An organocatalytic cascade approach toward polysubstituted quinolines and chiral 1,4-dihydroquinolines-unanticipated effect of N-protecting groups

Article abstract of DOI:10.1002/anie.201202161

A matter of protection: The outcome of a divergent organocatalytic aza-Michael/aldol cascade process toward quinolines and 1,4-dihydroquinolines depends on the choice of the N-protecting group (see scheme; TEA=triethylamine, TMS=trimethylsilyl). Use of an electron-donating sulfonyl group results in an unanticipated aza-Michael/aldol/aromatization cascade to give polysubstituted quinolines (right). In contrast, chiral 1,4-dihydroquinolines are obtained with an electron-withdrawing sulfonyl group (left). Copyright

Full text of DOI:10.1002/anie.201202161

Angewandte
Chemie
DOI: 10.1002/anie.201202161
Cascade Reactions
An Organocatalytic Cascade Approach toward Polysubstituted
Quinolines and Chiral 1,4-Dihydroquinolines–Unanticipated Effect of
N-Protecting Groups**
Xishuai Zhang, Xixi Song, Hao Li, Shilei Zhang, Xiaobei Chen, Xinhong Yu,* and Wei Wang*
Organocatalytic cascade reactions have been established as
a viable and efficient approach to complex molecular
architectures,[1] however, examples of the combination of
powerful divergent synthesis with an organocatalytic cascade
strategy are rare.[2] Herein, we report a powerful divergent
organocatalytic cascade reaction that proceeds via a chiral
allenamine[3] and involves unprecedented aza-Michael/aldol
and aza-Michael/aldol/aromatization sequences to give chiral
1,4-dihydroquinolines and quinolines, respectively. Notably,
we made the unexpected discovery that the type of product
that is formed depends on the nature of the N-protecting
group of the starting material.[4] When aryl sulfonyl moieties
with electron-donating groups are used as N-protecting
groups, a Michael/aldol/aromatization cascade proceeds pre-
dominantly to give polysubstituted quinolines. However,
when sulfonyl moieties with electron-withdrawing groups,
such as the triflic group, are employed as N-protecting group,
chiral 1,4-dihydroquinolines are produced through a highly
enantioselective Michael/aldol cascade reaction.
a single example, reported by Mangeney and co-workers, was
developed by using a chiral auxiliary as stereocontrol.[14] To
our knowledge, a catalytic version has not been reported.
Our initial investigation focused on the model reaction of
N-tosyl-2-aminobenzaldehyde 2a with phenylpropargyl alde-
hyde 1a in the presence of 30 mol% of diphenylprolinol TMS
ether A[15] in CHCl3 at room temperature (Table 1, entry 1).
Table 1: Exploration of organocatalytic aza-Michael/aldol/aromatization
cascade reaction.[a]
The “privileged” status of quinolines and related chiral
hydroquinolines in organic synthesis[5] and biological appli-
cations[6] demands more efficient strategies for their prepa-
ration. Although classic annulation reactions[7] and new,
improved versions[8] have been developed, in general they
require multiple steps and/or highly functionalized substrates.
On the other hand, significant efforts have been made toward
chiral tetrahydroquinolines[9,10] and 1,2-dihydroquino-
lines.[11,12] Nevertheless, the asymmetric synthesis of 1,4-
dihydroquinoline architectures remains elusive,[13] and only
Entry
2
Additive
t [h] Yield 3 [%][b] Yield 4a [%][b]
1
2
2a none
2b none
2c none
2c K2CO3 (0.1 equiv)
30
28
35
16
0
54
0
64 (7%)[c]
3
0
0
51
4[d]
99[e]
[a] For reaction conditions, see Experimental Section. [b] Yields of
isolated products. [c] ee value. [d] 10 mol% of catalyst A used and
reaction performed at 508C. [e] After completion of the reaction, silica
gel (80 mg) was added and the mixture was stirred at RT for 24 h. Then,
Et3N (0.18 mmol) was added and the mixture was stirred at RT for
another 3 h to get free deprotonated quinoline 4a. TMS=trimethylsilyl.
