Useful, regioflexible methods for functionalization of 1-phenylpyrrole derivatives

Article abstract of DOI:10.1016/j.tet.2012.03.070

Highly regioselective mono-, di- and tribrominations of 1-[2-(trifluoromethyl)phenyl]-1H-pyrrole and several derivatives were accomplished with N-bromosuccinimide under mild conditions. Combined applications of these brominations with organometallic (e.g., bromine/lithium exchange or metalation) reactions provided a novel regioflexible route to new multifunctionalised 1-phenylpyrrole derivatives. The structures of the new products were determined by spectroscopic methods and confirmed in three cases with single crystal X-ray diffraction measurements.

Full text of DOI:10.1016/j.tet.2012.03.070

Tetrahedron 68 (2012) 4259e4266
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Useful, regioflexible methods for functionalization of 1-phenylpyrrole derivatives
,
b
,
b
a
c
c
d
Ferenc Faigl a , Bela Matravolgyi , Szilvia Deak , Tamas Holczbauer , Matyas Czugler , Laszlo Balazs ,
*
ꢀ
ꢀ
€
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
ꢀ
ꢀ
d
ꢀ
Istvan Hermecz
a
ꢀ
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1111 Budapest, Budafoki ut 8., Hungary
Research Group for Organic Chemical Technology, Hungarian Academy of Sciences, H-1111 Budapest, Budafoki ut 8., Hungary
Institute of Structural Chemistry, Hungarian Academy of Sciences, H-1025 Budapest, Pusztaszeri ut 59-67., Hungary
External Pharmaceutical Department, Budapest University of Technology and Economics, Chinoin Ltd., H-1045 Budapest, To utca 1-5., Hungary
b
ꢀ
c
ꢀ
d
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly regioselective mono-, di- and tribrominations of 1-[2-(trifluoromethyl)phenyl]-1H-pyrrole and
several derivatives were accomplished with N-bromosuccinimide under mild conditions. Combined
applications of these brominations with organometallic (e.g., bromine/lithium exchange or metalation)
reactions provided a novel regioflexible route to new multifunctionalised 1-phenylpyrrole derivatives.
The structures of the new products were determined by spectroscopic methods and confirmed in three
cases with single crystal X-ray diffraction measurements.
Received 2 December 2011
Received in revised form 1 March 2012
Accepted 19 March 2012
Available online 3 April 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Regioselectivity
1-Phenylpyrrole
Carboxylic acid
Bromination
X-ray crystallography
1. Introduction
M
N
Multisubstituted 1-phenylpyrrole derivatives are among the
known building blocks of active pharmaceutical ingredients having
cytostatic,1,2 antiviral,3 antibiotic4 activities or mineral corticoid
receptor antagonist effect.5 Preparation of these practically im-
portant compounds is usually accomplished by classical synthetic
methods.1e5 Recently, regioselective metalation processes have also
been developed for elaboration of 1-phenyl-1H-pyrrole derivatives
containing methoxy,6 halogen,7,8 alkyl9,10 or trifluoromethyl11
substituents on the aromatic ring. These organometallic ap-
proaches enable the introduction of new substituents selectively
β
α
M
M
N
N
R
1
6
2
3
N
R
R
R
M
into the Ca position of the pyrrole ring or, in other cases, into the
Scheme 1. General scheme of regioselective mono- and dimetalations of substituted
1-phenyl-1H-pyrroles.
neighbouring position of the phenyl substituent (Scheme 1).
Furthermore, regioselective dimetalation methods were also
developed in order to introduce substituents into the pyrrole
and the benzene ring in C
(Scheme 1).
a and C2 positions, simultaneously
(2, Scheme 2), the key intermediate of several new atropisomeric 1-
phenyl-1H-pyrrole derivatives.12
All reactions were straightforward and expeditious. For exam-
ple, 1-[2-(trifluoromethyl)phenyl]pyrrole (1) was dimetalated
according to the latter mentioned protocol in the synthesis of 1-[2-
carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid
However, further functionalization of such compounds (e.g., 2)
could not be accomplished using the above mentioned organo-
metallic route. Selective, stepwise introduction of different sub-
stituents into the Ca and C2 positions as well as regioselective
introduction of any substituent into C
required another synthetic approach.
b position of the pyrrole ring
In spite of the fact that no data have been available on the
brominations of 1-[2-(trifluoromethyl)phenyl]-1H-pyrrole (1),
* Corresponding author. Tel.: þ36 1 463 3652; fax: þ36 1 463 3648; e-mail ad-
dress: ffaigl@mail.bme.hu (F. Faigl).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.070

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F. Faigl et al. / Tetrahedron 68 (2012) 4259e4266
Table 1
Synthesis of brominated 1-[2-(trifluoromethyl)phenyl]-1H-pyrroles in different
COOH
COOH
1) 2.4 eq. n-BuLi/KOtBu
N
N
conditionsa,b
F3C
F3C
Et2O, − 40 °C
2) CO2
Entry
Solvent
Brominated productsc
2,3- and 2,4-d
2,3,5-
3) H+/H2O
90%
2-
2,5-
1
2
1
2
3
THF
12
<1
9
<1
88
55
74
89
99
6
13
10
1
<1
d
19
3
1
<1
d
1
CHCl3
DMF
DMF
DMF
12
d
d
d
Scheme 2. Synthesis of dicarboxylic acid 2.
4e
5e,f,g
a
NBS (2 M equiv) was used at 25 ꢀC.
Results are given in %.
Positions of the bromine are given below.
Results in the first column belong to compound dF ꢁ58.8 ppm and the results in
b
c
detailed investigations of such reactions were carried out in our
laboratory with the aim of developing highly regioselective bro-
minations of 1 and several other 1-phenyl-1H-pyrrole derivatives.
According to our strategy, combinations of regioselective bromi-
nations and organometallic reactions (e.g., metalations and halo-
gen/metal exchange reactions) could serve as efficient, regioflexible
methods for multifunctionalization of the above mentioned 1-
phenyl-1H-pyrrole derivatives.
d
the second column belong to compound dF ꢁ58.9 ppm (282 MHz DMSO-d6).
e
The reaction was carried out at 0 ꢀC.
NBS (1 M equiv) was used.
Conversion of the starting material was 94%.
f
g
Br
Br
2 eq. NBS
N
N
2. Results and discussion
F3C
F3C
DMF, 0 °C
98%
2.1. Improved synthesis of 1-[2-(trifluoromethyl)phenyl]-1H-
pyrrole (1)
1
3
Scheme 4. Synthesis of 2,5-dibromo-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole (3).
