An efficient synthesis of N-substituted pyrroles catalyzed by MgI2 etherate

Article abstract of DOI:10.1515/mgmc-2014-0031

We describe a convenient and useful procedure for the synthesis of various 2,5-dimethyl-N-substituted pyrrole derivatives by the addition of 2,5-hexadione with aromatic amines, heteroaromatic amines and aliphatic amines catalyzed by MgI₂ etherate (MgI₂·(OEt₂)_n) in good to excellent yields.

Full text of DOI:10.1515/mgmc-2014-0031

Main Group Met. Chem. 2014; 37(5-6): 131–135
Yongdong Zhang, Guodong Weng, Jingyan Chen, Danting Ma and Xingxian Zhang*
An efficient synthesis of N-substituted pyrroles
catalyzed by MgI2 etherate
Abstract: We describe a convenient and useful procedure and 1,4-diketones, have been developed in the presence
for the synthesis of various 2,5-dimethyl-N-substituted of various Lewis acid catalysts, such as Ti(OiPr)4 (Yu and
pyrrole derivatives by the addition of 2,5-hexadione with Quesne, 1995), ZrOCl2·8H2O (Rahmatpour, 2011), Sc(OTf)3
aromatic amines, heteroaromatic amines and aliphatic (Chen et al., 2006), Bi(NO3)3·5H2O (Banik et al., 2004),
amines catalyzed by MgI2 etherate (MgI2·(OEt2)n) in good UO2(NO3)2·6H2O (Satyanarayana and Sivakumar, 2011),
to excellent yields.
BiCl3/SiO2 (Aghapoor et al., 2012), InCl3 (Shanthi and
Perumal, 2009) and FeCl3 (Azizi et al., 2009). Some of the
Keywords: amines; 2,5-hexadione; MgI2 etherate; Paal- synthetic protocols suffer from disadvantages, such as the
Knorr condensation; pyrrole.
use of stoichiometric and even excess amounts of cata-
lyst, harsh reaction conditions, prolonged reaction time,
expensive reagents and low yield of the products. From
the above viewpoints, the development of less expensive,
environmentally benign and easily handled promoters for
the synthesis of N-substituted pyrroles by Paal-Knorr con-
densation under neutral, mild and convenient condition
is still highly desirable.
DOI 10.1515/mgmc-2014-0031
Received July 21, 2014; accepted September 26, 2014; previously
published online October 24, 2014
MgI2 etherate is easily preparative, inexpensive and
easier to be handled than other metal halides such as
Ti(OiPr)4, InCl3 and Sc(OTf)3. To the best of our knowledge,
there is no report of the use of MgI2 etherate as a mild cata-
lyst for the Paal-Knorr reaction. In the continuation of our
research field, herein, we will wish to report a simple and
efficient procedure for the Paal-Knorr pyrrole condensa-
tion of primary amines with 2,5-hexadione catalyzed by
MgI2 etherate under mild reaction conditions in good to
excellent yields (Scheme 1).
Introduction
Pyrroles are important heterocyclic compounds display-
ing remarkable pharmacological properties such as anti-
bacterial, antiviral, anti-inflammatory, antitumoral and
antioxidant activities (Fürstner et al., 1998; Jacobi et al.,
2000; Fürstner, 2003). Furthermore, pyrroles are also con-
sidered to be important building blocks in many naturally
occurring compounds such as heme, chlorophyll and
vitamin B12 (Santo et al., 1998; Ragno et al., 2000; Hoff-
mann and Lindel, 2003; Bellina and Rossi, 2006). In view
of their important significance, preparation of pyrroles
has attracted considerable attention of chemists in recent
years. Many methodologies have been developed for the
construction of the pyrrole moiety regarded as skeleton
(Fang et al., 2012; Heugebaert et al., 2012). Among them,
the Paal-Knorr synthesis remains the most useful prepara-
tive method for generating pyrroles (Aghapoor et al., 2012;
Balme, 2012; Rahmatpour, 2012).
