Fluorous TBAF: A convenient and selective reagent for fluoride-mediated deprotections

Article abstract of DOI:10.1021/jo901245m

(Chemical Equation Presented) A fluorous analogue of TBAF has been developed for its use in the clean removal of silicon-derived protecting groups. Purification of the crude mixtures by fluorous solid-phase extractions allowed alcohols, amines, and carboxylic acids to be obtained in high purity, with no need of chromatographic separations. The moderate reactivity of fluorous TBAF was exploited in selective deprotections of several bifunctional molecules.

Full text of DOI:10.1021/jo901245m

pubs.acs.org/joc
among the many applications of fluorous chemistry are the
Fluorous TBAF: A Convenient and Selective Reagent
for Fluoride-Mediated Deprotections
use of fluorous reagents as protecting groups, scavengers,
and tags for conventional, parallel, or mixture syntheses.3
Silicon-derived reagents are routinely employed in synth-
eses of complex molecules for the convenient protection
of alcohols (TMS and derived groups), carboxylic acids
[2-(trimethylsilyl)ethyl (TMSE) group], and amines [2-(tri-
methylsilyl)ethoxycarbonyl (Teoc) group].4 Many reaction
conditions for their removal that are compatible with other
functional groups have been described, but these usually
involve treatment with fluoride reagents. In the case of
acid-sensitive substrates, tetra-n-butylammonium fluoride
(TBAF) is the reagent of choice. However, TBAF-mediated
deprotections often suffer from the drawback that the elim-
ination of excess TBAF and/or tetra-n-butylammonium
(TBA) salts can be somewhat difficult. This is particularly
problematic in the case of water-soluble products or when
standard chromatographic separations are not possible.
Several solutions to this problem involve the precipitation
of insoluble TBA salts5 or the use of polymer-supported
scavengers.6 In these cases, filtration techniques can then be
used to isolate pure, TBAF-free, deprotected products.
These challenges motivated us to design and synthesize a
fluorous analogue of TBAF (FTBAF, 1) with the aim of
facilitating the separation of TBA byproducts. Thus, the
replacement of an n-butyl chain in TBAF with a perfluor-
oalkyl derivative would afford a light fluorous molecule that
would be suitable for purification through fluorous solid-
phase extractions (F-SPE)7 (Figure 1).
Santos Fustero,*,†,‡ Amador Garcıa Sancho,‡
´
†,‡
‡
Jose Luis Acena, and Juan F. Sanz-Cervera
ꢀ
~
†
´
ꢀ
Departamento de Quımica Organica, Universidad de
Valencia, E-46100 Burjassot, Spain, and ‡Laboratorio
ꢀ
ꢀ
ꢀ
de Moleculas Organicas, Centro de Investigacion
´
Prıncipe Felipe, E-46012 Valencia, Spain
santos.fustero@uv.es
Received June 11, 2009
A fluorous analogue of TBAF has been developed for its
use in the clean removal of silicon-derived protecting
groups. Purification of the crude mixtures by fluorous
solid-phase extractions allowed alcohols, amines, and
carboxylic acids to be obtained in high purity, with no
need of chromatographic separations. The moderate
reactivity of fluorous TBAF was exploited in selective
deprotections of several bifunctional molecules.
FIGURE 1. Structures of TBAF and FTBAF.
The synthesis of fluorous TBAF 1 was easily carried out in
two steps from commercially available iodide 2 (Scheme 1) on a
multigram scale. While treatment of 2 with n-Bu3N in refluxing
MeCN led to moderate yields of fluorous TBAI 3,8 the reaction
was considerably more efficient when performed in a sealed
vessel at 150 °C. Subsequent reaction of 3 with excess aqueous
HF was followed by treatment of the organic extracts with solid
KF. After filtration, the ethereal phase was carefully concen-
trated to afford a 0.1-0.3 M solution of FTBAF in THF. The
concentration of the resulting FTBAF solution was quantified
with the aid of 1H NMR integration of the perfluoroalkyl and
THF signals. Subsequent 19F NMR analysis confirmed that
full conversion was achieved, as judged by the integration of
both fluoride (-155.2 ppm) and fluorous signals.