[*] X.-S. Zhang, X.-X. Song, Dr. S.-L. Zhang, X. Chen, Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico
The tosyl (Ts) group was selected as protecting group for the
nitrogen atom, because its strong electron-withdrawing
nature enhances the acidity of the NH functionality, thus
facilitating ionization, which produces a more nucleophilic
nitrogen anion for the initial Michael addition.[12a] TLC and
1H NMR analysis of the crude showed that seemingly the aza-
Michael/aldol product 3a was produced. However, when the
reaction mixture was subjected to purification by column
chromatography on silica gel, unexpected compound 4a was
obtained instead in 54% yield (Table 1, entry 1). It appeared
that product 3a was transformed into 4a in the presence of
silica gel.
We believe that acidic silica gel promotes the aromatiza-
tion process through a dehydration–deprotection sequence of
the sulfonyl group (see Scheme S1 in the Supporting Infor-
mation). The driving force for the formation of product 4a
may be the tendency of 1,4-dihydroquinolines to dehydrate
MSC03 2060, Albuquerque, NM 87131-0001 (USA)
E-mail: wwang@unm.edu
Prof. Dr. H. Li, Prof. Dr. X.-H. Yu, Prof. Dr. W. Wang
Shanghai Key Laboratory of New Drug Design and School of
Pharmacy
East China University of Science & Technology (ECUST)
130 Mei-Long Road, Shanghai 200237 (China)
E-mail: xhyu@ecust.edu.cn
[**] Financial support of this research is provided by the National
Science Foundation (CHE-1057569, W.W.) and ECUST (W.W.), the
China 111 Project (Grant B07023, W. W.), NSFC (20972051, X.-H.
Y.), the Science and Technology Commission of Shanghai Munic-
ipality (08430703900 and 08431901800, X.-H. Y.), and the Shanghai
Committee of Science and Technology (Grant 11DZ2260600).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202161.
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Table 2: Scope of A-catalyzed one-pot synthesis of quinolines 4.[a]
and thus aromatize under acidic conditions. An aromatic
sulfonamide that bears an electron-donating moiety assists in
the development of the carbocationic character for a favorable
dehydration–aromatization process, while a sulfonamide that
bears a strong electron-withdrawing moiety will inhibit this
development. Indeed, when the Tf protecting group was used,
aromatization product 4a was not formed (Table 1, entry 2).
Instead, stable, chiral 1,4-dihydroquinoline 3b was obtained
in 64% yield, but with only 7% ee after column chromatog-
raphy on silica gel. We also found that the Michael/aldol
cascade proceeded rapidly (5 h), presumably because of the
tendency of the more acidic TfNH moiety to produce TfNꢀ
more easily. The influence of the electronic effect was further
demonstrated for aromatic sulfonyl groups that bear electron-
donating (2c; Table 1, entry 3), electron-neutral, and elec-
tron-withdrawing substituents (see Table S1). Based on these
studies, we decided to use p-MeOC6H4SO2 as protecting
group for further optimization of the reaction conditions. The
screening of solvents and bases (Table S1) led to the optimal
conditions, which include the use of K2CO3 (0.1 equiv) at
508C with 10 mol% catalyst loading (Table 1, entry 4). The
scope of Michael/aldol/aromatization cascade reactions cata-
lyzed by organocatalyst A was probed accordingly (Table 2).
The tandem process serves as a general approach to the
preparation of valuable polysubstituted quinolines. In the
cascade process, the reactions proceeded in high yields (76–
99%) with a broad substrate scope. It seems that the
electronic nature of aromatic ynals 1 has a limited effect on
the process. The electron-neutral (Table 2, entries 1, 15, 17–
20, and 23), electron-donating (entries 3, 4, 9, and 11), and
electron-withdrawing (entries 2, 5–8, 12, 16, 21, 22, and 24)
substituents could be tolerated with significant structural
variation. A similar trend was observed for heteroaromatic
ynals, such as thiophen-2-yl-propynal (Table 2, entry 10).
