Efficient synthesis of optically active 1-(2-carboxymethyl-6-ethylphenyl)-1H-pyrrole-2-carboxylic acid: a novel atropisomeric 1-arylpyrrole derivative

Article abstract of DOI:10.1016/j.tetasy.2009.01.010

An efficient synthesis and resolution of (±)-1-(2-carboxymethyl-6-ethylphenyl)-1H-pyrrole-2-carboxylic acid has been developed for the preparation of novel optically active atropisomers. The ee values were measured by a ¹H NMR spectroscopic met

Full text of DOI:10.1016/j.tetasy.2009.01.010

Tetrahedron: Asymmetry 20 (2009) 98–103
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient synthesis of optically active 1-(2-carboxymethyl-6-ethylphenyl)-1H-
pyrrole-2-carboxylic acid: a novel atropisomeric 1-arylpyrrole derivative
a
Ferenc Faigl a,b, , Bernadett Vas-Feldhoffer , Miklós Kubinyi c,d, Krisztina Pál c,
*
Gábor Tárkányi c, Mátyás Czugler c
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1111 Budapest, Budafoki út 8, Hungary
b Research Group for Organic Chemical Technology, Hungarian Academy of Sciences, H-1111 Budapest, Budafoki út 8, Hungary
c Institute of Structural Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1025 Budapest, Pusztaszeri út 59-67, Hungary
d Department of Physical Chemistry and Materials Science, Budapest University of Technology and Economics, H-1111 Budapest, Budafoki út 8, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis and resolution of ( )-1-(2-carboxymethyl-6-ethylphenyl)-1H-pyrrole-2-carboxylic
acid has been developed for the preparation of novel optically active atropisomers. The ee values were
measured by a 1H NMR spectroscopic method using quinidine as the chiral complexing agent. Absolute
configurations of the separated enantiomers were determined using single crystal X-ray diffraction mea-
surements of both the disodium salt and the (R)-1-phenylethylamine salt of the enantiomerically pure
dicarboxylic acid, separately. The analysis of the CD spectra with the aid of TD-DFT quantum chemical
calculations confirmed the assignment of configurations.
Received 9 October 2008
Accepted 20 January 2009
Available online 13 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
mercially available 2-ethyl-6-methylaniline and functionalisation
of one side of the pyrrole ring could already provide a racemic
Recently, numerous new C1-symmetric compounds have been
published as outstanding chiral ligands in transition metal catalysts
or as organocatalysts in enantioselective reactions. Besides proline1
and other pyrolidine derivatives,2–4 which contain asymmetric cen-
tre(s) in the molecules, compounds with axial chirality elements5,6
have also been applied in such reactions providing optically ac-
tive products in high ee, similar to the results achieved with
the well-known C2-symmetric ligands7 (e.g., BINOL,8 and TAD-
DOL9 and derivatives, Scheme 1). Several years ago, we described
the synthesis of 1-(2-carboxy-6-trifluoromethyl-phenyl)pyrrole-
2-carboxylic acid 1 (Scheme 1) enantiomers,10 the very first rep-
resentatives of the optically active, atropisomeric 1-arylpyrrole
derivatives.
mixture of atropisomers via a short synthetic route. Molecular
modelling calculations demonstrated that the rotational barriers
around the C(1)–N bond in 1-(2,6-disubstituted phenyl)-1H-pyr-
role-2-carboxylic acids are around 30–40 kcal/mol or higher
(AM1 calculations); high enough to separate and keep the enan-
tiomers of the target molecules for a long time without sponta-
neous racemisation at ambient temperature. Herein, the
development of efficient synthesis and resolution of 1-(2-car-
boxymethyl-6-ethylphenyl)-1H-pyrrole-2-carboxylic acid
3
is
reported.