In initial studies, compound 1 was prepared from 2-(tri-
fluoromethyl)aniline and cis,trans-2,5-dimethoxytetrahydrofuran
according to the classical synthesis, in glacial acetic acid.11,16
However, product 1 is acid sensitive, so the reaction resulted
in the formation of tarry by-products. The desired product
was obtained in higher yield when only a catalytic amount
(1 mol %) of p-toluenesulfonic acid was added into the toluene
solution of the reactants. Under these conditions much less by-
product formed and the workup procedure was also easier
(Scheme 3).
2.3. Regioselective bromination of 1-[2-carboxy-6-
(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid (2) and
its dimethyl ester (5)
Recently we have reported the synthesis and optical
resolution of 1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-
2-carboxylic acid (2).12 A good opportunity to improve the optical
stability of 2 is the introduction of a bulky substituent into the
unsubstituted side of the pyrrole ring (in Ca0 or Cb0 position).
Therefore bromination of 2 was carried out under the same con-
ditions as it was made at the parent compound (1). A slight excess
of NBS (10 mol %) was necessary to achieve complete conversion of
NH2
1 mol% p-TsOH
N
F3C
+
F3C
MeO
OMe
toluene, reflux
92%
O
2
into the C
b0 brominated compound (4, 4-bromo-1-[2-(tri-
fluoromethyl)phenyl]-1H-pyrrole, sole product, Scheme 5).
1
Scheme 3. Synthesis of 1-[2-(trifluoromethyl)phenyl]-1H-pyrrole (1).
Br
COOH
COOH
COOH
COOH
1.1 eq. NBS
N
N
F3C
F3C
DMF, 0 °C
95%
2.2. Regioselective dibromination of 1-[2-(trifluoromethyl)
phenyl]-1H-pyrrole (1)
2
4
Bromination of compound 1 was initially attempted using N-
bromosuccinimide (NBS) under a variety of conditions similar to
the literature procedure.13e15 Mono, and dibromo derivatives
were isolated, and a small amount of 2,3,5-tribromo-1-[2-(tri-
fluoromethyl)phenyl]-1H-pyrrole was also found in one reaction.
Separation of the above mentioned products from their mixture is
complicated and purification steps cause significant waste of these
materials. In addition, monobromination provided the desired
product in 88% selectivity, only (Table 1, entry 5).
Scheme 5. Selective b
0-bromination of dicarboxylic acid 2.
Bromination
of
methyl
1-[2-methoxycarbonyl-6-(tri-
fluoromethyl)phenyl]-1H-pyrrole-2-carboxylate (5) was in-
vestigated under the same reaction conditions. Using 1 equiv of
NBS, 6 was obtained as a sole product (Scheme 6).
Br
Therefore dibromination was carried out with 2 equiv of NBS.
As a result of the trials DMF was found to be a more suitable
solvent for the reaction than tetrahydrofuran or chloroform.
Under the optimized conditions (at 0 ꢀC), formation of 2,5-
dibromo-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole (3) occurred
with very high regioselectivity (99%) and in good yield (Scheme
4, Table 1).
COOMe
COOMe
COOMe
COOMe
1 eq. NBS
N
N
F3C
F3C
DMF, 0 °C
98%
5
6
Scheme 6. Selective b
0-bromination of the diester 5.

F. Faigl et al. / Tetrahedron 68 (2012) 4259e4266
4261
The structure of 6 was determined by 1H NMR spectroscopic
methods and the Cb0 position of bromine was confirmed by single
crystal X-ray diffraction measurement (Fig. 1).
observed in the bromination reaction of compound 8. The synthesis
of this tricyclic 1-phenyl-1H-pyrrole derivative was accomplished
several years ago in our laboratory.18 The bromination using NBS in
DMF was much slower than in the above mentioned cases. Despite
the smaller electron-withdrawing effect of the substituent in C
a
(compared to the methyl carboxylate group in case of compound 5),
the reaction was as Cb0 selective as in case of 5. The high selectivity
can be rationalized if one takes into consideration that the
CaeNeC1eC2 torsional angle is much smaller than it can be in the
cases of 2 or 5 because the benzoxazepine ring keeps the pyrrole
and phenyl rings close to the coplanar position. Therefore the steric
effect of the C6 substituent (CF3 group) is more significant.
The structure of 9 was determined by 1H NMR spectroscopic
methods and the Cb0 position of bromine was confirmed by single
crystal X-ray diffraction measurements (Fig. 2).
The reaction was also carried out starting from optically active
(R)-8, which gave benzoxazepine derivative (R)-9 in almost quan-
titative yield, with no loss of ee (Scheme 8).
2.5. Regioselective synthesis of the C
a,C2-dibrominated (10)
and the C ,C
a
a
0,C2-tribrominated (11) derivatives of 1-[2-
(trifluoromethyl)phenyl]-1H-pyrrole (1)
As shown in Scheme 4 and Table 2, dibromination of 1
occurred in two consecutive reactions and resulted in the 2,5-
dibromo compound (3). Another regioisomer, namely the Ca,C2-
dibrominated compound could be prepared via regioselective
dimetalation followed by a metal/halogen exchange reaction
(Scheme 9). Metalation of 1-[2-(trifluoromethyl)phenyl]-1H-pyr-
role (1) was accomplished according to our previously reported
Fig. 1. Ortep style diagram of the final crystal structure of 6 with atomic numbering
and 30% probability anisotropic displacement ellipsoids for non-H atoms.17
method.12 The C
a,C2-dilithiated organometallic compound formed
As mentioned above, earlier attempts to achieve selective bro-
mination of methyl 1H-pyrrole-2-carboxylate using a selection of
brominating agents were unseccesful.13 The best results reported
by these authors were obtained with bromine in carbon tetra-
with high regioselectivity, and its reaction with 1,2-dibromoethane
gave compound 10 in good yield (88%).
Compound 10 was found to be stable, and could easily be
Ca,Ca
0,C2-tribrominated derivative (11)
chloride when the Cb
0/Ca0 substitution ratios were in between 6/1
converted into the
using 1 M equiv of NBS with excellent regioselectivity (>99%)
(Scheme 10).
to 10/1, furthermore random bromination of the different pyrrole
positions was observed when N-bromosuccinimide was used as
brominating agent. Comparison of these results with our experi-
This new and highly efficient synthesis of compound 11 and
preparation of the other, above mentioned brominated derivatives
of 1 have opened new routes to produce new, multifunctionalised
atropisomeric 1-arylpyrrole derivatives having C1-symmetry. This
route is the step by step transformation of the halogen atoms into
the suitable groups by organometallic reactions, especially bro-
mine/lithium exchange reactions followed by addition of electro-
philic reagents. In the following we demonstrate that
advantageous chemical transformation strategy with several ex-
amples where carbon dioxide was used as the electrophile. It has to
be mentioned, that the precursors to the acids having invariably
been lithium species, any functional entity besides the carboxylic
group could have been introduced into the aromatic nucleus in the
same way.
mental findings, let us to conclude that the observed very high Cb0
-
regioselectivities in the cases of bromination of compounds 2 and 5
are due to two effects. One is the electron-withdrawing effect of the
carboxylic group or the carboxylic ester group in position Ca, the
other is the sterical effects of the two ortho substituents (at C2 and
C6) on the phenyl moiety.
