Synthesis of Borinic Acids and Borinate Adducts Using Diisopropylaminoborane

Article abstract of DOI:10.1021/acs.orglett.5b01620

In situ formation of aryl Grignard under Barbier condition and diisopropylaminoborane as boron source allows a complete control of the addition onto the boron electrophile. Analytically pure borinic acid derivatives were produced at the gram scale without column chromatography and isolated as borinates adducts, with ethanolamine or 8-hydroxyquinoline, after workup.

Full text of DOI:10.1021/acs.orglett.5b01620

Letter
pubs.acs.org/OrgLett
Synthesis of Borinic Acids and Borinate Adducts Using
Diisopropylaminoborane
Ludovic Marciasini, Bastien Cacciuttolo, Michel Vaultier, and Mathieu Pucheault*
Institut des Sciences Molec
Cedex, France
́
ulaires, UMR 5255, Universite
́
de Bordeaux, IPB, CNRS, 351 Cours de la liber
́
ation, F-33405 Talence
S
* Supporting Information
ABSTRACT: In situ formation of aryl Grignard under Barbier
condition and diisopropylaminoborane as boron source allows
a complete control of the addition onto the boron electrophile.
Analytically pure borinic acid derivatives were produced at the
gram scale without column chromatography and isolated as
borinates adducts, with ethanolamine or 8-hydroxyquinoline,
after workup.
rylboronic acids are versatile intermediates in organic
mixture of boronic and borinic acids, leading to purification
issues.17
A
synthesis.1 They are employed in numerous systems such as
Suzuki−Miyaura2 and Chan−Evans−Lam cross coupling
reactions,3,4 Petasis reaction,5 or transformed via functional
group interconversion to halogen, carboxylic acid, phenol, and
nitrile. Arylborinic acids are much less exemplified in literature.6
They can be used as a partner in cross-coupling reactions,7
transferring both aryl groups,8−11 as Lewis acid catalysts,12,13 in
Ca2+ regulation14,15 and OLEDs.16 The fewer applications may
be due to the relative difficulty for accessing these compounds in
a selective manner. In short, most methods are currently based
on the addition of strong organometallic reagents, derived mainly
from magnesium or lithium, to boron based electrophiles,
typically trialkylborates,7 boron halides,8 or diborane12 (Scheme
1). Less employed on preparative scale is the transmetalation
from tin to boron developed by Thorpe et al.6
We envisioned that using aminoborane could lead to a
difference in reactivity. Indeed, donation of the nitrogen lone pair
to the boron vacancy diminishes the Lewis acidity of the boron
center and reinforces the boron−nitrogen bond strength. Hence,
equilibrium between borate and borane could be largely affected
by this substitution. We started our investigation with
diisopropylaminoborane used largely in our group as cross
coupling partner.18−23 Diisopropylaminoborane is one of the few
aminoboranes that exists under a monomeric form in solution,
due to the steric bulkiness of the alkyl chain preventing
association in dimers, trimers, or oligomers.
Commercial phenyllithium addition to diisopropylaminobor-
ane in THF at −78 °C followed by an acidic workup showed the
formation of several species. Phenylborinic acid Ph2BOH and
phenylboronic acid PhB(OH)2, respectively, resulting from the
addition of two or one phenyllithium onto iPr2NBH2 were
mainly obtained, in various proportions, as determined by 11B
NMR (Table S1).
Scheme 1. Borinic Acid Synthesis
As witnessed by 11B NMR, a complex mixture was obtained
upon addition of one equivalent of phenyl lithium Li-2a on
aminoborane (Figure 1a). At room temperature, mostly
tetracoordinated borates were observed resulting from the
addition of one PhLi Li-2a ([PhBH2NiPr2]−Li+ Li-4a, triplet at
−12.8 ppm), two PhLi ([Ph2BHNiPr2]−Li+ Li-6a doublet at
−7.8 ppm), and the major compound, lithium diisopropyl-
aminoborohydride Li-7 observed ([BH3NiPr2]−Li+ quartet at
−23.5 ppm). Upon addition of two equivalents of PhLi Li-2a,
only tetravalent species were obtained (Figure 1b), with an
increased amount of the diarylcompound Li-6a, but still in
mixture with the boronic acid derivatives Li-4a and lithium
diisopropylaminoborohydride Li-7. A singlet at 0 ppm, which has
yet to be attributed, also appeared in a non-negligible quantity.
Using these methods, the main issue is related to the control of
the number of aryl residue transferred to the boron center.
Indeed, the equilibrium between borates and boranes with
reversible binding of halides and alkoxydes occurs rapidly above
−50 °C or even lower. Boronic acids are hence obtained by slow
addition of organometallic agent to an excess of boron
electrophile. In contrast, tetraarylborates are usually prepared
by extensive heating using a large excess of organometallic
reagents. Borinic acids, bearing only two aryl groups, stand in
between, and a 2:1 stoichiometry conducts, in most cases, a
Received: June 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01620
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Comparison between Magnesium and Lithium
Species
Figure 1. 11B NMR study of addition of phenyllithium and
phenylmagnesium bromide on diisopropylaminoborane.
