1,3-dicarbonyls on
ane, or CHCl3 (Table 1, entries 15–19) proved to be less yields.
effective.
To clarify mechanistic details, benzoylacetone with two
Although hydrogen bonding, homogeneity, charge stabi- different carbonyl groups from the viewpoint of steric hin-
lization, and dipolar effects may each play roles in pro- drance and electrophilicity was utilized in the three-com-
moting the reaction in EtOH–H2O, the superior yield of 2a ponent reaction of benzoylacetone, ammonium acetate,
in EtOH–H2O (50:50, Table 1, entry 7) may be due to the and benzoin, following by NMR spectroscopy. Two en-
tight association of anisoin and acetylacetone inside the aminones were expected for the reaction of each carbonyl
postulated molecular clusters [(EtOH)n (H2O)m] formed at with ammonium acetate in the first step of the reaction
this ratio of EtOH–H2O. The existence of such clusters in which would result in the formation of regioisomers 3a or
EtOH–H2O mixtures and the change in hydrophobic inter- 3b (Figure 1).
actions and molecular association in different aqueous
ethanol systems have been confirmed previously using
expected
δH: 2.55 ppm
δC: 29.6 ppm
expected
δH: 2.16 ppm
δC: 11.7 ppm
mass spectrometry by Nishi et al.23 The lower yield of 2a
in pure EtOH or H2O lends support to this postulate.
With the optimized catalyst-free conditions established,
various benzoins were tested in the reaction with acetyl-
acetone, benzoylacetone, cyclic 1,3-dicarbonyls, and
ammonium acetate (Table 2).24
COCH3
COPh
CH3
Ph
N
N
H
H
3a
3b
Notwithstanding our previously reported SSA-catalyzed
synthesis of pyrroles,14 electron-rich benzoins such as an-
isoin and 4-methylbenzoin led to the desired products in
Figure 1 Two expected regioisomers of tetrasubstituted 1H-pyrroles
Table 2 Influence of the R Group of 1,3-Dicarbonyl on the Reaction
Me
Ar
COR
Me
O
Ar
Ar
O
O
H2O–EtOH
reflux
+
NOAc
+
Ar
N
HO
H
R
Entry
R
Ar
Time (h)
Isolated yield (%)
Mp (°C) found/reported14
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Ph
Ph
4
5
98
92
94
96
87a
93a
90
175–179/170–172
237–238/–
4-MeC6H4
4-MeOC6H4
4-ClC6H4
Ph
4
154–160/–
3
235–237/234–235
223–225/221–223
248–252/247–249
258–261/259–260
–
6
Ph
4-ClC6H4
4-ClC6H4
Ph
3.5
3.5
10
CF3
CF3
b
–
O
O
O
O
b
9
Ph
10
–
–
Ph
Ph
Ph
b
10
4-ClC6H4
4-ClC6H4
10
10
–
–
–
Ph
b
11
dimedone
–
a Single regioisomer.
b No pyrrole product was obtained.
Synlett 2013, 24, 1791–1794
© Georg Thieme Verlag Stuttgart · New York

LETTER
Catalyst-Free Synthesis of Pyrroles in Aqueous Media
1793
The observed chemical shifts for the methyl group in the The concept of atom economy developed by Trost25 ex-
1
13C NMR and H NMR spectra of the isolated pyrrole presses the efficiency of a particular reaction as the per-
product were δ = 11.1 and 2.24 ppm, respectively, and are cent of atomic weight of all the starting materials
in accordance with the expected chemical shifts for regio- appearing in the final product (%AE of reaction = molec-
isomer 3b formed as a single product. Similarly, NMR ular mass of product/molecular mass of all reactants).
spectroscopic analysis of the product obtained from the
The atom economy of this catalyst-free, three-component
reaction of benzoylacetone, 4-chlorobenzoin, and ammo-
reaction of benzoin, acetylacetone, and ammonium ace-
nium acetate showed δH = at 2.21 ppm and δC = at 13.21
tate in this work was compared with our earlier reported
ppm for the methyl group which again confirmed the for-
mation of a single regioisomer 4b (Figure 2).
