Tetrabutylammonium tetra(tert-butyl alcohol)-coordinated fluoride as a facile fluoride source

Article abstract of DOI:10.1002/anie.200803150

(Figure Presented) F^- on: The title compound TBAF(tBuOH) ₄ can act as a highly effective fluoride source for nucleophilic fluorination thanks to its favorable properties, such as a stable structure (in which the fluoride ion is surrounded by four bulky nonpolar protic alcohol molecules), a dehydrated state, low hygroscopicity, good solubility in organic solvents, good nucleophilicity, and low basicity.

Full text of DOI:10.1002/anie.200803150

Communications
DOI: 10.1002/anie.200803150
Fluoride Sources
Tetrabutylammonium Tetra(tert-Butyl Alcohol)-Coordinated Fluoride
as a Facile Fluoride Source**
Dong Wook Kim,* Hwan-Jeong Jeong, Seok Tae Lim, and Myung-Hee Sohn
The generally favorable pharmaceutical properties of many
organic solvents; 3) a dehydrated state for anhydrous reaction
conditions; and 4) low hygroscopicity for easy handling.
Herein, we introduce tetrabutylammonium tetra(tert-butyl
alcohol) coordinated fluoride, TBAF(tBuOH)4 (1), as a
promising new fluoride source that meets the above require-
ments for nucleophilic fluorinations.
1
8
low fluorinated compounds and F-labeled radiopharma-
ceuticals for positron emission tomography (PET) molecular
imaging studies have made the incorporation of fluorine
[
1]
atoms into organic molecules increasingly important. Nucle-
ophilic substitution is the method typically used to introduce a
[2]
fluorine atom at a specific molecular site, and numerous
phase-transfer-type protocols and reagents for this reaction
TBAF(tBuOH) was prepared simply by using the proce-
4
dure shown in Scheme 1. Commercially available TBAF
[2–4]
have been developed over the past several decades.
Among the various reagents used, tetraalkylammonium
fluorides, which are represented by tetrabutylammonium
fluoride (TBAF), are used most widely for nucleophilic
fluorination on account of their good solubility and nucleo-
Scheme 1. Preparation of tetrabutylammonium tetra(tert-butyl alcohol)
coordinated fluoride.
[
2]
philicity in organic solvents. However, their hygroscopic
character makes them available only in the form of a hydrate.
Hydroxide typically competes with fluoride, leading to
[
5]
hydroxylations to form alcohols as a side reaction. To
solve this problem, some protocols of “anhydrous” TBAF
hydrate was heated in tBuOH/hexane to 908C for 30 min, and
recrystallized at room temperature to afford TBAF(tBuOH)4
as an anhydrous, white, crystalline solid in 92% yield. The
structure of TBAF(tBuOH)4 was characterized by X-ray
crystallography (Figure 1). Its X-ray crystal structure shows
[6]
(
TBAFanh), generated by heating under a dynamic vacuum
or prepared directly through the S Ar reaction of hexafluor-
N
obenzene using tetrabutylammonium cyanide (TBACN) in
[
7]
polar aprotic solvent, have been reported. However,
although reactions using “naked” fluoride from TBAFanh as
a good nucleophile are very fast at room temperature or
below, these reaction systems are generally strongly basic.
This restricts their synthetic utility because of the possibility
of side reactions, such as elimination of alkyl halide or
sulfonates to form alkenes. In addition, these materials are
difficult to handle and maintain their dehydrated state owing
[
2,5]
to their very high hygroscopicity.
Tetrabutylammonium
triphenyldifluorosilicate (TBAT), which was developed by
DeShong and co-workers, allows anhydrous and less basic
conditions than with TBAF. However, the fluorination
reaction using TBAT requires vigorous reaction conditions
and an excess of TBAT for the reaction to proceed on account
[
5]
of its low reactivity. Therefore, an ideal fluoride source
should have 1) good nucleophilicity with low basicity to
reduce the number of side reactions; 2) good solubility in
[
*] Prof. Dr. D. W. Kim, Dr. H.-J. Jeong, Dr. S. T. Lim, Dr. M.-H. Sohn
Department of Nuclear Medicine, Cyclotron Research Center,
Chonbuk National University School of Medicine
Jeonju, Jeonbuk 561-712 (Korea)
Fax: (+82)63-255-1172
E-mail: kimdw@chonbuk.ac.kr
[**] This study was supported by grant from the Atomic Energy
Technology and Development Program of KOSEF (M20704000037-
08M0400-03711 and M20702000003-08N0200-00310 to D.W.K). We
also thank Prof. John A. Katzenellenbogen for helpful discussions.
