Preparation of 2-fluoro-3-aminophenylboronates via directed ortho -metalation

Article abstract of DOI:10.1055/s-0030-1260019

The aromatic amine in fluoroanilines was protected with 2,2,5,5-tetramethyl-1-aza-2,5-disila-cyclopentane (stabase) in order to direct metalation ortho to the fluorine. A series of novel 2-fluoro-3- aminophenylboronates were prepared after quenching the metalated intermediate with triisopropylborate and deprotection in situ. The presented method is convenient and scalable, because all of the synthetic steps use crude intermediates. Several transformations are carried out in the same pot, and the final boronates are easily purified crystalline materials. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260019

1604
PAPER
Preparation of 2-Fluoro-3-aminophenylboronates via Directed
ortho-Metalation
Preparation of
a
2-Fluoro-3
u
-aminopheny
l
lboronates E. Zhichkin,a Sergiy G. Krasutsky,*a Catherine M. Beer,a W. Martin Rennells,a Seung H. Lee,b Jin-Ming Xiongb
a
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, P.O. Box 15098, Albany, NY, 12212, USA
Fax +1(518)5122079; E-mail: sergiy.krasutsky@amriglobal.com
b
Gilead Sciences, Inc., 36 East Industrial Rd., Branford, CT 06405, USA
Received 15 January 2011; revised 3 March 2011
F
Abstract: The aromatic amine in fluoroanilines was protected with
2,2,5,5-tetramethyl-1-aza-2,5-disila-cyclopentane (stabase) in or-
der to direct metalation ortho to the fluorine. A series of novel
2-fluoro-3-aminophenylboronates were prepared after quenching
the metalated intermediate with triisopropylborate and deprotection
in situ. The presented method is convenient and scalable, because
all of the synthetic steps use crude intermediates. Several transfor-
mations are carried out in the same pot, and the final boronates are
easily purified crystalline materials.
H2N
B(OR')2
O
N
R
O
HN
Key words: boronates, metalation, regioselectivity, protecting
groups, amines
O
F
N
H
N
N
Me
O
R
In the course of our work on the inhibitors of Bruton’s ty-
rosine kinase (Btk),1 we required a series of 2-fluoro-3-
aminophenylboronates to form the middle portion of the
inhibitor molecule (Scheme 1). To our surprise, there
have been limited precedents for their synthesis in the lit-
erature.1,2 An alternative preparation of compound 7a us-
ing palladium chemistry was previously reported in our
patent.1 A similar method was used in the preparation
of 4-chloro-3-(dimethylamino)-2-fluorophenylboronic
acid.2 However, the product was not isolated and was used
without any purification in the following step.2 In this pa-
per, we report a simple and high-yielding preparation of
these boronates via ortho-metalation reactions followed
by a borate quench.
BTK inhibitor
Scheme 1 2-Fluoro-3-aminophenylboronate and a Btk inhibitor de-
rived from it
tion occurs only at the para-position.7 We decided that a
similar bis-silyl protection should also be applicable to 2-
fluoroanilines 1. However, we chose the stabase group as
the protecting group.8
One of the advantages of using stabase over bis-TES and
bis-TMS is that the protection reaction does not require
the use of n-BuLi. It can be carried out on a multigram
scale under solvent-free conditions with the convenient,
commercially available silylating agent 1,2-bis[(dimeth-
ylamino)dimethylsilyl]ethane (2; Table 1).9
The reported reaction conditions (140 °C, 5 h)9 required
some optimization. While they worked well with crude 2
prepared in our laboratory, the reaction with pure com-
mercial material proceeded only sluggishly beyond the
uncyclized intermediate 3. This indicated that the cycliza-
tion of 3 to 4 could be catalyzed by impurities. Indeed,
adding 7 mol% dimethylamine hydrochloride (a likely
impurity in crude 2) at the beginning of the reaction accel-
erated the cyclization and increased the yield of 4. In order
for the general procedure to be applicable to hindered sub-
strates, we had to increase the amount of zinc iodide (from
1 to 25 mol%) and temperature (from 140 to 180–210 °C)
as compared to the original literature.9 Completion of the
reaction was monitored by GC or NMR analysis.