The purification of reaction products often constitutes the
most time-consuming step within a synthetic sequence.1
Several techniques have been developed in order to make
this part of the process faster and simpler, including the use
of solid-supported tags, reagents, and scavengers, all of
which facilitate the purification of reaction products by
means of simple washings and filtrations of the crude reac-
tion mixtures.2 In a similar manner, fluorous procedures
employ highly fluorinated (fluorous) reagents and materials
which can then be easily separated from nonfluorous species
through liquid-liquid or solid-liquid extractions, depend-
ing on the number of fluorine atoms introduced. Thus,
(1) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1174–1196.
(2) (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A.
G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J.
Chem. Soc. Perkin Trans. 1 2000, 3815–4195. (b) Solinas, A.; Taddei, M.
Synthesis 2007, 2409–2453.
(4) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic
Synthesis, 4th ed.; John Wiley and Sons: Hoboken, NJ, 2007.
(5) Craig, J. C.; Everhart, E. T. Synth. Commun. 1990, 20, 2147–2150.
(6) (a) Parlow, J. J.; Vazquez, M. L.; Flynn, D. L. Biorg. Med. Chem. Lett.
1998, 8, 2391–2394. (b) Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723–726.
(7) (a) Curran, D. P. Synlett 2001, 1488–1496. (b) Curran, D. P. Aldri-
chim. Acta 2006, 39, 3–9. (c) Zhang, W.; Curran, D. P. Tetrahedron 2006, 62,
11837–11865.
(3) (a) Zhang, W. Tetrahedron 2003, 59, 4475–4489. (b) Handbook of
ꢀ
Fluorous Chemistry; Gladysz, J. A., Curran, D. P., Horvath, I. T., Eds.; Wiley-
VCH: Weinheim, Germany, 2004. (c) Zhang, W. Chem. Rev. 2004, 104, 2531–
2556. (d) Zhang, W. Curr. Opin. Drug Discovery Dev. 2004, 7, 784–797.
(e) Zhang, W. Chem. Rev. 2009, 109, 749–795.
(8) For the synthesis of similar fluorous TBAI analogues, see: Gupta, O.
D.; Armstrong, P. D.; Shreeve, J. M. Tetrahedron Lett. 2003, 44, 9367–9370.
6398 J. Org. Chem. 2009, 74, 6398–6401
Published on Web 07/09/2009
DOI: 10.1021/jo901245m
r
2009 American Chemical Society

Fustero et al.
JOCNote
SCHEME 1. Synthesis of FTBAF
SCHEME 2. Deprotection of BnOTES
We next tested the synthetic applications of FTBAF, as
well as the ease with which the reaction products could be
purified, using silyl-protected benyl alcohols as model sys-
tems. The first experiment was a deprotection of BnOTES
(4a) (THF/DMF, rt, 30 min), which resulted in the isolation
of benzyl alcohol 5 (Scheme 2) in high yield and with high
purity (as per GC-MS analysis), with no trace of TBA salts
after a simple purification through F-SPE9 (Figure 2). In
contrast, a similar reaction with nonfluorous TBAF typically
requires a chromatographic separation.
FIGURE 2. GC analysis of the reaction of BnOTES (4a) with
FTBAF: (a) crude reaction mixture and (b) after purification by
F-SPE.
