Synthesis of new N-alkyl(aryl)-2,4-diaryl-1H-pyrrol-3-ols via aldol Paal-Knorr reactions

Article abstract of DOI:10.1007/s10593-011-0669-4

New N-alkyl(aryl)-2,4-diaryl-1H-pyrrol-3-ol derivatives have been synthesized in moderate to good yields in a novel and efficient process by aldol reaction of 1-(4-methoxyphenyl)propan-2-ones with phenylglyoxal in the presence of DABCO in water, followed

Full text of DOI:10.1007/s10593-011-0669-4

Chemistry of Heterocyclic Compounds, Vol. 46, No. 11, February, 2011 (Russian Original Vol. 46, No. 11, November, 2010)
SYNTHESIS OF NEW N-ALKYL(ARYL)-2,4-DIARYL-
1H-PYRROL-3-OLS VIA ALDOL PAALKNORR REACTIONS
B. Eftekhari-Sis1*, A. Akbari1, M. Amirabedi2
New N-alkyl(aryl)-2,4-diaryl-1H-pyrrol-3-ol derivatives have been synthesized in moderate to good
yields in a novel and efficient process by aldol reaction of 1-(4-methoxyphenyl)propan-2-ones with
phenylglyoxal in the presence of DABCO in water, followed by PaalKnorr reaction with amines in the
presence of a catalytic amount of p-TSA in toluene at reflux.
Keywords: 1,4-diazabicyclo[2.2.2]octane, phenylglyoxal, pyrrole derivatives, aldol reaction, PaalKnorr
reaction.
Pyrroles are important heterocycles widely used in material science (for recent work, see [1]) and found
in naturally occurring and biologically important molecules [2-8]. Pyrroles can be found in a large range of
natural products [9] and bioactive molecules [10-14], including the blockbuster drug Atorvastatin calcium [10],
as well as important anti-inflammatory agents [11], antitumor agents [12], and immunosuppressants [13].
Accordingly, substantial attention has been paid to develop efficient methods for the synthesis of pyrroles [1-8,
15-17].
One of the most common approaches to pyrrole synthesis is the PaalKnorr reaction in which
1,4-dicarbonyl compounds are converted to pyrroles via acid-mediated dehydrative cyclization in the presence
of a primary amine [18-30]. In this reaction, the 1,4-dicarbonyl compound provides the four carbons of the
pyrrole with their substituents, whereas the amine provides the nitrogen with its substituent. The main
limitations to intensive use of this reaction are the harsh reaction conditions required for cyclization (use of
boiling acetic acid for extended times) and the low availability of nonsymmetrically substituted 1,4-dicarbonyl
compounds. The classical approach to this class of products is the condensation of enolates with phenacyl
bromides [31], thus limiting the method to pyrroles with aryl substituents. Alternative approaches need several
reaction steps with chromatographic separations to obtain the intermediates for cyclization. Therefore, mild
reaction conditions that can overcome some of the shortcomings of the previous methods are necessary.
In this paper, we describe a simple method for synthesis of new N-alkyl(aryl)-2,4-diaryl-1H-pyrrol-3-ol
derivatives via aldol reaction of 1-(4-methoxyphenyl)propan-2-one with phenylglyoxal in the presence of a
catalytic amount of 1,4-diazabicyclo[2.2.2]octane (DABCO) in water at room temperature, followed by
_______
*To whom correspondence should be addressed, e-mail: eftekhari.sis@gmail.com.
1Department of Chemistry, Faculty of Science, University of Maragheh, Maragheh, Iran
2Faculty of Mechanics, Islamic Azad University of Ajabshir, Ajabshir, Iran.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1644-1648, November, 2010.
Original article received March 31, 2010.
1330
0009-3122/11/4611-1330©2011 Springer Science+Business Media, Inc.

