Synthesis of 2,2-disubstituted azaindolines by intramolecular cyclization in acidic media

Article abstract of DOI:10.1055/s-0030-1259678

The synthesis of a diverse array of 2,2-disubstituted azaindolines is reported. The bicyclic core is built by a simple acidic treatment of conveniently substituted aminopyridines. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259678

684
LETTER
Synthesis of 2,2-Disubstituted Azaindolines by Intramolecular Cyclization in
Acidic Media
S
ynthesis of 2,2
h
-Disubstitute
o
d
A
zaindoli
m
nes as-Xavier Métro,* Christine Fayet, Florian Arnaud, Nathalie Rameix, Pierre Fraisse, Simon Janody,
Mireille Sevrin, Pascal George, Rachel Vogel*
sanofi-aventis, Exploratory Unit, 371, Rue du Professeur Joseph Blayac, 34184 Montpellier, France
Fax +33(4)99776912; E-mail: thomasmetro@yahoo.fr; E-mail: rachel.vogel@sanofi-aventis.com
Received 10 August 2010
be generated by acidic treatment of a tertiary alcohol (type
1), a secondary alcohol (type 2), or an alkene (type 3).
Abstract: The synthesis of a diverse array of 2,2-disubstituted aza-
indolines is reported. The bicyclic core is built by a simple acidic
treatment of conveniently substituted aminopyridines.
A similar approach was developed successfully to obtain
structurally close 2-substituted 7-azaindoles from 2-ami-
no-3-(2-hydroxyethyl)pyridine derivatives although fur-
nishing the azaindoline intermediate with low yield.5,6
Cyclization of the substrates was obtained by transform-
ing the hydroxyl moiety into a good leaving group such as
a trifluoroacetate or a mesylate, followed by acidic treat-
ment. Similarly, 2-substituted 5-azaindolines were syn-
thesized through intramolecular cyclization of 4-tert-
butoxycarbonylamino-3-(2-mesyloxypropyl)pyridine
upon basic treatment.7
Key words: azaindolines, cyclization, nucleophilic addition, spiro
compounds, pyridines
2,2-Disubstituted azaindoline is an attractive scaffold as
no general method for synthesizing this heterocyclic
building block is described. The strategies furnishing the
scarce examples include intramolecular [1,5]-dipolar cy-
clization,1 addition of a malonate on an imine intermedi-
ate,2 intramolecular Chichibabin reaction,3 or palladium-
catalyzed C–H activation of a tert-butyl-aminopyridine.4
In addition, 2,2-disubstituted indolines have been isolated
from 2-(2,2-disubstituted 2-aminoethyl)anilines8 or from
2-(2,2-disubstituted hydroxyethyl)anilines derivatives af-
ter acidic treatment.9
Herein we report the synthesis of a variety of 2,2-disubsti-
tuted azaindolines from the cyclization of hydroxyalkyl-
or alkenyl-aminopyridines in acidic conditions.
Table 1 Synthesis of 4-(2-Hydroxyethyl)-3-pivaloylaminopy-
ridines of Type 1
Our strategy relies on the nucleophilic attack of an amino
group attached to a pyridine onto either a carbocationic or
an alkenyl intermediate (Scheme 1). These species could
HO
R
1) n-BuLi (2.2–2.5 equiv)
THF, 0 °C, 1 h
R
NHPiv
N
N
2) ketone (1.4–2.0 equiv)
NHPiv
R1
HO R1
R1
R2
HO
5
1a–j
R2
NHPG
R1
R2
ProductYield
(%)
R2
N
Entry Ketone
or
or
N
N
NHPG
NHPG
1
2
3
1
2
3
4
5
6
7
8
9
acetone
Me
Ph
Me
1a
1b
1c
1d
1e
1f
35
62
88
78
40
73
59
69
82
R1, R2 = aryl, alkyl, possibly cyclic
PG = protecting group
acetophenone
Me
– PG
(– H2O)
+ H+
tert-butylphenylketone Ph
t-Bu
cyclobutanone
-(CH2)3-
R1
R2
R1
+
cyclopentanone
cyclohexanone
tetrahydropyranone
-(CH2)4-
-(CH2)5-
R2
NH+
N
NH2
NH2
-(CH2)2O(CH2)2-
1g
N-benzyl-4-piperidinone -(CH2)2N(Bn)(CH2)2- 1h
R1
R2
N
cycloheptanone
-(CH2)6-
1i
1j
N
H
H
C
4
H2C
CH
CH2
HC
CH2
Scheme 1
SYNLETT 2011, No. 5, pp 0684–0688
10 2-adamantanone
75
H2C
C
H
CH2
x
x.
x
x.