Because a variety of substituted 2-fluoroanilines are com-
mercially available and inexpensive, we chose them as
our starting materials. The most straightforward approach
to 2-fluoro-3-aminophenylboronates is via the metalation
of these 2-fluoroanilines ortho to the fluorine atom.3
However, it is well-known from the work of Schlosser et
al. that tert-butylcarbamate-protected fluoroanilines are
metalated ortho to the nitrogen atom.4 Pivaloyl-protected
2-fluoroaniline behaves similarly.5 Therefore, the amine
moiety has to be protected in such a way as to negate its
ortho-directing properties. With 3- and 4-substituted
anilines, this effect can be achieved through bis-TMS or
bis-TES nitrogen protection.4,6 In the case of 3-fluoro-
aniline and 3,5-difluoroaniline, the 2,2,5,5-tetramethyl-1-
aza-2,5-disila-cyclopentane (stabase) group reduces the
directing effect of the aromatic amine moiety, and lithia-
Protected compound 4 was easily separated from zinc io-
dide, which formed a solid cake after the reaction mixture
was cooled. Adding hexanes to the mixture and decanting
SYNTHESIS 2011, No. 10, pp 1604–1608
Advanced online publication: 27.04.2011
DOI: 10.1055/s-0030-1260019; Art ID: M12111SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1

PAPER
Preparation of 2-Fluoro-3-aminophenylboronates
1605
Table 1 Stabase Protection of Anilines
NMe2
SiMe2
Me2N
SiMe2
Me2Si
R1
Me2Si
R1
SiMe2
F
SiMe2
NH2
NH
N
NMe2
2
R1
R2
F
F
180–210 °C
ZnI2, Me2NH⋅HCl
R2
R2
70–120 °C
1
3
4
Entry
R1
H
R2
Product
4a
Yield (%)
1
2
3
4
5
6
H
100
97
H
Cl
4b
H
Me
H
4c
100
99
Cl
F
4d
H
4e
96
Me
H
4f
100
the solution afforded 4, which was of sufficient purity crystallization or chromatography. Nevertheless, the final
(>85%) to be used in the following step directly.
products 7 and 8 were obtained as pure crystalline com-
pounds in high overall yield.
We first attempted to use s-BuLi to metalate 4a (–78 °C,
1 h), with subsequent quenching of the resulting anion
with triisopropyl borate. Unfortunately, a significant
amount of side product formed, and, after workup, a mix-
ture of the corresponding boronic and borinic acids was
isolated in approximately 60% yield.
Table 2 Preparation of Boronates
Me2Si
R1
SiMe2
F
Me2Si
R1
SiMe2
F
N
N
1. LTMP, B(Oi-Pr)3
2. NH4Cl
Unsatisfied with this result, we turned to the in situ
quench protocol, which employs a milder base lithium
2,2,6,6-tetramethylpiperidine (LTMP).10 The application
of these conditions was successful. Boronic acid 5, which
formed after treating the reaction mixture with ammoni-
um chloride, was not isolated. The stabase protecting
group was removed by treating the crude mixture with
aqueous potassium hydroxide (in most cases) or hydro-
chloric acid (for 5d and 5f; Table 2). An advantage of us-
ing a base is that the resulting polar ‘ate’ complexes 6
migrated into the aqueous phase, while all the impurities
remained in the organic layer.
R2
B(OH)2
R2
5
4
KOH
NH2
R1
R2
F
B–(OH)3 K+
6
OH OH
OH
OH
NH2
F
NH2
R1
R2
R1
R2
F
It was more convenient to isolate ester 7 or 8 rather than
the aminophenylboronic acid, which is water soluble. The
standard procedure would involve extracting the boronic
acid and treatment with a diol in the presence of a drying
agent. However, we discovered that highly crystalline
neopentyl glycolates 7a–e and pinacolate 8e readily pre-
cipitated from an aqueous solution of 6a–e after treatment
with neopentyl glycol or pinacol followed by acetic acid.