Figure 1. Top: X-ray crystal structure of TBAF(tBuOH) (1). Bottom:
4
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803150.
Demonstration of the hygroscopicity of TBAF(tBuOH) and commer-
cially available TBAF.
4
8404
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Angew. Chem. Int. Ed. 2008, 47, 8404 –8406

Angewandte
Chemie
four tBuOH molecules coordinated around a single fluoride
ion through hydrogen bonds each 1.83 ꢀ long. This result
provides further evidence that a “flexible” fluoride source is
generated in the fluorination system using an alkali metal
Table 1: Fluorination of mesylate 2 with TBAF(tBuOH)
alternative reagent.
4
or the stated
[
a]
[
8]
fluoride catalyzed by a nonpolar protic alcohol. Figure 1
À
[b]
shows that TBAF(tBuOH) is significantly less hygroscopic
Entry
F
source
Solvent
Yield [%]
4
than TBAF, which is expected to provide easy handling and
anhydrous conditions maintained during the reaction process.
The stability of the tetra(tert-butyl alcohol) coordinated
fluoride structure in solution was shown indirectly by carrying
(2 equiv)
2
3a
3b 3c
3d
[c]
1
2
3
4
5
6
7
TBAF(tBuOH)4 CH CN
TBAF(tBuOH)4 DMF
TBAF(tBuOH)
TBAF
TBAF
–
–
–
–
–
–
99 (98)
99 (97)
98
93 (92)
94 (92)
94
–
–
–
5
3
3
<0.5
<0.5
–
–
–
2
2
–
3
[
c]
out a desilylation reaction using TBAF(tBuOH) or TBAF in
4
tBuOH
2
–
–
2
2
7
–
4
[
c]
c]
CH CN
THF (Figure 2A). The reaction using TBAF(tBuOH) pro-
3
4
[
DMF
tBuOH
TBAF
CsF
tBuOH 68
tBuOH trace 92
95
30
[
d]
8
9
CsF (3 equiv)
KF/[18]crown-6 DMF
–
1
–
–
4
[a] Unless otherwise noted, all reactions were carried out on a 1.0 mmol
scale of mesylate 2 with 2 mmol of fluoride source in 4.0 mL of solvent
1
for 1 h at 708C. [b] Yield determined by H NMR spectroscopy. [c] Yield
of isolated product in parentheses. [d] Reference [8a]; this reaction was
performed at 808C for 6 h.
organic solvents, including tBuOH (Table 1, entries 4–6).
Moreover, TBAF(tBuOH) was proven to be significantly
4
reactive compared with alkali metal fluoride catalyzed by tert-
butyl alcohol or crown ether. In particular, the fluorination
using CsF in tert-butyl alcohol has the drawback that
alkoxylation by the alcohol solvent itself is a another side
reaction, affording 7% of the ether by-product 3c. Therefore,
it is favorable to use TBAF(tBuOH)4 in a polar aprotic
solvent, which forms very little ether by-product in the
fluorination reaction.
Table 2 summarizes the results of fluorination reactions
using TBAF(tBuOH) . To investigate its influence on the
4
reactions, the fluorination was carried out on two model
compounds that have some potential for elimination as a side
reaction when using TBAF(tBuOH) in CH CN. The level of
fluorination was compared with the same reactions using an
anhydrous “naked” fluoride source, such as TBAFanh, gen-
erated in situ, and commercially available TBAF (Table 2,
entries 1–6). The fluorination of 1-(2-mesylethyl)naphthalene
4
3
Figure 2. A) Desilylation using TBAF(tBuOH) or TBAF. B) Reactivity of
4
TBAF(tBuOH) and TBAF in a nucleophilic fluorination reaction. The
4
1
quantity of starting material remaining was determined by H NMR
spectroscopy. R=naphthyl, Ms=methanesulfonyl.
using TBAF(tBuOH) proceeded efficiently and provided the
4
ceeded much more slowly than with TBAF, which means that
the tetra(tBuOH) coordinated fluoride structure can be
maintained in an organic solution at room temperature to
corresponding fluoride in 71% yield and the styrene by-
product in 28% yield (Table 2, entry 1). In contrast, the same
reaction using TBAFanh and TBAF afforded the styrene in
91% and 61% yield, respectively, and the desired fluoro
product in only 9% and 33% yield, respectively. (Table 2,
entries 2 and 3; 5% alcohol was also formed in entry 3). The
use of tBuOH as a solvent to study the tert-butyl alcohol
some extent. Figure 2B shows that TBAF(tBuOH) could
4
produce a similar reaction rate in the nucleophilic fluorina-
tion reaction at 608C in CH CN to that using TBAF, which
3
means that TBAF(tBuOH) can be a good alternative reagent
4
[
8]
for nucleophilic fluorination.