Results and discussion
We initiated our studies by carrying out the Paal-Knorr con-
densation of aniline with 2,5-hexadione in the presence of 3
mol% of MgI2 etherate (1.0 m in Et2O/benzene 1:2) in CH2Cl2
at room temperature. After stirring for 2.0 h, the desired
2,5-dimethyl-N-phenyl pyrrole (2a) was afforded in 93%
yield. In order to evaluate the generality of this process,
a variety of diversified examples illustrating the present
method for the synthesis of 2,5-dimethyl-N-substituted pyr-
roles (2b–2o) were studied. The results are listed in Table
1. The reaction of 2,5-hexadione with a series of aromatic
substituted primary amines bearing either electron-donat-
ing (Table 1, entries 2–5) or electron-withdrawing (Table 1,
entries 6–9) groups on the aromatic ring was carried out
Recently, many methods for the synthesis of pyr-
roles, such as Paal-Knorr cyclization of primary amines
*Corresponding author: Xingxian Zhang, College of Pharmaceutical
Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang
310014, People’s Republic of China, e-mail: zhangxx@zjut.edu.cn
Yongdong Zhang, Guodong Weng, Jingyan Chen and Danting
Ma: College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou, Zhejiang 310014, People’s Republic of China
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132ꢀ ꢀY. Zhang et al.: Paal-Knorr condensation catalyzed by MgI2 etherate
O
an electron-donating group (i.e., -OMe, -OEt) reacted much
Me
faster than aniline-bearing electron-withdrawing group
(i.e. -Cl, -F, -NO2) and provided the corresponding prod-
ucts in excellent yields. The Paal-Knorr condensation of
2,6-diisopropylaniline with 2,5-hexadione also gave a good
yield although it has a more sterically hindered effect (Table
1, entry 5). Furthermore, we have examined the Paal-Knorr
reaction of aliphatic amines with 2,5-hexadione (Table 1,
entries 10 and 11). Also, the corresponding products were
obtained with excellent yields. Unfortunately, no reaction
of tert-butylamine with 2,5-hexadione was observed under
the same conditions, due to its higher steric hindrance.
Under further observation, it is observed that the reaction
of chiral amine such as (R)-(+)-1-(1-naphthyl)ethylamine 1l
with 2,5-hexadione provided the optically pyrrole deriva-
tive without racemization. Moreover, we examined the
reactivity of heterocyclic amines with 2,5-hexadione in
the presence of MgI2 etherate. Thus, using 3 mol% of MgI2
etherate the Paal-Knorr reaction of heterocyclic amine such
as 2-aminopyridine (1m) affords 2-(2,5-dimethyl-1H-pyrrol-
1-yl)pyridine (2m) in 92% yield (Table 1, entry 13). There-
fore, heterocyclic amines exhibited analogous behavior to
that of aromatic amines and aliphatic amines. Interestingly,
the condensation of (R)-2-amino-2-phenylacetamide, which
has two amino groups, exclusively gave (R)-2-(2,5-dimethyl-
1H-pyrrol-1-yl)-2-phenylacetamide (2n) with the retention of
absolute configuration.
The reaction using MgI2 etherate as a catalyst has
shown an important feature, that is, the ability to toler-
ate various amines including aliphatic, aromatic and
heterocyclic amines. To extend the scope of MgI2 etherate-
catalyzed Paal-Knorr condensation for the synthesis of
N-substituted pyrrole derivatives, other substituted dik-
etones such as 1,4-diphenylbutane-1,4-dione and 1-phe-
nylpentane-1,4-dione were investigated. Unfortunately, no
reaction of 1,4-diphenylbutane-1,4-dione with p-methoxy-
aniline occurred. The condensation of 1-phenylpentane-
1,4-dione with p-methoxyaniline or p-methoxybenzyl
amine resulted in good yields (Scheme 2).
3 mol% MgI2 (OEt2)n
CH2Cl2, reflux
Me
Me
+
R
NH2
N R
1a-1n
Me
2a-2n
O
R = aryl, heteroaryl, alkyl
Scheme 1ꢂMgI2 etherate catalyzed Paal-Knorr condensation.
Table 1ꢂPaal-Knorr condensation of 2,5-hexadione catalyzed by
MgI2 etheratea.
