A traceless perfluorooctylsulfonyl tag for deoxygenation of phenols under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2004.04.115

The perfluorooctylsulfonyl group is introduced as a traceless tag for solution-phase palladium-catalyzed deoxygenation reactions. The synthetic efficiency is improved by microwave irradiation for reaction and fluorous solid-phase extraction for separation. Further application of this traceless tag for multistep synthesis of substituted hydantoin and pyrimidine is also described.

Full text of DOI:10.1016/j.tetlet.2004.04.115

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4611–4613
A traceless perfluorooctylsulfonyl tag for deoxygenation of phenols
under microwave irradiation
Wei Zhang,* Tadamichi Nagashima, Yimin Lu and Christine Hiu-Tung Chen
Fluorous Technologies, Inc., University of Pittsburgh Applied Research Center, 970William Pitt Way, Pittsburgh, PA 15238, USA
Received 31 March 2004; revised 20 April 2004; accepted 21 April 2004
Abstract—The perfluorooctylsulfonyl group is introduced as a traceless tag for solution-phase palladium-catalyzed deoxygenation
reactions. The synthetic efficiency is improved by microwave irradiation for reaction and fluorous solid-phase extraction for
separation. Further application of this traceless tag for multistep synthesis of substituted hydantoin and pyrimidine is also
described.
Ó 2004Elsevier Ltd. All rights reserved.
The development and application of fluorous protecting
groups and tags as alternatives to solid-phase linkers
have become an active research area.1–3 We recently
reported the use of perfluorooctylsulfonates as fluorous
tag for palladium-catalyzed cross-coupling reactions to
form aryl C–S and C–C bonds.4 Commercially available
phenols are converted to perfluorooctylsulfonates by
reacting with perfluorooctylsulfonyl fluoride. The flu-
orous tagged intermediates are taken through several
reaction steps to transform the R1 to R2 and finally
detagged by microwave-assisted cross-coupling reac-
tions (Scheme 1). The perfluorooctylsulfonyl group
protects the hydroxy group during the multistep reac-
tions and activates the hydroxy group for the cross-
coupling reaction. This group also serves as a ‘phase tag’
for fluorous solid-phase extraction (F-SPE).5 We report
here a new application of the perfluorooctylsulfonyl
group as a traceless tag for the deoxygenation of phe-
nols.
Traceless linkers have important applications in pre-
paring molecules without residual functionality after
solid-phase organic synthesis.6;7 This kind of linkers
includes aryl silanes, alkyl selenides, alkyl sulfides sulf-
ones and aryl triazenes.8 The Holmes group recently
developed
a perfluorosulfonyl fluoride resin (PS-
NRC(O)CH2CF2CF2OCF2CF2O2SOF) as a traceless
linker.9 This resin has a loading of 0.31–0.36 mmol/g
and requires five steps to be synthesized. The perfluoro-
octylsulfonyl fluoride (C8F17SO2F) we selected is com-
C8F17O2SF
OH
OSO2C8F17
K2CO3
1
R1
mercially available, has
a much higher ‘loading’
R
F-SPE
(2.5 mmol/g), and priced modestly (ꢀ$0.60/g).10 More
importantly, because of fluorous sulfonyl-tagged sub-
strates are ‘light fluorous’ molecules, they usually have
good solubility in common organic solvents and normal
reactivity under general solution-phase conditions. The
fluorous tag also has good thermal stability and low
microwave absorption, it allows the use of microwave
irradiation in the palladium-catalyzed deoxygenation
reaction11 to accelerate the reaction process. In a typical
deoxygenation reaction,12 fluorous sulfonate 1 was
reacted with 5.0 equiv of formic acid using Pd(dppf)Cl2
(dppf ¼ 1,10-bis(diphenylphosphino)ferrocene) as a cat-
alyst, K2CO3 as a base, and 4:4:1 MePhH/Me2CO/H2O
as a co-solvent. The mixture in a sealed microwave tube
XR3
OSO2C8F17
cross-coupling
F-SPE
R2
R2
Scheme 1.
Keywords: Fluorous synthesis; Traceless tag; Perfluorooctylsulfonyl-
fluoride; Solid-phase extraction; Microwave.
* Corresponding author. Tel./fax: +1-412-826-3062; e-mail: w.zhang@
fluorous.com
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.115