TABLE 1. Deprotection of Silylated Derivatives of Benzyl Alcohol
Other silicon-derived protecting groups such as TBS or TIPS
proved to be much more resistant than a TES group when
removed with FTBAF under the same reaction conditions
(Table 1, entries 1-3). In contrast, BnOTBS (4b) and BnOTIPS
(4c) were easily deprotected with nonfluorous TBAF in only 10
or 30 min, respectively (entries 4 and 5). For the complete
entry
R
conditionsa time (h) t (°C) yield (%)b purity (%)c
1
2
3
4
5
6
7
8
9
TES 4a
TBS 4b
TIPS 4c
TBS 4b
TIPS 4c
TBS 4b
TIPS 4c
TBS 4b
TIPS 4c
A
A
A
B
0.5
0.5
0.5
0.15
0.5
25
25
25
25
25
25
25
60e
40e
99
4d
92
1d
100d
100d
92
F
removal of TBS and TIPS groups with TBAF much longer
B
reaction times were needed at room temperature (entries 6 and 7)
or alternatively the reaction was more conveniently carried out
under microwave irradiation (entries 8 and 9). The latter condi-
tions were also applied for the simultaneous removal of a primary
and a secondary TBS groups in compound 6 (Scheme 3).
After obtaining these results, we focused on molecules
which are commonly difficult to separate from TBA bypro-
ducts, such as amines or carboxylic acids, which were obtained
in high purity after F-SPE (Table 2, entries 1 and 2). Con-
versely, transesterification of TMSE-protected R-imino ester
12 through reaction with FTBAF/BnBr easily afforded the
corresponding benzyl ester 13 (entry 3).10
A
A
A
A
18
48
0.75
0.75
93
94
96
91
88
85
83
aConditions A: FTBAF (15equiv), THF/DMF, purification by F-SPE.
Conditions B: TBAF (1.5 equiv), THF/DMF. bIsolated yield after F-SPE
purification cMeasured with the aid of GC-MS dConversion determined
in the crude mixture through GC-MS; F-SPE was not carried outeReac-
tion performed under microwave irradiation
SCHEME 3. Deprotection of Primary and Secondary TBS Groups
(9) The crude mixture was eluted through fluorous silica gel with 67%
aqueous MeOH to afford pure BnOH, whereas all fluorous species remained
adsorbed onto the solid support. The low solubility of the TES-F byproduct
precluded its elution in the fluorophobic fraction.
(10) The R-imino acid was too unstable to allow its isolation, see:
ꢀ
ꢀ
ꢀ
Fustero, S.; Sanchez-Rosello, M.; Rodrigo, V.; Garcıa, A.; Catalan, S.; del
´
Pozo, C. J. Org. Chem. 2008, 73, 5617–5620.
(11) (a) Studer, A.; Curran, D. P. Tetrahedron 1997, 53, 6681–6696. (b)
Fluorous silyl protecting groups have recently been devel-
oped for the convenient protection of alcohols,11 carboxylic
acids,12 and amines.13 Still, when TBAF is used for their
€
Rover, S.; Wipf, P. Tetrahedron Lett. 1999, 40, 5667–5670. (c) Palmacci, E.
R.; Hewitt, M. C.; Seeberger, P. H. Angew. Chem., Int. Ed. 2001, 40, 4433–
4437. (d) Nakamura, H.; Linclau, B.; Curran, D. P. J. Am. Chem. Soc. 2001,
123, 10119–10120. (e) Zhang, W.; Luo, Z.; Chen, C. H.-T.; Curran, D. P. J.
Am. Chem. Soc. 2002, 124, 10443–10450. (f) Manzoni, L. Chem. Commun.
2003, 2930–2931. (g) Manzoni, L.; Castelli, R. Org. Lett. 2004, 6, 4195–4198.
(h) Crich, D.; Grant, D.; Bowers, A. A. J. Am. Chem. Soc. 2007, 129, 12106–
12107. (i) Carrel, F. R.; Seeberger, P. H. J. Org. Chem. 2008, 73, 2058–2065.
(12) Fustero, S.; Garcıa Sancho, A.; Chiva, G.; Sanz-Cervera, J. F.; del
´
~
Pozo, C.; Acena, J. L. J. Org. Chem. 2006, 71, 3299–3302.
(13) (a) Nakamura, Y.; Okumura, K.; Kojima, M.; Takeuchi, S. Tetra-
hedron Lett. 2006, 47, 239–243. (b) Nakamura, Y.; Takeuchi, S. QSAR
Comb. Sci. 2006, 25, 703–708.