O
Me
N R
Me
3 mol% MgI2 (OEt2)n
CH2Cl2, reflux
Me
Me
+
R
NH2
1a-1n
O
2a-2n
Entryꢁ
Amine
ꢁ
t (h)ꢁ
Productbꢁ
Yield (%)c
1ꢃ
2ꢃ
C6H5NH2
ꢃ
ꢃ
2ꢃ
4ꢃ
2aꢃ
2bꢃ
2cꢃ
2dꢃ
2eꢃ
2fꢃ
2gꢃ
2hꢃ
2iꢃ
93
80
95
92
76
74
73
86
78
90
97
78
3-MeOC6H4NH2
3ꢃ
3,4-(MeO)2C6H3NH2ꢃ
2ꢃ
4ꢃ
4-EtOC6H4NH2
2,6-(iPr)2C6H3NH2
2-FC6H4NH2
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
2ꢃ
5ꢃ
8ꢃ
6ꢃ
6ꢃ
7ꢃ
3,5-F2C6H3NH2
3-ClC6H4NH2
4ꢃ
8ꢃ
2ꢃ
9ꢃ
4-NO2C6H4NH2
10ꢃ
2ꢃ
10ꢃ
11ꢃ
12ꢃ
4-CH3OC6H4CH2NH2 ꢃ
2jꢃ
2kꢃ
2lꢃ
4-ClC6H4(CH2)2NH2
ꢃ
ꢃ
2ꢃ
2ꢃ
NH2
(R)
13ꢃ
14ꢃ
ꢃ
ꢃ
2ꢃ
2mꢃ
2nꢃ
92
N
NH2
8ꢃ
70
NH2
NH2
O
aThe reaction was carried out by the condensation of 2,5-hexadione
(6 mmol) with primary amine (5 mmol) catalyzed by 3 mol% of
MgI2 etherate.
The high coordinating ability of magnesium (II)
towards oxygen atoms of the carbonyl moiety is presumably
responsible for the effective activation of ketonic carbonyl.
To examine the halide anion effect, halogen analogs of MgI2
etherate, MgCl2 etherate and MgBr2 etherate were compared
bAll products were identified by their 1H NMR spectra.
cYields of products isolated by column chromatography.
as catalyzed by 3 mol% of MgI2 etherate under mild condi- under parallel reaction conditions (3 mol% of catalyst) in
tions. As shown in Table 1, the reaction proceeded smoothly the Paal-Knorr condensation of aniline with 2,5-hexadione.
in Dichloromethane (DCM) at reflux and provided a single MgCl2 etherate and MgBr2 etherate are less effective in terms
product without any side products in good to excellent of substrate conversion yield and provide the moderate
yields. Furthermore, the substitution group on the phenyl yields. Apparently, the unique reactivity of MgI2 etherate is
ring could affect the yield and reaction rate in the Paal-Knorr attributed to the dissociative character of iodide counterion
reaction. We have observed the reactivity of anilines bearing and a more Lewis acidic cationic [MgI]+ species.
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Y. Zhang et al.: Paal-Knorr condensation catalyzed by MgI2 etherateꢂ
ꢂ133
O
NH2
Ph
N
3 mol% MgI2 (OEt2)n
Me
Ph
+
OCH3
CH2Cl2, reflux
78%
Me
O
O
OCH3
2o
OCH3
H2N
Ph
N
3 mol% MgI2 (OEt2)n
Me
Ph
+
CH2Cl2, reflux
84%
Me
O
OCH3
2p
Scheme 2ꢂPaal-Knorr condensation with 1-phenylpentane-1,4-dione catalyzed by MgI2 etherate.
1
(lit. 48–50°C). H NMR (500 MHz, CDCl3) δꢁ=ꢀ2.11 (s, 6H), 5.98 (s, 2H),
In conclusion, we have demonstrated the unique reac-
tivity of MgI2 etherate in the Paal-Knorr reaction for the syn-
thesis of N-substituted pyrroles. Compared to previously
reported methodologies, the present protocol features
simple operation, mild condition and good to excellent
yield. Exploitation of this protocol for generation of novel
multicyclic structures is actively pursued in our lab.
