Synthesis of Amino- and Hydroxymethyl Benzoxaboroles: Prominent Scaffolds for Further Functionalization

Article abstract of DOI:10.1002/ejoc.201900013

Herein, we describe the development of a short, simple, and efficient synthesis of amino- and hydroxymethyl-substituted benzoxaboroles. The key step in our strategy was the early stage incorporation of the boron by the borylation of an aniline. The formed boronates were then elaborated to the final products in two additional steps, usually in good yields. The synthetic sequence was amenable to be performed on a preparative scale and 4-amino benzoxaborole 4b and 6-hydroxymethyl benzoxaborole 10c have been prepared, without any significant decrease in the overall yield. The amino and hydroxymethyl present at the molecules are useful for further elaboration and/or conjugation to bioactive molecules and therefore we believe that this method should be useful in the development of new compounds for Medicinal Chemistry.

Full text of DOI:10.1002/ejoc.201900013

A Journal of
Accepted Article
Title: Synthesis of Amino- and Hydroxymethyl Benzoxaboroles:
Prominent Scaffolds for further Functionalization
Authors: Rodrigo Fuscaldo, Pedro Vontobel, Eduam Boeira, Angélica
Venturini Moro, and Jessie da Costa
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900013
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10.1002/ejoc.201900013
European Journal of Organic Chemistry
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Synthesis of Amino- and Hydroxymethyl Benzoxaboroles:
Prominent Scaffolds for further Functionalization
Rodrigo S. Fuscaldo,[a] Pedro H. V. Vontobel,[a] Eduam O. Boeira,[a] Angélica V. Moro,*[a] and Jessie S.
da Costa*[a]
Abstract: Herein, we describe the development of a short, simple
and efficient synthesis of amino- and hydroxymethyl-substituted
benzoxaboroles. The key step in our strategy was the early stage
incorporation of the boron by the borylation of an aniline. The formed
boronates were then elaborated to the final products in two
additional steps, usually in good yields. The synthetic sequence was
amenable to be performed on a preparative scale and 4-amino
benzoxaborole 4b and 6-hydroxymethyl benzoxaborole 10c have
been prepared, without any significant decrease in the overall yield.
The amino and hydroxymethyl present at the molecules are useful
for further elaboration and/or conjugation to bioactive molecules and
therefore we believe that this method should be useful in the
development of new compounds for Medicinal Chemistry.
growing interest for the benzoxaborole motif has aroused from
the discovery of its exceptional sugar-binding properties at
physiological conditions.6,8 Even more recently, the FDA
approval of tavaborole has boosted the status of benzoxaborole
to an important scaffold in drug discovery, representing a useful
addition to the medicinal chemistry toolbox. Despite of the
growing medicinal relevance of benzoxaboroles, the study of
routes for their synthesis has been quite limited, and synthetic
methods for the rapid diversification of this scaffold are highly
desired.
Introduction
Organoboron compounds have found widespread use in several
areas of science. The most well-known application is the Suzuki
cross-coupling reaction which has been largely used in
academia and industry worldwide.1 In medicinal chemistry,
boronic acid are used as bioisosters of carboxylic acids.2 Due to
their ability to form hydrogen bonds and characteristic Lewis
acidity, boronic acids and esters present important biological
and chemical properties, since they can react with a number of
nucleophiles such as alcohols and amines.3 The first
organoboron compound to reach the market as a drug was
bortezomib (Velcade®, Figure 1A), a dipeptide bearing a boronic
acid fragment, approved by FDA for multiple myeloma and
mantle cell lymphoma. Although being rejected by some
companies at the time of its discovery in the 90’s, supposedly
because of its unusual boronic acid function,4 its approval gave
a boost for the area of boron in medicinal chemistry. More
recently, two other drugs have reached the FDA-approval status:
tavaborole (Kerydin®) for the treatment of onychomycosis and
crisaborole (Eucrisa®) for atopic dermatitis, which are
benzoxaborole derivatives.5,6 Benzoxaborole (1-hydroxy-3H-2,1-
benzoxaborole - Figure 1A) is a versatile boron-heterocyclic
scaffold which has found a broad spectrum of applications, as
anti-bacterial, anti-fungal, anti-protozoal, anti-viral, as well as
anti-inflammatory agent.7 The large majority of its derivatives
have been reported only over the last few years, and the
Figure 1. A) relevant bioactive boron-containing molecules and B) this work.
[a]
R. S. Fuscaldo, P. H. V. Vontobel, E. O. Boeira, Prof. Dr. A. V.
Moro, Prof. Dr. J. S. da Costa
Instituto de Química, Universidade Federal do Rio Grande do Sul,
Av. Bento Gonçalves 9500, 91501-970, Porto Alegre, RS, Brazil.
E-mail: angelica.venturini@ufrgs.br, jessie.sobieski@ufrgs.br
Homepage: www.iq.ufrgs.br
To the best of our knowledge, the most extensive study
towards the synthesis of benzoxaborole derivatives was
reported by Zhou et al.9 who developed a multi-step route for
the synthesis of 6- and 7-hydroxymethylbenzoxaborole, in
which several functional group manipulations and redox
adjustments are necessary. Furthermore, the reported strategy
was not extended to 4- and 5-substituted derivatives, which
suffer from the absence of efficient methods for their synthesis.
