A mild and facile one-pot synthesis of N-methyl-3-acyl- pyrroles

Article abstract of DOI:10.3390/molecules15052972

N-Methyl-3-acylpyrroles were synthesized via a multicomponent reaction of dimethylacetylene dicarboxylate (DMAD), N-methylhydroxylamine and acylchlorides in the presence of KHCO₃. For comparison both conventional and microwave protocols were examined in this procedure. The reaction is clean and gives the products in good to excellent yields under conventional heating conditions at 40 °C in anhydrous dichloromethane.

Full text of DOI:10.3390/molecules15052972

Molecules 2010, 15, 2972-2979; doi:10.3390/molecules15052972
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Mild and Facile One-Pot Synthesis of N-Methyl-3-Acyl-
Pyrroles
Hassan Valizadeh * and Ashraf Fakhari
Department of Chemistry, Faculty of Sciences, Azarbaijan University of Tarbiat Moallem, Tabriz, Iran
* Author to whom correspondence should be addressed; E-mail: h-valizadeh@azaruniv.edu;
Fax: +98-412-432-7541.
Received: 28 February 2010; in revised form: 23 March 2010 / Accepted: 18 April 2010 /
Published: 27 April 2010
Abstract: N-Methyl-3-acylpyrroles were synthesized via a multicomponent reaction of
dimethylacetylene dicarboxylate (DMAD), N-methylhydroxylamine and acylchlorides in
the presence of KHCO3. For comparison both conventional and microwave protocols were
examined in this procedure. The reaction is clean and gives the products in good to
excellent yields under conventional heating conditions at 40 ºC in anhydrous
dichloromethane.
Keywords: 3-acylpyrrole; multicomponent reaction; dimethylacetylene dicarboxylate
1. Introduction
Pyrrole is one of the most important heterocyclic compounds, having become increasingly
important in medicinal chemistry and organic synthesis [1-5]. Some of the recently isolated pyrrole-
containing marine natural products have been found to exhibit considerable cytotoxicity and function
as multi drug resistant (MDR) reversal agents. Many of these biologically active compounds have
emerged as chemotherapeutic agents [6]. Heterocyclic compounds containing a 3-acylpyrrole fragment
are of interest for making new pharmacological preparations. For example, the cannabinoid activity of
1-alkyl-3-(naphthoyl)pyrroles [7] and 1-alkyl-3-(naphthoyl)indoles [8] is known, as is the antibiotic
activity of verrucarin E (3-acetyl-4-hydroxymethylpyrrole) isolated from Myrothecium verrucaria [9].
3-Acylpyrroles and other 3-substituted pyrroles obtained from them are precursors of liquid crystal
materials [10] and polypyrroles [11], possessing high electrical conductivity in comparison with their

