Borinic Acids via Direct Arylation of Amine-Borane Complexes: An Air- and Water-Stable Boron Source

Article abstract of DOI:10.1055/s-0036-1588345

A synthesis of borinic acids and borinates was optimized using amine-borane complexes as a water and air insensitive borylating agent. The reaction operates under convenient conditions using a non-cryogenic temperature and with no flash chromatography, and it gives no boron impurities. The reaction proceeds through a tandem dehydrogenation-double addition mechanism.

Full text of DOI:10.1055/s-0036-1588345

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
feature
A
J. Richard et al.
Feature
Synthesis
Borinic Acids via Direct Arylation of Amine–Borane Complexes:
An Air- and Water-Stable Boron Source
Jimmy Richard
Mélodie Birepinte
Jean Baptiste Charbonnier
Virginie Liautard
Sandra Pinet*
Mathieu Pucheault*
Institut des Sciences Moléculaires, UMR 5255 CNRS - Université
de Bordeaux, 351 cours de la libération, 33405 Talence cedex,
France
sandra.pinet@u-bordeaux.fr
mathieu.pucheault@u-bordeaux.fr
Received: 07.10.2016
Accepted: 13.10.2016
Published online: 15.11.2016
DOI: 10.1055/s-0036-1588345; Art ID: ss-2016-z0712-fa
nation of borinic acid into the boronic acid occurs simulta-
neously leading to mixtures.10 Other boron electrophiles
have been used but lack practicability and selectivity, such
as diborane5a or boron halide.11 Overall a fine balance of
stoichiometry and temperature has to be found to obtained
good conversion as witnessed by the Dupont/Merck syn-
thesis of Losartan for which the intermediate preparation of
a non-symmetrical borinate was key to success.12 Recently
we proposed diisopropylaminoborane as a boron electro-
phile.13 It indeed solved the purity problem as the interme-
diate diarylaminoborane is not sufficiently electrophilic to
undergo a third addition. Hence the addition of an excess of
Grignard reagent led to the exclusive formation of the
borinic acid, after hydrolysis. However, despite the relative
low cost and ease of preparation of this reagent, the insta-
bility of aminoborane hampers the popularity of the meth-
od and prompted us to evaluate a better alternative.
We based our approach on turning to our advantage the
intrinsic instability of magnesium aminoborohydride
which we discovered during our previous study. In short,
compared to lithium aminoborohydride, magnesium ana-
logues are much more prone to hydride elimination, lead-
ing to the trivalent boron derivatives. This led to an efficient
synthesis of the borinic acid with Grignard reagents, but
when lithiated analogues were used it led mostly to boronic
acids. This phenomenon has also been observed during the
addition of ArMgBr to pinacol borane, a process in which
the hydride has proved to be a decent leaving group.14 In
our case we envisioned preparing directly the magnesium
aminoborohydride 3 via deprotonation of the amine–
borane complex 1 (Scheme 1, step A.1); the resulting com-
pound 3 would then upon HMgBr15 elimination (Scheme 1,
step A.2) lead to the corresponding aminoborane 4, which
then could react directly with the Grignard reagent 2, in ex-
cess, to form the diarylaminoborane 8 after two additions
Abstract A synthesis of borinic acids and borinates was optimized us-
ing amine–borane complexes as a water and air insensitive borylating
agent. The reaction operates under convenient conditions using a non-
cryogenic temperature and with no flash chromatography, and it gives
no boron impurities. The reaction proceeds through a tandem dehydro-
genation–double addition mechanism.
Key words borinic acids, borinates, amine–borane complexes, boryla-
tion
Among boron derivatives, borinic acids1 are probably
the least popular, and yet they display some of the most in-
teresting properties. Besides the peculiar biological activity
of some derivatives,2 borinic acids have mostly been used
for their enhanced Lewis acidity3 when compared to the
parent boronic acids,4 or for their selective and reversible
protection of diols, especially carbohydrates.5 They also
have been used in OLEDs6 or as cross-coupling partners
with aryl halides7 or arenes8 similarly to boronic acids, but
with the possibility of transferring both carbon-centered
groups. This relative scarcity of uses of borinic acids in or-
ganic chemistry is mostly related to the difficult access to
this structure, relying mostly on the careful addition of or-
ganolithium or -magnesium derivatives to trialkyl borates.1
Due to fast reversible binding of alkoxides or halides to bo-
ron, even at low temperatures, the selective addition of two
residue to classical borates, such as B(OMe)3 or B(OiPr)3, is
challenging and the product is often contaminated by the
trisubstituted borane and/or the corresponding boronic
9
acid. When B(OtBu)3 is used, steric hindrance limits the
third addition. Increasing the temperature is often required
to attain high conversions, but in many case protodeboro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
J. Richard et al.
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Synthesis
Biographical Sketches
Jimmy Richard was born in
Vitry-le-Francois (France) in 1992.
