Improved method for the conversion of pinacolboronic esters into trifluoroborate salts: facile synthesis of chiral secondary and tertiary trifluoroborates

Article abstract of DOI:10.1016/j.tet.2009.10.002

A general method for the preparation of virtually any potassium trifluoroborate salt from the corresponding pinacolboronic ester is reported. Thus, conditions for an azeotropic removal of pinacol from the reaction mixture were found to afford the desired potassium trifluoroborates of sufficient purity (>95%) in nearly quantitative yields irrespective of the nature of the product. The utility of this method is illustrated by the preparation of a broad range of enantioenriched secondary and tertiary potassium trifluoroborates.

Full text of DOI:10.1016/j.tet.2009.10.002

Tetrahedron 65 (2009) 9956–9960
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Improved method for the conversion of pinacolboronic esters into trifluoroborate
salts: facile synthesis of chiral secondary and tertiary trifluoroborates
*
Viktor Bagutski, Abel Ros, Varinder K. Aggarwal
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method for the preparation of virtually any potassium trifluoroborate salt from the corre-
sponding pinacolboronic ester is reported. Thus, conditions for an azeotropic removal of pinacol from the
reaction mixture were found to afford the desired potassium trifluoroborates of sufficient purity (>95%)
in nearly quantitative yields irrespective of the nature of the product. The utility of this method is il-
lustrated by the preparation of a broad range of enantioenriched secondary and tertiary potassium
trifluoroborates.
Received 21 August 2009
Received in revised form
16 September 2009
Accepted 2 October 2009
Available online 8 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
transformation of the a-branched pinacolboronic esters to the tri-
fluoroborate salts using Vedejs’ protocol and now report a simple
modification which enables the salts to be prepared routinely in
high yield and high purity.
Organotrifluoroborate salts have emerged in recent years as
versatile coupling partners across a broad spectrum of reactions,
often showing not only superior reactivity to their boronic ester
cousins but also superior stability.1 For example, whilst primary
trifluoroborate salts2 and alkyl boronic esters both readily partici-
pate in Suzuki–Miyaura reactions, the secondary alkyl substrates
are limited to the trifluoroborate salts.3 Rhodium-catalyzed 1,2-
and 1,4-additions of organotrifluoroborate salts to aldehydes and
Michael acceptors are also well established reactions.4 Recently,
enantioselective organocatalytic Michael additions of vinyl- and
2. Results and discussion
We recently reported a new method for the preparation of
enantioenriched secondary alcohols and amines11 as well as chiral
tertiary alcohols12 by homologation of boronic pinacol esters with
chiral primary and secondary lithiated carbamates (Scheme 2). The
methodology showed broad substrate scope in terms of the car-
bamates and boronic esters employed.
heteroaryltrifluoroborates to prochiral enals5 and
a-vinylations of
aldehydes with vinyltrifluoroborates6 have been reported. Fur-
thermore, Matteson has reported the first example of the prepa-
ration of chiral secondary trifluoroborates and their conversion into
amines.7 Numerous reports of functional group interconversions in
the presence of a trifluoroborate moiety, which remains intact to
a broad range of reaction conditions, also add significant synthetic
utility to this class of compounds.8 This considerable research ac-
tivity has been facilitated by Vedejs’ simple protocol9 for the
preparation of organotrifluoroborate salts from the corresponding
boronic acids (Scheme 1). Indeed, many salts are now commercially
available.10 However, we encountered a significant problem in the
1) sBuLi, (diamine)
R3
Et2O, –78 °C
R2
Bpin
2) R3Bpin, –78 °C
R2
R1
OCb
OCb
R1
1
R3
Δ
/ LA
R2
R1
Bpin
2
R3
R3
R2
R2
R1
(Ref. 10,11
NHR4
OH
H
10
R–B(OH)2 + 2 KHF2
R–BF3K + KF + 2 H2O
)
(Ref.
)
Scheme 2. Preparation of chiral boronic esters by homologation of boronic esters with
chiral
-lithiated primary and secondary carbamates (for R1–R3 see Table 1).
Scheme 1. Vedejs’ protocol for the preparation of trifluoroborate salts.
a
In order to enhance the utility of this chemistry further we
recognised that transformation of the intermediate boronic esters
into the corresponding trifluoroborate salts would open up new
* Corresponding author. Tel.: þ44 117 954 6315; fax: þ44 117 929 8611.