Molecules 2010, 15
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1-substituted analogs [12]. Such conjugated polymers may be used, for example, to construct gas
sensors [13], and also sensors capable of distinguishing DNA molecules [14]. Many methods for the
synthesis of diversely substituted pyrroles have been developed [15]. Conjugate addition reactions
[16], transition metal-mediated reactions [17], reductive couplings [18], aza-Wittig reactions [19], and
other multistep operations [20] have all been performed for the synthesis of pyrroles. Despite these
huge developments, the Paal-Knorr [21] reaction is still considered to be the most attractive method for
the synthesis of pyrroles. In the present work, we describe a simple method for the KHCO3-catalyzed
synthesis of 3-acylpyrroles in good yields starting from commercially available DMAD, N-
methylhydroxylamine and various acylchlorides.
2. Results and Discussion
Our research group has reported several studies directed toward the synthesis of some heterocyclic
compounds under solvent-free conditions [22-27]. Because of the biological activities of pyrrole
derivatives, we became interested in the one-pot synthesis of N-methyl-3-acylpyrroles under mild and
solvent-free conditions.
Electrophilic substitution in pyrrole occurs predominantly at the C2-position [28-30]. Thus, the
investigation of efficient methods for preparing C3-substituted pyrroles is one of the important goals in
pyrrole chemistry because of their frequent use for obtaining various biologically active compounds
like porphyrins. For the substitution on β-(C3) position, Friedel-Crafts acylation or alkylation on
pyrrole bearing an electron withdrawing substituent at C2 [31-32] or N1 [33-34] has been widely
investigated. Direct Friedel-Crafts acylation on 2,5-dimethylpyrrole also gives 3,4-symmetric acyl
compounds, but normally the yields are very low ( < 5%) when no electron withdrawing groups are on
the substituted pyrroles [18]. Very recently we prepared pentasubstituted pyrroles via the reaction of
DMAD with N-methylhydroxylamine under mild solvent-free conditions, so we studied the possibility
of synthesizing N-methyl-3-acylpyrroles 4a-e using a multicomponent reaction in anhydrous
dichloromethane of DMAD (1), N-methylhydroxylamine (2) and various acylchlorides 3a-e in the
presence of KHCO3 (Scheme 1).
Scheme 1. One-pot synthesis of N-methyl-3-acylpyrroles.
O
R
CO2Me
O
KHCO3 , CH2Cl2
MeNHOH, HCl
+
+
40oC
R
Cl
N
CO2Me
Me
4a: R= Ph
4b: R= Me
3a: R= Ph
3b: R= Me
4c: R= 4-Cl-Ph
4d: R= 2-MeO-Ph
4e: R= 4-NO2-Ph
3c: R= 4-Cl-Ph
3d: R= 2-MeO-Ph
3e: R= 4-NO2-Ph
1
2
We tried several different reaction conditions under microwave irradiation and conventional
heating, and found that the reaction took place efficiently and in good yield at 40 ºC in CH2Cl2. Firstly,
benzoyl chloride (3a) was chosen as a model for the reaction with DMAD and N-

Molecules 2010, 15
2974
methylhydroxylamine to optimize reaction conditions. It was observed that a low yield of 4a was
obtained in the absence of KHCO3 when the reaction was stirred at room temperature for 10 h. The
reaction in the presence of the KHCO3 at room temperature in CH2Cl2, afforded the corresponding
product in 61% yield (Table 1, entry 1). The reaction was also examined at 40 ºC and found to be
faster and to give higher yield (81%) than at room temperature (Table 1, entry 2). The procedure was
examined under microwave-assisted conditions and found that the yield of product was very low in
comparison with conventional heating in anhydrous CH2Cl2 (Table 1, entries 7-8). In another
experiment, for the same reaction, several common solvents were examined in the presence of KHCO3
at 40 ºC. The results showed that the reaction in CH2Cl2 resulted in higher yields in comparison with
the other tested solvents (Table 1, entries 2-5). There is no significant difference in the results using
different bases such as Na2CO3, K2CO3, KHCO3, NH4OAc, NaOH, and NH4Cl as the catalyst in this
procedure. The reaction of enamine, derived from addition of an N-methylhydroxylamine to DMAD,
and benzoylchloride proceeds by a smooth 1:1:1 addition reaction in anhydrous dichloromethane at
40ºC to produce N-mehyl-3-benzoylpyrrole (4a) in 81% yield.
Table 1. Study of the synthesis of 3-benzoylpyrrole 4a under different conditions.
Entry Solvent/Solid support
Mode of heating Temperature (ºC)
Time (h)
Yielda(%)
61
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CHCl3
Dioxane
THF
Conventional
25
3
2.5
Conventional
Conventional
Conventional
Conventional
Conventional
MW
40
81
40
3
63
40
40
2.5
60
2.5
63
Neat
40
3
53
Neat
Not detected
Not detected
10 min
10 min
<30
<30
Basic alumina
MW
a Isolated yields after column chromatography.
Having established the reaction conditions, various acyl chlorides were examined in this procedure
to investigate the reaction scope, and several representative examples are summarized in Table 2. The
reaction was clean and proceeded smoothly to give the corresponding 3-acylpyrroles in good to
excellent yields. There were no remarkable differences in yields and reaction times between aromatic
and aliphatic acyl halides in this procedure.
Table 2. One-pot synthesis of 3-acylpyrroles.
Time (h)
Entry
Product
4a
Yielda(%)
1
2
3
4
5
2.5
3
81
83
73
78
76
4b
3
4c
3.5
2.5
4d
4e
a Isolated yields after column chromatography.