He got his Master’s degree from
University of Reims in 2016. He
is now a Ph.D. candidate at the
University of Strasbourg.
Mélodie Birepinte was born
in Langon (France) in 1993. She
got her Master’s degree in or-
ganic chemistry from the Uni-
versity of Bordeaux in 2016. She
is now a Ph.D. candidate in the
group of Mathieu Pucheault
working on methodologies as-
sociated with boron chemistry.
Jean-Baptiste Charbonnier
was born in Vichy (France) in
1990. He graduated from
Ensiacet in Toulouse in chemical
process engineering with a spe-
cialization in microfluidic sys-
tem in 2014. He then joined the
group of Mathieu Pucheault as a
Ph.D. candidate on the synthe-
sis of active pharmaceutical in-
gredients using flow chemistry.
Dr. Virginie Liautard was
(France) in 2008 under the su-
pervision of Prof. O. R. Martin.
She then joined York University
(Canada) in 2009 as a post-doc-
toral fellow with Prof. M. G.
Organ. In 2010, she joined the
University of Bordeaux (France)
where she has worked with Prof.
Yannick Landais (2010–2013)
and Dr. Mathieu Pucheault.
born
in
Plessis-Bouchard
(France) in 1981. She received a
Ph.D. in organic chemistry from
the University of Orléans
Dr. Sandra Pinet was born in
Grenoble (France) in 1973. After
graduating from the University
Joseph Fourier (Univ. Grenoble-
Alpes), she joined the group of
Prof. Yannick Vallée and ob-
tained her Ph.D. in organic
chemistry in 1999. Then, she
moved to the University of Mi-
ami (Florida, USA) to work as a
postdoctoral fellow with Prof.
Robert E. Gawley. Her research
in Florida was directed toward
the development of chemosen-
sors for Saxitoxin. In 2001, she
worked on the alkynylation and
vinylation of nitrones as a teach-
ing fellow. In 2003 she was ap-
pointed Assistant Professor at
the Ecole Nationale Supérieur
de Chimie, Biologie et de Phy-
sique of Bordeaux (Bordeaux-
INP, France) at the Institute of
Molecular Sciences (University
of Bordeaux) in the group of
Mathieu Pucheault. Her re-
search interests include the
development of synthesis meth-
ods based on boron chemistry
and the elaboration of lumines-
cent supramolecular sensors.
Dr. Mathieu Pucheault was
born in Villeneuve St Georges
(France) in 1979. After graduat-
ing from the Ecole Normale
Supérieure (Paris, France), he
joined the group of Prof. Jean-
Pierre Genet where he got his
Ph.D. degree in 2004 in the field
of organometallic catalysis. Af-
ter a post-doctoral stay in the
group of Prof C. M. Crews at
Yale University (New Haven,
USA), where he studied small
molecule induced protein deg-
radation, he was appointed as
CNRS researcher in Rennes
(France). He is now CNRS Re-
search Director at the Institute
of Molecular Sciences at the
University of Bordeaux, where
his research interests cover,
since 2011, various areas includ-
ing
sustainable
chemistry,
nanocatalysis, and flow chemis-
try with a strong focus on boron
chemistry.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
J. Richard et al.
Feature
Synthesis
(Scheme 1, steps B.1 and C.1) and two hydride eliminations
(Scheme 1, steps B.2 and C.2). Hydrolysis (Scheme 1, step D)
would then afford the diarylborinic acid 9.
Ar
B
OH
Ar
9
(step D)
H
H
R
R
excess ArMgX
Ar
B
R
H
B
N
H
N
no 3rd addition
Ar
R
R = iPr, DIPAB, 1a
R = Cy, DICAB, 1b
8
Ar MgX
(step A.1)
Ar
(step
C.2)
HMgX
2
H
–
–
H
H
R
Ar
Ar
R
N
MgX+
MgX+
H
B
N
B
R
H
R
7
3
MgX2
+
HMgX
MgH2
Ar MgX
(step
C.1)
Figure 1 11B NMR of DIPAB reactivity in the presence of Grignard re-
agents: (a) DIPAB 1a in C6D6; (b) DIPAB + nBuMgBr (1 equiv), r.t., 10
min; (c) DIPAB + PhMgBr (5 mol%), r.t., 5 min; (d) DIPAB + PhMgBr (5
mol%), r.t., 5 min, then addition of DIPAB (4 equiv).
