Organometallic approach to the functionalization of alkyl groups containing 1-phenylpyrroles

Article abstract of DOI:10.1080/00397910600770672

Novel regioselective methods have been developed for the mono- and difunctionalization of alkyl groups containing 1-phenylpyrroles using different organometallic reagents. Tailoring the reagents and conditions allowed us to prepare several new mono- and r

Full text of DOI:10.1080/00397910600770672

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Organometallic Approach to the
Functionalization of Alkyl Groups Containing
1‐Phenylpyrroles
Ferenc Faigl a , Bernadett Vas Feldhoffer a & Angelika Thurner a
a Research Group at Department of Organic Chemical Technology ,
Hungarian Academy of Sciences, Budapest University of Technology and
Economics , Budapest, Hungary
Published online: 16 Feb 2007.
To cite this article: Ferenc Faigl , Bernadett Vas Feldhoffer & Angelika Thurner (2006) Organometallic
Approach to the Functionalization of Alkyl Groups Containing 1‐Phenylpyrroles, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:19, 2841-2849, DOI:
10.1080/00397910600770672
To link to this article: http://dx.doi.org/10.1080/00397910600770672
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Synthetic Communicationsw, 36: 2841–2849, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600770672
Organometallic Approach to the
Functionalization of Alkyl Groups
Containing 1-Phenylpyrroles
Ferenc Faigl, Bernadett Vas Feldhoffer, and
Angelika Thurner
Research Group at Department of Organic Chemical Technology,
Hungarian Academy of Sciences, Budapest University of Technology and
Economics, Budapest, Hungary
Abstract: Novel regioselective methods have been developed for the mono- and
difunctionalization of alkyl groups containing 1-phenylpyrroles using different organo-
metallic reagents. Tailoring the reagents and conditions allowed us to prepare several
new mono- and rotationally restricted dicarboxylic acid derivatives of 1-(alkylphenyl)-
pyrroles in good yields.
Keywords: 1-Arylpyrroles, dimetallation, regioselective metallation
INTRODUCTION
Substituted 1-phenylpyrroles are building blocks for the synthesis of
numerous compounds that have antibiotic and fungicide properties,[1]
cytostatic effects,[2] or central nervous system (CNS) activities.[3] In many
cases, standard preparative methods afford these products in low yields
because of the sensitivity of the pyrrole ring to acidic conditions.[4] A con-
venient way to overcome this problem would be to use organometallic
reactions in the synthesis of such targets.[5] In past years, efficient
organometallic methods for functionalization of 1-phenylpyrroles that have
electron-withdrawing substituents in the phenyl ring have been developed in
Received in the U.K. October 24, 2005
Address correspondence to Ferenc Faigl, Research Group at Department of Organic
Chemical Technology, Hungarian Academy of Sciences, Budapest University of
Technology and Economics, H-1521 Budapest, Hungary. E-mail: ffaigl@mail.bme.hu
2841

