The pyrrole moiety as a template for COX-1/COX-2 inhibitors

Article abstract of DOI:10.1016/S0223-5234(00)00150-1

Aroyl- and thiophene-substituted pyrrole derivatives have been synthesized as a new class of COX-1/COX-2 inhibitors. The inhibition of COX-1 was evaluated in a biological system using bovine PMNLs as the enzyme source, whereas LPS-stimulated human monocytes served as the enzyme source for inducible COX-2. The determination of the concentration of arachidonic acid metabolites was performed by HPLC for COX-1 and RIA for COX-2. Variation of the substitution pattern led to a series of active compounds which showed inhibition for COX-1 and COX-2. Structural requirements for the development of COX-1/COX-2 inhibitors are discussed. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

Full text of DOI:10.1016/S0223-5234(00)00150-1

Eur. J. Med. Chem. 35 (2000) 499−510
© 2000 Éditions scientifiques et médicales Elsevier SAS. All rights reserved
S0223523400001501/FLA
499
Original article
The pyrrole moiety as a template for COX-1/COX-2 inhibitors
Gerd Dannhardta*, Werner Kiefera, Godehard Krämera,b, Sabine Maehrleina, Ulrike Nowea,
Bernd Fiebichc
aJohannes Gutenberg-University of Mainz, Institute of Pharmacy, Staudingerweg 5, D-55099 Mainz, Germany
bHoffmann-La Roche AG, Dept. Pharmaceutical Technology, Emil-Barell-Str.1, D-79630 Grenzach-Wyhlen, Germany
cHospital of the Albert Ludwigs-University of Freiburg, Department of Psychiatry and Psychotherapy, Hauptstr. 5, D-79104
Freiburg, Germany
Received 13 September 1999; revised 3 December 1999; accepted 9 December 1999
Abstract – Aroyl- and thiophene-substituted pyrrole derivatives have been synthesized as a new class of COX-1/COX-2 inhibitors. The
inhibition of COX-1 was evaluated in a biological system using bovine PMNLs as the enzyme source, whereas LPS-stimulated human
monocytes served as the enzyme source for inducible COX-2. The determination of the concentration of arachidonic acid metabolites was
performed by HPLC for COX-1 and RIA for COX-2. Variation of the substitution pattern led to a series of active compounds which showed
inhibition for COX-1 and COX-2. Structural requirements for the development of COX-1/COX-2 inhibitors are discussed. © 2000 Éditions
scientifiques et médicales Elsevier SAS
COX-1/COX-2 inhibition / pyrrole derivatives / enzyme selectivity / structure–activity relationship
1. Introduction
inhibitors of COX-2 would have the advantage of target-
ing the enzyme involved in the inflammatory processes
and bypassing the constitutively expressed COX-1, i.e.
eliminating unwanted side effects such as stomach ulcer-
ation while providing anti-inflammatory COX-2 inhibi-
tion.
NSAIDs are of huge therapeutic benefit in the treat-
ment of inflammatory diseases. The most common side
effects associated with all currently available NSAIDs are
gastrointestinal haemorrhagia and ulceration [1]. These
side effects during anti-inflammatory therapy are caused
by interference with the physiological properties of pros-
taglandins.
The enzyme cyclooxygenase catalyses the addition of
molecular oxygen to arachidonic acid to form the un-
stable PGG2 which is then converted to the more stable
PGH2 by a peroxidase function. Two isoenzymes exist,
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-
2), which differ in their regulation and tissue distribution.
COX-1 is constitutively expressed in cells and prob-
ably plays a role as a ‘housekeeping enzyme’, for
example in maintaining the lining of the stomach and in
endothelial cells contributing to the normal function of
the cardiovascular system via the release of prostacyclin
(PGI2). In contrast, COX-2 is a regulated enzyme that is
induced by specific stimuli and is thought to be involved
in inflammation and mitogenesis responses. Specific
Recently, it has been shown that COX-2 is constitu-
tively expressed in the spinal cord [2], in the brain [3], in
the kidney [4], in stomach mucosa [5] and in the
pancreatic islet [6]. Although COX-2 inhibitors have
anti-inflammatory properties, their greatest effects, ac-
cording to recent clinical trial data, appear to be associ-
ated with pain relief and symptoms of osteoarthritis [7].
In human vessels COX-2 can produce beneficial media-
tors and possesses the same beneficial effects as COX-1,
i.e. highly selective (> 1 000-fold) COX-2 inhibitors
could have severe side effects, particularly in the cardio-
vascular system [8]. Therefore, it may be postulated that
moderately selective COX-2 inhibitors may well repre-
sent a safer alternative in patients with underlying car-
diovascular disease. There was no effect of celecoxib on
platelet aggregation at all doses used. However, an
inhibition of the urinary marker of systemic prostacyclin
suggests that while platelet function is not inhibited,
* Correspondence and reprints: dannhrdt@mail.uni-mainz.de

500
endothelial PG production may be reduced [9]. This may
have implications for high risk cardiovascular patients,
but there is no clinical experience yet to support this.
There is also evidence that administration of COX-2
preferential and selective drugs produce fewer GIT side
effects. However, once an ulcerative injury is present,
COX-2 expression is elevated in response to this inflam-
mation and the COX-2 enzyme seems to be essential for
wound healing in the stomach by enhancing gastric blood
flow, reducing gastric acid secretion and allowing epithe-
lial cell proliferation and granulation tissue contraction
[10, 11]. In consequence, highly selective COX-2 inhibi-
tors can aggravate the injury and delay wound healing.
COX-2 is believed to make an important contribution
to the increase in prostaglandins observed in pain and
inflammation [12, 13]. Interestingly, a selective COX-1
inhibitor was an equipotent inhibitor of PG formation in
an inflammatory exudate to the COX-2 selective inhibitor
celecoxib but did not reduce increased PG levels in the
cerebrospinal fluid, while non-selective COX-1/COX-2
inhibition appeared to be more effective in reducing signs
of inflammation [13, 14].
These and other data suggest that the functions of
COX-1 and COX-2 might be more complex than origi-
nally anticipated and that COX-1 inhibition might con-
tribute to inhibition of prostaglandin production in in-
flammatory exudates. Therefore, a combined inhibition of
COX-1 and COX-2 may result in a more efficient
inhibition of chronic inflammation than a selective inhi-
bition of COX-2.
There have been remarkable efforts concerning the
identification of selective COX-2 inhibitors [15] with an
attractive pharmacological profile; e.g. NS-398, DuP 697,
SC-57666 and SC-558 (figure 1) have been reported as
highly active COX-2-inhibitors [16–21]. Very recently
the COX-2-selective inhibitors celecoxib [22, 23] and
rofecoxib [24] (figure 1) have been pharmaceutically
marketed for the indications of osteoarthritis, rheumatoid
arthritis, acute pain in adults and dysmenorrhea, respec-
tively.
Another interesting class of compounds to minimize
the side effects of NSAIDs are dual COX/LOX-inhibitors.
Besides interfering with the production of prostaglandins
these substances inhibit the biosynthesis of chemotactic
leukotrienes, which are another important mediator in
inflammatory processes, i.e. they induce the invasion of
neutrophils into the inflamed area as a prerequisite for the
formation of gastric ulcers.
Figure 1. Structures of selective COX-2 inhibitors.
antirheumatic therapy by its pharmacodynamic and phar-
macokinetic properties [25–27]. Recently 7-tert-butyl-
2,3-dihydro-3,3-dimethylbenzofurane derivatives were
reported as COX-2/5-LOX-inhibitors. One of these sub-
stances was found to be the active metabolite of tebufelone
which acts as an antioxidant [28] (figure 2).
For meloxicam (figure 2) with IC50 values of 3.27 µM
for COX-1 and 0.25 µM for COX-2, reduced side effects
were reported according to the more selective COX-2
inhibition compared to COX-1 inhibition [29, 30].
COX-1/COX-2 inhibitors with similar inhibiting ca-
pacities – so called balanced or non-selective inhibitors
(the term used depends on the scientific dogma the
scientists are focusing on) – could improve the therapeu-
tic benefit in the treatment of inflammatory diseases
according to the phenomena discussed above.
Diarylpyrrolizines have been investigated as drugs
acting on the COX-1, COX-2 and 5-LOX pathways of
arachidonic acid metabolism. One potent compound of
this new class is ML-3000 (figure 2) which may improve