We observed the slow formation of the Ca b
0,C 0-dibrominated
product (7) when an excess of NBS was used. Therefore addition of
the accurate amount of NBS is very important to produce the de-
sired monohalogenated derivative (6) in pure form. On the other
hand, compound 7 can be prepared by the addition of 2 equiv of
NBS into the DMF solution of the starting material 5 (Scheme 7).
Br
2.6. Stepwise transformation of the brominated compounds
(3 and 11) into different carboxylic acid derivatives
COOMe
COOMe
Br
COOMe
COOMe
2 eq. NBS
N
N
F3C
F3C
DMF, 0°C
88%
First the symmetrically substituted 2,5-dibromo-1-[2-(tri-
fluoromethyl)phenyl]-1H-pyrrole (3) was tested for the synthesis of
mono- and dicarboxylic acid derivatives via a bromine/lithium
exchange followed by the reaction with carbon dioxide. The re-
action of 3 with an equivalent amount of n-butyllithium followed
by carboxylic acid formation gave the corresponding mono-
brominated acid (12) (Scheme 11).
5
7
Scheme 7. Dibromination of compound 5.
2.4. Regioselective bromination of 4,4,6,6-tetraphenyl-10-
trifluoromethyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine (8)
The structure of 12 was determined by 1H NMR spectroscopy
and the Ca0 position of bromine was confirmed by single crystal X-
ray diffraction (Fig. 3).
The combined directing effects of the above mentioned elec-
tronic and steric behaviours of the substituents could also be

4262
F. Faigl et al. / Tetrahedron 68 (2012) 4259e4266
Fig. 2. Ortep style diagram of the final crystal structure of 9 with atomic numbering and 30% probability anisotropic displacement ellipsoids for non-H atoms.17
Br
1) 1 eq. n-BuLi,
Et2O, −75°C
Ph
O
Ph
O
Br
Br
Br
COOH
N
N
Ph
Ph
F3C
F3C
1 eq. NBS
N
N
2) CO2
3) H+/H2O
85%
F3C
F3C
DMF, 0 °C
96%
Ph
Ph
Ph
Ph
3
12
8
9
Scheme 11. Formation of monocarboxylic acid 12 via a bromine/lithium exchange
reaction.
Scheme 8.
b
0-Bromination of the benzoxazepine derivative 8.
Table 2
Reaction of 11 with 1 equiv of n-butyllithiuma followed by the reaction with carbon
dioxide
Entry
Solvent
Product ratiob (15/16)
Yieldc (%)
1
2
THF
Et2O
35/65
80/20
89
60
a
All reactions were carried out at ꢁ75 ꢀC for half an hour.
Product ratios were determined by 19F NMR spectroscopy.
Yield of the crude product mixture.
b
c
Br
Br
1) 2.4 eq. n-BuLi/KOtBu
N
N
F3C
F3C
Et2O, − 40°C
2) (CH2Br)2
88%
1
10
Scheme 9. Regioselective Ca,C2-dibromination of 1 via dimetalation.
Br
N
Br
Br
Br
1 eq. NBS
N
F3C
Br
F3C
DMF, 0 °C
94%
10
11
Fig. 3. Ortep style diagram of the final crystal structure of 12 with atomic numbering
and 30% probability anisotropic displacement ellipsoids for non-H atoms.17
Scheme 10. Synthesis of the tribrominated compound 11.

F. Faigl et al. / Tetrahedron 68 (2012) 4259e4266
4263
When 2 equiv of n-butyllithium were used the expected di-
1) 2 eq. n-BuLi,
Et2O, − 75 °C
Br
Br
Br
Br
COOH
COOH
carboxylic acid (13) was obtained in low yield. The step by step
exchange of the bromines proved to be more efficient. Thus we
could prepare 13 from 12 in good yield (Scheme 12, 80%).
N
N
F3C
F3C
2) CO2
3) H+/H2O
87%
17
11
1) 2 eq. n-BuLi,
Et2O, − 75 °C
Scheme 15. Selective synthesis of dicarboxylic acid 17.
Br
COOH
HOOC
F3C
COOH
N
N
F3C
2) CO2
In this case, probably the ortho directing effect of the C
a
- (or
3) H+/H2O
80%
C2) monolithiated moiety determined the structure of the position
of the second bromine/lithium exchange. This reaction sequence
also provided a new, practically useful product (17). The bromo
substituent in the Ca0 position could be converted into any other
functions by another consecutive bromine/lithium exchange,
electrophile substitution reaction sequence, while the two car-
boxylic acids could potentially be transformed into any other
functions.
12
13
Scheme 12. Preparation of dicarboxylic acid 13.
Compound 13 is potentially a valuable intermediate in the
synthesis of new atropisomeric 1-phenyl-1H-pyrrole derivatives
having C1-symmetry because of the possible selective trans-
formation of the carboxylic groups.
Previous investigations into the regioselective mono- and dime-
talations of compound 1 followed by carboxylation enabled us to
prepare dicarboxylic acid 2 and 2-pyrrolo-3-trifluoromethylbenzoic
acid but we could not synthesize the regioisomeric 1-[2-(tri-
fluoromethyl)phenyl]-1H-pyrrole-2-carboxylic (14) by direct metal-
ation. With the monobrominated monocarboxylic acid 12 in hand
compound 14 could be easily prepared by consecutive bromine/lith-
ium exchange reaction followed by aqueous hydrolysis of the or-
ganometallic intermediate (Scheme 13).
3. Conclusion
Combined application of regioselective brominations and or-
ganometallic (metalation and/or bromine/metal exchange) re-
actions enabled us to prepare several new multisubstituted 1-
phenyl-1H-pyrrole derivatives. All selective brominations were
accomplished with NBS in dimethylformamide solution under mild
conditions.
Comparison of the directing effects of the two different C
a
substituents (bromine in preparation 3 and 11, carboxylic func-
tions in preparation of 4 and 6) led us to conclude that the dif-
ferent electronic effects of these substituents significantly
influence the result of the next bromination reaction. Even though
both substituents have ꢁI effects they have different mesomeric
effects. This difference, together with the steric (and electronic)
effects of the substituents in the C2 and C6 positions of the ben-
zene ring resulted in highly regioselective brominations in Ca0 of
the 2-bromopyrrole moiety (products 3 and 11) and clean Cb0
bromination of the 2-carboxyl group containing compounds
(products 4 and 6). These findings led us to develop novel,
regioflexible methods for the synthesis of multisubstituted de-
rivatives of 1-phenylpyrroles by consecutive applications of bro-
mination and lithium/bromine exchange reactions followed by
addition of carbon dioxide.