2. Results and discussion
It was also demonstrated that 1 is an outstanding shift re-
agent for determination of the ee values of dialkylaminomethyl
group containing chiral oxirane, oxetane and cis-but-2-ene-1,4-
diol derivatives by 1H NMR spectroscopy.11 Recently, several
new 1-(substituted phenyl)pyrrole derivatives have been syn-
thesised in our laboratory with the aim of further investigation
of their regioselective metallation reactions.12,13 In spite of the
fact that alkyl substituents of the benzene ring in C(2) and/or
C(6) positions decrease reactivity of the molecule against metal-
lation, we have choosen 1-(2-ethyl-6-methylphenyl)pyrrole 2 as
a model compound because it can be easily prepared from com-
2.1. Synthesis of 1-(2-carboxymethyl-6-ethylphenyl)-1H-pyrrole-
2-carboxylic acid 3
The starting material 2 was prepared from 2-ethyl-6-methy-
laniline and 2,5-dimethoxytetra-hydrofuran by Gross’s method,14
and then reacted with two molar equivalents of N,N,N0,N0-tetra-
methylethylenediamine-activated butyllithium (BuLi–TMEDA) in
diethyl ether (DEE) with the lithiated species being quenched
with dry ice at ꢀ75 °C. The crude products contained mixtures
of a dicarboxylic acid 3 and monocarboxylic acids 4 and 5
(Scheme 2). The yields and product ratios depended on the dura-
tion and the temperaure of the lithiation step (Table 1). The best
results could be achieved with a 3 h lithiation reaction at 23 °C
(Table 1, line 4).
* Corresponding author. Tel.: + 36 1 463 3652; fax: +36 1 463 3648.
E-mail address: ffaigl@mail.bme.hu (F. Faigl).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.01.010

F. Faigl et al. / Tetrahedron: Asymmetry 20 (2009) 98–103
99
Ph
Ph
O
O
OH
OH
COOH
COOH
N
OH
OH
F3C
Ph
Ph
TADDOL
BINOL
1
Scheme 1. Structures of BINOL, TADDOL and dicarboxylic acid 1.
COOH
N
Et
COOH
N
a, b,
Et
Me
3
c
COOH
N
N
2
Et
Me
Et
+
COOH
4
5
Scheme 2. Consecutive dilithiation and carboxylation of 2 (reaction conditions: (a) 2(TMEDA-BuLi), (b) CO2, (c) H+/H2O).
most racemic composition of the enantiomers of 3 in the crystal-
line phase while a much purer enantiomer remained in the
filtrate (Scheme 4). This method could be used for medium pure
samples of 3. Crystallisation of the racemate indicated that forma-
tion of the heterochiral associates is preferred against the homo-
chiral ones in solution (the melting points: rac-3: 212–213 °C;
(ꢀ)-3: 144–146 °C).
Table 1
Conditions and results of the consecutive dilithiation and carboxylation of 2
Conditions
Products (ratioa)
Yieldb (%)
Et2O, 0 °C, 2 h
Et2O, 0 °C, 4 h
Et2O, 22 °C, 2 h
Et2O, 23 °C, 3 h
3 + 4 + 5 (62:3:35)
3 + 5 (77:23)
3 + 4 + 5 (93:1:6)
3 + 4 + 5 (92:1:7)
19
49
77
80
The second method for enantiomeric enrichment was the re-
peated resolution of non-racemic enantiomeric mixtures with opti-
cally active 1-phenylethylamine. More than 90% of the major
enantiomer could be isolated from the diastereoisomeric salt in
>99% ee when the molar amount of the (R)-6 or (S)-6 resolving agent
used was equivalent to the molar amount of the major enantiomer
content of the enantiomeric mixture. Thus, both pure enantiomers
of 3 could be prepared using the corresponding enantiomer of 6.
Enantiomeric compositions (ee values) of the optically active
samples were determined by 1H NMR spectroscopy. Quinidine was
applied as a chiral shift reagent and the resonances of the b-protons
of the pyrrole ring were used for ee determination. On the basis of
these measurements, the specific rotation power of the enantiome-
a
Product distribution was determined from the 1H NMR spectra of the crude
product mixture.
b
The yield of the isolated crude carboxylic acid mixture related to the starting
material 2.
Pure dicarboxylic acid 3 was isolated from the crude mixture by
simple recrystallisation from chloroform, due to the much smaller
solubility of 3 than that of the monocarboxylic acids 4 and 5.
2.2. Resolution of dicarboxylic acid 3
Resolution of 3 could be accomplished via diastereoisomeric
salt formation with half equivalent amount of (R)-1-phenylethyl-
amine ((R)-6) in a mixture of ethyl acetate and ethanol (Scheme 3).
It should be mentioned that ethyl alcohol had a crucial role in
the enantiomeric discrimination process because a racemic mix-
ture of 3 was found in the crystallised diastereoisomeric salt when
pure ethyl acetate was used as the solvent. The best results could
be achieved when 1 g of rac-3 was dissolved in 40 ml of ethyl ace-
tate containing 0.1 ml of ethanol. Under these conditions, (ꢀ)-3
crystallised in the diastereoisomeric salt with (R)-6 and it could
be separated from the reaction mixture in good yield and ee
(Scheme 3). On the other hand, increased amount of ethyl alcohol
radically decreased the yield and the enantiomeric excess of the
crystalline diastereoisomeric salt.
rically pure (+)-3: [a]D = +85.5 (c 1, ethanol), ee 100%).
