Preparation of organotrifluoroborate salts: Precipitation-driven equilibrium under non-etching conditions

Article abstract of DOI:10.1002/anie.201203930

Simple, rapid, and scaleable: In contrast to current procedures using corrosive HF/MF or MHF₂ reagents (M=e.g. K), a wide range of trifluoroborates can be rapidly, simply, and safely prepared from MF (M=K, Cs), RCO₂H, and a boronic a

Full text of DOI:10.1002/anie.201203930

Angewandte
Chemie
DOI: 10.1002/anie.201203930
Synthetic Methods
Preparation of Organotrifluoroborate Salts: Precipitation-Driven
Equilibrium under Non-Etching Conditions**
Alastair J. J. Lennox and Guy C. Lloyd-Jones*
Dedicated to Professor Stefan Toma on the occasion of his 75th birthday
Although potassium organotrifluoroborates (RBF3K) were
first explored in the 1960s,[1] it was not until the mid 1990s that
the utility of these air-, moisture-, and thermally stable, free-
flowing crystalline solids began to be more fully appreci-
ated.[2,3] They have now become extremely popular reagents
in synthesis, with three major areas of application: 1) as
precursors to difluoroboranes[2a,d–g] for allylation,[2d,4] boronic
Mannich reactions,[5] and ether couplings;[6] 2) as readily
handled boron intermediates, thus facilitating distal func-
tional-group manipulation,[7] pinacol boronate cleavage,[8]
and halo,[9] oxidative,[10] or nitrosative[11] deboronations; and
3) in metal-catalyzed coupling reactions, such as copper-
catalyzed etherification[12] and rhodium-catalyzed additions
to aldehydes,[13] imines,[14] and enones,[15] as well as palladium-
catalyzed Suzuki–Miyaura reactions.[16] The latter has become
an area of intense activity,[3,16] with organotrifluoroborates
proving to be versatile and reliable reagents for a wide range
of direct or indirect[17] couplings.
Soxhlet extraction. Herein we report a new and operationally
simple method for RBF3M preparation (M = for example, K,
Cs) that can be routinely conducted in regular glassware by
employing readily handled reagents. It has been applied to
a wide range of boronic acids and pinacol boronates, allows
facile isolation of the trifluoroborate, and is readily scaled.
In their pioneering study on the generation of RBF3K
reagents, Vedejs et al. found that whilst KHF2 in MeOH
smoothly converted boronic acids (1) into potassium organo-
trifluoroborates (2), the much more readily handled KF did
not.[2a] We began with an in situ 19F NMR analysis of this latter
process, thus reacting the fluorine-bearing aryl boronic acid
p-FC6H4B(OH)2 (1a) with 4 equivalents of KF. This study
confirmed that whilst equilibrium with intermediates 3a/4a[24]
(see Scheme 1 for structures) is rapidly established, the
generation of the p-FC6H4BF3K species 2a could not be
detected (< 2%).
To consume the KOH that is formally liberated by HOÀ
displacement with FÀ, and to catalyze the equilibration,[17b,25]
we tested the effect of addition of mild organic acids (HA;
Scheme 1). Simple carboxylic acids were found to drive the
Despite this diverse repertoire, there are only two general
À
routes to RBF3K reagents: C B bond formation by reaction
[18]
of R-SnMe3 with BF3/KF[1] and B F bond formation by
À
reaction of R-B(OR’)2 with HF/KOH,[19] or with KHF2.[2a,20]
The latter procedure was introduced by Vedejs et al. and
involves addition of excess aqueous KHF2 to the parent
boronic acid (R’ = H) or ester (R’ = alkyl) in methanol.[2a]
This procedure was extended by Genet and co-workers to
boronates generated in situ from RMgX or RLi,[2b,c] and has
become the standard method for potassium organotrifluoro-
borate preparation. Its generality and reliability has engen-
dered their remarkably diverse application not only in
synthesis, but also ranging, for example, from carriers for
18F PET imaging[21] through to precursors for ionic liquids.[22]
However, although KHF2 is safer to handle than HF or BF3, it
is nonetheless corrosive, thus causing extensive etching of
glassware.[23] Moreover, the procedure usually requires sep-
aration of the RBF3K product from the mixture of salts
remaining after evaporation and sometimes necessitates
Scheme 1. Equilibrium between the boronic acid 1a (Ar=p-FC6H4) and
KF with the mixed species 3a/4a in either MeOH or MeCN as
monitored by 19F NMR spectroscopy. The second equation shows the
potential for acid (HA) to drive the generation of the trifluoroborate
2a.