2842
F. Faigl, B. Vas Feldhoffer, and A. Thurner
our laboratory.[5–8] These methods were successfully applied by others in the
synthesis of mono- and diphosphane derivatives of 1-phenylpyrrole for
palladium complexation.[9] However, data on site-selective mono- or dimetal-
lation of alkyl group containing 1-phenylpyrroles are practically missing from
the literature.[10]
1-(2-Ethylphenyl)pyrrole (1), 1-(2-ethyl-6-methylphenyl)pyrrole (2), and
2,5-dimethyl-1-(2-ethylphenyl)pyrrole (3) are easily accessible and quite
exciting model compounds for such metallation studies on alkyl-substituted
1-phenylpyrroles both from a theoretical and a practical point of view. First,
intramolecular competition among the Ca, C6 and all available benzylic
positions for hydrogen/metal interconversion can be studied to gain deeper
insight into the details of the organometallic base mediated site-selective func-
tionalization methods[11] because there are no data on the metallation of these
compounds in the literature. Second, introduction of different substituents into
the a vs. a0 positions of the pyrrole ring and into C2 vs. C6 positions of the
phenyl ring allowed us to prepare new representatives of 1-arylpyrrole-type
atropisomeric compounds. The very first member of that type of ligands
was prepared by our group,[12] and the optically active form of 1-[2-
carboxy-6-(trifluoromethyl)phenyl]pyrrole-2-carboxylic acid has been used
as a chiral discriminating agent for the determination of the ee values of
1
several optically active compounds by H NMR spectroscopy.[12]
To find efficient methods for the functionalization of the alkyl groups con-
taining model compounds 1, 2, and 3, systematic studies on their metallation
have been carried out in our laboratory.
RESULTS AND DISCUSSION
Consecutive treatment of 1-(2-ethylphenyl)pyrrole (1), 1-(2-ethyl-6-methyl-
phenyl)pyrrole (2), or 2,5-dimethyl-1-(2-ethylphenyl)pyrrole (3) with acti-
vated organometallic or alkali amide-type base and solid carbon dioxide
provided mono- and dicarboxylic acids (4–9) as mixtures or sole products
depending on the reaction conditions used. The reactions and the structures
of the products are shown in Scheme 1, and the conditions and results are
summarized in Table 1.
Compound 1 underwent perfect a monolithiation when it was treated
with N,N,N0,N00,N00-pentamethyldiethylenetriamine activated n-butyllithium
(BuLi-PMDTA). After quenching with dry ice, 4 was isolated as the sole
product, but the yield strongly depended on the reaction conditions. The
best results could be achieved at 08C in diethyl ether (Table 1, lines 1–4).
Metallation with lithium 2,2,6,6-tetramethyl-piperidide/potassium tert-
butoxide mixture (LiTMP-KOR) followed by carboxylation resulted in an
18:82 mixture of the two monocarboxylic acids 4 and 5 (Table 1, line 5),
showing the strong preference of the potassium-containing reagent to the
benzylic position of the model compound.

Metallation of 1-(Alkylphenyl)pyrroles
2843
Scheme 1.
Completely different site selectivity could be achieved by the use of
N,N,N0,N0-tetramethylethylenediamine activated butyllithium (BuLi-TMEDA)
at 08C in diethyl ether. In the first run, a 1:1 mixture of the a-mono- (4) and
the a,C6-dicarboxylic acid (6) was isolated, but the relative amount of the
compound 6 could be increased to 87% by fine-tuning the reaction conditions
Table 1. Conditions and results of metallation and consecutive carboxylation of 1, 2,
and 3
Starting
material
Products
(ratio)a
Yieldb
(%)
No.
Base (equivalent)
Conditions
1
2
1
1
1
1
1
1
1
1
2
2
2
2
2
3
3
BuLi-PMDTA (1)
BuLi-PMDTA (1)
BuLi-PMDTA (2)
BuLi-PMDTA (1)
LiTMP-KOR (1)
BuLi-TMEDA (2)
BuLi-TMEDA (2)
BuLi-TMEDA (2)
BuLi-PMDTA (1)
LiTMP-KOR (1)
LiC-KOR (1)
THF, 2758C, 1h 4 (100)
THF, 2758C, 4h 4 (100)
THF, 2758C, 1h 4 (100)
20
53
76
84
65
66
71
78
25
61
56
49
73
13
32
3
4
Et2O, 08C, 4h
4 (100)
5
THF, 2758C, 1h 4 þ 5 (18:82)
6
Et2O, 08C, 1h
Et2O, 08C, 4h
Et2O, 208C, 1h
4 þ 6 (50:50)
4 þ 6 (14:86)
4 þ 6 (13:87)
7
8
9
THF, 2758C, 1h 7 (100)
THF, 2758C, 4h 7 (100)
THF, 2758C, 1h 7 þ 8 (50:50)
10
11
12
13
14
15
BuLi-TMEDA (2)
BuLi-TMEDA (2)
LiTMP-KOR (1)
LiTMP-KOR (1)
Et2O, 08C, 4h
Et2O, 258C, 2h
7 þ 8 (23:77)
7 þ 8 (5:95)
THF, 2758C, 1h 9 (100)
THF, 2758C, 4h 9 (100)
1
aProduct ratios were determined from the H NMR spectra of the crude products.
bYields of the crude acidic products.

