Synthesis of novel 3,4-diaryl-1H-pyrroles

Article abstract of DOI:10.1002/jhet.5570440232

(Chemical Equation Presented) The synthesis of a series of novel 3,4-diaryl-1H-pyrroles and related arylalkenes from p-bromo thiophenol, tosylmethyl isocyanide and commercially available materials is reported. Arylalkenes having electron-withdrawing substituents gave higher yield of 3,4-diaryl-1H-pyrroles.

Full text of DOI:10.1002/jhet.5570440232

Mar-Apr 2007
471
Synthesis of Novel 3,4-Diaryl-1H-Pyrroles
Abbas Shafiee*1, Mohammad Z. Kassaee2, Ahamad R. Bekhradnia3
1Department of Chemistry and Pharmaceutical Science Research Center,
Tehran University of Medical Sciences, Tehran, Iran
2Department of Chemistry, University of Tarbiat Modarres, Pole-Gisha, Tehran, Iran
3Department of Chemistry and Pharmaceutical Science Research Center,
Mazandaran University of Medical Sciences, Sari, Iran
Received April 29, 2006
X
SO2CH3
SH
Br
SO2CH3
N
H
X
X = F, Cl, H, CH3, OCH3
The synthesis of a series of novel 3,4-diaryl-1H-pyrroles and related arylalkenes from p-bromo
thiophenol, tosylmethyl isocyanide and commercially available materials is reported. Arylalkenes having
electron-withdrawing substituents gave higher yield of 3,4-diaryl-1H-pyrroles.
J. Heterocyclic Chem., 44, 471 (2007).
number of these compounds have been shown to possess
antibacterial and fungicidal properties [3].
INTRODUCTION
The pyrrole ring is an important heterocycle in
biological system being incorporated into the porphyrin
ring systems of chlorophyll, heme, Vitamin B12, bile
pigments, and the anti-inflammatory drugs [1]. Hence, the
syntheses of pyrroles are by all means an attractive area in
heterocyclic chemistry, due primarily to the fact that
many pyrroles are subunits of natural products [2]. A
Previously, 4,5-diarylpyrroles having phenyl sulfone
substituent have been known as anti-inflammatory drugs
and COX-2 inhibitors [4]. In continuation of our research
program dealing with the syntheses of 1,2-diaryl five
membered heterocycles [5-8], we were interested in the
synthesis of 3,4-diaryl-1H-pyrroles as a possible effective
Scheme 1
SH
Br
SCH3
SO2CH3
Dimethylsulfate
0°-5°
Oxone
methanol (aq), temp<5°
Br
Br
1
2
SO2CH3
X
Pd(OAc)2, Bu4N+Cl-
2
+
LiOAc, LiCl, DMF, 120°
X
4a : X=F
4b : X=Cl
4c : X=H
4d : X=CH3
4e : X=OCH3
4
3
3a : X=F
3b : X=Cl
3c : X=H
3d : X=CH3
3e : X=OCH3
X
SO2CH3
tosylmethyl isocyanide, NaOt-Bu
DMSO, dry argon
N
H
5a : X=F
5b : X=Cl
5c : X=H
5
5d : X=CH3
5e : X=OCH3

472
A. Shafiee, M. Z. Kassaee and A. R. Bekhradnia
Vol 44
EXPERIMENTAL
anti- inflammatory drug. However, it is noteworthy to
mention that 3,4-disubstituted pyrrole system is probably
the most difficult to be prepared [9], but several
approaches have been recorded [10,11]. As such, a lot of
effort has been spent developing practical methods for the
synthesis of pyrrole units that incorporate appropriate
functionality [12]. However, there are no reports of the
synthesis of 3,4-diaryl-(1H)-pyrroles from sulfonyl
stilbenes [13].
1H NMR and 13C NMR spectra were recorded using a Bruker
DRX500 AVANCE spectrometer at 500.13 MHz (1H), 125.75
MHz (13C). Chemical shifts (δ) are given in ppm relative to
TMS, coupling constants (J) in Hz. The IR spectra were
obtained using a Nicolet FT-IR Magna 550 spectrograph. Mass
spectra were obtained on a Finnigan MAT TSQ 70 spectrometer
at 70 eV. Melting points were measured in open capillary tubes
with an Electrothermal-9200 melting point apparatus and are
uncorrected.