As the formation of boronates is reversible, acidification
to approximately neutral pH 6.5–7.9 and use of a concen-
trated solution of 6 and excess diol was necessary to ob-
tain good yields.
+
O
O
B
B
7
8
O
O
Entry
R1
R2
H
Product
7a
Yield (%)
1
2
3
4
5
6
7
H
75
70
84
73
84
84
80
H
Cl
Me
H
7b
H
7c
Cl
F
7d
It is noteworthy that all six steps of the synthesis: stabase
protection, lithiation, borate quench, aqueous quench, sta-
base deprotection, and borate ester formation were per-
formed with crude mixtures and did not involve
H
7e
F
H
8e
Me
H
8f
Synthesis 2011, No. 10, 1604–1608 © Thieme Stuttgart · New York

1606
P. E. Zhichkin et al.
PAPER
1-(5-Chloro-2-fluorophenyl)-2,2,5,5-tetramethyl-1,2,5-azadi-
To improve the base-induced deprotection of hindered de-
rivatives 5d and 5f, which was sluggish and required pro-
longed times, a more robust acidic deprotection procedure
for 5d and 5f employing HCl in a mixture of tetrahydro-
furan (THF) and water was also developed. The resulting
crude boronic acids were converted into esters 7d and 8f
following standard procedures. Although 8f required
chromatographic purification, pinacolates 8 have the ad-
vantage of being more stable than neopentyl glycolates 7.
This may be important if 7 or 8 are to be further deriva-
tized while preserving the boronate group.
silolidine (4b)
Following the typical procedure and heating at 210 °C for 1.5 h, 1b
(10.0 g, 68.7 mmol) was converted into 4b.
Yield: 19.1 g (97%); light-brown oil.
1H {19F} NMR (300 MHz, CDCl3): d = 6.93 (m, 3 H), 0.89 (s, 4 H),
0.11 (s, 12 H).
13C NMR (75 MHz, CDCl3): d = 157.1 (d, JC–F = 242.6 Hz), 135.7
(d, JC–F = 15.3 Hz), 129.7 (d, JC–F = 1.6 Hz), 128.7 (d, JC–F
=
3.2 Hz), 123.4 (d, JC–F = 8.2 Hz), 116.9 (d, JC–F = 24.0 Hz), 8.6,
–0.13, –0.15.
19F {1H} NMR (282 MHz, CDCl3): d = –124.0.
In conclusion, a convenient, high-yielding method for the
preparation of 2-fluoro-3-aminophenylboronates was de-
veloped. The method, which avoids purification or isola-
tion of the intermediates, consists of the lithiation of
stabase-protected 2-fluoroanilines, followed by deprotec-
tion of the stabase group. The desired 2-fluoro-3-ami-
nophenylboronates are precipitated in high purity from
the resulting aqueous solutions with a diol.
1-(2-Fluoro-5-methylphenyl)-2,2,5,5-tetramethyl-1,2,5-azadi-
silolidine (4c)
Following the typical procedure, 1c (8.60 g, 68.7 mmol) was con-
verted into 4c, affording 4c as a brown oil, which solidified on
standing.
Yield: 18.5 g (100%); purple solid; mp 20–25 °C.
1H {19F} NMR (300 MHz, CDCl3): d = 6.90 (d, J = 7.9 Hz, 1 H),
6.76 (m, 2 H), 2.27 (s, 3 H), 0.89 (s, 4 H), 0.09 (s, 12 H).
