A novel and convenient method for the preparation of 5-(diphenylmethylene)-1H-pyrrol-2(5H)-ones; synthesis and mechanistic study

Article abstract of DOI:10.1016/j.tet.2016.07.032

An efficient, regioselective synthesis has been developed for the preparation of 5-(diphenylmethylene)-1H-pyrrol-2(5H)-ones from readily available 1H-pyrroles by sequential dibromination and selective organometallic bromine/lithium exchange followed by reaction with benzophenone. Comparison of various N-substituents was shown to demonstrate the high tolerance of the transformation to functional groups. The structures of the new products were determined by spectroscopic methods and confirmed by single-crystal X-ray diffraction measurement. In addition, theoretical study of the reaction mechanism and selective functionalization of the endocyclic double bond were also presented.

Full text of DOI:10.1016/j.tet.2016.07.032

Accepted Manuscript
A novel and convenient method for the preparation of 5-(diphenylmethylene)-1H-
pyrrol-2(5H)-ones; synthesis and mechanistic study
Ferenc Faigl, Szilvia Deák, Zoltán Mucsi, Tamás Hergert, László Balázs, Sándor
Boros, Barbara Balázs, Tamás Holczbauer, Miklós Nyerges, Béla Mátravölgyi
PII:
S0040-4020(16)30655-X
10.1016/j.tet.2016.07.032
TET 27928
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 April 2016
Revised Date: 4 July 2016
Accepted Date: 7 July 2016
Please cite this article as: Faigl F, Deák S, Mucsi Z, Hergert T, Balázs L, Boros S, Balázs B,
Holczbauer T, Nyerges M, Mátravölgyi B, A novel and convenient method for the preparation of 5-
(diphenylmethylene)-1H-pyrrol-2(5H)-ones; synthesis and mechanistic study, Tetrahedron (2016), doi:
10.1016/j.tet.2016.07.032.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
A novel and convenient method for the preparation
Leave this area blank for abstract info.
of 5-(diphenylmethylene)-1H-pyrrol-2(5H)-ones;
Synthesis and mechanistic study
Ferenc Faigl, Szilvia Deák, Zoltán Mucsi, Tamás Hergert, László Balázs, Sándor Boros, Barbara
Balázs, Tamás Holczbauer, Miklós Nyerges and Béla Mátravölgyi*
*MTA-BME Organic Chemical Technology Research Group, Hungarian Academy of Sciences

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A novel and convenient method for the preparation of 5-(diphenylmethylene)-1H-
pyrrol-2(5H)-ones; Synthesis and mechanistic study
Ferenc Faigla,b, Szilvia Deáka,c, Zoltán Mucsid, Tamás Hergerta, László Balázse, Sándor Borosf, Barbara
Balázsg, Tamás Holczbauerh, Miklós Nyergesg and Béla Mátravölgyib*
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1111 Budapest, Budafoki út 8., Hungary
b MTA-BME Organic Chemical Technology Research Group, Hungarian Academy of Sciences, H-1111 Budapest, Budafoki út 8., Hungary
c Gedeon Richter Plc., H-1103 Budapest, Gyömrői út 19-21., Hungary
d Femtonics Ltd., H-1094 Budapest, Tűzoltó u. 59., Hungary
e External Pharmaceutical Department, Budapest University of Technology and Economics, Chinoin Ltd., H-1045 Budapest, Tó utca 1-5., Hungary
f Vichem Chemie Research Ltd., H-1022 Budapest, Herman Ottó utca 15., Hungary
g Servier Research Institute of Medicinal Chemistry, H-1031 Budapest, Záhony u. 7., Hungary
h Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Magyar Tudósok krt. 2A., Hungary
ARTICLE INFO
ABSTRACT
An efficient, regioselective synthesis has been developed for the preparation of
5-(diphenylmethylene)-1H-pyrrol-2(5H)-ones from readily available 1H-pyrroles by sequential
dibromination and selective organometallic bromine/lithium exchange followed by reaction with
benzophenone. Comparison of various N-substituents was shown to demonstrate the high
tolerance of the transformation to functional groups. The structures of the new products were
determined by spectroscopic methods and confirmed by single-crystal X-ray diffraction
measurement. In addition, theoretical study of the reaction mechanism and selective
functionalization of the endocyclic double bond were also presented.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
5-Ylidenepyrrol-2(5H)-one
Bromopyrrole
Butyllithium
Mechanistic study
X-ray crystallography
2009 Elsevier Ltd. All rights reserved
.
starting material. Most recently, reductive coupling33 of
succinimides with benzophenone and controlled oxidation
techniques34,35 of 2-alkyl-pyrroles have been developed. Thus,
transformations of 5-membered heterocycles to 5-ylidene
pyrrolones are valuable alternative methods, however, Kise’s
reductive coupling33 requires stoichiometric amount of transition
metal and limited to strong Lewis acid tolerant substrates. On the
other hand, readily available pyrroles have great synthetic
potential,34,35 although their oxidation usually leads to
uncontrolled polymerization and decomposition.36 Therefore, the
development of facile and effective novel methods for the
preparation of 5-ylidenepyrrol-2(5H)-ones under mild reaction
conditions remains a major challenge in organic synthesis.
1. Introduction
Over the past decades, numerous research papers have been
published describing the versatile methodology for the synthesis
of 5-ylidene butenolides.1-6 5-Ylidenefuran-2(5H)-ones are still
important targets for researchers due to their promising biological
activities.3-6 5-Ylidenepyrrol-2(5H)-one structural unit is also
found in
a
number of biologically important natural
compounds7-11 as well as synthetic pharmaceutical molecules.12-17
Recently, dyes having a 5-ylidenepyrrol-2(5H)-one scaffold have
also been described as chromophores for dye-sensitized solar
cells18 and electro-optic polymers.19
Although 5-ylidene butenolides have been extensively
studied, only a few examples are reported for the synthesis of
pyrrole analogues. Wittig-type reactions of maleimides20 and
lactamizations of 5-ylidenefuran-2(5H)-ones12,21,22 serve as
classical examples of these methods. Due to the growing interest,
several new synthetic ways have been published in the last few
years.15,23-32 Among them, cyclization strategies23-26 mostly
catalyzed by transition-metals27-30 represent new approaches.
These generally require the preparation of specific acyclic
Recently we have published
bromination method for N-substituted
a
highly regioselective
1H-pyrroles.37
Furthermore, we have demonstrated that the halogen atoms of
2,5-dibromo-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole could be
transformed selectively by stepwise organometallic reactions.37
Bromopyrroles have also great synthetic utility for the
preparation of unsaturated γ-lactam structural units. However,
2-bromo-1H-pyrroles decompose rapidly after isolation38
yielding a complex mixture of degradated products, substituted
*
Corresponding author. Tel.: +36 1 463 1884; fax: +36 1 463 4648.
E-mail address: bmatravolgyi@mail.bme.hu (B. Mátravölgyi)

2
Tetrahedron
ACCEPTED MANUSCRIPT
2-bromo-5-tosyl-1H-pyrrole could be easily transformed to
2(5H)-ones under similar conditions.46 Therefore, we initiated the
organometallic studies using benzophenone as the electrophile.
Selective bromine/lithium exchange reaction was performed
using 1 equiv of n-butyllithium at low temperature followed by
the addition of the ketone. LC-MS analysis indicated the
formation of the desired bromo alcohol as nearly sole product,
however, the first attempt to isolate 3a has failed. After work-up,
visible changes took place in the crude material, its colour slowly
altered to dark, and purification by flash column chromatography
resulted in a more polar compound as it was expected.
Characterisation of the obtained material showed that both of the
desired transformations, the elimination of water and the
formation of 1H-pyrrol-2(5H)-one unit were realized
simultaneously without any specific additives. Moreover,
compound 4a was obtained in excellent yield (Table 2, entry 2).
In addition, the exact structure of 4a was confirmed by
single-crystal X-ray diffraction measurement (Figure 1).
5-tosyl-1H-pyrrol-2(5H)-one derivative by acid catalysed
reaction.39 Moreover, oxidation of N-substituted 2,5-dibromo-1H-
pyrrole with concentrated nitric acid leads to the related
maleimide structure.40
In this paper the convenient synthesis of 5-(diphenyl-
methylene)-1H-pyrrol-2(5H)-ones from readily available
1H-pyrroles are described. The comparison of various
N-substituents is shown to demonstrate the high tolerance of
the transformation to functional groups. In addition, theoretical
study of the reaction mechanism and selective functionalization
of the endocyclic double bond are also presented.
2. Results and discussion
2.1. Synthesis of 5-(diphenylmethylene)-1H-pyrrol-2(5H)-ones
For initial studies of the formation of 5-ylidenepyrrol-2(5H)-
one structural units from easily accessible pyrroles, a series of
N-substituted 2,5-dibromo-1H-pyrroles were synthesised based
on the recently reported method by our group.37 Aliphatic and
various aromatic N-substituted dibromo-1H-pyrroles (2a-l)
bearing electron withdrawing or electron donating substituents at
different positions of the aromatic rings were prepared, in
excellent yields. Moreover N-tert-butoxycarbonyl protected
derivative (2m) was also synthesised (Table 1).
Table 2 Synthesis of 5-(diphenylmethylene)-1H-pyrrol-2(5H)-ones (4a-m)
Entry
1b
2
R group
Product
3a
Yielda (%)
Table 1 Synthesis of 2,5-dibromo-1-substituted-1H-pyrroles (2a-m)a
C6H5
72
89
81
87
80
82
88
92
70
90
93
69
88
48
C6H5
4a
3
4-Me-C6H4
2-Et-C6H4
2-Et-6-Me-C6H3
2-biphenyl
1-naphthyl
2-CF3-C6H4
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
Benzyl
4b
4c
4
5
4d
4e
Yieldb (%)
R group
Product
Entry
6
1
2
3
C6H5
2a38
2b41
2c
96
85
90
7
4f
4-Me-C6H4
2-Et-C6H4
8
4g
9
4h
4i
4
5e
6
2-Et-6-Me-C6H3
2-biphenyl
1-naphthyl
2-CF3-C6H4
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
Benzyl
2d
2e
91
88
93
98
94
97
94
97
86
10
11
12
13
4j
2f
2g37
2h
2i
4k
4l33
4m
7
8
CH3
14c
BOC → H
9
a Isolated yields.
10
11
12
2j
b The reaction mixture was worked up using basic conditions and 3a was
isolated using preparative RP-HPLC.
2k42
2l38
CH3
c Deprotection of tert-butyl 2-(diphenylmethylene)-5-oxo-2,5-dihydro-
1H-pyrrole-1-carboxylate took place during the transformation, resulting
5-(diphenylmethylene)-1H-pyrrol-2-(5H)-one (4m).
13
BOC
2m43
56
a The 1-aryl-1H-pyrrole derivatives were prepared by Clauson-Kaas
pyrrole synthesis44 following the literature procedures, using
2,5-dimethoxytetrahydrofuran in refluxing acetic acid and commercially
available anilines. N-Methyl and N-tert-butoxycarbonyl derivatives were
purchased from commercial source.
The alcohol intermediate 3a was presumed to form first in the
organometallic reaction, and we were interested in isolating and
characterising it. Although the rapid transformation of alcohol 3a
to 4a was observed, instant reversed phase HPLC separation
using slightly basic conditions allowed us to obtain 3a in pure
form (Table 2, entry 1). Immediate characterisation by NMR
spectroscopy was carried out successfully, but the elusive 3a was
found to be stable only for a short period of time.
b Isolated yields.
Earlier attempts to prepare diphenyl-(pyrrol-2-yl)-methanol
derivatives showed that under acidic conditions water elimination
can occur at elevated temperature to produce a corresponding
benzoxazepine in good yield45 Our main goal was to accomplish
the efficient combination of this results with the findings that
appropriate 2-bromopyrroles can be transformed to 1H-pyrrol-
To evaluate the scope of the present reaction, we next
investigated a wide range of N-substituted 2,5-dibromo-1H-
pyrroles (Table 2, entries 3-14).