2844
F. Faigl, B. Vas Feldhoffer, and A. Thurner
(Table 1, lines 6–8). The dicarboxylic acid 6 could easily be separated from
the minor product by treatment of the crude mixture with chloroform
because the monocarboxylic acid 4 proved to be soluble in this solvent
whereas 6 remained in the solid phase.
Lithiation of 2 with BuLi-PMDTA reagent occured selectively at the
benzylic position of the methyl side instead of the a position (or the
benzylic methylene position), as was observed in the case of compound 1.
As a consequence, dry ice quenching resulted in compound 7 as the sole
product in low yield. Reasonable yield (Table 1, line 10) could be achieved
with the LiTMP-KOR reagent, which exclusively attacked the methyl substi-
tuent of the phenyl ring. The so-called Schlosser’s base (1:1 mixture of butyl-
lithium and potassium tert-butoxide[11]) attacked both the benzylic and the
pyrrole a positions, yielding a 1:1 mixture of mono- and dicarboxylic acids
(7 and 8). Efficient dilithiation of compound 2 could be achieved again with
the di-dentate TMEDA activated butyllithium in diethyl ether (Table 1,
lines 12 and 13). By-product ratios indicate that probably the second
lithium/hydrogen exchange promoted faster within a mixed aggregate, con-
taining the a metallated species and another activated butyllithium, than in
the mixed aggregate of the activated butyllithium and 1-(2-ethyl-6-lithio-
methylphenyl)pyrrole. Optimization of the reaction time and the temperature
let us to achieve 95% selectivity in this case (Table 1, line 13) and one crystal-
lization of the crude product provided the dicarboxylic acid 8 in pure form.
To demonstrate the importance of the unsubstituted a position in the
lithiation of 1-phenylpyrroles, metallation of 2,5-dimethyl-1-(2-ethylphenyl)-
pyrrole (3) has also been investigated (Table 1, lines 14 and 15). Compound 3
did not react with the tertiary amines activated butyllithium under standard
conditions because the two a-positions of the pyrrole ring were blocked and
the activity of the organometallic reagents was not enough to promote
hydrogen/lithium exchange in the benzylic methylene group or in aromatic
positions. The potassium-containing superbase (LiTMP-KOR), however,
selectively deprotonated the benzylic methylene of 3; thus, after carboxyla-
tion, 2,5-dimethyl-1-[2-(1-carboxyethyl)phenyl]pyrrole (9) was produced as
the sole product.
CONCLUSIONS
Comparison of the reaction conditions, listed in Table 1, with the known
literature data let us to conclude that the alkyl substituents strongly
decreased the reactivity of 1, 2, and 3 related to unsubstituted 1-phenylpyr-
role[8] and its electron-withdrawing groups containing derivatives.[5–7]
Outcome of the intramolecular competition for hydrogen/metal exchange
among the available a, C6, benzylic methylene, and benzylic methyl
positions could be efficiently governed by the quality of the reagents and
the reaction conditions. To rationalize the results, we considered several