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1
The structures of compounds 4a–4e were deduced from their elemental analyses and their IR, H-
13
1
NMR, and C-NMR spectroscopic data and no side products were identified. For example, the H-
NMR spectrum of 4a exhibited one singlet identified as the N-methyl moiety (δ 3.50), phenyl proton
multiplets (δ 7.30, 3H and δ 7.41, 2H), along with multiplets [δ 7.51, 1H, δ 7.60, 1H and δ 7.81, 1H),
for the pyrrole protons. The H-decoupled 13C-NMR spectrum of 4a showed 10 distinct resonances
1
that confirm the proposed structure. The IR spectrum of 4a displayed a characteristic carbonyl
(1,732 cm-1) stretching vibration.
Although the mechanistic details of the reaction are not known, a plausible rationalization may be
advanced to explain the product formation. Presumably, the enamine 5 formed from N-methyl-
hydroxylamine and DMAD attacked to acyl chloride to furnish intermediate 6, which is converted to
intermediate 7. Subsequent reaction of 7 with DMAD yields intermediate 8, which undergoes an
intramolecular cyclization reaction to generate 9. Finally, products 4a-e were formed from
intermediate 9.
Scheme 2. Plausible mechanism for the formation of the products 4a-e.
O
OH
-
Cl
+
..
HO
Me
R
Me
N
R
Cl
N
O
H
MeO2C
CO2Me
CO2Me
O
CO2Me
OMe
6
5
-HCl
-
HO
OH R
CO2Me
+
..
MeO2C
CO2Me
N
Me
N
O
R
Me
O
O
CO2Me
MeO2C
CO2Me
OMe
8
7
-OH-
R
MeO2C
O
CO2Me
O
+
Me
N
N
R
CO2Me
MeO2C
Me
9
4a-e
3. Experimental
3.1 General
1
13
All reagents were purchased from Merck and used without further purification. H- and C-NMR
spectra were recorded on a Bruker Avance AC-400 MHz instrument using CDCl3 as the deuterated
solvent and TMS as internal standard. Elemental analyses were carried out on a Perkin-Elmer 240C