equilibrium in the desired direction, however a large excess
was required to effect a greater than 99% conversion into 2a.
Replacing MeOH with diethyl ether led to co-precipitation of
2a with other potassium salts (KF/RCO2K etc.), thus making
isolation of pure 2a nonfacile. Switching to MeCN kept
trifluoroborate 2a in solution, but an excess of carboxylic acid
(e.g. acetic or ortho-iodobenzoic acid) was still required
(Scheme 2).
We thus sought an acid that could be used stoichiometri-
cally, rather than in excess, and that also allowed facile
isolation of the pure trifluoroborate 2a. l-(+)-Tartaric acid
(5) was found to fit these criteria well: it is a cheap and readily
handled solid, and the monopotassium salt (potassium
[*] A. J. J. Lennox, Prof. Dr. G. C. Lloyd-Jones
School of Chemistry, University of Bristol, Cantock’s Close
Bristol, BS81TS (UK)
E-mail: guy.lloyd-jones@bris.ac.uk
[**] We thank AstraZeneca PR&D (Dr. M. Kenworthy, Dr. P. M. Murray,
Dr. M. Butters) for funding and Thomas Hornsby and Thomas
Carter (Bristol Synthesis DTC) for preliminary studies. G.C.L.-J. is
a Royal Society Wolfson Research Merit Award Holder.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203930.
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Table 1: Potassium trifluoroborate 2a–u preparation by bitartrate pre-
cipitation.
Entry
R
Yield [%][a]
1
2
4-FC6H4 (1a)
C6H5 (1b)
96[b] (2a)
90 (2b)
3
4
5
6
4-MeC6H4 (1c)
4-MeOC6H4 (1d)
4-tBuC6H4 (1e)
E-b-styryl (1 f)
89 (2c)
84 (2d)
98 (2e)
90 (2 f)
Scheme 2. Number of equivalents of acetic (pKa 4.8), ortho-iodoben-
zoic (pKa 2.9), and l-(+)-tartaric acid (5, pKa 3.0) acids required for
a greater than 99% conversion of 1a into 2a.
7
8
9
4-MeCOC6H4 (1g)
4-CNC6H4 (1h)
4-NO2C6H4 (1i)
1-naphthyl (1j)
3-NO2C6H4 (1k)
3-MeCOC6H4 (1l)
3-ClC6H4 (1m)
3,5-(CF3)2C6H3 (1n)
2,6-F2C6H3 (1o)
3-NH2C6H4 (1p)
cyclopropyl (1q)
cyclobutyl (1r)
57 (2g)
88 (2h)
78 (2i)
10
11
12
13
14
15
16
17
18
19
20
21
96 (99)[c] (2j)
87[d] (2k)
82 (95)[c] (2l)
93 (2m)
96[d] (2n)
78 (2o)
bitartrate, “cream of tartar”) is of very low solubility in most
organic solvents. By using just a stoichiometric amount of 5,
added as a THF solution, the precipitation of bitartrate
(RCO2K; Scheme 2) rapidly drives complete conversion of 1a
into 2a.