solvent effect also allowed the fluorination with TBAF-
Table 1 shows the results of the fluorination of mesylate 2
as a model compound using TBAF(tBuOH)4 or other
reagents in various solvents. The fluorination using TBAF-
(tBuOH) to proceed much more selectively compared with
4
the use of a polar aprotic solvent such as CH CN (Table 2,
3
[
9]
entry 4). The second example (Table 2, entries 5–7) with a
bromide substrate showed a similar trend. TBAF(tBuOH)4,
which is an anhydrous fluoride source shielded by tBuOH
molecules (mildly basic “flexible” fluoride), allowed the
fluorination to proceed much more selectively, by reducing
the elimination reaction significantly, than with TBAFanh or
(tBuOH)4 in various organic solvents proceeded almost
quantitatively at 708C in 1 h without forming any alcohol
by-product 3b owing to its anhydrous character (Table 1,
entries 1–3), whereas 3–5% alcohol by-product 3b was
formed in the same fluorination using TBAF in various
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Communications
Table 2: Nucleophilic fluorinations of the various substrates.
hexane (22 mL). The mixture was stirred for 30 min at 908C. During
this time TBAF dissolved completely. The solution was cooled to
room temperature, and a white crystalline solid precipitated. The
crystalline solid was filtered and washed rapidly with 40 mL of 70%
tBuOH/hexane. The filtrate was kept in vacuum for 15–20 min to
[
a]
[b]
Entry Substrate
Method
Yield [%]
product alkene alcohol
[
c]
1
2
3
4
A
B
C
D
71
9
33
88
29
91
61
10
–
–
5
–
remove residual solvent, and TBAF(tBuOH) (1, 1.63 g, 2.92 mmol)
4
1
was obtained as white crystalline solid in 92% yield. H NMR
(600 MHz, CDCl ): d = 1.01 (t, J = 9.0 Hz, 12H), 1.27 (s, 36H), 1.42–
3
1
.48 (m, 8H), 1.66–1.71 (m, 8H), 3.44 ppm (t, J = 9.0 Hz, 8H);
5
6
7
A
B
C
80
22
63
19
78
30
–
–
6
1
3
C NMR (150 MHz, CDCl ): d = 13.6, 19.6, 24.0, 31.1, 58.5, 68.2 ppm.
3
Typical procedure for fluorination (Table 1, entry 1, or Method A
in Table 2): 1 (1.1 g, 2 mmol) was added to a solution of mesylate 2
280 mg, 1.0 mmol) in CH CN (4.0 mL). The mixture was stirred for
(
3
[
d]
d]
8
A
A
A
98
93
–
–
–
–
–
1.0 h at 708C. The residue was dissolved in water (6.0 mL) and
extracted from the aqueous phase with diethyl ether (6.0 mL ꢁ 3). The
organic layer was dried (sodium sulfate) and evaporated under
reduced pressure. The residue was purified by short flash column
chromatography (5% EtOAC/hexane) to give 2-(3-fluoropropoxy)-
[
9
–
1
naphthalene (3a, 200 mg, 98%) as a colorless oil. H NMR (400 MHz,
CDCl ): d = 2.14–2.39 (m, 2H), 4.24 (t, J = 6.2 Hz, 2H), 4.72 (dt, J =
3
46.8, 5.8 Hz, 2H), 7.16–7.22 (m, 2H), 7.34–7.53 (m, 2H), 7.76–
1
3
7.83 ppm (m, 3H); C NMR (100 MHz, CDCl ): d = 30.4 (d, J =
3
2
1
2
0.1 Hz), 63.6 (d, J = 5.3 Hz), 80.8 (d, J = 163.9 Hz), 106.8, 118.8,
1
0
100
23.6, 126.4, 126.7, 127.6, 129.1, 129.4, 134.6, 156.7 ppm; MS (EI) m/z
+
+
04 [M ]; HRMS (EI) m/z calcd for C H FO [M ] 204.0950, found
13 13
[a] Method A: reactions were carried out on a 1.0 mmol scale of substrate with
204.0932.
2
.0 equiv of TBAF(tBuOH) at 708C for 1 h in 4.0 mL of CH CN; B: from the
4
3
protocol of reference [7a]; the reaction was carried out using 0.2 mmol scale
Received: July 1, 2008
Published online: September 29, 2008
of the substrate with 2.0 equiv of TBAFanh generated in situ in CD CN at 258C;
3
C: TBAF was used; D: TBAF(tBuOH)4 in tBuOH. [b] Yield determined by
1
H NMR spectroscopy. [c] Desired fluoro product. [d] Yield of isolated
Keywords: alcohols · fluorination · fluorine ·
product. [e] TBDMS=tert-butyldimethylsilyl, Ts=4-toluenesulfonyl.
