A traceless perfluoroalkylsulfonyl (PFS) linker for the deoxygenation of phenols

Article abstract of DOI:10.1021/ol0163732

(Equation presented) The synthesis of a novel perfluoroalkylsulfonyl (PFS) fluoride is described for use as a traceless linker in solid-phase organic synthesis. Attachment to the resin and subsequent coupling of a phenol affords a stable arylsulfonate that behaves as a support-bound aryl triflate. Palladium-mediated reductive cleavage of a wide variety of phenols generated the parent arenes. The resin-bound aryl triflate was shown to be stable to reductive amination conditions, and the traceless synthesis of Meclizine is reported.

Full text of DOI:10.1021/ol0163732

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2769-2771
A Traceless Perfluoroalkylsulfonyl (PFS)
Linker for the Deoxygenation of Phenols
Yijun Pan and Christopher P. Holmes*
Affymax Research Institute, 4001 Miranda AVenue, Palo Alto, California 94304
chris_holmes@affymax.com
Received June 29, 2001
ABSTRACT
The synthesis of a novel perfluoroalkylsulfonyl (PFS) fluoride is described for use as a traceless linker in solid-phase organic synthesis.
Attachment to the resin and subsequent coupling of a phenol affords a stable arylsulfonate that behaves as a support-bound aryl triflate.
Palladium-mediated reductive cleavage of a wide variety of phenols generated the parent arenes. The resin-bound aryl triflate was shown to
be stable to reductive amination conditions, and the traceless synthesis of Meclizine is reported.
The recent acceptance of combinatorial techniques into drug
discovery programs has created a demand for more sophis-
ticated linkers and polymer-supported reagents capable of
generating an increasing variety of chemical classes. Trace-
less linkers represent an exciting aspect of solid-phase
organic synthesis due to the desire to make molecules lacking
any extraneous functionality. Many traceless linkers reported
to date require chemical steps to be performed on the initial
building block prior to attachment to the resin, as with the
Group 14 metal-based linkers,1 or are restricted to classes
of starting materials with relatively few commercial mem-
bers, such as arylhydrazines2 or boronic acids.3 As part of
our interest in traceless linkers,4 we sought a linker where
the direct coupling of commercial compounds to a suitable
resin was possible without prior modification, and in
particular we sought to employ phenols as the initial
anchoring group due to the thousands available from com-
mercial sources. The oxygen atom of a phenol, once
activated, can undergo a subsequent reduction or cross-
coupling reaction and give rise to a variety of substituted
aromatics at the formally “inert” oxygen position.5,6 Aryl
triflates and nonaflates have been widely used as precursors
for aryl cations due to their excellent leaving group proper-
ties.7 A solid-phase strategy of capturing phenols on resin
as the triflate (or “tetraflate”), where subsequent chemistry
could be performed on the immobilized molecules followed
by reductive cleavage, would be a valuable combinatorial
chemistry approach to diverse collections of molecules. To
date there have been no reports in the literature regarding
polymer-supported triflate linkers, although many sulfonyl
chloride linkers have been prepared from polymer-bound
sulfonic acids using SOCl2, PCl5, POCl3, or related reagents.8
Wustrow first reported the reductive cleavage of phenols
from a sulfonyl chloride resin, but harsh cleavage conditions
(140 °C for 12 h) and electron-deficient phenols were
required due to the poor activating ability of the tosyl group.9
We now wish to describe our efforts in developing a highly
(5) (a) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 2271.
(b) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1986,
27, 5541. (c) Kotsuki, H.; Datta, Probal, K.; Hayakawa, H.; Suenaga, H.
Synthesis 1995, 11, 1348. (d) Lipshutz, B. H.; Buzard, D. J.; Vivian, R. W.
Tetrahedron Lett. 1999, 40, 6871.
(6) (a) Rottlaender, M.; Knochel, P. J. Org. Chem. 1998, 63, 203. (b)
Kamikawa, T.; Hayashi, T. J. Org. Chem. 1998, 63, 8922. (c) Littke, A.
F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. (d) Ciske, F. L.;
Jones, W. D. Synthesis 1998, 8, 1195. (e) Blettner, C. G.; Koenig, W. A.;
Stenzel, W.; Schotten, T. J. Org. Chem. 1999, 64, 3885. (f) Lipshutz, B.
H.; Blomgren, P. A.; Kim, S. Tetrahedron Lett. 1999, 40, 197. (g) Han,
X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600.
(7) Ritter, K. Synthesis 1993, 8, 735.
(8) (a) Hunt, J. A.; Roush, W. R. J. Am. Chem. Soc. 1996, 118, 9998.
(b) Baxter, E. W.; Rueter, J. M.; Nortey, S. O.; Reitz, A. B. Tetrahedron
Lett. 1998, 39, 975. (c) Kamahori, K.; Tada, S.; Ito, K.; Itsuno, S.
Tetrahedron: Asymmetry 1995, 6, 2547. (d) Zhong, H. M.; Greco, M. N.;
Maryanoff, B. E. J. Org. Chem. 1997, 62, 9326. (e) ten Holte, P.; Thijs,
L.; Zwanenburg, B. Tetrahedron Lett. 1998, 39, 7407.
(1) For excellent reviews of Si- and Ge-based linkers, see: (a) Spivey,
A. C.; Diaper, C. M.; Adams, H.; Rudge, A. J. J. Org. Chem. 2000, 65,
5253. (b) Lee, Y.; Silverman, R. B. J. Am. Chem. Soc. 1999, 121, 8407
and references therein.
(2) Stieber, F.; Grether, U.; Waldman, H. Angew. Chem., Int. Ed. 1999,
38, 1073.
(3) Pourbaix, C.; Carreaux, F.; Deleuze, H. J. Chem. Soc., Chem.
Commun. 2000, 1275.
(4) Tumelty, D.; Cao, K.; Holmes, C. P. Org. Lett. 2001, 3, 83.
10.1021/ol0163732 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/02/2001