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
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On the other hand, 4- and 7-amino-benzoxaborole was prepared
by Zhang and coworkers10-11 through a six-step sequence
starting from an aniline, with a Pd-catalyzed Miyaura borylation
reaction as the key step, while the 6-amino derivative was
obtained starting from 2-bromo-benzyl alcohol, and the synthetic
sequence includes bromine-lithium exchange, borylation,
nitration and nitro-reduction.12
The first attempt was using literature conditions,15 with HCl
as the acidic source in the diazotization step, followed by the
addition of 3 equiv of bis(pinacolato)diboron (entry 1). Under
these conditions the desired boronate 2b was obtained in only
43% yield. Decreasing the amount of B2pin2 to 2.0 and 1.2 equiv
did not result in any significant change in the reaction yield
(entries 2-3). On the other hand, using sodium acetate (2 equiv)
as an additive resulted in a slightly improved yield of 57% (entry
4). Gratifyingly, when the acid source was changed from HCl to
HBr, the overall reaction yield was improved to 78% (entry 5).
Attempts to reduce the amount of B2pin2 and NaOAc led to a
decrease in the isolated yield of product 2d (entries 6-7). The
replacement of NaOAc by catalytic amounts of CuBr (5 mol%)16
was also studied, and the desired boronate 2d was obtained in
70% yield (entries 9-10). Despite the good yield obtained using
CuBr during the optimization, scaling up the reaction resulted in
decreased isolated yields for compound 2b, alongside with
significant formation of the corresponding aryl bromide. This
decrease in yield was not observed for the reaction performed
using NaOAc, and therefore the conditions depicted in entry 5
were used for further experiments.
While useful, the reported routes are usually plagued with
protection-deprotection
steps,
several
chromatographic
purifications, and the use of pyrophoric organometallic reagents,
which detract from the overall synthetic efficiency and are
usually more challenging for scaling-up. Herein, we describe our
results on the development of a short, simple and efficient
synthesis of amino and hydroxymethyl benzoxaboroles using the
borylation of anilines as the key initial step (Figure 1B), which
are both valuable building blocks for the synthesis of biologically
relevant compounds.13,14
Results and Discussion
The borylation was then extended with success to anilines
1a and 1c and the corresponding boronates 2a and 2c were
obtained in 69% and 75% yield, respectively (Scheme 1).
However, when aniline 1d was used, boronate 2d was not
obtained, even when changes in reaction conditions have been
performed. When CuBr was added (1 equiv), the corresponding
aryl bromide was obtained, evidencing that the aryldiazonium
salt is formed, however the steric hindrance imposed by two
ortho substituents prevent the borylation step to occur.
We started our investigation by the synthesis of
pinacolboronates from anilines, and 2-methyl-4-nitro aniline 1b
was chosen as the model substrate (Table 1).
Table 1. Optimization of the borylation of 1b.
Entry
HX
B2pin2
(equiv.)
Additive
(equiv.)
Solvent
Yield
(%)[a]
HCl
3.0
2.0
1.2
2.0
2.0
1.5
1.1
1.0
1.5
2.0
-
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
MeCN
MeCN
43
1
2
3
4
5
6
7
8
9
10
HCl
HCl
HCl
HBr
HBr
HBr
HBr
HBr
HBr
-
50
38
57
78
47
45
49
70
70
-
NaOAc (2)
NaOAc (2)
NaOAc (1.5)
NaOAc (1.1)
CuBr (0.05)
CuBr (0.05)
CuBr (0.05)
Scheme 1. Synthesis of 4-, 5-, and 6-amino benzoxaborole products.
[a] Isolated yield.
The next step involved the benzylic bromination and it was
performed using benzoyl peroxide and NBS, in acetonitrile as
the solvent, at 100 oC for 24 h.17 The corresponding products 3a-
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10.1002/ejoc.201900013
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c were obtained in excellent yields, without the need of
chromatographic purification. The final benzoxaborole products
4a-c were obtained by a one-pot sequence involving benzylic
substitution of the bromine by a hydroxy group, followed by
acidic hydrolysis of the boronate with concomitant
benzoxaborole formation, and nitro-to-amino reduction by the
simple addition of zinc powder to the reaction mixture.18 Through
this one-pot three-step sequence the amino benzoxaborole
products were obtained in very good yields.
conversion of the ortho-disubstituted aniline 7d was difficult and
the desired product was not obtained under these conditions.
With boronates 8 in hands, we proceeded to the remaining steps
of the sequence and radical bromination occurred uneventfully
and the dibromides 9a-c were isolated in very high yields. Finally,
the one-pot benzylic substitution and hydrolysis led to the
desired hydroxymethyl benzoxaboroles 10a-c in 65%, 95%, and
61% yield, respectively.