3
of the bromo alcohol the removal of the BOC-group was also
ACCEPTED MANUSCRIPT
observed in this case, and the product was isolated in its
unprotected form (4m).
To further study the scope of the transformation,
2,3,5-tribomo- and 2,3,4,5-tetrabromo-1H-pyrroles (5a-c and
6a,b) were synthesised using the general method in the presence
of
3 or 4 equiv of NBS, respectively (Table 3). The
polyhalogenated products were isolated in high yields (71–88%).
Table 3 Synthesis of tribromo- and tetrabromo-1-substituted-1H-pyrroles
5a-c and 6a,b
Figure 1 The crystallographically independent molecule in the asymmetric
unit of the crystal 4a with the atomic labelling. Displacement ellipsoids are
drawn at the 50% probability level.
Entry
R group
Product
Yielda (%)
Simply allowing the crude products to stand overnight was
found to be sufficient for the complete conversions of
compounds 3 into 4. The transformations of both aliphatic and
aromatic compounds (2b-l) proceeded smoothly providing the
1
2
3
4
5
C6H5
5a
5b
5c
6a
6b
71
84
75
88
81
2-CF3-C6H4
CH3
corresponding
5-(diphenylmethylene)-1H-pyrrol-2-(5H)-ones
C6H5
(4b-l). Aromatic groups bearing electron donating (4b-c) or
withdrawing (4g-j) functions were equally tolerated,
irrespectively of the positions of substituents on the phenyl rings
high yields were observed. It is noted, that bromo substituted
CH3
a Isolated yields.
To explore the organometallic bromine/lithium exchange
reaction, first the tribomo-1H-pyrroles (5a-c) were tested using
1 equiv of n-butyllithium (Scheme 1, Table 4, entries1-3).
Applying the optimal conditions preferred halogen/metal
exchanges at the position 2 of the pyrrole rings of 5a-c were
observed and the corresponding 4-bromo compounds (7a-c) were
isolated in good yields.
The presence of the regioisomeric 3-bromo derivatives (9a-c)
in the crude products were also revealed, due to the simultaneous
lithiations at the other α-positions. The separation of the
regioisomers could easily be accomplished by simple column
chromatography resulting the major compounds in pure form In
addition, tetrabromo-1H-pyrroles (6a,b) were readily converted
to the 3,4-dibromo derivatives (8a,b, Scheme 1, Table 4,
entries 4 and 5).
derivatives
have
synthetic
importance
for
further
functionalizations by coupling reactions, however, the results of
the attempts for selective organometallic bromine/lithium
exchange is ambiguous. Therefore, the elaborated synthetic
strategy was also tested for the synthesis of bromobenzene
derivatives 4h-j. 4-Bromo- and 3-bromobenzene derivatives (2h
and 2i) showed good selectivities, the desired products were
obtained in excellent yields (Table 2, entries 10 and 11). In the
case of the 2-bromobenzene substituted 2j the transformation into
4j eventuated in satisfactory results, although the slightly
decreased yield (70%) indicated that side reactions had taken
place. This observation can be explained by the mechanism of
metalation of 1-phenyl-1H-pyrrole,47 the directing effect of the
lithium atom in the formed 2-lithiopyrrole derivative could give
greater possibility for the bromine/lithium exchange reaction on
the benzene ring also.
Table 4 Synthesis of brominated compounds on the endocyclic double bonds
7a-c and 8a,b
Another crucial aspect in the synthesis of 5-ylidenepyrrol-
2(5H)-ones is that most of the published methods for the
synthesis of the conjugated scaffold describe exclusively the
preparation of N-substituted products,15,23-27,29-32 and fewer studies
reported a readily applicable general method with success.20,33
Therefore, N-protected 2,5-dibromo-1H-pyrrole (2m) was
Entry
R group
Product
Yielda (%)
1
C6H5
7ab
7b
7c
58
55
64
77
41
2
2-CF3-C6H4
CH3
3
involved in these investigations to develop
a route to
4
C6H5
8a
8b
5-(diphenylmethylene)-1H-pyrrol-2-(5H)-one (4m). tert-Butoxy-
carbonyl group was found to be suitable for the protection of
pyrrole. Both reactions, the dibromination (Table 1, entry 13) and
the bromine/lithium exchange followed by the structural change
of the pyrrole ring (Table 2, entry 14), proceeded with moderate
yields. Due to the acidic environment during the transformation
5
CH3
a Isolated yields.
b The crude material contained 65% desired product based on 19F NMR
measurement.
Scheme 1 Synthesis of 7a-c and 8a-b.

4
Tetrahedron
ACCEPTED MANUSCRIPT
The intermediate alcohols of 7 and 8 showed somewhat
Initially, we studied the mechanism strating with water
increased stability compared to the unsubstituted compounds (3),
therefore catalytic amounts of trifluoroacetic acid were added to
the crude products to accelerate the completion of the
transformations. However, functionalization of the endocyclic
double bond was achieved preferably in the position 4 of the ring
of 7 by the transformation of the trihalogen derivatives (5), we
were also insisted on to develop an efficient and selective route to
the regioisomeric compounds (9). Our goal was accomplished by
the bromination of 5-(diphenylmethylene)-1H-pyrrol-2(5H)-ones
(Table 5). Albeit an excess of NBS were required for complete
conversions the 3-bromo derivatives (9a-c) were formed with
excellent regioselectivity and after purification the pure
compounds were isolated in high yields.
elimination, followed by
a
specific hydrolysis of the
bromopyrrole unit. The proposed reaction mechanism is
summarized in Route A (Scheme 2). At first formation of
hydrogen bonds between the polar groups of the phenylpyrrole
derivative and the acid leads to the Ia-TFA complex (IIa).
During this complexation an equilibrium between the TFA dimer
and the protonated molecule IIa was supposed, resulting in a
slightly endothermic process. In the next step, the hydroxyl group
is eliminated from the molecule as water via the protonation
process, providing an unexpectedly stable cationic intermediate
(IIIa). The corresponding transition state (TS1a) energy was
found to be moderate (80.4 kJ mol–1). The formed stable cationic
intermediate (IIIa), represented by two resonance structures,
changes its reaction partner from TFA anion – water to two
water, slowly reacts with one of the water molecule, involving a
well-defined, but high TS (TS2a; 116.2 kJ mol–1) and the
corresponding intermediate Va (–59.6 kJ mol–1). The process
finally leads to the product VIa through TS3a (41.6 kJ mol–1;
101.2 kJ mol–1 from Va).
2.2. Mechanistic study on the formation of 5-(diphenyl-
methylene)-1H-pyrrol-2(5H)-ones
2.2.1. Proposed reaction mechanism under acidic condition
(in the presence of TFA):
In accordance with the experimental results, both the acid and
the base catalyzed transformation were studied to gain insight
into the formation of 5-(diphenylmethylene)-1H-pyrrol-2(5H)-
ones by G0948 at B3LYP/6-31G(d,p) level of theory.49 For the
mechanistic study the computed molecules were signed by roman
letters. During the exploration of the reaction mechanism under
acidic condition, a single trifluoroacetic acid (TFA) molecule was
considered as the protonating agent. Under these conditions the
protonations of both the pyrrole ring and the alcohol moiety
could be presumed.45,46 Therefore, three different protonation
processes were taking into account for the starting material I by
aqueous TFA, initiating three potential reaction mechanisms
(Route A in Scheme 2 starting with the protonation of the alcohol
moiety; Route B and C in Scheme 3 starting with the protonation
of the pyrrole ring).
Table
5 Synthesis of 3-bromo-5-(diphenylmethylene)-1H-pyrrol-2(5H)-
ones (9a-c)
Entry
R group
Product
Yielda (%)
1
C6H5
2-CF3-C6H4
CH3
9a
9b
9c
82
88
73
2
5
a Isolated yields.
Scheme 2 The proposed reaction mechanism of the transformation of I to VI under acidic condition (Route A); a: R1,R2 = H (Ia ≡ 3a, VIa ≡ 4a);
b: R1 = H,R2 = Br (VIb ≡ 7a); c: R1 = Br,R2 = H (VIc ≡ 9a); d: R1,R2 = Br (VId ≡ 8a); The relating computed enthalpy (∆H) and Gibbs free energy (∆G) values
are listed in Table 6.

