N-heterocyclic NCN-pincer palladium complexes: A source for general, highly efficient catalysts in Heck, Suzuki, and Sonogashira coupling reactions

Article abstract of DOI:10.1055/s-2005-922754

Readily available NCN-pincer palladium complexes comprising two pyrazole units as the source of both N-donor atoms are successfully employed as catalysts in a range of C-C bond-forming reactions. Good to excellent results are obtained in all cases regardless of the electronic nature of the substrates, along with more convenient procedures and comparatively much lower catalysts loadings in Suzuki and Sonogashira couplings. This paper presents the first report of a Sonogashira coupling reaction by means of a NCN catalyst. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922754

3116
LETTER
N-Heterocyclic NCN-Pincer Palladium Complexes: A Source for General,
Highly Efficient Catalysts in Heck, Suzuki, and Sonogashira Coupling
Reactions
N
-Heterocycli
á
c
N
CN-Pin
timComplexes a Churruca, Raul SanMartin,* Imanol Tellitu, Esther Domínguez*
Kimika Organikoa II Saila, Zientzia eta Teknologia Fakultatea, Euskal Herriko Unibertsitatea, P.O. Box 644, 48080 Bilbao, Spain
Fax +34(94)6012748; E-mail: qopsafar@lg.ehu.es
Received 6 October 2005
Table 1 Heck Coupling of Aryl Bromides
Abstract: Readily available NCN-pincer palladium complexes
R2
Br
comprising two pyrazole units as the source of both N-donor atoms
are successfully employed as catalysts in a range of C–C bond-
forming reactions. Good to excellent results are obtained in all cases
regardless of the electronic nature of the substrates, along with more
convenient procedures and comparatively much lower catalysts
loadings in Suzuki and Sonogashira couplings. This paper presents
the first report of a Sonogashira coupling reaction by means of a
NCN catalyst.
2 (10–1 mol% Pd)
R2
+
R1
K2CO3, DMF
140 °C, 18 h
R1
Entry
R1
R2
2a
Yield (%)b
>99 (100)
>99 (100)
98 (99)
1
2
3
4
5
6
7
8
H
H
H
H
COOMe
COOMe
Ph
2a
2b
2a
2b
2a
2b
2a
2b
Key words: palladacycles, catalysis, pincer complexes, cross-cou-
pling
Ph
>99 (100)
81 (82)
Palladium catalysts have become the unquestionable tool
of choice for the achievement of many organic transfor-
mations, and among them quite a few C–C bond-forming
reactions.1 Remarkable advances in terms of their catalyt-
ic activity by suitable tuning of the ligand properties have
provided very effective systems for specific tasks.2
Ac
Ac
F
COOMe
COOMe
COOMe
COOMe
86 (86)
86 (88)
F
96 (98)
In our ongoing investigations towards the palladium-me-
diated construction of polyheterocyclic systems3 we en-
visaged the assembly of new heterogeneous catalysts 1 by
anchoring homogeneous palladium catalysts/ligands to
solid supports (Scheme 1). As such an approach required
a particularly robust metal–ligand connection we opted
for NCN-pincer complexes, in which the metal–carbon s-
bond, aided by two coordinating N-donor atoms would af-
ford the necessary thermal stability to avoid significant
disassociation (leaching).4 However, this approach was
not devoid of risks, since unlike other palladacycles5 in-
cluding CNC-, PCP-, and SCS-pincer complexes,6 the use
a Reaction conditions: ArBr (1 mmol), alkene (1.5 mmol), Na2CO3 (2
mmol), DMF (1 mL), 140 °C.
b Determined by NMR spectroscopy on the basis of the amount of
starting ArBr. Bis(ethylene glycol) dimethyl ether was used as internal
standard. The conversion is displayed in parenthesis. Only E-diaste-
reoisomers were detected in all cases.