Molecules 2010, 15
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elemental analyzer and are reported in percent atomic abundance. All melting points are uncorrected
and measured in open glass-capillaries using Stuart melting point apparatus. Microwave experiments
were conducted in a Milestone MicroSYNTH apparatus.
3.2. General procedure for preparation of 3-acylpyrroles 4a-e
Dimethylacethylene dicarboxylate (2 mmol) was added to a stirred solution of N-
methyhydroylamine hydrochloride (2 mmol) and KHCO3 (3 mmol) in anhydrous CH2Cl2 (10 mL). The
mixture was stirred for 15 min, and then a solution of an acyl chloride (2 mmol) and
dimethylacethylene dicarboxylate (2 mmol) in CH2Cl2 (5 mL) was added slowly at 40 ºC. After
completion of the reaction (2.5–3.5 h) as indicated by TLC on silica gel F254 (n-hexane/EtOAc 6:1),
the solvent from the reaction mixture was evaporated under reduced pressure to leave a residue that
was purified by column chromatography (n-hexane/EtOAc 6:1) to afford pure desired products 4a-e.
N-Methyl-3-benzoyl pyrrole (4a): IR (KBr) (νmax, cm-1): 1732 (C=O); 1H-NMR δH (ppm): 7.81 (m, 1H),
7.60 (m, 1H), 7.51 (m, 1H), 7.41 (m, Ph-H, 2H), 7.30 (m, Ph-H, 3H), 3.50 (s, 3H, N-Me); 13C-NMR δC
(ppm): 163.32, 133.14, 132.24, 129.92, 128.77, 127.62, 127.10, 126.84, 125.75, 36.24; Anal. Calcd
(%) for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found (%): C, 77.90; H, 5.91; N, 7.48.
1
N-Methyl-3-acetyl pyrrole (4b): IR (KBr) (νmax, cm-1): 1727 (C=O); H-NMR δH (ppm): 7.75 (m, 1H),
7.48-7.55 (m, 2H), 3.53 (s, 3H, N-Me), 2.09 (s, 3H, COMe); 13C-NMR δC (ppm): 160.22, 131.33,
129.12, 126.12, 124.78, 33.45, 27.50; Anal. Calcd (%) for C7H9NO: C, 68.27; H, 7.37; N, 11.37.
Found (%): C, 69.05; H, 7.29; N, 11.31.
1
N-Methyl-3-(4-chlorobenzoyl)-pyrrole (4c): IR (KBr) (νmax, cm-1): 1720 (C=O); H-NMR δH (ppm):
7.77 (m, 1H), 7.51-7.58 (m, 2H), 7.38 (d, J=7.56Hz, 2H), 7.31 (d, J=7.56Hz, 2H), 3.47 (s, 3H, N-Me);
13C-NMR δC (ppm): 164.56, 135.66, 134.32, 131.11, 129.32, 128.09, 127.99, 126.25, 126.15, 33.36;
Anal. Calcd (%) for C12H10ClNO: C, 65.61; H, 4.59; N, 6.38. Found (%): C, 65.65; H, 4.53; N, 6.34.
1
N-Methyl-3-(2-methoxybenzoyl)-pyrrole (4d): IR (KBr) (νmax, cm-1): 1721 (C=O); H-NMR δH (ppm):
7.83 (m, 1H), 7.49-7.54 (m, 2H), 7.31-7.38 (m, Ph-H, 4H), 3.87 (s, 3H, OMe), 3.50 (s, 3H, N-Me);
13C-NMR δC (ppm): 162.21, 137.62, 136.54, 135.66, 134.10, 133.22, 132.20, 130.34, 129.79, 127.40,
126.15, 67.71, 34.16; Anal. Calcd (%) for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found (%): C,
72.58; H, 5.98; N, 6.48.
N-Methyl-3-(4-nitrobenzoyl)-pyrrole (4e): IR (KBr) (νmax, cm-1): 1717 (C=O); 1H-NMR δH (ppm): 7.70
(m, 1H), 7.66 (d, J=7.87Hz, 2H), 7.45-7.53 (m, 2H), 7.37 (d, J=7.87Hz, 2H), 3.54 (s, 3H, N-Me); 13C-
NMR δC (ppm): 160.06, 133.06, 133.02, 131.21, 129.70, 128.56, 127.65, 127.05, 126.55, 37.09; Anal.
Calcd (%) for C12H10N2O3: C, 62.60; H, 4.38; N, 12.17. Found (%): C, 62.80; H, 4.35; N, 12.08.

Molecules 2010, 15
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4. Conclusions
In summary, we have described a highly efficient one-pot procedure for the preparation of N-
methyl-3-acylpyrroles by a three component reaction in CH2Cl2 using KHCO3 as catalyst. The reaction
products were prepared in moderate to good yield, even with different substituted acyl halides. We
believe that this procedure provides a valuable addition to current methodologies.
Acknowledgements
The partial financial assistance from the Research Vice Chancellor of Azarbaijan University of
Tarbiat Moallem is gratefully acknowledged.
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Sample Availability: Samples of compounds 4a-e are available from the authors.
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