Furthermore, the reaction worked well with less reactive
aliphatic ynals 1 (Table 2, entries 13 and 14), although
a higher catalyst loading (20 mol%) was needed and rela-
tively low yields were observed. On the other hand, the
reaction could be applied to substrates 2 with a broad
structural scope. Again, the survey of the electronic effect
shows that its impact is limited. Both electron-donating (X =
Me; Table 2, entries 15 and 16) and electron-withdrawing
(X = Cl; entries 17 and 18) groups are well tolerated. More-
over, significantly more hindered and less reactive ketone
moieties in substrates 2 (i.e., R2 ¼ H) are compatible with this
methodology (Table 2, entries 19–24). Structurally diverse
ketones can be used in the process to give trisubstituted
quinolines 4 with high efficiency. With an increased steric
Entry
R1, R2, X
4
t [h]
Yield [%][b]
1
2
3
4
Ph, H, H
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
16
16
24
21
16
16
20
16
16
16
16
13
16
20
24
24
16
16
22
12
12
16
16
16
99
97
92
95
96
98
91
92
95
92
97
95
80
83
98
90
94
91
84
80
78
76
96
98
4-BrC6H4, H, H
4-MeC6H4, H, H
4-MeOC6H4, H, H
2-ClC6H4, H, H
4-FC6H4, H, H
4-CNC6H4, H, H
4-ClC6H4, H, H
2-MeOC6H4, H, H
2-thienyl, H, H
3-MeOC6H4, H, H
3-CNC6H4, H, H
nC5H11, H, H
Ph(CH2)2, H, H
Ph, H, 6-Me
4-ClC6H4, H, 6-Me
Ph, H, 4-Cl
Ph, H, 5-Cl
Ph, Me, H
5
6
7[c]
8
9[d]
10
11[d]
12[c]
13[c]
14[c]
15[d]
16[d]
17
18
19[c]
20[c,e]
21[c,e]
22[e]
23[f]
24[f]
4s
4t
4u
4v
4w
4x
=
Ph, (E)-PhCH CH, H
4-ClC6H4, (E)-PhCH CH, H
4-FC6H4, (E)-PhCH CH, H
Ph, Ph, H
=
=
4-BrC6H4, Ph, H
[a] For reaction conditions, see Experimental Section. [b] Yields of
isolated products. [c] 20 mol% of catalyst A used. [d] 15 mol% of
catalyst A used. [e] The aromatization step required heating at 508C for
.
3 h in the presence of silica gel. [f] 1.0 equiv of NaHSO4 H2O added and
mixture stirred at 508C for 24 h. TEA=triethylamine, Tf=trifluorome-
thanesulfonyl, Ts=4-toluenesulfonyl.
aromatization (Table 1, entry 2). However, with catalyst A,
the 1,4-dihydroquinoline was only obtained with 7% ee.
When more bulky ketone 5a was used, the enantioselectivity
induced by (S)-diphenylprolinol TMS ether A improved
dramatically under similar reaction conditions (Table 3,
entry 1, 76% ee, 99% yield). A range of chiral a,a-diaryl-
prolinol silyl ether catalysts (A–D) were subsequently
probed, but the results were not encouraging (Table 3,
entries 2–4). It should be pointed out that for the model
reaction of phenylpropargyl aldehyde (1a) with 2’-(trifluoro-
methanesulfonyl)aminochalcone (5a), 5a and the formed
product 6a have the same polarity, thus rendering the
optimization process tedious because of difficult purification.
To minimize the work load, we chose more polar 3-nitro-
phenyl propargyl aldehyde as model substrate for the
subsequent optimization. A similar level of enantioselectivity
was obtained with catalyst A (Table 3, entry 5, 72% ee).
Gratifyingly, when C2-symmetric catalyst (2R,5R)-diphenyl-
pyrrolidine (E)[16] was employed, the enantioselectivity was
significantly enhanced to 87%, and full conversion was
achieved in only one hour (Table 3, entry 6). Furthermore,
solvent screening showed that the enantioselectivity was
2
2
=
hindrance of the R group, that is, R = CH3, (E)-PhCH CH,
and Ph, more drastic conditions for the aromatization
reaction were required, although high yields (76–98%)
could still be achieved under relatively mild conditions.