of NCN-pincers and, to be precise, those comprising two
heterocyclic units as the source of both N-donor atoms as
catalysts in Suzuki, Heck, or Sonogashira coupling reac-
tions, has been scarce or non-existent.7 The pioneering
work on the synthesis of structurally related complexes
R
R
N
N
Br
N
N
O
O
R
R
R
O
Pd Cl
R
CO
Pd Cl
O
N
N
N
N
Br
2a
2b
3
R = H
1
R
R
R = Me
Scheme 1
SYNLETT 2005, No. 20, pp 3116–3120
1
9
.1
2
.2
0
0
5
Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-922754; Art ID: G32205ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
N-Heterocyclic NCN-Pincer Palladium Complexes
3117
R
R
R
1) Pd(OAc)2,
R
HN
N
N
AcOH, reflux,
N
N
N
4
O
O
O
O
R
R
R
R
20 h
3
Pd Cl
2) LiCl,
N
Cs2CO3, MeCN
reflux, 2 h
N
N
acetone,
H2O, 2 d
N
2a
2b
5a
5b
R = H
R = Me
R = H
R
R
R = Me
Scheme 2
bearing no para-functionalization made by Steel et al.8 Before continuing with our programmed heterogenization
and a recent report about unconventional routes for ligand sequence, the catalytic activity of the so-formed pallada-
introduction for the preparation of other NCN catalysts4f cycles 2a and 2b11 was tested by a series of Heck reaction
finally encouraged us to execute the synthesis outlined in assays performed under standard conditions12 (Na2CO3,
Scheme 1.
DMF, 140 °C, 18 h) with several alkenes and aryl bro-
mides. Good to excellent yields were obtained in all cases
(Table 1), with moderate turnover numbers (TONs) up to
71000 (e.g. 71% yield of E-methyl cinnamate when 0.01
mol% Pd was employed) in some preliminary experi-
ments.
Although still far from our overall aim, the synthesis of 1,
we wish to report excellent preliminary results obtained
with intermediate palladacyclic systems 2a and 2b which
were employed as homogeneous catalysts of general ap-
plication to fundamental C–C bond forming reactions.
Encouraged by such promising results, our attention was
then focused on the Suzuki cross-coupling reaction. After
a more comprehensive study of different conditions,13 it
turned out that the best results were obtained when the
reaction was carried out in neat water14 (0.1 mol% 2a or
The synthesis of catalysts 2a and 2b was performed as de-
scribed in Scheme 2. Nucleophilic substitution9 by pyra-
zoles 4a and 4b with readily available dibromide 310
provided ligands 5a and 5b, which were palladated by
means of the procedure reported by Steel et al.8
Table 2 Suzuki Coupling of Aryl Bromides
2 (10–1 mol% Pd)
Br
B(OH)2
R1
R2
+
K2CO3, H2O
100 °C, 2 h
R1
R2
Entry
1
R1
R2
H
2a
Yield (%)b
>99 (100)
>99 (100)
>99 (100)
>99 (100)
>99 (100)
>99 (100)
>99 (100)
>99 (100)
92 (92)
Ac
Ac
Ac
F
2a
2ac
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2
H
3
H
4
H
5
F
H
6
H
H
7
H
H
8
Me
Me
OMe
OMe
Ac
Ac
H
9
H
10
11
12
13
H
94 (94)
H
93 (93)
OMe
OMe
>99 (100)
>99 (100)
a Reaction conditions: ArBr (1 mmol), ArB(OH)2 (1.5 mmol), K2CO3 (2 mmol), H2O (1 mL), 100 °C.
b Determined by NMR spectroscopy on the basis of the amount of starting ArBr. Bis(ethylene glycol) dimethyl ether was used as internal
standard. The conversion is displayed in parenthesis.
c Reaction conditions: ArBr (1 mmol), PhB(OH)2 (1.5 mmol), K2CO3 (2 mmol), toluene (2 mL), 130 °C, 6 h.
Synlett 2005, No. 20, 3116–3120 © Thieme Stuttgart · New York

3118
F. Churruca et al.
LETTER
2b, K2CO3, H2O, 100 °C, 2 h)15 which could be tentatively
attributed to the relatively high solubility of catalysts 2 in
water at such temperature (slightly higher than in other or-
ganic solvents or solvent mixtures).
Table 3 Sonogashira Coupling of Aryl and Naphthyl Iodides
H
R1
2 (10–1 mol% Pd)
R1
I
+
pyrrolidine, 100 °C, 6 h
R2
R2
As shown in Table 2, the excellent, and in most cases
quantitative, yields achieved from several electronically
divergent aryl bromides (bearing electron-withdrawing,
neutral, and electron-donating substituents) and aryl-
boronic acids reveal the general applicability of pincer
complexes 2a and 2b to Suzuki–Miyaura biaryl coupling.