RESULTS AND DISCUSSION
Preparation of trans-Diarylstilbenes 4. General
Procedure. To a solution of suitable styrene (6 mmoles) in
DMF (40 mL) at rt was added methyl-4- bromophenyl
sulfone (7 mmoles), LiCl (0.4 g), LiOAc- 2H2O (1.5 g),
Bu4N+Cl- (3.5 g) and Pd(OAc)2 (50 mg). The mixture was
heated in appropriate temperature for the optimized
reaction time (Table 1) and then cooled to room
temperature. The mixture was quenched with an NH4OAc
solution and extracted with ethyl acetate. The organic phase
was washed with water, saturated NaHCO3 solution, brine
and dried (MgSO4). The solvent was evaporated and the
residue was crystallized from ethanol/water to give the title
compounds 4 (Table 1, Table 2).
The synthesis of new 3,4-disubstituted-1H-pyrroles
having phenyl sulfone substituent is shown in Scheme 1.
In the first step, the related stilbenes as new Michael
acceptors were synthesized. Thus, p-bromothiophenol was
methylated with dimethyl sulfate to produce p-
bromothioanisole 1 at 0-5°C and then oxidized to
corresponding sulfone
persulfate.
2 using potassium hydrogen
Compound 2 was reacted with suitable styrenes (3a-e)
at various temperatures to give related stilbenes (4a-e)
(Table 1) [14].
Preparation of 3,4-Diaryl-1H-pyrroles 5. General
procedure. All experiments were carried out under an
atmosphere of dry argon. A solution of related stilbene 4 (2
mmoles) and tosylmethyl isocyanide (2.6 mmol) in DMSO (20
mL) was added to a suspension of NaOt-Bu (4 mmoles) in dry
DMSO (20 mL) at room temperature via cannula. The mixture
was stirred at the desired temperatures for 6-9 h (Table 1) then
cooled to room temperature and diluted with ethyl acetate (70
mL) and brine (50 mL). The organic layer was dried over
anhydrous sodium sulfate. After filtration and evaporation of the
solvent, the crude product was purified by silica gel column
chromatography with ethyl acetate/hexane (6:4), to give
corresponding 3,4-diaryl-(1H)-Pyrroles in good yields (Table 1,
Table 2).
Thus, p-flourostyrene 3a, p-chlorostyrene 3b, styrene
3c, p-methylstyrene 3d, and p-methoxystyrene 3e gave
corresponding trans-stilbenes (4a-e) after 8-12 h in 81%-
94% yields (Table 1). Reaction of compound 4 with
tosylmethyl isocyanide via cannula in the presence of
NaOt-Bu in DMSO gave the desired 3,4-diaryl-1H-
pyrroles (5a-e) after purification using silica gel column
chromatography.
In general, higher yields of the desired 3,4-diaryl-1H-
pyrroles were obtained at lower temperature and with
shorter reaction times when the aryl group of the related
stilbenes was more electron–withdrawing (Table 1).
In summary, we have demonstrated a convenient
method for the preparation of 3,4-diaryl-1H-pyrroles and
related arylalkenes in high yield starting from p-bromo
thiophenol using tosylmethyl isocyanide.
Acknowledgment. The authors gratefully acknowledge the
financial support of this work by the University of Tarbiat
Modarres, “Professorś projects funds” and Iran chapter of
TWAS.
Table 1
Physical and Analytical Data of Compounds 4 and 5.
Yield
(%)
Calcd.
