Biomimetic oxidation of alcohols catalyzed by tempo-functionalized polyethylene glycol and copper(I) chloride in compressed carbon dioxide

Article abstract of DOI:10.1055/s-0029-1218375

Recyclable TEMPO-functionalized polyethylene glycol [PEG ₆₀₀₀-(TEMPO)₂] in combination with cuprous chloride were developed for biomimetic oxidation of a series of benzylic, allylic, heterocyclic alcohols, and 2-phenylethanol into th

Full text of DOI:10.1055/s-0029-1218375

LETTER
3291
Biomimetic Oxidation of Alcohols Catalyzed by TEMPO-Functionalized
Polyethylene Glycol and Copper(I) Chloride in Compressed Carbon Dioxide
B
C
iomimetic
O
xid
h
ation of Alco
e
hols ng-Xia Miao, Liang-Nian He,* Jin-Quan Wang, Jian Gao
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. of China
Fax +86(22)23504216; E-mail: heln@nankai.edu.cn
Received 1 September 2009
attained in the case of soluble homogeneous supports in
comparison with heterogeneous analogues.
Abstract: Recyclable TEMPO-functionalized polyethylene glycol
PEG6000-(TEMPO) ] in combination with cuprous chloride were
[
2
developed for biomimetic oxidation of a series of benzylic, allylic, Polyethylene glycol (PEG) is an inexpensive, nonvolatile,
heterocyclic alcohols, and 2-phenylethanol into the corresponding
and environmentally benign solvent, which represents an
aldehydes or ketones in high selectivity and in moderate to high
interesting reaction medium in place of conventional sol-
vents. On the other hand, commercial availability of PEG
conversion in compressed CO , which enhanced the catalytic activ-
2
9
ity as well as improved the selectivity.
derivatives with either two or one CH OH end group
2
Key words: alcohol oxidation, TEMPO, carbon dioxide, polymer,
copper(I) chloride
make it easy to prepare a variety of PEG-supported
ligands and/or catalysts, for instance, PEG6000-(TEM-
PO)2.8 In addition, the PEG-supported catalyst could
precipitate quantitatively after reaction upon adjusting
certain parameters, such as temperature, solvent, polarity,
and pH value of the solution. At present, PEG-supported
c–g
The selective oxidation of primary and secondary alco-
hols into the corresponding aldehydes or ketones is un-
doubtedly one of the most important and challenging
catalysts have been widely used in many reactions for re-
1
transformations in organic chemistry. One particular in-
7d,10
cycling homogeneous catalyst.
Various strategies
terest in this field is use of stable nitroxyl radical 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) in conjunction
have been developed for chemical functionalization of
8c–g
PEG with TEMPO,
such as via 5-hydroxyisophthalic
2
with certain terminal oxidants. However, many explored
8d
acid or directly to generate PEG-supported TEMPO de-
rivatives, for example, PEG6000-(TEMPO)2 being used
systems based on TEMPO using stoichiometric amounts
of terminal oxidants such as bleach, sodium chlorite,
m-chloroperoxybenzoic acid (MCPBA), hypervalent
iodine(III) compounds generally suffer from the produc-
8d
as active, recoverable catalysts in the aerobic oxidation of
7a
alcohols, both in the presence of Cu(I) and of other metal
8g
salts. However, a stoichiometric amount of terminal ox-
3
tion from large amounts of waste. From economic and
idant such as NaOCl, 1,3,5-trichloro-2,4-triazinetrione
environmental perspectives, using molecular oxygen or
hydrogen peroxide as a terminal oxidant has received
great attention nowadays since only water is formed as a
byproduct. Unfortunately, the relatively expensive
TEMPO species is unable to be regenerated directly by
molecular oxygen alone, so a cocatalyst is required for ac-
tivation of molecular oxygen. In 1984, Semmelhack et al.4
ingeniously described the aerobic oxidation of primary
and secondary alcohols to the corresponding aldehydes
and ketones catalyzed by CuCl/TEMPO. The reaction was
regarded to go through a copper-centered oxidation,
which bears a superficial resemblance to the mononuclear
(
TCCA), or [bis(acetoxy)iodo]benzene (BAIB), whereby
easily resulting in a large amount of waste, is often re-
quired. On the other hand, metal salts such as CuCl or
Mn(NO ) and Co(NO ) in combination with the PEG-
supported TEMPO were used for the aerobic oxidation of
alcohols in toxic organic solvents or corrosive acids. So an
efficient and greener method for oxidizing of alcohols to
carbonyl compounds catalyzed by TEMPO-based catalyst
still remains challenging.