This poor selectivity was directly translated into moderate
yields when the reaction was performed on preparative scale.
Indeed, under optimized conditions, diphenylborinic acid 3a,
bis(4methoxyphenyl)borinic acid 3b, and diphenyleneoxaborine
3c were isolated only in 56%, 53%, and 40% yield, respectively
(Scheme 2).
Therefore, the second addition is facilitated in the case of the
magnesium derivatives. Similarly, LiH displayed a high tendency
to form the lithium aminoborohydride in the presence of the
starting aminoborane (Scheme 3), diminishing the availability of
boron electrophile in the mixture. Overall, Grignard reagents
were found to be superior to lithium species in many aspects.
This effect is currently rationalized through DFT calculation.
It is noteworthy that the addition of a third Grignard onto the
diarylaminoborane has never been observed, even at high
temperature, probably due to the poor reactivity of this
intermediate, deactivated by the donation of the amino residue
and the steric hindrance of the aryl groups. As such, the use of an
excess Grignard only led to the formation of borinic acid. At
refluxing THF, the addition of 4-MePhMgBr to BH2NiPr2
followed by hydrolysis using aqueous HCl afforded the expected
borinic acid 3d in 82% isolated yield (Table 1, entry 1). Switching
to Et2O decreased the yield to 49% (Table 1, entry 2). According
to precedent in literature,24 we attempted a one-pot protocol
under Barbier conditions, and it successfully led to an excellent
96% isolated yield in THF (Table 1, entry 3) and 77% in Et2O
Table 1, entry 4). Decreasing the large excess of aryl bromide to
2.2 equiv, the borinic acid was isolated in 83% yield (Table 1,
Scheme 2. Borinic Acid Synthesis Using Aryllithium
As the equilibrium between tri- and tetravalent species is
governed by the substituent but also the borate countercation, we
investigated magnesium derivatives behavior. Unlike phenyl-
lithium Li-2a, when phenylmagnesium bromide Mg-2a was
added to the same aminoborane, a full conversion was observed
as witnessed by the disappearance of the characteristic triplet at
35 ppm of the starting material 1 (Figure 1c). The resulting
mixture was mainly composed of the expected diisopropylami-
nophenylborohydride ([PhBH2NiPr2]−MgBr+ Mg-4a, triplet at
−12 ppm) together with the aminophenylborane (PhBHNiPr2
5a, broad doublet at 38.5 ppm) formed via elimination of
HMgBr. Low amounts of diisopropylami-nodiphenylborane
(Ph2BNiPr2 8a, broad singlet at 43 ppm) and magnesium
d i i s o p r o p y l a m i n o b o r o h y d r i d e w e r e o b s e r v e d
([BH3NiPr2]−MgBr+ Mg-7, q at −22 ppm) resulting respectively
from the second addition of PhMgBr Mg-2a and trapping of
“HMgBr” by iPr2NBH2 1. The same experiment was performed
using 2 equiv of PhMgBr Mg-2a (Figure 1d). The main product
is diisopropylaminodiphenylborane (Ph2BNiPr2 8a) with the
diisopropylaminephenylborohydride ([PhBH2NiPr2]−MgBr+
Mg-4a) resulting from a single PhMgBr Mg-2a addition.
Globally, magnesium borohydride displayed a higher tendency
for hydride elimination than the corresponding lithium species.
Hence, after the first addition of the organometallic species, the
equilibrium toward the formation of the arylaminoborane 5a is
favored in the case of magnesium and disfavored in the case of
lithium (Scheme 3).
Table 1. Optimization of the Borinic Acid Synthesis
a
entry
solvent
t (°C)
X
equiv ArX
method
yield (%)
1
2
3
4
5
6
7
THF
Et2O
THF
Et2O
THF
THF
THF
70
40
70
40
70
70
70
Br
Br
Br
Br
Br
I
3
A
A
B
B
B
B
B
82
49
96
77
83
60
<40
3
3
3
2.2
2.2
2.2
Cl
a
Isolated yield.
B
DOI: 10.1021/acs.orglett.5b01620
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Organic Letters
Letter
entry 5). In order to widen the scope of the methodology, iodides
and chlorides were tested but, unfortunately, iodide led only to a
moderate 60% yield (Table 1, entry 6). The generation of the
Grignard reagent from aryl chlorides did not reach completion
after 2 days in refluxing THF and will require a complete study
(Table 1, entry 7). Noticeably, all reactions were performed on
the gram scale (10 mmol).