Metallation of 1-(Alkylphenyl)pyrroles
2845
factors: (i) the relative acidity order of the previously mentioned positions for
metal/hydrogen exchange; (ii) the more ionic character of the organopotas-
sium-type compounds (e.g., metallation with LiTMP-KOR reagent) than the
organolithium species (metallation with BuLi-PMDTA or BuLi-TMEDA)
and the better charge distribution (stabilization) in a benzyl-type anion
compared to the case of an a-metallated, electron-rich pyrrole ring[11]
;
(iii) possible steric influence due to the alkyl groups in C2, C6 (compounds
1 and 2) or in a and a0 positions (compound 3); and (iv) the different coordi-
nation effects of the di-dentate (TMEDA) and three-dentate (PMDTA)
ligands[6,7] and the solvents (diethyl ether vs. tetrahydrofuran). Thus, clean
a-lithiation of compound 1 could be accomplished with the less polar,
three-dentate ligand activated butyllithium (BuLi-PMDTA), whereas the
potassium-containing (LiTMP-KOR) alkali amide reagent selectively
attacked the benzylic position of the 2-ethyl substituent, providing a more
polar benzylpotassium species in which the charge delocalization is
probably more efficient than it would be within the pyrrole ring. In
compound 2, the 6-methyl group contains more acidic hydrogen atoms than
the methylene group of the 2-ethyl substituent or the a position of the
pyrrole ring,[10] which is now deactivated by two alkyl substituents. Conse-
quently, both the lithium- and the potassium-containing organometallic
bases exclusively attacked the 6-methyl position. Because the a-positions of
the pyrrole ring are occupied by methyl groups in compound 3, the alkali
amide superbase (LiTMP-KOR) reacted with the only available benzylic
position of the 2-ethyl group. Thus, highly selective metalations of 1, 2, and
3 were accomplished, producing, after carboxylation, new monocarboxylic
acids 4, 7, and 9. Dimetallation of 1 and 2 could be carried out with the
di-dentate BuLi-TMEDA reagent at ambident temperature in diethyl ether,
and the two new dicarboxylic acids 6 and 8 were isolated in good yields.
Rotation around the N-C1 bond is hindered in these new C1 symmetrical
dicarboxylic acids; therefore, 6 and 8 seem to be suitable starting materials
for the preparation of new atropisomeric compounds.
EXPERIMENTAL
Generalities
All commercial starting materials were purchased from Fulka AG and Merck-
Schuchardt and were used without further purification. n-Butyllithium was
supplied by Chemetall GmbH Lithium Division, Frankfurt. Diethyl ether
and tetrahydrofuran were obtained anhydrous by distillation from sodium
wire after the characteristic blue color of in situ–generated sodium diphenylk-
etyl had been found to persist. TMEDA and PMDTA were also distilled from
sodium wire before use. Concentration of the butyllithium solution was
determined by the double titration method.[13] All experiments were carried

2846
F. Faigl, B. Vas Feldhoffer, and A. Thurner
out in Schlenk flasks under a dry nitrogen atmosphere. 1H NMR and 13C NMR
spectra were recorded in deuteriochloroform solution or hexadeuteriodi-
methylsulfoxide solution at 250 MHz (Bruker WP 250) or 300 MHz
(Bruker DRX 300) The signal of COOH group is absent because its place
and form are strongly concentration dependent. Chemical shifts are given in
parts per million (ppm) related to the internal standard tetramethylsilane
(d ¼ 0 ppm). IR spectra were recorded on a Perkin Elmer 1600 with a
Fourier transformer. Data are given in centimeters21
.
Preparation of 1-(Substituted phenyl)pyrroles
Compounds 1, 2, and 3 were prepared from the corresponding alkylanilines
and cis,trans-2,5-dimethoxytetrahydrofuran or acetonylacetone (in the case
of compound 3) in glacial acetic acid according to the literature procedure.[14]
1-(2-Ethylphenyl)pyrrole (1):[15] 73%; bp 120–1248C/18 mmHg; IR (KBr)
n
max: 725, 762 (ArC-H), 1502 (ArC-C), 2968 (AlkC-H); 1H NMR (CDCl3) dH:
1.10 (3H, t, J 7.6, Et), 2.52 (2H, q, J 7.6, Et), 6.27–6.38 (2H, t like m, J 2.0,
Hb), 6.73–6.83 (2H, t like m, J 2.0 Ha), 7.18–7.28 (2H, m, Ph), 7.28–7.37
(2H, m, Ph); 13C NMR (CDCl3) dC: 140.4, 140.3, 129.5, 128.1, 127.3,
126.6, 122.6, 108.8, 24.3, 15.4; MS (EI, m/z): 171 (Mþ), 170, 156, 144,
128, 103, 89, 77.
1-(2-Ethyl-6-methylphenyl)pyrrole (2):[14] 82%; bp 130–1328C/22 mmHg;
IR (KBr) nmax: 725, 759, 785 (ArC-H), 1495 (ArC-C), 2968 (AlkC-H); H
1
NMR (CDCl3) dH: 1.09 (3H, t, J 7.6, Et), 2.01 (3H, s, Me), 2.32 (2H, q, J
7.6, Et), 6.27–6.37 (2H, t like m, J 2.0, Hb), 6.57–6.67 (2H, t like m, J 2.0
Ha), 7.13 (1H, t, J 9.0, Ph), 7.15 (1H, d, J 9.0, Ph), 7.23 (1H, d, J 7.5, Ph);
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; MS (EI, m/z): 185 (Mþ), 184, 170, 144, 115, 91, 77.
2,5-Dimethyl-1-(2-ethylphenyl)pyrrole (3):[16] 74%; bp 128–1308C/
20 mmHg; IR (KBr) nmax: 751, 772, 1495 (ArC-C), 2959 (AlkC-H); 1H
NMR (CDCl3) dH: 1.09 (3H, t, J 7.7, Et), 1.92 (6H, s, Me), 2.16–2.35 (2H,
m, Et), 5.89 (2H, d, J 1.9, Hb), 7.14 (1H, d, J 7.5 Ph), 7.22–7.35 (1H, m,
Ph), 7.36 (2H, d, J 3.5, Ph); 13C NMR (CDCl3) dC: 142.9, 137.7; 129.2,
129.1, 128.8, 128.7, 126.7, 105.4, 23.5, 14.2, 12.8; MS (EI, m/z): 198 (Mþ-
H), 182, 168, 146, 90.
Metalation (General Procedure)
1-(Alkylphenyl)pyrrole (1, 2, or 3; 5.4 mmol, 0.92 g, 1.00 g or 1.08 g, respect-
ively) was added at the desired temperature to a solution of the activating