2
0
1
1
Advanced online publication: 22.02.2011
DOI: 10.1055/s-0030-1259678; Art ID: G23710ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2,2-Disubstituted Azaindolines
685
In order to study the feasibility of our approach, a first set pyridines 1a and 1b bearing dimethyl or methyl/phenyl
of 4-(2-hydroxyethyl)-3-pivaloylaminopyridines 1 was substituents in refluxing 2 M HCl led to the cyclized 2,2-
prepared starting from 3-pivaloylamino-4-methyl-pyri- disubstituted 6-azaindolines with good yields (Table 2,
dine (5). Treatment of 5 with more than two equivalents entries 1 and 2).13 Replacing the methyl R2 substituent in
of n-BuLi followed by the addition of ketones furnished 1b with a tert-butyl resulted in low yield of the cyclized
4-(2-hydroxyethyl)-3-pivaloylaminopyridines
moderate to good yields (Table 1).
1
with product 4c, even after prolonged heating (Table 2, entry
3). Co-products of this reaction were determined to be re-
sulting from hydrolysis of the pivalamide moiety along
Other synthetic approaches were also envisaged for
pyridines 1–3. Cyclopentylidenemethyl-pyridine 3e was
isolated from a Wittig reaction on the 4-formylated ana-
logue of 6e (Scheme 2).10 Compounds 2k and 2l were pre-
pared by addition of i-PrLi to formyl-aminopyridines 6k
and 6l, whereas 1m and 1n were obtained by trapping
with isobutylene the product, resulting from the regio-
selective ortho lithiation of aminopyridine 6m11 and 6n.10
Aminoisopropylidenepyridine 3o and aminoisopropy-
lidenepyrimidine 3p were synthesized by Suzuki
coupling12 between 2-methyl-1-propenylboronic acid
pinacol ester and unprotected 6o and 6p, respectively
(Scheme 2).
with isomeric alkenes coming from dehydration.
Table 2 Cyclization of Substrates Possessing Alkyl and/or Aryl as
R1 and R2 Substituents
Entry Substrate
Product
Conditions
Yield
(%)
HO
2 M HCl, reflux,
96 h
1
71
81
N
N
H
N
NHPiv
4a
1a
HO
Ph
Ph
Ph
2 M HCl, reflux,
18 h
At first, cyclization of substrates possessing alkyl and/or
aryl R1 and R2 substituents was envisaged. Treating
2
N
N
H
N
NHPiv
4b
1b
1) n-BuLi, TMEDA, Et2O
2) DMF
HO
Ph
+
3)
n-BuLi, THF
N
PPh3
Br–
N
2 M HCl, reflux,
144 h
NHPiv
NHPiv
OH
N
t-Bu
3
7
N
H
3e
6e
N
33%
NHPiv
4c
1c
i-PrLi, THF, –78°C
78%
N
N
O
NHBoc
NHBoc
OH
We next turned our attention to the synthesis of 6-azain-
dolines with cyclic R1-R2 substituent. When treated in re-
fluxing 2 M HCl, 4-(2-hydroxyethyl)-3-pivaloylamino-
pyridines 1e, 1f, 1i, and 1j were converted into their cor-
responding 2,2-disubstituted 6-azaindolines with good to
excellent yields (Table 3, entries 2, 4, 7, and 8). It is worth
noting that when R1-R2 formed a strained spirocyclobutyl
ring, cyclized product 4d was obtained with a low yield
whereas very bulky groups such as spiroadamantyl in 1j
were not an obstacle in forming the cyclized product 4j in
good yield (Table 3, entries 1 and 8).