The development of one-pot three-step sequence was not
achieved without some optimization. For example, using CaCO3
instead of NaOH resulted in low yields of the corresponding
product, with significant formation of the protodeboronated
product. The nitro-to-amine reduction step also required
optimization, since erosion of yields has been observed due to
parallel protodeboronation reaction. Selected reduction
conditions studied are summarized in Table 2. When the
reduction was performed using H2 and Pd/C in methanol as the
solvent, the desired product 4b was not observed and only
protodeboronated product 6b was obtained (entry 2). Replacing
the solvent to THF did not result in any conversion of the starting
material after
3 h (entry 3). In an attempt to prevent
protodeboronation, the reaction was performed in THF under
acidic conditions.10 After 2 h, the desired product 4b was formed,
but again the protodeboronated product 6b was also formed in
significant amount (entry 4). Reducing the reaction time to 1 h
led to complete recovery of the starting material (entry 5). Finally,
the reduction using a Fe/CaCl2 system led to a mixture of
unreacted 5b and products 4b and 6b (entry 6).
Scheme 2. Synthesis of 4-, 5-, and 6-hydroxymethyl benzoxaborole products
10a-c.
In order to showcase the efficiency of our route for
preparative purposes, we have scaled-up the synthetic
Table 2. Nitro-reduction reaction under different conditions.
sequence
for
aminobenzoxaborole
4b
hydromethylbenzoxaborole 10c (Scheme 3). Starting from 1.5
gram (10 mmol) of aniline 1b, we were able to prepare 0.75
grams 4-aminobenzoxaborole 4b in an overall yield of 67% for
the three steps. In addition, starting from 3 grams (25 mmol) of
aniline 7c, we were able to prepare 1.8 grams 6-
hydroxymethylbenzoxaborole 10c in an overall yield of 45% for
the three steps, which is consistent with the yields observed in
small scale reactions.
Entry
Conditions
Zn, HCl, MeOH
t (h)
Yield (%)[a]
5b : 4b : 6b[b]
1
2
3
1
3
2
1
1
95
64
95
74
70
58
0 : 60 : 40
0 : 0 : 100
100 : 0 : 0
0 : 70 : 30
100 : 0 : 0
30 : 46 : 24
H2, Pd/C, MeOH
H2, Pd/C, THF
3
4
H2, Pd/C, AcOH, THF
H2, Pd/C, AcOH, THF
Fe, CaCl2, EtOH
5
6[c]
[a] Crude yield. [b] The ratio was determined by 1H-NMR of the crude product
[c] 40 oC was used.
After developing an efficient strategy for the synthesis of
amino benzoxaboroles we turned our attention to the
hydroxymethyl-functionalized benzoxaboroles (Scheme 2). The
strategy was similar to the previous one, and dimethyl
substituted anilines 7a-c were converted to the corresponding
pinacolboronates 8a-c in good yields. As observed before,
Scheme 3. Scaled-up synthesis of amino- and hydromethyl benzoxaborole 4b
and 10c.
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8.1, 1.2 Hz, 1H), 7.33 – 7.27 (m, 1H), 2.68 (s, 3H), 1.36 (s, 12H). 13C
NMR (100 MHz, CDCl3) δ 151.2, 139.8, 138.3, 126.3, 125.9, 84.4, 25.0,
18.0 (C-B signal does not appear).
Conclusions
In summary, we have reported an efficient, short synthesis of
amino- and hydroxymethyl benzoxaboroles. The key step was
the early stage incorporation of the boron by the borylation of an
aniline, which constitutes a significant advantage over previous
routes, because avoids functional group manipulations and
results in a less costly approach to these compounds. The
formed boronates were then elaborated to the final products in
two additional steps, usually in good yields. The synthetic
sequence was amenable to be performed on a preparative scale
as demonstrated for 4-amino benzoxaborole 4b and 6-
hydroxymethyl benzoxaborole 10c which have been prepared
without any significant decrease in overall yields. Furthermore,
benzoxaboroles bearing either an amino or a hydroxymethyl
functional group at several positions of the ring have been
prepared, with the exception of 7-position. These are valuable
functional groups for further elaboration and/or conjugation to
bioactive molecules and therefore, we believe that this method
should be useful in the development of new compounds for
Medicinal Chemistry.
4,4,5,5-tetramethyl-2-(2-methyl-4-nitrophenyl)-1,3,2-dioxaborolane (2b).17
Pale yellow solid. Yield: 616 mg (78%). 1H NMR (400 MHz, CDCl3) δ
8.02 – 7.98 (m, 1H), 7.97 (dd, J = 8.2, 1.9 Hz, 1H), 7.89 (d, J = 8.2 Hz,
1H), 2.63 (s, 3H), 1.37 (s, 12H). 13C NMR (100 MHz, CDCl3) δ 149.4,
146.7, 136.8, 124.1, 119.5, 84.4, 25.0, 22.3 (C-B signal does not appear).
4,4,5,5-tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3,2-dioxaborolane (2c).
Pale yellow solid. Rf = 0.48 (5% EtOAc/hexanes). Yield: 608 mg (74%).
1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 2.6 Hz, 1H), 8.14 (dd, J = 8.4,
2.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 2.63 (s, 3H), 1.37 (s, 12H). 13C
NMR (100 MHz, CDCl3) δ 152.9, 145.7, 130.8, 125.5, 84.4, 25.0, 22.6 (C-
B signal does not appear). IR (max, cm-1): 3016, 1519, 1334, 1215, 754,
667. HRMS (ESI) m/z calcd for C13H18BNO4 [M-H]- 262,1256 found
262,1258.