E-mail address: v.aggarwal@bristol.ac.uk (V.K. Aggarwal).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.002

V. Bagutski et al. / Tetrahedron 65 (2009) 9956–9960
9957
opportunities in synthesis. We therefore decided to first isolate the
boronic esters, which were found to be sufficiently stable to silica
gel for purification. Thus, following the reaction shown in Scheme
2, neutral aqueous work-up (1 M aqueous KH2PO4 was used) and
subsequent ‘dry-column’ flash chromatography13 gave the pina-
colboronic esters in excellent yields, especially for the tertiary
boronic esters 2g–q (Table 1, entries 7–17).
derivatives has been achieved by re-crystallization14 or by distilling
off pinacol under vacuum.15
These literature procedures were initially employed but prob-
lems were invariably encountered. Thus, amongst the boronic es-
ters 2a–r, crystallization of the trifluoroborate salt (acetone/
hexane) worked well for boronic ester 2o, affording the salt 3o in
moderate yield (41%) but this procedure was not general. Hartwig’s
Table 1
Synthesis of
a
-branched boronic esters 2a–r and potassium trifluoroborates 3a–ra
1) s-BuLi, Et2O, –78 °C
2) R3Bpin, –78 °C
4.5
M aq. KHF2,
R3
R3
R2
MeOH, n cycles
3) Δ / (LA)
R2
R2
R1
OCb
Bpin
BF3K
(Method A, B or C)[a]
R1
(Method D or E)[a]
R1
3a-v
2a-r
1a-d,g,k,m,n
Entry
R3Bpin
R3
R2
R3
R2
R1
3a-v
R2
R1
2a-r
R1
1a-d,g,k,m,n
OCb
BF3K
Bpin
R1
R2
R3
Method
Yield % (ee)
Method
Yield % (n)
1
2
3
4
5
6
7
8
a
b
c
d
d
e
f
g
h
i
i
j
k
l
m
n
o
p
p
q
r
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Et
i-Pr
Ph(CH2)2–
Ph(CH2)2–
Ph(CH2)2–
Ph(CH2)2–
Me
Me
Me
Me
Me
Et
Me
Me
Me
Ph
Ph
Ph
Et
Et
i-Pr
Ph
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
C
B
B
B
C
B
63 (94)
75 (92)
67 (92)
87 (94)
87 (94)
64 (96)
91 (94)
77 (99)
93 (90)
89 (96)
89 (96)
92 (99)
90 (n.d.)
78 (97)
83 (99)
91 (96)
79 (99)
70 (99)
70 (99)
76 (96)
65 (98)
D
D
D
D
E
D
D
D
D
D
E
D
D
D
D
D
D
D
E
95 (4)
92 (4)
87 (4)
87 (5)
95 (5)
86 (5)
91 (3)
98 (1)
99 (3)
98 (3)
97 (4)
99 (6)
99 (3)
99 (6)
98 (6)
99 (9)
95 (8)
94 (8)
96 (9)
94 (9)
98 (4)
Et
9
i-Pr
Vinyl
Vinyl
Allyl
Allyl
Bn
10
11
12
13
14
15
16
17
18
19
20
21
4-ClC6H4–
4-MeOC6H4–
Ph
Ph
Et
Et
Me
Me
Me
Me
4-ClC6H4–
4-MeOC6H4–
4-MeOC6H4–
4-ClC6H4–
3-furyl
Ph
4-MeOC6H4–
Ph
D
D
Me
Bpin
22
s
E
96 (3)
N
Cl
Bpin
23
t
E
73 (4)
24
25
u
v
CH2]C]CH–Bpin
Ph–C^C–Bpin
E
E
73 (3)
68 (2)
a
Method A. Primary carbamates (0.2 M in Et2O) were deprotonated with 1.3 M sec-BuLi at ꢁ78 ꢀC in the presence of 1 equiv of (ꢁ)-sparteine over 5 h and reacted with
boronic ester. After formation of ate-complex, 1 equiv of 1 M ethereal solution of MgBr2 was added and the reaction mixture was refluxed for 16 h. Method B. Secondary
benzylic carbamates (0.25 M in Et2O) were deprotonated with 1.3 M sec-BuLi at ꢁ78 ꢀC within 20 min, reacted with an excess of boronic ester. After 30 at ꢁ78 ꢀC, the reaction
mixture was warmed up at room temperature and stirred for 4 h. Method C. Same as Method B except the deprotonation was performed within 5 min in the presence of
1 equiv of TMEDA. Method D. 0.2 M soln of boronic ester was treated at ambient temperature with saturated aq soln of KHF2 (4.5 mmol per 1 mmol of substrate). After solvents
removal, the residue was dissolved in aq MeOH, and the solvents were evaporated again. Dissolution–evaporation cycles were repeated n times. Method E. Method D was
followed, except that 2.2 mmol of KHF2 per 1 mmol of boronic ester was used. For details see Supplementary data and references therein.