´
(j) Garcıa Sancho, A.; Wang, X.; Sui, B.; Curran, D. P. Adv. Synth. Catal.
2009, 351, 1035–1040.
J. Org. Chem. Vol. 74, No. 16, 2009 6399

Fustero et al.
JOCNote
TABLE 2. FTBAF-Mediated Deprotection of Silylated Substrates
aIsolated yield after F-SPE purificationbMeasured with the aid of GC-MS or HPLCcReaction performed with 10equiv of BnBr. dReaction performed under
microwave irradiationFTIPS = Si(i-Pr)2(CH2)2C8F17. FTMSE = (CH2)2SiMe2(CH2)3C8F17.
TABLE 3. FTBAF-Mediated Selective Deprotections
aIsolated yield after F-SPE purification bMeasured with the aid of GC-MScConversion determined in the crude mixture through GC-MS; F-SPE was
not carried outd92:8 ratio of TIPS-protected diol and free diole98:2 ratio of mono-TBS-protected diol and starting material
removal, further purification may be needed after F-SPE in
order to remove the TBA salts completely. In this kind of
process, however, the combination of FTIPS group11c-e
protection and FTBAF deprotection is extremely useful for
the efficient deprotection of alcohols (entries 4 and 5). In a
similar fashion, the FTMSE group developed by our group12
was also easily and efficiently cleaved by the action of
FTBAF (entry 6).
was possible to discriminate between primary and secon-
dary TBS groups of compound 6 by the action of FTBAF
(entry 3). On the other hand, silyl-protected alcohols 24
and 26 were completely deprotected in the presence of a
TMSE ester or a Teoc carbamate, respectively (entries 4
and 5).15 It should be noted that all those selective deprotec-
tions are more difficult to achieve with nonfluorous
TBAF, and usually need to be buffered with AcOH.16 For
instance, deprotection of compound 6 afforded an almost
equimolecular mixture of starting material and monopro-
tected products 23 and 28 when TBAF/AcOH was used, in
stark contrast with the results achieved with FTBAF
(Scheme 4).
The observed moderate reactivity of FTBAF is probably a
consequence of the electron-withdrawing effect of the per-
fluoroalkyl chain. This prompted us to undertake several
selective deprotections,14 all of which proceeded smoothly in
several bis-silylated subtrates with careful control of the
amount of FTBAF and the reaction conditions (Table 3).
For instance, a primary TES group was selectively cleaved in
the presence of primary TBS or TIPS groups in compounds
19 and 21, respectively (entries 1 and 2). Furthermore, it
In summary, fluorous tetra-n-butylammonium fluoride
(FTBAF) has been easily prepared in two steps from
commercial sources and tested in the efficient cleavage of
silicon-based protecting groups. The deprotected products
(14) For reviews, see: (a) Nelson, T. D.; Crouch, R. D. Synthesis 1996,
1031–1069. (b) Crouch, R. D. Tetrahedron 2004, 60, 5833–5871. For selected
examples, see: (c) Shah, S. T. A.; Singh, S.; Guiry, P. J. J. Org. Chem. 2009,
74, 2179–2182. (d) Chen, M.-Y.; Lee, A. S.-Y. J. Org. Chem. 2002, 67, 1384–
1387. (e) Schwarz, S.; Schumacher, M.; Ring, S.; Nanninga, A.; Weber, G.;
Thieme, I.; Undeutsch, B.; Elger, W. Steroids 1999, 64, 460–471. (f) Col-
lington, E. W.; Finch, H.; Smith, I. J. Tetrahedron Lett. 1985, 26, 681–684.
(15) Both the TMSE and Teoc groups in compounds 24 and 26
(Table 3, entries 4 and 5) were stable even in the presence of a larger excess
of FTBAF. In contrast, 2 equiv of nonfluorous TBAF fully deprotected both
substrates.
(16) For examples, see ref 14b and: Yashunsky, D. V.; Borodkin, V. S.;
Ferguson, M. A. J.; Nikolaev, A. V. Angew. Chem., Int. Ed. 2006, 45, 468–
474.