Although further assays must be performed to establish
the minimum amount of catalyst required, TONs up to
8,600,000 have been achieved for catalyst 2a in the
reaction between bromobenzene and phenylboronic acid
(86% yield and 100% conversion were obtained with
10–5% Pd, TOF = 1433333).
Entry
1
R1
R2
2a
Yield (%)b
>99 (100)
>99 (100)
88 (98)
4-ClPh
4-ClPh
4-NO2Ph
4-NO2Ph
Ph
Ph
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2a
2b
2b
2
Ph
3
Ph
4
Ph
90 (100)
92 (100)
96 (98)
5
Ph
6
Ph
Ph
7
Naphthyl
Naphthyl
3-MePh
3-MePh
4-OMePh
4-OMePh
4-ClPh
4-ClPh
Ph
80 (82)
In addition, the use of water as a solvent, apart from the
advantage in terms of sustainability, provides an extreme-
ly easy work-up/purification protocol.
8
Ph
79 (80)
9
Ph
91 (92)
Only two examples of possible NCN tridentate ligands ap-
plied to Suzuki coupling have been reported so far, and in
both cases lower TONs (20–100 and 177500) featured
along with t-BuOK and DMF or toluene as base and sol-
vents, respectively.7a,d In reality, a search in the literature
revealed that the catalyst loading presented in this paper is
the lowest achieved for a Suzuki–Miyaura coupling cata-
lyzed by any pincer complex.16
10
11
12
13
14
Ph
94 (94)
Ph
77 (79)
Ph
79 (80)
n-Hex
n-Hex
>99 (100)
>99 (100)
The fact that the coupling reaction between alkynes and
aryl halides (Sonogashira) had never been tried with a
NCN-pincer complex prompted us to attempt it with cata-
lysts 2. After several assays, the optimized conditions (0.1
mol% 2a or 2b, pyrrolidine, 100 °C, 6 h),17 which avoided
the use of any copper co-catalyst or co-solvent, provided
target aryl acetylenes in good to excellent yields
(Table 3).
a Reaction conditions: ArI (1 mmol), alkyne (1.5 mmol), pyrrolidine
(2 mL), 100 °C.
b Determined by NMR spectroscopy on the basis of the amount of
starting ArI. Bis(ethylene glycol) dimethyl ether was used as internal
standard. The conversion is displayed in parenthesis.
Although inferior to the above shown TONs in Heck and
Suzuki coupling reactions, the excellent value of 80000
obtained in such copper-free Sonogashira reactions18 con-
stitutes a substantial improvement in comparison with the
results provided by previously employed pincer-based
catalysts.19
Acknowledgment
This research was supported by the University of the Basque
Country (Project UPV 41.310-13656) and the Spanish Ministry of
Science and Technology (MCYT BQ2001-0313). Petronor S.A. is
gratefully acknowledged for the generous donation of hexane.
To sum up, two readily prepared NCN-pincer palladium
complexes feature excellent homogeneous catalytic prop-
erties as their application in three of the most common
palladium-catalyzed C–C bond forming reactions demon-
strates (Heck, Suzuki, and Sonogashira). Good to excel-
lent yields were observed in all cases regardless of the
electronic nature of the substrates involved.
References
(1) For a review, see: Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; De Meijere, A.; Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004.
(2) See, for example: (a) DeVasher, R. B.; Moore, L. R.;
Shaughnessy, K. H. J. Org. Chem. 2004, 69, 7919.
(b) Braunstein, P. J. Organomet. Chem. 2004, 689, 3953.
(c) Van de Weghe, P. Lett. Org. Chem. 2005, 2, 113.
(3) (a) Hernández, S.; SanMartin, R.; Tellitu, I.; Domínguez, E.
Org. Lett. 2003, 5, 1095. (b) Churruca, F.; SanMartin, R.;
Tellitu, I.; Domínguez, E. Eur. J. Org. Chem. 2005, 2481.