In Vedejs’ procedure (Scheme 1), a methanolic solution of
a boron derivative RBY2 (Y¼OH was originally described but other
derivatives have also been used,1b,c e.g., Y¼halogen, –OR or –NR2) is
simply treated with an excess (3–4 equiv) of saturated aqueous
solution of KHF2. After solvents removal and re-crystallization, the
trifluoroborate salt is then isolated in pure form. This procedure has
been applied to a range of alkyl, alkenyl and aryl substrates but
occasionally yields are only moderate, perhaps reflecting problems
in finding suitable solvents for re-crystallization. In the case of the
popularly used pinacolboronic esters purification of simple aryl
procedure15 of removing pinacol by distillation in vacuo worked
well only for 2g (50 ꢀC/0.05 mbar, over P2O5). When we applied
Hartwig’s modification of Vedejs’ protocol to boronic ester 2k, the
crude trifluoroborate 3k remained as an oil even after attempted
continuous removal of pinacol in a Kugelrohr apparatus at 60 ꢀC
and 0.05 mbar. Furthermore, no crystallization of trifluoroborate
salt 3k could be induced even in hexane, in which it seemed sol-
uble! In fact, repeated manipulation of the trifluoroborate salt in
different solvents resulted in partial decomposition of 3k via hy-
drolytic cleavage of the C–B-bond as well as increased amounts of

9958
V. Bagutski et al. / Tetrahedron 65 (2009) 9956–9960
the starting boronic ester (Scheme 3, Eq. 1). Evidently, the pinacol
by-product inhibited formation of the crystalline trifluoroborate
salt and furthermore its presence may cause reformation of the
boronic ester to some extent16 (Scheme 3, Eq. 2).
Having developed an improved and simple procedure for the
synthesis of -branched secondary and tertiary trifluoroborates
a
in nearly quantitative yields, we were encouraged to expand its
scope towards other classes of trifluoroborate salts. Thus, the syn-
thetically useful (2-chloro-3-pyridyl) pinacolboronic ester 1s was
converted into (2-chloro-3-pyridyl)trifluoroborate 3s in excellent
yield (entry 22). We also tested challenging boronic esters that are
prone to decomposition/protodeboronation which included vinyl-,
allenyl- and alkynyl substrates. These were converted into the
corresponding substituted trifluoroborates in good yields (entries
23–25), showing that the new method has broad scope.
OH2
OH
H2O
[KHF]+
R BF2
R
R
BF3K
KF + R BF2
RH + B(OH)3 + KHF2 + HF
(eq. 1)
a
R
H
BF3K +
HO
+ KF
OH
Bpin + 2 KHF2
b
3. Conclusions
In conclusion, we have developed a general method for the
conversion of virtually any pinacolboronic ester into the corre-
sponding potassium trifluoroborate irrespective of its physical na-
ture. With the increasing application of trifluoroborate salts in
synthesis, this improved route to their preparation should facilitate
such developments in the future. Further work in this area is on-
going in our laboratories.
(eq. 2)
b
b
R
O
O
B
– 2 HF
– KF
H
F2
Scheme 3. Rationale for formation–decomposition of trifluoroborate salts.
Clearly, a more effective method for removal of pinacol was
required. After some experimentation, a simple and general solu-
tion for the purification of the trifluoroborate salts was discovered.