(Step A.2)
2
Ar MgX
HMgX
–
2
H
R
R
Ar
R
N
H
H
R
R
B
N
B
Ar
B
N
MgX+
H
H
R
(step B.1)
(step B.2)
4
5
6
mediate reactivity between organolithium species and true
Grignard reagents, such as iPrMgCl, EtMgBr, or ethynylMg-
Br. Overall the best system turned out to be 5 mol% PhMgBr
in THF at room temperature which led to a complete dehy-
drogenation of DIPAB 1a or DICAB 1b within 5 minutes
(Scheme 2). Mechanistically, the reaction is thought to pro-
ceed via an autocatalytic cycle, one of the reaction products
[BH3NR2]MgBr 3a being the reagent as well (Scheme 3).
Scheme 1 Possible mechanism for the addition of arylmagnesium ha-
lide to amine–borane complexes
In benzene-d6, the reaction between diisopropylamine–
borane (DIPAB, 1a) and nBuMgBr led to the exclusive for-
mation of the magnesium bromide diisopropylaminoboro-
hydride 3a. But after 10 minutes, some addition product
was already observed with a mixture of butylaminoborane
6a and aminoborohydride 3a (Figure 1, b). With PhMgBr,
deprotonation was rapid, and selective, but the addition
still resulted into some addition product 6. Using only 5
mol% of PhMgBr (Figure 1, c), the formation of the aminob-
orane 4a was quantitative after 5 minutes. This can be ex-
plained by the direct reaction between the aminoborohy-
dride and the amine–borane complex, leading to H2 evolu-
tion and the formation of the aminoborane. This was
confirmed by the addition of 4 equivalents of DIPAB 1a to
the previous reaction mixture (Figure 1, d). After 9 minutes,
all the additional DIPAB 1a was converted into the aminob-
orane 4a. For lithiated species, deprotonation was fast, but
38 hours were required to achieve full conversion with BuLi
and 25 hours with PhLi (see the Supporting Information).
Hence we found that a catalytic amount of Grignard re-
agent was sufficient to dehydrogenate bulky dialkylamine–
borane complexes. A fast optimization showed that lithi-
um-based organometallics were, as expected, inefficient.
Lithium magnesiate, such as iPrMgCl–LiCl, display an inter-
H
H
R
R
H
H
5 mol% PhMgBr
THF, r.t.
H
B
N
H
B
NR2
H2
+
4
1
H
H
H
H
H
H
H
H
B
NH
O
H
B
N H
H
B
N
H
H
B
N H
H
B
N H
H
H
H
H
5 min, >95%
5 min, >95%
5 h, 6%
5 h, <1%
H
5 h, <1%
H
H
Ph
H
H
H
H
H
n-Hex
H
H
B
N H
H
B
N
H
H
B
N H
H
B
N
H
H
B
N H
H
H
H
H
H
H
H
5 h, <1%
5 h, <1%
5 h, <1%
5 h, <1%
5 h, <1%
Scheme 2 Dehydrogenation of amine–borane complexes
Unfortunately, the reaction was not as general as we
wished for, and few amine–boranes can be dehydrogenated
via this PhMgBr promoted autocatalysis. The most probable
reason is related to the steric bulkiness introduced by large
iPr or Cy group on the amine. In solution, aminoboranes de-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
J. Richard et al.
Feature
Synthesis
equiv, 12.5 mmol), DIPAB 1a (5 mmol), and Mg (3.3 equiv,
16.5 mmol) in THF led in most cases to the borinic acid in
good yields. However, in some cases the reactivity of the in
situ generated Grignard was too low to promote the DIPAB
or DICAB dehydrogenation (Scheme 4, R = NO2). A proce-
dure using a catalytic amount of PhMgBr to induce dehy-
drogenation was then optimized and most compounds
were isolated using this two-step procedure.
H
H
iPr
H
H
B
N
iPr
1a
PhMgBr
2
H
H
iPr
H
H
H
MgBr+
B– NiPr2
H
B
N
H
iPr
PhH
3a
1a
H
H
H
NiPr2
+
H
B
4a
Reaction scope was investigated, and few limitations
have so far been found (Scheme 5). The main downside is
the requirement of having a strong organometallic reagent
and substitution was, therefore, limited to functional
groups unreactive to Grignard reagents. Orthometalation or
reaction with iPrMgBr·LiCl,16 known to tolerate more func-
tional groups have yet to be tested and prove their compati-
bility with the rest of the addition sequence. Nonetheless,
chlorides were tolerated due to the poor reactivity of mag-
nesium with aryl chlorides. Unsurprisingly, alkyl and aryl
group are compatible and borinic acids were isolated in
good yields. In all cases, products were isolated as borinic
acids 9 if an HCl/H2O workup was performed or as ethanol-
amine borinates 11 if the amino alcohol was added in
MeOH during workup. In all cases, no column chromatogra-
phy was required to obtain >95% purity and less than 3% of
boronic acid was observed in the crude mixture. For elec-
tron-deficient Grignard reagents, typically substituted by a
trifluoromethyl group (Scheme 6, B), the second addition
was inefficient due to both the higher stability of the inter-
mediate arylaminoborohydride, and the poor nucleophilici-
ty of the Grignard reagent.
