Metal-free electrophilic fluorination of alkyl trifluoroborates and boronic acids

Article abstract of DOI:10.1016/j.tetlet.2009.04.077

Secondary alkyl trifluoroborates undergo facile electrophilic fluorination under mild conditions to afford the corresponding benzylic fluorinated adducts in excellent yield.

Full text of DOI:10.1016/j.tetlet.2009.04.077

Tetrahedron Letters 50 (2009) 3936–3938
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Tetrahedron Letters
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Metal-free electrophilic fluorination of alkyl trifluoroborates and boronic acids
Clément Cazorla, Estelle Métay, Bruno Andrioletti, Marc Lemaire *
Université de Lyon, UCBL, ICBMS, UMR-CNRS 5246, Campus de la Doua, Bâtiment Curien-CPE, 3° étage, 43, Boulevard du 11 Novembre 1918, 69622 Villeurbanne cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Secondary alkyl trifluoroborates undergo facile electrophilic fluorination under mild conditions to afford
the corresponding benzylic fluorinated adducts in excellent yield.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 6 April 2009
Revised 17 April 2009
Accepted 20 April 2009
Available online 24 April 2009
This work is dedicated to Dr. Bernard
Langlois on the occasion of his 60th birthday
Keywords:
Electrophilic fluorination
Alkyl groups
Boronic derivatives
Metal-free
The number of fluorinated organic molecules reported in the lit-
erature drastically increased over the past decades.1 This infatua-
tion is motivated by the fact that the introduction of fluorine
ative stability of the trifluoroborate moiety tolerates valuable
8
N
chemical transformations such as reductive amination or S 2 ha-
9
lide substitution of potassium bromomethyltrifluoroborate. On
the other hand, the trifluoroborate functionality constitutes an
excellent partner for Suzuki–Miyaura type cross-couplings giving
access to a large range of elaborated molecules.
2
atoms generally enhances the lipophilicity —hence the bioavail-
ability—of the molecule, and limits its degradation as the C–F bond
is more stable than the almost isosteric C–H bond (480 vs
À1
3
4
10 kJ mol ). Consequently, much effort is currently dedicated
Yet, boron derivatives have been scarcely considered as suitable
candidates for electrophilic substitution. Thus, Kabalka et al. re-
ported that alkyl, alkenyl, or alkynyl organotrifluoroborates
smoothly react with sodium iodide or bromide in the presence of
chloramines T to afford the corresponding iodinated or brominated
to the development of new synthetic methods for the selective
introduction of fluorine atoms. Both electrochemical (Simons pro-
4
cess) and chemical methods were proposed. Due to the difficulty
2
in handling HF or F , synthetic electrophilic or nucleophilic fluori-
1
0
nating reagents were developed. Yet, the selective insertion of a
fluorine atom remains challenging. Herein, we disclose a general-
ization of the electrophilic fluorination of boronic esters or acids
adducts in good yield. On the other hand, this strategy did not ap-
pear successful for the preparation of fluorinated analogues. Con-
versely, Petasis et al. reported that alkenyl trifluoroborates react
5
TM
pioneered by Petasis, Prakash, and Olah in the late 90s. In partic-
with Selectfluor to afford the fluorinated adducts. Surprisingly,
ular, we demonstrate that the electrophilic fluorination works with
aromatic trifluoroborates and boronic acids and more importantly
with alkyl trifluoroborates. To the best of our knowledge, electro-
philic fluorination of alkyl boronates has never been reported to
date.
they limited their study to alkenyl trifluoroborates and they did
not use their methodology for the fluorination of alkyl or aromatic
boron derivatives. In addition, they did not consider boronic acids
as suitable partners as in their hands, the reaction between alkenyl
TM
boronic acid and Selecfluor appeared slow and contaminated
Boronic acids and trifluoroborate salts are generally used as
cross-coupling partners in the Suzuki reaction or for 1,4 rho-
dium-catalyzed addition reaction. Recently Molander and Genet
reported that organotrifluoroborate salts constitute a versatile,
new class of reagents particularly suitable for the elaboration of
highly functionalized molecules. Indeed, on the one hand, the rel-
with variable amounts of reduced compound.
In this Letter, we report that the electrophilic fluorination is
much more general than the reaction reported earlier, and actu-
ally constitutes a reliable alternative route for the introduction
of fluorine atoms at key positions. In particular, we demonstrate
that this strategy can be applied for the smooth and efficient
preparation of fluorinated alkyl derivatives via the metal-free
electrophilic fluorination of the boronic acid or trifluoroborate
precursors.
6
7
*
Corresponding author.
E-mail address: marc.lemaire@univ-lyon1.fr (M. Lemaire).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.077

