Use of fluorous silica gel to separate fluorous thiol quenching derivatives in solution-phase parallel synthesis

Article abstract of DOI:10.1016/S0040-4020(02)00209-0

A general fluorous thiol quenching method is introduced. Excess α-bromoketones or benzyl bromides in parallel N-alkylation reactions are quenched with a fluorous thiol (C₆F₁₃CH₂CH₂SH). The resulting fluorous der

Full text of DOI:10.1016/S0040-4020(02)00209-0

TETRAHEDRON
Pergamon
Tetrahedron 58 .2002) 3871±3875
Use of ¯uorous silica gel to separate ¯uorous thiol quenching
derivatives in solution-phase parallel synthesis
Wei Zhang,a,p Dennis P. Curranb and Christine Hiu-Tung Chena
aFluorous Technologies, Inc., 970 William Pitt Way, Pittsburgh, PA 15238, USA
bDepartment of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 4 January 2002; revised 24 January 2002; accepted 30 January 2002
AbstractÐA general ¯uorous thiol quenching method is introduced. Excess a-bromoketones or benzyl bromides in parallel N-alkylation
reactions are quenched with a ¯uorous thiol .C6F13CH2CH2SH). The resulting ¯uorous derivatives can be separated from the reaction mixture
by a solid phase extraction on ¯uorous silica gel. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Thiols are good nucleophiles and have been used as
covalent scavengers. For example, addition of aminothiol
resin 1 to an N-alkylation reaction mixture scavenges excess
a-haloketones.7,8 The resulting polymer-bound thioethers
can be easily separated from the product mixture by
®ltration. Another report describes the use of 3-mercapto-
1-propanesulfonic acid sodium salt 2 as a scavenger.9
Puri®cation can be carried out by water±organic biphasic
workupif the thioethers are hydrohpilic or by anion-
exchange resin chromatography if the thioethers are hydro-
phobic. Development of the ¯uorous scavenger 3 will
provide a new thiol quenching agent that relies on solid
phase extraction for separation.
The attachment of `tags' to organic reaction components has
become a general practice in combinatorial and parallel
syntheses to facilitate the separation process. The most
commonly used tags are solid-phase polymers. In both
solid phase organic synthesis1 .tagged substrates) and
polymer-assisted solution-phase organic synthesis2 .tagged
reagents), polymers are involved in reactions such that the
reaction medium becomes heterogeneous. The use of
polymer-bound scavengers,3 however, allows the reaction
to proceed in homogeneous fashion because the scavengers
are added only after the reaction is complete.
Fluorous synthesis4 performed in homogeneous media over-
comes some drawbacks of heterogeneous reactions
associated with solid-phase synthesis. In principle, any
polymer-bound synthetic technology has a counterpart in
¯uorous synthesis. Early ¯uorous synthesis technologies
relied on heavy ¯uorous tags and liquid±liquid extraction
to separate tagged-¯uorous molecules from untagged
organics.5 In the recently introduced light ¯uorous synthesis
method, fewer ¯uorines are used in the tag and the liquid±
liquid extraction is replaced by a solid±liquid extraction
over ¯uorous silica gel.6 Fluorous solid phase extraction
.FSPE) was developed based on the observation that the
¯uorine±¯uorine interaction is strong and selective, such
that the mobility of the ¯uorous molecules on ¯uorous
reverse phase silica gel is dictated by the ¯uorous group.
We describe here a new application of FSPE in the separa-
tion of ¯uorous species generated by ¯uorous scavengers.
Although ¯uorous quenching was introduced about ®ve
years ago,5 only three ¯uorous quenching applications
have been reported so far. Fluorous trialkyltin hydride 410
and ¯uorous amine 511 have been used to scavenge excess
alkenes and isocyanates, respectively, while ¯uorous vinyl
ether 612 has been used as a catch-and-release agent to
separate alcohol products from a reaction mixture. These
quenching agents have two or more ¯uorous chains and
depend on liquid±liquid extraction for puri®cation. The
thiol scavenger 3 described in this paper has a single
¯uorous chain, yet its quenched derivatives can be easily
separated by solid phase extraction. In addition to the
scavenging uses introduced herein, ¯uorous thiols have
been used recently as precursors of ¯uorous sul®des,
Keywords: ¯uorous; scavengers; thiol quenching; solid phase extraction;
parallel synthesis.
p
Corresponding author. Tel.: 11-412-826-3050; fax: 11-412-826-3053;
e-mail: w.zhang@¯uorous.com
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020.02)00209-0

3872
W. Zhang et al. / Tetrahedron 58 /2002) 3871±3875
Scheme 1.