General procedure for benzylic bromination of nitro derivatives. The
following procedure was based on the literature.17
A solution of
arylboronate (524 mg, 2 mmol) in degassed ACN (20 mL) was added to
NBS (531 mg, 3 mmol, 1.5 eq.) and (PhCOO)2 (120 mg, 0.5mmol, 25
mol%) in a pre-purged Schlenk flask. The flask was sealed under N2and
the reaction mixture was heated to 100 ºC for 24 h under magnetic
stirring. Then, the solvent was removed under reduced pressure, DCM
(25 mL) was added and the organic phase was washed with of saturated
NaHCO3 (aq) (2 x 25 mL). The organic phase was dried with Na2SO4 and
the solvent was removed under reduced pressure to afford the desired
product, which was used without further purification.
Experimental Section
General Information. NMR spectra were recorded in solution on a 400
MHz spectrometer at room temperature. Chemical shifts (δ) are given in
parts per million from the peak of tetramethylsilane (δ = 0.00 ppm) as
internal standard or from the solvent peak. BF3.OEt2 was used as an
external reference for 11B NMR spectra. ESI-QTOF-MS measurements
were performed in the negative ion mode (m/z 50-2000 range). IR
spectra were obtained on a FTIR-ATR instrument and (max are given in
cm-1. Melting points were determined in open glass capillaries using a
Büchi M-565 apparatus. Column chromatography was performed with
70-230 mesh SiO2. Thin layer chromatography (TLC) was performed
using supported silica gel GF254, 0.25 mm thickness. For visualization,
TLC plates were placed under UV light 254 nm, stained with iodine vapor,
KMnO4 or ninhidrin solutions. Acetonitrile was degassed by refluxing
under N2. 1,4-dioxane was dried with 4 A molecular sieves.19 All other
reagents were purchased at common chemical suppliers and used as
received.
2-(2-(bromomethyl)-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (3a). Amber solid. M.P.: 99,1-100,4 ºC. Rf = 0.34 (5%
EtOAc/hexanes). Yield: 681 mg (95%). 1H NMR (400 MHz, CDCl3) δ 8.07
(dd, J = 7.5, 1.5 Hz, 1H), 7.94 (dd, J = 8.1, 1.5 Hz, 1H), 7.46 (dd, J = 8.1,
7.5 Hz, 1H), 5.23 (s, 2H), 1.42 (s, 12H). 13C NMR (100 MHz, CDCl3) δ
149.7, 140.8, 138.0, 128.6, 127.4, 84.8, 26.5, 24.9 (C-B signal does not
appear). IR (max, cm-1): 3018, 1529, 1340, 1215, 742, 667. HRMS (ESI)
m/z calcd for C13H16BBrNO4 [M-H]- 340.0361, found 340.0363.
2-(2-(bromomethyl)-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (3b).21 Amber oil. Yield: 681 mg (95%). 1H NMR (400 MHz,
CDCl3) δ 8.22 (d, J = 2.1 Hz, 1H), 8.10 (dd, J = 8.2, 2.1 Hz, 1H), 7.98 (d,
J = 8.2 Hz, 1H), 4.93 (s, 2H), 1.40 (s, 12H). 13C NMR (100 MHz, CDCl3) δ
149.7, 146.3, 137.6, 124.4, 122.0, 84.9, 31.9, 25.0 (C-B signal does not
appear).
General procedure for borylation of nitroanilines. The following
procedure was adapted from the literature.15 A mixture of aniline (456 mg,
3 mmol) and HBr 14% (6 mL) was cooled to 0 ºC and a solution of
NaNO2 (228 mg, 3 mmol, 1.1 eq.) in water (2.4 mL) was slowly added,
care being taken not to raise the temperature above 0 ºC. The resulting
mixture was left under magnetic stirring at 0 ºC for 30 min. Then, it was
added to a stirring solution of B2pin2 (1.011 g, 6 mmol, 2 eq.) and NaOAc
(490 mg, 6 mmol, 2 eq.) in methanol (6 mL) at room temperature, quickly
and in small portions, using a Pasteur pipette. The resulting mixture was
left stirring for 1 h at room temperature. Then, methanol was removed
under reduced pressure and water (30 mL) was added. The aqueous
layer was extracted with DCM (3 x 30 mL), the organic extracts were
dried with Na2SO4 and evaporated to obtain the crude product, which
was purified by SiO2 column chromatography using 1-5% EtOAc in
hexanes as eluant to afford the desired compound.
2-(2-(bromomethyl)-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (3c). Amber solid. M.P.: 71,4-73,3 ºC. Rf = 0.42 (5%
EtOAc/hexanes). Yield: 566 mg (85%). 1H NMR (400 MHz, CDCl3) δ 8.65
(d, J = 2.6 Hz, 1H), 8.23 (dd, J = 8.5, 2.6 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H),
4.92 (s, 2H), 1.39 (s, 12H). 13C NMR (100 MHz, CDCl3) δ 151.2, 131.3,
131.2, 126.1, 84.9, 31.5, 25.0 (C-B signal does not appear). IR (max, cm-
1): 3018, 1525, 1332, 1215, 1120, 746, 669. HRMS (ESI) m/z calcd for
C13H16BBrNO4 [M-H]- 340.0361, found 340.0363.