2.3. Single crystal X-ray diffraction measurements
Our attempts to get single crystals from the enantiomerically
pure 3 samples have failed. Single crystal X-ray diffraction mea-
surements could be carried out using the disodium salt of (ꢀ)-3
which crystallised from an aqueous solution as a tetrahydrate.
The asymmetric unit arrangement of (ꢀ)-3ꢁNa2ꢁ(H2O)4 is shown
in Figure 1, some parameters of the unit cell of the crystal and
the diffraction measurement are listed in Table 2. The crystal struc-
ture reveals an infinite catemer-polymeric structure, which creates
pseudo centrosymmetric ladder-type arrangements in the vicinity
of the Na+ cations and their ligand sphere.
In order to prepare enantiomerically pure 3, two methods were
developed. First, the non-racemic enantiomeric mixture (ꢀ > +)-3
[or (+ > ꢀ)-3] could be recrystallised from ethanol providing an al-
A single crystal structuredetermination was also performed for the
(R)-(ꢀ)-3ꢁ(R)-6 salt, resulting in the structure depicted in Figure 2.

100
F. Faigl et al. / Tetrahedron: Asymmetry 20 (2009) 98–103
COOH
COOH
NH2
N
(+>-)-3 (in solution)
H
EtOAc,
EtOH
+
Et
Me
(->+)-3.(R)-6
HCl
3
(R)-6
rac-
3
(->>+)-
yield 83 %, ee 94 %
recryst. or repeated resoln.
(-)-3 ee >99 %
Scheme 3. Resolution of dicarboxylic acid 3.
COOH
COOH
Recrystallization,
EtOH
N
3
(-)-3 (in solution)
+
( )-
Et
yield 65 %
ee 83 %
yield 22 %
ee 1 %
(->+)-3, ee 65 %
Scheme 4. Enantiomeric enrichment of (ꢀ > +)-3 by recrystallisation.
Table 2
Selected crystal data for (R)-(ꢀ)-3ꢁNa2ꢁ(H2O)4 salt and (R)-(ꢀ)-3ꢁ(R)-6 salt
Property
Compound
(R)(ꢀ)-3ꢁNa2ꢁ(H2O)4
(R)-(ꢀ)-3ꢁ(R)-6
Formula weight
Crystal system
Space group
a (Å)
b (Å)
c (Å)
389.31
Orthorhombic
P212121 (No. 19)
7.828(1)
8.273(1)
27.154(4)
90
394.46
Monoclinic
P21 (No. 4)
10.7946(3)
6.6627(2)
14.3178(4)
90
a
(°)
b (°)
90
90
1758.5(4)
153
103.898(3)
90
999.61(5)
140
c
(°)
V (Å3)
T (K)
Crystal size (mm)
Z
0.09 ꢂ 0.15 ꢂ 0.18
0.05 ꢂ 0.05 ꢂ 0.20
4
2
D(calcd) (g/cm3)
1.470
1.311
Radiation
l(Å)
0.7107
1.5418
Tot./Uniq. Data, R(int)
56213, 1826, 0.101
1826, 254
0.0372, 0.0809, 1.08
n.a.
8837, 2191, 0.060
2191, 280
0.0400, 0.0916, 0.95
0.0(3)
Nref, Npar
Figure 1. Structure of the asymmetric unit from the (R)-(ꢀ)-3ꢁNa2ꢁ(H2O)4 catemer
R1, wR2, S
crystal.
Flack x
Some parameters of the unit cell of the (R)-(ꢀ)-3ꢁ(R)-6 salt crystal
and the diffraction measurement are also listed in Table 2.