(4) For a review on the use of pincer complexes, see:
(a) Singleton, J. T. Tetrahedron 2003, 59, 1837. (b) See
also: Beletskaya, I. P.; Cheprakov, A. V. J. Organomet.
Chem. 2004, 689, 4055 . The synthesis and properties of
several NCN-pincer palladium complexes have been
Especially remarkable are the convenient procedure and
exceedingly high TON achieved in the Suzuki cross-cou-
pling. Also this is the first Sonogashira reaction catalyzed
by a NCN-pincer-type catalyst, with the additional bonus
of its very low catalyst loading.
Heterogeneization of such advantageous catalysts is
currently under investigation in our laboratories.
Synlett 2005, No. 20, 3116–3120 © Thieme Stuttgart · New York

LETTER
described in: (c) Rietveld, M. H. P.; Grove, D. M.; van
N-Heterocyclic NCN-Pincer Palladium Complexes
3119
152.5 (C-3¢), 154.6 (C-4), 166.8 (CO). Anal. calcd for
Koten, G. New J. Chem. 1997, 21, 751. (d) Dijkstra, H. P.;
Slagt, M. Q.; McDonald, A.; Kruithof, C. A.; Kreiter, R.;
Mills, A. M.; Lutz, M.; Spek, A. L.; Klopper, W.; van Klink,
G. P. M.; van Koten, G. Eur. J. Inorg. Chem. 2003, 830.
(e) Slagt, M. Q.; van Zwieten, D. A. P.; Moerkerk, A. J. C.
M.; Gebbink, R. J. M. K.; van Koten, G. Coord. Chem. Rev.
2004, 248, 2275. (f) Takenaka, K.; Minakawa, M.; Uozomi,
Y. J. Am. Chem. Soc. 2005, 127, 12273.
There is discussion about the real role of pincer complexes
in palladium-catalyzed reactions, as their decomposition to
generate Pd(0) in several Heck reaction conditions is well
documented. See, for example: (g) Sommer, W. J.; Yu, K.;
Sears, J. S.; Ji, Y.; Zheng, X.; Davis, R. J.; Sherill, C. D.;
Jones, C. W.; Weck, M. Organometallics 2005, 24, 4351.
(h) Olsson, D.; Nilsson, P.; El Masnaouy, M.; Wendt, O. F.
Dalton Trans. 2005, 1924. (i) Bergbreiter, D. E.; Osburn, P.
L.; Frels, J. D. Adv. Synth. Catal. 2005, 347, 172.
C20H23ClN4O2Pd: C, 48.70; H, 4.70; N, 11.36. Found: C,
48.74; H, 4.67; N, 11.35.
(12) General procedure: A dry 5-mL round-bottom flask was
charged with aryl bromide (1 mmol), alkene (1.5 mmol),
catalyst 2 (0.001 mmol Pd), and anhyd DMF (1 mL). The
mixture was stirred at 140 °C under argon for 18 h. After
cooling, H2O (10 mL) was added, and the aqueous layer was
extracted with EtOAc (3 × 10 mL). The combined organic
extracts were dried over anhyd Na2SO4 and evaporated in
vacuo. The residue was dissolved in CDCl3 and analyzed by
1H NMR and 13C NMR spectroscopy [bis(ethylene glycol)
dimethyl ether as an internal standard]; the identity of every
product was confirmed by comparison with spectroscopic
data in the literature.
(13) The range of assays performed was based on the following
reports, basically replacing the employed catalysts by
palladacycles 2, see: (a) Alo, B. I.; Kandil, A.; Patil, P. A.;
Sharp, M. J.; Siddiqui, M. A.; Snieckus, V.; Josephy, P. D.
J. Org. Chem. 1991, 56, 3763. (b) Müller, W.; Lowe, D. A.;
Neijt, H.; Urwyler, S.; Herrling, P. L.; Blaser, D.; Seebach,
D. Helv. Chim. Acta 1992, 75, 855. (c) Coleman, R. S.;
Grant, E. B. Tetrahedron Lett. 1993, 34, 2225. (d) Shieh,
W.-C.; Carlson, J. A. J. Org. Chem. 1992, 57, 379.
(e) Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59,
5034. (f) Marck, G.; Villiger, A.; Buchecker, R.