1) 2 eq. n-BuLi,
Et2O, − 75 °C
Br
COOH
COOH
N
N
F3C
F3C
2) H2O
3) H+/H2O
90%
12
14
Scheme 13. Synthesis of carboxylic acid 14.
Stepwise bromine/lithium exchange starting from the tri-
brominated compound 11 is an exciting challenge. First one
bromine atom was exchanged to lithium using 1 equiv of n-butyl-
lithium in different solvents (Scheme 14).
The synthetized new compounds (3, 4, 6, 9, 10e17) demonstrate
the usefulness of the novel regioflexible synthetic method.
Br
Br
Br
Br
Br
Br
COOH
Br
1) 1 eq. n-BuLi
2) CO2
N
N
N
+
F3C
F3C
COOH
F3C
4. Experimental section
4.1. General
11
15
16
Scheme 14. Reaction of 11 with 1 equiv of n-butyllithium followed by the reaction
with carbon dioxide.
All commercial starting materials were purchased from
SigmaeAldrich and Merck-Schuchardt and were used without
further purification. Tetrahydrofuran and diethyl ether were
obtained anhydrous by distillation from sodium wire after the
characteristic blue colour of the in situ generated sodium
diphenylketyl had been found to persist. The organometallic re-
actions and the reductions were carried out in Schlenk-flasks
under a dry nitrogen atmosphere. TLC was carried out on Kie-
selgel 60 F254 (Merck) sheets (called front with UV or the aqueous
solution of (NH4)6Mo7O24, Ce(SO4)2 and sulfuric acid). Routine 1H,
13C and 19F NMR spectra were recorded in CDCl3, acetone-d6 or
DMSO-d6 solution on a BRUKER AV 300 or DRX 500 spectrometer.
Proton chemical shifts are reported in parts per million relative to
the internal standard (dTMS¼0 ppm) or solvents (dAcetone¼2.05,
dDMSO¼2.50 ppm), carbon chemical shifts are reported in ppm
relative to the solvent (dChloroform¼77.0). The equipment was
In tetrahydrofuran the product ratio reflected the statistically
expected numbers (Table 2, entry 1), but in diethyl ether formation
of 15 dominated against 16.
The observed strong solvent effect can be explained if the
electron-withdrawing effect of the trifluoromethyl substituent of
the benzene ring is also taken into consideration beside the dif-
ferent solvating abilities of tetrahydrofuran and diethyl ether.
When the bromine/lithium exchange reaction was accom-
plished with 2 equiv of n-butyllithium in diethyl ether, the reaction
resulted in the selective formation of the C
a,C2-dilithiated com-
pound, which was converted into 5-bromo-1-[2-carboxy-6-(tri-
fluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid by reaction
with an excess of dry ice (Scheme 15).

4264
F. Faigl et al. / Tetrahedron 68 (2012) 4259e4266
calibrated to CFCl3
(
dFluorotrichloromethane¼0 ppm) for fluorine
as colourless oil (0.270 g, 93%, purity 88%). Analyses were obtained
from measurements of the product mixture. Retention time:
10.3 min; dH (300 MHz DMSO-d6) 7.94 (1H, dd, J 7.5, 1.2 Hz), 7.85
(1H, t, J 7.5 Hz), 7.76 (1H, t, J 7.5 Hz), 7.48 (1H, d, J 7.5 Hz), 7.04 (1H, s),
6.34 (1H, dd, J 3.3, 1.8 Hz), 6.27 (1H, t, J 3.3 Hz); dC (75 MHz DMSO-
d6) 136.5, 133.5, 131.7, 130.0, 126.9 (q, J 5.6 Hz), 126.4 (q, J 27.3 Hz),
125.5, 122.8 (q, J 274.2 Hz), 111.1, 109.7, 103.1; dF (282 MHz DMSO-
d6) ꢁ59.9. HRMS (ESI): MHþ, found 289.9799. C11H7Br2F3N requires
289.9792.
The dibromination was tested with 2 M equiv amount of NBS in
THF, chloroform and DMF solvents at room temperature as well.
The relative amounts of bromo-1-[2-(trifluoromethyl)phenyl]-1H-
pyrroles are given in Table 1. The other halogenated products
formed [compound, retention time (GC), 19F NMR (282 MHz DMSO-
d6)]: 2,3- and 2,4-dibromo-1-[2-(trifluoromethyl)phenyl]-1H-pyr-
roles, 17.5 min, dF ꢁ58.9 and 17.7 min, dF ꢁ58.8; 2,3,5-tribromo-1-
[2-(trifluoromethyl)-phenyl]-1H-pyrrole, 28.1 min, dF ꢁ59.5.
chemical shifts. IR spectra were recorded on an appliance
type PERKIN ELMER 1600 with a Fourier Transformer. Data-
are given in cmꢁ1. Specific rotation of the optically active sample
was determined on a PERKIN ELMER 245 MC polarimeter using
sodium lamp (589 nm). Melting points were determined on
a Gallenkamp Melting Point Apparatus (in capillaries). High res-
olution mass spectra (HRMS) were recorded on Waters LCT Pre-
mier XE spectrometer in electrospray ionization (ESI, 2.5 or
3.5 kV) mode using water (0.035% trifluoroacetic acid)/acetoni-
trile (0.035% trifluoroacetic acid) as eluent in gradients (5e95%
acetonitrile); samples were made up in acetonitrile. The 79Br
isotope (M¼78.91834) was used for the calculation and data
interpretation of the bromine containing compounds. Single
crystal X-ray diffraction measurements were accomplished
using a Rigaku R-AXIS RAPID diffractometer (graphite mono-
ꢁ
chromator Cu K
a
radiation,
l
¼1.54187 A).
CCDC 851927 (for 6), CCDC 851926 (for 9) and CCDC 851925 (for
12) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_-
request/cif.
4.2.4. 4-Bromo-1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-
pyrrole-2-carboxylic acid (4). To a stirred solution of 1-[2-carboxy-
6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic
acid12
2
(1.00 mmol, 0.300 g) in DMF (3 mL) a solution of N-bromosucci-
nimide (1.10 mmol, 0.196 g) in DMF (2 mL) was added dropwise at
0 ꢀC. Stirring was continued for 2 h after the addition of NBS. Ethyl
acetate (5 mL) and water (15 mL) were added, the phases were
separated and the aqueous phase was washed with ethyl acetate
(3ꢂ5 mL). The organic solutions were collected and dried over
sodium sulfate and concentrated in vacuo. The residue was crys-
tallised from chloroform (2 mL) to yield 4 as a white crystalline
solid (0.345 g, 91%); mp: 217e218 ꢀC (decomp.); nmax (KBr) 3130,
4.2. Synthesis
4.2.1. 1-[2-(Trifluoromethyl)phenyl]-1H-pyrrole (1).11 2-(Trifluoro-
methyl)aniline (100 mmol, 12.4 mL) and cis,trans-2,5-dimethoxy-
tetrahydrofuran (105 mmol, 13.6 mL) were dissolved in toluene
(40 mL). After the addition of p-tolunesulfonic acid (1.00 mmol,
0.17 g, 1 mol %) the reaction mixture was heated at reflux for 1 h.