Having established an efficient protocol for the prepara-
tion of quinolines through an organocatalytic aza-Michael/
aldol/aromatization cascade process, we turned our attention
to aza-Michael/aldol cascade reactions for the one-pot
preparation of structurally diverse chiral 1,4-dihydroquino-
lines. The above-mentioned study showed that the use of Tf as
protecting group led to the product without subsequent
2
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Table 3: Optimization of reaction conditions for organocatalytic enan-
tioselective aza-Michael/aldol cascade reactions toward 1,4-dihydro-
quinolines 6.[a]
Table 4: Enantioselective organocatalytic cascade aza-Michael/aldol
reactions between ynals 1 and 2’-(trifluoromethanesulfonyl)amino-
ketones 5.[a]
Entry R1, R2
6
t
Yield
ee
[h] [%][b] [%][c]
1[d]
2
Ph, (E)-PhCH CH
6a
6b
6c
6d
6e
6 f
18
3
18
3
4
3
8
5
9
18
9
95
99
93
99
99
91
98
96
99
92
90
99
98
70
96
84
97
99
98
98
98
99
98
98
97
96
96
96
97
94
95
99
=
=
3-NO2Ph, (E)-PhCH CH
Ph, (E)-(4-BrC6H4)CH CH
3-NO2Ph, (E)-(4-BrC6H4)CH CH
4-ClPh, (E)-PhCH CH
4-CNPh, (E)-(4-BrC6H4)CH CH
4-CNPh, (E)-(3-MeOC6H4)CH CH 6g
4-BrPh, (E)-(4-NO2C6H4)CH CH
4-BrPh, (E)-(2-MeC6H4)CH CH
4-MeOPh, (E)-PhCH CH
2-thienyl, (E)-PhCH CH
Ph(CH2)2, (E)-PhCH CH
n-C5H11, (E)-PhCH CH
3[d]
4
=
=
Entry
R
Cat.
Solvent
t [h]
Yield [%][b]
ee [%][c]
=
5
6
7
8
=
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
3-NO2Ph
3-NO2Ph
3-NO2Ph
3-NO2Ph
3-NO2Ph
3-NO2Ph
3-NO2Ph
A
B
C
D
A
E
E
E
E
E
E
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(CH2Cl)2
toluene
MeOH
tBuOMe
toluene
12
12
12
12
12
1
1
1
6
4
99
93
92
84
93
97
99
99
61
96
99
76
75
71
40
72
87
94
98
75
98
99
=
=
=
6h
6i
6j
6k
6l
6m 20
6n
6o
6p
9
10[d]
11
12[d]
13[e]
14[f]
15[f]
=
=
=
12
=
=
=
(E)-PhCH CH, (E)-PhCH CH
18
18
3
9
Ph, Me
10
16[e,g] 3-NO2C6H4, Ph
11[d]
3
[a] For reaction conditions, see Experimental Section. [b] Yields of
[a] For reaction conditions, see Experimental Section. [b] Yields of
isolated products. [c] Determined by HPLC analysis on a chiral stationary
Phase (Chiralpak AS-H or IB column). [d] Reaction performed at 08C with
1 mol% of catalyst loading.
isolated products. [c] Determined by HPLC analysis on a chiral stationary
phase (Chiralpak AS-H or IB column). [d] 5 mol% of catalyst E used.
[e] 20 mol% of catalyst E used. [f] 8 mol% of catalyst E used.
[g] Reaction carried out at RT.
highly dependent on the solvent. Remarkably, compared with
dichloromethane, significantly higher enantioselectivity was
observed with toluene and tBuOMe (Table 3, entries 8 and
10). Polar protic solvents, such as MeOH, had a deleterious
effect on both the yield and enantioselectivity of the reaction
(Table 3, entry 9). Given the high reaction rate and the
practical advantage of carrying out the reaction at 08C, the
catalyst loading was drastically reduced to 1 mol% and the
reaction was performed at 08C in toluene, thus affording the
desired product almost quantitatively and with 99% ee within
only three hours (Table 3, entry 11).