7.27–7.29 (m, 2H), 7.44–7.47 (m, 1H), 7.50–7.54 (m, 2H).
1-(3-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole (2b)ꢀ(Lee and
Kim, 2013): light yellow liquid. Rfꢁ=ꢀ0.42 (100% PE), 1H NMR (500 MHz,
CDCl3) δꢁ=ꢀ2.18 (s, 6H), 3.92 (s, 3H), 6.01(s, 2H), 6.88 (d, Jꢁ=ꢀ2.2 Hz, 1H),
6.89–6.94 (m, 1H), 7.05–7.7.07 (m, 1H), 7.46 (t, Jꢁ=ꢀ8.0 Hz, 1H).
1-(3,4-Dimethoxyphenyl)-2,5-dimethyl-1H-pyrroleꢀ(2c)ꢀ(Noberini
et al., 2008): pale yellow liquid. Rfꢁ=ꢀ0.18 (100% PE). 1H NMR (500 MHz,
CDCl3) δꢁ=ꢀ2.09 (s, 6H), 3.90 (s, 3H), 3.97 (s, 3H), 5.93 (s, 2H), 6.78 (d, Jꢁ=ꢀ
2.3 Hz, 1H), 6.83 (dd, Jꢁ=ꢀ2.3, 8.4 Hz, 1H), 6.97 (d, Jꢁ=ꢀ8.4 Hz, 1H).
Experimental section
General methods
1-(4-Ethoxyphenyl)-2,5-dimethyl-1H-pyrroleꢀ(2d)ꢀ(Hazlewood
et al., 1937): white solid. Rfꢁ=ꢀ0.33 (100% PE). m.p. 59–61°C (lit. 63°C),
FT-IR (KBr) υ (cm-1): 2983, 1514, 1475, 1404, 1290, 1246, 1169, 1052, 845,
For product purification by flash column chromatography, silica gel
1
768. H NMR (500 MHz, CDCl3): δꢁ=ꢀ1.55 (t, Jꢁ=ꢀ7.0 Hz, 3H), 2.12 (s, 6H),
(200–300 mesh) and light petroleum ether (PE, b.p. 60–90°C) were
1
4.16 (dd, Jꢁ=ꢀ5.0, 10.0 Hz, 2H), 5.98 (s, 2H), 7.03–7.07 (m, 2H), 7.19–7.23
(m, 2H). 13C NMR (125 MHz, CDCl3): δꢁ=ꢀ13.01, 14.90, 63.56, 105.06,
114.45, 128.72, 128.94, 131.31, 157.94. EI-MS-215 ([M]+, 100), 186 (62), 172
(10), 145 (14), 117 (12), 77 (5). Elemental analyses: calculated (%) for
C16H21NO (243.16 g/mol): C 78.97; H 8.70; N 5.76, found: C 78.85, H 8.58,
N 5.65.
used. H NMR spectra were taken on a Bruker Avance III 500 MHz
spectrometer (Switzerland) with Tetramethylsilane (TMS) as an inter-
nal standard and CDCl3 as solvent. The reaction monitoring was accom-
plished by thin layer chromatography (TLC) on silica gel polygram
SILG/UV 254 plates. FT-IR spectra were recorded with a Nicolet 6700
spectrophotometer with NaCl optics (Thermo Company, USA). Melting
points were measured on BUCHI B-540. High resolution mass spectro-
scopy (HRMS) were determined on a Waters GCT Premier spectrometer
(Waters Company, USA). Elemental analysis was performed on a Vari-
oEL-3 instrument (Elementar, Germany). All compounds were identified
by 1H NMR and are in good agreement with those reported. All starting
materials and reagents are purchased from the Sigma-Aldrich company.
1-(2,6-Diisopropylphenyl)-2,5-dimethyl-1H-pyrrole (2e)ꢀ(Chen et al.,
2009): white solid. Rfꢁ=ꢀ0.73 (PE:EAꢁ=ꢀ10:1). m.p. 56–57°C (lit. 56–58°C).