5
Table 6 Calculated enthalpy (∆H, kJ mol–1) and Gibbs free energy (∆G, kJ mol–1) values for Route A mechanism of transformation of I to VI with different
ACCEPTED MANUSCRIPT
substituents (a–d); computations were carried out at B3LYP/6-31G(d,p) level of theory with the IEF-PCM solvent model, using the parameter set of DCM.a
R1 = R2 = H
R1 = H; R2 = Br
R1 = Br; R2 = H
R1 = R2 = Br
(a)
(b)
(c)
(d)
∆H
∆G
∆H
∆G
∆H
∆G
∆H
∆G
II
19.9
80.4
46.3
32.7
116.2
-59.6
41.6
-72.0
19.5
22.0
23.9
21.2
98.6
61.5
30.0
115.9
-51.6
39.8
-63.5
22.6
22.0
94.1
69.6
15.7
106.5
-53.0
40.2
-66.2
23.9
TS1
III
92.1
107.3
61.0
123.0
58.1
110.7
59.3
106.2
67.0
44.8
IV
28.4
17.9
24.8
21.3
18.2
TS2
V
TS3b
133.0
-53.0
39.2
108.8
-48.9
56.4
127.1
-51.4
54.1
128.8
-51.4
38.6
125.4
-52.2
39.4
VI
-115.5
-73.4
-115.1
-106.7
-110.0
a The ∆H(Ia-d) values were set as zero points (0 kJ mol-1) during the calculations, respectively.
b Estimated values from fixed geometry near to the theoretical transition states.
Noteworthy, that the rate determining step of the entire
process is the water attack on the α-carbon atom of the
heterocyclic ring, which exhibits the highest enthalpy of
activation value (Ia → TS2a; 116.2 kJ mol–1), however, the next
Br-elimination step (Va → TS3a; 101.2 kJ mol–1) also represents
significant, but somewhat lower enthalpy value. This highest
activation enthalpy, however, does not represent extreme value,
allowing relatively fast reaction rate even at room temperature, in
agreement with the experimental findings. As can be seen in
Table 6, the standard enthalpy of formation of VIa
[∆H (VIa) – ∆H (Ia)] is –72.0 kJ mol–1 (solvent model was
taking into consideration).
The two monobromo (Ib and Ic) as well as the dibromo (Id)
derivatives were also subjected to theoretical investigations
(Scheme 1) in order to find the answer to their lower reactivities
under acidic conditions compared to the unsubstituted Ia, as
observed experimentally. Studying the same reaction mechanism
(Route A) for Ib–Id, very close enthalpy values were calculated.
Decisive difference can be found only for the protonation-water
elimination process, where all these transition states exhibited
higher enthalpy values by 15–20 kJ mol–1 (Table 6, TS1, ∆Hs).
The rate determining steps of the formation of the products (VIb-
d) reamind the water attack on the α-carbon atom of the
heterocyclic ring (IV V), however, the higher enthalpy values
of TS1s can significantly decrease the reaction rate of the
transformations. Noteworthy, that the two monobromo
derivatives (IIb and IIc) had larger values, than the dibromo
compound (IId).
As Lightner’s research group showed that the efficient
hydrolysis of substituted 2-bromopyrroles could be easily
accomplished by TFA yielding 1H-pyrrol-2(5H)-ones,46 we were
insisted on studying the possibiltiy of this way (Scheme 3). In the
case of Route B and C, the protonations occurred at positions C5
and C2 of the pyrrole rings, respectively. Interestingly, the
activation enthalpies of the two carbon protonation processes
(TS4 and TS6) showed very close values to the OH-protonation
(Route A, TS1) which make these mechanisms legible on the first
sight. However, the cationic intermediates (VIII and XI)
represented quite high instabilities. Moreover, the subsequent
steps (TS5 and TS8) possessed larger enthalpy gaps, which were
computed for Route A (TS2a), ranking these mechanisms (Route
B and C) backward.
→
Scheme 3 The two alternative reaction mechanisms via Route B (upper line) and C (lower line) for the transformation of Ia to VIa under acidic condition. The
computed enthalpy (∆H) values are given in kJ mol–1 under the related structures. Computations were carried out at B3LYP/6-31G(d,p) level of theory with the
IEF-PCM solvent model, using the parameter set of DCM.

6
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 4 The proposed reaction mechanism under basic condition via Route D for the transformation of Ia to VIa. Computations were carried out at
B3LYP/6-31G(d,p) level of theory with the IEF-PCM solvent model, using the parameter set of DCM.
and nucleus independent chemical shift51 (NICS in ppm) methods
2.2.2. Proposed reaction mechanism under basic condition
(in the presence of base):
for Ia and VIa. From systems chemistry aspect,52,53 three
parameters should be considered in the light of the reaction
After the completion of the addition of the ketone, the reaction
mechanism, aromaticity (AR, blue),50,54 olefinicity (OL, red)55,56
was quenched with water. The resulting alkaline media could be
and amidicity (AM, green).57,58,59 The computed percentage
able to change the reaction mechanism significantly (Route D in
values for these so called icity parameters can be easily
Scheme 4). In this way, the basic condition allowed intermediate
transformed to their resonance enthalpy values (∆HRE; eq 1.). The
Ia to form a complex with LiOH (XII), which is able to react
results for the corresponding molecules are summarized in
with water through a relatively high enthalpy gap (TS9,
Figure 2.
122.1 kJ mol–1), meanwhile the bromine anion is eliminating
from the structure in a parallel way toward the solvent, resulting
lithium bromide. In this mechanism, the 122.1 kJ mol–1 (TS9)
represents a considerably high gap, which could allows only a
quite slow transformation of Ia to VIa at room temperature,
making possible the safe isolation of Ia (≡ 3a in Table 2)
experimentally.
Based on the studied mechanisms and computed energy
values for the formation 5-(diphenylmethylene)-1H-pyrrol-
2(5H)-ones, we concluded that the possibility of the realization of
the acid catalyzed Route A is much grater than the other studied
ways. Moreover, we found that the protonation of the hydroxyl
group is depending on the substituents of the pyrrole ring;
bromine atom(s) at positions 3 and/or 4 could hinder the
protonation-water elimination process decreasing the reaction
rate of the transformations significantly, however, the rate
determing step of the formation of the products remains the water
attack on the α-carbon atom of the heterocyclic rings in all cases.
∆HRE = %(icity)/m(icity)
eq. 1.
where ∆HRE is the resonance enthalpy in kJ mol–1, %(icity) can be the
aromaticity(AR), amidicity(AM) or olefinicty(OL) percentage, while m(icity)
is the slope of the corresponding icity parameters.52
The resonance enthalpies (∆HRE) are comparable values with
enthalpies of formation, moreover, the resonance enthalpies can
be added to each other’s, in contrast to the non-comparable icity
values. Therefore, the transformation of icity parameters to their
resonance enthalpies is required for comparison of different
values.
In the case of structure Ia, only one parameter, the aromaticity
is enough to describe the center ring of the molecule, however,
VIa may require a more sophisticated consideration to describe
the detailed structural interactions properly. Structure VIa can be
analyzed from two aspects. In the first instance the determinant
substructure can be composed of two olefinic (OL1, OL2; red)
and one amide groups (AM; green), on the other hand it can be
considered as only a slightly aromatic, central pyrrole ring (AR;
blue number) as well.
2.2.3. Systems chemistry analysis
The change of the aromaticity shows interesting evaluation
through the reaction, therefore the aromaticity of the central
pyrrole ring was examined by aromaticity percentage50 (in %)
Figure 2 Systems chemistry analysis of the reaction of Ia to VIa. AR = aromaticity, OL = olefinicity, AM = amidicity in percentage, ∆HRE = resonance enthalpy
in kJ mol–1; ∆∆HRE = resonance enthalpy change in kJ mol–1; ∆H(Ia→VIa) = reaction enthalpy.

7
Studying only the change of the aromaticity, it can be
concluded, that the level of the aromaticity decreases
significantly from 57.5% of Ia to 22.8% of VIa, which gives a
quite unfavorable character for the overall process from this
aspect. The calculated NICS values for Ia and VIa confirmed the
previous trend. The original –13.2 ppm for Ia represents a nice
aromaticity, however, the corresponding value is only –2.7 ppm
for VIa, indicating the weak aromatic character of the product.
Investigating the structure of the product VIa from another
point of view a more realistic description of the heterocyclic ring
could be obtained. A nice cooperation could be recognized
between the amide (AM, green) and the olefinic (OL1, red)
functional groups, where the amide and the endocyclic double
bond of VIa intensified each other’s icity values (AM = 117.7%
and OL1 = 39.6%) due to the fact that their strong conjugation
resulted in a slightly aromatic system. In addition, the exocyclic
olefin group provides extra electron density to C5, forming the
6-π electron sextet for the ring, resulting in an also high
olefinicity value for the exocyclic double bond (OL2 = 60.1%).
These olefinicity values (OL1 = 39.6%, OL2 = 60.1%) compared
to the relative minimum (OLethylene = 0%)55 and maximum
(OLallyl anion = 100%)55 values refer to a substantial conjugated
nature of the functions. As can be seen in Figure 2, the final of
the resonance enthalpy of the heteroycle can be considered for
the sum of the endocyclic olefin (OL1) and the amide groups
(AM), which provide 145.6 kJ mol–1 of resonance enthalpy in
summary. The difference between the Σ∆HRE(VIa) and
Σ∆HRE(Ia) is 57.0 kJ mol–1. This value is in a good agreement
with the enthalpy gain of the transformation of Ia to VIa
[∆H (Ia) – ∆H (VIa) = 61.2 kJ mol–1], calculated in vacuo. These
results suggest that the exothermic change in the enthalphy value
practically comes from the resonance energy change. In other
word, the loss of aromaticity during the transformation of Ia to
VIa is compensated by the resulted new molecular system
(aromatic pyrrole → conjugated amide + olefin).
were carried out in Schlenk-flasks under a dry nitrogen
ACCEPTED MANUSCRIPT
atmosphere. Solvents were typically freshly distilled or dried
over molecular sieves. Diethyl ether was obtained anhydrous by
distillation from sodium wire after the characteristic blue colour
of the in situ generated sodium diphenylketyl had been found to
persist. All reactions were monitored by thin-layer
chromatography. TLC was carried out on Kieselgel 60 F254
(Merck) aluminium sheets (visualization of the product was made
by exposing the plate to UV radiation or by staining it with the
aqueous solution of (NH4)6Mo7O24, Ce(SO4)2 and sulfuric acid).
Flash column chromatography was performed using
a
CombiFlash® (Teledyne ISCO). Routine H, 13C and 19F NMR
spectra were obtained on a Bruker AV 300 or DRX 500
spectrometer. The chemical shifts (δ) are reported in parts per
million (ppm) and the coupling constants (J) in Hz. Deuterated
chloroform (CDCl3) with tetramethylsilane (TMS), aceton-d6 and
dimethyl sulfoxide-d6 (DMSO-d6) were used as solvents, and
signal positions were measured relative to the signals of TMS or
solvents (δTMS = 0 ppm, δAcetone = 2.05 ppm, δDMSO = 2.50 ppm for
1
1H NMR
and
δCDCl3 = 77.0 ppm,
δAcetone = 29.8 ppm,
δDMSO = 39.4 ppm for 13C NMR). Infrared (IR) spectra were
recorded on an appliance type Perkin Elmer 1600 with a Fourier
Transformer. Data are given in cm–1. Melting points were
determined in capillary tubes, using a Gallenkamp melting point
apparatus. High-resolution mass spectra (HRMS) were recorded
on Waters LCT Premier XE spectrometer in electrospray
ionization (ESI, 2.5 kV) mode, using water (0.035%
trifluoroacetic acid)/acetonitrile (0.035% trifluoroacetic acid) as
eluent in gradient elution (5%–95% acetonitrile); samples were
made up in acetonitrile. The 79Br isotope (M = 78.91834) was
used for the calculation and data interpretation of the bromine
containing compounds. Single-crystal X-Ray diffraction
measurement was accomplished using a Rigaku R-AXIS RAPID
diffractometer (graphite monochromator Cu-Kα radiation,
λ = 1.54187 Å). CCDC 1017198 (for 4a) contains the
supplementary crystallographic data (including structure factors)
for this paper. These data can be obtained free of charge from
3. Conclusion
The
Cambridge
Crystallographic
Data
Centre
via
In summary, we have demonstrated the new approach of the
efficient, regioselective synthesis of 5-(diphenylmethylene)-1H-
pyrrol-2(5H)-ones from readily available 1H-pyrroles. Bromo
alcohols prepared by sequential dibromination and selective
organometallic bromine/lithium exchange followed by reaction
with benzophenone proved to be easily transformable
intermediates to highly conjugated systems. Comparison of a
series of N-substituted pyrroles demonstrated the high tolerance
of the transformation to functional groups, and single-crystal X-
ray diffraction measurement confirmed the structure of the
5-ylidenepyrrolone scaffold. Regioselective mono and
difunctionalizations of the endocyclic double bond also shown
the versatile usefulness of the elaborated method. Mechanistic
study of the reaction mechanism revealed the nature of the
process – water elimination followed by hydrolysis of the
bromopyrrole unite influenced by acidic additive – and system
chemistry analysis suggest that the formation of the conjugated
system serves as driving force for the transformation. On the
basis of these experimental and mechanistic results this approach
could be applied for preparation of highly functionalized divers
conjugated systems.
www.ccdc.cam.ac.uk/data_request/cif.
4.2. General procedure for the synthesis of polybrominated
1H-pyrrole derivatives37
The 1-aryl-1H-pyrrole derivatives (1a-k) were prepared by
Clauson-Kaas pyrrole synthesis44 following the literature
procedures, using 2,5-dimethoxytetrahydrofuran in refluxing
acetic acid and commercially available anilines. N-Methyl (1l)
and N-tert-butoxycarbonyl (1m) derivatives were purchased from
Sigma-Aldrich Kft. Hungary.
A solution of N-bromosuccinimide (NBS, 15.0 mmol, 2.67 g,
2 equiv.) in dry DMF (10 mL) was added dropwise to a stirred
solution of 1H-pyrrole derivative (1, 7.50 mmol) in dry DMF
(20 mL) at 0 °C. The mixture was stirred for 30 min after the
addition of the solution of NBS was complete. The reaction was
monitored by TLC (pure hexane). Hexane (20 mL) and water
(60 mL) were added, the phases were separated, and the aqueous
phase was washed with hexane (3 × 25 mL). The organic
solutions were collected and most part of the solvent was
evaporated. The residue was filtered through a short silica
column, eluted with hexane and concentrated in vacuo to yield
pure product. In case of other purification method, it is noted.
For the synthesis of tribrominated products 3 equiv., for the
4. Experimental Section
4.1. General
synthesis
of
tetrabrominated
products
4 equiv.
of
N-bromosuccinimide were used.
2,5-Dibromo-1-phenyl-1H-pyrrole (2a).38 The reaction was
carried out using 1-phenyl-1H-pyrrole (1a)60 as starting material.
All commercial starting materials were purchased from
Sigma-Aldrich Kft. Hungary and Merck Kft. Hungary and were
used without further purification. The organometallic reactions