C. Cazorla et al. / Tetrahedron Letters 50 (2009) 3936–3938
3937
During the course of our study, we became interested in devel-
Table 1
Fluorination of boronic derivatives
oping a suitable method for the selective introduction of electro-
philes on aromatic and alkyl boron derivatives. To this end, we
first extended the scope of the methodology first developed by
Petasis et al. to vinyl trifluoroborates for the functionalization of
aromatic boron derivatives and—more interestingly—of secondary
alkyl boronates that were recently proven very valuable intermedi-
Entry
1a
Substrate
Product
Conversion
90%
B(OH)2
F
F
1
1
ate for the elaboration of functionalized chiral molecules.
Accordingly, we envisioned reacting stoichiometric amounts of
BF3K
TM
Selecfluor with aromatic boronic acids or trifluoroborates in dry
2a
79% (+21% naphtalene)
acetonitrile at room temperature (Scheme 1).12
As low molecular weight fluorinated aromatics are known to be
extremely volatile, we started with naphthyl boronic acid (Table 1,
entry 1). Interestingly, a GC analysis revealed that the conversion
into the expected fluorinated naphthalene reached 90%. When
the reaction was repeated using the trifluoroborate derivative (Ta-
ble 1, entry 2), the results were slightly lower, as the expected 1-
fluoronaphthalene was present in 79% yield, along with 21% of
naphthalene. In order to test the versatility of our method, we also
applied the strategy to the preparation of 4-tert-butylfluoroben-
3a
4a
tBu
tBu
tBu
75% (+12% BuPh)
t
B(OH)2
F
F
t
BF K
tBu
F
53% (+47% BuPh)
3
B(OH)2
5a
100%
TM
zene. As expected, Selectfluor efficiently converted the corre-
BnO
BnO
OBn
sponding boronic of trifluoroborate derivatives into the
fluorinated species in 75% and 53% yield, respectively (Table 1, en-
tries 3 and 4). In this case, it is worth noting that the boronic acid
affords the expected compound in a slightly higher yield than the
boronate salts. Indeed, in the latter case, 47% of tert-butylbenzene
was also isolated. Interestingly, this result confirms that the pres-
ence of electron donating groups (Table 1, entries 1–4) enhances
the electronic density on the boron atom that undergoes elimina-
tion rather than substitution. This observation constitutes an
exception to the sequence of reactivity observed so far by us and
others. To validate our hypothesis, we investigated the electro-
philic substitution on a series of benzyloxyphenylboronic acids.
Thus, we reacted ortho, meta, and para substituted (benzyl-
F
6a
67% (+33% BnOPh)
OBn
B(OH)2
F
7a
—
BnO
B(OH)2
OBn
F
8a
BF K
3
91%
TM
oxy)phenylboronic acids with selectfluor . As expected, the less
hindered para-substituted phenylboronic acid was the most reac-
tive coupling partner affording quantitatively the expected fluori-
nated adduct (Table 1, entry 5). The ortho-substituted isomer
was also converted into the substituted fluorobenzene in decent
yield (Table 1, entry 6). On the other hand, 3-(benzyloxy)phenylbo-
ronic acid did not react at all (Table 1, entry 7). These results high-
light the crucial influence of the electron density on the outcomes
of the reaction. This behavior was also confirmed by testing the
electrophilic fluorination of nitro-substituted electron-poor boron
derivatives. In the latter case, very little conversion was observed
and the palladium-mediated fluorination reported by Ritter et al.
remains the most appropriate method for the selective
a
Conditions: MeCN, 0.5 M, room temperature, 24 h.
1
BF K
F
3
MeCN, rt, 24 h
2
Scheme 2. Electrophilic fluorination of alkyl boronates.
1
3
fluorination.
Based on these promising preliminary tests, we then considered
the electrophilic fluorination of alkyl trifluoroborates that are ex-
pected to be more reactive than their boronic acid analogues
and 75% isolated yield.14 However, in the case of 2-phenylethyltri-
fluoroborate, a complete racemization was observed. Indeed, start-
ing from enantio-enriched or racemic mixture afforded 1-(1-
fluoroethyl)benzene as a racemic mixture.
(Scheme 2).
To the best of our knowledge such a transformation had never
been reported before in the literature as alkyl boronic acids or tri-
fluoroborates are generally considered as very poor coupling part-
In summary, we have demonstrated that in the case of electron-
rich systems, the electrophilic fluorination constitutes a competi-
tive method for the introduction of fluorine atoms at key positions.
More interestingly, this methodology was also proved powerful for
the introduction of fluorine atom at benzylic positions starting
from the readily available 1-phenylethyltrifluoroborate. Work is
currently in progress for elucidating the mechanism and for deter-
mining the factors that govern the reaction.
ners. Interestingly, reacting
Selectfluor with 1-phenylethyltrifluoroborate (Table 1, entry 8)
a
stoichiometric amount of
TM
afforded the expected fluorinated adduct 2 in 91% conversion,
ArB(OH)
or
N
Cl
,
2
ArF
+
2BF4-
N
MeCN, rt, 24 h
Acknowledgment
ArBF K
F
3
1
C.C. thanks the French Ministry for teaching and research
(MESR) for financial support.
Scheme 1. Access to the fluorinated aromatic compounds.