6k
2k
2l
O
i-PrLi, THF, –78°C
37%
NHPiv
NHPiv
OH
N
6l
N
1) n-BuLi, THF
2) isobutylene oxide
3) BF3⋅OEt2
N
N
22%
NHPiv
NHPiv
6m
1m
1) n-BuLi, THF
2) isobutylene oxide
3) BF3⋅OEt2
Introducing heteroatoms, such as oxygen or nitrogen, into
the cyclic R1-R2 chain resulted in disrupting the formation
of the cyclized products. For instance, oxygen-containing
1g required 6 M HCl to reach full conversion furnishing
6-azaindoline 4g in 53% yield (Table 3, entry 5). When
this oxygen atom was replaced by a benzylamine in 1h,
cyclized product 4h could not be isolated (Table 3, entry
6). In this particular case, only the products resulting from
hydrolysis of the pivalamide moiety along with isomeric
alkenes coming from dehydration could be isolated. Other
acidic conditions such as PTSA in refluxing toluene, sul-
furic acid, methanesulfonic acid, concentrated or diluted
hydrochloric acid could not produce the cyclized azaindo-
line.
OH
4) HCl 2 M, reflux
36%
Cl
N
NHPiv
Cl
N
1n
NH2
6n
2-methyl-1-propenylboronic
acid pinacol ester
Pd(OAc)2, SPhos, K2CO3
F3C
Cl
F3C
MeCN–H2O, reflux
44%
N
NH2
N
3o
NH2
6o
2-methyl-1-propenylboronic
acid pinacol ester
Pd(OAc)2, SPhos, K2CO3
Cl
N
N
MeCN–H2O, reflux
88%
N
NH2
N
3p
NH2
6p
Confirming our initially proposed strategy, acidic treat-
ment of 4-cyclopentylidenemethyl-pyridine 3e produced
SPhos : 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl
Scheme 2
Synlett 2011, No. 5, 684–688 © Thieme Stuttgart · New York

686
T.-X. Métro et al.
LETTER
Table 3 Cyclization of Substrate Possessing Cyclic Alkyl R1–R2
Substituents
6-azaindoline 4e in good yield (Table 3, entry 3). This re-
sult shows that starting material containing an alkenyl
functionality as the electrophile can be an excellent alter-
native to their corresponding tertiary alcohol analogues.
HO
X
X
H+
or
X
With this efficient methodology toward 6-azaindolines in
hand, we turned our attention to 4-, 7-, and 5-isomeric
azaindolines. Starting from the corresponding pyridines
2k, 2l, and 1m, 4-, 7-, and 5-azaindolines 4k–m could be
obtained with good yields (Table 4, entries 1–3). While
many 6-azaindolines of type 4 were obtained from
pyridines bearing either a tertiary alcohol or an alkene
moiety, synthesis of 4-azaindolines 4k and 7-azaindolines
4l was achieved from the corresponding secondary alco-
hol 2k and 2l (Table 4, entries 1 and 2). The lower lability
of the secondary alcohol in an acidic media was circum-
vented by using a higher concentration of HCl (6 M).
N
N
N
N
NHPiv
NHPiv
H
1d–j
3e
4d–j
Entry Substr. Product
Conditions
Yield
(%)
1
1d
6 M HCl, reflux, 48 h
6
N
N
H
4d
2
3
1e
3e
2 M HCl, reflux, 18 h 84
2 M HCl, reflux, 6 h 90
N
N
H
The presence of substituents on the pyridine ring can ham-
per the formation of cyclized azaindolines as 4n was iso-
lated with 33% yield when 1n was treated with refluxing
6 M HCl for 90 hours (Table 4, entry 4). This issue was
overcome for 1n and 3o by using concentrated sulfuric ac-
id, a more acidic medium, affording 4n and 4o in high
yields (Table 4, entry 5 and 6).
4e
4
5
6
7
8
1f
1g
1h
1i
2 M HCl, reflux, 12 h 98
N
N
H
4f
O
6 M HCl, reflux, 120 h 53
N
While sulfuric acid was inefficient in furnishing 4p from
pyrimidine 3p, heating at 200 °C under microwave irradi-
ation a solution of 3p in methanesulfonic acid gave diaza-
indoline 4p with good yield (Table 4, entry 8). Isolation of
4o and 4p confirmed that alkenyl containing starting ma-
terials are suitable substrates for this cyclization.