13C NMR (75 MHz, CDCl3): d = 157.1 (d, JC–F = 240.3 Hz), 133.4
All metalation reactions were carried out under a positive pressure
of nitrogen in anhydrous solvents. Stabase protection of 1, basic
deprotection of 5, and handling of easily oxidizable basic solutions
of 6 were also carried out under nitrogen. Commercially available
reagents and anhydrous solvents were used as supplied without fur-
ther purification. 1H, 19F, and 13C NMR spectra were recorded with
a Bruker AVANCE 300 or a Bruker AVANCE 500 NMR spectrom-
eter. All chemical shifts (d) are reported in ppm, using TMS as a
(d, JC–F = 3.5 Hz), 133.1 (d, JC–F = 13.9 Hz), 130.9, 124.1 (d, JC–F
7.1 Hz), 115.6 (d, JC–F = 21.9 Hz), 20.9, 8.6, –0.10, –0.12.
=
19F {1H} NMR (282 MHz, CDCl3): d = –126.6.
1-(2-Chloro-6-fluorophenyl)-2,2,5,5-tetramethyl-1,2,5-azadi-
silolidine (4d)
Following the typical procedure and heating at 190 °C for 2 h, 1d
(7.00 g, 47.9 mmol) was converted into 4d.
1
standard for H, 13C and 19F NMR and CFCl3 for 19F NMR. High
resolution mass spectra (HRMS) were obtained with a Waters Q-
Tof micro mass spectrometer using ESI(+) ionization. Melting
points were determined with an Electrothermal Mel-Temp appara-
tus and are uncorrected. All final compounds 7 and 8 had purity
greater than 95% (area percent) as judged by HPLC analysis. Inter-
mediates 4 had purity of 85–95% (1H NMR analysis), which was
sufficient for the following transformations.
Yield: 13.8 g (97%); yellow oil.
1H {19F} NMR (300 MHz, CDCl3): d = 7.19 (m, 1 H), 6.97 (m, 2 H),
0.96 (s, 4 H), 0.19 (s, 6 H), 0.09 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 161.1 (d, JC–F = 245.1 Hz), 136.0,
132.1 (d, JC–F = 16.2 Hz), 125.5 (d, JC–F = 3.3 Hz), 124.3 (d, JC–F
9.1 Hz), 114.5 (d, JC–F = 23.2 Hz), 8.7, 0.5, –0.4.
=
19F {1H} NMR (282 MHz, CDCl3): d = –115.8.
Stabase Protection: 1-(2-Fluorophenyl)-2,2,5,5-tetramethyl-
1,2,5-azadisilolidine (4a); Typical Procedure
1-(2,6-Difluorophenyl)-2,2,5,5-tetramethyl-1,2,5-azadisiloli-
dine (4e)
Following the typical procedure, 1e (5.00 g, 38.8 mmol) was con-
verted into 4e.
A mixture of 1a (7.62 g, 68.7 mmol), 2 (17.8 g, 76.6 mmol), freshly
opened anhydrous ZnI2 (5.50 g, 17.2 mmol), and Me2NH·HCl (0.38
g, 4.8 mmol) was slowly heated to 190 °C over 1 h. Evolution of a
gas (dimethylamine) was observed, and two layers formed. Heating
was continued at 190 °C for 1 h with vigorous stirring, and the re-
action was monitored by either 19F or 1H NMR. After cooling to r.t.,
the upper organic layer was decanted from the solidified zinc salts
and poured into hexanes (100 mL). The solids were further washed
with hexanes (3 × 5 mL), decanting every time. The combined hex-
anes solutions were clarified by filtering through a pad of Cellpure
P65. The filtrate was evaporated under reduced pressure to afford
4a.
Yield: 10.2 g (96%); colorless oil.
1H {19F} NMR (300 MHz, CDCl3): d = 6.97 (t, J = 8.2 Hz, 1 H),
6.97 (d, J = 8.2 Hz, 2 H), 0.93 (s, 4 H), 0.05 (s, 12 H).
13C NMR (75 MHz, CDCl3): d = 161.2 (dd, JC–F = 245.2, 5.1 Hz),
123.7 (t, JC–F = 9.2 Hz), 122.4 (t, JC–F = 17.4 Hz), 111.5 (dd, JC–F
17.2, 9.1 Hz), 8.5, –0.5.