.
nucleophilic substitution · tetrabutylammonium fluoride
TBAF. The displacement of a benzylic bromide using TBAF-
[
1] See: a) Special Issue: Fluorine in the Life Sciences in Chem-
BioChem 2004, 5, 557 – 726; b) M. E. Phelps, Proc. Natl. Acad.
Sci. USA 2000, 97, 9226 – 9233.
(
tBuOH) proceeds smoothly with nearly complete conver-
4
sion to the fluoride (Table 2, entry 8). A fluoro-flumazenile,
[
10]
[2] For reviews on nucleophilic fluorination, see: a) M. R. C.
Gerstenberger, A. Haas, Angew. Chem. 1981, 93, 659 – 680;
Angew. Chem. Int. Ed. Engl. 1981, 20, 647 – 667; b) O. A.
Mascaretti, Aldrichimica Acta 1993, 26, 47 – 58.
[3] a) G. W. Gokel, Crown Ethers and Cryptands, Royal Society of
Chemistry, Cambridge, 1991; b) E. V. Dehmlow, S. S. Dehmlow,
Phase Transfer Catalysis, 3rd ed., VCH, Weinheim, 1993.
which can be a molecular probe for PET, was produced in
3% yield by reaction with the corresponding tosylate
9
precursor (Table 2, entry 9). In the final example, the
desilylation reaction at 708C using TBAF(tBuOH)4 pro-
ceeded quantitatively within 30 min (Table 2, entry 10).
In summary, we report tetrabutylammonium tetra(tert-
[
4] a) D. W. Kim, C. E. Song, D. Y. Chi, J. Am. Chem. Soc. 2002, 124,
butyl alcohol) coordinated fluoride, TBAF(tBuOH) , as a
4
1
4
0278 – 10279; b) D. W. Kim, D. Y. Chi, Angew. Chem. 2004, 116,
89 – 491; Angew. Chem. Int. Ed. 2004, 43, 483 – 485.
highly effective nucleophilic fluorination reagent along with
its characteristics. TBAF(tBuOH)4 has various favorable
properties, such as a unique and stable structure surrounded
by four bulky nonpolar protic tert-butyl alcohol molecules (a
[
[
5] A. S. Pilcher, H. L. Ammon, P. DeShong, J. Am. Chem. Soc.
995, 117, 5166 – 5167.
6] D. P. Cox, J. Terpinski, W. Lawrynowicz, J. Org. Chem. 1984, 49,
1
“
flexible” fluoride form), a dehydrated state for anhydrous
3216 – 3219.
reaction conditions, low hygroscopicity, and good nucleophi-
licity with low basicity. These favorable properties not only
suppress the side reactions (hydroxylation, alkoxylation, and
elimination) in the fluorination reaction but also allow easy
handling. Further studies on the development of a more
efficient protocol with an alcohol coordinated fluoride species
[7] a) H. Sun, S. G. DiMagno, J. Am. Chem. Soc. 2005, 127, 2050 –
2
2
051; b) H. Sun, S. G. DiMagno, Angew. Chem. 2006, 118, 2786 –
791; Angew. Chem. Int. Ed. 2006, 45, 2720 – 2725.
[
8] a) D. W. Kim, D. S. Ahn, Y. H. Oh, S. Lee, S. J. Oh, S. J. Lee, J. S.
Kim, J. S. D. H. Moon, D. Y. Chi, J. Am. Chem. Soc. 2006, 128,
16394 – 16397; b) D. W. Kim, H. J. Jeong, S. T. Lim, M. H. Sohn,
J. A. Katzenellenbogen, D. Y. Chi, J. Org. Chem. 2008, 73, 957 –
962.
1
8
and the application of F labeling for radiopharmaceuticals
for PET are currently underway.
[9] For a comparison of TBAF(tBuOH) and TBAF for fluorination
4
in tBuOH, see Table 8S in the Supporting Information.
10] M. Mitterhauser, W. Wadsak, L. Wabnegger, L. K. Mien, S.
Togel, O. Langer, W. Sieghart, H. Viernstein, K. Kletter, R.
Dudczak, Nucl. Med. Biol. 2004, 31, 291 – 295.
[
Experimental Section
Preparation of TBAF(tBuOH) : Commercially available TBAF
4
hydrate (1.0 g, 3.17 mmol) was added to tBuOH (88 mL) and n-
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