N
H
4g
NBn
a
6 M HCl, reflux, 48 h
–
N
N
H
4h
In conclusion, acidic treatment can be an easy way to pro-
duce 2,2-disubstituted azaindolines from hydroxyalkyl-
or alkenyl-aminopyridines. While formation of the cy-
clized products is highly dependent on the acidic condi-
tions, all 4-, 5-, 6-, and 7-(2,2-disubstituted)-azaindolines
isomers could be synthesized starting from a broad range
of substrates, showing the wide applicability of this origi-
nal methodology.13
2 M HCl, reflux, 18 h 95
2 M HCl, reflux, 18 h 65
N
N
H
4i
1j
N
N
H
4j
a Not observed.
Table 4 Synthesis of 4-, 5-, and 7-Isomeric 2,2-Dimethylazaindolines
Entry
Substrate
Product
Conditions
Yield (%)
63
OH
N
N
1
6 M HCl, reflux, 72 h
N
H
NHBoc
OH
4k
2k
2
3
6 M HCl, reflux, 48 h
6 M HCl, reflux, 120 h
80
72
N
H
N
N
NHPiv
OH
4l
2l
N
N
N
H
NHPiv
4m
1m
Synlett 2011, No. 5, 684–688 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,2-Disubstituted Azaindolines
687
Table 4 Synthesis of 4-, 5-, and 7-Isomeric 2,2-Dimethylazaindolines (continued)
Entry
Substrate
Product
Conditions Yield (%)
OH
4
5
6 M HCl, reflux, 90 h
H2SO4 96%; r.t., 2 h
33
96
N
Cl
N
H
Cl
N
NH2
4n
1n
F3C
F3C
6
H2SO4 96%; r.t., 4 h
95
N
N
N
NH2
H
3o
4o
a
7
8
H2SO4 96%; r.t., 4 h
MsOH, MW, 200 °C, 5 min
–
N
N
68
N
N
N
NH2
H
3p
4p
a Not observed.
m/z = 251 [M + H]+. ESI-HRMS: m/z calcd for C14H23N2O2
[M + H+]: 251.1752; found: 251.1760.
Compound 1b
References and Notes
(1) Walter, H.; Sundermann, C. Heterocycles 1998, 48, 1581.
(2) Mérour, J.-Y.; Gadonneix, P.; Malapel-Andrieu, P.;
Desarbre, E. Tetrahedron 2001, 57, 1995.
(3) Ciganek, E. J. Org. Chem. 1992, 57, 4251.
(4) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008,
Off-white powder; mp 179–181 °C. IR (neat): 3350, 3060,
2970, 1675, 1566, 1520, 1478, 1416, 1310, 1207, 1064, 751,
698 cm–1. 1H NMR (500 MHz, DMSO-d6): d = 9.91 (s, 1 H),
8.80 (s, 1 H), 8.10 (d, J = 4.9 Hz, 1 H), 7.48 (dd, J = 7.5, 1.4
Hz, 2 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.23 (dd, J = 7.5, 1.4 Hz,
1 H), 6.99 (d, J = 4.9 Hz, 1 H), 6.36 (s, 1 H), 2.94 (d, J = 13.3
Hz, 2 H), 1.49 (s, 3 H), 1.29 (s, 9 H). 13C NMR (125 MHz,
DMSO-d6): d = 176.3, 148.3, 145.4, 144.3, 138.6, 134.6,
128.0, 126.9, 126.6, 124.9, 75.5, 45.8, 28.5, 27.5. ESI-MS:
m/z = 313 [M + H]+. Anal Calcd for C19H24N2O2: C, 73.05;
H, 7.74; N, 8.97. Found: C, 72.76; H, 8.02; N, 9.05.