8
Tetrahedron
ACCEPTED MANUSCRIPT
TLC was performed in hexane eluent (Rf = 0.40). Pure 2a is a
2,5-Dibromo-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole (2g).37
colourless oil. Yield was 96%; δH (300 MHz, CDCl3) 7.54–7.42
(3H, m), 7.34–7.15 (2H, m), 6.31 (2H, s).
The reaction was carried out using 1-[2-(trifluoromethyl)phenyl]-
1H-pyrrole (1g)37 as starting material. TLC was performed in
hexane eluent (Rf = 0.44). Pure 2g is a white solid. Yield was
96%; δH (300 MHz, DMSO–d6) 7.99 (1H, d, J 7.5 Hz), 7.90 (1H,
t, J 7.5 Hz), 7.83 (1H t, J 7.8 Hz), 7.49 (1H d, J 8.0 Hz), 6.45
(2H, s).
2,5-Dibromo-1-(p-tolyl)-1H-pyrrole (2b).41 The reaction was
carried out using 1-p-tolyl-1H-pyrrole (1b)61 as starting material.
TLC was performed in hexane eluent (Rf = 0.51). Pure 2b is a
colourless oil. Yield was 85%; δH (300 MHz, DMSO–d6) 7.35
(2H, d, J 8.0Hz), 7.16 (2H, d, J 8.0Hz), 6.42 (2H, s), 2.39 (3H, s).
2,5-Dibromo-1-(2-bromophenyl)-1H-pyrrole
(2h).
The
reaction was carried out using 1-(2-bromophenyl)-1H-pyrrole
(1h)65 as starting material. TLC was performed in hexane eluent
(Rf = 0.42). Pure 2h is a white solid (2.68 g, 94%); m.p. 82–
83 °C; νmax (KBr) 3127, 1513, 1483, 1439, 1417, 1300 cm–1;
δH (300 MHz, DMSO–d6) 7.87 (1H, d, J 7.8 Hz), 7.59 (1H, t,
J 7.4 Hz), 7.55–7.44 (2H, m), 6.45 (2H, s); δC (75 MHz, CDCl3)
137.3, 133.3, 131.3, 131.0, 128.1, 124.7, 112.5 (2C), 102.2 (2C);
HRMS (ESI): M+, found 376.8044. C10H6Br3N requires
376.8050.
2,5-Dibromo-1-(2-ethylphenyl)-1H-pyrrole (2c). The reaction
was carried out using 1-(2-ethylphenyl)-1H-pyrrole (1c)62 as
starting material. TLC was performed in hexane eluent
(Rf = 0.44). Pure 2c is a colourless oil (2.22 g, 90%); νmax (liquid
film) 2970, 1515, 1494, 1455, 1421, 1297, 1158 cm–1; δH
(300 MHz, CDCl3) 7.45 (1H, t, J 7.5 Hz), 7.39 (1H, d, J 7.0 Hz),
7.31 (1H, t, J 7.4 Hz), 7.12 (1H, d, J 7.8 Hz), 6.32 (2H, s), 2.31
(2H, q, J 7.6 Hz), 1.13 (3H t, J 7.6 Hz); δC (75 MHz, CDCl3)
143.0, 136.5, 129.8, 129.6, 129.0, 126.4, 112.1 (2C), 102.4 (2C),
23.7, 13.8; HRMS (ESI): MH+, found 327.9352. C12H12Br2N
requires 327.9336.
2,5-Dibromo-1-(3-bromophenyl)-1H-pyrrole (2i). The reaction
was carried out using 1-(3-bromophenyl)-1H-pyrrole (1i)65 as
starting material. TLC was performed in hexane eluent
(Rf = 0.57). Pure 2i is a white solid (2.62 g, 97%); m.p. 78–
80 °C; νmax (KBr) 3068, 1591, 1575, 1514, 1475, 1429, 1295,
1163 cm–1; δH (300 MHz, CDCl3) 7.62 (1H, d, J 8.0 Hz), 7.44
(1H, t, J 1.8 Hz), 7.37 (1H, t, J 8.0 Hz), 7.22 (1H, d, J 7.9 Hz),
6.32 (2H, s); δC (75 MHz, CDCl3) 138.7, 132.3, 132.2, 130.1,
127.9, 122.1, 112.9 (2C), 102.2 (2C); HRMS (ESI): M+, found
376.8047. C10H6Br3N requires 376.8050.
2,5-Dibromo-1-(2-ethyl-6-methylphenyl)-1H-pyrrole (2d). The
reaction was carried out using 1-(2-ethyl-6-methylphenyl)-1H-
pyrrole (1d)63 as starting material. TLC was performed in hexane
eluent (Rf = 0.44). Pure 2d is a colourless oil (2.34 g, 91%);
νmax (liquid film) 3130, 2970, 2934, 2875, 1515, 1472, 1419,
1298 cm–1; δH (300 MHz, DMSO-d6) 7.40 (1H, t, J 7.5 Hz), 7.29
(1H, d, J 7.8 Hz), 7.27 (1H, d, J 7.6 Hz), 6.48 (2H, s), 2.18 (2H,
q, J 7.5 Hz), 1.87 (3H, s), 1.09 (3H, t, J 7.5 Hz); δC (75 MHz,
DMSO-d6) 142.1, 136.6, 134.9, 129.6, 128.0, 126.5, 112.2 (2C),
101.3 (2C), 23.3, 17.0, 13.8; HRMS (ESI): MH+, found
341.9496. C13H14Br2N requires 341.9493.
2,5-Dibromo-1-(4-bromophenyl)-1H-pyrrole (2j). The reaction
was carried out using 1-(4-bromophenyl)-1H-pyrrole (1j)67 as
starting material. TLC was performed in hexane eluent
(Rf = 0.54). Pure 2j is a colourless oil (2.68 g, 94%); νmax (liquid
film) 3130, 1517, 1489, 1423, 1387, 1308 cm–1; δH (300 MHz,
DMSO–d6) 7.77 (2H, d, J 8.6 Hz), 7.29 (2H, d, J 8.6 Hz), 6.45
(2H, s); δC (75 MHz, DMSO–d6) 136.3, 132.1 (2C), 131.0 (2C),
122.5, 112.7 (2C), 102.0 (2C); HRMS (ESI): M+, found
376.8046. C10H6Br3N requires 376.8050.
1-Benzyl-2,5-dibromo-1H-pyrrole (2k).42 The reaction was
carried out using 1-benzyl-1H-pyrrole (1k)68 as starting material.
TLC was performed in hexane eluent (Rf = 0.54). Pure 2k is a
white solid. Yield was 97%; δH (300 MHz, DMSO–d6) 7.35 (2H,
t, J 7.1 Hz), 7.27 (1H, t, J 6.9 Hz), 7.00 (2H, d, J 7.2 Hz), 6.37
(2H, s), 5.24 (2H, m).
2,5-Dibromo-1-methyl-1H-pyrrole (2l).38 The reaction was
carried out using 1-methyl-1H-pyrrole (1l) as starting material.
After the general work-up procedure a few drops of triethyl
amine were added to the concentrated organic phases. Elution
through a short silica column was carried out using hexane
(0.1 m/m% TEA) as eluent. In the absence of TEA, after the
elution through a short silica column and evaporation of the
solvent under reduced pressure the pure material decomposes
violently. Taking the stability issue into account the product was
immediately transferred into the polar organometallic reaction.
Therefore the full characterisation of 2,5-Dibromo-1-methyl-1H-
pyrrole was missed. TLC was performed in hexane/ethyl
acetate = 20/1 eluent (Rf = 0.66). Pure 2l is a colourless oil. Yield
was 86%.
1-[(1,1'-Biphenyl)-2-yl]-2,5-dibromo-1H-pyrrole (2e). The
reaction was carried out using 1-(biphenyl-2-yl)-1H-pyrrole
(1e)64 as starting material. Methylene chloride (20 mL) and water
(60 mL) were added. The phases were separated, the aqueous
phase was washed with methylene chloride (3 × 25 mL) and the
collected organic solutions were washed with brine (15 mL),
dried over sodium sulfate, concentrated in vacuo. The residue
was purified by recrystallisation from hexane (10 mL). TLC was
performed in hexane eluent (Rf = 0.30). Pure 2e is a white solid
(2.49 g, 88%); m.p. 91–92 °C; νmax (KBr) 3127, 3056, 1504,
1482, 1455, 1420, 1305, 1158 cm–1; δH (300 MHz, CDCl3) 7.62–
7.42 (3H, m), 7.33–7.21 (4H, m), 7.20–7.12 (2H, m), 6.16 (2H,
s); δC (75 MHz, CDCl3) 141.6, 138.1, 135.3, 130.9, 130.3, 129.8,
128.6 (2C), 128.0 (2C), 127.9, 127.5, 112.2 (2C), 102.7 (2C);
HRMS (ESI): MH+, found 375.9312. C16H12Br2N requires
375.9336.
2,5-Dibromo-1-(naphthalen-1-yl)-1H-pyrrole
(2f).
The
reaction was carried out using 1-(naphthalen-1-yl)-1H-pyrrole
(1f)64 as starting material. Methylene chloride (20 mL) and water
(60 mL) were added to the reaction mixture. The phases were
separated, the aqueous phase was washed with methylene
chloride (3 × 20 mL) and the collected organic solutions were
washed with brine (15 mL), dried over sodium sulfate,
concentrated in vacuo. The residue was purified by
recrystallisation from hexane (10 mL). TLC was performed in
hexane eluent (Rf = 0.36). Pure 2f is a white solid (2.44 g, 93%);
m.p. 130–131 °C; νmax (KBr) 3127, 3056, 1504, 1420, 1305,
1158 cm–1; δH (300 MHz, CDCl3) 8.00 (1H, d, J 8.3 Hz), 7.94
(1H, d, J 7.8 Hz), 7.62–7.46 (3H, m), 7.42 (1H, d, J 7.2 Hz), 7.16
(1H, d, J 8.1 Hz), 6.42 (2H, s); δC (75 MHz, CDCl3) 134.5, 134.0,
131.4, 130.0, 128.2, 127.6, 127.5, 126.8, 125.0, 122.8, 112.4
(2C), 103.5 (2C); HRMS (ESI): MH+, found 349.9176.
C14H10Br2N requires 349.9180.
tert-Butyl 2,5-dibromo-1H-pyrrole-1-carboxylate (2m).43 The
reaction was carried out using tert-butyl 1H-pyrrole-1-
carboxylate (1m) as starting material. TLC was performed in
hexane eluent (Rf = 0.24). Pure 2m is a colourless oil. Yield was
56%; δH (300 MHz, DMSO–d6) 6.44 (2H, s), 1.59 (9H, s).