Metallation of 1-(Alkylphenyl)pyrroles
2847
agent [TMEDA (5.4 mmol, 0.63 g or 10.8 mmol, 1.26 g) or PMDTA
(5.4 mmol, 0.94 g or 10.8 mmol, 1.88 g) or potassium tert-butoxide
(5.4 mmol, 0.56 g or 10.8 mmol, 1.12 g) or TMP (5.94 mmol, 0.84 g)],
potassium tert-butoxide (5.4 mmol, 0.56 g), and a hexane solution of
butyllithium (1.3 mol/l, 5.94 mmol, 4.6 ml or 11.88 mmol, 9.2 ml) in dry
THF (15 ml) or dry Et2O (15 ml). After stirring for 1, 2, or 4 h at the
desired temperature (see in Table 1), the reaction mixture was quenched
with dry ice. At 208C, distilled water (20 ml) and Et2O (15 ml) were added,
the phases were separated, and the aqueous solution was washed with Et2O
(3 ꢀ 15 ml). The aqueous solution was acidified with 15% citric acid
solution. The product precipitated as an oil, or as crystals. In the case of an
oil, the aqueous phase was extracted with ethyl acetate (3 ꢀ 20 ml). The
collected organic solutions were dried over sodium sulfate and concentrated
in vacuo. The crystalline product was filtered, washed with water
1
(2 ꢀ 5 ml), and dried. Product distributions were determined from the H
NMR spectra of the crude products. To obtain the pure compounds, the
crude products were recrystallized from hexane or ethyl acetate, respectively.
Products are not known from the literature. The structures were established by
measuring the melting point, the IR, the 1H NMR, 13C NMR spectra, and high-
resolution mass spectra. Yields of the crude products are given in Table 1,
whereas the yields given below in parentheses refer to the efficiency of the
recrystallizations of the new products.
1-(2-Ethylphenyl)pyrrole-2-carboxylic acid (4): colorless crystals (76%
1
from hexane). Mp: 126–1278C; IR (KBr) nmax: 3447 (OH), 1669 (CO); H
NMR (DMSO-d6) dH: 0.96 (3H, t, J 7.7, Et), 2.21 (2H, q, J 7.7, Et), 6.23–
6.31 (1H, t like m, J 2.9, Hb), 6.96 (1H, dd, J 2.9, 1.8, Ha), 7.01 (1H, wide
s, Hb), 7.14 (1H, d, J 7.7, Ph), 7.19–7.41 (3H, m, Ph); 13C NMR (DMSO-
d6) dC: 161.4, 141.0, 140.0, 130.5, 129.1, 128.8, 128.0, 126.6, 125.0, 118.0,
109.3, 23.9, 14.9; HRMS (FAB): C13H14NO2 (M þ H)þ found 216.10319,
calculated 216.10245.
1-[2-(1-Carboxyethyl)phenyl]pyrrole (5): in a mixture with compound 4. 1H
NMR (DMSO-d6) dH: 1.28 (3H, dd, J 7.1, 1.3, Et), 3.47 (1H, qd, J 7.1, 1.3, Et),
6.15–6.38 (2H, t like m, J 1.5, Hb), 6.80–6.96 (2H, t like m, J 1.5 Ha),
7.10–7.55 (4H, m, Ph).
1-(6-Carboxy-2-ethylphenyl)pyrrole-2-carboxylic acid (6): colorless
crystals (61% from chloroform). Mp: 202–2038C; IR (KBr) nmax: 3449
(OH), 1677 (CO); H NMR (DMSO-d6) dH: 0.99 (3H, t, J 7.9, Et), 2.16
1
(2H, q, J 7.9, Et), 6.19–6.29 (1H, t like m, J 2.9, Hb), 6.96 (2H, wide s,
Ha þ Hb), 7.45 (1H, t, J 7.6, Ph), 7.54 (1H, d, J 7.3, Ph), 7.68 (1H, d, J 7.3,
Ph); 13C NMR (DMSO-d6) dC: 166.9, 161.0, 142.4, 138.4, 131.9, 130.6,
129.7, 128.2, 127.7, 125.1, 116.9, 108.8, 23.2, 14.8; HRMS (FAB of the
dimethyl ester): C16H17NO4 (M)þ found 287.11439; calculated 287.11576.