Seemingly normal displacement ellipsoids for both crystal struc-
tures may exclude racemic twinning or rough errors such as space
group ambiguities. On the basis of these measurements, we could
not conclude with certainty on the absolute configuration of (ꢀ)-3
unequivocally. Uncertainty of the diffraction measurements stems
from a combination of the size and of inferior quality of the available
single crystals, also hampered possibly by a pseudo-centric arrange-
ment of Na+- and Oꢀ-ions in the (ꢀ)-3ꢁNa2ꢁ(H2O)4 salt.
zene derivatives cannot be applied here since the electronic systems
of the various chromophores are strongly interacting. The spectra of
the two isomers of 3 can be assigned by comparison with the spectra
of the stereochemically known isomers of 1, a molecule differing
from 3 only in possessing a CF3 group instead of an ethyl group in
the C(6) position of the benzene ring. As reported in an earlier paper,
the absolute configurations of the enantiomers of 1 could be deter-
mined reliably by XRD measurements, which concluded that (+)-1
corresponds to the (R)- and (ꢀ)-1 to the (S)-isomer.10 The CD spectra
obtained from (+)-(R)-1 and (ꢀ)-(S)-1 are shown in Figure 3b. As can
be seen, the spectrum of (+)-3 shows a close similarity to the spec-
trum of (ꢀ)-1, whereas the spectrum of (ꢀ)-3 looks similar to the
spectrum of (+)-1, which supports the assignment of (+)-3 as the
(S)- and (ꢀ)-3 as the (R)-isomer.
2.4. Determination of the absolute configuration by CD
spectroscopy
The CD spectra of (+)-3 and (ꢀ)-3 are shown in Figure 3a. The CD
spectroscopic empirical rules employed frequently for the determi-
nation of the absolute configuration of carbonyl compounds or ben-
More detailed information on the relationship between the ste-
reostructure and CD spectrum of 3 was obtained with help of the-

F. Faigl et al. / Tetrahedron: Asymmetry 20 (2009) 98–103
101
synthesis of atropisomeric 1-(disubstituted phenyl)pyrrole deriva-
tives. The conformationally stable dicarboxylic acid 3 could be pre-
pared in good yield and in 93% selectivity.
Resolution of 3 could be accomplished with a half equivalent
method using (R)-1-phenylethylamine (R)-6 as the resolving agent.
Efficiency (S = yield ꢂ ee)17 of the enantiomer separation strongly
depended on the ethanol content of the solvent. Without any eth-
anol almost racemic mixture crystallised in the diastereoisomeric
salt. The yield radically decreased if the ethyl acetate contained
more than 1% ethanol, and an optimum resolution could be
achieved when the ethanol content of the solvent was at about
0.3% (S = 0.78). The non-racemic enantiomeric mixture of com-
pound 3 behaved as a true racemate: an almost racemic mixture
crystallised from ethanol during rectrystallization while the enan-
tiomerically enriched mixture remained in the filtrate.
A sensitive 1H NMR method was also developed using quinidine
as the chiral complexing agent for the determination of the ee val-
ues of optically active dicarboxylic acid 3. The chiral alkaloid
seemed to be much better additive than the usual transition metal
containing shift reagents because of the narow shape of the NMR
peaks. In spite of the single crystal growing difficulties, a combina-
tion of the XRD measurements of (ꢀ)-3ꢁNa2ꢁ(H2O)4 and (ꢀ)-3ꢁ(R)-6
salts with comparative CD spectroscopic investigations and molec-
ular mechanics calculations on optically active dicarboxylic acids 1
and 3 provided strong evidence for the absolute configuration of
(R)-(ꢀ)-3 and (S)-(+)-3. The prepared new atropisomeric com-
pounds can serve as precursors of chiral ligands or building blocks.
Figure 2. The asymmetric unit structure of the (R)-(ꢀ)-3ꢁ(R)-6 salt in 50%
probability atomic displacements representation.
4
(a)
(-)-3
0
(+)-3
4. Experimental
4.1. General
-4
8
(b)
(+)-(R)-1
4
All commercial starting materials were purchased from FULKA
AG and Merk-Schuchardt and were used without further purifica-
tion. Diethyl ether and tetrahydrofuran were obtained anhydrous
by distillation from sodium wire after the characteristic blue colour
of in situ generated sodium diphenylketyl had been found to per-
sist. TMEDA was also distilled from sodium wire before use. Con-
centration of the butyllithium solution was determined by
double titration method.18 All experiments were carried out in
Schlenk-flasks under a dry nitrogen atmosphere.
0
-4
(-)-(S)-1
-8
200
250
300
350
wavelength [nm]
1H NMR and 13C NMR spectra were recorded in deuterochloroform
solution or hexadeutero dimethylsulfoxide solution at 300 MHz
proton resonance frequency (BRUKER DRX 300). The signals of COOH
groups are absent because their place and form are strongly concen-
tration dependent. Chemical shifts are given in ppm related to the
internal standard tetramethylsilane (d = 0 ppm). IR spectra were
recorded on an appliance type PERKIN ELMER 1600 with a Fourier
Transformer. Data are given in cmꢀ1. The UV and CD spectra were
obtained in ethanol. The UV spectra were taken on an Agilent 8453
diode array spectrometer, the CD spectra were recorded on a Jasco
J-810 spectropolarimeter.