9
2,3,5-Tribromo-1-phenyl-1H-pyrrole (5a).38 The reaction was
carried out using 1-phenyl-1H-pyrrole (1a)60 as starting material.
TLC was performed in hexane eluent (Rf = 0.44). Pure 5a is a
colourless oil. Yield was 71%; δH (300 MHz, CDCl3) 7.52–7.48
(3H, m), 7.25–7.20 (2H, m), 6.42 (1H, s).
141.3, 139.3, 139.3, 137.4, 132.4 (2C), 131.7 (2C), 130.6,
ACCEPTED MANUSCRIPT
129.2, 129.0 (2C), 128.5 (2C), 128.4, 128.2 (2C), 128.1 (2C),
126.5, 122.4; HRMS (ESI): MH+, found 324.1382. C23H18NO
requires 324.1388.
(5-Bromo-1-phenyl-1H-pyrrol-2-yl)diphenylmethanol (3a).
The reaction was carried out using 2a38 as starting material. After
the general work-up procedure, the collected organic phases were
concentrated under reduced pressure and the residue was purified
instantly by preparative RP-HPLC. Gilson pump (333 PUMP);
Gilson sampler (GX-281); Detector (UV-VIS-155), Column:
Phenomenex, Gemini 250 × 50 mm; 10 µm, C18, 110A, gradient
elution (ammonium bicarbonate in water (4 g/L) and
acetonitrile). Pure 3a is a colourless oil (0.87 g, 72%); δH
(500 MHz, DMSO–d6) 7.25–7.13 (11H, m), 7.08 (2H, t,
J 7.5 Hz), 6.81 (2H, d, J 7.3 Hz), 6.23 (1H, OH, s), 6.20 (1H, d,
J 3.9 Hz), 5.52 (1H, d, J 3.9 Hz), δC (126 MHz, DMSO–d6) 146.3
(2C), 141.3, 138.9, 130.7 (2C), 128.1, 127.7 (6C), 127.5 (4C),
127.1 (2C), 112.1, 109.3, 105.6, 77.6.
2,3,5-Tribromo-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole
(5b).37 The reaction was carried out using 1-[2-
(trifluoromethyl)phenyl]-1H-pyrrole (1b)37 as starting material.
TLC was performed in hexane eluent (Rf = 0.37). Pure 5b is a
colourless oil. Yield was 84%; δH (300 MHz, DMSO-d6) 8.01
(1H, d, J 7.5 Hz), 7.92 (1H, t, J 7.2 Hz), 7.84 (1H, t, J 7.4 Hz),
7.58 (1H, d, J 7.6 Hz), 6.72 (1H, s).
2,3,5-Tribromo-1-methyl-1H-pyrrole (5c).38 The reaction was
carried out using 1-methyl-1H-pyrrole (1l) as starting material.
TLC was performed in hexane eluent (Rf = 0.61). Pure 5c is a
colourless oil. Yield was 75%; δH (300 MHz, CDCl3) 6.27 (1H,
s), 3.61 (3H, s).
2,3,4,5-Tetrabromo-1-phenyl-1H-pyrrole (6a).38 The reaction
was carried out using 1-phenyl-1H-pyrrole (1a)60 as starting
material. TLC was performed in hexane/ethyl acetate = 8/1 eluent
(Rf = 0.68). Pure 6a is a colourless oil. Yield was 88%; δH
(300 MHz, CDCl3) 7.55–7.48 (3H, m), 7.25-7.19 (2H, m).
5-(Diphenylmethylene)-1-(p-tolyl)-1H-pyrrol-2-(5H)-one (4b).
The reaction was carried out using 2b41 as starting material. Flash
column chromatography was performed in hexane/ethyl
acetate = 4/1 eluent (Rf = 0.34). Pure 4b is a yellow solid (0.82 g,
81%); m.p. 108–110 °C; νmax (KBr) 3042, 2923, 1700, 1552,
1443, 1176 cm–1; δH (300 MHz, DMSO-d6) 7.47–7.34 (3H, m),
7.26–7.22 (2H, m), 7.18 (1H, d, J 5.7 Hz), 7.02–6.88 (3H, m),
6.85–6.75 (6H, s), 6.34 (1H, d, J 5.7 Hz), 2.10 (3H, s);
δC (75 MHz, DMSO–d6) 170.9, 140.3, 140.2, 137.9, 137.7, 134.8,
133.2, 131.2 (2C), 130.5 (2C), 129.6, 128.3, 128.1 (2C), 128.0
(2C), 127.2, 127.0 (2C), 127.0 (2C), 121.5, 20.3; HRMS (ESI):
MH+, found 338.1549. C24H20NO requires 338.1539.
2,3,4,5-Tetrabromo-1-methyl-1H-pyrrole (6b).38 The reaction
was carried out using 1-methyl-1H-pyrrole (1l) as starting
material. TLC was performed in hexane/ethyl acetate = 8/1 eluent
(Rf = 0.59). Pure 6b is a white solid. Yield was 81%;
δH (300 MHz, DMSO-d6) 3.64 (s, 3H).
4.3. General procedure for the synthesis of 5-ylidenepyrrol-
2(5H)-one derivatives
5-(Diphenylmethylene)-1-(2-ethylphenyl)-1H-pyrrol-2-(5H)-
one (4c). The reaction was carried out using 2c as starting
material. Flash column chromatography was performed in
hexane/ethyl acetate = 4/1 eluent (Rf = 0.40). Pure 4c is a yellow
solid (0.92 g, 87%); m.p. 115–116°C; νmax (KBr) 2972, 1697,
1491, 1373, 1219, 1161 cm–1; δH (300 MHz, CDCl3) 7.39–7.31
(3H, m), 7.25–7.18 (3H, m), 6.97–6.84 (7H, m), 6.83–6.76 (2H,
m), 6.31 (1H, d, J 5.7 Hz), 2.55 (1H, sex, J 7.6 Hz), 2.36 (1H,
sex, J 7.6 Hz), 1.17 (3H, t, J 7.6 Hz); δC (75 MHz, CDCl3) 171.9,
141.0, 140.7, 139.6, 138.5, 137.6, 134.5, 131.5 (2C), 130.8, 130.3
(2C), 129.4, 128.3, 128.1 (2C), 128.0, 127.7, 127.5, 127.0 (2C),
125.8, 122.2, 24.0, 13.4; HRMS (ESI): MH+, found 352.1691.
C25H22NO requires 352.1696.
The corresponding bromo-1H-pyrrole derivative (3.00 mmol)
was dissolved in dry diethyl ether (10 mL) under dry nitrogen
atmosphere and was cooled to –78 °C. A hexane solution of
n-butyllithium (3.20 mmol, 2.00 mL, 1.6 M) was added dropwise
and after 15 min stirring benzophenone (3.30 mmol, 0.60 g) was
added to the reaction mixture. After warming up to room
temperature the solvent was changed to methylene chloride and
water (5 mL) was added into it. The phases were separated and
the aqueous phase was washed with methylene chloride
(3 × 4 mL) then the collected organic phases were dried over
sodium sulfate and concentrated in vacuo. The crude product was
alloowed to stand overnight for the complition of the
transformation to the corresponding 5-ylidenepyrrol-2(5H)-one
derivative. The resulted dark material was purified by flash
column chromatography.
In the cases of 3- and/or 4-bromo substituted derivatives a
catalytic amounts of trifluoroacetic acid were added before the
dried organic phases were concentrated in vacuo. The crude
products were allowed to stand overnight for the completions of
the transformation to the corresponding 5-ylidenepyrrol-2(5H)-
one derivatives. The resulted materials were purified by flash
column chromatography.
5-(Diphenylmethylene)-1-(2-ethyl-6-methylphenyl)-1H-pyrrol-
2(5H)-one (4d). The reaction was carried out using 2d as starting
material. Flash column chromatography was performed in
hexane/ethyl acetate = 4/1 eluent (Rf = 0.40). Pure 4d is a yellow
oil (0.88 g, 80%); νmax (liquid film) 3056, 2967, 1701, 1468,
1365, 1217, 1159 cm–1; δH (500 MHz, DMSO–d6) 7.41–7.36 (3H,
m), 7.26 (1H, d, J 5.9 Hz), 7.18–7.15 (2H, m), 6.96–6.84 (4H,
m), 6.80-6.76 (2H, m), 6.74 (2H, t, J 7.7 Hz), 6.44 (1H, d,
J 5.9 Hz), 2.41–2.27 (2H, m), 2.01 (3H, s), 1.05 (3H, t, J 7.6 Hz);
δC (75 MHz, DMSO–d6) 170.2, 141.3, 140.1, 139.2, 137.1, 136.8,
135.8, 133.5, 130.7 (2C), 129.5, 128.4 (2C), 128.1 (2C), 128.1,
127.6, 127.3, 127.2, 126.8 (2C), 125.2, 122.5, 23.7, 17.8, 13.5;
HRMS (ESI): MH+, found 366.1849. C26H24NO requires
366.1852.
5-(Diphenylmethylene)-1-phenyl-1H-pyrrol-2-(5H)-one (4a).
The reaction was carried out using 2a38 as starting material. Flash
column chromatography was performed in hexane/ethyl
acetate = 4/1 eluent (Rf = 0.27). Pure 4a is a yellow solid (0.86 g,
89%); m.p. 153–155 °C; νmax (KBr) 3050, 1693, 1498, 1369,
1213, 1163 cm–1; δH (500 MHz, Acetone-d6) 7.46–7.40 (3H, m),
7.34–7.27 (2H, m), 7.25 (1H, d, J 5.9 Hz), 7.02–6.85 (10H, m),
6.26 (1H, d, J 5.9 Hz); δC (75 MHz, Acetone–d6) 171.8, 141.7,
1-[(1,1'-Biphenyl)-2-yl]-5-(diphenylmethylene)-1H-pyrrol-2-
(5H)-one (4e). The reaction was carried out using 2e as starting
material. Flash column chromatography was performed in
hexane/ethyl acetate = 4/1 eluent (Rf = 0.32). Pure 4e is a white

