Fluorous synthesis of mono-dispersed poly(ethylene glycols)

Article abstract of DOI:10.1016/j.tetlet.2014.02.047

Mono-dispersed poly(ethylene glycols) (PEGs) are of great value in the development of biopharmaceuticals. However, tedious synthesis limits the availability of mono-dispersed PEGs. To address this issue, a fluorous synthesis of mono-dispersed PEGs, discretely PEGylated surfactants and ¹⁹F magnetic resonance imaging (MRI) agents has been developed. During the synthesis, both fluorous and normal phase silica gel-based solid-phase extractions were successfully employed to simplify the purifications. This synthesis provided an easy access to valuable mono-dispersed PEGs and related molecules for biomedical application on multi-gram scales.

Full text of DOI:10.1016/j.tetlet.2014.02.047

Tetrahedron Letters 55 (2014) 2110–2113
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fluorous synthesis of mono-dispersed poly(ethylene glycols)
Yu Li a, , Qi Guo a, , Xuefei Li a, Hua Zhang a, Fanghua Yu a, Weijiang Yu a, Guiquan Xia a, Mingyang Fu a,
a,b,c,
Zhigang Yang a,b, , Zhong-Xing Jiang
⇑
⇑
a Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, PR China
b Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan 430071, PR China
c Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Mono-dispersed poly(ethylene glycols) (PEGs) are of great value in the development of biopharmaceuti-
cals. However, tedious synthesis limits the availability of mono-dispersed PEGs. To address this issue, a
fluorous synthesis of mono-dispersed PEGs, discretely PEGylated surfactants and 19F magnetic resonance
imaging (MRI) agents has been developed. During the synthesis, both fluorous and normal phase silica
gel-based solid-phase extractions were successfully employed to simplify the purifications. This synthe-
sis provided an easy access to valuable mono-dispersed PEGs and related molecules for biomedical appli-
cation on multi-gram scales.
Received 6 December 2013
Revised 24 January 2014
Accepted 13 February 2014
Available online 26 February 2014
Keywords:
Fluorous chemistry
Solid-phase extraction
Fluorinated surfactant
Mono-dispersed PEGs
Ó 2014 Elsevier Ltd. All rights reserved.
PEGs are a class of flexible, water soluble, and biocompatible
polymers which play important roles in biopharmaceutical formu-
lations.1 The history of PEGylation can be dated back to the 1970’s
when Davis et al., first conjugated PEGs to bioactive proteins and
found PEGylated proteins exhibited dramatically longer in vivo
half-time and lower immunogenicity than their parent proteins.2
Since this pioneering work, PEGylation has been extensively
explored in biomedical research and PEGs have set the ‘golden
standard’ for polymers used in pharmaceutical research. Now, the
so-called ‘stealth effect’ of PEGs has been routinely employed in drug
development to increase solubility and stability, reduce immuno-
genicity and dosing frequency, and optimize the pharmacokinetics
profiles of therapeutics.1 Till 2012, there are already a dozen of
PEGylated drugs approved by the FDA. For example, Neulastim, a
PEGylated filgrastim protein, and Pegasys, a PEGylated interferon
alfa, have a combined annual sale of over $5 billion in 2011.
As a class of widely used polymers, the heterogeneity of PEGs
has brought a range of problems in their biomedical applications.
Since the 1970’s, PEGs with polydispersity indexes (PDI) within
1.09, such as PEG400, PEG2000, PEG4000 etc., are routinely used in
biomedical research. However, commercially available PEGs with
6 and more ethylene glycol units are usually a mixture of
homologs. For example, over 30 components were detected by
MALDI-TOF from a commercially available PEG3400 with a PDI of
1.01.3a Such heterogeneity complicates many stages of PEGs’
biomedical applications, such as PEGylation,3e purification, charac-
terization, clinical application, and drug regulatory approval.3a To
avoid such heterogeneity, mono-dispersed PEGs are highly pre-
ferred for biomedical applications. Unfortunately, mono-dispersed
PEGs are either not commercially available, or very expensive.
Therefore, it is of great importance to synthesize mono-dispersed
PEGs on preparative scales.