19F {1H} NMR (282 MHz, CDCl3): d = –119.3.
=
Yield: 17.4 g (100%); colorless oil.
1-(2-Fluoro-6-methylphenyl)-2,2,5,5-tetramethyl-1,2,5-azadi-
silolidine (4f)
Following the typical procedure, 1f (49.9 g, 0.399 mol) was con-
1H NMR (300 MHz, CDCl3): d = 7.10–6.90 (m, 4 H), 0.89 (s, 4 H),
0.09 (s, 6 H), 0.08 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 159.4 (d, JC–F = 243.3 Hz), 133.8
verted into 4f.
(d, JC–F = 13.7 Hz), 130.4, 124.1 (d, JC–F = 3.5 Hz), 123.7 (d, JC–F
7.4 Hz), 116.2 (d, JC–F = 21.9 Hz), 8.6, –0.13, –0.15.
=
Yield: 107 g (100%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 6.98–6.84 (m, 3 H), 2.23 (s, 3 H),
0.93 (s, 4 H), 0.05 (s, 12 H).
19F {1H} NMR (282 MHz, CDCl3): d = –121.6.
13C NMR (75 MHz, CDCl3): d = 160.5 (d, JC–F = 241.6 Hz), 139.6,
131.7 (d, JC–F = 13.7 Hz), 125.8 (d, JC–F = 2.9 Hz), 123.8 (d, JC–F
=
Synthesis 2011, No. 10, 1604–1608 © Thieme Stuttgart · New York

PAPER
Preparation of 2-Fluoro-3-aminophenylboronates
1607
8.9 Hz), 113.3 (d, JC–F = 23.0 Hz), 18.4 (d, JC–F = 3.1 Hz), 8.7, 0.6,
–0.5.
19F {1H} NMR (282 MHz, CDCl3): d = –118.9.
1H NMR (500 MHz, CDCl3): d = 6.86 (d, J = 3.0 Hz, 1 H), 6.66 (d,
J = 8.5 Hz, 1 H), 3.79 (s, 4 H), 3.61 (br s, 2 H), 2.22 (s, 3 H), 1.04
(s, 6 H).
13C NMR (125 MHz, CDCl3): d = 154.2 (d, JC–F = 240.2 Hz), 134.0
(d, JC–F = 15.6 Hz), 133.2 (d, JC–F = 3.3 Hz), 125.0 (d, JC–F =
Neopentyl Glycol Boronates: 3-(5,5-Dimethyl-1,3,2-dioxa-
borinan-2-yl)-2-fluoroaniline (7a); Typical Procedure
LTMP was prepared by treating a solution of 2,2,6,6-tetramethylpi-
peridine (9.0 mL, 7.56 g, 53.6 mmol) in THF (50 mL) with n-BuLi
(2.5 M in hexanes, 20 mL, 50 mmol) at –10 to –5 °C and then stir-
ring the mixture for 15 min at that temperature.
7.3 Hz), 120.1 (d, JC–F = 4.0 Hz), 120.0–117.0 (br s), 72.5, 31.8,
21.9, 20.8.
HRMS: m/z calcd for C12H17BFNO2 + H: 238.1415; found:
238.1418.
The resulting LTMP solution was cooled to –75 °C and 4a (8.72 g,
34.4 mmol) was added dropwise at –75 to –65 °C followed by tri-
isopropylborate (16 mL, 13.0 g, 69.4 mmol). The reaction mixture
was slowly warmed to 0 °C over 2 h, quenched with 25% NH4Cl
(15 mL, 72 mmol) and stirred at r.t. for 30 min. The resulting sus-
pension was filtered, and the filter cake was washed with THF
(3 × 10 mL). The organic layer of the filtrate was separated and
evaporated at 30 °C under reduced pressure.