10
Tetrahedron
solid (0.98 g, 82%); m.p. 174–176 °C; νmax (KBr) 3056, 1694,
HRMS (ESI): MH+, found 402.0475. C23H17BrNO requires
ACCEPTED MANUSCRIPT
1482, 1437, 1368, 1215, 1158 cm–1; δH (500 MHz, DMSO–d6)
7.44–7.34 (4H, m), 7.31–7.26 (1H, m), 7.24 (1H, td, J 7.7,
1.4 Hz), 7.19 (2H, t, J 7.7 Hz), 7.09 (1H, td, J 7.6, 1.2 Hz), 7.04–
6.99 (1H, m), 6.96 (2H, t, J 7.5 Hz), 6.90–6.85 (3H, m), 6.78
(1H, d, J 5.8 Hz), 6.76–6.66 (2H, m), 6.34 (1H, d, J 5.8 Hz), 6.31
(2H, d, J 7.5 Hz); δC (75 MHz, DMSO–d6) 172.1, 140.2, 139.9,
138.7, 137.8, 137.6, 136.3, 133.4, 131.9, 130.8 (2C), 130.7 (2C),
129.9, 129.6, 128.1 (3C), 127.6, 127.6 (2C), 127.6, 127.3 (2C),
127.2, 127.1, 126.5 (2C), 120.9; HRMS (ESI): MH+, found
400.1709. C29H22NO requires 400.1696.
402.0488.
1-(4-Bromophenyl)-5-(diphenylmethylene)-1H-pyrrol-2-(5H)-
one (4j). The reaction was carried out using 2j as starting
material. Flash column chromatography was performed in
hexane/ethyl acetate = 4/1 eluent (Rf = 0.40). Pure 4j is a yellow
solid (1.12 g, 93%); m.p. 101–103 °C; νmax (KBr) 3074, 1695,
1487, 1363, 1209, 1155 cm–1; δH (300 MHz, DMSO-d6) 7.47–
7.38 (3H, m), 7.30–7.24 (2H, m), 7.23 (1H, d, J 5.9 Hz), 7.17
(2H, d, J 8.6 Hz), 7.08–6.94 (3H, m), 6.92 (2H, d, J 8.6 Hz), 6.83
(2H, d, J 7.0 Hz), 6.37 (1H, d, J 5.9 Hz); δC (75 MHz, DMSO–d6)
170.6, 140.6, 139.9, 137.7, 137.5, 135.1, 131.2 (2C), 130.5 (2C),
130.4 (2C), 129.9, 129.1 (2C), 128.4, 128.1 (2C), 127.5, 127.2
(2C), 121.5, 118.4; HRMS (ESI): MH+, found 402.0489.
C23H17BrNO requires 402.0488.
5-(Diphenylmethylene)-1-(naphthalen-1-yl)-1H-pyrrol-2-
(5H)-one (4f). The reaction was carried out using 2f as starting
material. Flash column chromatography was performed in
hexane/ethyl acetate = 4/1 eluent (Rf = 0.40). Pure 4f is a beige
solid (0.99 g, 88%); m.p. 182–184 °C; νmax (KBr) 3098, 3075,
1693, 1404, 1219, 1170 cm–1; δH (300 MHz, DMSO-d6) 7.75
(1H, d, J 8.1 Hz), 7.62 (1H; d, J 8.1 Hz), 7.59–7.38 (6H, m), 7.36
(1H, d, J 5.9 Hz), 7.27–7.20 (2H, m), 7.19–7.12 (2H, m), 6.74–
6.64 (1H, m), 6.57–6.45 (5H, m); δC (75 MHz, DMSO–d6) 171.2,
140.0, 139.9, 138.7, 137.2, 133.2, 132.7, 130.9 (2C), 130.2,
130.0, 129.4 (2C), 128.2, 128.1 (2C), 127.7, 127.3, 127.1, 126.9,
126.1 (3C), 125.6, 124.7, 123.0, 121.9; HRMS (ESI): MH+,
found 374.1526. C27H20NO requires 374.1539.
1-Benzyl-5-(diphenylmethylene)-1H-pyrrol-2(5H)-one (4k).
The reaction was carried out using 2k42 as starting material. Flash
column chromatography was performed in hexane/ethyl
acetate = 4/1 eluent (Rf = 0.40). Pure 4k is a yellow solid (0.70 g,
69%); m.p. 135–137 °C; νmax (KBr) 3061, 3027, 1687, 1448,
1363, 1129 cm–1; δH (500 MHz, CDCl3) 7.35–7.20 (6H, m), 7.11–
7.07 (3H, m), 7.06 (1H, d, J 5.8 Hz), 7.04–7.01 (2H, m), 6.97
(2H, d, J 7.6 Hz), 6.56–6.52 (2H, m), 6.29 (1H, d, J 5.8 Hz), 4.59
(2H, s); δC (75 MHz, CDCl3) 173.4, 140.6, 140.2, 138.7, 138.0,
137.5, 131.4 (2C), 131.2 (2C), 131.1, 128.5, 128.3, 128.0 (2C),
127.9 (4C), 126.7, 126.2 (2C), 122.2, 45.0; HRMS (ESI): MH+,
found 338.1536. C24H20NO requires 338.1539.
5-(Diphenylmethylene)-1-methyl-1H-pyrrol-2(5H)-one (4l).33
The reaction was carried out using 2l38 as starting material. Flash
column chromatography was performed in hexane/ethyl
acetate = 4/1 eluent (Rf = 0.16). Pure 4l is a pale yellow solid
(0.69 g, 88%); m.p. 116–117 °C; νmax (KBr) 1684, 1592, 1542,
1442, 1422, 1137 cm–1; δH (300 MHz, CDCl3) 7.43–7.30 (6H, m),
7.28–7.15 (4H, m), 7.02 (1H, d, J 5.8 Hz), 6.20 (1H, d, J 5.8 Hz),
2.71 (3H, s); δC (75 MHz, CDCl3) 173.0, 140.5, 139.7, 139.2,
138.7, 131.5 (2C), 131.0 (2C), 129.6, 128.5, 128.3, 128.2 (2C),
128.1 (2C), 122.7, 30.2; HRMS (ESI): MH+, found 262.1218.
C18H16NO requires 262.1232.
5-(Diphenylmethylene)-1-[2-(trifluoromethyl)phenyl]-1H-
pyrrol-2-(5H)-one (4g). The reaction was carried out using 2g37
as starting material. Flash column chromatography was
performed in hexane/ethyl acetate = 4/1 eluent (Rf = 0.24). Pure
4g is a beige solid (1.08 g, 92%); m.p. 182–184 °C; νmax (KBr)
3054, 1701, 1374, 1317, 1159, 1126 cm–1; δH (300 MHz, CDCl3)
7.45–7.31 (4H, m), 7.27 (1H, d, J 5.9 Hz), 7.24–7.17 (3H, m),
7.15 (1H, d, J 7.9 Hz), 7.08 (1H, d, J 7.8 Hz), 7.02–6.78 (5H, m),
6.30 (1H, d, J 5.8 Hz); δC (75 MHz, CDCl3) 172.0, 140.3, 140.2,
139.0, 137.6, 134.0(J 1.8 Hz), 132.9, 131.8, 131.3 (2C), 131.2,
130.7 (2C), 128.5, 128.1 (2C), 128.0, 127.9 (J 30.9 Hz), 127.7,
127.4 (2C), 127.2 (J 4.8 Hz), 123.3 (J 273.9 Hz), 121.7;
δF (282 MHz, CDCl3) –61.04 (3F, s); HRMS (ESI): MH+, found
392.1254. C24H17F3NO requires 392.1257.
1-(2-Bromophenyl)-5-(diphenylmethylene)-1H-pyrrol-2-(5H)-
one (4h). The reaction was carried out using 2h as starting
material. Flash column chromatography was performed in
hexane/ethyl acetate = 4/1 eluent (Rf = 0.28). Pure 4h is a yellow
solid (0.84 g, 70%); m.p. 142–143 °C; νmax (KBr) 3052, 1701,
1477, 1443, 1216, 1161 cm–1; δH (300 MHz, DMSO-d6) 7.44–
7.36 (3H, m), 7.30 (1H, d, J 7.8 Hz), 7.26 (1H, d, J 5.8 Hz),
7.24–7.18 (2H, m), 7.15 (1H, d, J 7.5 Hz), 7.06 (1H, t, J 7.5 Hz),
7.00–6.85 (6H, m), 6.42 (1H, d, J 5.8 Hz); δC (75 MHz, DMSO–
d6) 170.3, 140.0, 139.9, 137.3, 137.1, 135.3, 132.2, 132.0, 131.0
(2C), 129.8 (2C), 129.7, 128.9, 128.3, 128.1 (2C), 128.0 (2C),
127.5, 127.3, 122.5, 121.9; HRMS (ESI): MH+, found 402.0504.
C23H17BrNO requires 402.0488.
5-(Diphenylmethylene)-1H-pyrrol-2-(5H)-one
(4m).
The
reaction was carried out using 2m43 as starting material. Flash
column chromatography was performed in hexane/ethyl
acetate = 4/1 eluent (Rf = 0.11). Pure 4m is a white solid (0.36 g,
48%); m.p. 174–176 °C; νmax (KBr) 3259, 3046, 1683, 1444,
1334, 1209 cm–1; δH (300 MHz, DMSO-d6) 9.84 (1H, br s), 7.45–
7.31 (6H, m), 7.23 (2H, d, J 6.9 Hz), 7.19–7.11 (2H, m), 7.02
(1H, d, J 5.4 Hz), 6.23 (1H, d, J 5.5 Hz); δC (75 MHz, DMSO–d6)
172.1, 139.2, 138.5, 137.6, 136.6, 130.8 (2C), 130.2 (2C), 128.4
(2C), 128.1 (2C), 127.9 (2C), 126.5, 124.6; HRMS (ESI): MH+,
found 248.1072. C17H14NO requires 248.1070.
4-Bromo-5-(diphenylmethylene)-1-phenyl-1H-pyrrol-2(5H)-
one (7a). The reaction was carried out using 5a38 as starting
material. Flash column chromatography was performed in
hexane/ethyl acetate = 8/1 eluent (Rf = 0.18). Pure 7a is a yellow
solid (0.70 g, 58%); m.p. 167–168 °C; νmax (KBr) 3115, 3044,
1772, 1533, 1508, 1443, 1349, 1295, 1150 cm-1; δH (500 MHz,
CDCl3) 7.43 (1H, t, J 7.3 Hz), 7.38 (2H, t, J 7.4 Hz), 7.24 (1H, s),
7.03–6.94 (5H, m), 6.91 (3H, t, J 7.4 Hz), 6.88–6.77 (3H, m),
6.57 (1H, s); δC (126 MHz, CDCl3) 169.1, 139.6, 139.4, 136.5,
136.2, 134.4, 132.5 (2C), 131.4 (2C), 131.0, 129.4, 128.4, 128.2
(2C), 128.1 (2C), 127.4 (2C), 127.2 (2C), 126.6, 126.3; HRMS
(ESI): MH+, found 402.0473. C23H17BrNO requires 402.0494.
1-(3-Bromophenyl)-5-(diphenylmethylene)-1H-pyrrol-2(5H)-
one (4i). The reaction was carried out using 2i as starting
material. Flash column chromatography was performed in
hexane/ethyl acetate = 8/1 eluent (Rf = 0.13). Pure 4i is a yellow
solid (1.08 g, 90%); m.p. 139–140 °C; νmax (KBr) 1693, 1588,
1557, 1476, 1364, 1201, 1160 cm–1; δH (300 MHz, DMSO–d6)
7.47–7.36 (3H, m), 7.31–7.25 (2H, m), 7.24 (1H, d, J 5.9 Hz),
7.16–7.10 (2H, m), 7.05–6.93 (5H, m), 6.88–6.80 (2H, m), 6.38
(1H, d, J 5.8 Hz); δC (75 MHz, DMSO–d6) 170.6, 140.7, 139.9,
137.7, 137.4, 137.1, 131.3 (2C), 130.3 (2C), 130.0, 129.9, 129.2,
128.5, 128.4, 128.1 (2C), 127.7, 127.2 (2C), 126.2, 121.4, 120.2;