Scheme 2.
which in turn have their own uses as reagents and ligands.
An accompanying paper by Rocaboy and Gladysz13 in this
issue introduces ¯uorous sul®de metal complexes and
provides a nice summary of prior work with highly ¯uori-
nated organic sulfur compounds.
silica gel.14 A ¯uorophobic solvent .MeOH/H2O) is used to
elute product 9 while 3 and 10 are retained. The ¯uorous
compounds can be eluted out and the cartridge can be
reconditioned by washing with a more ¯uorophilic solvent
such as methanol or THF.
An initial experiment was carried out to test the quenching
ef®ciency of C6F13CH2CH2SH and to establish conditions
for the solid phase extraction .Scheme 2). In the presence of
2.0 equiv. of diisopropylethylamine as a base, the quench-
ing reaction of 2-bromo-40-methoxyacetophenone 11
.23 mg, 0.1 mmol) with 2 equiv. of thiol 3 .76 mg,
0.2 mmol) was ®nished in less than 30 min. TLC analysis
was used to monitor the disappearance of bromide 11. The
reaction mixture was then loaded directly onto a 5 g Fluoro-
Flashe cartridge. This was eluted with CH3OH/H2O
.80/20) to collect the ®rst fraction and then with CH3OH
to collect the second fraction. Both fractions were concen-
trated and submitted to HPLC and 1H NMR analyses.
Neither bromide 11 nor thiol 3 but only diisopropylethyl-
amine and its derived salt were detected from the ®rst
fraction. The quenched bromides .as thioether 12) together
with excess thiol 3 were found in the second fraction.
Further puri®cation by ¯ash column chromatography
afforded thioether 12 .50 mg) in 95% yield.15 The quench-
ing and the solid phase extraction processes are thus
validated.
2. Results and discussion
Existing thiol quenching reagents 1 and 2 are mainly used in
N-alkylation reactions, so we designed a similar reaction to
evaluate the ¯uorous thiol scavengers. Commercially avail-
able 1H,1H,2H,2H-per¯uorooctanethiol .C6F13CH2CH2SH,
3) was identi®ed as a potential ¯uorous quenching agent.14
The ethylene spacer between the C6F13 tag and SH groupis
expected to minimize the strong electron-withdrawing
effect from the per¯uoroalkyl group and maintain the
nucleophilicity of the thiol. Cyclic amines were selected
as substrates and a-bromoketones/benzyl bromides were
selected as electrophiles for the N-alkylation reactions.
We also compared the reactivity of ¯uorous thiol 3 with the
The general reaction and separation processes pursued in
this work are outlined in Scheme 1. In the alkylation and
thiol quenching steps, excess electrophile .bromide 8) and
excess quenching agent .thiol 3) are used to drive the
respective reaction to completion. In the presence of a
base, a secondary amine 7 can be alkylated by the appro-
priate bromide 8 to give the corresponding tertiary amine 9.
We expect that the unreacted electrophile 8 will be
converted to the ¯uorous thioether 10 by reaction with the
¯uorous thiol scavenger 3. The mixture that contains the
desired product 9, the thioether 10 and excess thiol 3 is
loaded onto a cartridge charged with FluoroFlashe ¯uorous
Scheme 3.

W. Zhang et al. / Tetrahedron 58 /2002) 3871±3875
3873
Scheme 4.
polymer-supported thiol 1 under identical conditions in
quenching of a-bromoketone 11. The preliminary results
listed in Scheme 3 indicate that the reaction of ¯uorous
thiol is signi®cantly fast. It took only 5 min for ¯uorous
thiol 3 to achieve .95% quenching of bromide 11, while
50 min was required for polymer-supported thiol 1.
Doubling the amount of thiol 1 from 2 to 4 equiv. cut the
reaction to 25 min, but that still does not match the speed of
thiol 3. The fast ¯uorous quenching is probably due to the
fact that it occurring in solution. The bene®ts of solution
phase quenching must be substantial since the strong
electron-withdrawing per¯uoroalkyl group should make
¯uorous thiol 3 inherently less reactive than 1.