Further studies clearly showed that the first addition
occurs at room temperature or even below, and that exten-
sive heating is required for sterically hindered borinic acids.
Indeed, when using 2-bromoanisole (10r), after 16 hours at
70 °C, the borinic/boronic ratio is only 70:30 which can be
further increased to 95:5 after 48 hours of reaction
(Scheme 6, A). After workup, the bis(2-methoxyphe-
nyl)borinic acid (9r) was isolated in 75% yield. Alternatively
the reaction time can be lowered using a solvent such as
diglyme, with a higher boiling point and similar Grignard
stabilizing properties (Scheme 6, A). In this case, after 5
hours at 110 °C, the borinic/boronic ratio was 94:6; the iso-
lated yield was lower (45%) due to higher product degrada-
tion at higher temperatures.
Scheme 3 Mechanistic hypothesis for the autocatalytic DIPAB dehy-
drogenation
rived from these compounds are stable in their monomeric
form, in contrast lower analogues aggregate with the for-
mation of cyclic or acylic oligomers. In our system, the in-
termediate aminoborohydride 3a, responsible for the key
deprotonation of the amine–borane complex, may form
clusters for lower analogues. Hence, the basicity of the hy-
dride would then be significantly reduced both thermody-
namically, due to base stabilization, and kinetically, due to
increased steric hindrance around the boron center. We are
currently investigating how this reaction could be extended
as it would have significant applications in hydrogen stor-
age.
As expected, the addition of 2.2 equivalents of phenyl-
lithium into a THF solution of DIPAB 1a at 0 °C, followed by
6 hours at 70 °C, led to a mixture of mono- and bis-adducts,
the boronic acid being the major product (Scheme 4, A). In
contrast, due to the efficient hydride elimination with mag-
nesium species, slow addition of phenylmagnesium bro-
mide to DIPAB, led under the same reaction conditions to
the diphenylborinic acid in near quantitative yield (Scheme
4, A, 95%), with only traces of the boronic acid in the crude
product. Under Barbier conditions, the formation of borinic
acids was very efficient (Scheme 4, B) and a simple proce-
dure consisting of refluxing a mixture of aryl bromide (2.5
(A)
H
H
iPr
H
H
B
N
iPr
OH
B
OH
B
1a
1. THF, 0 °C then 70 °C
2. MeOH/H2O
M = Li
+
OH
+
M
75
<5
:
:
25
>95
M = MgBr
It clearly proves that the second addition is rate deter-
mining. This is corroborated by the previously mentioned
meagre reactivity of electron-poor Grignard reagents,
which are weaker nucleophiles, disfavor hydride elimina-
tion after the first addition, and induce a stronger donation
of the nitrogen lone pair on the arylaminoborane interme-
diate, leading to a weaker electrophilicity of the boron cen-
ter. Overall, obtaining electron-poor boronic acids with
amine–borane complexes is still a challenge we are current-
ly addressing (Scheme 6, B).
2.2 equiv
2a
(B)
OH
B
H
H
iPr
1. Mg (3.5 equiv), THF, 70 °C
2. MeOH/H2O
Br
H
B
N
H
+
iPr
R
R
R
1a
2b–d
9
R = Me: 9b, 91%
R = OMe: 9c, 92%
R = NO2: 9d, <5%
Scheme 4 Synthesis of borinic acids, influence of the organometallic
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

E
J. Richard et al.
Feature
Synthesis
1. PhMgBr (5 mol%), 10 min
2. Mg (3 equiv), THF, 70 °C
OH
B
O
NH2
H
H
iPr
Br
B
or
H
B
N
H
+
R
3. Workup
R
R
iPr
R
R
1a
Workup: MeOH, H2O/HCl
OH
10, 3 equiv
9
11
Workup: MeOH, NH2CH2CH2OH
OH
B
NH2
NH2
NH2
O
O
O
Cl
B
Cl
B
B
B
OMe
MeO
N
N
Cl
Cl
9m, 77%
9n, 85%
11b, 90%
11e, 79%
11f, 77%
OH
B
OH
B
NH2
NH2
O
NH2
O
O
B
B
B
Cl
Cl
MeO
OMe
Cl
Cl
9o, 85%
9c, 81%
11g, 89%
11h, 74%
11i, 88%
OH
B
OH
B
O
NH2
O
NH2
O
NH2
MeO
MeO
OMe
OMe
B
B
B
OMe
9q, 74%
OMe
F
F
9p, 85%
11j, 89%
11k, 80%
11l, 79%
Scheme 5 Synthesis of borinic acids and borinates
(A)
BH2NiPr2 4a in excess) and addition of the second aryl bro-
mide. However, a complex mixture was obtained, which in-
cluded boronic acids 12b and 12c, and biaryl compounds
13bc and 13b likely originating from Würtz reaction (Table
1, entry 1).