Recently, a few methods for preparing mono-dispersed PEGs
from commercially available oligo(ethylene glycols) of defined
length have been developed.3 However, due to the high polarity
of PEGs, normal phase chromatography can hardly purify
the desired products. Therefore, reverse phase chromatography3e
or gel-permeation chromatography3c is usually required. Such
tedious purification dramatically limited the availability of
mono-dispersed PEGs. To this end, fluorous technology provides
a number of convenient purification methods, such as fluorous
liquid-phase extraction, fluorous solid-phase extraction (FSPE),
and fluorous HPLC.4 As a separation technology that is based not
on the polarity but on the fluorous interaction,5 fluorous separation
would be a good choice for the rapid purification of fluorous-
tagged PEGs. In this way, it can dramatically improve synthesis
efficiency. Herein, we describe a fluorous synthesis of mono-
dispersed PEGs with up to 20 ethylene glycol units on multi-gram
scales.
⇑
Corresponding authors. Tel.: +86 27 68759220; fax: +86 27 68759850.
E-mail addresses: zgyang@whu.edu.cn (Z. Yang), zxjiang@whu.edu.cn
(Z.-X. Jiang).
These two authors contributed equally to this work.
http://dx.doi.org/10.1016/j.tetlet.2014.02.047
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

Y. Li et al. / Tetrahedron Letters 55 (2014) 2110–2113
2111
With these ideas in mind, our attention was first paid to the
preparation of a suitable fluorous tag. Here, the fluorous tag played
two roles: (1) as a protective group for the hydroxyl group in PEGs,
(2) as a fluorous separative tag for fluorous purification. The benzyl
During the deprotecting-coupling cycle, FSPE and normal phase
silica gel based solid phase extraction (SPE) can efficiently purify
the intermediates. Removal of the triphenylmethyl group in 10
with catalytic amount of p-toluene-sulfonic acid gave alcohol
11.9 Quenching the reaction with a base is crucial, otherwise
p-toluene-sulfonic acid would catalyze the reverse reaction to
provide the starting material 10 when evaporating methanol from
the reaction mixture. To avoid silica gel-based chromatography,
FSPE was initially used to isolate 11 from the reaction mixture.
However, the hydrophobic triphenylmethyl-related impurities
which have poor solubility in methanol and water can hardly be
washed out from fluorous silica gel with a cocktail of methanol/
water (8/2). Fortunately, the normal phase silica gel-based SPE
successfully purified alcohol 11 by taking advantage of the large
polarity difference between alcohol 11 and the impurities. It was
also found that most of impurities can be easily removed by filtra-
tion of the cold reaction mixture. With fluorous alcohol 11 in hand,
fully protected octa(ethylene glycol) 12 was prepared by coupling
alcohol 11 with excess amount of tosylate 9 in the presence of
sodium hydride.10 The resulting octa(ethylene glycol) 12 was
purified with FSPE. After one cycle of deprotecting-coupling from
fluorinated ether 10, fluoroalkyl-substituted octa(ethylene glycol)
12 was prepared on a scale of over 10 grams with a 74.5% yield
in two steps. NMR and mass spectra indicate that mono-dispersed
12 was prepared with high purity after SPE.
group has been widely used as
a protective group in PEG
modification because it is stable under basic and acidic conditions
and it can be removed under mild condition. Therefore, the para-
perfluorooctylethyl substituted benzyl bromide 6 was employed
in this synthesis (Scheme 1). Initially, the fluorous benzyl bromide
6 was prepared according to Curran’s strategy.6 However, it turned
out that the synthesis efficiency was very low (14% yield over 4
steps) and the purification was very tedious. These drawbacks
promoted us to develop an alternative synthetic method for this
fluorous tag. Then, a Suzuki cross-coupling7 reaction between
4-(methoxycarbonyl)phenyl boronic acid and b-(perfluorooctyl)-
ethyl iodide 1 was explored. This Suzuki cross-coupling reaction
is not moisture sensitive and the product 5 can be conveniently
prepared on a multi-gram scale with good yield. After reduction
of ester 5 with lithium aluminum hydride, the newly formed ben-
zyl alcohol 4 was then transformed into benzyl bromide 6 with
phosphorous tribromide. In this way, the fluorous benzyl bromide
6 was prepared on a multi-gram scale with a 49% yield in 3 steps.