extraction to separate the base and derivatives from the
reaction mixture. The reaction conditions were thus
optimized and a general procedure was developed by the
reaction of 1,2,3,4-tetrahydroisoquinoline 13 with 2-bromo-
40-methoxyacetophenone 11 .Scheme 4). The reaction was
carried out by addition of 2.0 equiv. of bromide 11 .46 mg,
0.2 mmol) to a solution of cyclic amine 13 .14 mg,
0.1 mmol) in 0.3 mL of THF. Excess diisopropylethylamine
.55 mL, 3 equiv.) was employed to promote both alkylation
and thiol quenching reactions. After 30 min, TLC analysis
showed two spots corresponding to the alkylated product 14
.lower Rf) and the unreacted bromide 11 .higher Rf). Thiol 3
.2.5 equiv.) was then added to scavenge the remaining
bromide 11. After an additional 30 min, TLC analysis
again showed two spots: the alkylated product 11 remained
unchanged, while the thioether 12 appeared at a slightly
higher Rf than the corresponding bromide 11. The excess
thiol 3 lacks a chromophore and cannot be detected in this
The product in the planned N-alkylation synthesis was
expected to quickly elute from the cartridge. To avoid
contamination of diisopropylethylamine and its salt, an
aqueous workup was employed prior to the solid phase
Table 1. Structures, yields and purities of the tertiary amines
Number in the parenthesis shows the purity by HPLC; column: Novapak C18, 4.6£150 mm2, 5 mm; mobile phase: CH3OH/H2O .85/15) 1 mL/min; UV
detection at 254 nm.

3874
W. Zhang et al. / Tetrahedron 58 /2002) 3871±3875
analysis. A quick aqueous workupwas conducted by addi-
tion of aqueous NH4Cl to the reaction mixture. The water
layer was pipetted out to remove diisopropylethylamine and
its salt. The organic phase was loaded onto a 5 g Fluoro-
Flashe cartridge and eluted with MeOH/H2O .80/20). The
®rst fraction containing the desired product was collected
and concentrated to afford N-alkylated amine 14 in 93%
yield. The structure of 14 was characterized by H NMR
and MS analyses. The purity was checked by HPLC
analysis.
Then an elution with MeOH was performed and a second
fraction of 10 mL was collected .¯uorous compounds).
Concentration of the ®rst fraction afforded N-alkylated
1
amine 14 .26 mg) in 93% yield. H NMR .CDCl3) d 3.07
.br s, 2H), 3.17 .br s, 2H), 3.85 .s, 3H), 4.07 .s, 2H), 4.18 .s,
2H), 6.95 .d, Jˆ8.8 Hz, 2H), 7.00±7.25 .4H), 8.24 .d,
Jˆ8.8 Hz, 2H). MS m/z .rel. intensity) 281 .M1, 6%), 267
.39%), 146 .45%), 135 .59%), 114 .84%). HRMS calcu-
lated for C17H17NO2 .M12CH2) 267.1259, found 267.1247.
The purity of 14 is 89% as determined by HPLC analysis on
a Novapak C18 column .4.6£150 mm2, 5 mm) using
CH3OH/H2O .85/15) as a mobile phase .1 mL/min) and
UV detection at 254 nm.
1
Following the general procedure described above, four
cyclic amines were each alkylated with two a-bromo-
ketones and a benzyl bromide to generate a 12-compound
library in parallel. The structures of the products are shown
in Table 1, including tetrahydroisoquinoline, N-substituted
piperazine and acetal piperidine derivatives. The structures
1
15: H NMR .CD3OD) d 2.75±3.15 .m, 6H), 3.90 .s, 2H),
6.85±7.10 .m, 4H), 7.16 .t, Jˆ9.0 Hz, 2H), 8.03 .m, 2H).
MS m/z .rel. intensity) 269 .M1, 3%), 241 .4%), 190 .6%),
160 .35%), 123 .100%), 95, 44%).
1
of the ®nal products were con®rmed by H NMR and MS
analyses.16 The product yields are in the range of 75±95%
and the purities are between 85±95% as determined by
HPLC analysis.
16: 1H NMR .CDCl3) d 2.87 .br, 2H), 2.97 .m, 2H), 3.73 .s,
2H), 3.76 .s, 2H), 6.90±7.25 .6H), 7.43 .m, 2H). MS m/z
.rel. intensity) 241 .M1, 40%), 240 .67%), 132 .16%), 109
.100%).
The heavier ¯uorous thiol C8F17CH2CH2SH was also used
for thiol quenching in the preparation of 15, 16, 20, 21 and
24, and results comparable to those shown in Table 1 were
obtained. In these cases, a 2 g FluoroFlashe cartridge
instead of a 5 g one is enough for an ef®cient separation
of quenching derivatives by FSPE. The stronger retention
of the heavier ¯uorous scavenger derivatives on a SPE
cartridge suggests that C8F17CH2CH2SH has potential utility
in quenching of larger electrophilic molecules.