Figure 3. Experimental CD spectra of the enantiomers of 1-arylpyrrole derivatives
3 and 1 in ethanol solution.
oretical chemical calculations carried out for the (S)-isomer. First, a
conformational analysis based on molecular mechanics calcula-
tions was performed. The geometries of the 15 most stable con-
formers were fully optimised then by density functional theory
(DFT) method. It was found that conformers (S)-3a and (S)-3b
(see Fig. 4a) have the lowest energies, their concentrations are
48% and 35%, respectively, at 25 °C. The energies, the oscillatory
strengths and the rotatory strengths of the electronic transitions
of these two conformers were computed in time-dependent DFT
(TD-DFT) calculations.15 The calculated CD spectrum of (S)-3 was
obtained as the weighted sum of the computed spectra of (S)-3a
and (S)-3b, presuming Gaussian band shapes of widths
4.2. X-ray data collections and structure determinations
The (ꢀ)-3ꢁNa2ꢁ(H2O)4 salt X-ray diffraction experiments were
carried out on a Rigaku R-AXIS Rapid IP diffractometer using an
X-Stream 2000 unit operating at T = 153 K. Data were collected
r
= 0.3 eV.16 The resulting spectrum is displayed in Figure 4b. As
can be seen, the calculated spectrum of (S)-3 is in satisfactory
agreement with the observed spectrum of (+)-3, providing further
evidence for the assignment of the absolute configuration.
using standard
x-scan procedures, with monochrome (graphite)
Mo radiation: C15H21NNa2O8 Fwt.: 389.31, colourless
Ka
chunk, size: 0.09 ꢂ 0.15 ꢂ 0.18 mm, orthorhombic, space group
P212121 (No. 19), a = 7.828(1) Å, b = 8.273(1) Å, c = 27.154(4) Å,
V = 1758.5(4) Å3, T = 153(2) K, Z = 4, DC = 1.470 Mg/m3, numerical
absorption correction (Tmax/Tmin = 0.971/0.985). 56,213 reflections,
3. Conclusion
1826 unique [Rint = 0.10]; and 1616 > 2
by direct methods, hydrogen atoms either calculated from as-
r(I), initial structure model
On the basis of our experimental results, we have concluded
that the organometallic approach can be applied efficiently to the

102
F. Faigl et al. / Tetrahedron: Asymmetry 20 (2009) 98–103
(a)
(S)-3a
(S)-3b
(b)
60
45
30
15
0
30
20
10
0
-15
-30
-45
-10
-20
200
250
300
wavelength [nm]
350
400
Figure 4. (a) The most stable conformers of (S)-3. (b) The theoretically calculated CD spectrum of (S)-3. The rotatory strengths of conformers (S)-3a and (S)-3b, weighted by
their molar ratios, are denoted by black and red bars, respectively.
sumed geometries or located from difference density maps and
kept riding, model refined by least-squares, final R1 = 0.0372 and
wR2 = 0.0809 for all (1826) intensity data, number of parame-
ters = 254, goodness-of-fit = 1.08, an absolute structure parameter
was not used/determined as Friedel pairs were merged in the
refinement procedure due to low anomalous dispersion with Mo
radiation.
3ꢁNa2ꢁ(H2O)4) and CCDC 690326 (for the (ꢀ)-3ꢁ(R)-6 salt). Copies
of the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223336033
or e-mail: deposit@ccdc.cam.ac.uk].