7a
8g
3
2
3 2
Compressed CO has attracted much attention as a re-
placement for organic solvents, because CO is consid-
ered nontoxic, relatively cheap, and nonflammable. In
particular, CO appears to be an ideal medium for oxida-
tions. Unlike almost any organic solvent, CO will not be
oxidized further, and hence the use of CO as a reaction
medium eliminates byproducts originating from the sol-
vent. In addition, high miscibility of O in compressed
2
2
11
5
copper enzyme galactose oxidase. Consequently, many
2
efforts have been devoted to developing effective ligands
6
2
or additives for the Cu(I)/TEMPO system. Unfortunate-
2
ly, separation of products required tedious workup proce-
dures. In this context, recycling TEMPO has been realized
7
2
by immobilizing it onto inorganic or organic supports. In
1
2
CO could eliminate interphase transport limitations.
2
particular, supporting TEMPO species onto soluble ho-
8
mogeneous polymers would be promising. Increased sol- On the basis of our previous work on PEG-supported cat-
vent compatibility with accelerated reaction rate is alysts, such as PEG-supported quaternary ammonium
salts, quaternary phosphonium salts, or guanidinium bro-
mide for the cycloaddition reaction of aziridines or ep-
oxides with CO2, we would like to perform biomimetic
oxidation of alcohols catalyzed by the TEMPO-function-
SYNLETT 2009, No. 20, pp 3291–3294
Advanced online publication: 18.11.2009
DOI: 10.1055/s-0029-1218375; Art ID: W13609ST
x
x
.x
x
.2
0
0
9
13
©
Georg Thieme Verlag Stuttgart · New York

3
292
C.-X. Miao et al.
LETTER
PEG6000-(TEMPO)2 (2.5 mmol%)
CuCl (5 mmol%), O2, CO2 (6 MPa)
Table 1 The Aerobic Oxidation of Benzyl Alcohol Catalyzed by
OH
R2
O
a
PEG6000-(TEMPO) and CuCl
2
R1
R1
R2
Entry Temp
PO2
PO2 + PCO2 Conversion Yield
O
O
O
b
b
(°C)
(MPa) (MPa)
(%)
(%)
n
N
N
Aldehyde Acid
O
O
•
•
1c
2d
3
60
60
60
60
60
60
60
60
60
60
60
60
30
1
1
0
1
1
1
1
1
1
1
1
1
1
1
7
7
1
1
0
PEG6000-(TEMPO)2, MW = 6000
trace
trace
30
trace
trace
29
0
Scheme 1 The aerobic oxidation of alcohol catalyzed by PEG6000
TEMPO) /CuCl in compressed carbon dioxide
-
(
0
0
2
4
1
0
alized PEG/CuCl in compressed CO (Scheme 1) through
2
a so-called ‘mono-phase reaction, two-phase separation’
process to recover the catalyst, thus leading to conducting
a homogeneous catalysis in a continuous mode. In partic-
5
4
43
42
0.5
0
6
7
60
60
ular, compressed CO in this study could not only provide
7e
8f
9
2
7
61
61
0
a safe environment for the oxidation reaction by using
molecular oxygen as an oxidant under solvent-free condi-
tions, but also enhance the catalytic activity as well as im-
prove the selectivity.
7
59
59
0
8
60
60
0
1
0
9
62
62
0
In an exploratory study, the oxidation of benzyl alcohol
into benzyl aldehyde was chosen as a model reaction 11
12
7
27
27
0
14
(
Table 1). As shown in Table 1, CuCl, PEG 000-(TEMPO)2,
and oxygen were essential for this oxidation (Table 1, en-
6
2g
1
22
22
0
tries 1–3). To our delight, the presence of CO improved 13
7
11
10
0
2
the reaction (entry 4 vs. 5), and the reaction was further fa-
1
4
100
7
70
69
0
cilitated by altering CO pressure to 8 MPa (entries 6, 9,
2
a
and 10). As a consequence, an appropriate pressure of
Reaction conditions: benzyl alcohol (0.2 mL, 1.93 mmol), PEG6000
-
CO could accelerate the reaction. This would be presum- (TEMPO)
(0.3045 g, 2.5 mmol%), CuCl (9.6 mg), 2 h.