The optimized protocol can be employed for the reactions
of a variety of ynals 1 and 2’-(trifluoromethanesulfonyl)ami-
noketones 5 (Table 4). Notably, the reactions served as
a synthetically efficient one-pot approach to diverse enan-
tioenriched 1,4-dihydroquinolines with a quaternary stereo-
genic center. They proceeded in high yields (70–99%) and
with excellent enantioselectivities (94–99% ee). Both sub-
strates, ynals 1 and aminoketones 5, can be tolerated with
significant structural variations. The electronic and steric
factors associated with the a,b-unsaturated ketone moieties
of 2’-(trifluoromethanesulfonyl)aminochalcones 5 appeared
to have minimal impact on the reaction efficiencies with
regard to enantioselectivity and yields (Table 4, entries 1–14).
The electronic effect of ynals 1 also influences the reaction
rate. Electron-withdrawing groups on aromatic ynal sub-
strates tend to accelerate the reaction, which is illustrated by
the higher turnover (1 mol% of catalyst loading) and short
reaction time (3–9 h; Table 4, entries 2 and 4–9). For ynals
1 that bear electron-neutral (Table 4, entries 1 and 3) or
electron-donating substitutents (entry 10), an increase of the
catalyst loading is necessary to guarantee full conversion. Less
reactive aliphatic ynals can also efficiently participate in the
process to give desired products 6l and 6m in excellent yields
(99 and 98%, respectively) and with excellent ee values (96
and 97%, respectively), but with relatively small reaction
rates (Table 4, entries 12 and 13). We have also investigated
more sterically hindered aliphatic alkynals, such as tert-butyl
propynal and cyclopentyl propynal, however, no reaction was
observed. Structurally altered ketones 5, such as acetophe-
none and benzophenone, are also compatible with the
protocol, thus leading to compounds 6o and 6p with different
substituents next to the chalcone moiety (Table 4, entries 15
and 16) with high efficiency. The absolute configuration of 6g,
which was prepared under the optimized conditions, was
determined by X-ray crystallography (Figure S1).[17] The
observed stereochemistry and high enantioselectivity can be
rationalized by the proposed transition state (Scheme S2).
In conclusion, we have developed a divergent organo-
catalytic cascade approach to synthetically valuable polysub-
stituted quinolines and highly enantioenriched 1,4-dihydro-
quinolines. The type of product that is formed depends on the
sulfonyl protecting group that is used for the nitrogen atom.
Electron-donating aryl sulfonamides facilitate the dehydra-
tion–aromatization of the aza-Michael/aldol adducts to give
quinolines. However, when the strongly electron-withdrawing
Tf group is used, chiral 1,4-dihydroquinolines are produced.
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Pꢁrez-Carriꢃn, M. del Pozo C. Sꢂnche-Rosellꢃ, Chem. Eur. J.
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The studies show a scarce example of the electronic effect on
the course of the reaction and the nature of the products.[11]
Further exploration of this powerful divergent organocata-
lytic cascade strategy in synthesis is currently pursued in our
laboratories.
Experimental Section
General procedure for aza-Michael/aldol/aromatization cascade
reactions (Table 2): Compound 2c (0.15 mmol) and K2CO3
(0.015 mmol) were added to a solution of ynal 1 (0.16 mmol) and
organocatalyst A (10–20 mol%) in chloroform (1.0 mL). The result-
ing solution was stirred at 508C for the specified time. After the
reaction (monitored by TLC) was finished, silica gel (80 mg) was
added and the mixture was stirred at RT for 24 h, then Et3N
(0.18 mmol) was added and the mixture was stirred at RTanother for
3 h. The reaction mixture was directly purified by column chroma-
tography on silica gel (eluent: hexane/EtOAc = 20:1) to afford the
desired product.