It was found that pinacol could form an azeotrope with water under
moderate vacuum, which was sufficiently volatile to be removed
from the reaction mixture using a rotary evaporator. Moreover, the
trifluoroborates displayed excellent stability against proto-
deboronation even upon prolonged/repeated treatment with
a saturated aqueous-methanolic solution of KHF2. Presumably, in
spite of reversibility of the entire process, the equilibrium is shifted
completely towards formation of the trifluoroborate salt due to the
presence of excess of fluoride-anion (Scheme 3, Eq. 2). This feature
is important when numerous repetitions of evaporation cycles are
required. In a typical procedure, to a stirred 0.2 M solution of bo-
ronic ester in methanol an excess of saturated aqueous solution of
KHF2 (4.5 mmol per 1 mmol of substrate) was added and after
stirring at room temperature all of the volatile materials were re-
moved on a rotary evaporator (Tbath 45–50 ꢀC/25–15 mbar). The
solid residue was then re-dissolved in 50% aqueous methanol and
the volatile materials were evaporated again. This step was re-
peated until 1H NMR spectra of the crude mixture displayed less
4. Experimental section17
4.1. General procedure for the preparation of chiral
secondary pinacolboronic esters (GP1A, Method A, Table 1)
To a stirred solution of alkylcarbamate (7.5 mmol) and freshly
distilled (ꢁ)-sparteine (1.76 g, 7.5 mmol) in anhyd Et2O (40 mL)
chilled below ꢁ75 ꢀC (dry ice/acetone bath) was added sec-BuLi
(5.8 mL of 1.3 M solution in cyclohexane/hexane, 92:8, 7.5 mmol) at
such a rate to keep the reaction temperature below ꢁ70 ꢀC (w10–
20 min). The reaction mixture was stirred at ꢁ78 ꢀC for 5 h, and
then the respective boronic ester (5 mmol, dissolved in 10 mL of
anhyd Et2O) was added at such a rate to keep the reaction tem-
perature below ꢁ70 ꢀC (w5–10 min). The reaction mixture was
stirred at this temperature for an additional 30 min, the cooling
bath was then removed, and w0.5 M ethereal solution of MgBr2
(10 mL; prepared prior use from 273 mg of Mg and 650 mL of 1,2-
dibromoethane) was added all at once. The reaction mixture was
stirred under reflux overnight, then cooled to 0–5 ꢀC (ice-water
bath) and 1 M aqueous KHSO4 (20 mL) was added by vigorous
stirring (Caution! Gas evolution!). After stirring at ambient tem-
perature for an additional 10 min, the layers were separated, and
the aqueous one was extracted with Et2O (3ꢂ20 mL). The combined
organic phases were washed with water (25 mL), brine (50 mL) and
dried (MgSO4). A crude product left after solvents removal was
purified by flash chromatography, eluting with PE/EtOAc, 100:1/
50:1 to give the pure secondary boronic ester.
than 1 mol % of pinacol remaining [d (CD3CN) 1.14 ppm]. Finally, the
crude mixture was extracted with acetone followed by filtration
and evaporation to give, after drying in vacuo, the trifluoroborate
salt in high purity. The number of dissolution–evaporation cycles
(n) was found to depend on the physical nature of the product.
Thus, for tertiary dialkylaryltrifluoroborates, three cycles were
enough to ensure almost complete removal of pinacol (Table 1,
entries 9–13; typically, less than 0.5 mol % of pinacol was detected
by 1H NMR spectroscopy). Secondary alkylaryl- or dialkyltri-
fluoroborates required 3–5 cycles (Table 1, entries 1–4, 6 and 7),
whereas 6–9 cycles were necessary to remove pinacol contamina-
tion from tertiary diarylalkyltrifluoroborates. In general, the fol-
lowing trend was observed: if the crude product was already
crystalline, no or few (up to three) dissolution–evaporation cycles
were required for its purification (entries 8–10 and 13), whereas if it
was a waxy syrup, then up to nine cycles were sometimes necessary
(entries 14–18 and 20). Of particular note is that this method was
also effective in the preparation of non-crystalline trifluoroborates
3d, and 3e (Table 1, entries 4 and 6).
4.1.1. (R)-2-(1-Phenylethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(2a). According to GP1A, carbamate 1a (1.82 g, 10.5 mmol) reacted
with phenylboronic acid pinacol ester (1.43 g, 7.0 mmol) to give,
after flash chromatography, 1.02 g (63%) of pure 2a as a colourless
oil. Oxidation of an aliquot of 2a according to GP217 gave the cor-
responding alcohol in 94% ee. HPLC separation conditions: CHIR-
ALCEL OD column, hexane/2-propanol (97.5:2.5), flow rate: 1.0 mL/
min, T 20 ꢀC; tR 14.0 min for (R)-enantiomer (major) and 18.6 min
for (S)-enantiomer (minor). The spectroscopic data have matched
the previously published ones.18
[
a]
ꢁ12.0 (c 1.5, CHCl3).