The solution was washed with aqueous sodium carbonate (2 M,
10 mL), water (20 mL) and dried over sodium sulfate. The toluene
was evaporated and the residue was distillated in vacuo to yield
pure 1 as a colourless oil (19.4 g, 92%); bp: 64 ꢀC/0.3 mmHg; dH
(250 MHz CDCl3) 7.79 (1H, dd, J 7.6,1.0 Hz), 7.61 (1H, td, J 7.6,1.0 Hz),
7.50 (1H, t, J 7.8 Hz), 7.40 (1H, d, J 7.8 Hz), 6.88e6.80 (2H, m), 6.33
(2H, t, J 2.1 Hz).
3008, 2896, 1707, 1678, 1485, 1434, 1283, 1149, 1133 cmꢁ1
; dH
(300 MHz acetone-d6) 9.07 (2H, br s), 8.20 (1H, d, J 7.8 Hz), 7.90 (1H,
d, J 7.8 Hz), 7.62 (1H, t, J 7.8 Hz), 7.05 (1H, d, J 1.8 Hz), 6.82 (1H, s); dC
(75 MHz acetone-d6) 165.3, 160.5, 138.7 (d, J 1.6 Hz), 135.7, 133.1,
131.0 (q, J 5.2 Hz), 130.8, 130.5, 129.4 (q, J 30.3 Hz), 127.8, 124.1 (q, J
273.4 Hz), 119.5, 97.2; dF (282 MHz acetone-d6) ꢁ60.6 (s); HRMS
(ESI): MHþ, found 377.9600. C13H8BrF3NO4 requires 377.9589.
4.2.2. 2,5-Dibromo-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole (3). A
solution of N-bromosuccinimide (40.0 mmol, 7.12 g) in DMF (15 mL)
was added dropwise over 15 min to a stirred solution of 1-[2-(tri-
fluoromethyl)phenyl]-1H-pyrrole 1 (20.0 mmol, 4.22 g) in DMF
(30 mL) at 0 ꢀC. Stirring was continued for 20 min after the addition
of NBS was complete. The reaction was monitored by TLC (hexane,
Rf¼0.44). Hexane (40 mL) and water (70 mL) were added, the
phases were separated and the aqueous phase was extracted with
hexane (3ꢂ25 mL). The organic solutions were collected and most
of the solvent was evaporated. The residue was filtered through
a short silica column, eluted with hexane and concentrated in
vacuo to yield pure 3 as a white crystalline material (7.37 g, 96%,
regioselectivity 99%). The samples were analyzed by GC (Agilent
4890 D instrument equipped with an Agilent J&W HP-1 capillary
4.2.5. Methyl 4-bromo-1-[2-methoxycarbonyl-6-(trifluoromethyl)-
phenyl]-1H-pyrrole-2-carboxylate (6). Methyl 1-[2-methoxy-car-
bonyl-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylate16
5
(1.00 mmol, 0.327 g) was dissolved in DMF (3 mL). A solution of N-
bromosuccinimide (1.00 mmol, 0.178 g) in DMF (2 mL) was added
dropwise to the stirred solution at 0 ꢀC. Stirring was continued for
2 h after the addition of NBS. The reaction was monitored by TLC
(toluene, Rf¼0.15). Ethyl acetate (5 mL) and water (15 mL) were
added, the phases were separated and the aqueous phase was
washed with ethyl acetate (3ꢂ5 mL). The organic solutions were
collected and dried over sodium sulfate and concentrated in vacuo
to yield 6 as a white crystalline solid (0.398 g, 98%); mp: 90e92 ꢀC;
nmax (KBr) 3133, 2956, 1736, 1720, 1535, 1457, 1440, 1267, 1219,
1137 cmꢁ1
; dH (300 MHz CDCl3) 8.18 (1H, d, J 7.8 Hz), 7.95 (1H, d, J
column (0.250 mm/0.25
m
m, 30 m, 70e160 ꢀC, 10 ꢀC/min, 100 kPa))
7.8 Hz), 7.67 (1H, t, J 7.8 Hz), 7.06 (1H, s), 6.83 (1H, s), 3.69 (3H, s),
3.66 (3H, s); dC (75 MHz CDCl3) 164.3, 159.9, 137.5, 134.3,131.4, 130.1
(q, J 5.1 Hz), 129.2, 129.1 (q, J 30.8 Hz), 126.2, 122.6 (q, J 274.1 Hz),
119.0, 117.1, 97.3, 52.8, 51.4; dF (282 MHz CDCl3) ꢁ60.3 (s); HRMS
(ESI): MHþ, found 405.9903. C15H12BrF3NO4 requires 405.9902.
and 19F NMR (282 MHz DMSO-d6) measurements. Retention time:
14.8 min; mp: 40e41 ꢀC; nmax (KBr) 3133, 3076, 1651, 1504, 1460,
1426, 1388, 1317, 1139 cmꢁ1
; dH (500 MHz DMSO-d6) 7.99 (1H, d, J
7.8 Hz), 7.90 (1H, t, J 7.8 Hz), 7.83 (1H, t, J 7.8 Hz), 7.49 (1H, d, J
7.8 Hz), 6.45 (2H, s); dC (75 MHz DMSO-d6) 134.8 (d, J 1.8 Hz), 133.9,
132.4, 131.1, 127.5 (q, J 30.6 Hz), 127.3 (q, J 4.9 Hz), 122.8 (q, J
274.2 Hz), 112.4, 103.3; dF (282 MHz DMSO-d6) ꢁ59.6 (s); HRMS
(ESI): MHþ, found 367.8911. C11H7Br2F3N requires 367.8897.