6-Chloro-3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-
aniline (7d)
Following the typical procedure, 4d (6.60 g, 22.9 mmol) was con-
verted into 5d. The deprotection of 5d with KOH was sluggish, and
the acidic deprotection (see the preparation of 8f below) was ap-
plied. After reacting with neopentyl glycol (pH 7.5), 7d was ob-
tained.
Yield: 4.30 g (73%); brown solid; mp 59–61 °C.
The residue containing 5a was mixed with methyl tert-butyl ether
(MTBE; 35 mL) and a degassed (N2 sparging) solution of KOH
(86% assay, 6.10 g, 93 mmol) in H2O (50 mL). The resulting emul-
sion was stirred vigorously for 2 h (more KOH can be added if the
deprotection stalls). The aqueous layer containing 6a was separated,
treated with neopentyl glycol (7.78 g, 74.8 mmol) and stirred until
a clear solution formed. AcOH was then added dropwise until
pH 7.6. The precipitated product was filtered, washed with ice-cold
H2O (3 × 10 mL) and dried overnight under vacuum at 45 °C to af-
ford 7a (5.56 g, 72%). After standing overnight, a second crop of 7a
(0.26 g, 3%) precipitated and was filtered. Combining the two crops
gave 7a.
1H NMR (500 MHz, CDCl3): d = 7.00 (m, 2 H), 4.02 (br s, 2 H),
3.78 (s, 4 H), 1.03 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 155.6 (d, JC–F = 245.8 Hz), 132.3
(d, JC–F = 17.5 Hz), 124.2 (d, JC–F = 2.9 Hz), 123.5 (d, JC–F
=
8.7 Hz), 122.6 (d, JC–F = 4.9 Hz), 117.5–116.5 (br s), 72.5, 31.9,
21.9.
HRMS: m/z calcd for C11H14BClFNO2 + H: 258.0868; found:
258.0861.
3-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2,6-difluoroaniline
(7e)
Following the typical procedure, 4e (9.34 g, 34.4 mmol) was con-
verted into 5e. The deprotection of 5e was sluggish and required 4 h
and a large excess of KOH (7.65 g, 116 mmol). After the solution
of 6e and neopentyl glycol was acidified to pH 7.4, 7e was obtained.
Yield: 5.83 g (75%); white solid; mp 55–56 °C.
1H NMR (300 MHz, CDCl3): d = 7.06 (ddd, J = 7.2, 5.4, 1.7 Hz,
1 H), 6.92 (t, J = 7.4 Hz, 1 H), 6.84 (td, J = 7.8, 1.8 Hz, 1 H), 3.79
(s, 4 H), 3.68 (br s, 2 H), 1.04 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 155.8 (d, JC–F = 242.7 Hz), 134.5
(d, JC–F = 15.1 Hz), 124.7 (d, JC–F = 7.1 Hz), 123.8 (d, JC–F
Yield: 6.94 g (84%); off-white solid; mp 58–60 °C.
1H {19F} NMR (300 MHz, CDCl3): d = 7.04 (d, J = 8.4 Hz, 1 H),
6.79 (d, J = 8.4 Hz, 1 H), 3.78 (s, 4 H), 3.67 (br s, 2 H), 1.03 (s,
6 H).
=
3.4 Hz), 119.0–118.5 (br s), 119.3 (d, JC–F = 3.8 Hz), 72.5, 31.8,
21.9.
13C NMR (125 MHz, CDCl3): d = 156.5 (dd, JC–F = 244.1, 7.6 Hz),
154.2 (dd, JC–F = 243.2, 7.0 Hz), 123.7 (dd, JC–F = 18.5, 15.8 Hz),
123.4 (t, JC–F = 9.3 Hz), 115.9–113.6 (br s), 110.7 (dd, JC–F = 18.1,
3.0 Hz), 72.6, 32.0, 22.0.
HRMS: m/z calcd for C11H15BFNO2 + H: 224.1258; found:
224.1265.