17: 1H NMR .CDCl3) d 2.77 .br t, 4H), 3.27 .br t, 4H), 3.83
.s, 2H), 3.87 .s, 3H), 6.80±6.95 .5H), 7.26 .t, Jˆ9.0 Hz,
2H), 8.03 .d, Jˆ9.0 Hz, 2H). MS m/z .rel. intensity) 310
.M1, 6%), 281 .12%), 253 .6%), 207 .80%), 191 .12%),
175 .100).
18: 1H NMR .CDCl3) d 2.82 .br, 4H), 3.28 .br, 4H), 3.88 .s,
2H), 6.87 .t, Jˆ6.0 Hz, 1H), 6.94 .d, Jˆ9.0 Hz, 2H), 7.13 .t,
Jˆ9.0 Hz, 2H), 7.27 .t, Jˆ6.0 Hz, 2H), 8.08 .br t, 2H). MS
m/z .rel. intensity) 298 .M1, 3%), 207 .7%), 175 .100%),
160 .9%), 132 .32%).
3. Conclusion
We have demonstrated that commercially available thiols
C6F13CH2CH2SH and C8F17CH2CH2SH can be used to
scavenge excess a-bromoketones/benzyl bromides from
alkylation reactions. The quenching derivatives can be
readily separated from the mixture by solid phase extraction
on ¯uorous silica gel. In addition to quenching active
bromides, ¯uorous thiols have the potential to scavenge
other electrophiles and have broad utility in solution phase
parallel synthesis.
1
19: H NMR .CD3OD) d 2.92 .br s, 4H), 3.22 .br s, 4H),
3.89 .s, 2H), 6.78 .t, Jˆ6.0 Hz, 1H), 6.90 .d, Jˆ9.0 Hz, 2H),
7.07 .t, Jˆ9.0 Hz, 2H), 7.16 .t, Jˆ6.0 Hz, 2H), 7.43 .dd,
Jˆ9.0, 6.0 Hz, 2H). MS m/z .rel. intensity) 270 .M1, 78%),
161 .45%), 137 .46%), 109 .100).
1
20: H NMR .CDCl3) d 2.78 .t, Jˆ5.0 Hz, 4H), 3.68 .t,
Jˆ5.0 Hz, 4H), 3.88 .s, 2H), 3.88 .s, 3H), 6.60±6.70 .m,
2H), 6.95 .d, Jˆ6.9 Hz, 2H), 7.51 .t, 1H), 8.02 .d,
Jˆ6.9 Hz, 2H), 8.20 .dd, 1H). MS m/z .rel. intensity) 311
.M1, 12%), 176 .100%), 147 .40%), 121 .72%).
4. Experimental
1
21: H NMR .CD3OD) d 2.75 .br, 4H), 3.30±3.60 .6H),
4.1. General procedure for alkylation, thiol quenching
and solid phase extraction; preparation of 14
6.61 .t, 1H), 6.77 .d, Jˆ6.0 Hz, 1H), 7.16 .t, Jˆ9.0 Hz),
7.49 .t, 1H), 7.90±8.20 .2H). MS m/z .rel. intensity) 299
.M1, 4%), 285 .12%), 207 .8%), 176 .32%), 147 .17%), 133
.66%), 107 .100%), 95 .52%).
To a 5 mL vial charged with a solution of 1,2,3,4-tetra-
hydroisoquinoline 13 .14 mg, 0.1 mmol) in 0.3 mL of
THF was added 2-bromo-40-methoxyacetophenone 11
.46 mg, 0.2 mmol) followed by diisopropylethylamine
.55 mL, 0.3 mmol). After stirring at 258C for 30 min, thiol
3 .95 mg, 0.25 mmol) was added and the mixture was stirred
for an additional 30 min. Aqueous NH4Cl .0.8 mL) was
added, the aqueous layer was pipetted out and the organic
phase was loaded onto a 5 g FluoroFlashe cartridge14 that
has been pre-conditioned with MeOH/H2O .80/20). The
cartridge was eluted with 5 mL of MeOH/H2O .80/20)
and was collected as the ®rst fraction .desired product).