Compound 2 was prepared from 2-ethyl-6-methylaniline and
cis,trans-2,5-dimethoxy-tetrahydrofuran in glacial acetic acid
according to the literature procedure.14
The (ꢀ)-3ꢁ(R)-6 salt X-ray diffraction experiments were carried
out on an Oxford Diffraction Gemini CCD diffractometer at low
temperatures using an Oxford—Cryostream unit operating at
4.3. 1-(2-Ethyl-6-methylphenyl)pyrrole 213,14
82%; Bp 130–132 °C/22 mmHg; IR (film) mmax: 725, 759, 785
T = 140 K. Data were collected using standard
x
-scan procedures,
(ArC-H), 1495 (ArC-C), 2968 (AlkC-H); 1H NMR (CDCl3) dH: 7.23
(1H, d, J 7.5, Ph), 7.15 (1H, d, J 9.0, Ph), 7.13 (1H, t, J 9.0, Ph),
with monochrome (graphite) Cu K
a
radiation: C15H14NO4ꢁC8H12N,
Fwt.: 394.46, colourless chunk, size: 0.05 ꢂ 0.05 ꢂ 0.20 mm, mono-
clinic, space group P21 (No. 4), a = 10.7946(3) Å, b = 6.6627(2) Å,
c = 14.3178(4) Å, b = 103.898(3)°, V = 999.61(5) Å3, T = 140(2) K,
6.57–6.67 (2H, t like m, J 2.0 H ), 6.27–6.37 (2H, t like m, J 2.0,
a
Hb), 2.32 (2H, q, J 7.6, Et), 2.01 (3H, s, Me), 1.09 (3H, t, J 7.6, Et);
13C NMR (CDCl3) dC: 142.4, 139.5, 136.6, 128.4, 128.1, 126.6,
122.1, 108.6, 24.3, 17.5, 15.9.
Z = 2, DC = 1.311 Mg/m3, numerical absorption correction (Tmax
/
Tmin = 0.995/0.981). 8837 reflections, 2191 unique [Rint = 0.06];
and 1677 > 2 (I), initial structure model by direct methods, hydro-
r
4.4. Consecutive dimetallation and carboxylation of 2
Compound 2 (5.4 mmol, 1.00 g) was added at the desired tem-
perature, (Table 1) to a solution of the activating agent TMEDA
gen atoms either calculated from assumed geometries or located
from difference density maps and kept riding, model refined by
least-squares, final R1 = 0.0400 and wR2 = 0.0916 for all (2191)
intensity data, number of parameters = 280, goodness-of-fit =
0.95. The absolute structure parameter Flack x = 0.0(3) resulted in
a too high standard uncertainty from the refinement procedure
rendering the absolute structure unreliable. Crystallographic data
(excluding structure factors) for the structures in this paper have
been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers CCDC 690325 (for (ꢀ)-
(10.8 mmol, 1.26 g) and
a hexane solution of butyllithium
(1.3 mol/l, 11.88 mmol, 9.2 ml) in dry diethyl ether (15 ml). After
stirring for 1, 2, or 4 h at the desired temperature the reaction mix-
ture was quenched with dry ice. At 20 °C, distilled water (20 ml)
and diethyl ether (15 ml) were added, the phases were separated
and the aqueous solution was washed with diethyl ether
(3 ꢂ 15 ml). The aqueous solution was acidified with 15% citric acid
solution. The aqueous phase was extracted with ethyl acetate

F. Faigl et al. / Tetrahedron: Asymmetry 20 (2009) 98–103
103
(3 ꢂ 20 ml). The collected organic solutions were dried over so-
dium sulfate and concentrated in vacuo. Product distributions
were determined from the 1H NMR spectra of the crude acidic
products. In order to obtain the pure dicarboxylic acid 3, the crude
product was recrystallised from chloroform. The yield given below
in parentheses refers to the efficiency of the recrystallisation.
The products (after diastereoisomeric salt decomposition) were
(R)-(ꢀ)-3, mp 144–146 °C, [ D = ꢀ85.5 (c 1, ethanol) ee > 99%, CD
a
]
(ethanol, k [nm],
D
e
[Mꢀ1 cmꢀ1]): 271, +2.85; 233, ꢀ3.86 and (S)-
(+)-3 mp 144–146 °C, [a]D = +85.5 (c 1, ethanol), ee > 99%, CD (eth-
anol, k [nm],
D
e
[Mꢀ1 cmꢀ1]), respectively, 271, ꢀ2.64; 233, +3.09.
Other spectroscopic data of the optically active products were
identical with those of the racemic compound.
