FluoMar, a fluorous version of the Marshall resin for solution-phase library synthesis

Article abstract of DOI:10.1021/ol0274864

(Matrix presented) The fluorous counterpart of the Marshall resin, 4-(1H,1H,2H,2H-perfluorodecylsulfanyl)phenol (FluoMar), is prepared by S-alkylation of 4-mercaptophenol with C₈F₁₇CH ₂CH₂I and employed in the s

Full text of DOI:10.1021/ol0274864

ORGANIC
LETTERS
2003
Vol. 5, No. 7
1015-1017
FluoMar, a Fluorous Version of the
Marshall Resin for Solution-Phase
Library Synthesis
Christine Hiu-Tung Chen and Wei Zhang*
Fluorous Technologies, Inc., UniVersity of Pittsburgh Applied Research Center,
970 William Pitt Way, Pittsburgh, PennsylVania 15238
w.zhang@fluorous.com
Received December 17, 2002
ABSTRACT
The fluorous counterpart of the Marshall resin, 4-(1H,1H,2H,2H-perfluorodecylsulfanyl)phenol (FluoMar), is prepared by S-alkylation of
4-mercaptophenol with C F17CH CH I and employed in the synthesis of amide and diamide analogues. The final products are purified by
8
2
2
solid-phase extraction (SPE) over FluoroFlash silica cartridges.
Resin-based solid-phase organic synthesis (SPOS) is popular
in drug discovery.1 Its advantage of easy separation, however,
is usually counterbalanced by the time-consuming method
of development, the limitation of reaction scope, and the
difficulty of analysis and purification of attached intermedi-
ates. Recently Curran and co-workers developed a fluorous
tag strategy to overcome some disadvantages associated with
the SPOS.2 Functionalized perfluoroalkyl groups instead of
polymer supports are employed as the “phase tags”.2b,3 The
separation of fluorous-tagged molecules is carried out over
fluorous silica gel based on the strong and selective fluorine-
fluorine interaction.4
can be cleaved with primary and secondary amines to afford
the corresponding amides either directly or after oxidation
of the sulfide to the sulfone.6 Described in this paper is the
synthesis of the fluorous version of the Marshall resin,
perfluoroalkylsulfanylphenol 2 (FluoMar). The utility of this
compound is illustrated by the solution-phase synthesis of
amides and diamides.
The Marshall resin 1 has been widely used as a carbonate
and carbamate linker in solid-phase syntheses.5 The linker
FluoMar 2 was readily prepared by S-alkylation of
4-mercaptophenol with C8F17CH2CH2I and purified by flash
column chromatography on normal silica gel (Scheme 1).7,8
(1) Reviews: (a) Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000,
100, 2091. (b) Dorwald, F. Z. Organic Synthesis on Solid Phase; Wiley-
VCH: Weinheim, Germany, 2000. (c) Burgess, K. Solid-Phase Organic
Synthesis; John Wiley & Sons: New York, 2000. (d) Handbook of
Combinatorial Chemistry; Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.;
Wiley-VCH: Weinheim, Germany, 2002; Vols. 1 and 2.
Scheme 1. Preparation of FluoMar 2
(2) (a) Curran, D. P. Chemtracts-Org. Chem. 1996, 9, 75. (b) Curran,
D. P. Angew. Chem., Int. Ed. 1998, 37, 1175. (c) Curran, D. P. In Stimulating
Concepts in Chemistry; Stoddard, F., Reinhoudt, D., Shibasaki, M., Eds.;
Wiley-VCH: New York, 2000; p 25. (d) Curran, D. P.; Hadida, S.; Studer,
A.; He, M.; Kim, S.-Y.; Luo, Z.; Larhed, M.; Hallberg, M.; Linclau, B. In
Combinatorial Chemistry: A Practical Approach; Fenniri, H., Ed.; Oxford
University Press: Oxford, UK, 2001; Vol. 2, p 327.
(3) (a) Yoshida, J.-I.; Itami, K. Chem. ReV. 2002, 102, 3693. (b)
Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller, S.; Hebel, A.; Haag,
R. Angew. Chem., Int. Ed. 2002, 41, 3964.
The ethylene spacer between the C8F17 tag and the sulfur is
expected to minimize the strong electron-withdrawing effect
(4) Curran, D. P. Synlett 2001, 1488.
10.1021/ol0274864 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/04/2003