To further improve the synthesis efficiency, a Suzuki cross-
coupling reaction between 4-hydroxymethylphenyl boronic acid
and b-(perfluorooctyl)-ethyl iodide 1 was carried out to provide
the fluorinated benzyl alcohol 4 in one step with a 60% yield. It is
With this protocol in hand, a range of procurers for mono-dis-
persed PEGs can be conveniently prepared by repeating the depro-
tecting-coupling cycle. Therefore, alcohol 19 with 20 ethylene
glycol units was conveniently synthesized by repeating the depro-
tecting-coupling cycle 5 times from intermediate 10 (Scheme 2).
The fluorinated benzyl protective group in 19 was removed by
hydrogenolysis under 1 atm of hydrogen atmosphere and the
mono-dispersed PEG 20 was prepared on a gram scale. It is note-
worthy that the resulting fluorous toluene can be recovered by
simple liquid-phase extraction of the reaction mixture with ether.
As expected, all the intermediates can be rapidly purified by either
FSPE or silica gel-based SPE. It is worth pointing out that some fine
tuning is necessary when purifying intermediates with higher
molecular weight due to their increased hydrophilicity and
decreased fluorophilicity. In these cases, the percentage of water
in the FSPE eluant system was increased (from 20% to 50%) to
retain the fluorous component on the fluorous silica gel while
washing the non-fluorinated impurities out. In this synthesis, silica
gel-based solid-phase extraction complements FSPE when low
polar impurities are very hydrophobic and insoluble in the
methanol/water system.
noteworthy that all the intermediates and bromide
conveniently purified by FSPE.
6 were
With the fluorous tag 6 in hand, a fluorous synthesis of mono-
dispersed PEGs with up to 20 ethylene glycol units was then inves-
tigated. The tetra(ethylene glycol) was chosen as the building block
for the synthesis because it is the longest commercially available
oligo(ethylene glycol) with defined molecular weight and reason-
able price. A divergent synthesis of mono-dispersed PEGs with
4n (n = 2, 3, 4, 5) ethylene glycol units was designed by repetitively
attaching the modified tetra(ethylene glycol) to the fluorous tag 6
(Scheme 2). In this way, all the synthetic intermediates contain a
fluorous tag for rapid fluorous purification. After selectively pro-
tecting one of the hydroxyl groups in tetra(ethylene glycol) 7 with
triphenylmethyl chloride,8 the resulting alcohol 8 was then tosy-
lated to give intermediate 9 in 84.2% yield over two steps. In order
to simplify fluorous solid-phase extraction (FSPE), fluorous tag 6
was coupled with excess mono-protected tetra(ethylene glycol) 8
in the presence of sodium hydride. As expected, the fluorinated
ether 10 was obtained with high yield after convenient FSPE
purification.
a). Zn, TMSCl, THF, rt.
b). IC6H4Br, Pd(PPh3)4,
C8F17
BuLi, DMF, -40oC
THF, 45oC
C8F17
I
Br
C8F17
34%
46%
1
O
3
2
LiAlH4
THF, rt
99%
(HO)2B
CO2Me
Pd(PPh3)4,NaHCO3
DME, H2O, reflux
60%
C8F17
C8F17
LiAlH4, THF, rt.
CO2Me
93%
OH
5
4
OH
PBr3
DCM, rt.
(HO)2B
88%
Pd(PPh3)4,NaHCO3
DME, H2O, reflux
C8F17
4
Br
60%
6 (Rf-Br)
Scheme 1. Synthesis of fluorous benzyl bromide 6.

2112
Y. Li et al. / Tetrahedron Letters 55 (2014) 2110–2113
TrtCl, Et3N, DMAP,
TosCl, NaOH
H2O-THF, rt
DCM, reflux
O
O
O
HO
OH
HO
OTrt
TosO
OH
OTrt
3
99%
85%
3
3
7
8
9
6
TosOH, MeOH, rt
NaH, 9, THF, rt.
NaH, , THF, rt.
O
O
8
RfO
OH
RfO
OTrt
85%
FSPE
3
81%
FSPE
3
92%
SPE
10
11
NaH, 9, THF, rt.
TosOH, MeOH, rt
O
O
O
RfO
RfO
OTrt
RfO
RfO
OTrt
86%
SPE
7
87%
7
11
12
13
FSPE
14
NaH, 9, THF, rt.