H
iPr
H
H
B
N
H
iPr
1a
O
OH
B
O
OH
O
1. Mg (3 equiv), solvent, T
2. MeOH, H2O/HCl
Br
B
+
+
OH
O
As the first addition occurs at room temperature, reac-
tion temperatures were lowered to 20 °C and 40 °C for the
first and second ArBr addition, respectively. Conversely, the
reaction time for the first addition was extended to 3 hours
to insure full p-tolyl bromide (10b) conversion. Reaction
purity was improved but some boronic acids 12 were still
present in the mixture accounting for more than 20% of the
product (Table 1, entry 2). Slow addition at 40 °C of p-bro-
moanisole (10c), allowed for a better purity, with more
than 88% of unsymmetrical diarylborinic acid obtained af-
ter hydroalcoholic work up (Table 1, entry 3). Indeed, heat-
ing at 40 °C favored the first addition of 4-tolylMgBr, while
slowly adding the next nucleophile, which required to go
through the metal halide exchange before undergoing the
addition to the arylaminoborane. Overall, the B-(4-meth-
oxyphenyl)-B-(4-methylphenyl)borinic acid was isolated in
86% yield. Even if we showed that the unsymmetrical borin-
ic acid could be isolated in a one-pot procedure using our
reagent, realistically, the procedure is far from being gener-
al and obtaining decent yields and purities still requires
careful optimization for each substrate.
THF, 70 °C, 16 h 100% conv.
THF, 70 °C, 48 h 100% conv.
diglyme, 110 °C, 5 h 100% conv.
30
5
6
:
:
:
70
95
94
10r, 3 equiv
(B)
H
iPr
H
B
N
H
H
iPr
OH
B
OH
1a
1. Mg (3 equiv), THF, 70 °C
B
+
+
OH
2. MeOH, H2O/HCl
R
Br
R
R
R
R = CF3, 16 h 100% conv.
R = NO2, 16 h 100% conv.
>80
>90
:
:
<20
<10
10d or 10s
3 equiv
Scheme 6 Current limitation of the reaction
Aiming for unsymmetrical borinic acids, we envisioned
performing a sequential addition of two aryl bromides un-
der Barbier conditions. We adapted the procedure from our
previous method,13 with a sequential addition of the first
bromide, evacuation of volatiles (including remaining
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
J. Richard et al.
Feature
Synthesis
Table 1 Nonsymmetrical Borinic Acid Preparation
Br
1.5 equiv
OMe
NiPr2
OH
B
DIPAB 1a (1 equiv), Mg (3 equiv)
Br
B
H
10c
THF, T1 (°C), t1 (h)
THF, T2 (°C), t2 (h)
OMe
9bc
+ impurities
10b
6b
OMe
OH
B
OH
B
HO
HO
OMe
12c
12b
13bc
13b
Entry
T1 (°C)
t1 (h)
T2 (°C)
t2 (h)
Conv. (%)
Yield (%)
9bc
12c
12b
13bc
13b
1a
2
70
20
20
1
3
3
70
40
40
14
14
14
100
99
56
73
88c
22
12
<5
14
9
4
3
1
4
2
1
3b
100
<5
a Volatiles were removed between each aryl bromide addition.
b 4-Bromoanisole (10c) was added by means of a syringe pump over 4 h.
c Isolated yield 86%.
Overall, we have develop a general synthesis of borinic
acids which has several advantages over previously report-
ed methods: (a) a water and air stable reagent, (b) the ab-
sence of cryogenic conditions, (c) the possibility of working
under Barbier conditions, (d) a simple procedure by simply
mixing the aryl halide, magnesium, and the amine–borane
complex in refluxing THF, (e) easy workup and isolation
without flash chromatography, (f) the absence of boron-
containing impurities [ArB(OH)2 or Ar3B, typically]. DIPAB
1a and DICAB 1b are now currently commercially available
from Sigma Aldrich: DIPAB [55124-35-1] catalogue No.
900347, DICAB [131765-96-3] catalogue No. 900348. In ad-
dition to these practical aspects, we unraveled an intriguing
yet promising dehydrogenation of amine–borane promoted
by 5 mol% of PhMgBr, which has to be extended to other
amine–borane complexes.
a J&W Scientific DB-1701 capillary column, a Agilent 5975C triple
axis detector (EI) using the following method: 50 °C for 5 min then 10
°C/min until 220 °C.
