Fluorous-tethered quenching reagents for solution phase parallel synthesis

Article abstract of DOI:10.1016/S0040-4039(02)00748-7

Commercially available fluorous-tethered reagents are employed to quench excess reactants and remove known impurities from crude reaction mixtures generated via solution phase parallel synthesis. Fluorous quenching reagents are expediently removed via FluoroFlash SPE columns to afford products in high yields and purities.

Full text of DOI:10.1016/S0040-4039(02)00748-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4225–4228
Fluorous-tethered quenching reagents for solution phase parallel
synthesis
Craig W. Lindsley,* Zhijian Zhao and William H. Leister
Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck Research Laboratories, PO Box 4,
West Point, PA 19486, USA
Received 27 March 2002; revised 9 April 2002; accepted 16 April 2002
Abstract—Commercially available fluorous-tethered reagents are employed to quench excess reactants and remove known
impurities from crude reaction mixtures generated via solution phase parallel synthesis. Fluorous quenching reagents are
expediently removed via FluoroFlash™ SPE columns to afford products in high yields and purities. © 2002 Elsevier Science Ltd.
All rights reserved.
The need for expedient chemical lead identification in
early stage medicinal chemistry programs is crucial for
the development of these programs and the rapid deliv-
ery of safety assessment candidates for clinical evalua-
tion. In recent years, the pharmaceutical industry has
addressed this issue by establishing groups whose mis-
sion is to synthesize analog arrays based on high
throughput screening hits while employing solution
phase parallel synthesis.1 The key to the success of this
approach was the application of resin-bound reagents
and scavengers to drive reactions to completion and
quench excess reagents in the solution phase (Scheme
1).2 Simple filtration with or without solid phase extrac-
tion (SPE) protocols (SCX, SAX) can afford pure,
single compounds in sufficient quantities (50 mg) for
screening, full characterization and archiving.3 How-
ever, resin-bound reagents and scavengers do have lim-
itations. First, hindered access to functional groups
within the resin core, especially in higher loading resins,
and the biphasic nature of the reaction systems that
contain polymer-bound entities result in slower overall
kinetics.4 Second, solvent selection for both the syn-
thetic and scavenging steps is dictated by the swelling
requirements of the resin matrix as well as the large
solvent volumes.5 Third, resin-mediated reactions are
not readily scaleable (increasing from 0.1 to 10 mmol)
for the resynthesis of active compounds.6 These limita-
tions impact the widespread use of resin-based scav-
engers across medicinal chemistry departments. With
the goal of addressing these issues, our group began to
examine new technologies for solution phase parallel
synthesis.
Evaluation of emerging fluorous technologies pioneered
by Curran, indicated to us the efficiency of employing
fluorous protecting groups in combination with Fluo-
roFlash™ SPE columns as exemplified in Scheme 2.7
Moreover, high chemical yields and purities were
obtained both in the literature and in our hands. Based
on our heavy reliance on scavenger resins for parallel
purification, we hoped to contribute to this new field by
developing a ‘toolkit’ of fluorous-tethered quenching
reagents (scavengers) that could be employed as tradi-
tional solution phase reagents. We envisioned that these
fluorous-tethered reagents would provide rapid quench-
ing due to homogeneous solution phase kinetics, could
be easily removed in parallel by FluoroFlash™ SPE
and might reduce the barrier for the general practice of
solution phase parallel synthesis. This new application
of fluorous technology (Scheme 3) would compliment
the existing scavenger resin paradigm depicted in
Scheme 1.
Scheme 1.
Keywords: combinatorial chemistry; fluorine and compounds.
* Corresponding author. Tel.: 215-652-2265; fax: 215-652-6345;
We initially examined a set of six inexpensive, function-
alized fluorous-tethered reagents (Fig. 1) that we felt
e-mail: craig lindsley@merck.com
–
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00748-7

4226
C. W. Lindsley et al. / Tetrahedron Letters 43 (2002) 4225–4228
Reagents 1 and 2 are utilized in the general scavenging
1.