from the perfluoroalkyl group and maintain the nucleophi-
licity of the hydroxy group. This compound has the general
features of organic molecules: it dissolves well in common
solvents such as CH2Cl2, THF, and AcOEt, and can be
analyzed by traditional chromatographic and spectroscopic
methods.
With compound 2 in hand, we first validated the attach-
ment to carboxylic acids 3 and the tag cleavage by the amine
displacement (Scheme 2). The coupling of 2 with indole-5-
Encouraged by the preliminary results, we next explored
the use of FluoMar 2 in a multistep parallel synthesis of
diamides (Scheme 3). The N-Boc isonipecotic acid 7 was
Scheme 3. Synthesis of a 3 × 3 Array of Diamides
10{R1,R2}a
Scheme 2. Synthesis of a 2 × 3 Array of Amides 6{R1,R2}
a Reagents and conditions: (i) 1.0 equiv of 2, 2.0 equiv of 7,
2.0 equiv of DIC, 1.0 equiv of DMAP, DMF, 25 °C, 8 h, SPE,
71%. (ii) 9.0 equiv of TFA, CH2Cl2, 25 °C, 8 h, SPE, 100%. (iii)
1.5 equiv of R1PhCO2Cl, 1.5 equiv of Et3N, THF, 55 °C, SPE,
73-78%. (iv) 1.5 equiv of R2NH2, THF, 60 °C, 5 h, SPE, 21-
100%.
carboxylic acid 3{1} (2.0 equiv) or 7-methoxy-2-benzo-
furancarboxylic acid 3{2} was carried out under standard
solution-phase conditions with 2.0 equiv of diisopropylcar-
bodiimide (DIC) and 1.0 equiv of (dimethylamino)pyridine
(DMAP) in DMF. This intermediate was purified by regular
flash column chromatography. Compounds 4{1} and 4{2}
were each split to three portions and directly displaced with
three primary amines 5{1-3} without oxidation of the sulfur
to give the corresponding amides 6{1-2,1-3}. After a quick
acidic workup with 1.0 N HCl to remove the unreacted
amine,9 the crude product was loaded onto a FluoroFlash
cartridge and the MeOH/H2O fraction was collected to give
analytically pure product. The FluoMar tag 2 was recovered
in the MeOH fraction in 65-70% yield.
coupled with 2 followed by deprotection with TFA and
N-acylation with three different acid halides. The resulting
compounds 9{1-3} were each split into three portions and
displaced by three amines resulting in a demonstration library
of diamides 10{1-3,1-3}.11 The final products were purified
by SPE and cleaved FluoMar 2 was recovered in an average
1
yield of 65%. Figure 1 shows a typical H NMR trace of
the products prior to and after SPE: the crude mixture
containing 10{1,2} and cleaved tag 2 (top trace of Figure
1), the MeOH/H2O fraction containing 10{1,2} (middle trace
of Figure 1), and the MeOH fraction containing recovered
FluoMar 2 (bottom trace of Figure 1).
We also carried out a simple experiment to estimate the
reactivity difference between the Marshall resin 1 and
(5) Marshall, D. L.; Liener, I. E. J. Org. Chem. 1970, 35, 867.
(6) (a) Johnson, C. R.; Zhang, B.; Fantauzzi, P.; Hocker, M.; Yager, K.
M. Tetrahedron 1998, 54, 4097. (b) Breitenbucher, J. G.; Johnson, C. R.;
Haight, M.; Phelan, J. C. Tetrahedron Lett. 1998, 39, 1295. (c) Fantauzzi,
P. P.; Yager, K. M. Tetrahedron 1998, 39, 1291. (d) Dressman, B.; Singh,
U.; Kaldor, S. W. Tetrahedron Lett. 1998, 39, 3631. (e) Breitenbucher, J.
G.; Hui, H. C. Tetrahedron Lett. 1998, 39, 8207. (f) Yan, B.; Nguyen, N.;
Liu, L.; Holland, G.; Raju, B. J. Comb. Chem. 2000, 2, 66. (g) Beech, C.;
Coope, J.; Fairley, G.; Gilgert, P.; Main, B.; Ple, K. J. Org. Chem. 2001,
66, 2240. (h) Fang, L.; Demee, M.; Sierra, T.; Kshirsagar, T.; Celebi, A.
A.; Yan, B. J. Comb. Chem. 2002, 4, 362.
(7) Selective S-alkylation of 4-mercaptophenol, see: Breitenbucher, J.
G.; Johnson C. R.; Haight, M.; Phelan, J. C. Tetrahedron Lett. 1998, 39,
1295.
(8) Perfluoroalkylsulfanylphenol 2 has been used as a photoimaging
compound, see: Wakamatsu, K.; Wakata, Y.; Satomura, M.; Namiki, T.
European Patent 468531 A1, 1992.
(9) Our recent study and an independent work from Lindsley (ref 10)
demonstrated that amines could be retained on the SPE cartridge by adding
acidic ion-exchange resin on top of the fluorous silica. No more acidic
workup was needed prior to the SPE.
(10) Lindsley, C. W.; Zhao, Z.; Leister, W. H.; Strauss K. A. Tetrahedron
Lett. 2002, 43, 6319.
(11) A general protocol for the synthesis of diamide 10 from 9. FluoMar-
bound intermediate 9 (0.127 mmol) was dissolved in THF (1.0 mL) in a
capped vial. The amine (1.2 equiv) was added and the reaction mixture
was stirred at 60 °C for 5 h. An aqueous solution of 1.0 N HCl (1.0 mL)
was added and the vial was shaken with 0.5 mL of EtOAc. The EtOAc
layer was loaded onto a 2 g FluoroFlash cartridge and eluted with MeOH/
H2O (80/20). The first 8-mL fraction contained the desired product and the
subsequent fraction eluted with MeOH contained the displaced fluorous
tag.
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Org. Lett., Vol. 5, No. 7, 2003