20
D
We recognised that it would also be desirable to reduce the
stoichiometry of KHF2 if possible since its acidic character might
interfere with basic functional groups. In fact our established
method worked just as well when a slight excess (10%, i.e., 2.2 equiv
instead of 4.5 equiv initially used) of KHF2 was used, affording tri-
fluoroborates 3d,i,p (entries 5, 11 and 19) in similarly high yields.
4.2. General procedure for the preparation of chiral tertiary
pinacolboronic esters (GP1B, Method B, Table 1)
To a stirred solution of a benzylcarbamate (5 mmol) in anhyd
Et2O (20 mL) chilled below ꢁ75 ꢀC (dry ice/acetone bath) was

V. Bagutski et al. / Tetrahedron 65 (2009) 9956–9960
9959
added sec-BuLi (4.3 mL of 1.3 M solution in cyclohexane/hexane,
4.5. General procedure for the preparation of potassium
alkyltrifluoroborates from pinacolboronic esters using
stoichiometric amounts of KHF2 (GP3B, Method E, Table 1)
92:8, 5.6 mmol) at such a rate to keep the reaction temperature
below ꢁ70 ꢀC (w10 min). The reaction mixture was stirred at this
temperature for an additional 15 min, and the respective boronic
ester (6–10 mmol, neat if it is a liquid, or as a 2 M solution in anhyd
Et2O when solid) was added by vigorous stirring at such a rate to
keep the reaction temperature below ꢁ70 ꢀC (w10 min). The re-
action mixture was stirred at this temperature for an additional
30 min, the cooling bath was then removed and stirring was con-
tinued at ambient temperature for 4 h. After work-up with 1 M aq
KH2PO4 (3 mL/mmol of carbamate; see Method A), the crude prod-
uct was purified by ‘dry-column’ flash chromatography,13 eluting
with PE/MTBE, 50:1/30:1 to give the pure tertiary boronic ester.
Method GP3A was followed, except that 0.5 mL of 4.5 M aqueous
KHF2 per 1 mmol of boronic ester was used (2.25 equiv, 1.1-fold
excess).
4.5.1. Potassium (R)-1-phenylethyltrifluoroborate (3a). According to
GP3A, boronic ester 2a (3.9 mmol, 900 mg) was subjected to four
evaporation cycles to afford 780 mg (95%) of pure 3a as a colourless
solid. 1H NMR (CD3CN, 400 MHz):
d 7.15–7.11 (m, 4H), 7.99–6.95 (m,
1H), 1.73 (m, 1H), 1.13 (d, J¼7.3 Hz, 3H) ppm; 13C NMR (CD3CN,
100 MHz)
96.2 MHz):
d
153.0, 128.7, 128.3, 123.9, 17.3 ppm; 11B NMR (CD3CN,
4.3. GP1C (Method C, Table 1)
d
3.7 (br s) ppm; 19F NMR (CD3CN, 283 MHz):
d
ꢁ145.8
(br s) ppm; IR (neat) nu(tilde) 2966, 2878, 1609, 1491, 1220, 956,
GP1B was followed, except that the deprotonation of a carba-
mate was performed in the presence of 1.1 equiv of TMEDA within
5 min.
915 cmꢁ1; HRMS (ESI) calcd for C8H9BF3 [MꢁKþ] 173.0755, found
20
173.0759; [
a
]
þ4.0 (c 1.0, CH3CN).