General procedure for the synthesis of amino benzoxaboroles. To a
solution of arylboronate (341 mg, 1 mmol) in 1,4-dioxane (6.6 mL), a
solution of NaOH (200 mg, 5 mmol, 5 eq.) in water (9.8 mL) was added
and the resulting mixture was left under magnetic stirring at 60 ºC for 1 h.
Substrate consumption was monitored by TLC using 10% EtOAc in
hexanes as eluant. Then, conc. HCl (2.1 mL, 25 mmol, 25 eq.) was
slowly added and the reaction mixture was left under magnetic stirring at
4,4,5,5-tetramethyl-2-(2-methyl-3-nitrophenyl)-1,3,2-dioxaborolane (2a).20
Pale yellow solid. Rf = 0,41 (5% EtOAc/hexanes). Yield: 546 mg (69%).
1H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 7.4, 1.2 Hz, 1H), 7.80 (dd, J =
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10.1002/ejoc.201900013
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60 ºC overnight. The reaction was cooled to room temperature, Zn (705
mg, 11 mmol, 11 eq.) powder was added and the resulting mixture was
magnetically stirred for 1 h at room temperature, when substrate
consumption was confirmed by TLC (5% methanol in DCM). The reaction
was neutralized with saturated NaHCO3 (aq) (~24 mL), the formed solid
was filtered and washed with EtOAc (3 x 10 mL). The two phases of the
filtrate were separated and the aqueous phase was extracted with EtOAc
(4 x 25 mL). The combined organic extracts were dried with Na2SO4,
evaporated and pinacol was removed by azeotropic distillation with H2O
2-(2,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(8c).24
Orange oil. Yield: 362 mg (78%). 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J
= 1.5 Hz, 1H), 7.13 (dd, J = 7.7, 1.5 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H),
2.49 (s, 3H), 2.31 (d, J = 10.2 Hz, 3H), 1.34 (s, 12H). 13C NMR (100 MHz,
CDCl3) δ 141.8, 136.5, 134.0, 131.7, 129.9, 83.5, 25.0, 21.8, 20.9 (C-B
signal does not appear). 11B NMR (128 MHz, CDCl3) δ 30.3.
General procedure for benzylic bromination of dimethyl derivatives.
The following procedure was adapted from the literature.17 A solution of
arylboronate (232 mg, 1.0 mmol) in degassed ACN (10 mL) was added
to NBS (478 mg, 2.7 mmol, 2.7 eq.) and (PhCOO)2 (65 mg, 0.27 mmol,
27 mol%) in a pre-purged Schlenk flask. The flask was sealed under N2
and the reaction mixture was heated to 100 ºC for 24 h under magnetic
stirring. Then, the solvent was removed under reduced pressure, DCM
(25 mL) was added and the organic phase was washed with of saturated
NaHCO3 (aq) (3 x 25 mL). The organic phase was dried with Na2SO4 and
the solvent was removed under reduced pressure to afford the desired
product, which was used without further purification.
(7
x 3 mL). The crude material was purified by SiO2 column
chromatography using 0.5-5% methanol in DCM as eluant. If necessary,
trace pinacol was removed again by azeotropic distillation.
4-aminobenzo[c][1,2]oxaborol-1(3H)-ol (4a).10 Pale yellow solid. Yield:
112 mg (75%, over 3 steps). 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s,
1H), 7.11 – 6.99 (m, 1H), 6.94 (d, J = 7.1 Hz, 1H), 6.65 (d, J = 7.7 Hz,
1H), 5.00 (s, 2H), 4.79 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 142.2,
138.0, 127.9, 118.1, 115.4, 68.7 (C-B signal does not appear). 11B NMR
(128 MHz, DMSO-d6) δ 37.2.
2-(2,3-bis(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(9a). Amber oil. Yield: 331 mg (84%). H NMR (400 MHz, CDCl3) δ 7.80
1
5-aminobenzo[c][1,2]oxaborol-1(3H)-ol (4b).18 Pale yellow solid. Yield: 51
mg (34%, over 3 steps). 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H),
7.34 (d, J = 7.9 Hz, 1H), 6.50 (dd, J = 7.9, 1.9 Hz, 1H), 6.49 – 6.45 (m,
1H), 5.42 (s, 2H), 4.78 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 156.1,
151.4, 131.3, 113.6, 105.1, 69.5 (C-B signal does not appear). 11B NMR
(128 MHz, DMSO-d6) δ 38.5.
(dd, J = 7.4, 1.5 Hz, 1H), 7.40 (dd, J = 7.7, 1.5 Hz, 1H), 7.28 – 7.22 (m,
1H), 5.15 (s, 2H), 4.65 (s, 2H), 1.35 (s, 12H). 13C NMR (100 MHz, CDCl3)
δ 142.9, 137.3, 136.8, 133.7, 128.3, 84.0, 30.5, 28.8, 24.8 (C-B signal
does not appear). 11B NMR (128 MHz, CDCl3) δ 31.6. IR (max, cm-1):
2980, 1371, 1348, 1321, 1143, 966, 858, 665. HRMS (ESI) m/z calcd for
C14H18BBr2O2 [M-H]- 386.9772, found 386.9774.