501
Figure 4. (a) KOH 15%, MeOH, 25 °C, 2 h, 63–93% yield. (b)
TosMIC, NaH, THF, 25 °C, 0.5 h, 15–98% yield. (c) KOH,
n-Bu4NHSO4, R4I, CH2Cl2, 2 °C, 24 h, 45–96% yield; for Ar1,
Ar2, R4, see table I.
Figure 2. Structures of dual inhibitors (for explanations see
text).
2. Chemistry
On our way to balanced COX-1/COX-2 inhibitors we
intended to combine the structures of typical COX-2
inhibitors with the chemical requirements for COX-1
inhibition.
Chalcones as precursors for the chemical synthesis
were appropriate tools for the synthesis of the desired
aryl-aroyl-pyrrole derivatives. Chalcones themselves have
been reported as substances with anti-inflammatory po-
tency [36] on the one hand but cytotoxic effects on the
other [37].
We followed the synthesis described by Artico and Di
Santo [38, 39] starting from 1,3-diarylprop-2-en-1-ones
with tosylmethyl isocyanide (TosMIC) to give 3-aroyl-4-
arylpyrroles. TosMIC was used as a synthone for the
pyrrole moiety which reacts with the corresponding
chalcones in an intramolecular cyclization to the 3,4-
disubstituted pyrroles. The ring carbons C(2) and C(5)
neighbouring the nitrogen originate from TosMIC and
C(3) and C(4) from the chalcones which act as Michael
acceptors [40]. Variation at the substitution pattern was
accomplished by using different kinds of chalcones (fig-
ure 4).
Altogether five structural classes of selective COX-2
inhibitors and a class bearing little or no resemblance to
one another in their molecular structure have been iden-
tified [31]. In context with the known anti-inflammatory
potency of keterolac [32] and tolmetin [33], characterized
by an aroyl pyrrole moiety (figure 3), and the selective
COX-2 inhibition of 1,2-diaryl pyrroles [20], we focused
on 3-aroyl 4-aryl pyrrole derivatives inserting a carbonyl
unit into the vicinal diaryl substitution which is the
structural feature of a great member of selective COX-2
inhibitors. Thus, these structural modifications will verify
the importance of vicinal aryl aroyl arrangements on
potency and enzyme selectivity within the pyrrole series
synthesized.
Ketorolac [32] and tolmetin [33] (figure 3) have mean-
while been withdrawn as systematically acting analgesics
in Germany because of possible nephrotoxic risks [34,
35].
3. Biological assays
All the compounds were tested in an intact cell assay
described earlier [41]. This assay was established to
determine 5-LOX, 12-LOX and COX-1 activity. Bovine
blood is used as the enzyme source and isolated platelets
as the source for COX-1 activity. The cells were incu-
bated with the compounds and stimulated with calcium
ionophore A 23187. The amounts of LTB4, 5-HETE,
12-HHT, PGE2 and 12-HETE were determined by HPLC.
IC50 values were calculated with the program GraFit,
Erithacus Software Ltd., UK. The standard deviations of
Figure 3. Structures of the pyrrole analgesics ketorolac and
tolmetin.

502
Table I. Results of the in vitro assays with the aryl/aroyl-substituted
pounds 3a, 3a’ and 3b are less active COX-1 inhibitors
compared to the corresponding unsubstituted 2a and 2b.
We chose 2a with an IC50 value of 3.3 µM for COX-1 as
a lead structure for further modifications in order to
increase COX-1 and COX-2 inhibition. As shown in
table II introduction of thienyl residues increased the
potencies remarkably.
pyrroles.
Compound R1
R2
R3
R4
IC50 (µM)
COX-1
a
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
CH3O
F
H
H
H
CF3
H
H
H
H
H
H
H
CH3O
H
H
H
H
Cl
H
H
F
H
CH3O
H
CF3
H
H
H
H
H
H
H
H
H
H
3.3
4.8
3.3
1.5
6.7
10.0
1.8
3.6
2.6
4.2. Pyrroles with a thienyl/thienoyl moiety
The potency of anti-inflammatory drugs often depends
on their lipophilicity, especially, replacement of a phenyl
residue by a thiophene moiety significantly increases
COX-1 inhibition [44]. Looking for balanced COX-1/
COX-2 inhibitors we modified 2a systematically by
thiophene substitution to obtain more potent compounds
(table II). Compared to 2a the thienyl derivatives 2k and
2m are 2- and 3-fold more active inhibitors of COX-1.
H
3a
3a’
3b
H
H
H
CH3
C2H5
CH3
8.5
9.8
10.0
H
H
Cl
a IC50 values represent the mean value of four determinations.
Table II gives further information about structure–ac-
tivity relationships improving COX-1 inhibition. Com-
pound 2k compared to 2m (1.45 vs. 1.15 µM) and 2j
compared to 2n (1.2 vs. 0.37 µM) proves that chlorination
of the phenyl moiety amplifies the activity, probably due
to increased lipophilicity. The same phenomenon is seen
with the exchange of a thiophene (2j) by a chlorothiophene
moiety (2l) (1.2 vs. 0.18 µM) due to increased lipophi-
licity. The most potent compound in this series with an
IC50 value of 0.07 µM for COX-1 is 2o with a chlorophe-
nyl and a chlorothienyl moiety.
The most potent COX-inhibitors (2j–2p) underwent
COX-2 screening in the model mentioned. Figure 5
proves that the increase of COX-1 inhibition is correlated
with a proportional improvement of COX-2 inhibition.
According to the IC50 values for COX-2, 2l, 2m, 2n and
2o are characterized as balanced inhibitors of both
COX-1 and COX-2 (IC50 ratios between 0.26 and 1.15).
As shown in tables I and II, N-alkylation in general
decreases the inhibitory potency (3l, 3l’ and 3o).
Clearly, an unsubstituted pyrrole-nitrogen atom to-
gether with the thiophene nucleus represents a require-
ment for optimal COX-1/COX-2 inhibition. It is not easy
to explain COX-1 and COX-2 inhibitory effects by
structural differentiation of the compounds. Especially,
the isoform COX-2 seems to tolerate a lot of different
structural parameters, as reflected by the great variety of
COX-2 pharmacophores [31]. The aspect of lipophilicity
is important for COX-1 and COX-2 inhibition as seen by
thiophene and chlorothiophene substitution.
the obtained values (n = 4) were less than 12% of the IC50
values of COX-1. Diclofenac, indomethacin and 4’’-Cl-
SC57666 were used as reference substances.
This method does not give any information about the
inhibition of COX-2. Meanwhile different systems to
measure COX-2 activity are available; for example Patrig-
nani [42] describes a method quantifying PGE2 produc-
tion in plasma from LPS-stimulated human whole blood
using a specific RIA. We used the method of Bauer and
Fiebich [43] where the inhibition of LPS-induced (10 ng/
ml) COX-2 production of PGE2 in human monocytes is
determined. This in vitro model uses monocytes which
are collected from the peripheral blood of healthy donors
with a cell number of 106 cells/well on a microtitre plate.
The amounts of PGE2 are determined by RIA.
4. Results and discussion
Tables I and II show the compounds synthesized by the
general procedure (figure 4). A differentiation can be
made between N-unsubstituted aryl-aroyl-pyrroles,
thienoyl-aryl-pyrroles or thienyl-aroyl-pyrroles and the
corresponding N-substituted compounds. At first, all the
compounds were tested for their ability to inhibit COX-1.
The most potent compounds underwent further investi-
gation to ascertain their COX-2 inhibiting potency.
4.1. Aryl-aroyl-pyrroles
Table I summarizes the impact of additional substitu-
ents both on the aryl and aroyl moiety. The compounds
inhibit the COX pathway significantly. Alkylation at the
pyrrole nitrogen reduces the inhibitory potency. Com-
Figure 6 gives the IC50 values for diclofenac, in-
domethacin and 4’’-Cl-SC 57666 and leads to the ques-
tion: what makes cyclopentene derivative 4’’-Cl-SC 57666