C8F17
O
CN
Ph
of electrophiles when used in slight excess (typically, 1.0
equiv. of scavenger for every 0.3 equiv. of excess elec-
trophile) in under 1 h at room temperature.10 Represen-
tative examples are shown in Scheme 4.11 In the event,
treatment of isocyanate 7 with amine 8 for 2 h followed
by addition of 1 to scavenge excess 7 provided, after
FluoroFlash™ SPE, urea 9 in excellent yield and >98%
purity.12 In a similar fashion, 2 removed excess 10 to
afford the a-aminoester 12 in high yield and purity.
O
O N
NH
THF, rt, 10 min
FluoroFlashTM
2.
SPE
O
95% yield
>98% purity
N
O
C8F17
Reagents 3, 4, 5 and 6 are utilized in the general
scavenging of nucleophiles when used in slight excess
(typically, 1.0 equiv. of scavenger for every 0.3 equiv. of
excess nucleophile) in under 1 h at room temperature.10
Representative examples are shown in Scheme 5 and
include amide and sulfonamide formation, alkoxide
alkylation and epoxide openings wherein fluorous
reagents scavenge amines, anilines, alkoxides and epox-
ides, respectively.13 For the cases examined, good chem-
ical yields (>80%) and excellent purities (>95%) were
obtained.12
Scheme 2.
F
R
C + D
A + B
FluoroFlashTM
D
C
C +
F
R
SPE
Scheme 3.
In cases where a resin-bound base is also employed, the
SPE column serves as a general filtration method for
removal of both the resin-bound base and the fluorous-
tethered scavenger as illustrated in several examples in
Schemes 4 and 5. The entire compendium of resin-
bound reagents is compatible under this protocol and
multi-step reactions can be undertaken with various
combinations of resin-bound reagents and fluorous-
tethered scavengers (Scheme 6). In this instance, the
reductive amination of 25 with 26 using MP-CNBH3
proceeds smoothly, and excess 26 is removed by the
addition of 1 providing 27 in 84% yield and >98%
purity after FluoroFlash™ SPE. Sulfonylation of 27
with 28 utilizing a resin-bound base, PS-NMM, results
in sulfonamide 29 in 88% yield and >95% purity after
FluoroFlash™ SPE.12
F
F
F
F
F
F
F
R = CH2NH2
(CH2)2SH
COCl
1
2
3
4
5
6
n = 2
n = 1
n = 2
n = 3
n = 2
n = 1
R
F
F F F F
n = 1, 2, 3
F
n
SO3H
SO2Cl
CH2
O
R
F
Figure 1. Fluorous-tethered quenching reagents.
would allow for general scavenging of the most com-
mon chemical moieties we encounter in parallel synthe-
sis libraries.8 In general, the fluorous-tethered reagents
contain between 13 and 17 fluorine atoms. We chose to
generically represent the reagents by an open circle with
an embedded ‘F’ to compliment the generic resin con-
vention. All six reagents are liquids that can be used
neat or stored and dispensed as 0.5 to 2.0 M THF stock
solutions. The key to the success of this new approach
is the removal of the fluorous scavengers in a rapid and
general manner with FluoroFlash™ SPE columns.7,9
In summary, we have developed a novel protocol for
the parallel purification of solution phase libraries using
fluorous-tethered quenching reagents (scavengers) in
conjunction with FluoroFlash™ SPE. This new
fluorous technology has several advantages over tradi-
tional resin-bound scavenger reagents: (1) fluorous
reagents are inexpensive and available from several
commercial sources; (2) FluoroFlash™ SPE columns
can be reused up to ten times; (3) homogeneous solu-
1.
Ph
NH2
8
H
N
H
N
FluoroFlashTM SPE
FluoroFlashTM SPE
NCO
Ph
(1.0 equiv.)