1H NMR (500 MHz, CDCl3) δꢁ=ꢀ1.16 (d, Jꢁ=ꢀ6.9, 12H), 1.95 (s, 6H), 2.0–2.1 (m,
2H), 5.98 (s, 2H), 7.28 (d, Jꢁ=ꢀ7.7 Hz, 2H), 7.44 (t, Jꢁ=ꢀ7.7 Hz, 1H).
1-(2-Fluorophenyl)-2,5-dimethyl-1H-pyrrole (2f)ꢀ(Chen et al.,
2009): yellow liquid. Rfꢁ=ꢀ0.62 (PE:EAꢁ=ꢀ10:1). 1H NMR (500 MHz,
CDCl3) δꢁ=ꢀ1.95 (s, 6H), 5.94 (s, 2H), 7.29 (t, Jꢁ=ꢀ7.8 Hz, 1H), 7.61 (t, Jꢁ=ꢀ7. 8
Hz, 1H), 7.69 (t, Jꢁ=ꢀ7.6 Hz, 1H), 7.84–7.86 (m, 1H).
General procedure for the synthesis of N-substituted
pyrroles
1-(3,5-Difluorophenyl)-2,5-dimethyl-1H-pyrrole
(2g)ꢀ(Thomas
To a mixture of amine (5 mmol) and 2,5-hexadione (6 mmol, 1.1 equiv)
in 5 mL dichloromethane was added 3 mol% freshly prepared MgI2
etherate (Arkley et al., 1962). The mixture was stirred at reflux for the
appropriate time. The progress of the reaction was monitored by TLC.
Afer reaction, the mixture was concentrated and the residue was
purified on silica gel with petroleum ether/ethyl acetate as eluent.
et al., 2004): white solid. Rfꢁ=ꢀ0.68 (PE:EAꢁ=ꢀ10:1). m.p. 54.8–55.3°C.
1H NMR (500 MHz, CDCl3) δꢁ=ꢀ2.09 (s, 6H), 5.93 (s, 2H), 6.81 (dd, J1ꢁ=ꢀ
2.2, 7.4 Hz, 2H), 6.88–6.92 (m, 1H).
1-(3-Chlorophenyl)-2,5-dimethyl-1H-pyrrole (2h)ꢀ(Jafari et al.,
2012): white solid. Rfꢁ=ꢀ0.43 (100% PE). m.p. 48–49°C (lit. 47–49°C).
1H NMR (500 MHz, CDCl3) δꢁ=ꢀ2.07 (s, 6H), 5.93 (s, 2H), 7.13–7.16 (m,
1H), 7.25–7.28 (m, 1H), 7.40–7.44 (m, 2H).
1-Phenyl-2,5-dimethyl-1H-pyrrole(2a)ꢀ(Satyanarayana and Siva-
kumar, 2011): light yellow solid. Rfꢁ=ꢀ0.67 (100% PE). m.p. 49–50°C
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134ꢀ ꢀY. Zhang et al.: Paal-Knorr condensation catalyzed by MgI2 etherate
1-(4-Nitrophenyl)-2,5-dimethyl-1H-pyrrole (2i)ꢀ(Satyanarayana elemental analyses: calculated (%) for C19H19NO (277.15 g/mol): C
and Sivakumar, 2011): yellow solid. Rfꢁ=ꢀ0.35 (PE:EAꢁ=ꢀ10:1). m.p. 82.28, H 6.90, N 5.05, found: C 82.41, H 6.79, N 5.15.
1
142–143°C (lit. 143–144°C). H NMR (500 MHz, CDCl3) δꢁ=ꢀ2.10 (s, 6H),
5.98 (s, 2H), 7.39–7.43 (m, 2H), 8.35–8.38 (m, 2H).
Acknowledgments: We are grateful to the National Natural
Science Foundation of China (No. 21372203 and 21272076)
1-(4-Methoxybenzyl)-2,5-dimethyl-1H-pyrrole (2j)ꢀ(Chen et al.,
2009): white solid. Rfꢁ=ꢀ0.23 (100% PE). m.p. 75–76°C (lit. 76–77°C). 1H
NMR (500 MHz, CDCl3) δꢁ=ꢀ2.20 (s, 6H), 3.82 (s, 3H), 5.00 (s, 2H), 5.90
(s, 2H), 6.85–6.90 (m, 4H).
and the National University Student Innovation Test Plan
(201310337007) for financial support.