503
Table II. Results of the in vitro assays with 2a and the thiophene substituted pyrroles.
a
Compound
R1
R2
R3
IC50 (µM)
COX-1
COX-1/ COX-2 ratio
COX-2
6.00
2a
H
3.30
1.20
1.45
0.18
1.15
0.55
n.d.
2j
H
H
H
H
16% (10 µM)
5.00
2k
2l
0.29
0.51
1.15
0.35
2m
1.00
2n
2o
H
H
0.37
0.07
0.95
0.27
0.39
0.26
2p
3l
H
0.10
3.90
2.20
0.70
0.14
n.d.
n.d.
n.d.
CH3
C2H5
C2H5
27% (10 µM)
3l’
3o
n.t.
n.t.
33% (10 µM)
diclofenac
indomethacin
4’’-Cl-SC 57666
0.0028
0.004
> 10
0.0004
0.0005
0.016
7
8
> 625
n.t.: not tested;. n.d.: not determined.. a IC50 values represent the mean values of four determinations and were calculated by regression
analysis.
[45] a highly selective COX-2 inhibitor compared to
diclofenac and indomethacin?
The interaction of drugs with the protein structures of
COX-1 [46] or COX-2 [47] is an appropriate tool for
elucidating pharmacological action. The structure of bo-
vine COX-1 complexed with several NSAIDs as well as
the structure of unliganded murine COX-2 and the
corresponding complexes with flurbiprofen, indometha-

504
clooxygenase which allows access to the additional
pocket, whereas access to this ‘side pocket’is restricted in
COX-1 because of the bulkier isoleucine. Hence, COX-2
offers an additional pocket beside the main channel which
is responsible for the selectivity [46]. A further exchange
valine/isoleucine at position 434 of the amino acid chain
leads to the formation of a ‘gate’. This gate is closed in
COX-1 because of the larger isoleucine side chain. In
COX-2 with the smaller side chain at position 434, the
gate has room to swing open allowing the entrance of
more bulky compounds such as 4’’-Cl-SC-57666, a
selective COX-2 inhibitor [45] and modified indometha-
cin derivatives [48].
The selectivity of 4’’-Cl-SC-57666 seems to result
from the phenylsulphone moiety which binds in a pocket
that is more restricted in COX-1 and is unoccupied in
complexes of COX-2 with non-selective inhibitors. 4’’-
Cl-SC-57666, a weak competitive COX-1 inhibitor, in-
hibits COX-2 in a slow, time-dependent process.
Figure 5. Graphic comparison of IC50 values (COX-1 and
COX-2) of the pyrrole derivatives.
cin and the selective COX-2 inhibitor SC-558 have been
published [46, 47]. The time-dependent inhibition of
COX-2 as a consequence of conformational changes is
based on this information.
Consistant with a high sequence identity (approxi-
mately 60%) the overall structures of COX-1 and COX-2
are highly conserved. The significant difference between
the two enzymes seems to be the much larger binding site
in COX-2 for NSAIDs.
Indomethacin causes a slow, time-dependent inhibition
of COX-1 and COX-2. The time-dependence may result
from the formation of a salt bridge between the carboxy-
lic function of the drug and Arg 120 of the enzyme.
Indomethacin, which initiates conformational changes of
the enzyme, binds deeply within the cyclooxygenase
binding site and penetrates furthest into the hydrophobic
channel, but not deeply enough to enhance COX-2
selectivity. The benzoyl moiety seems to play another
important role for the COX-1 activity of indomethacin. It
can be deduced that the benzoyl group enhances COX-1
This binding site seems to be a pocket caused by the
substitution of a valine (COX-2) for an isoleucine
(COX-1) at position 523 at the active site of the cy-
Figure 6. Chemical structures, IC50 values for COX-1 and COX-2 and the corresponding COX-1/COX-2 ratios of diclofenac,
indomethacin and cyclopentene derivative 4’’-Cl-SC-57666.