D
4.5.2. Potassium(S)-(2-phenylbut-3-en-2-yl)trifluoroborate(3i). Accor-
ding to GP3A, boronic ester 2i (410 mg, 1.59 mmol) was subjected to
three evaporation cycles to afford 373 mg (98%) of pure 3i as a col-
ourless solid. Alternatively, racemic boronic ester 2i (516 mg, 2 mmol)
subjected to four evaporation cycles according to GP3B, afforded
4.3.1. (S)-2-(2-Phenylbut-3-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-diox-
aborolane (2i). According to GP1B, carbamate 1g (748 mg, 3 mmol)
reacted with vinylboronic acid pinacol ester (2.3 mL of 2 M solution
in Et2O, 4.6 mmol) to give, after flash chromatography and Kugel-
rohr distillation, 689 mg (89%) of pure 2i as a colourless oil. Oxi-
dation of an aliquot of 2i according to GP217 gave the corresponding
alcohol in 96% ee. For HPLC separation conditions see Ref. 11. 1H
462 mg (97%) of pure 3i. 1H NMR (CD3CN, 400 MHz):
d 7.40–7.38 (m,
2H), 7.19–7.15 (m, 2H), 6.99 (tt, J¼7.3, 1.3 Hz, 2H), 6.41 (dd, J¼17.5,
10.8 Hz, 1H), 4.79 (dd, J¼10.8, 2.5 Hz, 1H), 4.75 (dd, J¼17.5, 2.5 Hz, 1H),
NMR (CDCl3, 400 MHz):
d
7.32–7.27 (m, 4H), 7.25–7.22 (m, 4H), 7.17
1.21 (s, 3H) ppm; 13C NMR (CD3CN, 100 MHz):
d
153.1, 151.7, 128.6,
4.6 (q,
ꢁ146.1 (q, JF–B¼
(tt, J¼7.2, 1.5 Hz, 1H), 6.27 (dd, J¼17.4, 10.6 Hz, 1H), 5.15 (dd, J¼10.6,
128.0, 124.1, 107.6, 21.2 ppm; 11B NMR (CD3CN, 96.2 MHz):
d
1.4 Hz,1H), 5.05 (dd, J¼17.4, 1.4 Hz,1H),1.44 (s, 3H),1.25 (s, 6H),1.23
JB–F¼60 Hz) ppm; 19F NMR (CD3CN, 282 MHz):
d
(s, 6H) ppm; 13C NMR (CDCl3, 75 MHz)
d
146.6, 144.1, 128.2, 127.3,
60 Hz) ppm; IR (neat) nu(tilde) 3084, 2967, 2873, 1627, 1597, 1576,
1493, 1467, 1443, 1410, 1370, 1318, 1223, 1175, 1148, 1071, 954, 923, 905,
125.5, 112.3, 83.6, 24.5, 24.4, 22.2 ppm; 11B NMR (CDCl3, 96 MHz)
32.3 (s) ppm; IR (neat) nu(tilde) 3084, 3055, 2978, 2931, 2866,
d
885, 837, 825, 757, 704, 688, 656 cmꢁ1; HRMS (ESI) [MꢁKþ] calcd for
24
1629, 1600, 1492, 1457, 1445, 1410, 1372, 1358, 1319, 1272, 1214,
1166,1143,1115,1103,1070,1030,1008, 965, 904, 869, 850, 762, 698,
671 cmꢁ1; MS (EI, 70 eV) m/z (%) 258 (87) [Mþ], 243 (9), 231 (2), 201
(9), 185 (9), 172 (4), 158 (94), 142 (37), 131 (59), 115 (24), 105 (19),
C10H11BF3, 199.0906, found 199.0911; [
a
]
ꢁ77.0 (c 4.8, CD3CN).
D
4.5.3. Potassium (2-chloropyrid-3-yl)trifluoroborate (3s). According
to GP3B, boronic ester 2s (481 mg, 2 mmol) was subjected to three
evaporation cycles to afford 423 mg (96%) of sufficiently pure 3s (1H
NMR has shown <0.4 mol % of starting material 2s and <0.1 mol %
101 (26), 91 (25), 84 (100), 77 (10), 69 (22), 55 (17); HRMS (EI) calcd
23
for C16H23BO2 [M]þ 258.1791, found 258.1790; [
CH2Cl2).
a
]
ꢁ15.6 (c 10,
D
of pinacol) as a colourless crystals. 1H NMR (CD3CN, 300 MHz)
d
8.12
(dd, J¼4.8, 2.1 Hz, 1H), 7.86 (br m, 1H), 7.11 (dd, J¼7.3, 4.8 Hz, 1H)
ppm; 13C NMR (CD3CN, 125.7 MHz)
156.3 (C), 148.6 (CH), 144.3
2.7 (q,
ꢁ142.8 (q, JF–B¼
4.4. General procedure for preparation of chiral secondary
and tertiary potassium alkyltrifluoroborates from
pinacolboronic esters (GP3A, Method C, Table 1)
d
(CH), 123.0 (CH) ppm; 11B NMR (CD3CN, 96.2 MHz)
d
JB–F¼48 Hz) ppm; 19F NMR (CD3CN, 282 MHz)
d
48 Hz) ppm; IR (neat) nu(tilde) 3073, 1576, 1560, 1379, 1261, 1234,
1215, 1184, 1120, 1089, 1044, 1013, 982, 970, 951, 939, 881, 796, 753,
670 cmꢁ1; HRMS (ESI) [MꢁKþ] calcd for C5H3BClF3N 180.0005/
181.9975, found 180.0008/181.9973.