1-(4-Chlorophenethyl)-2,5-dimethyl-1H-pyrrole (2k)ꢀWhite solid.
Rfꢁ=ꢀ0.29 (100% PE). m.p. 64–66°C. FT-IR (KBr) υ (cm-1): 2970, 1518,
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1492, 1411, 1298, 1094, 1017, 811, 715. H NMR (500 MHz, CDC13): δꢁ=ꢀ
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123.4, 124.4, 126.7, 128.0, 128.4, 128.8, 129.4, 132.3, 135.3, 137.0. EI-MS:
249.1 (10), 155.2 (100), 149.2 (31), 95.2 (43), 81.2 (23). Elemental analy-
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l3
6.85 (s, 1H), 7.25–7.28 (m, 2H), 7.30 (s, 1H), 7.31–7.36 (m, 2H). C NMR
(125 MHz, CDC13): δꢁ=ꢀ13.6, 61.1, 107.7, 127.8, 128.1, 128.4, 128.8, 135.4,
171.6. EI-MS: 228.1 (7), 185.4 (11), 184.3 (43), 94.7 (100), 106.4 (10). Ele-
mental analyses: calculated (%) for C14H16N2O (228.13 g/mol): C 73.66, Fürstner, A. Chemistry and biology of roseophilin and the prodigi-
H 7.06, N 12.27, found: C 73.78, H 6.96, N 12.36.
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1-(4-Methoxyphenyl)-2-methyl-5-phenyl-1H-pyrrole (2o)ꢀ(Lee and Fürstner, A.; Szillat, H.; Gabor, B.; Mynott, R. Platinum- and acid-
l
Kim, 2013): yellow solid. Rfꢁ=ꢀ0.49 (PE:EAꢁ=ꢀ10:1). m.p. 104–106°C. H
NMR (500 MHz, CDC13): δꢁ=ꢀ2.19 (s, 3H), 3.86 (s, 3H), 6.15 (d, Jꢁ=ꢀ3.0 Hz,
1H), 6.42 (d, Jꢁ=ꢀ3.4 Hz, 1H), 6.94 (d, Jꢁ=ꢀ8.8 Hz, 2H), 7.12–7.16 (m, 5H), 7.20
(t, Jꢁ=ꢀ7.6 Hz, 2H).
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Hazlewood, S. J.; Hughes, G. K.; Lions, F.; Baldick, K. J.; Cornforth,
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1-(4-Methoxybenzyl)-2-methyl-5-phenyl-1H-pyrrole
(2p)ꢀYel-
low solid. Rfꢁ=ꢀ0.68 (PE:EAꢁ=ꢀ10:1). m.p. 91–92°C. FT-IR (KBr) υ (cm-1):
2930, 1550, 1510, 1444, 1403, 1240, 1170, 1033, 820. lH NMR (500 MHz,
CDC13): δꢁ=ꢀ2.28 (s, 3H), 3.87 (s, 3H), 5.20 (s, 2H), 6.18 (d, Jꢁ=ꢀ3.0 Hz, Heugebaert, T. S. A.; Roman, B. I.; Stevens, C. V. Synthesis of
1H), 6.37 (d, Jꢁ=ꢀ3.3 Hz, 1H), 6.97 (dd, Jꢁ=ꢀ5.2, 8.9 Hz, 4H), 7.27–7.36
isoindoles and related iso-condensed heteroaromatic pyrroles.
Chem. Soc. Rev. 2012, 41, 5626–5640.
(m, 1H), 7.40–7.46 (m, 4H). l3C NMR (125 MHz, CDC13): δꢁ=ꢀ12.5, 47.0,
55.1, 107.2, 107.9, 114.0, 126.5, 126.7, 128.3, 128.5, 130.3, 130.9, 133.8, Hoffmann, H.; Lindel, T. Synthesis of the pyrrole-imidazole alka-
134.5, 158.1. EI-MS: 277.1 (8), 156.2 (2), 121.2 (100), 91.4 (11), 77.3 (13);
loids. Synthesis 2003, 12, 1753–1783.
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