505
inhibition because derivatives with a benzyl instead of a
benzoyl group do not show COX-1 but COX-2 selectivity
[48].
In addition, COX-1 inhibitors such as indomethacin
lose their COX-1 potency if bulkier substituents at the
heterocyclic nucleus prevent an efficient binding to the
restricted COX-1 pocket.
Compounds 2l, 2m, 2n and 2o combine the structural
requirements for both COX-1 and COX-2 inhibition. The
keto group attached to the pyrrole nucleus might be a
reason for the COX-1 activity being similar to indo-
methacin where the benzoyl residue at the nitrogen atom
enhances the affinity for COX-1.
All reagents were of analytical grade and obtained as
follows: salt for buffer solutions, solvents: Merck, Darm-
stadt (Germany); chalcone derivatives 1a–c and 1g,
calcium ionophore A 23187, diclofenac, indomethacin:
Sigma, München (Germany), HPLC reference substances
12-HHT, internal standards PGB2 and 15-keto-PGE2:
Paesel, Frankfurt/Main (Germany). Bovine blood was
obtained from the local abattoir. Synthesis of 4’’-Cl-SC
57666 was carried out according to ref. [45].
6.1. Chemistry
6.1.1. General procedure
for the preparation of compounds 1d–f and 1h–p
The mixture of the aromatic aldehyde (10 mmol) and
the acetylated aromate (10 mmol) were dissolved in
30 mL of MeOH and stirred during addition of 5 mL of
potassium hydroxide (15% m/V). After some minutes the
product precipitated. About 2 mL of glacial acetic acid
were added. Solids were then filtered with suction and
washed twice with cold MeOH. The chalcones formed in
this manner were directly used for the preparation of the
corresponding pyrroles without any further purification.
Furthermore, it is possible that the NH-function of
these pyrrole derivatives leads to H-bridges between the
nitrogen of the ligand and the protein structure of the
enzyme. Analogous to indomethacin it can be supposed
that the ‘selectivity pocket’ of COX-2 is not completely
occupied by 2l, 2m, 2n and 2o, i.e. these compounds are
less potent COX-2 inhibitors than the reference 4’’-Cl-
SC-57666.
5. Conclusions
6.1.1.1. (E)-3-(4-Fluorophenyl)-
1-phenylprop-2-en-1-one 1d [49]
Our results indicate that the compounds tested repre-
sent a new template for anti-inflammatory drugs. It is
evident that the combination of structural elements which
are so far known for COX-1 and COX-2 inhibition leads
to active compounds which show a balanced inhibition of
the COX-isoenzymes and offers the opportunity to treat
inflammatory diseases with better tolerated drugs, thus
enhancing patient compliance. Further investigations to
refine structural parameters for an optimum efficacy and
to study the tolerance of the drugs are ongoing.
4-Fluorobenzaldehyde (50 mmol, 6.21 g), acetophe-
none (50 mmol, 6.01 g), KOH-soln. approx. 2 mL; 89%
yield (10.1 g) as yellow crystals, m.p. 84–86 °C (MeOH);
IR mmax (KBr, cm–1) mAr–H 3 050, mC=O 1 650, mAr C=C
1
1 580, 1 500, mC–F 1 200; H-NMR (200 MHz, CDCl3,
ppm) d 6.6–8.0 (m, 11H, aromatic and vinylic H); MS m/z
(rel. int.) = 226 (100%, M+), 149 (49%, M+–C6H5), 130
(18%, M+–C6H5–F); calcd. for C15H11FO = 226.08 g/
mol.
6.1.1.2. (E)-1-(4-Fluorophenyl)-
3-phenylprop-2-en-1-one 1e [50]
6. Experimental protocols
Benzaldehyde (20 mmol, 2.14 g), 4-fluoroacetophenone
(20 mmol, 2.76 g), KOH-soln. approx. 1 mL, 71% (3.2 g)
yield as yellow crystals, m.p. 73–75 °C (MeOH); IR mmax
(KBr, cm–1) mAr–H 3 050, mC=O 1 650, mAr C=C 1 580,
Melting points were determined on a Büchi SMP-20
apparatus and are uncorrected. Proton and 13C-NMR
were run on Bruker AC-200 and AC-400 spectrometer
using TMS as the internal standard. Mass spectra (EI)
were obtained at 70 eV with a Varian MAT 7 spectrom-
eter. IR spectra were obtained on a Perkin-Elmer 1310
spectrometer with KBr disks. Microanalyses were deter-
mined on an Heraeus CHN rapid or a Carlo Erba
Strumentazione 1106 and were within ± 0.4% of theo-
retical values. TLC plates of silica gel (Merck G254) were
used to monitor reaction development and to check purity
of all the compounds. Column liquid chromatography
(silica gel 200–400 mesh, Merck) was used for product
isolation from reaction mixtures.
1
1 500, mC–F 1 200; H-NMR (200 MHz, CDCl3, ppm) d
7.3–8.3 (m, 11H, aromatic and vinylic H); MS m/z (rel.
int.) = 226 (100%, M+), 131 (34%, M+–C6H5–F), 103
(37%, C6H5–CH=CH); calcd. for C15H11FO = 226.08 g/
mol.
6.1.1.3. (E)-1-(4-Chlorophenyl)-
3-(2-methoxy-phenyl)prop-2-en-1-one 1f
2-Methoxybenzaldehyde (30 mmol, 4.08 g), 4-chloro-
acetophenone (30 mmol, 4.64 g), KOH-soln. approx.
1.5 mL, 85% yield (6.96 g) as yellow powder, m.p.