To a stirred solution of boronic ester (2 mmol) in methanol
(10 mL) was added KHF2 (2 mL of 4.5 M saturated aqueous solution,
9 mmol, 4.5 equiv, 2.25-fold excess) dropwise at ambient temper-
ature and the reaction mixture was stirred for 30 min. Then, all of
the volatile materials were removed on a rotary evaporator (50/
15 mbar/45–50 ꢀC; undesirable bumping of the mixture can be
significantly minimized by adjusting the rotation speed), the resi-
due was re-dissolved in 50% aq MeOH (12 mL) and all volatile
materials were evaporated again. Evaporation–dissolution cycles
were repeated until 1H NMR analysis of an aliquot of the reaction
4.5.4. Potassium (2-cyclopropylethenyl)trifluoroborate (3t). Accor-
ding to GP3B, boronic ester 2t (194 mg, 1 mmol) was subjected to
four evaporation cycles to afford 127 mg (73%) of sufficiently pure
3t as a colourless crystals. 1H NMR (CD3CN, 300 MHz)
d 5.38 (ddt,
J¼17.6, 7.6, 3.7 Hz, 1H), 5.15 (J¼17.6, 8.1 Hz, 1H), 1.30–1.23 (m, 1H),
0.61–0.52 (m, 2H), 0.29–0.21 (m, 2H) ppm; 13C NMR (CD3CN,
mixture showed less than 1 mol % of pinacol (
d
1.14 [s, 12H]) ppm in
75.4 MHz)
(CD3CN, 96.2 MHz)
d
140.2 (CH), 17.2 (CH), 7.1 (2 CH2) ppm; 11B NMR
acetonitrile-d3; exact number of repetitions for any particular case
is given in Table 1. The solid residue was then triturated with dry
acetone (8 mL), the liquid phase was carefully decanted, and the
residual inorganic salts were washed with additional acetone
(3ꢂ2 mL). The combined washings were collected and concen-
trated in vacuo to give the desired trifluoroborate as a colourless
crystalline or amorphous solid, which was finally dried over P2O5
(50 ꢀC/0.1 mbar) overnight. Yields were typically quantitative;
some minor loss of product is mainly associated with evaporation/
drying/substance transfer manipulations.
d
1.7 (q, JB–F¼55.9 Hz) ppm; 19F NMR (CD3CN,
282 MHz)
d
ꢁ140.7 (q, JF–B¼55.9 Hz) ppm; IR (neat) nu(tilde) 3080,
3005, 2961, 1640, 1451, 1427, 1359, 1309, 1258 cmꢁ1; HRMS (ESI)
[MꢁKþ] calcd for C5H7BF3 135.0598, found 135.0602.
Acknowledgements
We thank EPSRC for support of this work and Frontier Scientific
for their generous donation of boronic esters. We also thank Merck
for unrestricted support. V.K.A. thanks the Royal Society for

9960
V. Bagutski et al. / Tetrahedron 65 (2009) 9956–9960
(g) Ros, A.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2009. doi:10.1002/anie.
200901900
5. Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438–15439.
6. Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 398–399.
7. Matteson, D. S.; Kim, G. Y. Org. Lett. 2002, 4, 2153–2155.
a Wolfson Research Merit Award and EPSRC for a Senior Research
Fellowship. A.R. thanks the European Union for a Marie Curie Intra-
European Postdoctoral Fellowship within the 7th European Com-
munity Framework Program.
8. Epoxidation of double bond: (a) Molander, G. A.; Rigaborda, M. J. Am. Chem. Soc.
2003, 125, 11148–11149; Oxidation of hydroxymethyl group: (b) Molander,
G. A.; Petrillo, D. E. J. Am. Chem. Soc. 2006, 128, 9634–9635; ‘Click-chemistry’: (c)
Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2767–2770; Lithiations: (d) Molander,
G. A.; Ellis, N. J. Org. Chem. 2006, 71, 7491–7493; Nucleophilic substitutions: (e)
Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031–2034; (f) Molander, G. A.;
Febo-Ayala, W.; Ortega-Guerra, M. J. Org. Chem. 2008, 73, 6000–6002; Ozo-
nolysis of double bond: (g) Molander, G. A.; Cooper, D. J. J. Org. Chem. 2007, 72,
3558–3560; HWE reactions: (h) Molander, G. A.; Figueroa, R. J. Org. Chem. 2006,
71, 6135–6140.