(%)
Found
(%)
Compounds
X
t°C/time
m.p.°C
Formula
C
H
N
C
H
N
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
F
Cl
H
CH3
OCH3
F
Cl
H
CH3
OCH3
115/12h
110/10h
110/9h
105/8h
105/8h
65/6h
75/7h
85/8h
85/9h
95/9h
81
85
88
91
94
91
86
80
75
71
171-173
179-181
178-179
179-181
181-183
164-165
185-186
174-175
175-177
179-180
C15H13FO2S
C15H13ClO2S
C15H14O2S
C16H16O2S
C16H16O3S
C17H14FNO2S
C17H14ClNO2S
C17H15NO2S
C18H17NO2S
C18H17NO3S
65.20
61.53
69.74
70.56
66.64
64.75
61.53
68.66
69.43
66.03
4.74
4.48
5.46
5.92
5.59
4.47
4.25
5.08
5.50
5.23
-
-
-
-
-
65.35
61.35
69.96
70.39
66.46
64.93
61.35
68.85
69.61
66.21
4.96
4.29
5.68
5.98
5.78
4.65
4.06
5.23
5.73
5.41
-
-
-
-
-
4.44
4.22
4.71
4.50
4.28
4.64
4.43
4.90
4.32
4.49

Mar-Apr 2007
Synthesis of Novel 3,4-Diaryl-1H-Pyrroles
473
Table 2
Spectroscopic Data of compounds 4 and 5
1HNMR (δ, ppm)
13CNMR(δ, ppm)
Compounds
3.12 (s, 3H, CH3); 7.32 (d, 1H, J= 16.4Hz), 7.47 (d, 1H,
J= 16.4Hz) (Olefinic hydrogens); 7.18 (dd, 2H, JHH=
8.5Hz, JHF= 8.6Hz), 7.71 (dd, 2H, JHH= 8.5Hz, JHF=
7.2Hz), 7.83 (d, 2H, J=8.1Hz), 7.93 (d, 2H, J=8.1Hz)
(Aromatic hydrogens)
44.8 (CH3); 128.0, 128.4 (Olefinic
carbons); 118.1, 131.1, 131.8, 132.2,
134.2, 140.3, 142.1, 162 (Aromatic
carbons)
4a
3.07 (s, 3H, CH3); 7.09 (d, 1H, J=16.3Hz), 7.20 (d, 1H,
J=16.3Hz) (Olefinic hydrogens); 7.36 (d, 2H, J=7.9Hz),
7.47 (d, 2H, J=7.9Hz), 7.67 (d, 2H, J=7.9 Hz), 7.92 (d,
2H, J=7.9Hz) (Aromatic hydrogens)
3.06 (s, 3H, CH3); 7.01 (d, 1H, J=16.1Hz), 7.12 (d, 1H,
J=16.1Hz) (Olefinic hydrogens); 7.23-7.40 (m, 5H), 7.66
(d, 2H, J=7.3Hz), 7.90 (d, 2H, J=7.3Hz) (Aromatic
hydrogens)
44.6 (CH3); 127.8, 128..3 (Olefinic
carbons); 130.8, 131.1, 131.6, 134.0,
134.2, 135.1, 140.2, 141.8 (Aromatic
carbons)
44.5 (CH3); 126.5, 128.9 (Olefinic
carbons); 127.1, 127.9, 129.2, 131.5,
133.8, 136.3, 140.0, 142.1 (Aromatic
carbons)
4b
4c
3.08 (s, 3H, CH3), 2.41 (s, 3H, Ar-CH3); 7.14 (d, 1H, 44.6 (SO2-CH3), 21.3 (Ar-CH3); 125.5,
J=16.2Hz), 7.38 (d, 1H, J=16.2Hz) (Olefinic hydrogens); 126.8 (Olefinic carbons); 129.0, 130.1,
4d
4e
5a
7.20 (d, 2H, J=7.2Hz), 7.48 (d, 2H, J=7.2Hz), 7.60 (d,
2H, J=7.7Hz), 7.97 (d, 2H, J=7.7Hz) (Aromatic
hydrogens)
3.07 (s, 3H, CH3), 3.70 (s, 3H, Ar-OCH3); 7.13 (d, 1H, 44.9 (SO2-CH3), 55.2 (Ar-OCH3);