2848
F. Faigl, B. Vas Feldhoffer, and A. Thurner
1-(6-Carboxymethyl-2-ethylphenyl)pyrrole (7): colorless crystals (55%
1
from hexane). Mp: 132–1338C; IR (KBr) nmax: 3462 (OH), 1704 (CO); H
NMR (DMSO-d6) dH: 1.00 (3H, t, J 7.6, Et), 2.21 (2H, q, J 7.6, Et), 3.18
(2H, s, CH2), 6.18–28 (2H, t like m, J 1.8, Hb), 6.58–6.72 (2H, t like m, J
1.8, Ha), 7.12–7.48 (3H, m, Ph); 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, HRMS
(FAB): C14H16NO2 (M þ H)þ found 230.11705; calculated 230.11810.
1-(6-Carboxymethyl-2-ethylphenyl)pyrrole-2-carboxylic acid (8): colorless
crystals (47% from chloroform). Mp: 212–2138C; IR (KBr) nmax: 3448
(OH), 1667, 1716 (CO); H NMR (DMSO-d6) dH: 0.97 (3H, t, J 7.6, Et),
1
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, 109.2, 36.4, 23.5, 14.9; HRMS (FAB of the dimethyl
ester): C17H19NO4 (M)þ found 301.13013; calculated 301.13141.
2,5-Dimethyl-1-[2-(1-carboxyethyl)phenyl]pyrrole (9): brown crystals
(30%, from hexane). Mp: 144–1458C; IR (KBr) nmax: 3447 (OH), 1711
(CO); H NMR (DMSO-d6) dH: 1.23 (3H, t, J 7.2, Me), 2.99 (1H, q, J 7.2,
1
CH), 1.81 (3H, s, Me), 1.86 (3H, s, Me), 5.80 (2H, wide s, Hb), 7.16 (1H,
d, J 7.6, Ph), 7.30–7.62 (3H, m, Ph); 13C NMR (DMSO-d6) dC: 174.9,
140.2, 136.7, 129.2, 129.2, 128.5, 128.0, 127.5, 105.7, 18.7, 12.6, 12.3;
HRMS (FAB): C15H17NO2 (M þ H)þ found 244.13347; calculated
244.13375.
ACKNOWLEDGMENT
Financial support from the Hungarian Scientific Research Found is gratefully
acknowledged (OTKA T 048362). The work was carried out in the framework
of the COST D24 0006/02 project.
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