506
66–68 °C (MeOH); IR mmax (KBr, cm–1) mAr–H 3 090,
mC=O 1 650, mAr C=C 1 580, 1 500; MS m/z (rel. int.) = 272
(9%, M+·), 241 (100%, M+–OCH3), 139 (12%,
Cl–C6H4–CO); calcd. for C16H13ClO2 = 272.55 g/mol.
213 (24%, M+–Cl), 145 (53%, M+–C6H5–CH=CH), 103
(68%, C6H5–CH=CH); calcd. for C13H9ClOS = 248.49 g/
mol.
6.1.1.9. (E)-1-(4-Chlorophenyl)-3-
6.1.1.4. (E)-1-Phenyl-3-(4-
(thien-2-yl)- prop-2-en-1-one 1m [56]
trifluoromethylphenyl)prop-2-en-1-one 1h [51]
4-Trifluoromethylbenzaldehyde (30 mmol, 5.22 g), ac-
etophenone (30 mmol, 4.95 g), KOH-soln. approx.
1.5 mL, 68% yield (5.68 g) as yellow crystals, m.p.
116–118 °C (MeOH); IR mmax (KBr, cm–1) mAr–H 3 090,
mC=O 1 650, mAr C=C 1 570, mC–F 1 200; MS m/z (rel. int.)
= 276 (87%, M+·), 207 (25%, M+–CF3), 199 (21%,
M+–C6H5), 103 (50%, C6H5–CH=CH); calcd. for
C16H11F3O = 276.08 g/mol.
Thiophene-2-carbaldehyde
(10 mmol,
1.12 g),
4-chloroacetophenone (10 mmol, 1.54 g), KOH-soln. ap-
prox. 2 mL, 75% yield (1.86 g) as yellow powder, m.p.
111–113 °C (MeOH); IR mmax (KBr, cm–1) mAr–H 3 100,
mC=O 1 640, mAr C=C 1 570, 1 540, mC–Cl 1 000; MS m/z
(rel. int.) = 248 (100%, M+·), 213 (24%, M+–Cl), 139
(47%, M+–C6H5–CH=CH), 109 (71%, C6H5–CH=CH);
calcd. for C13H9ClOS = 248.49 g/mol.
6.1.1.10. (E)-3-(4-Chlorophenyl)-1-
6.1.1.5. (E)-1-(4-Trifluoromethylphenyl)-
3-phenylprop-2-en-1-one 1i [52]
(thien-2-yl)-prop-2-en-1-one 1n [53]
2-Acetylthiophene (15 mmol, 2.10 g), 4-chloro-
benzaldehyde (15 mmol, 1.89 g), KOH-soln. approx.
3 mL, 75% yield (2.82 g) as white–yellow crystals, m.p.
132–133 °C (MeOH); IR mmax (KBr, cm–1) mAr–H 3 080,
mC=O 1 640, mAr C=C 1 570, 1 540, mC–Cl 1 000; MS m/z
(rel. int.) = 247 (100%, M+·–1), 212 (57%, M+·–Cl), 196
(36%), 110 (68%); calcd. for C13H9ClOS = 248.49 g/mol.
Benzaldehyde
(25 mmol,
2.40 g),
4-trifluoro-
methylacetophenone (25 mmol, 3.76 g), KOH-soln. ap-
prox. 1.5 mL, 63% yield (3.46 g) as white–yellow crys-
tals, m.p. 108–111 °C (MeOH); IR mmax (KBr, cm–1)
mAr–H 3 100, mC=O 1 660, mAr C=C 1 570, 1 450, mC–F
1 220; MS m/z (rel. int.) = 276 (100%, M+·), 145 (23%,
F3C–C6H4), 103 (28%, C6H5–CH=CH); calcd. for
C16H11F3O = 276.08 g/mol.
6.1.1.11. (E)-3-(4-Chlorophenyl)-1-
(5-chloro-thien-2-yl)-prop-2-en-1-one 1o [56]
6.1.1.6. (E)-3-Phenyl-1-
(thien-2-yl)prop-2-en-1-one 1j [53]
2-Acetyl-5-chlorothiophene
(20 mmol,
3.21 g),
4-chlorobenzaldehyde (20 mmol, 2.81 g), KOH-soln. ap-
prox. 3 mL, 93% yield (5.29 g) as white–yellow crystals,
m.p. 132–133 °C (MeOH); IR mmax (KBr, cm–1) mAr–H
3 080, mC=O 1 650, mAr C=C 1 570, 1 540, mC–Cl 1 010; MS
m/z (rel. int.) = 281 (100%, M+·–1), 246 (95%, M+–Cl),
164 (37%, M+–C4H2S–Cl), 144 (72%, CO–C4H2S–Cl);
calcd. for C13H8Cl2OS = 282.94 g/mol.
Benzaldehyde (30 mmol, 3.21 g), 2-acetylthiophene
(30 mmol, 3.79 g), KOH-soln. approx. 1.5 mL, 92% yield
(5.91 g) as yellow powder, m.p. 77–79 °C (MeOH); IR
mmax (KBr, cm–1) mAr–H 3 090, mC=O 1 650, mAr C=C 1 570,
1 450; MS m/z (rel. int.) = 213 (100%, M+–1), 185 (20%);
calcd. for C13H10OS = 214.05 g/mol.
6.1.1.7. (E)-3-(Thien-2-
yl)-1-phenylprop-2-en-1-one 1k [54]
6.1.1.12. (E)-3-(5-Bromothien-2-yl)-1-
(5-chloro-thien-2-yl)-prop-2-en-1-one 1p
Thiophene-2-carbaldehyde (50 mmol, 5.61 g), aceto-
phenone (50 mmol, 6.0 g), KOH-soln. approx. 2 mL,
89% yield (9.48 g) as yellow powder, m.p. 67–69 °C
(MeOH); IR mmax (KBr, cm–1) mAr–H 3 090, mC=O 1 650,
2-Acetyl-5-chlorothiophene (24.5 mmol, 3.95 g),
5-bromothiophene-2-carbaldehyde (24.5 mmol, 4.68 g),
KOH-soln. approx. 3 mL, 69% yield (5.65 g) as dark
yellow powder, m.p. 139–140 °C (MeOH); IR mmax (KBr,
cm–1) mAr–H 3 080, mC=O 1 640, mAr C=C 1 580, 1 540,
mC–Cl 1 020; MS m/z (rel. int.) = 334 (11%, M+·), 253
(100%, M+–Br), 145 (72%, CO–C4H2S–Cl); calcd. for
C11H6BrClOS2 = 333.34 g/mol.
m
1 560, 1 470; MS m/z (rel. int.) = 214 (99%, M+·),
Ar C=C
137 (57%, M+–C6H5), 109 (41%, M+–C6H5–CO); calcd.
for C13H10OS = 214.05 g/mol.
6.1.1.8. (E)-1-(5-Chlorothien-2-yl)-
3-phenylprop-2-en-1-one 1l [55]
6.1.2. General procedure
for preparation of the pyrroles 2a–2p
To a stirred suspension of sodium hydride in abs. THF
under nitrogen, the solution of the 1:1 mixture of TosMIC
and the corresponding chalcone was added so slowly that
the hydrogen formation could be easily controlled. After
Benzaldehyde (60 mmol, 6.42 g), 2-acetyl-5-chloro-
thiophene (60 mmol, 9.63 g), KOH-soln. approx. 3 mL,
89% yield (13.48 g) as yellow powder, m.p. 91–93 °C
(MeOH); IR mmax (KBr, cm–1) mAr–H 3 100, mC=O 1 640,
m
1 580, 1 520; MS m/z (rel. int.) = 248 (100%, M+·),
Ar C=C