4.2.6. Methyl 4,5-bromo-1-[2-methoxycarbonyl-6-(trifluoromethyl)-
phenyl]-1H-pyrrole-2-carboxylate (7). Methyl 1-[2-methoxy-car-
bonyl-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylate16
5
(1.00 mmol, 0.327 g) was dissolved in DMF (3 mL). A solution of
N-bromosuccinimide (2.00 mmol, 0.356 g) in DMF (4 mL) was
added dropwise to the stirred solution at 0 ꢀC. Stirring was con-
tinued for 2 h after the addition of NBS. The reaction was moni-
tored by TLC (toluene, Rf¼0.3). Ethyl acetate (5 mL) and water
4.2.3. 2-Bromo-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole. The halo-
genation of 1 (1.00 mmol, 0.211 g) was carried out with 1 mol equiv
amount of NBS (1.00 mmol, 0.178 g) using the procedure described
above, to yield 2-bromo-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole

F. Faigl et al. / Tetrahedron 68 (2012) 4259e4266
4265
(15 mL) were added, the phases were separated and the aqueous
phase was washed with ethyl acetate (3ꢂ5 mL). The organic so-
lutions were collected, dried over sodium sulfate and concen-
trated in vacuo. The crude product was purified by flash
chromatography in toluene to yield 6 as a colourless oil (0.427 g,
88%); nmax (KBr) 3132, 3003, 2955, 1735, 1721, 1606, 1477, 1439,
[2-bromo-6-(trifluoromethyl)phenyl]-1H-pyrrole 10 (7.02 mmol,
2.58 g) in DMF (22 mL) at 0 ꢀC. Stirring was continued for 20 min
after the addition of NBS was complete. Hexane (30 mL) and water
(60 mL) were added, the phases were separated and the aqueous
phase was washed with hexane (3ꢂ20 mL). The organic solutions
were collected and most of the solvent was evaporated. The residue
was filtered through a short silica column, eluted with hexane and
concentrated in vacuo to yield pure 11 as a white crystalline ma-
terial (2.94 g, 94%); mp: 68e69 ꢀC; nmax (KBr) 3422, 1524, 1476,
1260, 1148 cmꢁ1
; dH (300 MHz CDCl3) 8.31 (1H, d, J 7.8 Hz), 8.00
(1H, d, J 7.8 Hz), 7.72 (1H, t, J 7.8 Hz), 7.14 (1H, s), 3.72 (3H, s), 3.65
(3H, s); dC (75 MHz CDCl3) 163.7, 159.3, 136.8 (d, J 1.4 Hz), 134.9,
130.9, 130.7 (q, J 5.0 Hz), 129.8, 129.6 (q, J 30.9 Hz), 126.6, 122.3 (q,
J 274.4 Hz), 119.4, 114.3, 100.6, 52.8, 51.5; dF (282 MHz CDCl3)
ꢁ60.9 (s); HRMS (ESI): MHþ, found 482.8935. C15H11Br2F3NO4
requires 482.8929.
1458, 1311, 1291, 1211, 1178, 1133, 1089 cmꢁ1
; dH (300 MHz CDCl3)
7.95 (1H, d, J 8.1 Hz), 7.81 (1H, d, J 8.1 Hz), 7.52 (1H, t, J 8.1 Hz), 6.37
(2H, s); dC (75 MHz CDCl3) 136.9, 135.1 (d, J 0.8 Hz), 131.7 (q, J
31.5 Hz), 131.2, 128.2, 126.2 (q, J 3.7 Hz), 121.9 (q, J 274.9 Hz), 113.1,
102.7; dF (282 MHz CDCl3) ꢁ61.0 (s). HRMS (ESI): MHþ, found
445.8013. C11H6Br3F3N requires 445.8002.
4.2.7. (R)-2-Bromo-4,4,6,6-tetraphenyl-10-(trifluoromethyl)-4H,6H-
pyrrolo-[1,2-a][4,1]benzoxazepine(9). Compound (R)-817 (1.00 mmol,
0.558 g) was dissolved in DMF (5 mL) and a solution of N-bromo-
succinimide (1.00 mmol, 0.178 g) in DMF (2 mL) was added dropwise
to the stirred solution at 0 ꢀC. Stirring was continued for 2 h after the
addition of NBS. The reaction was monitored by TLC (hexane/ethyl
acetate¼10/1, Rf¼0.5). Ethyl acetate (5 mL) and water (20 mL) were
added, the phases were separated and the aqueous phase was
washed with ethyl acetate (3ꢂ5 mL). The organic solutions were
collected, dried over sodium sulfate and concentrated in vacuo to
4.2.10. General procedure for the synthesis of carboxylic acids
from bromo-1-[2-(trifluoromethyl)phenyl]-1H-pyrroles. The bromo-
compound (0.50 mmol) was dissolved in dry diethyl ether (4 mL)
under a dry nitrogen atmosphere and was cooled to ꢁ75 ꢀC. A
hexane solution of n-butyllithium (0.50 mmol, 315 mL, 1.6 M) was
added dropwise and after 15 min stirring the reaction mixture was
cooled to ꢁ190 ꢀC with liquid nitrogen. Dry ice was added to the
solid mixture and the melting suspension was continuously stirred
with a glass stick. After warming up to room temperature the sol-
vent was changed to ethyl acetate and a solution of aqueous hy-
drogen chloride (2 M, 2 mL) was added into it. The phases were
separated and the aqueous phase was washed with ethyl acetate
(3ꢂ4 mL) then the collected organic phases were dried over sodium
sulfate and concentrated in vacuo.
yield (S)-9 as a white solid (0.610 g, 96%); mp: >250 ꢀC; ½a D25
ꢁ326.2
ꢃ
(c 0.5, CHCl3); nmax (KBr) 3447, 3150, 3094, 3058, 3026, 1599, 1482,
1462, 1447, 1313, 1172, 1129, 1026 cmꢁ1
; dH (500 MHz CDCl3) 8.55
(1H, br s), 7.80 (2H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.60 (1H, br s),
7.41 (1H, d, J 7.5 Hz), 7.35e7.29 (4H, m), 7.25e7.22 (2H, m), 7.18 (1H,
br s), 7.07 (1H, t, J 7.3 Hz), 7.02e6.93 (5H, m), 6.86 (1H, t, J 7.3 Hz),
6.80 (1H, d, J 8.0 Hz), 6.67 (1H, br s), 6.63e6.59 (2H, m), 5.53 (1H, d, J
1.5 Hz); dC (75 MHz CDCl3) 145.6, 145.0, 144.5, 143.9, 139.7, 137.1,
135.8, 134.9, 129.9, 128.5, 128.1 (q, J 5.3 Hz), 127.9, 127.6, 127.2, 127.0,
126.8, 126.7, 126.5, 126.4, 126.4, 126.3, 124.3, 124.3 (q, J 30.4 Hz),124.2
(q, J 3.8 Hz), 123.2 (q, J 273.6 Hz), 117.1, 97.0, 85.4, 80.7; dF (282 MHz
CDCl3) ꢁ56.5 (s); HRMS (ESI): MHþ, found 636.1152. C37H26BrF3NO
requires 636.1150.