Table 2. Borinate Synthesis
Treatment of the crude borinic acid with ethanolamine or 8-
hydroxyquinoline at room temperature, gave the analytically
pure borinate adducts after precipitation in Et2O or pentane
(Table 2). Some variations were done on aryl bromides with
methyl and methoxy groups in meta and para positions (Table 2,
entries 1−4); simple aryl groups such as naphthyl or phenyl led
to good yields (Table 2, entries 5−6). Para substituted aryl
Grignards with t-butyl groups, n-butyl chains, or when using 4-
bromobiphenyl as starting materials gave the expected borinates
in good yields (Table 2, entries 7−9). Bromodimethylarenes led
to similar results, leading to bis(3,5-dimethylphenyl)borinate
and bis(3,4-dimethylphenyl)borinate in 72% and 77% yield,
respectively (Table 2, entries 10−11). More elaborated borinic
acids were synthesized with this methodology isolated as
ethanolamine adducts. 5-Bromobenzothiophene led to the
corresponding borinate 9m in 76% yield (Table 2, entry 12),
and 4-bromophenyldiphenylamine led to the bis-
(triphenylamine)borinate 9n in an excellent 95% yield (Table
2, entry 13). This methodology was applied to the synthesis of
active pharmaceutical ingredient AN0128, effective in the
treatment of periodontal diseases.25 The classical treatment by
ethanolamine at the end of the reaction was replaced by a 5-
hydroxy-2-pyridinecarboxylic acid in EtOH and give the desired
product 9o in 74% yield (Scheme 4). As the previous NMR study
Scheme 4. Unsymmetrical Borinic Derivative Synthesis
clearly emphasized, the addition of Grignard proceeded stepwise,
and we envisioned extending the scope of our methodology to
the preparation of nonsymmetrical borinic acids. Reports for the
preparation of such species are very scarce. In 1959, Mikhailov
first reported the addition of a Grignard to a pinacol
arylboronate.26 To our knowledge, other reports25,27,28 led to
similar derivatives, using a similar approach of aryl lithium
addition to pinacol boronates. Overall all previous approaches
require isolation of the boronic acid and proceed in two distinct
steps. As a 1:1 mixture of ArMgBr:1 we used an excess of
diisopropylaminoborane to generate arylaminoborane 5b as a
sole product. After volatile removal, a different aryl bromide
reacted with the excess magnesium, leading to the diary-
a
b
Isolated yield of analytically pure borinates. Cond. a: 2-amino-
ethanol, 1.2 equiv, rt, Et2O. Cond. b: hydroxyquinoleine, 1.2 equiv, rt,
c
Et2O. 5-Hydroxy-2-pyridinecarboxylic acid addition in EtOH.
laminoborane. Finally hydrolysis and aminoethanol treatment
led to the nonsymmetrical borinate 9p in 78% yield (Scheme 4).
In summary, we developed a novel procedure for the synthesis
of aryl borinic acids derived in good overall yield. The method
C
DOI: 10.1021/acs.orglett.5b01620
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Organic Letters
Letter
(19) Guerrand, H. D. S.; Marciasini, L. D.; Jousseaume, M.; Vaultier,
M.; Pucheault, M. Chem. - Eur. J. 2014, 20, 5573−5579.
(20) Pascu, O.; Marciasini, L.; Marre, S.; Vaultier, M.; Pucheault, M.;
Aymonier, C. Nanoscale 2013, 5, 12425−12431.
requires neither purification by column chromatography nor
cryogenic conditions. Our methodology can easily provide those
compounds on the multigram scale, allowing the deepest use of
borinic acids in organic synthesis or electronics applications.
Diisopropylaminoborane had shown a nice reactivity and
selectivity providing clean borinic acids. Investigations are
currently in progress to better understand the reaction
mechanism and allow the synthesis of more elaborated borinic
acid derivatives.
(21) Marciasini, L. D.; Richy, N.; Vaultier, M.; Pucheault, M. Adv.
Synth. Catal. 2013, 355, 1083−1088.
(22) Marciasini, L.; Richy, N.; Vaultier, M.; Pucheault, M. Chem.
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(23) Gendrineau, T.; Marre, S.; Vaultier, M.; Pucheault, M.; Aymonier,
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R. Bioorg. Med. Chem. Lett. 2006, 16, 5963−5967.
ASSOCIATED CONTENT
* Supporting Information
Experimental details, characterizations, and NMR data. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01620.
■
S
(26) Mikhailov, B. M.; Fedotov, N. S. Zh. Obshch. Khim. 1959, 29,
2244.
(27) Hofer, A.; Kovacs, G.; Zappatini, A.; Leuenberger, M.; Hediger,
M. A.; Lochner, M. Bioorg. Med. Chem. 2013, 21, 3202−3213.
(28) Benkovic, S. J.; Baker, S. J.; Alley, M. R. K.; Woo, Y.-H.; Zhang, Y.-
K.; Akama, T.; Mao, W.; Baboval, J.; Rajagopalan, P. T. R.; Wall, M.;
Kahng, L. S.; Tavassoli, A.; Shapiro, L. J. Med. Chem. 2005, 48, 7468−
7476.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: m.pucheault@ism.u-bordeaux1.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
L.M. thanks the Reg
́
ion d’Aquitaine for funding. Johnson Mattey
is acknowledged for a gift of transition metal halides. ANR
NANOCAUSYS no. 12-CDII-0010 is acknowledged for funding;
this work has been cofunded by the CNRS, Universite
Bordeaux, and Conseil Regional d’Aquitaine.
́
de
́
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