TosOH, MeOH, rt
TosOH, MeOH, rt
O
O
OH
11
RfO
OTrt
15
93%
SPE
94%
88%
FSPE
15
SPE
16
NaH, 9, THF, rt.
TosOH, MeOH, rt
O
O
O
RfO
OH
HO
RfO
OH
RfO
OTrt
15
88%
FSPE
85%
SPE
19
19
17
19
18
H2, Pd/C, MeOH, rt
O
OH
55%
FSPE
19
20
Scheme 2. Fluorous synthesis of mono-dispersed PEGs.
F3C
CF3
OH
It is noteworthy that these synthetic intermediates 13, 15, 17,
and 19 are precursors for both mono-dispersed PEGs and novel
fluorinated surfactants. A range of mono-dispersed PEGs can be ob-
tained by hydrogenolysis of the fluorous benzyl protective group in
these intermediates. In the meanwhile, they are a class of novel
fluorinated non-ionic surfactants. In terms of surfactants, these
fluorinated surfactants have the same hydrophobic head (fluori-
nated benzyl moiety) and a serial of well-defined hydrophilic tails
(PEGs with 4n ethylene glycol units). Comparing the aqueous
behaviors of these fluorous surfactants would provide important
information on the relationship between oligo(ethylene glycol)
length and surfactant properties. Therefore, the 1-octanol/water
partition coefficients (logP) of these fluorinated surfactants were
evaluated with the aid of 19F NMR. It was found that, for surfac-
tants 11, 13, and 15, no 19F NMR signal could be detected in the
aqueous phase which indicates that these three surfactants are
highly hydrophobic. Surfactant 17 is preferentially soluble in the
aqueous phase with a logP of À0.93. Surfactant 19 is very hydro-
philic and no 19F NMR signal was detected in the 1-octanol phase.
This indicates that increasing the oligo(ethylene glycol) length can
gradually improve the hydrophilicity of the parent compound. A
qualitative aqueous solubility measurement was also carried out
by dissolving 100 mg of surfactants in 1 mL water. For surfactants
11, 13, and 15, very poor aqueous solubility was observed. For sur-
factant 17, a cloudy solution was obtained. Surfactant 19 is freely
soluble in water and forms a clear solution. If taking the fluorine
contents (F%) of these surfactants into account (11 (F% = 44.2%),
13 (F% = 35.6%), 15 (F% = 29.8%), 17 (F% = 25.7%), and 19
(F% = 22.5%), a threshold of ca. 30F% can be identified. This thresh-
old corresponds with a dramatic increase in aqueous solubility.
This hydrophilicity/solubility trend has also been observed in
oligo(ethylene glycol)-based linear and dendritic multi-trifluorom-
ethylated surfactants.11
HO
F3C CF3
8O
F3C
CF3
O
O
Rf
13
O
Rf
DIAD, Ph3P,
8
o
F3C CF3
4A MS, THF, 45oC
21
52%
FSPE
H2(40 atm),
Pd/C, MeOH
85% FSPE
F3C CF3
O
O
H
8
O
8O
H
F3C CF3
22
Scheme 3. Fluorous synthesis of 19F MRI agent 22.
has been synthesized in this lab.11 However, it was synthesized
over 6 steps and flash chromatography was required for each syn-
thesis step. With fluorinated octa(ethylene glycol) 13 in hand, the
19F MRI agent 22 had been efficiently synthesized in 2 steps
(Scheme 3). FSPE dramatically simplified the purification proce-
dures and conveniently recovered the fluorous tag. Therefore,
these fluorous intermediates (13, 15, 17, and 19) can act not only
as building blocks for introducing mono-dispersed PEGs but also
as separative tags for downstream purification with FSPE.