6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (4c).13c Pale yellow solid. Yield:
80 mg (54%, over 3 steps, purification was not necessary). 1H NMR (400
MHz, DMSO-d6) δ 8.91 (s, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.97 – 6.82 (m,
1H), 6.71 (dd, J = 8.1, 1.8 Hz, 1H), 4.98 (s, 2H), 4.82 (s, 2H). 13C NMR
(100 MHz, DMSO-d6) δ 148.0, 141.9, 121.9, 118.0, 115.1, 70.1 (C-B
signal does not appear). 11B NMR (128 MHz, DMSO-d6) δ 38.4.
2-(2,4-bis(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(9b).25 Amber oil. Yield: 370 mg (94%). 1H NMR (400 MHz, CDCl3) δ 7.80
(d, J = 7.7 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.30 (dd, J = 7.7, 1.6 Hz, 1H),
4.89 (s, 2H), 4.46 (s, 2H), 1.36 (s, 12H). 13C NMR (100 MHz, CDCl3) δ
145.0, 140.9, 137.2, 130.6, 128.2, 84.1, 33.4, 32.8, 25.0 (C-B signal does
not appear). 11B NMR (128 MHz, CDCl3) δ 31.2.
General procedure for borylation of dimethylanilines. The following
procedure was adapted from the literature.15 A mixture of aniline (242 mg,
2 mmol), HBr 14% (4 mL) and methanol (4 mL) was cooled to 0 ºC and a
solution of NaNO2 (166 mg, 2.4 mmol, 1.2 equiv.) in water (1.6 mL) was
slowly added, care being taken to not raise the temperature above 0 ºC.
The resulting mixture was left under magnetic stirring at 0 ºC for 30 min.
Then, it was added to a stirring solution of B2pin2 (910 mg, 3.6 mmol, 1.8
equiv.) and NaOAc (327 mg, 4.0 mmol, 2.0 equiv.) in methanol (8.0 mL)
at room temperature, quickly and in small portions, using a Pasteur
pipette. The resulting mixture was left stirring for 1 h at room temperature.
Then, methanol was removed under reduced pressure and water (20 mL)
was added. The aqueous layer was extracted with DCM (3 x 20 mL), the
organic extracts were dried with Na2SO4 and evaporated to obtain the
crude product, which was purified by SiO2 column chromatography using
1% EtOAc in hexanes as eluant to afford the desired compound.
2-(2,5-bis(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(9c). Amber oil. Yield: 374mg (95%). 1H NMR (400 MHz, CDCl3) δ 7.81
(d, J = 1.9 Hz, 1H), 7.44 (dd, J = 7.9, 2.1 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H),
4.90 (s, 2H), 4.47 (s, 2H), 1.38 (s, 12H). 13C NMR (100 MHz, CDCl3) δ
144.6, 137.2, 137.0, 132.1, 130.8, 84.2, 33.3, 33.0, 25.0 (C-B signal does
not appear). 11B NMR (128 MHz, CDCl3) δ 31.1. IR (max, cm-1): 3016,
1346, 1215, 1139, 852, 756. HRMS (ESI) m/z calcd for C14H18BBr2O2 [M-
H]- 386.9772, found 386.9775.
General procedure for the synthesis of hydroxylmethyl
benzoxaboroles. To a solution of arylboronate (97 mg, 0.25mmol) in
THF (0.35 mL), a solution of NaOH (100 mg, 2.5 mmol, 10 eq.) in water
(0.65 mL) was added and the resulting mixture was left under magnetic
stirring at 50 ºC for 1 h. Then, HCl 6 M (1.25 mL, 7.5 mmol, 30 eq.) was
slowly added and the reaction mixture was left under magnetic stirring at
50 ºC for 2 h. The reaction was cooled, water was added (5 mL) and the
product was extracted with EtOAc (3 x 10 mL), dried with Na2SO4 and
the combined organic extracts were evaporated under reduced pressure.
Pinacol was removed by azeotropic distillation with water. The product
was purified by SiO2 column chromatography using 0-5% methanol in
DCM.
2-(2,3-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(8a).22
Orange oil. Yield: 339 mg (73%). 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J
= 7.3 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.13 – 7.04 (m, 1H), 2.47 (s, 3H),
2.27 (s, 3H), 1.35 (s, 12H). 13C NMR (100 MHz, CDCl3) δ 143.2, 136.6,
133.6, 132.4, 125.0, 83.6, 25.0, 20.6, 18.6 (C-B signal does not appear).
11B NMR (128 MHz, CDCl3) δ 30.7.
2-(2,4-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(8b).23
4-(hydroxymethyl)benzo[c][1,2]oxaborol-1(3H)-ol (10a). White solid. M.P.:
257 ºC (decomposition). Yield: 103 mg (63%, after 2 steps). 1H NMR
(400 MHz, D2O) δ 7.63 (d, J = 7.2 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.41
(t, J = 7.2 Hz, 1H), 5.05 (s, 2H), 4.60 (s, 2H). 13C NMR (100 MHz,
Methanol-d4) δ 153.3, 135.9, 130.4, 130.3, 128.5, 71.5, 62.9 (C-B signal
does not appear). 11B NMR (128 MHz, Methanol-d4) δ 31.9. IR (max, cm-
Orange oil. Yield: 362 mg (78%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J
= 8.1 Hz, 1H), 7.02 – 6.95 (m, 2H), 2.50 (s, 3H), 2.31 (s, 3H), 1.33 (s,
12H). 13C NMR (100 MHz, CDCl3) δ 145.1, 141.0, 136.2, 130.9, 125.7,
83.4, 25.0, 22.3, 21.6 (C-B signal does not appear).