507
finishing addition, the mixture was stirred for another
15 min, then concentrated in vacuo and quenched with
100 mL of water. The aqueous phase was acidified with
1 N sodium hydroxide solution, extracted three times
with ethyl acetate. Combined organic phases were dried
over sodium sulphate, concentrated in vacuo and the
residue was treated with cold MeOH to obtain the product
which was recrystallized using cold ethylacetate.
MS m/z (rel. int.) = 265 (88%, M+·), 188 (100%,
M+–C6H5). Anal. C17H12FNO (C, H, N).
6.1.2.5. 3-(4-Fluorobenzoyl)-4-phenyl-1H-pyrrole 2e
(E)-1-(4-Fluorophenyl)-3-phenylprop-2-en-1-one (1e,
14 mmol, 3.17 g), TosMIC (14 mmol, 2.73 g), sodium
hydride (17 mmol, 0.40 g), 93% yield (3.47 g) as white
crystals, m.p. 217–219 °C (ethyl acetate); IR mmax (KBr,
cm–1) mN–H 3 180, mAr–H 2 980, 2 950, mC=O 1 610, mAr
C=C 1 590, 1 550, mC–F 1 210; 1H-NMR (200 MHz,
DMSO-d6, ppm) d 7.0–7.8 (m, 11H, H arom), 11.8 (s, 1H,
NH); MS m/z (rel. int.) = 265 (85%, M+·), 170 (100%,
C6H4–CO–C4H3N), 115 (40%). Anal. C17H12FNO (C, H,
N).
6.1.2.1. 3-Benzoyl-4-phenyl-1H-pyrrole 2a [56]
1,3-Diphenylprop-2-en-1-one (1a, 60 mmol, 16.66 g),
TosMIC (60 mmol, 11.71 g), sodium hydride (72 mmol,
1.73 g), 91% yield (13.53 g) as white powder, m.p.
229–231 °C (ethyl acetate); IR mmax (KBr, cm–1) mN–H
3 180, mAr–H 2 980, mC=O 1 610, mAr C=C 1 570, 1 550;
1H-NMR (200 MHz, DMSO-d6, ppm) d 7.1–7.8 (m, 12H,
H arom), 11.7 (s, 1H, NH); MS m/z (rel. int.) = 247 (68%,
M+·), 170 (100%, M+–C6H5). Anal. C17H13NO (C, H, N).
6.1.2.6. 3-(4-Chlorobenzoyl)-4-
(2-methoxyphenyl)-1H-pyrrole 2f
(E)-1-(4-Chlorophenyl)-3-(2-methoxyphenyl)-prop-2-
en-1-one (1f, 25 mmol, 6.81 g), TosMIC (25 mmol,
4.88 g), sodium hydride (30 mmol, 0.72 g), 71% yield
(5.49 g) as white powder, m.p. 219–221 °C (ethyl ac-
etate); IR mmax (KBr, cm–1) mN–H 3 200, mAr–H 2 970,
6.1.2.2. 3-(4-Chlorbenzoyl)-4-phenyl-1H-pyrrole 2b
(E)-1-(4-Chlorphenyl)-3-phenylprop-2-en-1-one (1b,
60 mmol, 14.49 g) TosMIC (60 mmol, 11.71 g), sodium
hydride (72 mmol, 1.73 g), 95% yield (16.05 g) as white
powder, m.p. 219–221 °C (ethyl acetate); IR mmax (KBr,
cm–1) mN–H 3 180, mAr–H 2 980, mC=O 1 610, mAr C=C
1
2 950, mC=O 1 620, mAr C=C 1 570, mC–Cl 1 010; H-NMR
(200 MHz, DMSO-d6, ppm) d 3.7 (s, 3H, CH3O), 7.0–7.8
(m, 11H, H arom), 11.8 (s, 1H, NH); MS m/z (rel. int.) =
311 (72%, M+·), 280 (110%, M+–CH3O), 185 (28%), 171
(68%, C6H4–CO–C4H3N). Anal. C18H14ClNO2 (C, H,
N).
1
1 570, 1 550, mC–Cl 1 020; H-NMR (200 MHz, DMSO-
d6, ppm) d 7.0–7.4 (m, 7H, H arom), 7.4–7.5 (d, 2H, J =
8.1 Hz, H-3’, H-5’), 7.6–7.7 (d, 2H, J = 8.2 Hz, H-2’,
H-6’), 11.7 (s, 1H, NH); MS m/z (rel. int.) = 281 (67%,
M+·), 170 (100%, M+–C6H5), 115 (42%). Anal.
C17H12ClNO (C, H, N).
6.1.2.7. 3-(4-Methoxybenzoyl)-4-phenyl-1H-pyrrole 2g
(E)-1-(4-Methoxyphenyl)-3-phenylprop-2-en-1-one
(1g, 25 mmol, 5.96 g), TosMIC (25 mmol, 4.88 g), so-
dium hydride (30 mmol, 0.72 g), 15% yield (1.03 g) as
white powder, m.p. > 180 °C (decomp., ethyl acetate); IR
mmax (KBr, cm–1) mN–H 3 200, mAr–H 2 980, 2 950, mC=O
1 620, mAr C=C 1 590, 1 500; 1H-NMR (200 MHz, DMSO-
d6, ppm) d 3.7 (s, 3H, CH3O), 7.0–7.8 (m, 11H, H arom),
11.8 (s, 1H, NH); MS m/z (rel. int.) = 277 (17%, M+·),
262 (26%, M+–CH3), 184 (40%), 135 (75%,
CO–C6H4–OCH3), 84 (100%). Anal. C18H15NO2 (C, H,
N).
6.1.2.3. 3-Benzoyl-(4-
methoxyphenyl)-1H-pyrrole 2c [56]
(E)-3-(4-Methoxyphenyl)-1-phenylprop-2-en-1-one
(1c, 25 mmol, 5.95 g), TosMIC (25 mmol, 4.88 g), so-
dium hydride (30 mmol, 0.72 g), 59% yield (4.10 g) as
white powder, m.p. 218–220 °C (ethyl acetate); IR mmax
(KBr, cm–1) mN–H 3 190, mAr–H 2 990, mC=O 1 610, mAr C=C
1 580, 1 550; 1H-NMR (200 MHz, DMSO-d6, ppm) d 3.7
(s, 3H, CH3O), 6.7–7.8 (m, 11H, H arom), 11.7 (s, 1H,
NH); MS m/z (rel. int.) = 277 (100%, M+·), 219 (13%).
Anal. C18H15NO2 (C, H, N).
6.1.2.8. 3-Benzoyl-4-(4-
trifluoromethylphenyl)-1H-pyrrole 2h
6.1.2.4. 3-Benzoyl-4-(4-fluorophenyl)-1H-pyrrole 2d
(E)-3-(4-Fluorophenyl)-1-phenylprop-2-en-1-one (1d,
40 mmol, 9.04 g), TosMIC (40 mmol, 7.81 g), sodium
hydride (48 mmol, 1.15 g), 98% yield (10.35 g) as white
crystals, m.p. 204–206 °C (ethyl acetate); IR mmax (KBr,
cm–1) mN–H 3 180, mAr–H 2 980, mC=O 1 610, mAr C=C
(E)-1-Phenyl-3-(4-trifluoromethylphenyl)prop-2-en-1-
one (1h, 10 mmol, 2.76 g), TosMIC (10 mmol, 1.95 g),
sodium hydride (12 mmol, 0.29 g), 74% yield (2.33 g) as
white powder, m.p. 249–251 °C (ethyl acetate); IR mmax
(KBr, cm–1) mN–H 3 170, mAr–H 2 980, mC=O 1 610, mAr C=C
1
1
1 570, 1 550, mC–F 1 210; H-NMR (200 MHz, DMSO-
1 570, 1 550, mC–F 1 210; H-NMR (200 MHz, DMSO-
d6, ppm) d 7.0–7.8 (m, 11H, H arom), 11.8 (s, 1H, NH);
d6, ppm) d 7.1–8.0 (m, 11H, H arom), 11.8 (s, 1H, NH);