2
2
b
Determined by GC using biphenyl as an internal standard.
Without CuCl.
Without PEG6000-(TEMPO)2.
The second run of PEG6000-(TEMPO) recovered by the procedure
B after the run in entry 6.
ably ascribed to high miscibility of O in compressed CO ,
2
2
c
d
e
thus eliminating interphase transport limitation. Addition-
ally, the ‘expandable effect’ of PEG in compressed CO2
would also be beneficial to the reaction. Indeed, as judged
by visual inspection through a window-equipped high-
2
f
The third run of PEG6000-(TEMPO) recovered after the run in entry
2
7
pressure reactor, it was found that PEG6000-(TEMPO) can
2
g
CuCl (13 mg) was used instead of CuCl.
2
be expandable with CO , which possibly improves the
2
solubility of O and CO in PEG-supported catalyst as re-
2
2
5
1
3,15
based mechanism. The presence of base should be crucial
for the oxidation of alcohols, which could deprotonate the
alcohol and coordinate to Cu.6 So the base effect was
also evaluated, and the results were summarized in
ported in the literature.
However, the yield decreased
when CO pressure was further increased to 11 MPa (en-
2
a,17
try 11), probably due to the dilution effect of CO2.
The reaction temperature also had a great influence on the
reaction. Screening the reaction temperature revealed that
6a
Table 2. In Wei’s system, sodium hydroxide and trieth-
ylamine with low coordinating ability still showed accel-
erative effect with moderate activity compared to the
blank experiment. In contrast, pyridine and 1-methylim-
idazole played an accelerative role in our study (entries 3
and 4). Both inorganic bases and organic bases such as
DMAP and DBU with bulky steric hindrance showed a
detrimental effect upon the reaction (entries 1, 2, and 5–
). In addition, the optimal amount of 1-methyl-imidazole
was found to be one equivalent of CuCl in the experiment
conditions (entry 4 and 9–12).
6
0 °C was the appropriate temperature in terms of energy
consumption and reaction efficiency (entries 6, 13, and
4). Interestingly, CuCl was more active in comparison to
1
CuCl (entries 6 and 12), being consistent with the report-
2
4
ed results. In addition, a series of catalytic cycles were
examined to test the catalyst recycling. In each cycle, the
catalyst [PEG6000-(TEMPO) /CuCl] was solidified by
2
8
cooling the resultants, followed by addition of diethyl
ether, and thus recovered by the simple filtration [about
9
5% of PEG6000-(TEMPO)2 could be recycled every
1
6
To evaluate the utility of the present methodology, the
reaction was carried out with alcohol (1.93 mmol), 2.5
mmol% of PEG6000-(TEMPO) , 5 mmol% of CuCl, 5
mmol% 1-methylimidazole, 1 MPa of oxygen, and 6 MPa
of CO . It was found that benzylic, allylic, heterocyclic,
run]. It was found that the catalytic system retained ex-
cellent catalytic performance after 3 runs (entries 7 and 8).
2
According to the accepted mechanism of the biomimetic
oxidation process, the reaction was completed through a
copper-mediated oxidation rather than an oxoammonium-
2
and aliphatic alcohols were selectively converted into
Synlett 2009, No. 20, 3291–3294 © Thieme Stuttgart · New York

LETTER
Biomimetic Oxidation of Alcohols
3293
Table 2 The Effect of the Basea
selectivity and moderate to high yields. The ‘expandable
effect’ of TEMPO-functionalized PEG and miscibility
Entry
Base
Conversion (%)b Yield (%)b
with oxygen in compressed CO could improve the reac-
2
DMAPc
tion rate and enhance the selectivity. This process looks
promising as a strategy for homogeneous catalyst recy-
cling.