4612
W. Zhang et al. / Tetrahedron Letters 45 (2004) 4611–4613
Table 1. Deoxygenation of fluorous sulfonates
was irradiated in a single-mode cavity at 100 °C for
20 min. The reaction mixture was then loaded onto a
FluoroFlashTM cartridge for F-SPE separation. The
desired product 2 was eluted with 80:20 MeOH/H2O,
whereas the cleaved fluorous tag was retained on the
cartridge. Reaction substrates listed in Table 1 include
fluorous sulfonates with aldehyde, ketone, benzyloxy,
and heterocyclic substitutions. The yields were between
80% and 90% and purities were greater than 90% by
LC–MS.
C8F17O2SO
a
R
R
2
1
a) HCO2H (5 equiv), Pd(dppf)Cl2 (5 mol%), K2CO3 (2 equiv),
MePhH/Me2CO/H2O (4/4/1), mw (150w, 1000C, 20 min)
Entry F-sulfonate 1
Product 2
Yield
(%)
C8F17O2SO
a
87
The utility of fluorous sulfonate tags has been demon-
strated in the synthesis of trisubstituted hydantoin 6
(Scheme 2). Fluorous benzaldehyde 1a was reacted with
an amino ester under general reductive amination con-
ditions to give 3 in 60% yield. Amine 3 was then treated
with an isocyanate in the presence of Et3N to form urea
intermediate 4, which spontaneously cyclized to gener-
ate the hydantoin ring of 5. Microwave-assisted deoxy-
genation of fluorous sulfonate 5 afforded trisubstituted
hydantoin 6 in 70% yield. In this multistep synthesis,
intermediates 3 and 5 and final product 6 were purified
by F-SPE. The purity of product 6 was 90%.
H
H
H
O
O
O
b
82
92
H
H
C8F17O2SO
C8F17O2SO
O
OMe
OMe
c
H
O
O
The application of fluorous tag has been further dem-
onstrated in the synthesis of triaryl-substituted pyrimi-
dine 10 (Scheme 3).13Fluorous benzaldehyde 1a was
condensed with phosphonate 7 to form a,b-unsaturated
ketone 8. No significant amount of detagged byproduct
was observed under the basic condition. The cycload-
dition of 8 with a benzamidine followed by the tag
cleavage afforded the desired product 10 in 83% yield.
Because of the relatively low solubility of intermediate 8
and 9 in organic solvents, these two fluorous compounds
were purified by crystallization instead of F-SPE.
Compound 8 was purified by crystallization with hex-
anes/Et2O, whereas compound 9 was precipitated out by
addition of water to the reaction mixture. Purification of
fluorous intermediates by a simple, nonfluorous method
demonstrates the technical compatibility of fluorous
synthesis.
OMe
H
OMe
C8F17O2SO
d
85
O
O
H
C8F17O2SO
e
f
90
79
O
O
N
N
C8F17O2SO
C8F17O2SO
g
82
In summary, the perfluorooctylsufonyl fluoride has been
introduced as a new traceless tag. Compared to its resin
O
Ph
O
Ph
OEt
p-MeOPhNCO
1.0 equiv
N
H NCHMeCO Et
CHO
2
21.2 equiv
OEt
O
N
H
F17C8O2SO
HN
O
O
NaBH(OAc)3
F17C8O2SO
F17C8O2SO
Et3N, DCM
F-SPE
AcOH, DCM
F-SPE
1a
3, 60%
4
OMe
O
N
O
N
O
a
N
N
F17C8O2SO
O
OMe
OMe
6,70%
5, 90%
Scheme 2. Reagents and conditions: (a) HCO2H (5 equiv), Pd(dppf)Cl2 (5 mol %), K2CO3 (2 equiv), MePhH/Me2CO/H2O (4/4/1), mw (150 w, 100 °C,
20 min), F-SPE.