1
22: H NMR .CD3OD) d 3.05 .br s, 4H), 3.67 .br s, 4H),
4.08 .s, 2H), 6.68 .t, 1H), 6.83 .d, Jˆ9.0 Hz, 1H), 7.12 .t,
Jˆ9.0 Hz, 2H), 7.30±7.65 .4H), 8.05 .br, 1H). MS m/z .rel.
intensity) 271 .M1, 24%), 177 .25%), 164 .20%), 133
.16%), 120 .28%), 107 .100%), 95 .23%), 84 .45%).
1
23: H NMR .CD3OD) d 1.81 .br s, 4H), 3.15 .br s, 4H),
3.69 .s, 3H), 3.80 .s, 4H), 4.52 .s, 1H), 4.66 .s, 1H), 6.87
.d, Jˆ7.5 Hz, 2H), 7.81 .d, Jˆ7.5 Hz, 2H). MS m/z .rel.

W. Zhang et al. / Tetrahedron 58 /2002) 3871±3875
3875
intensity) 291 .M1, 5%), 276 .25%), 205 .45%), 177 .26%),
156 .66%), 135 .53%).
Studer, A.; He, M.; Kim, S.-Y.; Luo, Z.; Larhed, M.; Hallberg,
M.; Linclau, B. Combinatorial Chemistry: A Practical
Approach; Fenniri, H., Ed.; Oxford University: Oxford,
2001; p. 327.
1
24: H NMR .CD3OD) d 1.85 .br, 4H), 3.04 .br 4H), 3.89
5. .a) Curran, D. P. ChemtractsÐOrg. Chem. 1996, 9, 75.
.b) Curran, D. P.; Hoshino, M. J. Org. Chem. 1996, 61,
6480. .c) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S. Y.;
Jeger, P.; Wipf, P.; Curran, D. P. Science 1997, 275, 823.
6. .a) Curran, D. P. Synlett 2001, 1488. .b) Curran, D. P.; Hadida,
S.; He, M. J. Org. Chem. 1997, 62, 6714. .c) Curran, D. P.;
Luo, Z. Y. J. Am. Chem. Soc. 1999, 121, 9069. .d) Luo, Z. Y.;
Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P. Science 2001,
291, 1766.
.s, 4H), 7.18 .t, Jˆ9.0 Hz, 2H), 8.02 .t, Jˆ9.0 Hz, 2H). MS
m/z .rel. intensity) 279 .M1, ,1%), 193 .3%), 156 .100%),
123 .10%), 99 .13%).
25: 1H NMR .CDCl3) d 1.97 .br s, 4H), 2.85 .br s, 4H), 3.82
.s, 2H), 3.96 .s, 4H), 7.07 .t, Jˆ8.7 Hz, 2H), 7.50 .br t, 2H).
MS m/z .rel. intensity) 251 .M1, 16%), 206 .12%), 164
.20%), 156 .11%), 109 .100%).
7. Bolton, G. L.; Booth, R. J.; Creswell, M. W.; Hodges, J. C.;
Warmus, J. S.; Wilson, M. W.; Kennedy, R. M. WO97/42230,
1997.
5. Note added in proof
In parallel, independent work, Lindsley and co-workers
from Merck are reporting the successful use of a number
of ¯uorous-tethered quenching reagents for parallel
synthesis, including thiol 3. See Lindsley, C.; Zhao, Z.;
Leister, W., submitted for publication.
8. Solid-bound mercaptopropanol .Aldrich) and polymer-bound
thiolphenol .Argonaut) are also commercially available.
9. Jung, M. E.; Cook, P. D.; Kawasaki, A. M. US Patent
5,632,898, 1997.
10. Curran, D. P.; Hadida, S.; Kim, S. Y.; Luo, Z. Y. J. Am. Chem.
Soc. 1999, 121, 6607.
11. Linclau, B.; Singh, A. K.; Curran, D. P. J. Org. Chem. 1999,
64, 2835.
Acknowledgements
12. Wipf, P.; Reeves, J. T.; Balachandran, R.; Giuliano, K. A.;
Hamel, E.; Day, B. W. J. Am. Chem. Soc. 2000, 122, 9391.
13. Rocaboy, C.; Gladysz, J. A. Tetrahedron, 2002, 4007±4014.
We thank Dr PhilipYeske for helfpul suggestions and
stimulating discussions.
14. FluoroFlashe
Fluorous
silica
gel
cartridges,
C6F13CH2CH2SH and C8F17CH2CH2SH are available from
Fluorous Technologies, Inc:www.¯uorous.com.
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2H). MS m/z .rel. intensity) 528 .M1, 15%), 509 .42%), 499
.32%), 486 .40%), 453 .19%), 435 .35%), 150 .37%), 135
.100%).
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