1
2
3
4
5
6
7
8
9e
39
38
74
86
20
10
18
16
43
69
58
19
39
38
74
86
20
10
18
16
42
69
58
19
DBUd
pyridine
Table 3 Catalytic Aerobic Oxidation of Alcohola
1-methylimidazole
Entry Substrate
1c
Product
TempTimeConv. Yield
(°C) (h) (%) (%)
b
b
Et N
3
NaHCO3
CHO
60
2
2
86
99
86
94
OH
Na CO3
2
2
CHO 100
NaOH
OH
1-methylimidazole
1-methylimidazole
1-methylimidazole
1-methylimidazole
O2N
2
O N
0f
3
CHO
NO2
100
3
85
82
1
1
OH
1g
NO2
2h
4
5
CHO 60
3
3
78
99
76
92
1
OH
100
a
Reaction conditions: benzyl alcohol (0.2 mL, 1.93 mmol), PEG6000
TEMPO) (0.3045 g, 2.5 mmol%), base (0.098 mmol), CuCl (9.6
-
MeO
MeO
(
2
6
CHO
60
3
83
82
mg), 60 °C, 2 h.
OH
OH
b
Determined by GC using biphenyl as an internal standard.
c
4-Dimethylaminopyridine.
d
e
f
1
,8-Diazabicyclo[5.4.0]undec-7-ene.
OMe
OMe
Based (0.025 mmol), nCuCl/nbase = 4:1.
Based (0.049 mmol), nCuCl/nbase = 2:1.
Based (0.194 mmol), nCuCl/nbase = 1:2.
Based (0.388 mmol), nCuCl/nbase = 1:4.
7
CHO
OMe
60
60
3
3
63
19
62
g
h
OMe
OH
8c
9
16
91
c
60 10 95
CHO
their corresponding aldehydes or ketones, as summarized
in Table 3. And the overoxidized products were rarely de-
tected. The reaction rate was not significantly affected by
electronic properties of the substituents on the benzene
ring in the cases of primary benzylic alcohols (entries 1–
O
O
O
1
1
0
1
OH
100 24 30
26
38
Ph
Ph
OH
Ph
Ph
O
100 24 42
7
), which was similar to the reported results.6a,b However,
ortho-substituted primary benzyl alcohols were less ac-
tive compared to other primary benzylic alcohols, pre-
sumably owing to steric hindrance. In addition, other
activated primary alcohols, such as allylic alcohol, could
be effectively and selectively oxidized to the correspond-
ing aldehyde (entry 13). Fortunately, a type of hetero-
cyclic alcohol (such as 2-furfurylmethanol), which was
less active in many systems, could also be converted to the
desired compounds (entries 8 and 9). Furthermore, even
secondary alcohols such as diphenylmethanol and 1-phe-
nylethanol with bulky groups and aliphatic alcohols (2-
1
1
a
2
OH
60 24 30
26
95
CHO
3c
OH
60
3
98
CHO
Reaction conditions: alcohol (1.93 mmol), PEG6000-(TEMPO)2
0.3045 g), 2.5 mmol% catalyst loading with respect to the initial
amount of benzyl alcohol), CuCl (9.6 mg), 1-methylimidazole (7.7
(
phenyl ethanol) were, respectively, oxidized to ketones mL), P = 1 MPa, Ptotal = 7 MPa.
o2
b
and aldehyde in high selectivity by prolonging the reac-
tion time (entries 10–12).
Isolated yield.
Determined by GC.
c
In summary, recyclable TEMPO-functionalized PEG
combined with copper(I) chloride, that is, PEG6000-(TEM-
PO) /CuCl, was developed to efficiently catalyze the aer-
obic oxidation reaction of benzylic, allylic, heterocyclic
2
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
alcohols, and 2-phenylethanol in compressed CO pro-
2
ducing the corresponding aldehydes or ketones with high
Synlett 2009, No. 20, 3291–3294 © Thieme Stuttgart · New York

3
294
C.-X. Miao et al.
LETTER
Acknowledgment
(10) Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103,
3
401.
11) (a) Jessop, P. G.; Ikariya, T.; Noyori, R. Chem. Rev. 1999,
9, 475. (b) Baiker, A. Chem. Rev. 1999, 99, 453.