activated perfluoroalkylsulfonyl (PFS) linker suitable for the
deoxygenation of phenols.
The synthesis of the polymer-supported perfluoroalkyl-
sulfonyl fluoride linker 6 is shown in Scheme 1. Thus,
Scheme 1
Figure 1. 282 MHz 19F NMR spectra of solution-phase acid 4 in
CDCl3 (top trace) and gel-phase resin 6a in CDCl3 (bottom trace)
using trifluoroacetic acid as reference.
at 121 ppm allows one to readily monitor the stability of
the resin and assess the extent of loading during the next
step. Several phenols with disparate steric and electronic
environments were attached to resin 6 via sulfonate formation
by using K2CO3 or Et3N as base in DMF at room temper-
ature. The actual loading of the phenols on resin 6 is in the
range of 0.31-0.36 mmol/g resin as determined by elemental
analysis. Cleavage and concomitant deoxygenation of the
polymer-supported aryl perfluoroalkylsulfonate species was
studied by a palladium-mediated reduction (Scheme 2).
commercial iodide 1 was allowed to react with ethyl vinyl
ether through a radical mechanism to give intermediate 2.10
The intermediate 2 was hydrolyzed to aldehyde 3 and then
oxidized with aqueous NaClO2, NaH2PO4, and acetone at
10 °C using 2-methyl-2-butene as chlorine scavenger to
afford acid 4 in 62% overall yield from 1.11 To minimize
the hydrolysis of the SO2F group in 3 and 4, low temperatures
(0-10 °C) and short reaction times are needed for the
preparation and subsequent workup steps. Acid 4 was
converted to acid chloride 5 with oxalyl chloride in CH2Cl2
using DMF as the catalyst. The sulfonyl fluoride resin 6 was
prepared by either coupling 5 to amine resins12 in CH2Cl2
or alternatively by direct coupling of acid 4 with O-(7-
azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexaflu-
orophosphate (HATU) as activating reagent. We initially
prepared both the tertiary and secondary amide resins 6b
and 6a due to concerns over the reactive amide present in
6a, although we have not yet observed any differences
between the two resins with the chemistries explored to date.
The structures of the sulfonyl fluoride resins 6 were
confirmed by gel-phase 19F NMR analysis, and the result
was compared with the solution-phase 19F NMR spectra of
the starting acid 4 (Figure 1). The sulfonyl fluoride signal
Scheme 2
The polymer-bound aryl sulfonates were efficiently cleaved
with Et3N-HCO2H in the presence of a catalytic amount of
Pd(OAc)2 and 1,3-bis(diphenylphosphino)propane (dppp) to
afford high yields of reduced arenes under mild conditions
(Table 1). The desired products were easily isolated by two-
phase extraction, and the residual metal catalyst was removed
by eluting the organic solution through a thin pad of silica
gel to give products 8a-l with purity suitable for high
throughput screening (∼90%). The compounds were further
purified to homogeneity to obtain yield information. That a
broad range of functionality is tolerated offers proof of the
advantages inherent in this perfluoroalkylsulfonate strategy.
The cleavage does not appear to suffer from steric nor
electronic effects. The 2,6-dimethyl substitution pattern of
entry 6 is noteworthy and represents the most challenging
case studied. Entry 10 illustrates the chemoselectivity obtain-
able when one has both a phenolic and an aliphatic alcohol
available for coupling. The use of symmetric bisphenols with
(9) Jin, S.; Holub, D. P.; Wustrow, D. J. Tetrahedron Lett. 1998, 39,
3651.
(10) Tang, X.; Hu, C. J. Chem. Soc., Perkin Trans. 1 1994, 15, 2161.
(11) Acid 4, clear oil.1H NMR (CDCl3, δ): 3.18 (t, J ) 16.8 Hz, 2 H,
CF2CH2CO2H), 8.68 (b, 1 H, CO2H). 13C NMR (CDCl3, δ): 36.39 (t,
CF2CH2CO2H), 169.53 (CO2H). 19F NMR (CDCl3, δ): -39.70 (CF2),
-36.14 (CF2), -11.51 (CF2), -6.08 (CF2), 121.61 (-SO2F), trifluoroacetic
acid was used as reference. ESIMS (negative): calcd for C6H3F9O5S 357.96;
found m/z 357.0 (M - H).
(12) The secondary N-Et amine resin was prepared by acylation of
TentaGel-NH2 resin (RAPP Polymere, loading: 0.43 mmol/g) with acetyl
chloride and subsequent reduction with LiAlH4.
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Org. Lett., Vol. 3, No. 17, 2001