11
4-Bromo-5-(diphenylmethylene)-1-[2-(trifluoromethyl)phenyl]-
1H-pyrrol-2(5H)-one (7b). The reaction was carried out using
5b37 as starting material. Flash column chromatography was
performed in hexane/ethyl acetate = 4/1 eluent (Rf = 0.32). Pure
7b is a yellow solid (0.78 g, 55%); m.p. 108–109°C; νmax (KBr)
1704, 1542, 1454, 1316, 1266, 1125 cm-1; δH (300 MHz, CDCl3)
7.44–7.28 (5H, m), 7.21–6.93 (7H, m), 6.91–6.79 (1H, m), 6.74–
6.63 (1H, m), 6.59 (1H, s); δC (75 MHz, CDCl3) 169.0, 139.3,
139.2, 136.9, 134.5, 133.7 (d, J 1.7 Hz), 133.3, 132.8, 131.8,
131.4, 131.2, 130.9, 130.7, 129.2, 128.3, 128.1, 128.0 (2C), 127.9
(2C), 127.4 (q, J 30.5 Hz), 127.2 (q, J 4.6 Hz), 126.8, 123.3 (d,
J 273.8 Hz). δF (282 MHz, CDCl3) –60.82; HRMS (ESI): MH+,
found 470.0380. C24H16BrF3NO requires 470.0367.
3-Bromo-5-(diphenylmethylene)-1-phenyl-1H-pyrrol-2(5H)-
ACCEPTED MANUSCRIPT
-one (9a). The reaction was carried out using 4a as starting
material. Flash column chromatography was performed in
hexane/ethyl acetate = 8/1 eluent (Rf = 0.26). Pure 9a is a yellow
solid (0.82 g, 82%); m.p. 178–179 °C; νmax (KBr) 3057, 1726,
1702, 1493, 1443 1372, 1197, 1078 cm-1; δH (300 MHz,
Acetone-d6) 7.51–7.42 (3H, m), 7.40 (1H, s), 7.38–7.28 (2H, m),
7.09–6.88 (10H, m); δC (75 MHz, Acetone-d6) 166.7, 141.3,
139.5, 138.9, 137.6, 137.1, 132.4 (2C), 132.2, 131.8 (2C), 129.5,
129.1 (2C), 128.7, 128.6 (2C), 128.3 (2C), 128.2 (2C), 127.0,
115.5; HRMS (ESI): MH+, found 402.0487. C23H17BrNO
requires 402.0494.
3-Bromo-5-(diphenylmethylene)-1-(2-(trifluoromethyl)phenyl)-
1H-pyrrol-2(5H)-one (9b). The reaction was carried out using
4g as starting material. Flash column chromatography was
performed in hexane/ethyl acetate = 4/1 eluent (Rf = 0.40). Pure
9b is a yellow solid (1.03 g, 88%); m.p. 164–165 °C; νmax (KBr)
1709, 1496, 1454, 1373, 1315, 1141 cm-1; δH (300 MHz, CDCl3)
7.41–7.31 (5H, m), 7.24–7.13 (4H, m), 7.08 (1H, d, J 7.6 Hz),
6.99–6.83 (5H, m); δC (75 MHz, CDCl3) 166.7, 140.0, 138.4,
137.4, 133.6 (d, J 1.5 Hz), 132.7, 132.0, 131.9, 131.3 (2C), 130.7
(2C), 128.8, 128.3 (4C), 128.0, 127.8 (q, J 30.9 Hz), 127.5 (2C),
127.2 (q, J 4.5 Hz), 123.2 (q, J 273.9 Hz), 115.1; δF (282 MHz,
CDCl3) -60.93 (3F, s); HRMS (ESI): MH+, found 470.0365.
C24H16BrF3NO requires 470.0367.
4-Bromo-5-(diphenylmethylene)-1-methyl-1H-pyrrol-2(5H)-
one (7c). The reaction was carried out using 5c38 as starting
material. Flash column chromatography was performed in
hexane/ethyl acetate = 4/1 eluent (Rf = 0.27). Pure 7c is a yellow
solid (0.65 g, 64%). m.p. 145–146 °C; νmax (KBr) 2921, 1675,
1559, 1445, 1420, 1362, 1317, 1101 cm-1; δH (300 MHz, CDCl3)
7.43–7.31 (6H, m), 7.22–7.12 (4H, m), 6.48 (1H, s), 2.67 (3H, s);
δC (75 MHz, CDCl3) 170.3, 140.3, 139.6, 137.6, 132.8, 132.5
(2C), 131.3 (2C), 129.2, 129.1, 129.0, 128.3 (2C), 128.2 (2C),
127.6, 31.4; HRMS (ESI): MH+, found 340.0317. C18H15BrNO
requires 340.0337.
3,4-Dibromo-5-(diphenylmethylene)-1-phenyl-1H-pyrrol-
2(5H)-one (8a). The reaction was carried out using 6a38 as
starting material. Flash column chromatography was performed
in hexane/ethyl acetate = 8/1 eluent (Rf = 0.16). Pure 8a is a
yellow solid (1.11 g, 77%); m.p. 184–185 °C; νmax (KBr) 3056,
1708, 1596, 1539, 1490, 1445, 1357, 1296, 1104 cm–1; δH
(500 MHz, CDCl3) 7.45 (1H, t, J 7.4 Hz), 7.39 (2H, t, J 7.5 Hz),
7.25 (2H, d, J 8.3 Hz), 7.03–6.96 (5H, m), 6.95–6.90 (3H, m),
6.86 (2H, d, J 7.2 Hz); δC (126 MHz, CDCl3) 164.7, 139.8, 139.4,
136.2, 135.7, 134.7, 132.4 (2C), 131.5 (2C), 130.3, 129.6, 128.6,
128.3 (2C), 128.2 (2C), 127.5 (2C), 127.2 (2C), 126.6, 121.5;
HRMS (ESI): MH+, found 479.9592. C23H16Br2NO requires
479.9599.
3-Bromo-5-(diphenylmethylene)-1-methyl-1H-pyrrol-2(5H)-
one (9c). The reaction was carried out using 4l33 as starting
material. Flash column chromatography was performed in
hexane/ethyl acetate = 4/1 eluent (Rf = 0.40). Pure 9c is a yellow
solid (0.62 g, 73%); m.p. 139–140 °C; νmax (KBr) 2948, 1697,
1590, 1489, 1465, 1444, 1363, 1177, 1133, 1102 cm–1; δH
(300 MHz, CDCl3) 7.43–7.31 (6H, m), 7.25–7.15 (4H, m), 7.13
(1H, s), 2.76 (3H, s); δC (75 MHz, CDCl3) 167.7, 140.1, 138.8,
138.0, 136.7, 131.4 (2C), 131.0 (2C), 130.5, 128.8, 128.7, 128.3
(2C), 128.3 (2C), 116.0, 31.4; HRMS (ESI): MH+, found
340.0321. C18H15BrNO requires 340.0337.
Acknowledgments
3,4-Dibromo-5-(diphenylmethylene)-1-methyl-1H-pyrrol-
2(5H)-one (8b). The reaction was carried out using 6b38 as
starting material. Flash column chromatography was performed
in hexane/ethyl acetate = 8/1 eluent (Rf = 0.16). Pure 8b is a
yellow solid (0.51 g, 41%); m.p. 199–200 °C; νmax (KBr) 3053,
1699, 1570, 1472, 1443, 1358, 1295, 1269, 1110, 1011 cm–1;
δH (300 MHz, CDCl3) 7.47–7.31 (6H, m), 7.23–7.14 (4H, m),
2.74 (3H, s); δC (75 MHz, CDCl3) 165.9, 140.1, 139.7, 136.8,
133.2, 132.4 (2C), 131.3 (2C), 129.5, 129.2, 128.5 (2C), 128.4,
128.3 (2C), 122.1, 32.6; HRMS (ESI): MH+, found 417.9428.
C18H14Br2NO requires 417.9442.
The project was supported by the Hungarian Scientific
Research Fund (OTKA K104528) and the Richter Gedeon
Talentum Foundation.
Supplementary data
Supplementary data including the copies of NMR spectra,
XRD crystallographic data of 4a and detailes of computational
methods can be found in the online version, at http://dx.doi.org/.
References and notes
4.4. General procedure for the bromination of 5-(diphenyl-
methylene)-1H-pyrrol-2(5H)-ones
1.
2.
3.
Negishi, E.; Kotora, M. Tetrahedron 1997, 53, 6707-6738.
Brückner, R. Curr. Org. Chem. 2001, 5, 679-718.
Liu, G.-Z.; Guan, Y.-B.; Wu, Y.; Liu, H.-M. Journal of Chemistry
2013, 1-8.
Zhang, R.; Chan, D.; Jessica, S.; Iskander, G.; Black, D.; Kumar, N.
Arkivoc 2009, 102-115.
Fáková, H.; Pour, M.; Kuneš, J.; Šenel, P. Tetrahedron Lett. 2005, 46,
8137-8140.
Schmidt-Leithoff, J.; Brückner, R. Helv. Chim. Acta 2005, 88, 1943-
1959.
A solution of N-bromosuccinimide (NBS, 5.00 mmol, 0.89 g)
in dry DMF (5 mL) was added dropwise to a stirred solution
4.
5.
6.
of
5-(diphenylmethylene)-1H-pyrrol-2(5H)-one
derivative
(4, 2.50 mmol) in dry DMF (10 mL) at 0 °C. The mixture was
stirred for overnight at room temperature after the addition of the
solution of NBS was complete. The reaction was monitored by
TLC (hexane/ethyl acetate). Ethyl acetate (10 mL) and water
(30 mL) were added, the phases were separated, and the aqueous
phase was washed with ethyl acetate (3 × 10 mL). The combined
organic phases were dried over sodium sulfate and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography.
7.
8.
Liras, P. Appl. Microbiol. Biotechnol. 2014, 98, 1023-1030.
Bermejo, F. A.; Rico-Ferreira, R.; Bamidele-Sanni, S.; García-Granda,
S. J. Org. Chem. 2001, 66, 8287-8292.
9.
Cardellina, J. H.; Moore, R. E. Tetrahedron Lett. 1979, 20, 2007-2010.
10. Falk, H.; Grubmayr, K.; Herzig, U.; Hofer, O. Tetrahedron Lett. 1975,
16, 559-562.