SSA- and MSA-catalyzed versions.14 Due to the similarity
of reactants, products, and %AE of the reaction, for each
method %AE was calculated by multiplying the %AE in
the yield of SSA-catalyzed,14b MSA-catalyzed,14a and this
Cl
catalyst-free synthesis of pyrroles. As Table 4 shows, the
catalyst-free method is superior to its acid-catalyzed ver-
sions.
COPh
Me
COPh
Me
N
N
Table 4 Comparative Performances of Catalyst-Free and Acid-Cat-
alyzed Pyrrole Synthesis
H
H
Cl
4b
3b
Entry Catalyst
Time
(h)
Isolated Atom-economy reaction
yield (%) method (%)
Figure 2 Single regioisomers obtained
To access the 3-alkoxycarbonyl-substituted pyrroles, var-
ious benzoins were reacted with β-keto esters such as
methyl, ethyl, and benzyl acetoacetate (Table 3).24
1
2
3
SSA
0.6
0.4
4
96
96
98
72.32–69.45
72.32–69.45
72.32–70.78
MSA
this work
Table 3 Synthesis of 3-Alkoxycarbonyl-Substituted Pyrroles
Me
Ar
Ar
COOR
Me
O
Ar
Ar
The chemoselectivity of the protocol was further investi-
gated by reacting NH4OAc, 4-chlorobenzoin, anisoin,
acetylacetone, and ethyl acetoacetate in EtOH–H2O under
reflux conditions which led solely to the formation of the
pyrrole from 4-chlorobenzoin and acetylacetone (Scheme
1).
O
O
H2O–EtOH
reflux
NOAc
+
+
N
HO
H
RO
Entry OR
Ar
Time Isolated Mp (°C)
(h)
yield (%) found/reported14
1
2
OMe
Ph
Ph
7
6
95
94
178–180/177–179
206–208/205–206
–
MeO
OMe
Me
OEt
OEt
OEt
OMe
OEt
OMe
OEt
OMe
OEt
O
O
O
a
+
3
4-MeOC6H4 10
–
O
EtO
Me
a
+
Me
4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
4-FC6H4
2-furyl
10
6
–
–
HO
O
H2O–EtOH
reflux
NH4OAc
Cl
anisoin
+
+
5
91
92
213–214/212–213
155–156/155–156
216–218/–
Cl
4-ClH4C6
COMe
Me
Me
O
+
6
5
4-ClH4C6
N
7
4.5 93
O
H
OEt
HO
O
8
4
4
4
93
90
91
160–162/–
Scheme 1 Chemoselectivity of reaction
9
188–190/–
10
2-furyl
168–170/–
These results show that the electronic nature of the sub-
stituents on benzoin or the steric effect of the substituents
on the 1,3-dicarbonyl precursors have a clear influence
upon the progress of the reaction. According to these re-
sults and formation of a single regioisomer from benzoyl-
acetone, we propose a mechanism wherein steric
influence on the 1,3-dicabonyl precursor is more impor-
tant than the electrophilicity of carbonyl groups of the
benzoin (Scheme 2).
a No pyrrole product was obtained.
According to Table 3, the electronic nature of the substit-
uents on benzoin is important for the progress of the reac-
tion. Electron-deficient furoin, 4-fluorobenzoin, and 4-
chlorobenzoin resulted in the desired products in excellent
yields (Table 3, entries 5–10), while no product was ob-
tained from methyl- or methoxy-substituted benzoins and
β-keto esters under similar reactions (Table 3, entries 3
and 4).
In summary, we have developed an efficient one-pot and
catalyst-free method for the synthesis of tetrasubstituted
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1791–1794

1794
F. Tamaddon, F. Amirpoor
LETTER
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NH
H
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Scheme 2 Proposed mechanism for the catalyst-free synthesis of
substituted 1H-pyrroles
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Acknowledgment
We gratefully acknowledge financial support from the Research
Council of Yazd University.
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To a mixture of benzoin derivative (2 mmol) and 1,3-
dicarbonyl compound (2 mmol) in H2O–EtOH (2 mL, 50:50)
was added NH4OAc (4 mmol), and the mixture was stirred
under reflux for the requisite time. After completion of the
reaction (TLC), ice was added, and the product was isolated
by filtration.
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Synlett 2013, 24, 1791–1794
© Georg Thieme Verlag Stuttgart · New York