508
MS m/z (rel. int.) = 315 (100%, M+·), 238 (89%,
M+–C6H5), 141 (70%, C6H5–C4H3N). Anal. C18H12F3NO
(C, H, N).
170 (18%, C6H5–CO–C4H2N), 115 (100%). Anal.
C15H10ClNOS (C, H, N).
6.1.2.13. 3-(4-Chlorobenzoyl)-
4-(thien-2-yl)-1H-pyrrole 2m
(E)-1-(4-Chlorobenzoyl)-3-(thien-2-yl)-prop-2-en-1-
one (1m, 10 mmol, 2.49 g), TosMIC (10 mmol, 1.95 g),
sodium hydride (12 mmol, 0.29 g), 70% yield (2.0 g) as
yellow crystals, m.p. 191-193 °C (ethyl acetate); IR mmax
(KBr, cm–1) mN–H 3 300, mAr–H 2 990, 2 940, mC=O 1 610,
6.1.2.9. 4-Phenyl-3-(4-
trifluoromethylbenzoyl)-1H-pyrrole 2i
(E)-1-(4-Trifluoromethylphenyl)-3-phenylprop-2-en-1-
one (1i, 10 mmol, 2.76 g), TosMIC (10 mmol, 1.95 g),
sodium hydride (12 mmol, 0.29 g), 52% yield (1.64 g) as
white powder, m.p. 215–217 °C (ethyl acetate); IR mmax
(KBr, cm–1) mN–H 3 180, mAr–H 2 980, mC=O 1 600, mAr C=C
1
mAr C=C 1 590, 1 510, mC–Cl 1 020; H-NMR (200 MHz,
1
1 560, 1 500, mC–F 1 210; H-NMR (200 MHz, DMSO-
DMSO-d6, ppm) d 6.95–7.0 (t, 1H, J = 4.1 Hz,
H-4thiophene), 7.2–7.35 (m, 4H, H arom), 7.5–7.55 (d,
2H, J = 8 Hz), 7.7–7.75 (d, 2H, J = 8.3 Hz), 11.8 (s, 1H,
NH); MS m/z (rel. int.) = 287 (87%, M+·), 176 (100%,
M+–C4H3S–CO). Anal. C15H10ClNOS (C, H, N).
d6, ppm) d 7.1–8.0 (m, 11H, H arom), 11.8 (s, 1H, NH);
MS m/z (rel. int.) = 315 (6%, M+·), 290 (14%), 231
(13%), 139 (32%), 100 (100%). Anal. C18H12F3NO (C,
H, N).
6.1.2.10. 3-Phenyl-4-(thien-2-oyl)-1H-pyrrole 2j [56]
(E)-3-Phenyl-1-(thien-2-yl)prop-2-en-1-one (1j, 30 mmol,
5.57 g), TosMIC (30 mmol, 5.08 g), sodium hydride
(36 mmol, 0.86 g), 66% yield (4.34 g) as white–
yellow powder, m.p. 168–171 °C (ethyl acetate); IR mmax
(KBr, cm–1) mN–H 3 190, mAr–H 2 980, mC=O 1 630, mAr C=C
6.1.2.14. 3-(4-Chlorophenyl)-
4-(thien-2-oyl)-1H-pyrrole 2n
(E)-3-(4-Chlorophenyl)-1-(thien-2-yl)-prop-2-en-1-one
(1n, 10 mmol, 2.48 g), TosMIC (10 mmol, 1.95 g), so-
dium hydride (13 mmol, 0.31 g), 97% yield (2.81 g) as
white crystals, m.p. 184–185 °C (diisopropyl ether); IR
mmax (KBr, cm–1) mN–H 3 180, mAr–H 2 990, 2 940, mC=O
1
1 580, 1 510; H-NMR (200 MHz, DMSO-d6, ppm) d
7.09 (t, 1H, J = 2.5 Hz, H-4’’), 7.15–7.20 (m, 2H, H-2’’,
H-6’’), 7.23–7.29 (t, 2H, J = 7.5 Hz, H-3’’, H-5’’),
7.33–7.38 (d, 2H, J = 6.7 Hz, H-5, H-5’), 7.52 (t, 1H,
J = 2.5 Hz, H-2), 7.72 (d, 1H, J = 4.2 Hz, H-4’), 7.92 (d,
1H, J = 4.6 Hz, H-3’), 11.7 (s, 1H, NH); MS m/z (rel. int.)
= 253 (100%, M+·),220 (69%), 170 (44%, M+–C4H3S),
115 (44%). Anal. C15H11NOS (C, H, N).
1
1 620, mAr C=C 1 590, 1 510, mC–Cl 1 020; H-NMR (200
MHz, DMSO-d6, ppm) d 7.1–7.9 (m, 9H, H arom), 11.8
(s, 1H, NH); MS m/z (rel. int.) = 286 (10%, M+·), 155
(51%), 91 (100%). Anal. C15H10ClNOS (C, H, N).
6.1.2.15. 3-(4-Chlorophenyl)-4-
(5-chlorothien-2-oyl)-1H-pyrrole 2o
(E)-3-(4-Chlorophenyl)-1-(5-chlorothien-2-yl)-prop-2-
en-1-one (1o, 13 mmol, 3.68 g), TosMIC (13 mmol,
2.54 g) sodium hydride (17 mmol, 0.40 g), 81% yield
(3.40 g) as white–yellow powder, m.p. 229–230 °C (di-
isopropyl ether); IR mmax (KBr, cm–1) mN–H 3 200, mAr–H
2 990, 2 940, mC=O 1 600, mAr C=C 1 580, 1 520, mC–Cl
6.1.2.11. 3-Benzoyl-4-(thien-2-yl)-1H-pyrrole 2k
(E)-3-(Thien-2-yl)-1-phenylprop-2-en-1-one (1k, 43 mmol,
9.20 g), TosMIC (43 mmol, 8.40 g), sodium hydride
(52 mmol, 1.25 g), 73% yield (7.94 g) as white–
yellow powder, m.p. 224–226 °C (ethyl acetate); IR mmax
(KBr, cm–1) mN–H 3 160, mAr–H 2 970, mC=O 1 590, mAr C=C
1
1
1 030; H-NMR (200 MHz, DMSO-d6, ppm) d 7.1–7.6
1 590, 1 550; H-NMR (200 MHz, DMSO-d6, ppm) d
(m, 8H, H arom), 11.8 (s, 1H, NH); MS m/z (rel. int.) =
320 (100%, M+·-1), 285 (60%, M+–Cl), 203 (62%,
M+–C4H2–Cl). Anal. C15H9Cl2NOS (C, H, N).
7.0–7.8 (m, 10H, H arom), 11.8 (s, 1H, NH); MS m/z (rel.
int.) = 253 (80%, M+·), 176 (100%, M+–C6H5). Anal.
C15H11NOS (C, H, N).
6.1.2.16. 3-(5-Bromothien-2-yl)-4-
(5-chlorothien-2-oyl)-1H-pyrrole 2p
6.1.2.12. 3-(5-Chlorothien-
2-oyl)-4-phenyl-1H-pyrrole 2l [56]
(E)-1-(5-Chlorothien-2-yl)-3-phenylprop-2-en-1-one
(1l, 10 mmol, 2.49 g), TosMIC (10 mmol, 1.95 g), so-
dium hydride (12 mmol, 0.29 g), 42% yield (1.20 g) as
white powder, m.p. 188–191 °C (ethyl acetate); IR mmax
(KBr, cm–1) mN–H 3 300, mA1r–H 2 990, mC=O 1 610, mAr C=C
1 590, 1 510, mC–Cl 1 020; H-NMR (200 MHz, DMSO-
d6, ppm) d 7.0–7.8 (m, 10H, H arom), 11.8 (s, 1H, NH);
MS m/z(rel. int.) = 287 (19%, M+·), 252 (10%, M+–Cl),
(E)-3-(5-Bromothien-2-yl)-1-(5-chlorothien-2-yl)-prop-
2-en-1-one (1p, 15 mmol, 5.0 g), TosMIC (15 mmol,
2.93 g), sodium hydride (20 mmol, 0.48 g), 59% yield
(3.29 g) as dark-yellow fine crystals, m.p. 156–157 °C
(diisopropyl ether); IR mmax (KBr, cm–1) mC–H 3 220,
mAr–H 2 990, 2 940, mC=O 1 600, mAr C=C 1 580, 1 520,
1
mC–Br 1 130, mC–Cl 1 030; H-NMR (200 MHz, DMSO-
d6, ppm) d 7.0–7.6 (m, 6H, H arom), 11.9 (s, 1H, NH);