76 (2p)
Potassium bitartrate tends to precipitate as a metastable
suspension, thus making filtration problematic and leading us
to screen a wide range of inorganic salts and additives to find
a suitable flocculating agent. Ultimately, a small quantity of
water (conveniently added as aqueous KF, ca. 10m) was found
to readily effect flocculation, thus allowing rapid filtration. A
slight excess of l-(+)-tartaric acid (2.05 equiv) reliably
accommodated variations in stoichiometry arising from
anhydrides (boroxines) and boric acid in commercial samples
of boronic acids.[26] As residual KF and water, as well as any
traces of in situ generated KHF2 co-flocculate with the
potassium bitartrate, the product isolation simply involves
filtration and then evaporation[27] to directly obtain the
RBF3K reagent 2 in high yield and analytically pure form
(19F/11B/1H NMR spectroscopy, elemental analysis).[26,28] With
these reaction conditions in hand, a range of aromatic, vinylic,
allylic, and alkyl boronic acids were smoothly converted into
the corresponding trifluoroborates (2a–u; 1 mmol scale;
Table 1) using commercial grade solvents under air.
Upon scale-up, the KF/l-(+)-tartaric acid process was
equally efficient and easy to conduct, thus generating, for
example, 4.2 g (99%) of 1j and 3.9 g (95%) of 1l (Table 1,
entries 10 and 12). Of note is the rapid and simple procedure
for product isolation, thus contrasting the extensive extrac-
tion processes which can be required with the classic KHF2
method.[29] In addition, the HF2À anion can result in extensive
etching of glassware,[23] with most reports advocating use of
PTFE or polyethylene vessels. In stark contrast, there was no
evidence for either etching or the solution-phase HF2À anion
(19F NMR soectroscopy) with the KF/l-(+)-tartaric acid
procedure. To further test this, 2a (0.75 mmol) was prepared
by each method using two new 25 mL glass round bottomed
flasks, and the procedures were repeated several times using
the same flask for each method. With the KHF2 method,
cumulative etching soon led to the entire flask becoming
opaque.[23] In contrast, with the KF/l-(+)-tartaric acid proce-
dure, even after 30 sequential preparations (average yield
70[d] (2q)
57[d] (2r)
85[d,e] (2s)
90 (2t)
2-F-3-pyridyl (1s)
N-Boc-5-Br-2-indolyl (1t)
3-quinolinyl (1u)
69[d,e,f] (2u)
[a] Yield of isolated and analytically pure RBF3K;[28] see the Supporting
Information for full details. [b] Average of 30 runs. [c] Value within
parentheses is for an 18-fold scale-up; [d] Used 4.5 equiv KF and
2.5 equiv 5. [e] Used MeCN/MeOH (1:1) as the solvent. [f] The crude
product obtained after evaporation, predominantly the K salt, was
refined with K2CO3/acetone to give 2u (69%).
96%), no trace of etching could be detected (see the
Supporting Information).
We next explored whether pinacol boronates (6) undergo
analogous transformations. These species are of considerable
utility in synthesis, but are often converted with KHF2 into the
corresponding trifluoroborate to aid hydrolysis or isolation.[8]
A slight modification of solvent was required with the KF/
l-(+)-tartaric acid methodology as, unlike boronic acids
(Scheme 1), the pinacol boronate does not substantially pre-
complex[30] the KF (19F NMR spectroscopy) in MeCN,
thereby resulting in incomplete conversion of 6 into 2
before the onset of bitartrate flocculation. Reaction in
MeCN/MeOH (1:1) negated this problem, thus giving
RBF3K products in good yield and high purity
(Scheme 3).[28,31] We also briefly tested whether boronates
prepared in situ[2b,c] from organolithium[32] species can be
converted into trifluoroborates using KF/5. Sequential addi-
tion of 1.0 equivalent of BuLi, 1.01 equivalents of B(OMe)3,
5.0 equivalents of KF, and then 3.05 equivalents of 5 to phenyl
acetylene gave the alkynyl trifluoroborate in comparable
yield to that obtained with the KHF2 procedure (see the
Supporting Information).