2-Aminoethyl Borinates 11; General Procedure A
To a solution of aryl bromide (3 equiv), Mg (3 equiv), and DIPAB or
DICAB (1 equiv) in dry THF (1 mL/mmol) was added at r.t. a solution
of 2 M PhMgBr in THF (0.05 equiv). After 10 min (or at the end of gas
evolution on large scale), the mixture was heated to 70 °C until no
aryl bromide remained in the mixture (8–16 h). At 0 °C, dry MeOH (1
mL/mmol) was added (caution, exothermic reaction). After 1 h, the
mixture was concentrated under reduced pressure, and diluted in a
mixture of 1 M HCl/MeOH (7:3, 10 mL/mmol), after 1 h, the product
was extracted with Et2O (3 × 10 mL/mmol) and the combined organic
phases were washed with 1 M HCl (10 mL/mmol) and brine (3 × 10
mL/mmol). Organic phases were then dried (anhyd Na2SO4), and con-
centrated under reduced pressure. The residue was dissolved in Et2O
(4 mL/mmol) and ethanolamine (1.2 equiv) was added. Depending on
the substituents, precipitation occurs spontaneously or requires the
addition of pentane. Crystals were filtered, washed with pentane and
dried under vacuum to yield the pure 2-aminoethyl borinate.
THF was dried over Na/benzophenone and freshly distilled before use.
MeOH was dried over Mg/I2 and freshly distillated before use. All pro-
cesses were performed under an atmosphere of argon. All commer-
cially available reagents were used directly as received unless speci-
fied. Cy2NH and iPr2NH were dried over CaH2 and distilled before use.
All laboratory glassware was oven dried and cooled under vacuum be-
fore use. Analytical TLC was carried out using 0.25-mm silica plates
purchased from Merck. Eluted plates were visualized using KMnO4
solution. NMR spectra were recorded on Bruker Avance 300, Avance
400, or Avance 600 spectrometers relative to TMS (external standard).
11B NMR chemical shifts are given relative to BF3·OEt2 (external stan-
dard). GC-MS analysis was realized on a Agilent 7890A equipped with
Borinic Acids 9; General Procedure B
The procedure is identical to general procedure A. The pure 2-amino-
ethyl borinate 11 was dissolved in acetone/EtOH (1:1, 2 mL/mmol)
and 1 M HCl was added at r.t. After 3 h, the mixture was diluted with
Et2O (10 mL/mmol), and water (10 mL/mmol). The product was ex-
tracted with Et2O (3 × 10 mL/mmol) and the combined organic phases
were washed with 1 M HCl (10 mL/mmol) and brine (3 × 10
mL/mmol). Organic phases were then dried (anhyd Na2SO4), and con-
centrated under reduced pressure to yield the pure borinic acid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
J. Richard et al.
Feature
Synthesis
Diisopropylamine–Borane Complex (DIPAB, 1a)
11B NMR (100 MHz, acetone-d6): δ = 42.1.
13C NMR (75 MHz, acetone-d6): δ = 137.0, 132.5, 132.3, 21.3.
[CAS Reg. No. 55124-35-1]
A 3000-mL three-necked round-bottomed flask equipped with a me-
chanical stirrer, a thermometer, and a dropping funnel was charged
with THF (1500 mL) and NaBH4 (56.75 g, 1.5 mol) The heterogeneous
mixture was vigorously agitated using a mechanical stirrer and
cooled with an ice/salt bath below 0 °C. The dropping funnel was
charged with H2SO4 (37.8 mL, 0.71 mol) The H2SO4 was added drop-
wise maintaining the internal temperature below –5 °C over 3 h. A
solution of iPr2NH (140 mL, 1 mol) in THF (100 mL) was added drop-
wise maintaining the temperature below 0 °C over 90 min. The mix-
ture was vigorously agitated for 20 h at r.t. The mixture was filtered
through a No. 3 fritted funnel and the resulting solid was triturated
with THF (3 × 400 mL). The THF filtrate was concentrated under re-
duced pressure, and the residue was taken up in CH2Cl2 and then fil-
tered to eliminate all solid residues. The filtrate was washed with wa-
ter (4 × 200 mL). The organic phase was dried (Na2SO4) and concen-
trated under reduced pressure to give DIPAB (102 g, 90%) as colorless
oil which solidified upon cooling.
B,B-Bis(4-tert-butylphenyl)borinic Acid (9p)
[CAS Reg. No. 1802148-70-4]
Following general procedure B using DIPAB 1a (575 mg) gave 9p
(1.471 g, 85%) as a pale yellow solid.