4.2.11. 2-Bromo-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole-5-
carboxylic acid (12). The reaction was carried out starting
from compound 3 (0.50 mmol, 0.185 g). The crude product was
purified by column chromatography (hexane/ethyl acetate¼2/1,
Rf¼0.22e0.35). The pure product 12 is a white solid (0.142 g,
85%); mp: 163e166 ꢀC (decomp.); nmax (KBr) 3423, 2880, 2662,
2609, 1673, 1539, 1442, 1414, 1317, 1128 cmꢁ1
; dH (300 MHz CDCl3)
4.2.8. 2-Bromo-1-[2-bromo-6-(trifluoromethyl)phenyl]-1H-pyrrole
(10). Potassium tert-butoxide (17.3 mmol, 1.94 g) was suspended
in dry diethyl ether (30 mL) under a dry nitrogen atmosphere
then it was cooled to ꢁ75 ꢀC stirred continuously and a hexane
solution of n-butyllithium (17.3 mmol, 10.8 mL, 1.6 M) was added
dropwise into the reaction mixture. After stirring for 30 min, 1-[2-
(trifluoromethyl)phenyl]-1H-pyrrole 1 (7.11 mmol, 1.50 g) was
added. The cooling bath was changed to ꢁ40 ꢀC and stirring was
continued for 1 h at the given temperature. The mixture was
cooled to ꢁ75 ꢀC and 1,2-dibromoethane (17.5 mmol, 1.5 mL) was
added and the reaction mixture was allowed to warm up. At
25 ꢀC, water (12 mL) was added, then the phases were separated
and the aqueous phase was extracted with diethyl ether
(5ꢂ5 mL). The organic solutions were collected and the solvent
was evaporated. The residue was dissolved in hexane (10 mL)
filtered through a short silica column, eluted with hexane and
concentrated in vacuo, to give 10 as a white solid (2.31 g, 88%);
mp: 79e80 ꢀC; nmax (KBr) 3129, 3108, 3080, 1973, 1911, 1722, 1647,
10.30 (1H, br s), 7.77 (1H, d, J 7.2 Hz), 7.64 (1H, t, J 8.1 Hz), 7.59
(1H, t, J 8.1 Hz), 7.24 (1H, d, J 7.2 Hz), 7.11 (1H, d, J 3.3 Hz), 6.38
(1H, d, J 3.3 Hz); dC (75 MHz CDCl3) 164.0, 136.5 (d, J 1.5 Hz), 132.4,
130.8, 129.5, 128.3 (q, J 31.1 Hz), 127.0 (q, J 4.9 Hz), 125.6, 122.7 (q,
J 273.8 Hz), 120.3, 114.1, 112.7; dF (282 MHz CDCl3) ꢁ61.4 (s).
HRMS (ESI): MHþ, found 333.9683. C12H8BrF3NO2 requires
333.9690.
4.2.12. 1-[2-(Trifluoromethyl)phenyl]-1H-pyrrole-2,5-dicarboxylic
acid (13). The reaction was carried out starting from the cooled
diethyl ether solution of compound 12 (0.50 mmol, 0.167 g) by
addition of 2 M equiv amount of n-butyllithium (1.00 mmol, 625 mL,
1.6 M, hexane solution). The crude product was purified by column
chromatography (hexane/ethyl acetate¼2/1, Rf¼0.05e0.18). Pure 13
is a white solid (0.120 g, 80%); mp: >250 ꢀC; nmax (KBr) 3423, 2925,
2745, 1697, 1533, 1459, 1419, 1353, 1320, 1260, 1170 cmꢁ1
; dH
(300 MHz DMSO-d6) 12.62 (2H, br s), 7.78 (1H, d, J 7.5 Hz), 7.69 (1H,
t, J 7.5 Hz), 7.62 (1H, t, J 7.5 Hz), 7.41 (1H, d, J 7.5 Hz), 6.99 (2H, s); dC
(75 MHz DMSO-d6) 160.3, 137.8 (q, J 2.1 Hz), 132.5, 130.5, 130.0,
128.8, 126.1 (q, J 4.9 Hz), 125.8 (q, J 30.0 Hz), 123.4 (q, J 273.3 Hz),
116.4; dF (282 MHz DMSO-d6) ꢁ60.0 (s); HRMS (ESI): MHþ, found
300.0478. C13H9F3NO4 requires 300.0484.
1594, 1461, 1313 cmꢁ1
; dH (300 MHz CDCl3) 7.91 (1H, d, J 8.0 Hz),
7.77 (1H, d, J 8.0 Hz), 7.47 (1H, t, J 8.0 Hz), 6.72 (1H, s), 6.35 (2H,
s); dC (75 MHz CDCl3) 136.8, 131.1 (q, J 31.2 Hz), 130.5, 127.7, 125.9
(q, J 5.1 Hz), 123.6, 122.2 (q, J 274.4 Hz), 111.8, 110.6, 109.2, 103.7; dF
(282 MHz CDCl3) ꢁ60.6 (s). HRMS (ESI): MHþ, found 367.8888.
C11H7Br2F3N requires 367.8897.
4.2.13. 1-[2-(Trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid
(14). The reaction was carried out starting from compound 12
(0.50 mmol, 0.167 g). In this case, after the addition of the hexane
4.2.9. 2,5-Dibromo-1-[2-bromo-6-(trifluoromethyl)phenyl]-1H-pyr-
role (11). A solution of N-bromosuccinimide (7.02 mmol, 1.25 g) in
DMF (8 mL) was added dropwise to a stirred solution of 2-bromo-1-
solution of n-butyllithium (1.00 mmol, 625
mL, 1.6 M), water was
poured into the reaction mixture and it was allowed to warm up to

4266
F. Faigl et al. / Tetrahedron 68 (2012) 4259e4266
room temperature. The crude product was purified by column
chromatography (hexane/ethyl acetate¼2/1, Rf¼0.3). Pure 14 is
a white solid (0.115 g, 90%); mp: 140e141 ꢀC; nmax (KBr) 3046, 2880,
pure 17 as a white solid (0.165 g, 87%); mp: 200e202 ꢀC (decomp.);
nmax (KBr) 3422, 3047, 2925, 1710, 1677, 1542, 1325, 1284, 1156,
1138 cmꢁ1
; dH (300 MHz acetone-d6) 8.38 (1H, dd, J 8.1 Hz, 1.2 Hz),
2626, 2563, 1677, 1609, 1538, 1441, 1322, 1298, 1138 cmꢁ1
;
dH
8.09 (1H, dd, J 8.1 Hz, 1.2 Hz), 7.85 (1H, t, J 8.1 Hz), 7.85 (1H, d, J
3.9 Hz), 6.41 (1H, d, J 3.9 Hz); dC (75 MHz acetone-d6) 165.0, 160.6,
138.2 (q, J 1.6 Hz), 136.0, 133.1, 131.4 (q, J 5.2 Hz), 130.9, 130.1 (q, J
30.5 Hz), 128.3, 124.0 (q, J 273.7 Hz), 118.9, 113.2, 113.0; dF (282 MHz
acetone-d6) ꢁ61.2 (s); HRMS (ESI): MHþ, found 377.9597.