1)
2)
THF, rt
7
9
O
(1.3 equiv.)
2. 1 (1.0 equiv.)
(93% yield, >98% pure)
NH2
11
O
O
H
Ph
1.
(1.0 equiv.)
Br
N
O
O
Ph
12
(94% yield, >98% pure)
10
PS-DIEA (1.5 equiv.)
(1.3 equiv.)
2. 2 (1.0 equiv.)
Scheme 4.

C. W. Lindsley et al. / Tetrahedron Letters 43 (2002) 4225–4228
4227
14
1.
PhCOCl
H
N
FluoroFlashTM SPE
FluoroFlashTM SPE
Ph
NH2
(1.0 equiv.)
1)
2)
15
O
13
(1.3 equiv.)
PS-DIEA (1.5 equiv.)
2. 3 (1.0 equiv.)
(96% yield, >98% pure)
17
SO2Cl
Ph
O
1.
Cl
NH2
(1.0 equiv.)
Cl
N
H
S
Ph
O
PS-DIEA (1.5 equiv.)
16
18
2. 4 (1.0 equiv.)
(80% yield, >95% pure)
(1.3 equiv.)
NMe2
20
1.
Cl
(1.0 equiv.)
FluoroFlashTM SPE
FluoroFlashTM SPE
NMe2
O
Ph
O-Na+
3)
4)
21
19
THF, rt
2. 5 (1.0 equiv.)
(1.3 equiv.)
O
(88% yield, >98% pure)
SPh
OH
PhSH
(1.0 equiv.)
23
1.
F
PS-DIEA (1.5 equiv.)
F
22
24
2. 6 (1.0 equiv.)
(1.3 equiv.)
(90% yield, >96% pure)
Scheme 5.
Scheme 6.
tion phase kinetics are observed, and (4) reactions are
easily scaleable and free from solvent limitations. Cur-
rent work is focused on the preparation of more spe-
cialized fluorous-tethered scavengers and reagents and
will be reported in due course.
4882–4886; (c) Gallop, M., et al. J. Med. Chem. 1994, 37,
1233–1251.
2. 1(b): Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman,
B. A.; Hahn, P. Tetrahedron Lett. 1996, 37, 7193–7196.
3. Siegel, M. G.; Hahn, P.; Dressman, B. A.; Fritz, J. E.;
Grunwell, J. R.; Kaldor, S. W. Tetrahedron Lett. 1997,
38, 3357–3360.
Note added in proof: In parallel, independent work,
Curran and co-workers at FTI report the successful
application of the fluorous thiol 2 as a fluorous quench-
ing agent in combination with FluoroFlash™ SPE
columns. See, Zhang, W.; Curran, D. P.; Chen, C.
H.-T. Tetrahedron, in press.
4. Charette, A. B.; James, J. K.; Boezio, A. A. J. Org.
Chem. 2001, 66, 2178–2180 and references cited therein.
5. (a) See Refs.
1 and 2 and references therein; (b)
www.argotech.com.
6. The large amounts of solvent required (ꢀ1 L) to scale-up
from 0.1 to 10 mmol employing resin-bound scavengers
makes this unattractive versus 40 mL for fluorous
reagents.
Acknowledgements
7. (a) FluoroFlash™ columns are commercially available
from FTI, Fluorous Technologies Incorporated;
www.fluorous.com; (b) for excellent reviews of the area
see: (1) Curran, D. P. Synlett 2001, 1488–1496; (2) Cur-
ran, D. P. Pure A Chem. 2000, 72, 1649–1653; (c) Lou, Z.
Y.; Williams, J.; Read, R. W.; Curran, D. P. J. Org.