PaalKnorr cyclization with primary amines in the presence of p-TSA in toluene at reflux condition. To the best of
our knowledge, there are few reports in the literature [32] for the formation of pyrrol-3-ol derivatives via
condensation of ketones with arylglyoxals.
Phenylglyoxal monohydrate (2) was prepared from commercially available acetophenone (1) using
selenium dioxide [33].
O
O
SeO2
H .
H2O
Ph
Ph
Me
dioxane/H2O,
reflux
OH
HO
2
1
2-Hydroxy-3-(4-methoxyphenyl)-1-phenylpentane-1,4-dione (4) was synthesized in 89% yield via aldol
reaction of 1-(4-methoxyphenyl)propan-2-one (3) with phenylglyoxal monohydrate (2) in the presence of a
catalytic amount of DABCO in water at room temperature. The structure of compound 4 was established by
elemental analysis and IR, 1H, and 13C NMR spectra.
MeO
MeO
MeO
Me
Me
Me
DABCO
water, r. t.
–
O
O
O
–
3
MeO
MeO
MeO
Me
Ph
Me
Me
R
N
H
RNH2
–H2O
2
O
O
N
R
–H2O
O
HO
HO
HO
Ph
Ph
4
5a–e
5, 6 a R = Pr, b R = Bn, c R = Ph, d R = 4-MeOC6H4, e R = 4-ClC6H4
The reactions were performed by adding primary amines to the solution of the 1,4-dicarbonyl compound
4 in toluene in the presence of a catalytic amount of p-TSA at reflux. Arylamines as well as alkyl-amines
worked well in the PaalKnorr reaction with 1,4-dicarbonyl compound 4. The structure of pyrroles 5a-e was
established by elemental analysis and IR, 1H, and 13C NMR spectra.
The proposed mechanism involves the attack of the in situ generated enolate on the phenylglyoxal. The
obtained 1,4-dicarbonyl compound 4 in the presence of primary amine is converted to enamine, which attacks
the second carbonyl group, and the loss of H2O molecule affords the pyrrol-3-ol derivatives 5a-e.
New fully substituted pyrrol-3-ol derivatives were synthesized in moderate to good yields via aldol
reactions of 1-(4-methoxyphenyl)propan-2-ones with phenylglyoxal in the presence of DABCO in water,
followed by PaalKnorr reaction with amines in the presence of a catalytic amount of p-TSA in toluene at
reflux. Synthesis of the pyrrole ring with hydroxyl substituent is one of the most noticeable characteristics of
this work.
EXPERIMENTAL
All chemicals were purchased and used without any further purification. Melting points were determined
on an Electrothermal MEL-TEMP apparatus (model 1202D) and are uncorrected. FT-IR spectra
1331