4.4.1. 1-(6-Carboxymethyl-2-ethylphenyl)pyrrole-2-carboxylic
acid 313
4.6. Enantiomeric enrichment of (ꢀ > +)-3 via recrystallisation
Colourless crystals (50% from chloroform) mp: 212–213 °C; IR
(KBr) m
max: 3448 (OH), 1667, 1716 (CO); 1H NMR (DMSO- d6) dH:
A sample of (+ > ꢀ)-3 (2.28 g, [
was recrystallised from ethanol (6.8 ml). The solid racemic was fil-
tered off (0.49 g, [ D = +0.9 (c 1, ethanol), ee 1%) then the filtrate
a]D = +56.4 (c 1, ethanol), ee 66%)
0.97 (3H, t, J 7.6, Et), 2.10 (2H, q, J 7.6, Et), 2.98 (1H, d, J 16.2
CH2), 3.28 (1H, d, J 16.2, CH2), 6.28–6.34 (1H, t like m, J 2.7, Hb),
6.77–6.82 (1H, t like m, J 1.7, H), 6.95–7.01 (1H q like m, J 1.5, H)
7.18–7.40 (3H, m, Ph); 13C NMR (DMSO-d6) dC: 172.1, 160.8,
141.1, 138.7, 132.9, 129.8, 128.2, 128.1, 127.2, 124.2, 117.5,
a]
was concentrated in vacuo to yield (+)-3 (1.45 g, [a]D = +70.9 (c 1,
ethanol), ee 83%).
109.2, 36.4, 23.5, 14.9. UV–vis (EtOH, k [nm],
e
[Mꢀ1 cmꢀ1]): 262,
5. Calculations
25300; 215 (sh), 28700.
Pure sample of the monocarboxylic acid 5 could be obtained by
monometallation of 2 in the presence of N,N,N0,N00,N00-pentamethy-
lethylenetriamine as it is described in the literature.13
The conformational analysis was carried out applying MMFF94
force field19 and Monte-Carlo algorithm. The quantum chemical
calculations were performed using the 5.9 version of TURBOMOLE pro-
gram package.20 The DFT and TD-DFT calculations were carried out
applying Becke-Perdew 86 (BP-86) functional21,22 in combination
with triple zeta valence polarised (TZVP) basis set23 (in DFT calcu-
lations) or with triple zeta valence double polarised (TZVPP) basis
set (in TD-DFT calculations), and using resolution of identity (RI)
approximation.24
4.4.2. 1-(6-Carboxymethyl-2-ethylphenyl)pyrrole 513
Colourless crystals (55% from hexane) mp: 132–133 °C; IR (KBr)
m
max: 3462 (OH), 1704 (CO); 1H NMR (DMSO- d6) dH: 7.12–7.48
(3H, m, Ph), 6.58–6.72 (2H, t like m, J 1.8, H ), 6.18–28 (2H, t like
a
m, J 1.8, Hb), 3.18 (2H, s, CH2), 2.21 (2H, q, J 7.6, Et), 1.00 (3H, t, J
7.6, Et); 13C NMR (DMSO-d6) dC: 172.5, 141.7, 139.0, 133.3, 128.6,
128.4, 127.7, 122.4, 108.7, 36.2, 23.7, 15.7.
The minor component 5 of the monocarboxylic acids crystal-
lised together with 4 from the filtrate of the recrystallised dicar-
boxylic acid 3, therefore its spectral data were partially
determined from that mixture.
Acknowledgements
Financial support from the Hungarian Scientific Research Fund
(OTKA) is gratefully acknowledged for Grants T 048362 and NF
72194. The authors thank Dr. M. Winter and Dr. N. Brooks at Oxford
Diffraction for the X-ray data collection of the (R)-(ꢀ)-3ꢁ(R)-6 salt.
The authors are grateful to Dr. Mihály Kállay for the fruitful discus-
sions. MC also acknowledges the National Science and Technology
Office for an X-ray diffractometer purchase Grant (MU-00338/2003).
4.4.3. 1-(2-ethyl-6-meylphenyl)pyrrole-2-carboxylic acid 413
Inamixturewith5, 1H NMR(DMSO-d6)dH: 7.10–7.40 (3H, m), 6.97
0
(1H, dd, J 2.2, 3.4, Hb), 6.92 (1H, t like m, J 2.0, H ), 6.32 (1H, t like m, J
a
0
3.1, Hb ), 2.13 (2H, q, J 7.5, Et), 1.83 (3H, s Me), 0.93 (3H, t, J 7.5, Me).
References
4.5. Resolution of 3
1. Hajós, Z. G.; Parris, D. R. J. Org. Chem. 1974, 39, 1615–1621.
2. Cao, Ch.-L.; Ye, M.-Ch.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901–2904.
3. Kondo, K.; Kazuta, K.; Fujita, H.; Sakamoto, Y.; Murakami, Y. Tetrahedron 2002,
58, 5209–5214.
4. Mino, T.; Tanaka, Y.; Sato, Y.; Saito, A.; Sakamoto, M.; Fujita, T. Tetrahedron Lett.
2003, 44, 4677–4679.