1H NMR (300 MHz, CDCl3): δ = 7.80–7.76 (dt, J = 6, 3 Hz, 4 H), 7.50–
7.46 (dt, J = 6, 3 Hz, 4 H), 5.81 (s, 1 H), 1.37 (s, 18 H).
11B NMR (100 MHz, CDCl3): δ = 46.3.
13C NMR (75 MHz, CDCl3): δ = 154.2, 134.7, 124.9, 34.9, 31.2.
B,B-Bis(3,4,5-trimethoxyphenyl)borinic Acid (9q)
Following general procedure B using DIPAB 1a (575 mg) gave 9q (1.34
g, 74%) as a pale yellow solid.
1H NMR (300 MHz, acetone-d6): δ = 7.88 (s, 1 H), 7.72 (d, J = 8.7 Hz, 2
H), 6.77 (d, J = 8.7 Hz, 2 H), 3.01 (s, 6 H), 2.87 (s, 12 H).
1H NMR (400 MHz, CDCl3): δ = 2.72–2.90 (m, 2 H), 1.91 (q, JH–B = 91
Hz, 3 H), 1.05 (d, J = 6.6 Hz, 6 H), 0.96 (d, J = 6.6 Hz, 6 H).
11B NMR (128 MHz, CDCl3): δ = –20.4 (q, JH–B = 91 Hz).
11B NMR (96 MHz, acetone-d6): δ = 44.0.
13C NMR (76 MHz, acetone-d6): δ = 153.0 (1 C), 137.3 (2 C), 117.7 (4
C), 112.0 (2 C), 40.2 (3 C).
B,B-Bis(4-methoxyphenyl)borinic Acid (9c)
B,B-Bis(4-methylphenyl)borinic Acid 2-Aminoethyl Ester (11b)
[CAS Reg. No. 73774-45-5]
[CAS Reg. No. 19565-45-8]
Following general procedure B using DIPAB 1a (575 mg) gave 9c (980
Following general procedure A using DIPAB 1a (577 mg) gave 11b
mg, 81%) as a white solid.
(1.155 g 90%) as a white solid.
1H NMR (300 MHz, DMSO-d6): δ = 7.80 (d, J = 7.1 Hz, 2 H), 7.00 (d, J =
7.1 Hz, 2 H), 3.89 (s, 3 H).
11B NMR (100 MHz, DMSO-d6): δ = 44.8.
13C NMR (75 MHz, DMSO-d6): δ = 161.9, 136.6, 111.4, 55.1.
1H NMR (300 MHz, DMSO-d6): δ = 7.27–7.24 (d, J = 9 Hz, 4 H), 6.95–
6.93 (d, J = 9 Hz, 4 H), 5.94 (br s, 2 H), 3.76–3.72 (t, J = 6 Hz, 2 H), 2.80
(m, J = 6 Hz, 2 H), 2.21 (s, 6 H).
11B NMR (100 MHz, DMSO-d6): δ = 5.0.
13C NMR (75 MHz, DMSO-d6): δ = 133.7, 132.1, 129.1, 127.7, 62.8,
41.7, 21.3.
B,B-Bis(3-chloro-4-methylphenyl)borinic Acid (9m)
[CAS Reg. No. 515157-47-8]
B,B-Bis(3-methoxyphenyl)borinic Acid 2-Aminoethyl Ester (11e)
Following general procedure B using DIPAB 1a (575 mg) gave 9m
(1.070 g, 77%) as a pale yellow solid.
[CAS Reg. No. 1809269-41-7]
1H NMR (300 MHz, DMSO-d6): δ = 7.75 (d, J = 1.3 Hz, 1 H), 7.56 (dd, J =
7.5, 1.3 Hz, 1 H), 7.33 (d, J = 7.5 Hz, 1 H), 2.46 (s, 3 H).
Following general procedure A using DIPAB 1a (575 mg) gave 11e
(974 mg, 79%) as a white solid.
1H NMR (300 MHz, DMSO-d6): δ = 7.09–7.04 (t, J = 8 Hz, 2 H), 6.62–
6.59 (dd, J = 9, 2 Hz, 2 H), 6.05 (br s, 2 H), 3.78–3.74 (t, J = 6 Hz, 2 H),
3.68 (s, 6 H), 2.86–2.80 (m, J = 6 Hz, 2 H).
11B NMR (100 MHz, DMSO-d6): δ = 45.6.
13C NMR (75 MHz, DMSO-d6): δ = 139.3, 135.0, 134.6, 132.9, 130.8,
20.3.
11B NMR (100 MHz, DMSO-d6): δ = 4.5.