12) Heldebrant, D. J.; Jessop, P. G. J. Am. Chem. Soc. 2003, 125,
600.
13) (a) Du, Y.; Wu, Y.; Liu, A.-H.; He, L.-N. J. Org. Chem.
008, 73, 4709. (b) Tian, J.-S.; Miao, C.-X.; Wang, J.-Q.;
Cai, F.; Du, Y.; Zhao, Y.; He, L.-N. Green Chem. 2007, 9,
66. (c) Du, Y.; Wang, J.-Q.; Chen, J.-Y.; Cai, F.; Tian,
J.-S.; Kong, D.-L.; He, L.-N. Tetrahedron Lett. 2006, 47,
271. (d) Dou, X.-Y.; Wang, J.-Q.; Du, Y.; Wang, E.; He,
The work was financially supported by the National Natural Sci-
ence Foundation of China (No. 20421202, 20672054, 20872073)
and the 111 project (B06005), and the Committee of Science and
Technology of Tianjin.
(
(
(
9
5
2
References and Notes
5
(
1) Hudlicky, M. Oxidations in Organic Chemistry; American
Chemical Society: Washington DC, 1990.
1
(2) (a) De Souza, M. V. N. Mini-Rev. Org. Chem. 2006, 3, 155.
L.-N. Synlett 2007, 3058.
14) Representative Procedure for the Aerobic Oxidation of
(
b) Minisci, F.; Recupero, F.; Pedulli, G. F.; Lucarini, M.
(
J. Mol. Catal. A: Chem. 2003, 204-205, 63. (c) Sheldon, R.
A.; Arends, I. W. C. E.; Brink, G.-J. T.; Dijksman, A. Acc.
Chem. Res. 2002, 35, 774. (d) Sheldon, R. A.; Arends, I. W.
C. E. J. Mol. Catal. A: Chem. 2006, 251, 200. (e) Piera, J.;
Bäckvall, J.-E. Angew. Chem. Int. Ed. 2008, 47, 3506.
Alcohols
A mixture of substrate (1.93 mmol), PEG6000-(TEMPO)2
(
0.3045 g, 2.5 mmol%), and CuCl (9.6 mg, 5 mmol%) was
placed in a 25 mL autoclave equipped with an inner glass
tube. 2 MPa CO and 1 MPa O were introduced into the
(
f) Bragd, P. L.; van Bekkum, H.; Besemer, A. C. Top.
2
2
autoclave, and the reactor was heated to the reaction
temperature. Then final pressure was adjusted to the desired
pressure at the reaction temperature by introducing amount
Catal. 2004, 27, 49.
(
3) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org.
Chem. 1987, 52, 2559. (b) Anelli, P. L.; Banfi, S.;
Montanari, F.; Quici, S. J. Org. Chem. 1989, 54, 2970.
of CO . The mixture was stirred continuously for the
2
designed reaction time. After cooling, products were then
(c) Rychnovsky, S. D.; Vaidyanathan, R. J. Org. Chem.
extracted by Et O and analyzed by gas chromatography with
1
999, 64, 310. (d) Sourkouni-Argirusi, G.; Kirschning, A.
2
a Shimadzu GC-2014 equipped with a capillary column
Org. Lett. 2000, 2, 3781. (e) Mico, A. D.; Margarita, R.;
(
RTX-5, 30 m × 0.25 mm) using a flame-ionization detector.
Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997,
The residue was purified by column chromatography on
silica gel (200–300 mesh, eluting with 20:1 PE–EtOAc) to
afford the desired product. The structure and purity of
products were further identified using NMR (Bruker 300 or
6
2, 6974.
(
(
(
4) Semmelhack, M. F.; Schmid, C. R.; Cortes, D. A.; Chou,
C. S. J. Am. Chem. Soc. 1984, 106, 3374.
5) Dijksman, A.; Arends, I. W. C. E.; Sheldon, R. A. Org.
Biomol. Chem. 2003, 1, 3232.
6) (a) Liu, L.; Ji, L. Y.; Wei, Y. Y. Catal. Commun. 2008, 9,
400 MHz), GC-MS (HP G1800A), HPLC-MS (LCQ
Advantage), GC, and HPLC by comparing retention times
and fragmentation patterns with those of authentic samples.