(5) (a) Najera, C.; Gil-Moltó, J.; Karlström, S.; Falvello, L. R.
Org. Lett. 2003, 5, 1451. (b) Iyer, S.; Jayanthi, A. Synlett
2003, 1125. (c) Wang, A.-E.; Xie, J.-H.; Wang, L.-X.; Zhou,
Q.-L. Tetrahedron 2005, 61, 259.
(6) (a) CNC: Loch, J. A.; Albrecht, M.; Peris, E.; Mata, J.;
Faller, J.; Crabtree, R. H. Organometallics 2002, 21, 700.
(b) PCP: Lee, H. M.; Zeng, J. Y.; Hu, C.-H.; Lee, M.-T.
Inorg. Chem. 2004, 43, 6822. (c) SCS: Zim, D.; Grubber,
A. S.; Ebeling, G.; Dupont, J.; Monteiro, A. L. Org. Lett.
2000, 2, 2881.
(7) The application of such NCN-palladacycles in Heck
coupling is restricted to the following reports: (a)Magill,A.
M.; McGuiness, D. S.; Cavell, K. J.; Britovsek, G. J. P.;
Gibson, V. C.; White, A. J. P.; Williams, D. J.; White, A. M.
J. Organomet. Chem. 2001, 617-618, 546. (b) Díez-Barra,
E.; Guerra, J.; Hornillos, V.; Merino, S.; Tejeda, J.
Organometallics 2003, 22, 4610. (c) Jung, I. G.; Son, S. U.;
Park, K. H.; Chung, K.-C.; Lee, J. W.; Chung, Y. K.
Organometallics 2003, 22, 4715. (d) We found only two
reports that use the above-mentioned heterocyclic NCN-
pincers in the Suzuki reaction: Gupta, A. K.; Rim, C. Y.; Oh,
C. H. Synlett 2004, 2227; see also ref. 7a.
(8) Hartshorn, C. M.; Steel, P. J. Organometallics 1998, 17,
3487. In our case, overall yield of complexes 2a–b starting
from commercially available 1,3-bis(bromomethyl)-1-
methylbenzoate (3) was 90–95%.
(9) Abe, T.; Matsunaga, H.; Mihira, A.; Sato, C.; Ushirogochi,
H.; Sato, K.; Takasaki, T.; Venkatesan, A. M.; Mansour, T.
S. U.S. Patent US2004132708, 2004; Chem. Abstr. 2004,
141, 106320.
(10) Liu, P.; Chen, Y.; Deng, J.; Tu, Y. Synthesis 2001, 2078.
(11) 2a: white powder, mp >300 °C (EtOAc). FTIR (neat film):
1714, 1592, 1510, 1412 cm–1. 1H NMR (500 MHz, DMSO):
d = 3.83 (3 H, s, CH3), 5.55 (4 H, s, CH2), 6.46 (2 H, dd, J =
2.0, 1.6 Hz, H-4¢), 7.70 (2 H, s, H2, H-6), 7.92 (2 H, d, J =
1.6 Hz, H-5¢), 8.14 (2 H, d, J = 2.1 Hz, H-3¢). 13C NMR (63
MHz, DMSO): d = 52.1 (CH3), 56.7 (CH2), 106.6 (C-4¢),
125.9 (C-2, C-6), 126.4 (C-1), 133.1 (C-5¢), 137.2 (C-3, C-
5), 143.2 (C-3¢), 150.7 (C-4), 166.2 (CO). Anal. calcd for
C16H15ClN4O2Pd: C, 43.96; H, 3.46; N, 12.82. Found: C,
43.93; H, 3.48; N, 12.83.
Tetrahedron Lett. 1994, 35, 3277. (g) Watanabe, T.;
Miyaura, N.; Suzuki, A. Synlett 1992, 207. (h) Kelly, T. R.;
García, A.; Lang, F.; Walsh, J. J.; Bhaskar, K. V.; Boyd, M.
R.; Götz, R.; Keller, P. A.; Walter, R.; Bringmann, G.
Tetrahedron Lett. 1994, 35, 7621.
(14) Similar reaction conditions employing a silica-supported
tetradentate NHC catalyst were performed by: Zhao, Y.;
Zhou, Y.; Ma, D.; Liu, J.; Li, L.; Zhang, T. Y.; Zhang, H.