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10.1002/ejoc.201900013
European Journal of Organic Chemistry
FULL PAPER
1): 2940, 2880, 1965, 1933, 1857, 1605, 1437, 1414, 1013. HRMS (ESI)
m/z calcd for C8H8BO3 [M-H]- 163.0572, found 163.0577.
[12] a) V. Zhdankin, P. J. Persichini III, L. Zhang, S. Fix, P. Kiprof,
Tetrahedron Lett. 1999, 40, 6705-6708. b) M. Lin, G. Chen, M. Jiang,
Polym. Chem. 2014, 5, 234 - 240.
5-(hydroxymethyl)benzo[c][1,2]oxaborol-1(3H)-ol (10b).26 White solid.
Yield: 164 mg (95%, after 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 9.13
(s, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.35 (s, 1H), 7.28 (d, J = 7.5 Hz, 1H),
5.27 (t, J = 5.5 Hz, 1H), 4.97 (s, 2H), 4.55 (d, J = 5.5 Hz, 2H). 13C NMR
(100 MHz, DMSO-d6) δ 154.1, 145.4, 130.2, 125.2, 119.0, 69.9, 63.0 (C-
B signal does not appear). 11B NMR (128 MHz, DMSO-d6) δ 32.6.
[13] For the use of amino benzoxaboroles in the synthesis of biactive
molecules, see: a) D. Ding, Y. Zhao, Q. Meng, D. Xie, B. Nare, D. Chen,
C. J. Bacchi, N. Yarlett, Y. K. Zhang, V. Hernandez, Y. Xia, Y. Freund,
M. Abdulla, K. H. Ang, J. Ratnam, J. H. McKerrow, R. T. Jacobs, H.
Zhou, J. J. Plattner, ACS Med. Chem. Lett. 2010, 1, 165-169. b) C. Z.
Ding, Y. K. Zhang, X. Li, Y. Liu, S. Zhang, Y. Zhou, J. J. Plattner, S. J.
Baker, L. Liu, M. Duan, R. L. Jarvest, J. Ji, W. M. Kazmierski, M. D.
Tallant, L. L. Wright, G. K. Smith, R. M. Crosby, A. A. Wang, Z. J. Ni, W.
Zou, JWright, Bioorg. Med. Chem. Lett. 2010, 20, 7317-7322. c) V.
Alterio, R. Cadoni, D. Esposito, D. Vullo, A. D. Fiore, S. M. Monti, A.
Caporale, M. Ruvo, M. Sechi, P. Dumy, C. T. Supuran, G. D. Simone, J.
Y. Winum, Chem. Commun. 2016, 52, 11983-11986.
6-(hydroxymethyl)benzo[c][1,2]oxaborol-1(3H)-ol (10c).27 White solid.
Yield: 100mg (61%, after 2 steps). 1H NMR (400 MHz, Methanol-d4) δ
7.54 (s, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 4.96 (s,
2H), 4.53 (s, 2H). 13C NMR (100 MHz, Methanol-d4) δ 154.5, 141.6,
131.1, 129.8, 122.1, 72.2, 65.2 (C-B signal does not appear). 11B NMR
(128 MHz, Methanol-d4) δ 31.9.
[14] For the use of hydroxymethyl benzoxaboroles in the synthesis of
bioactive molecules, see: a) Y. K. Zhang, J. J. Plattner, E. E. Easom, D.
Waterson, M. Ge, Z. Li, L. Li, Y. Jian, Tetrahedron Lett. 2011, 52, 3909-
3911. b) Y. K. Zhang, J. J. Plattner, Y. R. Freund, E. E. Easom, Y. Zhou,
L. Ye, H. Zhou, D. Waterson, F. J. Gamo, L. M. Sanz, M. Ge, Z. Li, L. Li,
H. Wang, H. Cui, Bioorg. Med. Chem. Lett. 2012, 22, 1299-1307. c) J.
Zhang, F. Yang, Z. Qiao, M. Zhu, H. Zhou, Bioorg. Med. Chem. Lett.
2016, 26, 5797–5801. d) D. Ding, Q. Meng, G. Gao, Y. Zhao, Q. Wang,
B. Nare, R. Jacobs, F. Rock, M. R. K. Alley, J. J. Plattner, G. Chen, D.
Li, H. Zhou, J. Med. Chem. 2011, 54, 1276-1287. e) R. W. Gunasekara,
Y. A. Zhao, J. Am. Chem. Soc. 2017, 139, 829-835. f) J. M. Gamrat, G.
Mancini, S. J. Burke, R. C. Colandrea, N. R. Sadowski, B. C. Figula, J.