Compound 1j
White powder; mp 246–248 °C. IR (neat): 3269, 2916, 2862,
1671, 1515, 1417, 1326, 1168, 1055, 928, 699, 667 cm–1. 1H
NMR (500 MHz, DMSO-d6): d = 9.77 (s, 1 H), 8.79 (s, 1 H),
8.20 (d, J = 4.9 Hz, 1 H), 7.27 (d, J = 4.9 Hz, 1 H), 5.23 (s,
1 H), 2.93 (s, 2 H), 2.16 (d, J = 12.6 Hz, 2 H), 2.07 (d,
J = 12.6 Hz, 2 H), 1.85 (s, 1 H), 1.72 (s, 2 H), 1.69 (s, 1 H),
1.65 (s, 2 H), 1.60 (s, 2 H), 1.45 (d, J = 12.6 Hz, 2 H), 1.25
(s, 9 H). 13C NMR (125 MHz, DMSO-d6): d = 176.4, 145.6,
144.3, 139.1, 135.0, 126.3, 76.6, 38.1, 36.6, 34.2, 32.3, 27.5,
27.0, 26.8. ESI-MS: m/z = 343 [M + H]+. Anal Calcd for
C21H30N2O2: C, 73.65; H, 8.83; N, 8.18. Found: C, 73.40; H,
9.00; N, 7.99.
10, 1759.
(5) Parcerisa, J.; Romero, M.; Pujol, M. D. Tetrahedron 2008,
64, 500.
(6) Hands, D.; Bishop, D.; Cameron, M.; Edwards, J. S.;
Cottrell, I. F.; Wright, S. H. B. Synthesis 1996, 877.
(7) Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H. J. Org.
Chem. 1999, 64, 9430.
(8) Sánchez, I.; Sobrino, M.; Pujol, M. D. Tetrahedron Lett.
2004, 45, 1737.
(9) (a) Yoshihiko, I.; Kazuhiro, K.; Takeo, S. Chem. Lett. 1980,
1563. (b) Yoshihiko, I.; Kazuhiro, K.; Norihiko, S.;
Masayuki, M.; Takeo, S. Heterocycles 1980, 14, 106.
(10) Turner, J. A. J. Org. Chem. 1990, 55, 4744.
(11) Janiak, C.; Deblon, S.; Uehlin, L. Synthesis 1999, 959.
(12) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2006, 45, 3484.
(13) Representative Procedures for the Synthesis of 4-(2-
Hydroxyethyl)-3-pivaloylaminopyridines of Type 1
Compound 1a
To a solution of pyridine 5 (960 mg, 4.9 mmol, 1.0 equiv) in
anhyd THF (10 mL) at –78 °C was added n-BuLi (2.5 M in
hexanes, 4.3 mL, 10.8 mmol, 2.2 equiv), and the solution
was stirred at 0 °C for 1 h. After addition at –78 °C of
acetone (547 mL, 7.4 mmol, 1.5 equiv), the mixture was
stirred for 1 h at –78 °C then overnight at r.t. The reaction
medium was quenched by addition of H2O (10 mL), the
aqueous phase was extracted with EtOAc, and the combined
organic extract was dried over Na2SO4, filtered, and
concentrated under reduced pressure. Flash column
chromatography on silica gel (cyclohexane–EtOAc, 20:80)
afforded 1a as a yellow solid (430 mg, 35%); mp 159–
161 °C. IR (neat): 3380, 3278, 2972, 2933, 2870, 1652,
1564, 1521, 1469, 1411, 1379, 1365, 1179, 1113, 914, 779,
722 cm–1. 1H NMR (500 MHz, DMSO-d6): d = 9.87 (s, 1 H),
8.82 (s, 1 H), 8.22 (d, J = 4.9 Hz, 1 H), 7.22 (d, J = 4.9 Hz,
1 H), 5.64 (s, 1 H), 2.71 (s, 2 H), 1.25 (s, 9 H), 1.19 (s, 6 H).
13C NMR (125 MHz, DMSO-d6): d = 176.3, 145.5, 144.4,
139.3, 134.6, 126.9, 71.5, 44.5, 29.5, 27.5. ESI-MS:
Representative Procedures for the Synthesis of
2,2-Disubstituted Azaindoline of Type 4
Compound 4a
A solution of 1a (215 mg, 0.86 mmol) in 2 M HCl (8.6 mL)
was heated at reflux for 96 h. After cooling to r.t., aq NaOH
was added until pH 10. The crude was extracted with
EtOAc. The organic layer was separated, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Flash
column chromatography on silica gel (n-heptane–EtOAc)
afforded 4a as a brown solid (90 mg, 71%); mp 49–51 °C.