5-Chloro-3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-
aniline (7b)
Following the typical procedure (acidified to pH 7.7 in the last step),
HRMS: m/z calcd for C11H14BF2NO2 + H: 242.1164; found:
242.1168.
4b (10.0 g, 34.7 mmol) was converted into 7b.
2,6-Difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)aniline (8e)
Yield: 6.26 g (70%); off-white solid; mp 125–128 °C.
1H NMR (300 MHz, CDCl3): d = 7.00 (dd, J = 4.3, 2.7 Hz, 1 H),
6.79 (dd, J = 7.6, 2.6 Hz, 1 H), 3.78 (s, 4 H), 3.75 (br s, 2 H), 1.03
(s, 6 H).
13C NMR (75 MHz, CDCl3): d = 154.2 (d, JC–F = 242.7 Hz), 135.8
(d, JC–F = 16.9 Hz), 128.9 (d, JC–F = 2.0 Hz), 123.7 (d, JC–F
Following the typical procedure above, 4e (6.77 g, 24.9 mmol) was
converted into 6e. Then, instead of adding neopentyl glycol, pinacol
(6.50 g, 54.9 mmol) was added to the aqueous layer. The solution
was stirred for 2 h, cooled to 0 °C and neutralized to pH 7 with 1 M
aq HCl. The product was filtered, washed with H2O (3 × 7 mL) and
dried to afford 8e.
=
7.3 Hz), 122.5–119.2 (br s), 118.5 (d, JC–F = 4.1 Hz), 72.6, 31.9,
21.9.
Yield: 4.80 g (84%); off-white solid; mp 50–51 °C.
HRMS: m/z calcd for C11H14BClFNO2 + H: 258.0868; found:
258.0870.
1H NMR (300 MHz, CDCl3): d = 7.05 (m, 1 H), 6.81 (m, 1 H), 3.70
(br s, 2 H), 1.35 (s, 12 H).
13C NMR (125 MHz, CDCl3): d = 156.5 (dd, JC–F = 245.3, 7.8 Hz),
154.4 (dd, JC–F = 244.3, 7.1 Hz), 123.9 (t, JC–F = 9.1 Hz), 123.8 (dd,
JC–F = 17.5, 15.5 Hz), 111.8–111.0 (br s), 110.9 (dd, JC–F = 18.1,
2.9 Hz), 83.9, 24.9.
3-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-5-methyl-
aniline (7c)
Following the typical procedure (acidified to pH 7.9 in the last step),
4c (9.21 g, 34.4 mmol) was converted into 7c.
MS (ESI+): m/z = 256.2 [M + H].
Yield: 6.82 g (84%); white solid; mp 98–99 °C.
HRMS: m/z calcd for C12H16BF2NO2 + H: 256.1320; found:
256.1331.
Synthesis 2011, No. 10, 1604–1608 © Thieme Stuttgart · New York

1608
P. E. Zhichkin et al.
PAPER
2-Fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)aniline (8f)
References
(1) Whitney, J. A.; Di Paolo, J.; Valleca, M. A.; Brittelli, D. R.;
Currie, K. S.; Darrow, J. W.; Kropf, J. E.; Lee, T.; Gallion,
S. L.; Mitchell, S. A.; Pippin, D. A. I.; Blomgren, P. A.;
Stafford, D. G. PCT Int. Appl. WO 2008033858, 2008.
(2) (a) Jeffrey, B.; Schmitzer, P. B.; Ruiz, J. M.; Balko, T. W.;
Siddall, T. L.; Yerkes, C. N. PCT Int. Appl. WO
2007082076, 2007. (b) Jeffrey, B.; Schmitzer, P. B.; Ruiz, J.
M.; Balko, T. W.; Siddall, T. L.; Yerkes, C. N.; Lo, W. C.
PCT Appl. US 20090088322, 2009. (c) Jeffrey, B.;
Schmitzer, P. B.; Guenthenspberger, K. A.; Lo, W. C.;
Siddall, T. L. PCT Appl. US 20090062125, 2009.
