Synthesis and structural analysis of conjugated benzoxazaborine derivatives

Article abstract of DOI:10.1016/j.tetlet.2018.10.022

Benzoxazaborine derivatives were synthesized by the dehydration condensation reaction of 2-aminobenzyl alcohols with arylboronic acids. The insensitivity of the benzoxazaborines to hydrolysis allowed these compounds to be isolated by silica gel column chr

Full text of DOI:10.1016/j.tetlet.2018.10.022

Accepted Manuscript
Synthesis and structural analysis of conjugated benzoxazaborine derivatives
Tomoyuki Ohishi, Kaori Igarashi, Hiroki Kadosono, Shoko Kikkawa, Isao
Azumaya, Akihiro Yokoyama
PII:
S0040-4039(18)31203-6
https://doi.org/10.1016/j.tetlet.2018.10.022
TETL 50332
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
3 August 2018
2 October 2018
5 October 2018
Please cite this article as: Ohishi, T., Igarashi, K., Kadosono, H., Kikkawa, S., Azumaya, I., Yokoyama, A., Synthesis
and structural analysis of conjugated benzoxazaborine derivatives, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.10.022
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Synthesis and structural analysis of conjugated benzoxazaborine derivatives
Tomoyuki Ohishia,, Kaori Igarashia, Hiroki Kadosonoa, Shoko Kikkawab, Isao Azumayab, Akihiro
Yokoyamaa,

1
Tetrahedron Letters
Synthesis and structural analysis of conjugated benzoxazaborine derivatives
Tomoyuki Ohishia,, Kaori Igarashia, Hiroki Kadosonoa, Shoko Kikkawab, Isao Azumayab, Akihiro
Yokoyamaa,
aDepartment of Materials and Life Science, Faculty of Science and Technology, Seikei University, 3-3-1 Kichijoji-kitamachi, Musashino, Tokyo 180-8633, Japan
bFaculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Benzoxazaborine derivatives were synthesized by the dehydration condensation reaction of 2-
aminobenzyl alcohols with arylboronic acids. The insensitivity of the benzoxazaborines to
hydrolysis allowed these compounds to be isolated by silica gel column chromatography. The
single crystal X-ray structural analysis demonstrated the highly planar structure of the
benzoxazaborine unit, and the B–N bond length indicated an extended -conjugated system.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Condensation reaction
Reversible reaction
Benzoxazaborine
2-Aminobenzyl alcohol
Boronic acid
Recently, the synthesis of various self-assembling boron-
containing compounds has been reported.1,2 These compounds
show several interesting features under thermodynamic
equilibrium, such as reversible bond cleavage,1c,d,2d molecular
recognition,2c,d and molecular structure exchange.1a,d The
frequently used backbones of the boron-containing self-
assembling compounds are dioxaborole, diazaborole, and
dioxaborolane. Compounds having these backbones are mainly
synthesized by the condensation of boronic acids with 1,2-diols
or 1,2-diamines.1 Boroxin has also been used as the backbone of
self-assembling compounds, and this type of compound has been
constructed by the self-condensation of aryl boronic acids.2 In
any case, the starting materials and the target products exist in
equilibrium. Therefore, to push equilibrium towards the
condensed product side, a Dean-Stark apparatus is often used to
remove the water formed by the condensation reaction.1d,3 In
addition, precipitation of the products outside the reaction system
can also be used.1a,b,c,4 Synthesis utilizing the difference in the
solubility of the products to suppress the reverse reactions is an
efficient method for constructing self-assembling compounds
with specific structures such as macrocycles, cage type molecules,
and polymers. However, their low solubility and sensitivity to
hydrolysis have hampered their detailed structural analysis and
characterization in solution. If a boron heterocycle with tolerance
to hydrolysis and with high solubility in organic solvents were
available, various self-assembling boron-containing compounds
soluble in organic solvents could be synthesized. Furthermore,
acid which can be converted into other functional groups, and be
used as a scaffold for carbon–carbon bond formation in the
synthesis of various organic compounds and polymer
materials.2c,5
Azaborines and oxazaborines are highly stable under ambient
conditions and have attracted attention because of their
luminescent properties.6,7 Oxazaborine derivatives having BPh2
moieties can be synthesized from the corresponding polarized
ethylenes such as β-enaminones and β-enaminoamides in a
homogeneous solution and are not hydrolyzed by water.7a,b,e In
contrast, benzoxazaborininones are hydrolyzed readily, and their
synthesis can be carried out under special conditions. For
example, Kaupp and co-workers reported the quantitative
synthesis of the benzoxazaborininone 3a by the ball-milling of
s—uc—h a—boron heterocycle could be used as a protected boronic
 Corresponding author.
E-mail addresses: t-ohishi@st.seikei.ac.jp (T. Ohishi), ayokoyama@st.seikei.ac.jp (A. Yokoyama)