12
Tetrahedron
Celmer, W. D.; Solomons, I. A. J. Am. Chem. ASocC. 1C95E5,P77T, E28D61- MANUSCRIPT
11.
46. Brower, J. O.; Lightner, D. A.; McDonagh, A. F. Tetrahedron 2001,
2865.
57, 7813-7827.
12. Ho, K. K. K.; Chen, R.; Willcox, M. D. P.; Rice, S. A.; Cole, N.;
Iskander, G.; Kumar, N. Biomaterials 2014, 35, 2336-2345.
13. Birru, W.; Fernley, R. T.; Graham, L. D.; Grusovin, J.; Hill, R. J.;
Hofmann, A.; Howell, L.; James, P. J.; Jarvis, K. E.; Johnson, W. M.;
Jones, D. A.; Leitner, C.; Liepa, A. J.; Lovrecz, G. O.; Lu, L.; Nearn,
R. H.; O’Driscoll, B. J.; Phan, T.; Pollard, M.; Turner, K. A.; Winkler,
D. A. Bioorg. Med. Chem. 2010, 18, 5647-5660.
14. Li, B.; Lyle, M. P. A.; Chen, G.; Li, J.; Hu, K.; Tang, L.; Alaoui-
Jamali, M. A.; Webster, J. Bioorg. Med. Chem. 2007, 15, 4601-4608.
15. Adhikari, R.; Jones, D. A.; Liepa, A. J.; Nearn, R. H. Aust. J. Chem.
2005, 58, 882-890.
16. Arai, K.; Sato, M. 1997, WO9732847.
17. Goh, W. K.; Iskander, G.; Black, D. S.; Kumar, N. Tetrahedron Lett.
2007, 48, 2287-2290.
18. Bürckstümmer, H.; Kronenberg, N. M.; Meerholz, K.; Würthner, F.
Org. Lett. 2010, 12, 3666-3669.
19. Wang, L.; Bo, S.; Liu, J.; Zhen, Z.; Liu, X. Polymer Science, Ser. B
2012, 54, 297-305.
47. Faigl, F.; Schlosser, M. Tetrahedron 1993, 49, 10271-10278.
48. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, X.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Montgomery Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd,
J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S.
S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J.
E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A.
D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.
Gaussian 09; Gaussian Inc., Wallingford CT, 2009.
49. Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5656.
50. Mucsi, Z.; Viskolcz, B.; Csizmadia, I. G. J. Phys. Chem. A 2007, 111,
1123-1132.
20. Gill, G. B.; James, G. D.; Oates, K. V.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1 1993, 2567-2579.
21. Yamada, K.; Kato, T.; Hirata, Y. J. Chem. Soc. D 1969, 1479-1480.
22. Klopfleisch, M.; Seidel, R. A.; Görls, H.; Richter, H.; Beckert, R.;
Imhof, W.; Reiher, M.; Pohnert, G.; Westerhausen, M. Org. Lett. 2013,
15, 4608-4611.
51. Schleyer, P. R.; Maerker, C.; Dransfeld, A.; Jiao, H.; Hommes, N. J. R.
E. J. Am. Chem. Soc. 1996, 118, 6317-6318.
52. Mucsi, Z.; Chass, G. A.; Csizmadia, I. G. J. Phys. Chem. B 2009, 113,
10308-10314.
23. Cherry, K.; Thibonnet, J.; Duchêne, A.; Parrain, J.-L.; Abarbri, M.
Tetrahedron Lett. 2004, 45, 2063-2066.
53. Mucsi, Z.; Porcs-Makkay, M.; Simig, Gy.; Csizmadia, I. G.; Volk, B.
J. Org. Chem. 2012, 77, 7282-7290.
24. Tang, Y.; Li, C. Org. Lett. 2004, 6, 3229-3231.
25. Yoshimatsu, M.; Machida, K.; Fuseya, T.; Shimizu, H.; Kataoka, T. J.
Chem. Soc., Perkin Trans. 1 1996, 1839-1843.
26. Khlebnikov, A. F.; Novikov, M. S.; Kostikov, R. R. Chem. Heterocycl.
Compd. 1987, 23, 1070-1076.
27. Hou, W.; Zhou, B.; Yang, Y.; Feng, H.; Li, Y. Org. Lett. 2013, 15,
1814-1817.
28. Grigg, R. D.; Schomaker, J. M.; Timokhin, V. Tetrahedron 2011, 67,
4318-4326.
29. Saito, T.; Sugizaki, K.; Osada, H.; Kutsumura, N.; Otani, T.
Heterocycles 2010, 80, 207-211.
30. Wuckelt, J.; Döring, M.; Langer, P.; Beckert, R.; Görls, H. J. Org.
Chem. 1999, 64, 365-372.
31. Murakami, M.; Hayashi, M.; Ito, Y. J. Org. Chem. 1994, 59, 7910-
7914.
32. Fiorenza, M.; Reginato, G.; Ricci, A.; Taddei, M.; Dembech, P. J. Org.
Chem. 1984, 49, 551-553.
33. Kise, N.; Kinameri, S.; Sakurai, T. Tetrahedron Lett. 2013, 54, 6944-
6948.
34. Kancharla, P.; Lu, W.; Salem, S. M.; Kelly, J. X.; Reynolds, K. A. J.
Org. Chem. 2014, 79, 11674-11689.
35. Howard, J. K.; Hyland, C. J. T.; Just, J.; Smith, J. A. Org. Lett. 2013,
15, 1714-1717.
36. Kang, H. C.; Geckeler, K. E. Polymer 2000, 41, 6931-6934.
37. Faigl, F.; Mátravölgyi, B.; Deák, S.; Holczbauer, T.; Czugler, M.;
Balázs, L.; Hermecz, I. Tetrahedron 2012, 68, 4259-4266.
38. Gilow, H. M.; Burton, D. E. J. Org. Chem. 1981, 46, 2221-2225.
39. Sabido, P.; Lightner, D. Monatsh. Chem. 2014, 145, 775-789.
40. Wang, S.; Hong, W.; Ren, S.; Li, J.; Wang, M.; Gao, X.; Li, H. J.
Polym. Sci., Part A: Polym. Chem. 2012, 50, 4272-4276.
41. Hildebrandt, A.; Lang, H. Dalton Trans. 2011, 40, 11831-11837.
42. Choi, D.-S.; Huang, S.; Huang, M.; Barnard, T. S.; Adams, R. D.;
Seminario, J. M.; Tour, J. M. J. Org. Chem. 1998, 63, 2646-2655.
43. Chen, W.; Cava, M. P. Tetrahedron Lett. 1987, 28, 6025-6026.
44. Elming, N.; Clauson-Kaas, N. Acta Chem. Scand. 1952, 6, 867-874.
45. Faigl, F.; Tárkányi, G.; Fogassy, K.; Tepfenhardt, D.; Thurner, A.
Tetrahedron 2008, 64, 1371-1377.
54. Mucsi, Z.; Körtvélyesi, T.; Viskolcz, B.; Csizmadia, I. G.; Novák, T.;
Keglevich, G. Eur. J. Org. Chem. 2007, 1759-1767.
55. Mucsi, Z.; Chass, G. A.; Viskolcz, B.; Csizmadia, I. G. J. Phys. Chem.
A 2009, 113, 7953-7962.
56. Novak, T.; Mucsi, Z.; Balazs, B.; Keresztely, L.; Blasko, G.; Nyerges,
M. Synlett 2010, 16, 2411-2414.
57. Mucsi, Z.; Tsai, A.; Szori, M.; Chass, G. A.; Viskolcz, B.; Csizmadia,
I. G. J. Phys. Chem. A 2007, 111, 13245-13254.
58. Pilipecz, M.; Mucsi, Z.; Varga, T.; Scheiber, P.; Nemes, P.
Tetrahedron 2008, 64, 5545-5550.
59. Mucsi, Z.; Chass, G. A.; Csizmadia, I. G. J. Phys. Chem. B 2008, 112,
7885-7893.
60. Wu, P.; Zhang, J.; Meng, Q.; Nare, B.; Jacobs, R. T.; Zhou, H. Eur. J.
Med. Chem. 2014, 81, 59-75.
61. La Regina, G.; Bai, R.; Coluccia, A.; Famiglini, V.; Pelliccia, S.;
Passacantilli, S.; Mazzoccoli, C.; Ruggieri, V.; Sisinni, L.; Bolognesi,
A.; Rensen, W. M.; Miele, A.; Nalli, M.; Alfonsi, R.; Di Marcotullio,
L.; Gulino, A.; Brancale, A.; Novellino, E.; Dondio, G.; Vultaggio, S.;
Varasi, M.; Mercurio, C.; Hamel, E.; Lavia, P.; Silvestri, R. J. Med.
Chem. 2014, 57, 6531-6552.
62. Faigl, F.; Vas Feldhoffer, B.; Thurner, A. Synth. Commun. 2006, 36,
2841-2849.
63. Faigl, F.; Vas-Feldhoffer, B.; Kubinyi, M.; Pál, K.; Tárkányi, G.;
Czugler, M. Tetrahedron: Asymmetry 2009, 20, 98-103.
64. Paillet-Loilier, M.; Fabis, F.; Lepailleur, A.; Bureau, R.; Butt-Gueulle,
S.; Dauphin, F.; Delarue, C.; Vaudry, H.; Rault, S. Bioorg. Med. Chem.
Lett. 2005, 15, 3753-3757.
65. Liu, H.; Duan, T.; Zhang, Z.; Xie, C.; Ma, C. Org. Lett. 2015, 17,
2932-2935.
66. Lee, D. H.; Lee, S. G.; Jung, D. I.; Hahn, J. T. Asian J. Chem. 2013,
25, 501-504.
67. Castro, M. C. R.; Belsley, M.; Fonseca, A. M. C.; Raposo, M. M. M.
Tetrahedron 2012, 68, 8147-8155.
68. Richards, J. J.; Reed, C. S.; Melander, C. Bioorg. Med. Chem. Lett.
2008, 18, 4325-4327.