(d) Balko, T. W.; Schmitzer, P. B.; Daeuble, J. F.; Yerkes, C.
N.; Siddall, T. L. PCT Appl. US 20070179060, 2007.
(3) (a) Bridges, A.; Lee, A.; Maduakor, E.; Schwartz, C.
Tetrahedron Lett. 1992, 33, 7495. (b) Bridges, A.; Lee, A.;
Maduakor, E.; Schwartz, C. Tetrahedron Lett. 1992, 33,
7499.
(4) Takagishi, S.; Katsoulos, G.; Schlosser, M. Synlett 1992,
360.
(5) Jaroch, S.; Rehwinkel, H.; Holscher, P.; Sulzle, D.;
Hillmann, M.; Burton, G. A.; McDonald, F. M. US Patent
6391887, 2002.
(6) (a) Baston, E.; Maggi, R.; Friedrich, K.; Schlosser, M. Eur.
J. Org. Chem. 2001, 3985. (b) Leroux, F.; Castagnetti, E.;
Schlosser, M. J. Org. Chem. 2003, 68, 4693.
(7) Similar reasoning was used for stabase protection of
3-fluoroaniline and 3,5-difluoroaniline prior to an ortho-
metalation reaction, see: Grega, K. C.; Barbachyn, M. R.;
Brickner, S. J.; Mizsak, S. A. J. Org. Chem. 1995, 60, 5255.
(8) Djuric, S.; Venit, J.; Magnus, F. Tetrahedron Lett. 1981, 22,
1787.
Following the typical procedure, 4f (24.7 g, 92.5 mmol) was con-
verted into 5f. The organic layer obtained after NH4Cl quench and
subsequent filtration was mixed with hexanes (500 mL), 2 M aq
HCl (500 mL) and H2O (100 mL), and vigorously stirred at r.t. for
18 h. Completion of the reaction was monitored by disappearance
of the product from the organic layer. The aq layer was separated,
neutralized with NH4OH to pH 8.0 and concentrated under reduced
pressure to approximately 200 mL of a semi-solid residue. This res-
idue was shaken with EtOAc (500 mL) and the suspension was fil-
tered. The filter cake was washed with EtOAc (2 × 100 mL), and the
organic layer of the filtrate was separated, dried over sodium sulfate
for 3 d and filtered. Pinacol (71.0 g, 601 mmol) and -350 mesh
CaSO4 (109 g, 801 mmol) were added and the suspension was heat-
ed at reflux for 2 h. After filtering the solids and concentrating, the
reaction mixture was purified by flash chromatography on silica
(EtOAc–hexanes, 10%) to afford 8f.
Yield: 80% (80.7 g); white solid; mp 41–42 °C.
1H NMR (300 MHz, CDCl3): d = 7.02 (t, J = 6.6 Hz, 1 H), 6.84 (d,
J = 7.5 Hz, 1 H), 3.62 (s, 2 H), 2.20 (s, 3 H), 1.35 (s, 12 H).
13C NMR (125 MHz, CDCl3): d = 155.7 (d, JC–F = 242.7 Hz), 132.7
(d, JC–F = 14.7 Hz), 128.4 (d, JC–F = 3.7 Hz), 125.3 (d, JC–F
=
2.3 Hz), 124.5 (d, JC–F = 8.1 Hz), 114.3–111.7 (br s), 83.7, 24.9,
17.3 (d, JC–F = 3.3 Hz).
HRMS: m/z calcd for C13H19BFNO2 + H: 252.1571; found:
252.1575.
(9) Guggenheim, T. L. Tetrahedron Lett. 1984, 25, 1253.
(10) (a) Kristensen, J.; Lysén, M.; Vedsø, P.; Begtrup, M. Org.
Lett. 2001, 3, 1435. (b) Kristensen, J.; Lysén, M.; Vedsø, P.;
Begtrup, M. Organic Synthesis 2005, 81, 134.
Synthesis 2011, No. 10, 1604–1608 © Thieme Stuttgart · New York