Figure 1. 1H NMR spectra of product 10{1,2} and recovered 2. Top trace: crude product containing 10{1,2} and 2. Middle trace: product
10{1,2}. Bottom trace: recovered tag 2.
and washed with DMF and CH2Cl2. The filtrate was analyzed
by HPLC and the ratio of product 11 to the unreacted 2 was
73:27 with the assumption that the 27% unreacted FluoMar
2 was due to a competitive reaction of acid 3 with the
Marshall resin. This result suggested that despite the electron-
withdrawing effect of the fluorous chain, FluoMar still
reacted as least 2.7 times faster than the resin.
FluoMar 2 toward a typical carboxylic acid. Equimolar
amounts of 112 and 2 (1.0 equiv each) were mixed with 1.0
equiv of benzofuran carboxylic acid under a standard
coupling condition used in the synthesis of amide 4 and
diamides 8 (Scheme 4). The reaction was stopped after 8 h
In summary, we have employed FluMar 2 as a recyclable
phase tag in the solution-phase synthesis of amides and
diamides. This reagent can be used as an alternative to the
Marshall resin in combinatorial and parallel synthesis.
Scheme 4. Competitive Tagging of 3 with Marshall Resin 1
and FluoMar 2a
Acknowledgment. We thank Dr. John Hodges (Pfizer)
and Professor Dennis Curran (University of Pittsburg) for
important suggestions and helpful discussions and the
National Institutes of General Medical Sciences SBIR
funding (2R44GM062717-02).
a Reagents and conditions: (i) 1.0 equiv of 1, 1.0 equiv of 2,
1.0 equiv of 3, 2.0 equiv of DIC, 1.0 equiv of DMAP, DMF, 25
°C, 8 h.
OL0274864
(12) Purchased from Aldrich, loading 1.0-1.5 mmol/g, polystyrene with
1% cross linking with DVB. An average loading of 1.25 mmol/g was used
for the calculation.
when all the acid was consumed as indicated by TLC
analysis. The resin was filtered off from the reaction mixture
Org. Lett., Vol. 5, No. 7, 2003
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