IR (neat): 3199, 2958, 1604, 1496, 1445, 1363, 1258, 1227,
1176, 1038, 817, 725 cm–1. 1H NMR (250 MHz, DMSO-d6):
d = 7.75 (d, J = 4.6 Hz, 1 H), 7.73 (s, 1 H), 7.01 (d, J = 4.6
Hz, 1 H), 5.69 (br s, 1 H), 2.74 (d, J = 0.9 Hz, 2 H), 1.22 (s,
6 H). 13C NMR (125 MHz, DMSO-d6): d = 147.7, 138.2,
136.2, 129.3, 120.0, 60.8, 43.0, 28.6. ESI-MS: m/z = 149
[M + H]+. Anal Calcd for C9H12N2: C, 72.94; H, 8.16; N,
Synlett 2011, No. 5, 684–688 © Thieme Stuttgart · New York

688
T.-X. Métro et al.
LETTER
18.90. Found: C, 72.62; H, 8.19; N, 18.89.
Compound 4j
Compound 4b
A solution of 1j (1.0 g, 2.92 mmol) in 2 M HCl (25 mL) was
heated at reflux for 18 h. After cooling to r.t., aq NaOH was
added until pH = 10. The crude was extracted with EtOAc.
The organic layer was separated, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Flash column
chromatography on silica gel (CH2Cl2–MeOH) afforded 4j
as an off-white powder (456 mg, 65%); mp 234–236 °C.
IR (neat): 3252, 2885, 2856, 1603, 1498, 1460, 1449, 1254,
1099, 1036, 816, 721 cm–1. 1H NMR (500 MHz, DMSO-d6):
d = 7.77 (s, 1 H), 7.71 (d, J = 4.4 Hz, 1 H), 6.98 (d, J = 4.4
Hz, 1 H), 6.27 (s, 1 H), 2.93 (s, 2 H) 2.08 (d, J = 12.6 Hz, 2
H), 1.88–1.80 (4 H), 1.71–1.58 (8 H). 13C NMR (125 MHz,
DMSO-d6): d = 147.4, 137.8, 135.8, 128.9, 119.8, 68.2, 37.7,
37.0, 34.1, 32.9, 26.5, 26.4. ESI-MS: m/z = 241 [M + H]+.
Anal. Calcd for C16H20N2: C, 79.96; H, 8.39; N, 11.66.
Found: C, 79.56; H, 8.62; N, 11.73.
A solution of 1b (200 mg, 0.64 mmol) in 2 M HCl (6.4 mL)
was heated at reflux for 18 h. After cooling to r.t., aq NaOH
was added until pH 10. The crude was extracted with Et2O,
and the combined organic extracts were dried over Na2SO4,
filtered, and concentrated under reduced pressure to afford
4b as a white powder (109 mg, 81%); mp >118 °C (dec.).
IR (neat): 3164, 2963, 1603, 1491, 1441, 1276, 1170, 1080,
1037, 824, 763, 696 cm–1. 1H NMR (500 MHz, DMSO-d6):
d = 7.86 (s, 1H), 7.80 (d, J = 4.5 Hz, 1H), 7.47 (dd, J = 7.5,
1.3 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.22 (dd, J = 7.5, 1.3
Hz, 1H), 7.04 (d, J = 4.5 Hz, 1H), 6.43 (s, 1H), 3.22 (d,
J = 16.6 Hz, 1H), 3.05 (d, J = 16.6 Hz, 1H), 1.51 (s, 3H).
13C NMR (125 MHz, DMSO-d6): d = 148.5, 147.8, 138.6,
136.0, 129.4, 128.3, 126.4, 125.3, 120.2, 66.5, 44.7, 29.4.
ESI-MS: m/z = 211 [M + H]+. ESI-HRMS: m/z calcd for
C14H15N2 [M + H+]: 211.1238; found: 211.1235.
Synlett 2011, No. 5, 684–688 © Thieme Stuttgart · New York

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