W. Zhang et al. / Tetrahedron Letters 45 (2004) 4611–4613
4613
Ph
O
H2N
NH
NaH
O
P
O
CHO
+
1.5 equiv
10 equiv
(EtO)2
THF
Li2CO3, 10 equiv
F17C8O2SO
OMe
F17C8O2SO
0-25 oC, 1h
OMe
1.7 equiv
DMA
95 oC, 24 h
1a
8, 71%
7
Ph
N
N
a
N
N
F17C8O2SO
OMe
9, 63%
10, 83%
OMe
Scheme 3. Reagents and conditions: (a) HCO2H (29 equiv), Pd(dppf)Cl2 (13 mol %), K2CO3 (3.3 equiv), MePhH/Me2CO/H2O (4/4/1), mw (150 w,
100 °C, 20 min).
3. Fluorous tags: (a) Wipf, P.; Methot, J.-L. Org. Lett. 1999,
1, 1253; (b) Zhang, W. Org. Lett. 2003, 5, 1011; (c) Chen,
C. H.-T.; Zhang, W. Org. Lett. 2003, 5, 1015; (d) Zhang,
W.; Lu, Y. Org. Lett. 2003, 5, 2555; (e) Cioffi, C. L.;
Berlin, M. L.; Herr, R. J. Synlett 2004, 84 .
analogues, this solution-phase fluorous tag is cheaper
and readily available. It can be used in conjunction with
F-SPE and conventional separation methods as well as
microwave technology.
4. (a) Zhang, W.; Lu, Y.; Chen, C. H.-T. Mol. Diversity 2003,
7, 199; (b) Zhang, W.; Chen, C. H.-T.; Lu, Y.; Nagashima
Org. Lett. 2004, 6, 1473.
Acknowledgements
5. Curran, D. P. Synlett 2001, 1488.
6. According to an IUPAC report ‘Glossary of terms used in
combinatorial chemistry’ by Maclean, D.; Baldwin, J. J.;
Ivanov, V. T.; Kato, Y.; Shaw, A.; Schnerider, P.;
Gordon, E. M. Pure Appl. Chem. 1999, 71, 2349, traceless
linkers should leave no residue on the compound after
cleavage (i.e., replaced by hydrogen).
We thank the National Institutes of General Medical
Sciences for SBIR funding (1R43 GM066415-01 and
2R44GM062717-02).
References and notes
7. Reviews on traceless linkers: (a) Brase, S.; Dahmen, S. In
Handbook of Combinatorial Chemistry; Nicolaou, K. C.,
Hanko, R., Hartwig, Eds.; Wiley-VCH: Weinheim, 2002;
Vol. 1, pp 59–169; (b) Brase, S.; Dahmen, S. Chem. Eur. J.
2000, 6, 1899; See also: (c) Blaney, P.; Grigg, R.;
Sridharan, V. Chem. Rev. 2002, 102, 2607; (d) Phoon, C.
W.; Sim, M. M. Curr. Org. Chem. 2002, 6, 937.
8. Stieber, F.; Grether, U.; Waldmann, H. Chem. Eur. J.
2003, 9, 3270, and references cited therein.
9. Pan, Y.; Holmes, C. P. Org. Lett. 2001, 3, 2769.
10. C8F17SO2F is available from Fluorous Technologies, Inc.
(www.fluorous.com), Aldrich and other commercial
sources.
1. Reviews: (a) Curran, D. P. In Stimulating Concepts in
Chemistry; Stoddard, F., Reinhoudt, D., Shibasaki, M.,
Eds.; Wiley-VCH: New York, 2000; pp 25–37; (b) Yosh-
ida, J.; Itami, K. Chem. Rev. 2002, 102, 3693; (c)
Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller,
S.; Hebel, A. Angew. Chem., Int. Ed. 2002, 41, 3964; (d)
Zhang, W. Tetrahedron 2003, 59, 4475; (e) Zhang, W. In
Hand Book of Fluorous Chemistry, Gladysz, J. A.; Curran,
D. P.; Horvath, I. T. Eds.; Wiley-VCH: Weinheim (in
press).
2. Fluorous protecting groups: (a) Wipf, P.; Reeves, J. T.
Tetrahedron Lett. 1999, 40, 4649; (b) Luo, Z.; Williams, J.;
Read, R. W.; Curran, D. P. J. Org. Chem. 2001, 66, 4261;
(c) Schwinn, D.; Bannwarth, W. Helv. Chim. Acta 2002,
85, 255; (d) Zhang, W.; Luo, Z.; Chen, C. H.-T.; Curran,
D. P. J. Am. Chem. Soc. 2002, 124, 10443; (e) Filippov, D.
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11. Subramanian, L. R. Synthesis 1984, 481.
12. A general procedure for the deoxygenation reaction: A
septum-sealed microwave tube charged with aryl perfluoro-
octylsulfonate
1
(0.1 mmol), HCO2H (0.5 mmol),
Pd(pddf)Cl2 (0.005 mmol), K2CO3 (0.2 mmol) in 0.3 mL
of 4:4:1 acetone/toluene/H2O was irradiated in a mono-
mode microwave cavity (150 w, 100 °C, 20 min). The
reaction mixture was washed with 0.5 mL of H2O. The
organic layer was loaded onto a 2 g FluoroFlashTM
cartridge, eluted with 5 mL of 80:20 MeOH/H2O. The
fraction was concentrated to give product 2.
13. Solid-phase synthesis of substituted pyrimidines: Marzi-
nzik, A. L.; Felder, E. R. J. Org. Chem. 1998, 63, 723.