J=16.4Hz), 7.19 (d, 1H, J=16.4Hz) (Olefinic hydrogens); 126.3, 127.5 (Olefinic carbons); 116.8,
7.24 (d, 2H, J=7.1Hz), 7.60 (d, 2H, J=7.1Hz), 7.65 (d,
2H, J=7.9Hz), 7.96 (d, 2H, J=7.9Hz) (Aromatic
hydrogens)
3.30 (s, 3H, CH3); 7.04 (s, 1H), 7.53 (s, 1H)
(Heterocyclic hydrogens); 7.10 (dd, 2H, JHH= 8.4Hz,
JHF= 8.4Hz), 7.22 (d, 2H, J= 7.7Hz), 7.37 (dd, 2H,
JHH= 8.4, JHF= 9.11Hz), 7.42 (d, 2H, J= 7.7Hz)
(Aromatic hydrogenes); 11.2 (bs, 1H, N-H)
3.29 (s, 3H, CH3); 7.02 (s, 1H), 7.51 (s, 1H)
(Heterocyclic hydrogens); 7.12 (d, 2H, J=8.2Hz), 7.23
(d, 2H, J=7.4Hz), 7.40 (d, 2H, J=8.2Hz), 7.55 (d, 2H,
J=7.4Hz) (Aromatic hydrogenes); 11.4 (bs, 1H, N-H)
3.29 (s, 3H, CH3); 6.92 (s, 1H), 7.42 (s, 1H)
(Heterocyclic hydrogens); 6.40- 6.71 (m, 5H), 7.27 (d,
2H, J=7.3Hz), 7.44 (d, 2H, J=7.3Hz) (Aromatic
hydrogenes); 10.6 (bs, 1H, N-H)
131.7, 134.1, 134.2, 137.8, 140.4,
142.5 (Aromatic carbons)
129.9, 130.2, 131.8, 134.2, 159.8,
140.4, 142.6 (Aromatic carbon)
44.9 (CH3); 87.7, 114.8, 117.0
(Heterocyclic carbons); 111.1, 126.9,
128.2, 131.1, 135.1, 137.8, 137.9,
161.5 (Aromatic carbons)
44.9 (CH3); 84.8, 115.1, 117.1
(Heterocyclic carbons); 126.8, 127.1,
131.0, 131.3, 132.1, 133.2, 137.8,
137.9 (Aromatic carbons)
44.9 (CH3); 83.3, 117.0, 118.0
(Heterocyclic carbons); 124.8, 126.3,
125.9, 128.5, 130.2, 133.9, 136.7,
138.1 (Aromatic carbons)
5b
5c
3.29 (s, 3H, SO2-CH3); 2.54 (s, 3H, Ar-CH3); 6.94 (s,
1H), 7.48 (s, 1H) (Heterocyclic hydrogens); 6.85 (d, 2H,
J=7.8Hz), 7.29 (d, 2H, J=7.5Hz), 7.44 (d, 2H, J=7.8Hz),
7.50 (d, 2H, J=7.5Hz) (Aromatic hydrogenes); 10.9 (bs,
1H, N-H)
3.30 (s, 3H, SO2-CH3); 3.77 (s, 3H, Ar-OCH3); 6.99 (s,
1H), 7.50 (s, 1H) (Heterocyclic hydrogens); 6.05 (d, 2H,
J=8.3Hz), 6.90 (d, 2H, J= 8.3Hz), 7.24 (d, 2H, J=7.6Hz),
7.43 (d, 2H, J=7.6Hz) (Aromatic hydrogenes); 11.1 (bs,
1H, N-H)
44.9 (SO2-CH3); 22.1 (Ar-CH3); 84.2,
117.0, 117.2 (Heterocyclic carbons);
126.7, 128.4, 130.9, 131.3, 131.5,
137.6, 138.6, 140.1 (Aromatic
carbons)
44.9 (SO2-CH3); 56.2 (Ar-OCH3);
84.3, 117.2, 119.3 (Heterocyclic
carbons); 114.2, 126.7, 126.8, 130.2,
131.1, 137.7, 138.9, 157.1 (Aromatic
carbons)
5d
5e
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