In conclusion, a FSPE- and SPE-assisted sequential synthesis of
mono-dispersed PEGs on gram-scales has been developed. The
modified synthesis of fluorous benzyl-based tags provides a more
practical way for fluorous tag preparation. It was found that,
although fluorous solid phase extraction can rapidly separate fluor-
ous components from nonfluorous ones, it is not suitable for the re-
moval of low polar impurities which have poor solubility in the
methanol/water eluent system. To this end, silica gel-based nor-
mal-phase extraction can complement fluorous solid-phase extrac-
tion. Therefore, this synthetic method represents a convenient
alternative to the existing synthesis of mono-dispersed PEGs. A
mono-dispersed PEG with 20 ethylene glycol units was success-
fully synthesized to illustrate the potential of this method in the
synthesis of a broad range of valuable mono-dispersed PEGs. It is
interesting to point out that these fluorous intermediates are also
These fluorinated intermediates (13, 15, 17, and 19) are also
valuable building blocks for the fluorous synthesis of novel pre-
cisely PEGylated molecules of biomedical interest. To this end,
developing novel 19F MRI agents for image-guided drug therapy
is our ongoing research.5,11 Recently, a very promising 19F MRI
agent 22 containing two mono-dispersed octa(ethylene glycols)

Y. Li et al. / Tetrahedron Letters 55 (2014) 2110–2113
2113
5. Jiang, Z.-X.; Yu, Y. B. J. Org. Chem. 2010, 75, 2044–2049.
novel fluorinated non-ionic surfactants and building blocks for
mono-dispersed PEGylated molecules of biomedical importance.
A
intermediates. Along with this sequential synthesis, a series of
such fluorinated surfactants can be conveniently prepared. By
comparing the physicochemical properties of these fluorinated
surfactants, certain insight on the structure-property relationship
of fluorinated surfactants may be revealed. These quantitative
measurements and synthesis of biomacromolecules with mono-
dispersed PEGs are still going on in this lab.
6. (a) Kainz, S.; Koch, D.; Baumann, W.; Leitner, W. Angew. Chem., Int. Ed. 1997, 36,
1628–1630; (b) Zhang, Q.; Luo, Z.; Curran, D. P. J. Org. Chem. 2000, 65, 8866–
8873; (c) Curran, D. P.; Oderaotoshi, Y. Tetrahedron 2001, 57, 5243–5253; (d)
Curran, D. P.; Amatore, M.; Guthrie, D.; Campbell, M.; Go, E.; Luo, Z. J. Org. Chem.
2003, 68, 4643–4647.
7. (a) Yang, G.-S.; Xie, X.-J.; Zhao, G.; Ding, Y. J. Fluorine Chem. 1999, 98, 159–161;
(b) Yin, Y.-Y.; Zhao, G.; Yang, G.-S.; Yin, W.-X. Chin. J. Chem. 2002, 20, 803–808.
8. (a) Hernández, A.-I.; Familiar, O.; Negri, A.; Rodríguez-Barrios, F.; Gago, F.;
Karlsson, A.; Camarasa, M.-J.; Balzarini, J.; Pérez-Pérez, M.-J. J. Med. Chem. 2006,
49, 7766–7773; (b) Menger, F. M.; Lu, H.; Lundberg, D. J. Am. Chem. Soc. 2007,
129, 272–273.
9. Typical experimental procedure for the removal of triphenylmethyl protective
group: To a solution of 10 (32.0 g, 32.9 mmol) in MeOH (200 mL) was added p-
toluene-sulfonic acid monohydrate (1.3 g, 0.7 mmol) and the mixture was
stirred at rt overnight. At 0 °C, the reaction was quenched with 50% NaOH
solution (0.053 g, 1.32 mmol) and the mixture was stirred for 15 min. Then, the
precipitate was removed by filtration. Concentrated under vacuum, the residue
was dissolved in hexane/ethyl acetate (10/1) and purified by solid extraction
on silica gel (washed with 200 mL petroleum ether/ethyl acetate (10/1), then
200 mL ethyl acetate). The ethyl acetate solution was collected and
concentrated under vacuum to give 11 as a clear oil (14.0 g, yield: 72 %). 1H
NMR (CDCl3, 400 MHz): d 2.40–2.25 (m, 2H), 2.94–2.87 (m, 2H), 3.74–3.58 (m,
16H), 4.54 (s, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H); 19F NMR
(CDCl3, 376 MHz): d À129.17 to À129.31 (m, 2F), À126.51 to À126.67 (m, 2F),
À125.68 to À125.94 (m, 2F), À124.92 to À125.14 (m, 4F), À124.70 to À124.90
(m, 2F), À117.71 to À117.86 (m, 2F), À83.90 (t, J = 9.4 Hz, 3F); MS (ESI) m/z
753.3 ((M+Na)+).
19F MRI agent was conveniently synthesized from one of these
Acknowledgements
The research was financially supported by the National Natural
Science Foundation of China (No. 21372181) and the Scientific
and Technological innovative Research Team of Wuhan (No.