1
were obtained with a Bruker Tensor 27 spectrometer. H and 13C NMR spectra were recorded with a Bruker
spectrometer operating at 500 and 125 MHz, respectively, in CDCl3 (compound 4) and DMSO-d6 (compounds 5a-e),
relative to TMS as the internal standard. Elemental analyses were done by a Vario EL III Elementar instrument.
2-Hydroxy-3-(4-methoxyphenyl)-1-phenylpentane-1,4-dione (4). To the stirred solution of phenyl-
glyoxal monohydrate 2 (0.76 g, 0.5 mmol) in water, 1-(4-methoxyphenyl)propan-2-one 3 (0.82 g, 0.5 mmol) and
DABCO (0.15 g) were added at room temperature. After 0.5 h, the reaction mixture solidified. The obtained
solid was filtered off and crystallized from ethanol, and compound 4 was obtained as a colorless crystalline
solid, yield 89%; mp 95-95.3°C. FT-IR spectrum, , cm1: 3316 (O–H), 2891-3068 (C–H), 1712 (C=O), 1674
(C=O), 1645 (C=C), 1051 (C–O). 1H NMR spectrum, , ppm (J, Hz): 7.90 (2H, dd, J = 7.9, J=8.4, H Ar); 7.66
(1H, m, H Ar); 7.53 (2H, t, J = 7.9, H Ar); 7.01 (2H, d, J = 9.5, H Ar); 6.86 (2H, d, J = 9.6, H Ar); 5.85 (1H, d,
J = 4.0, CH); 4.03 (1H, d, J = 4.1, CH); 3.82 (3H, s, OCH3); 3.26 (1H, br. s, OH, exchange with D2O); 2.14 (3H,
s, CH3). 13C NMR spectrum, , ppm: 206.8 (C=O), 200.4 (C=O), 159.9, 134.8, 134.2, 131.5, 129.3, 129.0,
125.4, 114.6, 73.3, 62.1, 55.6, 29.5. Found, %: C 72.51; H 6.10. C18H18O4. Calculated, %: C 72.47; H 6.08.
Pyrrole Derivatives 5a-e (General Method). To the solution of ompound 4 (0.12 g, 0.4 mmol) in
toluene, primary amine (1.5 mmol) and p-TSA (0.15 g) were added. The reaction mixture was heated at reflux
conditions overnight. After completion of the reaction (monitored by TLC), upon cooling to room temperature,
the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, and
concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel using
hexane–ethyl acetate mixture as eluent.
4-(4-Methoxyphenyl)-5-methyl-2-phenyl-1-propyl-1H-pyrrol-3-ol (5a). Yield 82%. White solid, mp
233°C (decomp.). FT-IR spectrum, , cm1: 3209 (O–H), 2883-3060 (C–H), 1659 (C=C), 1038 (C–O). 1H NMR
spectrum, , ppm (J, Hz): 7.32-7.38 (4H, m, H Ar); 7.23 (1H, t, J = 7.1, H Ar); 6.87 (2H, d, J = 8.4, H Ar); 6.61
(2H, d, J = 8.3, H Ar); 6.46 (1H, s, OH); 3.93 (2H, t, J = 7.3, CH2); 3.81 (3H, s, OCH3); 2.51 (3H, s, CH3);
1.301.27 (2H, m, CH2); 0.51 (3H, t, J = 7.4, CH3). 13C NMR spectrum, , ppm: 161.3, 136.6, 134.5, 130.0,
129.9, 127.5, 127.4, 127.1, 124.8, 116.4, 98.8, 55.8, 51.2, 23.9, 18.1, 12.0. Found, %: C 78.34; H 7.14; N 4.51.
C21H23NO2. Calculated, %: C 78.47; H 7.21; N 4.36.
1-Benzyl-4-(4-methoxyphenyl)-5-methyl-2-phenyl-1H-pyrrol-3-ol (5b). Yield 76%. White solid, mp
262°C (decomp.). FT-IR spectrum, , cm1: 3211 (O–H), 28913064 (C–H), 1660 (C=C), 1042 (C–O). 1H NMR
spectrum, δ, ppm (J, Hz): 7.51 (2H, d, J = 6.1, H Ar); 7.41-7.33 (3H, m, H Ar); 7.27 (2H, d, J = 8.6, H Ar); 7.22
(2H, t, J = 7.0, H Ar); 7.18 (1H, t, J = 7.1, H Ar); 6.83 (2H, d, J = 7.4, H Ar); 6.65 (2H, d, J = 8.4, H Ar); 6.42 (1H,
s, OH); 5.47 (2H, s, CH2); 3.76 (3H, s, OCH3); 2.49 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 161.3, 136.7,
135.4, 134.7, 132.4, 132.2, 130.2, 129.6, 128.7, 127.7, 126.7, 124.9, 115.3, 99.0, 56.0, 48.7, 18.3. Found, %:
C 81.20; H 6.38; N 3.91. C25H23NO2. Calculated, %: C 81.27; H 6.27; N 3.79.
4-(4-Methoxyphenyl)-5-methyl-1,2-diphenyl-1H-pyrrol-3-ol (5c). Yield 71%. White solid, mp 203°C
1
(decomp.). FT-IR spectrum, , cm1: 3218 (O–H), 2880-3051 (C–H), 1648 (C=C), 1032 (C–O). H NMR
spectrum, δ, ppm (J, Hz): 7.41-7.30 (5H, m, H Ar); 7.04 (2H, t, J = 7.3, H Ar); 6.84 (2H, d, J = 7.1, H Ar); 6.65
(2H, d, J = 8.0, H Ar); 6.63 (1H, t, J = 7.3, H Ar); 6.50 (2H, d, J = 7.7, H Ar); 6.31 (1H, s, OH); 3.73 (3H, s,
OCH3); 2.51 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 161.3, 136.6, 134.6, 134.5, 130.0, 129.9, 127.6, 127.5,
127.1, 124.8, 122.0, 120.0, 116.4, 100.6, 54.9, 19.7. Found, %: C 81.11; H 6.04; N 3.88. C24H21NO2. Calculated,
%: C 81.10; H 5.96; N 3.94.
1,4-Bis(4-methoxyphenyl)-5-methyl-2-phenyl-1H-pyrrol-3-ol (5d). Yield 63%. White solid, mp
283°C (decomp.). FT-IR spectrum, , cm1: 3206 (O–H), 2887-3054 (C–H), 1653 (C=C), 1019 (C–O). 1H NMR
spectrum, δ, ppm (J, Hz): 7.36 (2H, d, J = 7.1, H Ar); 7.32 (2H, t, J = 7.4, H Ar); 7.23 (1H, t, J = 7.2, H Ar); 6.76
(2H, d, J = 8.9, H Ar); 6.63 (2H, d, J = 7.4, H Ar); 6.58 (2H, d, J = 7.8, H Ar); 6.46 (2H, d, J = 8.9, H Ar); 6.23
(1H, s, OH); 3.82 (3H, s, OCH3); 3.70 (3H, s, OCH3); 2.48 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 160.6,
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157.4, 143.3, 133.1, 132.6, 129.9, 129.7, 129.2, 128.7, 127.5, 127.1, 123.4, 114.9, 114.8, 100.8, 55.8, 55.7, 20.7.
Found, %: C 78.02; H 5.98; N 3.56. C25H23NO3. Calculated, %: C 77.90; H 6.01; N 3.63.
1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-5-methyl-2-phenyl-1H-pyrrol-3-ol (5e). Yield 61%. White
solid, mp 278°C (decomp.). FT-IR spectrum, , cm1: 3211 (O–H), 2879-3049 (C–H), 1660 (C=C), 1023 (C–O). 1H
NMR spectrum, δ, ppm (J, Hz): 7.39-7.26 (5H, m, H Ar); 7.04 (2H, d, J = 8.3, H Ar); 6.83 (2H, d, J = 8.4,
H Ar); 6.62 (2H, d, J = 8.6, H Ar); 6.50 (1H, d, J = 8.2, H Ar); 6.29 (1H, s, OH); 3.80 (3H, s, OCH3); 2.45 (3H,
s, CH3). 13C NMR spectrum, δ, ppm: 160.5, 150.0, 133.1, 132.5, 131.1, 129.7, 129.4, 129.2, 128.7, 127.5, 127.1,
123.4, 120.7, 114.8, 100.8, 55.6, 20.9. Found, %: C 74.06; H 5.14; N 3.49. C24H20ClNO2. Calculated, %:
C 73.94; H 5.17; N 3.59.
We thank Research Affairs of University of Maragheh for financial support.
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