Supplementary data
Complete experimental procedures and characterisations are
provided. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2009.10.002.
9. (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem.
1995, 60, 3020–3027; (b) Vedejs, E.; Fields, S. C.; Hayashi, R.; Hitchcock, S. R.;
Powell, D. R.; Schrimpf, M. R. J. Am. Chem. Soc. 1999, 121, 2460–2470; (c) Darses,
References and notes
ˆ
S.; Michaud, G.; Genet, J.-P. Eur. J. Org. Chem. 1999, 1875–1883.
1. For reviews on preparation and use of trifluoroborates, see: (a) Darses, S.;
Geneˆt, J.-P. Eur. J. Org. Chem. 2003, 4313–4327; (b) Molander, G. A.; Fig-
ueroa, R. Aldrichimica Acta 2005, 38, 49–56; (c) Molander, G. A.; Ellis, N.
Acc. Chem. Res. 2007, 40, 275–286; (d) Darses, S.; Geneˆt, J.-P. Chem. Rev.
2008, 108, 288–325; (e) For seminal contributions to the area see: Darses,
S.; Geneˆt, J.-P.; Brayer, J.-L.; Demoute, J.-P. Tetrahedron Lett. 1997, 38,
4393–4396; (f) Darses, S.; Michaud, G.; Geneˆt, J.-P. Tetrahedron Lett. 1998,
39, 5045–5048.
2. (a) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393–396; (b) Molander, G. A.; Yun,
C.-S.; Rigaborda, M.; Biolatto, B. J. Org. Chem. 2003, 68, 5534–5539.
3. (a) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am. Chem. Soc.
2008, 130, 9257–9259; (b) Van den Hoogenband, A.; Lange, J. H. M.; Terpstra, J.
W.; Koch, M.; Visser, G. M.; Visser, M.; Korstanje, T. J.; Jastrzebski, J. T. B. H.
Tetrahedron Lett. 2008, 49, 4122–4124; (c) For a recent breakthrough in the
Suzuki–Miyaura coupling of secondary benzylic boronic esters see: Imao, D.;
Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131,
5024–5025.
10. According to SciFinder, 135 organic trifluoroborates are currently commercially
available.
11. Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew. Chem., Int. Ed.
2007, 46, 7491–7494.
12. Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456,
778–782.
13. (a) Harwood, L. M. Aldrichimica Acta 1985, 18, 25; (b) Pedersen, D. S.; Rose-
nbohm, C. Synthesis 2001, 2431–2434.
14. Yuen, A. K. L.; Hutton, C. A. Tetrahedron Lett. 2005, 46, 7899–7903.
15. Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Org. Lett. 2007, 9, 757–760.
16. Although after one cycle the 11B NMR spectra of the reaction mixture from 2k
showed no starting boronic ester 2k, the final 1H NMR spectra of the oil ob-
tained after numerous manipulations (vide supra) showed the following:
64 mol % of 3k, 16 mol % of 2k and 20 mol % of pinacol. Direct evidence for
reversibility of the reaction of boronic ester with KHF2 was obtained by 11B
NMR monitoring of reaction of trifluoroborate 3k with an excess of neat pi-
nacol. Thus, at 50 ꢀC, 12% of 3k was converted into 2k after 20 h, whereas, after
12 h at 80 ꢀC, the conversion reached 40%. It is also worthy to note that 3k
could eventually be recrystallised (10% acetone in hexane, w0.1 g/mL) after
three evaporation–dissolution cycles had been applied, though the yield
decreased significantly.
4. (a) Batey, R. A.; Thadani, A. N.; Smil, D. V. Org. Lett. 1999, 1, 1683–1686; (b)
Pucheault, M.; Darses, S.; Geneˆt, J.-P. Tetrahedron Lett. 2002, 43, 6155–6157;
ˆ
(c) Pucheault, M.; Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2002, 3552–3557;
(d) Pucheault, M.; Darses, S.; Geneˆt, J.-P. Chem. Commun. 2005, 4714–4716;
(e) Lalic, G.; Corey, E. J. Org. Lett. 2007, 9, 4921–4923; (f) Lalic, G.; Corey, E. J.
17. See Supplementary data.
18. Chen, A.; Ren, L.; Crudden, C. M. J. Org. Chem. 1999, 64, 9704–9710.
Tetrahedron Lett. 2008, 49, 4894–4896 for
a recent example of the cou-
pling of secondary and tertiary benzylic trifluoroborates with aldehydes see: