An Efficient Deprotection of 2,6-Bis(trifluoromethyl)phenylboronic Esters via Catalytic Protodeboronation Using Tetrabutyl ammonium Fluoride

Article abstract of DOI:10.1055/s-0039-1690236

We herein describe an efficient deprotection of 2,6-bis(trifluoromethyl)phenylboronic esters, which serve as effective protective groups for 1,2- or 1,3-diols in various organic transformations, via protodeboronation by using a catalytic amount of tetrabutylammonium fluoride (TBAF).

Full text of DOI:10.1055/s-0039-1690236

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
S. Urata et al.
Letter
Synlett
An Efficient Deprotection of 2,6-Bis(trifluoromethyl)phenylbo-
ronic Esters via Catalytic Protodeboronation Using Tetrabutyl-
ammonium Fluoride
Sari Urata
R
n
Shinya Nojima
Kazuishi Makino
Naoyuki Shimada*
F
TBAF (10 mol%)
H2O (3.0 equiv)
O
O
R
B
n
N
F3C
CF3
HO
OH
0
0
0
0-0
0
0
2-0
1
4
3-
7
8
6
7
H
13 examples
tetrabutylammonium
fluoride (TBAF)
Laboratory of Organic Chemistry for Drug Development and
Medical Research Laboratories, Department of Pharmaceutical
Sciences, Kitasato University, Tokyo 108-8641, Japan
shimadan@pharm.kitasato-u.ac.jp
80 to >99% yield
F3C
CF3
o-FXylboronic esters:
protective groups for diols
b.p. 116 °C
Catalytic Protodeboronation for Deprotection of o-FXylboronic Esters
Received: 20.09.2019
Accepted after revision: 16.10.2019
Published online: 30.10.2019
trolled transesterification of the boronic ester with excess
diols, although relatively long reaction times are required
(Scheme 1, a).6a,b This protective group is also removable by
treatment with aqueous potassium hydrogen fluoride
(Scheme 1, b).6a In this protocol, the protective reagent o-
FXylB(OH)2 can be recovered and reused by hydrolysis of its
potassium trifluoroborate salt.
DOI: 10.1055/s-0039-1690236; Art ID: st-2019-u0498-l
Abstract We herein describe an efficient deprotection of 2,6-bis(tri-
fluoromethyl)phenylboronic esters, which serve as effective protective
groups for 1,2- or 1,3-diols in various organic transformations, via pro-
todeboronation by using a catalytic amount of tetrabutylammonium
fluoride (TBAF).
Previous work: development of o-FXylboronic ester protective group for diols6a,b
R
Key words protective groups, diols, deprotection, 2,6-bis(trifluoro-
methyl)phenyl boronic esters, tetrabutylammonium fluoride, pro-
todeboronation, catalysis
HO
OH
n
B
R
neutral
conditions
O
O
n
F3C
CF3
B
HO
OH
– 2 H2O
F3C
CF3
n = 1 or 2
2,6-(CF3)2C6H3B(OH)2
(o-FXylB(OH)2)
1,2- or 1,3-
diols
Since diols are fundamental functional groups that can
be found in the structure of biomolecules such as carbohy-
drates, nucleosides, and many other biologically active nat-
ural products, the development of effective diol protective
groups still plays an indispensable role in various molecular
transformations. A large number of protective groups for
diols including cyclic acetals, ketals, carbonates, and silox-
anes have been developed to date.1 It is also well known
that boronic acid forms covalent bonds with 1,2- or 1,3-di-
ols to generate five- or six-membered cyclic boronic esters
under mild and neutral conditions.2,3 Therefore, boronic ac-
ids such as phenylboronic acid have been used as protective
or transient masking agents for diols.4,5 We have recently
found that 2,6-bis(trifluoromethyl)phenylboronic acid (o-
FXylB(OH)2) forms highly stable cyclic boronic esters, and
hence o-FXylboronic esters can be used as effective protec-
tive groups for 1,2- or 1,3-diols.6a The key features of our
method are its operability in protecting the diols under
neutral conditions without any additives and its applicabil-
ity to a wide range of organic transformations (Scheme 1).
Subsequent deprotection of o-FXylboronic esters can be
achieved under mild conditions by thermodynamically con-
• o-FXylboronic esters as
protective group for 1,2- or 1,3-diols
a) Previous work: deprotection of o-FXylboronic esters via transesterification6a,b
R
R
R
n
R = CH3 or NH2
(excess)
OH
O
O
R
O
O
B
HO
n
B
F3C
CF3
HO
OH
F3C
CF3
• thermodynamically controlled transesterification
• mild but slow conditions
6a
b) Previous work: deprotection of o-FXylboronic esters promoted by KHF2
R
B
n
O
O
F3C
CF3
R
KHF2 (3.0 equiv)
B
n
F3C
CF3
HO
OH
• recoverable and reusable
protocol for protective agent
TMSCl
MeCN/H2O
B = BF3K
B = B(OH)2
c) This work: deprotection of o-FXylboronic esters via catalytic protodeboronation
R
n
TBAF (10 mol%)
H2O (3.0 equiv)
H
O
O
R
B
F3C
CF3
n
F3C
CF3
HO
OH
• catalytic conditions
• protodeboronation of o-FXylboronic esters
Scheme 1 2,6-Bis(trifluoromethyl)phenylboronic ester (o-FXylboronic
ester) as protective group for diols and its deprotection conditions
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Urata et al.
Letter
Synlett
To expand this synthetic strategy using organoboron-
based diol protective groups, we herein report an alterna-
tive method for the deprotection of o-FXylboronic esters
using a catalytic amount of tetrabutylammonium fluoride
(TBAF; Scheme 1, c).
within 24 h (entry 6). It is noteworthy that the deprotection
reaction of boronic ester derived from simple phenylboron-
ic acid and 2a hardly proceeded under the same condi-
tions.22 These results indicate that the highly electron-defi-
cient trifluoromethyl groups at 2,6-positions effectively
promote the catalytic deprotection reaction.23 Elevating the
reaction temperature improved the reaction rates and
product yields, affording 2a in quantitative yield within 8.5
h at 50 °C (entry 7) and within 2 h under reflux conditions
(entry 8). Attempts to further reduce the catalyst amount of
TBAF to 5 mol% required longer reaction time (24 h), result-
ing in a slightly lower yield (96%, entry 9).24
We focused on protodeboronation reactions7,8 as a novel
deprotection method. Although the base-promoted pro-
todeboronation9 has been known as a side reaction in Suzuki–
Miyaura coupling reactions, a few recent reports have
revealed that the protodeboronation of organoboron com-
pounds promoted by acid10 or complexes containing met-
als, such as gold,11 silver,12 copper,13 and bismuth,14 can be
applied in synthetic organic transformations.15 Aggarwal16,17
reported the protodeboronation of tertiary boronic esters
with essentially complete retention of configuration,
promoted by a stoichiometric amount of CsF,H2O- or
TBAF·3H2O (Scheme 2). They suggest that the protodeboro-
nation of boronic esters proceeds via protonation of a
tetracoordinated borate intermediate generated by coordi-
nation of a fluoride anion to the boron atom of the boronic
esters. On the basis of this result, we considered that the
protodeboronation reaction using easily handled TBAF
could be applicable to the deprotection of o-FXylboronic esters.
Table 1 Optimization of Deprotection Conditions via Protodeboronationa
OBn
TBAF (x mol%)
O
O
H2O (y equiv)
OBn
B
HO
OH
F3C
CF3
THF (0.1 M)
2a
1a
Entry
TBAF (x mol%) H2O (y equiv) Temp (°C) Time (h) Yield (%)b
1
2
3
4
5
6
7
8
9
120
20
20
20
20
10
10
10
5
–
rt
0.2
24
>99
90c
>99
>99
35c
92c
>99
>99
96c
–
rt
TBAF·3H2O
(1.5 equiv)
H
H
H
O
1.0
3.0
10.0
3.0
3.0
3.0
1.5
rt
13
11
24
24
O
O
O
O
O
B
O
B
Et
Ph
THF
B
rt
F
Ph
HO
OH
Et
Et
Ph
rt
Scheme 2 TBAF-promoted protodeboronation of tertiary boronic es-
ters with essentially complete stereocontrol, reported by Aggarwal
(2010)16
rt
50
reflux
reflux
8.5
2
We initially examined the deprotection of boronic ester
1a with TBAF18 (Table 1). In the presence of a stoichiometric
amount of TBAF (120 mol%),19 the reaction proceeded
smoothly at room temperature in THF within 0.2 h. After
completion of the reaction, the reaction mixture was fil-
tered through a short pad of amino silica gel to give diol 2a
in quantitative yield (entry 1).20 Encouraged by this result,
we next attempted the catalytic use of TBAF. However, the
use of 20 mol% of TBAF resulted in a slight drop in conver-
sion yield (90%) even after a longer reaction time of 24 h
(entry 2). To achieve completion of the reaction under cata-
lytic conditions, we evaluated the effect of water as an addi-
tive. Gratifyingly, the addition of 1.0 equivalent of water im-
proved the reaction rate, providing 2a within 13 h (entry 3).
Although the same excellent yield within a shorter reaction
time (11 h) was maintained even increasing the water
amount to 3.0 equivalents (entry 4), the addition of excess
water (10.0 equivalents) was deleterious to the reaction
(entry 5).21 In an attempt to further reduce the amount of
TBAF to 10 mol%, the reaction was carried out in the pres-
ence of 3.0 equivalents of water in THF at room tempera-
ture, affording a satisfactory level of product yield (92%)
24
a Performed on 0.2 mmol scale.
b Isolated yield.
c Conversion yield determined by 1H NMR spectroscopy of crude reaction
mixture using 1,1,2,2-tetrachloroethane as an internal standard.
Next, we explored the substrate generality under the
conditions described in Scheme 3 (10 mol% of TBAF, 3.0
equivalents of water, reflux). It was found that the reaction
was applicable not only to 1,3-diol-derived boronic esters
1b–h but also to 1,2-diol-derived boronic esters 1i and 1j,
affording the corresponding diols 2b–j in high to excellent
yields (80–99%). Functional groups such as ester (2b), am-
ide (2c), amine (2d), olefin (2e), and alcohol (2f) were com-
patible under the deprotection conditions. However, car-
boxylic acid functional group was not tolerated under the
same conditions.25 Since silyl ethers are usually deprotected
by TBAF, it is noteworthy that the selective deprotection of
o-FXylboronic ester 1g incorporating the TBS ether pro-
ceeded to give 2g in high yield (88%) under the catalytic
conditions. Moreover, boronic esters derived from cyclic
1,2-diols were also applicable, giving diols 2k–m in high
yields (90–99%).
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

C
S. Urata et al.
Letter
Synlett
vealed the presence of the peak due to 1,3-bis(trifluoro-
methyl)benzene (3) and the disappearance of the peaks of
the o-FXylboronic ester 1a (Scheme 4, chart A). These re-
sults reveal that the deprotection reaction of 1a proceeds
through a protodeboronation mechanism. Interestingly, the
new peaks observed around  = 3.9 ppm were low-field
shifted compared to those of the authentic diol 2a ( = 3.7
ppm, Scheme 4, chart A). This suggests that the diol inter-
acts with boric acid in the reaction mixture. However, the
1H NMR spectrum was obtained after filtration of the reac-
tion mixture through a short pad of amino silica gel, and
subsequent evaporation was in good agreement with that
of the authentic diol 2a (Scheme 4, chart B), which suggests
that the boric ester is decomposed to the corresponding
diol during the workup procedure using amino silica gel.
For further investigation of the deprotection mecha-
nism, the reaction was carried out using deuterated water
(D2O) as additive (Scheme 5). The result confirmed that the
deprotection proceeds via a protodeboronation mecha-
nism, since 1,3-bis(trifluoromethyl)benzene, deuterated at
the 2-position (3-d), was obtained in high yield (75%) along
with diol 2a.
R
n
O
O
R
TBAF (10 mol%)
H2O (3.0 equiv)
B
n
F3C
CF3
HO
OH
THF (0.1 M), reflux
2b–m
n = 1 or 2
n = 1 or 2
1b–m
O
OAc
NHBn
NHBn
OTBS
HO
HO
OH
2b
HO
HO
OH
HO
HO
OH
2d
2c
91% (2 h)
94% (1.5 h)
94% (1.5 h)
OH
OH
OH
OH
2e
2f
2g
99% (2 h)
80% (6 h)
88% (2 h)
Ph
Ph
Ph
m
HO
OH
HO
OH
HO
OH
HO
OH
2k (m = 1): 90% (0.5 h)
2l (m = 2): 99% (20 h)
2m (m = 3): 99% (1 h)
2h
99% (0.5 h)
2i
88% (5 h)
2j
99% (5 h)
Scheme 3 Catalytic deprotection of o-FXylboronic esters using TBAF
OBn
D
OBn
TBAF (10 mol%)
To gain insights into the reaction mechanism, the
deprotection reaction of 1a was monitored by 1H NMR
spectroscopy in THF-d8 (Scheme 4). After completion of the
HO
OH
O
O
B
2a
F3C
CF3
D2O (3.0 equiv)
F3C
CF3
96%
1
reaction, the H NMR spectrum of the reaction mixture re-
THF-d8 (0.1 M)
reflux, 2 h
3-d
1a
75%
OBn
Scheme 5 Deprotection of boronic ester 1a in the presence of D2O
filtration through
O
O
TBAF (10 mol%)
H2O (3.0 equiv)
a pad of silica gel
(amino silica gel)
B
F3C
CF3
(chart A)
1H NMR of
(chart B)
1H NMR of
crude mixture
in THF-d8
On the basis of these results, we propose the catalytic
cycle shown in Scheme 6. Tetracoordinated borate interme-
diate I is formed initially by the coordination of fluoride an-
ion to the boron atom of o-FXylboronic ester 1. Subsequent-
ly, C–B bond cleavage and protonation at the ipso-position
occur from intermediate II16 by the reaction of I with water.
As a result, an ionic pair III and 1,3-bis(trifluorometh-
yl)benzene (3) having a newly formed C–H bond are gener-
ated. Finally, TBAF is regenerated for the next catalytic cycle,
and the hydrolysis of boric ester gives deprotected diol 2.
In conclusion, we describe a new method for the depro-
tection of 2,6-bis(trifluoromethyl)phenylboronic esters (o-
FXylboronic esters) via protodeboronation using commer-
cially available TBAF. To the best of our knowledge, this is
the first example of the catalytic use of TBAF for the pro-
todeboronation of boronic esters. In this catalytic method
with easy protocol,26 the deprotection proceeds more rap-
idly compared to the previously reported methods.6
then evaporation
THF-d8 (0.1 M)
reaction mixture
in THF-d8
reflux, 2 h
1a
H
F3C
CF3
3
OBn
HO OH
2a
chart B
chart A
OBn
O
O
B
F3C
CF3
1a
Funding Information
Japan Society for the Promotion of Science [JSPS KAKENHI Grant
19K07000 (N.S.) for Scienfic Research (C)], Japan Society for the Pro-
motion of Science [JSPS KAKENHI Grant 17K08218 (K.M.) for Scienfic
Scheme 4 1H NMR studies for the catalytic deprotection of 1a using TBAF
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

D
S. Urata et al.
Letter
Synlett
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R
R
amino
silica gel
n
R
n
n
O
O
O
O
B
HO
OH
B
H2O
n-Bu4N F
2
OH
F3C
CF3
(TBAF)
1
R
n-Bu4N
n
R
(6) (a) Shimada, N.; Urata, S.; Fukuhara, K.; Tsuneda, T.; Makino, K.
Org. Lett. 2018, 20, 6064. (b) Shimada, N.; Fukuhara, K.; Urata,
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O
F
O
n
B
O
O
F3C
CF3
B
n-Bu4N
F
OH
III
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D. S. J. Organomet. Chem. 1999, 581, 51. (b) Lee, C.-Y.; Cheon, C.-
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R
n-Bu4N
n
I
H
O
O
F
H
B
O
H
F3C
CF3
F3C
CF3
H2O
II
3
Scheme 6 Proposed reaction mechanism for the catalytic deprotec-
tion using TBAF
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Research (C)], Sasakawa Scientific Research Grant from The Japan Sci-
ence Society (S.U.), and Kitasato University Research Grant for Young
Researchers (N.S.).(J
a
p
a
n
S
o
c
i
etyforth
e
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oti
o
n
of
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c
i
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n
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7
0
0
0
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p
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o
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oti
o
n
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8
2
1
8
Acknowledgment
We thank Dr. K. Nagai and Ms. M. Sato at Kitasato University for in-
strumental analyses.
(11) Barker, G.; Webster, S.; Johnson, D. G.; Curley, R.; Andrews, M.;
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Supporting Information
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orit
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p
p
orti
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o
n
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(18) TBAF (ca. 1 mol/L in tetrahydrofuran including maximum 10%
of water) was purchased from Tokyo Chemical Industry Co., Ltd
and used.
(19) In this study, maximun 6.7 equiv of water are included when
120 mol% of TBAF were used.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

E
S. Urata et al.
Letter
Synlett
(20) The only byproduct of this reaction is 1,3-bis(trifluoro-
methyl)benzene (3) with low boiling point (b.p. 116 °C), which
can be easily removed by evaporation during the workup proce-
dure. Therefore, the desired diol at satisfactory level of purity
was obtained by simple filtration of reaction mixture through a
pad of basic amino silica gel eluting with EtOAc. See Supporting
Information for experimental details.
(21) For a report on the effect of water in reactivity of fluoride ion,
see: Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050.
(22) Deprotection of the corresponding phenylboronic ester only
gave the small amount of diol 2a (16% conversion yield) after 24
h under the conditions using 10 mol% of TBAF in the presence of
3.0 equiv of water at room temperature. See the Supporting
Information for details.
(23) The Perrin and Lloyd-Jones groups independently reported that
two ortho electron-withdrawing substituents on arylboronic
acid accelerate base-catalyzed protodeboronation, see:
(a) Lozada, J.; Liu, Z.; Perrin, D. M. J. Org. Chem. 2014, 79, 5365.
(b) Cox, P. A.; Reid, M.; Leach, A. G.; Campbell, A. D.; King, E. J.;
Lloyd-Jones, G. C. J. Am. Chem. Soc. 2017, 139, 13156.
(24) The reaction in the presence of 3.0 equiv of water with 5 mol%
of TBAF resulted in a remarkably decreased yield (53%).
(25) Our attempt to deprotect under the optimized conditions using
boronic ester derived from 4,6-dihydoroxyhexanoic acid failed,
resulting in a nearly quantitative recovery of the starting mate-
rial.
(26) General Procedure for the Deprotection of the Boronic Esters
with TBAF; Method A (Catalytic Conditions, Table 1, Entry 8)
TBAF (0.20 M in THF, 100 L, 0.0200 mmol, 10 mol%) and H2O
(6.0 M in THF, 100 L, 0.600 mmol, 3.0 equiv) were added to a
solution of 1a (89.2 mg, 0.200 mmol, 1.0 equiv) in dry THF (1.8
mL, total 0.10 M) at room temperature. After stirring for 2 h
under reflux and cooling to room temperature, the reaction
mixture was filtered through a short pad of amino silica gel
(800 mg) eluting with EtOAc (20 mL), and the filtrate was con-
centrated under reduced pressure to give 2a (46.8 mg, 0.200
mmol, >99% yield) as a colorless oil.
Analytical Data for 2a
Rf = 0.13 (n-hexane/EtOAc, 4:1). 1H NMR (400 MHz, CDCl3):  =
7.38–7.27 (m, 5 H), 4.53 (s, 2 H), 3.90–3.79 (m, 3 H), 3.57–3.49
(m, 2 H), 2.34 (br s, 2 H), 1.79–1.52 (m, 6 H). 13C NMR (100 MHz,
CDCl3):  = 137.9, 128.4, 127.8, 127.7, 73.1, 71.9, 70.5, 61.7, 38.3,
35.2, 26.2. IR (neat):  = 3372, 2942, 2865, 1278, 1099 cm–1
.
HRMS (ESI): m/z calcd for C13H20O3Na [M + Na]+: 247.1310;
found: 247.1311.
Method B (Stoichiometric Conditions, Table 1, Entry 1)
TBAF (1.0 M in THF, 0.24 mL, 0.240 mmol, 120 mol%) was added
to a solution of 1a (89.2 mg, 0.200 mmol, 1.0 equiv) in dry THF
(1.8 mL, total 0.10 M) at room temperature. After stirring for 2 h
under reflux, cooling to room temperature, the reaction
mixture was filtered through a short pad of amino silica gel
(800 mg) eluting with EtOAc (20 mL), and the filtrate was con-
centrated under reduced pressure to give 2a (44.8 mg, 0.200
mmol, >99% yield) as a colorless oil.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E