2013070204020048).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
02.047.
10. Typical experimental procedure for the coupling of fluorinated alcohol and tosylate
9: To a suspension of NaH (1.0 g, 80% in mineral oil, 34.9 mmol, in 50 mL THF)
under an argon atmosphere was added
a solution of alcohol 11 (17.0 g,
23.3 mmol, in 150 mL THF) at rt. After stirring for 10 min, a solution of 9
(20.6 g, 34.9 mmol, in 50 mL THF) was added into the suspension and the
resulting mixture was stirred at rt for 24 h. After quenching the reaction with
brine (200 mL), the mixture was extracted with DCM (100 mL, three times).
Then the combined organic phase was concentrated under vacuum and the
residue was purified by solid-phase extraction on fluorous silica gel (An eluant
of MeOH/H2O (9/1) was used to remove all non-fluorinated impurities and,
then, 100% MeOH was used to wash out the product.) to give 12 as a clear oil
(21.6 g, yield: 81%). 1H NMR (CDCl3, 400 MHz): d 2.27–2.44 (m, 2H), 2.87–2.94
(m, 2H), 3.23 (t, J = 6.0 Hz, 2H), 3.59–3.71 (m, 30H), 4.54 (s, 2H), 7.16–7.33 (m,
13H), 7.46 (d, J = 8.0 Hz, 6H); 19F NMR (CDCl3, 376 MHz): d À129.20 to À129.33
(m, 2F), À126.55 to À126.70 (m, 2F), À125.75 to À125.98 (m, 2F), À124.95 to
À125.18 (m, 4F), À124.73 to À124.93 (m, 2F), À117.71 to À117.83 (m, 2F),
À83.91 (t, J = 9.4 Hz, 3F); MS (ESI) m/z 1171.8 ((M+Na)+).
References and notes
1. For recent reviews, see: (a) Harris, J. M.; Chess, R. B. Nat. Rev. Drug Disc. 2003, 2,
214–221; (b) Veronese, F. M.; Pasut, G. Drug Discovery Today 2005, 10, 1451–
1458; (c) Veronese, F. M.; Mero, A. Biodrug 2008, 22, 315–329; (d) Fishburn, C.
S. J. Pharm. Sci. 2008, 97, 4167–4183; (e) Knop, K.; Hoogenboom, R.; Ficher, D.;
Schubert, U. S. Angew. Chem., Int. Ed. 2010, 49, 6288–6308.
2. (a) Abuchowski, A.; van Es, T.; Palczuk, N. C.; Davis, F. F. J. Biol. Chem. 1977, 252,
3578–3581; (b) Abuchowski, A.; McCoy, J. R.; Palczuk, N. C.; van Es, T.; Davis, F.
F. J. Biol. Chem. 1977, 252, 3582–3586; (c) Davis, F. F.; Abuchowski, A.; van Es,
T.; Palczuk, N. C.; Chen, R.; Savoca, K.; Wieder, K. Enzyme Eng. 1978, 4, 169–173.
3. (a) Niculesco-Duvaz, D.; Getaz, J.; Springer, C. J. Bioconjugate Chem. 2008, 19,
973–981; (b) Loiseau, F. A.; Hii, K. K.; Hill, A. M. J. Org. Chem. 2004, 69, 639–647;
(c) Ahmed, S.; Tanaka, M. J. Org. Chem. 2006, 71, 9884–9886; (d) Harada, A.; Li,
J.; Kamachi, M. J. Am. Chem. Soc. 1994, 11, 3192–3196; (e) French, A. C.;
Thompson, A. L.; Davis, B. G. Angew. Chem., Int. Ed. 2009, 48, 1248–1252.
4. Gladysz, J. A.; Curran, D. P.; Horváth, I. T. Handbook of Fluorous Chemistry;
Wiley-VCH: Weiheim Germany, 2004.
11. (a) Jiang, Z.-X.; Liu, X.; Jeong, E.-K.; Yu, Y. B. Angew. Chem., Int. Ed. 2009, 48,
4755–4758; (b) Li, Y.; Thapa, B.; Zhang, H.; Li, X.; Yu, F.; Jeong, E.-K.; Yang, Z.;
Jiang, Z.-X. Tetrahedron 2013, 69, 9586–9590.