Safety warning: Experiments using large amounts of
compressed gases, especially molecular oxygen and
supercritical fluids, are potentially hazardous and must only
be carried out by using the appropriate equipment and under
1379. (b) Liu, L. N.; Ma, J. J.; Ji, L. Y.; Wei, Y. Y. J. Mol.
Catal. A: Chem. 2008, 291, 1. (c) Mannam, S.; Alamsetti,
S. K.; Sekar, G. Adv. Synth. Catal. 2007, 349, 2253.
(
d) Ragaanin, G.; Betzemeier, B.; Quici, S.; Knochel, P.
Tetrahedron 2002, 58, 3985. (e) Ansari, I. A.; Gree, R. Org.
Lett. 2002, 4, 1507.
rigorous safety precautions. In particular, CO is introduced
2
into the substrate-loaded reactor before oxygen is added.
(
(
7) (a) Ferreira, P.; Phillips, E.; Rippon, D.; Tsang, S. C. Appl.
Catal., B: 2005, 61, 206. (b) Luo, J.; Pardin, C.; Lubell,
W. D.; Zhu, X. X. Chem. Commun. 2007, 2136. (c) Lu, N.;
Lin, Y.-C. Tetrahedron Lett. 2007, 48, 8823.
(
(
15) (a) Daneshvar, M.; Kim, S.; Gulari, E. J. Phys. Chem. 1990,
94, 2124. (b) Kazarian, S. G.; Chan, K. L. A.
Macromolecules 2004, 37, 579.
16) The Typical Procedure for the Recycling of TEMPO-
Functionalized PEG
(
d) Bergbreiter, D. E.; Tian, J. H.; Hongfa, C. Chem. Rev.
009, 109, 530.
8) (a) Wu, X.-E.; Ma, L.; Ding, M.-X.; Gao, L.-X. Synlett 2005,
07. (b) Qian, W. X.; Jin, E. L.; Bao, W. L.; Zhang, Y. M.
2
(A) The reaction mixture was extracted with compressed
CO (202.7 bar, 50 °C) to afford the corresponding carbonyl
6
2
compound. The TEMPO-functionalized PEG phase
containing CuCl was reused without further purification
or activation.
Tetrahedron 2006, 62, 556. (c) Pozzi, G.; Cavazzini, M.;
Quici, S.; Benaglia, M.; Dell’Anna, G. Org. Lett. 2004, 6,
441. (d) Ferreira, P.; Phillips, E.; Rippon, D.; Tsang, S. C.;
(
B) Extract procedure with Et O: after addition of Et O
Hayes, W. J. Org. Chem. 2004, 69, 6851. (e) Ferreira, P.;
Hayes, W.; Phillips, E.; Rippon, D.; Tsang, S. C. Green
Chem. 2004, 6, 310. (f) Chung, C. W. Y.; Toy, P. H. J.
Comb. Chem. 2007, 9, 115. (g) Benaglia, M.; Puglisi, A.;
Holczknecht, O.; Quici, S.; Pozzi, G. Tetrahedron 2005, 61,
2
2
(
3 × 10 mL) to the resulting mixture upon completion of
reaction, the PEG phase was solidified when cooled to
10 °C to –20 °C, and followed by simple decantation of the
–
ether phase containing oxidized products. Subsequently, the
PEG phase was dried under vacuum for next run. We
conducted further oxidation by addition of successive
portions of the alcohol and run the reaction under identical
reaction conditions.
12058.
(
9) (a) Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D.
Green Chem. 2005, 7, 64. (b) Hou, Z. S.; Theyssen, N.;
Brinkmann, A.; Leitner, W. Angew. Chem. Int. Ed. 2005, 44,
(
17) (a) Jiang, N.; Ragauskas, A. J. Org. Lett. 2005, 7, 3689.
1346. (c) Wang, J.-Q.; Cai, F.; Wang, E.; He, L.-N. Green
(
b) Mannam, S.; Alamsetti, S. K.; Sekar, G. Adv. Synth.
Chem. 2007, 9, 882.
Catal. 2007, 349, 2253.
Synlett 2009, No. 20, 3291–3294 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.