General procedure for cascade aza-Michael/aldol reactions
(Table 4): 2’-NH-Tf-protected ketone 5 (0.08 mmol) was added to
a solution of ynal 1 (0.0 8 mmol) and organocatalyst E (1 mol%) in
toluene (0.8 mL). The resulting solution was stirred at 08C for the
specified time. Then, the reaction mixture was directly purified by
column chromatography on silica gel (eluent: hexane/EtOAc = 8:1)
to afford the desired product. The ee value was determined by HPLC
analysis on a chiral stationary phase (see the Supporting Information
for details).
Received: March 19, 2012
Revised: April 20, 2012
Published online: && &&, &&&&
Keywords: 1,4-dihydroquinolines · cascade reactions ·
.
divergent synthesis · organocatalysis · quinolines
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Zhang, S.-L. Zhang, W. Wang, Angew. Chem. 2010, 122, 1523;
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[4] Fu and co-workers have reported an elegant study of the effect
of the N-protecting group on the stereoselectivity: E. C. Lee,
B. L. Hodous, E. Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc.
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Vargas Mꢁndez, C. M. Melꢁndez Gꢃmez, Curr. Org. Chem.
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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[17] The structure of compound 6g was determined by X-ray
crystallographic analysis. CCDC 865704 contains the supple-
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obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Angew. Chem. Int. Ed. 2012, 51, 1 – 7
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Cascade Reactions
X.-S. Zhang, X.-X. Song, H. Li,
S.-L. Zhang, X. Chen, X.-H. Yu,*
W. Wang*
&&&& — &&&&
An Organocatalytic Cascade Approach
toward Polysubstituted Quinolines and
Chiral 1,4-Dihydroquinolines–
Unanticipated Effect of N-Protecting
Groups
A matter of protection: The outcome of
a divergent organocatalytic aza-Michael/
aldol cascade process toward quinolines
and 1,4-dihydroquinolines depends on
the choice of the N-protecting group (see
scheme; TEA=triethylamine, TMS=tri-
methylsilyl). Use of an electron-donating
sulfonyl group results in an unanticipated
aza-Michael/aldol/aromatization cas-
cade to give polysubstituted quinolines
(right). In contrast, chiral 1,4-dihydroqui-
nolines are obtained with an electron-
withdrawing sulfonyl group (left).
Kaskadenreaktionen
X.-S. Zhang, X.-X. Song, H. Li,
S.-L. Zhang, X. Chen, X.-H. Yu,*
W. Wang*
&&&& — &&&&
An Organocatalytic Cascade Approach
toward Polysubstituted Quinolines and
Chiral 1,4-Dihydroquinolines–
Unanticipated Effect of N-Protecting
Groups
Eine Frage der Schutzgruppe: Das Er-
gebnis einer divergenten organokataly-
tischen Aza-Michael/Aldol-Kaskade zur
Herstellung von Chinolinen und 1,4-
Dihydrochinolinen hꢀngt von der Wahl
der N-Schutzgruppe ab (siehe Schema;
TEA=Triethylamin, TMS=Trimethyl-
silyl). Eine elektronenschiebende Sulfo-
nylgruppe fꢁhrt zu polysubstituierten
Chinolinen (rechts), wꢀhrend eine elek-
tronenziehende Sulfonylgruppe chirale
1,4-Dihydrochinoline ergibt (links).
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Cascade Reactions
X.-S. Zhang, X.-X. Song, H. Li,
S.-L. Zhang, X. Chen, X.-H. Yu,*
W. Wang*
&&&& — &&&&
An Organocatalytic Cascade Approach
toward Polysubstituted Quinolines and
Chiral 1,4-Dihydroquinolines–
Unanticipated Effect of N-Protecting
Groups
A matter of protection: The outcome of
a divergent organocatalytic aza-Michael/
aldol cascade process toward quinolines
and 1,4-dihydroquinolines depends on
the choice of the N-protecting group (see
scheme; TEA=triethylamine, TMS=tri-
methylsilyl). Use of an electron-donating
sulfonyl group results in an unanticipated
aza-Michael/aldol/aromatization cas-
cade to give polysubstituted quinolines
(right). In contrast, chiral 1,4-dihydroqui-
nolines are obtained with an electron-
withdrawing sulfonyl group (left).
Angew. Chem. Int. Ed. 2012, 51, 1 – 7
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!