Org. Biomol. Chem. 2003, 1, 1643.
(15) General procedure: A 5-mL round-bottom flask was charged
with ArBr (1 mmol), ArB(OH)2 (1.5 mmol), catalyst 2
(0.001 mmol Pd), K2CO3 (2 mmol), and H2O (1 mL). The
mixture was stirred at 100 °C in air for 2 h. After cooling,
Na2CO3 (5 mL of 10% solution in water) was added, and the
aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The
combined organic extracts were dried over anhyd Na2SO4
and evaporated in vacuo. The residue was dissolved in
CDCl3 and analyzed by 1H NMR spectroscopy [using
bis(ethylene glycol) dimethyl ether as an internal standard];
the identity of every product was confirmed by comparison
with spectroscopic data in the literature.
(16) NCN-, PCP-, CNC-, and NCP-pincer complexes have been
used as catalysts in Suzuki coupling reactions, TON values
varying from 20 to 177500, see: (a) Bedford, R. B.; Draper,
S. M.; Scully, P. N.; Welch, S. L. New J. Chem. 2000, 24,
745. (b) Steel, P. G.; Teasdale, C. W. T. Tetrahedron Lett.
2004, 45, 8977. (c) Rosa, G. R.; Ebeling, G.; Dupont, J.;
Monteiro, A. L. Synthesis 2003, 2894. (d) Vicente, J.;Abad,
J.-A.; López-Serrano, J.; Jones, P. G.; Nájera, C.; Botella-
Segura, L. Organometallics 2005, 24, 5044; see also ref. 6a,
6b, 7a, and 7d.
(17) A 5-mL round-bottom flask was charged with ArI (1 mmol),
alkyne (1.5 mmol), catalyst 2 (0.001 mmol Pd), and
pyrrolidine (2 mL). The mixture was stirred at 100 °C in air
for 6 h. After cooling, the solvent was evaporated in vacuo.
The residue was dissolved in CDCl3 and analyzed by 1H
NMR spectroscopy [using bis(ethylene glycol) dimethyl
ether as an internal standard]; the identity of every product
was confirmed by comparison with spectroscopic data in the
literature.
2b: white powder, mp >300 °C (EtOAc). FTIR (neat film):
1702, 1590, 1549, 1425 cm–1. 1H NMR (500 MHz, CDCl3):
d = 2.34 (6 H, s, C5¢-CH3), 2.61 (6 H, s, C3¢-CH3), 3.87 (3 H,
s, COOCH3), 4.95 (2 H, d, J 14.1 Hz, CHaHb), 5.66 (2 H, d,
J = 14.1 Hz, CHaHb), 5.82 (2 H, s, H-4¢), 7.58 (2H, s, H-2,
H-6). 13C NMR (63 MHz, CDCl3): d = 11.7 (C-5¢CH3), 15.5
(C-3¢CH3), 52.0 (COOCH3), 54.1 (CH2), 107.1 (C-4¢), 125.5
(C-2, C-6), 126.3 (C-1), 137.3 (C-3, C-5), 140.4 (C-5¢),
Synlett 2005, No. 20, 3116–3120 © Thieme Stuttgart · New York

3120
F. Churruca et al.
LETTER
(18) The highest value (80,000) was achieved by reaction of 4-
chlorobenzene and 1-octyne in the presence of catalyst 2b
(Table 3, entry 14). When 0.01 mol% Pd was employed,
100% conversion and 80% yield for the corresponding 1-
phenyloctyne were obtained; TOF = 4444.
pincer complexes have been reported so far, exhibiting TON
values of 20–100, see: (a) Eberhard, M. R.; Wang, Z.;
Jensen, C. M. Chem. Commun. 2002, 818. (b) Mas-Marzá,
E.; Segarra, A. M.; Claver, C.; Perisb, E.; Fernández, E.
Tetrahedron Lett. 2003, 44, 6595; see also ref. 6a.
(19) To the best of our knowledge, three examples of
Sonogashira coupling reactions catalyzed by palladium
Synlett 2005, No. 20, 3116–3120 © Thieme Stuttgart · New York