W. Tomsho, J. Org. Chem. 2018, 83, 6193−6201.
Acknowledgments
We acknowledge CAPES, CNPq and INCT-Catálise for financial
support. We are grateful to Prof. Francisco P. Dos Santos and
PhD student Eric F. Lopes for assistance with 11B NMR
experiments.
Keywords: synthetic methods • heterocycles • boron • borylation
[15] a) C. Zhao, D. Xue, Z. Jia, C. Wang, J. Xiao, Synlett 2014, 25, 1577-
1584. b) W. Erb, A. Hellal, M. Albini, J. Rouden, J. Blanchet, Chem. Eur.
J. 2014, 20, 6608-6612.
[1]
a) A. Suzuki, Angew. Chem. Int. Ed. 2011, 50, 6722-6737; b) N.
Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483.
P. C. Trippier, C. McGuigan, MedChemComm 2010, 1, 183-198.
D. G. Hall, Ed. Boronic Acids, Wiley-VCH, Weinheim, 2005.
U. Lücking, Angew. Chem. Int. Ed. 2013, 52, 9399-9408.
Z. J. Leśnikowski, Expert Opin. Drug Discov. 2016, 11, 569-578.
A. Adamczyk-Woźniak, K. M. Borys, A. Sporzyński, Chem. Rev. 2015,
115, 5224-5247.
[16] J. Zhang, X. Wang, H. Yu, J. Ye, Synlett 2012, 23, 1394-1396.
[17] S. Cao, R. Christiansen, X. Peng, Chem. Eur. J. 2013, 19, 9050-9058.
[18] B. Eastman, T. Glinka, S. Hecker, R. Higuchi, O. Rodny, WO
2012109164, 2012.
[2]
[3]
[4]
[5]
[6]
[19] D. B. G. Williams, M. Lawton, J. Org. Chem. 2010, 75, 8351-8354.
[20] L. D. Marciasini, M. Vaultier, M. Pucheault, Tetrahedron Lett. 2014, 55,
1702-1705.
[7]
A. Nocentini, C. T. Supuran, J. Y. Winum, Expert Opin. Ther. Pat. 2018,
493-504.
[21] H. Li, Y. Liu, J. Liu, Z. Liu, Chem. Commun. 2011, 47, 8169-8171.
[22] Y. Lee, S. Y. Baek, J. Park, S. T. Kim, S. Tussupbayev, J. Kim, M. H.
Baik, S. H. Cho, J. Am. Chem. Soc. 2017, 139, 976-984.
[8]
[9]
M. Dowlut, D. G. Hall, J. Am. Chem. Soc. 2006, 128, 4226-4227.
L. Ye, D. Ding, Y. Feng, D. Xie, P. Wu, H. Guo, Q. Meng, H. Zhou,
Tetrahedron 2009, 65, 8738.
[23] A. Zernickel, W. Du, S. A. Ghorpade, D. N. Sawant, A. A. Makki, N.
Sekar, J. Eppinger, J. Org. Chem. 2018, 83, 1842-1851.
[10] X. Li, S. Zhang, Y. K. Zhang, Y. Liu, C. Z. Ding, Y. Zhou, J. J. Plattner,
S. J. Baker, W. Bu, L. Liu, W. M. Kazmierski, M. Duan, R. M. Grimes, L.
L. Wright, G. K. Smith, R. L. Jarvest, J. J. Ji, J. P. Cooper, M. D. Tallant,
R. M. Crosby, K. Creech, Z. J. Ni, W. Zou, J. Wright, Bioorg. Med.
Chem. Lett. 2011, 21, 2048-2054.
[24] T. Furukawa, M. Tobisu, N. Chatani, J. Am. Chem. Soc. 2015, 137,
12211-12214.
[25] X. Peng, Y. Kuang, S. Cao, W. Chen, Y. Wang, US 20130045949,
2013.
[26] K.-D. Zhang, S. Matile, Angew. Chem. Int. Ed. 2015, 54, 8980-8983.
[27] Z. Qiao, Q. Wang, F. Zhang, Z. Wang, T. Bowling, B. Nare, R. T.
Jacobs, J. Zhang, D. Ding, Y. Liu, H. Zhou, J. Med. Chem. 2012, 55,
3553-3557.
[11] Y. Zhang, J. J. Plattner, Y. R. Freund, E. E. Easom, Y. Zhou, J. Gut, P.
J. Rosenthal, D. Waterson, F. Gamo, I. Angulo-Barturen, M. Ge, Z. Li, L.
Li, Y. Jian, H. Cui, H. Wang, J. Yang, Bioorg. Med. Chem. Lett. 2011,
21, 644–651.
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10.1002/ejoc.201900013
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Entry for the Table of Contents
FULL PAPER
Synthesis of Benzoxaboroles
Rodrigo S. Fuscaldo, Pedro H. V.
Vontobel, Eduam O. Boeira, Angélica V.
Moro,* and Jessie S. da Costa*
Page No. – Page No.
The development of a short, simple and efficient synthesis of amino- and
hydroxymethyl-substituted benzoxaboroles is described. The key step was
the early stage incorporation of the boron by the borylation of an aniline. The
formed boronates were then elaborated to the final products in two additional
steps, in good yields.
Synthesis of Amino- and
Hydroxymethyl Benzoxaboroles:
Prominent Scaffolds for further
Functionalization
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