2
Tetrahedron
anthranilic acid (1a) and phenylboronic acid (2) in the solid
introduction of a methyl group to the nitrogen atom of 1a would
increase the electron density of the amino group, and that 3b
would be less sensitive to hydrolysis than 3a. Next, we changed
the electron-withdrawing carbonyl group of 3 to the electron-
donating methylene and isopropylidene groups of 5. We found
that the benzoxazaborine 5b bearing a dimethyl group at the
benzyl position can be synthesized in a homogeneous reaction
system based on their thermodynamic stability. The structure of
state (Scheme 1).8 Furthermore, Molander and co-workers
reported the synthesis of various benzodiazaborininones and
benzoxazaborininones, including 3a, by the reaction of
organotrifluoroborates or boronic acids such as 2 with 1a,
anthranilamide, and salicylamide, taking advantage of SiO2 as a
fluorophile and a desiccant, or using Dean-Stark apparatus to
remove water.9 Their reports also indicate that these compounds
are very sensitive to water and are rapidly hydrolyzed in a
quantitative manner.10 Thus, we thought that an increase in the
electron density of the boron-connecting atoms could suppress
the hydrolysis of the boron heterocycles, resulting in the facile
synthesis of the boron heterocycles in
equilibrium reaction system. In this paper, we report the
dehydration condensation reaction of N-H and N-alkylated
anthranilic acids
phenylboronic acid 2 for the synthesis of boron heterocycles 3
and 5, respectively (Scheme 1). We first expected that the
1
the obtained boron heterocycles was investigated by H NMR
spectroscopy and single crystal X-ray analysis.
The dehydration condensations of anthranilic acid 1a and its
N-methylated counterpart 1b with an equimolar amount of 2
were carried out in tetrahydrofuran (THF) under reflux
conditions. Even after 24 h, both reaction mixtures were
homogeneous. The 1H NMR spectrum of the crude product
obtained by the reaction of 1a with 2 showed new signals
corresponding to 3a (Figure S1).9 The yield of 3a estimated by
a homogeneous
1 and 2-aminobenzyl alcohols 4 with
1
the integral ratios of the H NMR spectrum was 72%. However,
b, d
(a)
c
a
a
b
c
d
4a
e
g
(b)
(c)
f
e
f
g
boroxin
boroxin
2
F
A
D
E
B
C
B
D
G
E
C
A
F
G
5a
PPM
8.25
8.00
7.75
7.50
7.25
7.00
6.75
8.25
8.00
7.75
7.50
7.25
7.00
6.75
CHCl3
i, h
b, d
a
b
e
g
c
d
g
h
i
c
e
f
5b
a
PPM
8.25
8.00
7.75
7.50
7.25
7.00
6.75
8.25
8.00
7.75
7.50
7.25
7.00
6.75
TMS
H2O
*
f
*
*
PPM
8
8
7
7
6
6
5
5
4
4
3
3
2
2
1
1
0
0