3
938
C. Cazorla et al. / Tetrahedron Letters 50 (2009) 3936–3938
Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031–2034.
9.
References and notes
1
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Jeschke, P. Chem. Bio. Chem. 2004, 5, 570–589.
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1
2. Typical experimental procedure: a solution of boronic acid (4 mmol, 1 equiv) and
TM
selectfluor (4 mmol, 1 equiv) in dry acetonitrile (20 mL) was stirred at room
temperature under argon for 24 h. The reaction mixture was poured in 250 mL
of water and extracted with pentane. The combined organic layers were
1
949, 95, 47–52; (c) Bardin, V. V.; Yagupolskii, Y. L. New Fluorinating Agents in
Organic Synthesis; Springer: Berlin, Heidelberg, 1989; (d) Lal, G. S.; Pez, G. P.;
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3 4
washed with a saturated aqueous solution of NaHCO and dried over MgSO .
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purified over silica gel chromatography to yield the expected pure product.
2
005, 34, 1031–1037.
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997, 606–608.
5
.
.
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1
2
1
4. Data for 1-(1-fluoroethyl)benzene): isolated yield: 75%; H NMR (CDCl
3
): d
= 47.66 Hz,
= 76 Hz), 91.1 (d,
6
(a) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286; (b) Hayashi, T.
Synlett 2001, 879–887; (c) Sörgel, S.; Tokunaga, N.; Sasaki, K.; Okamoto, K.;
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ppm) 1.53 (dd, J3 = 6.4 Hz, J
= 23.92 Hz, 3H), 5.52 (qd, J3 = 6.4 Hz, J
): d (ppm) 23.0 (d, J
(
1
F
F
13
H), 7.24 (m, 5H); C NMR (CDCl
3
F
J = 168 Hz), 125.3 (d, J = 20 Hz), 128.3 (d, J = 6 Hz), 128.6, 141.7 (d, J = 57 Hz);
7
8
.
.
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19
F NMR (CD
2
2
Cl ): d (ppm) À167.4.
2
057.