Finally, we note that the solubility and stability of the
organotrifluoroborate salts can be tuned by variation of the
2
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(96 MHz, [D6]DMSO): d = 2.2 (br);[7a] 19F NMR (283 MHz,
[D6]DMSO): d = À139.3 (br). See the Supporting Information for
full details.
Received: May 21, 2012
Published online: && &&, &&&&
Keywords: boron · fluorine · synthetic methods · tartaric acid ·
trifluoroborates
Scheme 3. Reaction conditions: a) KF (10m aq.; 4 equiv) MeCN/
MeOH (1:1), 218C, 1 min; b) l-(+)-tartaric acid (5, 2.05 equiv, THF)
2–5 min; c) filter, evaporate, remove pinacol (6 mmHg, gentle heating,
15 min).[8b,31]
.
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conveniently prepared by using the reaction conditions shown
in Table 1, but replacing KF with CsF (Scheme 4); previous
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Scheme 4. Reaction conditions: a) CsF (10m aq.; 4 equiv), MeCN,
218C, 1 min; b) 5 (2.05 equiv, THF) 1-5 min; c) dilute with MeCN,
filter, evaporate. For 6a, MeCN/MeOH (9:1) employed.
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In summary, we have developed a new procedure for the
preparation of potassium organotrifluoroborate salts in good
yield and high purity by pre-equilibration of the boronic acid
or boronate with KFand then addition of a mild acid. By using
l-(+)-tartaric acid (5) the process is efficiently driven to
completion by precipitation of potassium bitartrate, thus
making product isolation very simple.[34–36] It is effective for
a wide range of boronic acids and pinacol boronates, including
aliphatic, vinylic, and allylic systems, as well as electron-poor
and electron-rich aryl rings. The method can also be
effectively applied for the preparation of RBF3Cs reagents.
Compared to current methodologies involving HF or MHF2,
the reaction conditions are very mild, thus allowing the use of
regular glassware, as there is no etching, and a simple and safe
scale-up.[27] In addition, the low solubility of K+ and Cs+
bitartrate salts suggests considerable potential for application
of l-(+)-tartaric acid (5) as an alkali-metal sponge in other
processes, for example by reaction of MF with 5 to release
HF/MHF2 in situ for silyl deprotection.
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Experimental Section
Preparation of potassium 3-acetylphenyltrifluoroborate (2l; Table 1,
entry 12): a solution of KF (4 equiv, 72 mmol, 4.18 g) in H2O[34]
(7.2 mL) was added to a suspension of the boronic acid 1l (2.95 g,
18 mmol) in MeCN (72 mL), and the mixture was stirred until
complete dissolution (1 min). l-(+)-Tartaric acid (5, 2.05 equiv,
37 mmol, 5.54 g in 27 mL THF) was added dropwise to the rapidly
stirring biphasic solution over a period of approximately 5 min,
during which a white precipitate formed and rapidly flocculated. The
mixture was filtered, washed through with more MeCN, and the
filtrate was concentrated in vacuo to give 2l (3.86 g, 95%). 11B NMR
[11] G. A. Molander, L. N. Cavalcanti, J. Org. Chem. 2012, 77, 4402 –
4413.
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(typically 0–0.7%) in the product 2 and is also present in
commercial samples and reference samples prepared using
KHF2. Prior recrystallization of 1 from water, affords 2 in
higher yield and purity.
[27] For scale-up, filtration after flocculation then addition of an anti-
solvent, for example, Et2O, allows isolation of 2 after a second
filtration.
[28] Elemental analysis of the RBF3K reagent obtained directly from
evaporation was indicative of comparable or higher purity to
commercial samples, and to reference materials prepared using
the KHF2 procedure (see the Supporting Information). If
required, further purification can be effected by crystallisation
from MeCN/Et2O.
[29] See for example: G. A. Molander, S. L. J. Trice, S. D. Dreher, J.