Scheme 3
Table 1. Palladium-Mediated Reductive Cleavage of
Polymer-Bound Aryl Perfluoroalkylsulfonates 7a
3-methyl-4-hydroxybenzaldehyde to resin 6b, and polymer-
supported amine 11 was prepared by a reductive amination
of 9 with amine 10 using Na(CN)BH3 as reducing agent.
Meclizine 12 was cleaved from the resin by a palladium-
mediated reductive cleavage in 80% yield.13 The synthesis
of 12 illustrates the stability of the linker to basic amines
and mild hydrides, while affording a high degree of activation
during cleavagesnote that the aryl chloride, the benzylamine,
and the benzhydrylamine groups all remained intact upon
cleavage. The stage is now set to further exploit this resin
in the synthesis of compound libraries.
In conclusion, we have developed a new polymer-
supported perfluoroalkylsulfonyl (PFS) linker that allows the
attachment of phenols to the solid phase and subsequent
reductive cleavage to afford the parent arene. The solid-phase
approach provided an operationally simple, inexpensive, and
general protocol for the activation/reductive cleavage of the
aryl-oxygen bond. The support-bound aryl perfluoroalkyl-
sulfonate functionality is also amenable to cross-coupling
reactions (e.g., Suzuki, Heck, and organozinc couplings)
which we will report in a following communication. We are
currently extending the PFS linker to the related vinyl triflate
species originating from ketones for the generation of
substituted olefins. We believe that the ease of preparation,
excellent stability, and synthetic versatility of the polymer-
supported perfluoroalkylsulfonyl fluorides 6a and 6b will
find broad application in solid-phase synthesis and combi-
natorial chemistry.
a Reductive cleavage was carried out by using resin 7 (80 mg, 0.014
mmol), Pd(OAc)2 (6.0 mg), dppp (16.0 mg), HCO2H (0.18 mL), and Et3N
(0.46 mL) in DMF (1.2 mL) at 85 °C for 120 min. b Isolated yields were
based on the actual loading of phenols on resin 6 as determined by elemental
analyses. c Obtained from 4-nitrophenol via reduction with SnCl2 after
coupling, followed by acylation with benzoyl chloride prior to reductive
cleavage.
resin 6 can be used to afford monophenols after cleavage
(entry 11). The linker is stable to nitro reduction conditions
(SnCl2 in NMP) and treatment with acid chlorides (entry 12)
which represents common reaction conditions used for
elaborating nitroaromatics into arylamides. In other experi-
ments it was found that the polymer-bound aryl perfluoro-
alkylsulfonate functionality is stable to acidic (20% TFA in
CH2Cl2) conditions. We are currently fine-tuning the cleavage
conditions to minimize the amount of palladium catalyst
required and to lower the reaction temperature.
Supporting Information Available: Experimental pro-
cedures for compounds 2-5 and resin 6a, reductive cleavage
conditions, and HPLC of 12. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0163732
Finally, we conducted the solid-phase synthesis of the
commercial drug Meclizine 12 to further explore the stability
of the aryl sulfonate linkage (Scheme 3). The polymer-
supported aryl sulfonate 9 was prepared by attaching
(13) The product 12 was characterized by ESIMS, HPLC, and 1H NMR,
and the results were compared with data for an authentic sample obtained
from Sigma.
Org. Lett., Vol. 3, No. 17, 2001
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