3
(a)
smoothly, and the obtained product, 5b, was purified by silica gel
column chromatography (Figure 2). The isolated 5b was a liquid
at room temperature and did not degrade even after more than six
months under ambient conditions. To determine the structure of
the oxazaborine ring by single crystal X-ray analysis, a
crystalline solid was required. Fortunately, the reaction of 4b
with 1,4-phenylenediboronic acid (6) under the same conditions
afforded a crystalline solid product 7 (Scheme 2). Single crystals
suitable for X-ray analysis were obtained by solvent diffusion of
hexane into a CHCl3 solution of 7. The crystal structure reveals
that the oxazaborine ring of 7 exhibits high planarity, and that the
three bonds attached to the boron atom (B–C, B–O, and B–N
bonds) are also in the same plane, and the sum of the three bond
angles is 360° (Figure 3). The torsion angles between the planes
defined by C2–N1–B1–O1 and C2–N1–B1–C10 are 12.12° and
−166.91°, respectively. The length of the B–N bond (1.421 Å)
corresponds to conjugated B–N bonds (1.407–1.417 Å) reported
in 1,2,3,4- or 1,2,5,6-tetrahydro-1,2-azaborines,11 and the length
of the B–O bond (1.368 Å) is consistent with typical B(sp2)–O
single bonds (1.31–1.38 Å).12,13 Thus, the crystal structure of 7
suggests that the -electrons are delocalized over the B–N bond
of the benzoxazaborine ring. The UV-vis spectrum of 7 in
O1
B1
N
B
C10
C2
N1
O
(b)
N
O1
B
B1
C10
O
N1
C2
we could not isolate 3a by silica gel column chromatography
because it was hydrolyzed readily. As for the reaction of 1b with
2, small new signals observed in the H NMR spectrum of the
1
crude product indicates the formation of a tiny amount of
products, but we could not determine the structure of the
products (Figure S2).
chloroform showed the maximum absorption wavelength (λmax
)
at 282 nm, which was longer by 15 nm than that of 4b (λmax
=
267 nm) (Figure S3). These results indicate that the two benzene
units in 5b and 7 are conjugated through the B–N bond of the
oxazaborine ring.
Therefore, we next tried the dehydration condensation of 2-
aminobenzyl alcohol (4a). When the reaction of 4a with 2 was
carried out in THF under reflux conditions for 24 h, the 1H NMR
spectrum of the crude product showed the almost complete
conversion of 4a and 2 to the target benzoxazaborine, 5a (Figure
1). However, purification of the crude product by silica gel
column chromatography resulted in the hydrolysis of 5a. To
increase the electron density of the boron atom, two electron-
donating methyl groups were introduced to the benzyl position of
4a. The steric bulkiness of the two methyl groups is also
expected to suppress the hydrolysis of 5b. The reaction between
Dioxaboroles are generally synthesized by the condensation of
arylboronic acids and diols and have frequently been used to
construct boron-containing self-assemblies.1 The thermodynamic
stability of dioxaborole was enhanced by the shift of electron
density from oxygen to boron.2a To compare the preference of the
formation of oxazaborine with that of dioxaborole, equal
amounts of 4b and catechol (8) were reacted with 0.5 equivalents
of 6 in THF (initial concentrations: [4b]0 = 0.2 M, [8]0 = 0.2 M,
[6]0 = 0.1 M) at room temperature for 30 min (Scheme 3). The 1H
NMR spectrum of the crude product showed that a large amount
n
l
m
o
f
k
i
f
e
j
d
h
g
CHCl3
c
b
a
7
10
G
J
B
C
E
F
H
I
A
D
e + k
9
8
E
D
4b
c + i
G
d + j
A + o
B + n
b + h
a + g
F
C
I
H + J
m
l
PPM
8.0
7.5
7.0
6.5
6.0
5.5
5.0
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4b and 2 in THF under reflux conditions also proceeded

4
Tetrahedron
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and 10 was 85/5/10. The reaction under reflux conditions for 30
min led to similar results (7/9/10 = 91/0/9) (Figure S4). Even
when twice the amount of 8 was used, that is, 1 equivalent of 4b
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reaction of 9 with 2 equivalents of 4b was carried out in THF at
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1
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In summary, the present study demonstrated the synthesis of
benzoxazaborine derivatives by dehydration condensation of 4
with 2. The oxazaborine compounds 5b and 7 were reasonably
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chromatography. The single crystal X-ray structural analysis of 7
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agreement with those of conjugated B–N bonds and B(sp2)–O
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exhibits high planarity. Furthermore, because the λmax of the UV-
vis spectrum of 7 in chloroform was found at a longer
wavelength (by 15 nm) than that of 4b, the two benzene units of
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oxazaborine rings. Further research into the synthesis of
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Acknowledgements
This work was supported by a JGC-Scholarship Foundation
and a JSPS KAKENHI Grant Number JP18K05221. A part of
this work was also supported by the Cooperative Research
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5
Highlights
 A novel boron-containing compound, benzoxazaborine,
was synthesized.
 The obtained benzoxazaborines were reasonably stable
to hydrolysis.
 The oxazaborine ring was the highly planar structure.
 The B–N bond length indicated an extended -
conjugated system.