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[31] Pinacol can be separated by evaporation[8b] or by a MeOH/H2O
azeotrope.[8c] The latter works well with the procedure by Vedejs
et al. (albeit with much bumping during evaporation) as KHF2 in
the residue supresses net regeneration of the pinacolate by
solvolysis. With the KF/l-(+)-tartaric acid procedure, removal of
the pinacol is best achieved under nonsolvolytic[17b] conditions
(6 mmHg/D), thus leaving pure RBF3K as the residue. Pinacol
evaporates more readily from pure RBF3K, than when excess
KF/KHF2 is present.[8c]
[32] The presence of magnesium salts, from analogous reactions of
RMgX species with borates (conditions from Ref. [2b]), led to
a 0% yield of isolated RBF3K using the KF/5 methodology.
Instead, the crude product should be isolated as the pinacol
boronate before conversion into RBF3K by using the reaction
conditions outlined in Scheme 3.
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[34] A reviewer who tested the procedure (3 examples; unspecified,
all successful) noted that a reduction in the amount of water
facilitated more efficient solvent evaporation and drying,
especially on scale-up. We note that a balance must be struck
between efficiency of filtrate evaporation versus the efficacy of
bitartrate flocculation; this latter issue is dependent on the
identity of the trifluoroborate being prepared.
[35] For RB(OH)2/RBF3K systems of low solubility, for example,
some heterocyclic systems, we recommend the use of MeOH/
MeCN (1:1) rather than pure MeCN. After addition of tartaric
acid the reaction mixture should then be diluted with an equal
volume of MeCN. See the Supporting Information for full
details. e.g. for preparation of 2s.
[36] For basic substrates, there is the possibility of generation of the
internal salt (J. Raushel, D. L. Sandrock, K. V. Josyula, D.
Packyz, G. A. Molander, J. Org. Chem. 2011, 76, 2762 – 2769).
The aniline 2p and pyridine 2s gave pure potassium salts
(elemental analysis), however, the crude quinoline 2u was
slightly deficient in potassium (elemental analysis). Stirring an
acetone solution of the crude 2u over K2CO3 gave the pure
potassium salt (69%) after filtration/evaporation.
[23] In the procedure reported by Vedejs et al., aqueous KHF2 and
the residue obtained after concentration of the reaction mixture
(prior to extraction of RBF3K), are both substantially more
corrosive towards the glassware than the reaction mixture itself.
Whilst KF/l-(+)-tartaric acid can generate KHF2, this is
transient/low in concentration and removed by co-precipitation
with the bitartrate.
[24] Intermediates 3a/4a have also been observed in basic aq. THF:
a) M. Butters, J. N. Harvey, J. Jover, A. J. J. Lennox, G. C. Lloyd-
Jones, P. M. Murray, Angew. Chem. 2010, 122, 5282 – 5286;
Angew. Chem. Int. Ed. 2010, 49, 5156 – 5160; and on reaction of
1a with nBu4NF in DMF: b) C. Amatore, A. Jutand, G. Le Duc,
Angew. Chem. 2012, 124, 1408 – 1411; Angew. Chem. Int. Ed.
2012, 51, 1379 – 1382.
[25] V. V. Bardin, S. G. Idemskaya, H.-J. Frohn, Z. Anorg. Allg.
Chem. 2002, 628, 883 – 890.
[26] B(OH)3 present in, or derived from 1 is converted into KBF4.
Thus KBF4 is generally detected as a minor contaminant
4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
Simple, rapid, and scaleable: In contrast
to current procedures using corrosive
HF/MF or MHF2 reagents (M=e.g. K),
a wide range of trifluoroborates can be
rapidly, simply, and safely prepared from
MF (M=K, Cs), RCO2H, and a boronic
acid/ester in regular glassware (see
figure; left versus right). The use of l-
(+)-tartaric acid as an alkali-metal
sponge is key and allows isolation of
RBF3M by a simple stir/filter/evaporate
sequence.
A. J. J. Lennox,
G. C. Lloyd-Jones*
&&&& — &&&&
Preparation of Organotrifluoroborate
Salts: Precipitation-Driven Equilibrium
under Non-Etching Conditions
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
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