509
MS m/z (rel. int.) = 372 (100%, M+·), 292 (59%, M+–Br),
145 (35%, Cl–C4H2S–CO). Anal. C13H7BrClNOS2 (C,
H, N).
(49%, M+·), 184 (100%, M+–Cl–C6H4), 115 (24%). Anal.
C18H15ClNO (C, H, N).
6.1.3.4. 3-(5-Chlorthien-2-oyl)-1-
methyl-4-phenyl-1H-pyrrole 3l [56]
6.1.3. General procedure
for N-alkylation of the pyrroles
3-(5-Chlorothien-2-oyl)-4-phenyl-1H-pyrrole (2l, 4 mmol,
1.15 g), potassium hydroxide (8 mmol, 0.45 g), methyl
iodide (8 mmol, 1.14 g), 74% yield (0.89 g) as light
yellow powder, m.p. 123–125 °C (diisopropyl ether); IR
mmax (KBr, cm–1) mC–H 3 110–3 060, mAr–H 2 950–2 900,
mC=O 1 600, mAr C=C 1 550, 1 510, mC=Cl 1 030; 1H-NMR
(200 MHz, CDCl3, ppm) d 3.7 (s, 3H, CH3), 7.0–7.6 (m,
9H, H arom); MS m/z (rel. int.) = 300 (16%, M+·–1), 225
(13%, M+–C6H5), 218 (12%), 145 (21%, CO–C4H2S–Cl),
130 (27%), 68 (100%). Anal. C16H12ClNOS (C, H, N).
The pyrrole was suspended in 40 mL dichloromethane.
Powdered potassium hydroxide and a catalytic amount of
tetra-n-butylammonium hydrogensulphate were added.
The mixture was sonicated for 2 min at room temperature
and then cooled to 0 °C. Alkyl iodide dissolved in
dichloromethane was added rapidly, the ice bath removed
and the mixture stirred overnight. After that 50 mL of
water were added, the aqueous layer extracted exhaus-
tively with dichloromethane, the combined organic layers
dried over sodium sulphate, concentrated under reduced
pressure and the residue purified by column chromatog-
raphy on silica using dichloromethane as eluent.
6.1.3.5. 3-(5-Chlorothien-2-oyl)-
1-ethyl-4-phenyl-1H-pyrrole 3l’
3-(5-Chlorothien-2-oyl)-4-phenyl-1H-pyrrole (2l, 8 mmol,
2.30 g), potassium hydroxide (16 mmol, 0.90 g), ethyl
iodide (16 mmol, 2.49 g), 93% yield (2.36 g) as light
yellow powder, m.p. 84–87 °C (diisopropyl ether); IR
mmax (KBr, cm–1) mC–H 3 100–3 020, mAr–H 2 960, mC=O
6.1.3.1. 3-Benzoyl-1-methyl-4-phenyl-1H-pyrrole 3a
3-Benzoyl-4-phenyl-1H-pyrrole (2a, 10 mmol, 2.47 g)
potassium hydroxide (20 mmol, 1.12 g), methyl iodide
(20 mmol, 2.84 g), 45% yield (1.18 g) as white powder,
m.p. 109–111 °C (diisopropyl ether); IR mmax (KBr, cm–1)
mC–H 3 140, mAr–H 2 990, 2 940, mC=O 1 630, mAr C=C
1 600, 1 550; 1H-NMR (200 MHz, CDCl3, ppm) d 3.7 (s,
3H, CH3), 6.7–7.8 (m, 12H, H arom); MS m/z (rel. int.) =
261 (78%, M+·), 184 (100%, M+–C6H5). Anal. C18H15NO
(C, H, N).
1
1 610, mAr C=C 1 550, 1 510, mC=Cl 1 030; H-NMR (200
MHz, CDCl3, ppm) d 1.4 (t, 3H, J = 7.3 Hz, CH3), 4.0
(quart, 2H, J = 7.3 Hz, CH2), 7.1–7.4 (m, 7H, H arom),
7.6–7.7 (m, 2H, H arom); MS m/z (rel. int.) = 315 (19%,
M+·), 269 (14%), 198 (21%), 155 (20%), 112 (52%,
C4H4S–CO), 84 (46%, C4H4S), 69 (74%), 56 (100%).
Anal. C17H14ClNOS (C, H, N).
6.1.3.2. 3-Benzoyl-1-ethyl-4-phenyl-1H-pyrrole 3a’
3-Benzoyl-4-phenyl-1H-pyrrole (2a, 5 mmol, 1.24 g),
potassium hydroxide (10 mmol, 0.56 g), ethyl iodide
(10 mmol, 1.56 g), 46% yield (0.63 g) as white powder,
m.p. 104–107 °C (diisopropyl ether); IR mmax (KBr,
6.1.3.6. 3-(4-Chlorophenyl)-4-
(5-chlorothien-2-oyl)-1-ethyl-1H-pyrrole 3o
3-(4-Chlorophenyl)-4-(5-chlorothien-2-oyl)-1H-pyrrole
(2o, 3.5 mmol, 1.13 g), ethyl iodide (8.75 mmol, 1.36 g),
potassium hydroxide (10.5 mmol, 0.59 g), 96% yield
(1.18 g) as yellow powder, m.p. 89–92 °C (diisopropyl
ether); IR mmax (KBr, cm–1) mC–H 2 950, mAr–H 2 940,
mC=O 1 610, mAr C=C 1 560, 1 520, mC=Cl 1 030; 1H-NMR
(400 MHz, CDCl3, ppm) d 1.5 (t, 3H, J = 7.3 Hz, CH3),
4.0 (quart, 2H, J = 7.3 Hz, CH2), 6.75–6.85 (2d, 2H, J =
3.5 Hz, Hthiophene), 7.2–7.4 (m, 6H, H arom); MS m/z (rel.
int.) = 350 (78%, M+·), 315 (65%, M+–Cl), 284 (20%,
M+–Cl–C2H5), 231 (100%), 196 (50%). Anal.
C17H13Cl2NOS (C, H, N).
cm–1) mC–H 3 040, mAr–H 2 970, mC=O 1 630, mAr
C=C
1 590, 1 540; 1H-NMR (200 MHz, CDCl3, ppm) d 1.5 (t,
3H, J = 7.3 Hz, CH3), 3.9 (quart, 2H, J = 7.3 Hz, CH2),
6.8–7.8 (m, 12H, H arom); MS m/z (rel. int.) = 275 (68%,
M+·), 198 (100%, M+–C6H5), 115 (24%). Anal. C19H17NO
(C, H, N).
6.1.3.3. 3-Chlorobenzoyl-1-
methyl-4-phenyl-1H-pyrrole 3b
3-(4-Chlorobenzoyl)-4-phenyl-1H-pyrrole (2b, 10 mmol,
2.82 g), potassium hydroxide (20 mmol, 1.12 g), methyl
iodide (20 mmol, 2.84 g), 94% yield (2.80 g) as white
powder, m.p. 218–221 °C (diisopropyl ether); IR mmax
(KBr, cm–1) mC–H 3 020, mAr1–H 2 940, mC=O 1 620, mAr C=C
1 570, 1 540, mC=Cl 1 030; H-NMR (200 MHz, CDCl3,
ppm) d 3.7 (s, 3H, CH3), 7.0–7.4 (m, 7H, H arom),
7.5–7.8 (2d, 4H, J = 8.2 Hz); MS m/z (rel. int.) = 295
6.2. Enzyme assays
For cell preparations and apparatus see refs. [41] and
[43].

510
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