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Fustero et al.
JOCNote
SCHEME 4. Nonselective Deprotection with TBAF
-126.7 (s, 2F). HRMS (FAB) calcd for C23H33F17N [M - I]+
646.2341, found 646.2331.
Synthesis of FTBAF (1). HF (40% aqueous, 20 mL, 460 mmol)
was added to a solution of 3 (1.55 g, 2 mmol) in THF (40 mL).
After 6 h, the mixture was diluted with Et2O, and the aqueous
layer was extracted with Et2O several times. The organic ex-
tracts were stirred in the presence of KF (26.7 g, 460 mmol). The
mixture was filtered then the filtrates were diluted with THF and
concentrated to a residual volume of ca. 10 mL. This process was
repeated three times to ensure the full evaporation of Et2O. The
final concentration of the FTBAF solution in THF (typically
0.1-0.3 M) was measured by 1H NMR analysis. This solution
was stored under argon at room temperature and used without
further purification. 1H NMR (300 MHz, CDCl3) δ 0.78 (t, J =
7.5 Hz, 9H), 1.19-1.26 (m, 6H), 1.50 (br, 6H), 1.83-1.85 (m,
2H), 2.18 (br, 2H), 3.14-3.16 (m, 6H), 3.37-3.42 (m, 2H).
19F NMR (282.4 MHz, CDCl3) δ -81.4 (br, 3F), -113.7 (br,
2F), -122.1 (br, 6F), -122.9 (s, 2F), -123.3 (s, 2F), -126.4 (s,
2F), -155.2 (br, 1F).
are obtained in high yields and with high purities after a
rapid, simple purification through F-SPE, making this
method particularly useful in the case of polar compounds
such as amines and carboxylic acids. The lower reactivity
of FTBAF compared to TBAF allowed the selective de-
protection of specific silyl groups. Further applications of
this novel reagent are currently under study in our labora-
tories.
General Procedure for the FTBAF-Mediated Deprotections.
FTBAF (THF solution) was added to a solution of the protected
substrate (1 equiv) in DMF (0.05M). The reaction was stirred at
the temperature and time indicated in each case. Then, the THF
was removed under a N2 stream and the crude material was
purified by F-SPE. The deprotected products were identified by
comparison with commercially available samples or previously
reported compounds.
Experimental Section
Synthesis of FTBAI (3). n-Bu3N (0.79 mL, 3.3 mmol) was
added to a solution of 2 (1.80 g, 3 mmol) in MeCN (30 mL). The
reaction was heated in a sealed tube at 150 °C. After 24 h the
solvent was removed under reduced pressure and the crude
material was purified with F-SPE to afford 1.98 g of 3 as a
ꢀ
Acknowledgment. We thank the Ministerio de Educacion
y Ciencia (CTQ2007-61462 and CTQ2006-01317) for finan-
cial support. A.G.S. thanks the CIPF for a predoctoral
ꢀ
fellowship and JLA thanks the M.E.C. for a Ramon y Cajal
research contract.
1
white solid (85% yield). Mp 82-83 °C. H NMR (300 MHz,
CDCl3) δ 0.82 (t, J = 7.4 Hz, 9H), 1.25-1.35 (m, 6H), 1.57 (br,
6H), 1.93 (br, 2H), 2.18-2.33 (m, 2H), 3.24-3.30 (m, 6H),
3.47-3.53 (m, 2H). 13C NMR (75.5 MHz, CDCl3) δ 13.1,
14.1, 19.1, 23.9, 27.2 (t, J = 22.0 Hz), 57.5, 59.1, (the signals
from the C8F17 group were obscured due to their low intensity).
19F NMR (282.4 MHz, CDCl3) δ -81.4 (t, 3F, J = 9.9 Hz),
-113.8 (br, 2F), -122.1 (s, 6F), -123.2 (s, 2F), -123.4 (s, 2F),
Supporting Information Available: Experimental proce-
dures and copies of NMR spectra and GC-MS and HPLC
chromatograms. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 6401