5. Hatano, M.; Yamanaka, M.; Mikami, K. Eur. J. Org. Chem. 2003, 14, 2552–2555.
6. Chen, Y.; Smith, M. D.; Shimizu, K. D. Tetrahedron Lett. 2001, 42, 7185–7187.
7. Ishitani, H.; Kamiyama, S.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762–766.
8. Yamagishi, T.; Yokomatsu, T.; Suemune, K.; Shibuya, S. Tetrahedron 1999, 55,
12125–12136.
Racemic dicarboxylic acid ( )-3 (21.5 mmol, 5.89 g) was dis-
solved in a hot mixture of ethyl acetate (235, 6 ml) and ethanol
(0.6 ml) and (R)-6 (10.79 mmol, 1.31 g) was added into it. The reac-
tion mixture was seeded with the (ꢀ)-3. (R)-6 diastereoisomeric
salt and it was allowed to crystallise during cooling to 20 °C. The
diastereoisomeric salt was filtered off, washed with ethyl acetate
(2 ꢂ 20 ml) and dried to yield white solid product (4.28 g, mp
184–186 °C, decomp.). This salt was dissolved in a mixture of ethyl
acetate (65 ml) and aqueous hydrochloric acid solution (5%, 30 ml).
The phases were separeted and the organic phase was washed with
5% aqueous hydrochloric acid solution (2 ꢂ 20 ml) and brine
(1 ꢂ 20 ml). Then, the organic solution was dried over sodium sul-
fate and concentrated in vacuo to yield (ꢀ)-3 (2.45 g, 83% of the
9. Seebach, D.; Pichota, A.; Beck, A. K.; Pinkerton, A. B.; Litz, T.; Karjalainen, J.;
Gramlich, V. Org. Lett. 1999, 1, 55–58.
}
10. Fogassy, K.; Harmat, V.; Böcskei, Zs.; Tárkányi, G.; Toke, L.; Faigl, F. Tetrahedron:
Asymmetry 2000, 11, 4771–4780.
11. Faigl, F.; Thurner, A.; Kovári, J.; Tárkányi, G.; Toke, L.; Mordini, A. Tetrahedron:
}
Asymmmetry 2002, 13, 59–68.
12. Faigl, F.; Thurner, A.; Vas, B.; Toke, L. J. Chem. Res. (S) 2003, 132–133.
}
13. Faigl, F.; Vas-Feldhoffer, B.; Thurner, A. Synth. Commun. 2006, 36, 2841–2849.
14. Gross, H. Chem. Ber. 1962, 95, 2270–2275.
(ꢀ)-enantiomer content of the racemate 3), [ D = ꢀ80.0 (c 1, eth-
a]
15. Autschbach, J.; Ziegler, T. J. Chem. Phys. 2002, 116, 891–896.
16. McCann, D. M.; Stephens, P. J. J. Org. Chem. 2006, 71, 6074–6098.
anol), ee 94%. The filtrate of the diastereoisomeric salt formation
was concentrated in vacuo and the (+ > ꢀ)-3 fraction (3.27 g,
111% of the (+)-enantiomer content of the racemate 3),
}
17. Fogassy, E.; Lopata, A.; Faigl, F.; Darvas, F.; Ács, M.; Toke, L. Tetrahedron Lett.
1980, 21, 647–648.
18. Schlosser, M. In Organometallics in Synthesis; Schlosser, M., Ed.; John Wiley:
Chichester, 2002; pp 295–297.
19. Halgren, A. J. Comput. Chem. 1996, 17, 490–519.
20. Ahlichs, R.; Bär, M.; Häser, M.; Horn, H.; Kölmel, C. Chem. Phys. Lett. 1989, 162,
165–169.
21. Becke, A. D. Phys. Rev. A 1988, 38, 3098–3100.
22. Perdew, J. P. Phys. Rev. B 1986, 33, 8822–8824.
23. Schäfer, A.; Huber, C.; Ahlrichs, R. J. Chem. Phys. 1994, 100, 5829–5835.
24. Weigend, F.; Häser, M. Theor. Chem. Acc. 1997, 97, 331–340.
[a]D = +58.3 (c 1, ethanol), ee 68%) was isolated from the residue
in an analogous way to the workup of the diastereomeric salt. Re-
peated resolution of the non-racemic enantiomeric mixtures was
carried out analogously but the amount of the applied resolving
agent was equivalent with the corresponding enantiomer content
of the starting optically active 3. The (ꢀ > +)-3 acid was resolved
with (R)-6 and (+ > ꢀ)-3 was treated with (S)-6 as resolving agent.