Chem. 2001, 66, 4261–4266; (d) in house data from an
FTI evaluation kit (Part c 801-1000S) of the fluorous
Boc reagent; (e) the exact ratio of water:methanol for the
FluoroFlash™ SPE column varies based on the polarity/
hydrophobicity of both the fluorous scavenger and the
substrate which is most readily determined by fluorous
We would like to thank Professor Dennis Curran and
Dr. Philip Yeske (FTI) for helpful conversations and
Dr. Charles W. Ross, III for obtaining HRMS (accu-
rate mass measurements).
References
1. (a) Furka, A. Drug Discovery Today 2002, 7, 1–4; (b)
Boothe, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119,

4228
C. W. Lindsley et al. / Tetrahedron Letters 43 (2002) 4225–4228
TLC analysis of a representative library member and the
scavenger.
vacuum manifold. Air was drawn through for 2 min, and
then 10 mL of a 15% aqueous methanol solution was
added and slowly eluted under an ꢀ−5 psi vacuum and
collected into a test tube. The test tube was concentrated
in a Genevac HT II-12 to afford 70.8 mg (93%) of urea 9
as a white solid. Analytical LCMS indicated a single peak
(2.817 min, CH3CN/H2O/0.1% TFA, 4 min gradient)
>98% pure by UV (214 nm) and 100% pure by ELSD.
(1H NMR, 300 MHz, CDCl3): l 7.23 (m, 10H), 4.61 (s,
1H), 4.36 (s, 1H), 4.31 (d, J=6 Hz, 2H), 3.44 (q, J=6.6
Hz, 2H), 2.78 (t, J=6.6 Hz, 2H). HRMS: calcd for
C16H18N2O (M+H), 255.1492; found 255.1492 (M+H).
11. Though not exemplified, 1 was also found to completely
scavenge acid chlorides, sulfonyl chlorides and iso-
cyanates. Similarly, 2 was found to completely scavenge
epoxides, a-bromo carbonyl derivatives, Michael accep-
tors and activated halides.
8. (a) Fluorous reagents are available from FTI, Aldrich,
Avocado and Lancaster and average $8/g; (b) the
fluorous reagents 1–6 were originally prepared decades
ago for use in the polymer and coatings industry and can
be prepared according to the following patent literature:
1: Ellzey, S. E.; Wittman, J. S.; Connick, W. J.; Guire, W.
A. US 3338968, 1967; 2 and 4: Haszeldine, R. N.; Tip-
ping, A. E. DE 2238458, 1973; 3: Platz, R.; Christof, P.
DE 1285999, 1969; 5: Millauer, H. DE 1964988, 1971; 6:
Anello, L. G.; Sweeney, R. F. US 3384627, 1968.
9. (a) Zhang, Q. S.; Luo, Z. Y.; Curran, D. P. J. Org. Chem.
2000, 65, 8866–8873; (b) By eluting the fluorous materials
by exhaustive washing with THF and drying overnight in
a vacuum oven at 40°, the columns can be reused up to
10 times with no loss of binding efficiency or contamina-
tion.
10. In a typical experiment, isocyanate 7 (60 mL, 0.39 mmol),
benzyl amine 8 (35 mL, 0.3 mmol) and THF (2 mL, 0.35
M) are placed in a 4 mL vial. The vial is placed on a
rotator for 3 h. After this time, 1 (300 mL, 0.3 mmol, 1.0
M THF) was added. After 50 min, the crude reaction was
applied to a silica transfer column (Part c: 622-0057S)
atop a 5 g FluoroFlash™ column (Part c: 801-0058S),
pre-washed with methanol and attached to a multi-port
12. All compounds fully characterized by HPLC (UV and
ELSD), NMR and HRMS (Accurate Mass MS).
13. Though not exemplified, 3 was also found to completely
scavenge amines (1° and 2°), anilines and alkoxides; 4
was found to completely scavenge amines (1° and 2°) and
anilines; 5 scavenged amines (1° and 2°), alcohols and
alkoxides; and 6 scavenged 1° amines, thiols, thiophenols
and organometallic reagents (RLi, RMgX, etc…).