C13H8BrF3NO4 requires 377.9589.
(300 MHz CDCl3) 10.21 (1H, br s), 7.74 (1H, d, J 7.2 Hz), 7.58 (1H, t, J
7.7 Hz), 7.53 (1H, t, J 7.7 Hz), 7.30 (1H, d, J 7.2 Hz), 7.14 (1H, d, J
1.8 Hz), 6.90 (1H, s), 6.31 (1H, d, J 1.8 Hz); dC (75 MHz CDCl3) 165.0,
138.4 (d, J 1.4 Hz), 132.2, 131.4, 130.1, 128.8, 127.5 (q, J 30.8 Hz), 126.6
(q, J 5.0 Hz), 124.3, 123.0 (q, J 273.5 Hz), 119.9, 109.6; dF (282 MHz
CDCl3) ꢁ60.6 (s); HRMS (ESI): MHþ, found 256.0574. C12H9F3NO2
requires 256.0585.
Acknowledgements
4.2.14. Synthesis of carboxylic acids 15 and 16. The reactions were
carried out starting from compound 11 (0.50 mmol, 0.223 g) in dry
diethyl ether as well as in dry tetrahydrofuran (4 mL) and after
30 min stirring the reaction mixture was cooled with liquid nitro-
gen according to the general procedure. The product ratios of the
formed compounds and the yields of the crude products are given
in Table 2. Analyses were obtained from the mixture of compounds
15 and 16.
This work is connected to the scientific program of the ‘De-
velopment of quality-oriented and harmonized RþDþI strategy and
functional model at BME’ project. The project is supported by the
New Hungary Development Plan (Project ID: TAMOP-4.2.1/B-09/1/
KMR-2010-0002).
ꢀ
References and notes
4.2.14.1. 2,5-Dibromo-1-[2-carboxy-6-(trifluoromethyl)phenyl]-
1H-pyrrole (15). dH (300 MHz DMSO-d6) 13.38 (1H, br s), 8.30 (1H,
d, J 7.8 Hz), 8.19 (1H, d, J 7.8 Hz), 7.93 (1H, t, J 7.8 Hz), 6.39 (2H, s); dC
(75 MHz DMSO-d6) 164.7, 135.1, 134.2, 134.1 (d, J 1.7 Hz), 131.4, 130.6
(q, J 4.9 Hz), 129.0 (q, J 30.9 Hz), 122.5 (q, J 274.6 Hz), 112.3, 103.7; dF
(282 MHz DMSO-d6) ꢁ59.2 (s); HRMS (ESI): MHþ, found 411.8804.
C12H7Br2F3NO4 requires 411.8796.
1. Remers, W. A.; Rao, S. N.; Singh, U. C.; Kollman, A. J. Med. Chem. 1986, 29,
1256e1263.
2. Campiani, G.; Morelli, E.; Fabbrini, M.; Nacci, V.; Greco, G.; Novellino, E. J. Med.
Chem. 1999, 42, 4462e4470.
3. Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn, M. R.; Emmert, D. E.;
Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.; Hutchinson, D. K.; Morris,
J.; Reischer, R. J.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert,
D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953e970.
4. Tatsuta, K.; Itoh, M. J. Antibiot. 1994, 47, 602e605.
5. WO 2010/042626 patent application (CAN 152:476951).
6. Faigl, F.; Fogassy, K.; Thurner, A.; Toke, L. Tetrahedron 1997, 53, 4883e4888.
4.2.14.2. 2-Bromo-1-[2-bromo-6-(trifluoromethyl)phenyl]-1H-
pyrrole-5-carboxylic acid (16). dH (300 MHz DMSO-d6) 12.53 (1H, br
s), 8.15 (1H, d, J 8.1 Hz), 7.94 (1H, d, J 7.8 Hz), 7.67 (1H, t, J 8.0 Hz),
7.05 (1H, d, J 3.9 Hz), 6.57 (1H, d, J 3.9 Hz); dC (75 MHz DMSO-d6)
159.8, 137.2, 135.9 (d, J 1.6 Hz), 131.5, 128.8 (q, J 30.5 Hz), 126.4 (q, J
4.9 Hz), 126.3, 126.2, 122.4 (q, J 274.4 Hz), 118.4, 112.7, 111.2; dF
(282 MHz DMSO-d6) ꢁ60.2 (s); HRMS (ESI): MHþ, found 411.8791.
C12H7Br2F3NO4 requires 411.8796.
}
ꢀ
ꢀ
}
7. Faigl, F.; Fogassy, K.; Szanto, Z.; Lopata, A.; Toke, L. Tetrahedron 1998, 54,
4367e4374.
ꢀ
}
}
8. Fogassy, K.; Kovacs, K.; Keseru, G. M.; Toke, L.; Faigl, F. J. Chem. Soc., Perkin Trans.
1 2001, 1039e1043.
9. Faigl, F.; Vas Feldhoffer, B.; Thurner, A. Synth. Commun. 2006, 36, 2841e2849.
ꢀ
ꢀ ꢀ
10. Faigl, F.; Vas Feldhoffer, B.; Kubinyi, M.; Pal, K.; Tarkanyi, G.; Czugler, M. Tet-
rahedron: Asymmetry 2009, 20, 98e103.
}
ꢀ
}
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11. Faigl, F.; Fogassy, K.; Szucs, E.; Kovacs, K.; Keseru, M. G.; Harmath, V.; Bocskei, Z.;
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Toke, L. Tetrahedron 1999, 55, 7881e7892.
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12. Fogassy, K.; Harmat, V.; Bolcskei, Z.; Tarkanyi, G.; Toke, L.; Faigl, F. Tetrahedron:
Asymmetry 2000, 11, 4771e4780.
4.2.15. 2-Bromo-1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-pyr-
role-5-carboxylic acid (17). The reaction was carried out starting
from compound 11 (0.50 mmol, 0.223 g) using the general pro-
cedure. In this case 2 M equiv of n-butyllithium (1.00 mmol, 625 mL,
1.6 M, hexane solution) was added to the precooled reaction mix-
ture. The crude product was recrystallized from chloroform to yield
13. Andersson, H. J.; Lee, S. F. Can. J. Chem. 1965, 43, 409e414.
14. Gilow, H. M.; Burton, D. E. J. Org. Chem. 1981, 46, 2221e2225.
15. Hasse, K.; Willis, A. C.; Banwell, M. G. Eur. J. Org. Chem. 2011, 1, 88e99.
16. Gross, H. Chem. Ber. 1962, 95, 2270e2275.
17. Program PLATON Spek, A. L. Acta Crystallogr. 2009, D65, 148e155.
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18. Faigl, F.; Tarkanyi, G.; Fogassy, K.; Tepfenhart, D.; Thurner, A. Tetrahedron 2008,
64, 1371e1377.