13C NMR (75 MHz, DMSO-d6): δ = 158.7, 128.0, 129.1, 127.0, 124.4,
B,B-Bis[4-(dimethylamino)phenyl]borinic Acid (9n)
117.4, 110.6, 62.8, 55.0, 41.7.
Following general procedure B using DIPAB 1a (575 mg) gave 9n
(1.140 g, 85%) as a white solid.
1H NMR (300 MHz, acetone-d6): δ = 7.88 (s, 1 H), 7.70 (d, J = 9 Hz, 4 H),
6.79 (d, J = 9 Hz, 4 H), 3.01 (s, 12 H).
B,B-Bis(4-chlorophenyl)borinic Acid 2-Aminoethyl Ester (11f)
[CAS Reg. No. 61733-90-2]
11B NMR (100 MHz, acetone-d6): δ = 44.7.
13C NMR (75 MHz, acetone-d6): δ = 152.1, 136.4, 116.8, 111.1, 39.3.
Following general procedure A using DIPAB 1a (575 mg) gave 11f
(1.132 g, 77%) as a white solid.
1H NMR (300 MHz, DMSO-d6): δ = 7.38–7.35 (dd, J = 9 Hz, 4 H), 7.19–
7.16 (t, J = 9 Hz, 4 H), 6.18 (br s, 2 H), 3.77–3.73 (t, J = 6 Hz, 2 H), 2.87–
2.79 (m, J = 6 Hz, 2 H).
11B NMR (100 MHz, DMSO-d6): δ = 4.0.
13C NMR (75 MHz, DMSO-d6): δ = 133.8, 130.5, 129.1, 127.0, 62.9,
B,B-Bis(3,5-dimethylphenyl)borinic Acid (9o)
[CAS Reg. No. 352212-19-2]
Following general procedure B using DIPAB 1a (115 mg) gave 9o (202
mg, 85%) as a pale yellow solid.
1H NMR (300 MHz, acetone-d6): δ = 7.29 (s, 4 H), 7.01 (s, 2 H), 2.22 (s,
41.8.
12 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
J. Richard et al.
Feature
Synthesis
Bis(3-methylphenyl)borinic Acid 2-Aminoethyl Ester (11g)
B,B-Bis(biphenyl-4-yl)borinic Acid 2-Aminoethyl Ester (11l)
[CAS Reg. No. 97979-11-8]
[CAS Reg. No. 102032-41-7]
Following general procedure A using DIPAB 1a (576 mg) gave 11g
Following general procedure A using DIPAB 1a (575 mg) gave 11l
(1.123 g, 89%) as a white solid.
(1.886 g, 79%) as a white solid.
1H NMR (300 MHz, DMSO-d6): δ = 7.22–7.18 (m, 4 H), 7.06–7.01 (t, J =
8 Hz, 2 H), 6.87–6.84 (d, J = 9 Hz, 2 H), 6.02 (br s, 2 H), 3.77–3.73 (t, J =
6 Hz, 2 H), 3.68–2.78 (m, 2 H), 2.24 (s, 6 H).
1H NMR (300 MHz, DMSO-d6): δ = 7.61–7.59 (d, J = 9 Hz, 4 H), 7.55–
7.52 (d, J = 9 Hz, 4 H), 7.47–7.40 (m, 8 H), 7.32–7.28 (t, J = 6 Hz, 2 H),
6.19 (s, 2 H), 3.85–3.81 (t, J = 6 Hz, 2 H), 2.93–2.85 (m, J = 6 Hz, 2 H).
11B NMR (100 MHz, DMSO-d6): δ = 4.7.
11B NMR (100 MHz, DMSO-d6): δ = 4.3.
13C NMR (75 MHz, DMSO-d6): δ = 135.3, 132.7, 129.1, 127.0, 126.0,
13C NMR (75 MHz, DMSO-d6): δ = 141.7, 137.4, 132.6, 129.2, 127.1,
62.8, 41.8, 21.9.
126.8, 125.6, 63.0, 41.9.
B,B-Bis(3,4-dichlorophenyl)borinic Acid 2-Aminoethyl Ester (11h)
B,B-Bis(2-methoxyphenyl)borinic Acid 2-Aminoethyl Ester (11r)
[CAS Reg. No. 131112-03-3]
[CAS Reg. No. 97979-12-9]
Following general procedure A using DIPAB 1a (574 mg) gave 11h
Following general procedure A using DIPAB 1a (575 mg) gave 11r
(1.343 g, 74%) as a white solid.
(1.123 g, 79%) as a white solid.
1H NMR (300 MHz, DMSO-d6): δ = 7.52 (s, 2 H), 7.42–7.39 (d, J = 9 Hz,
2 H), 7.31–7.28 (d, J = 9 Hz, 2 H), 6.34 (br s, 2 H), 3.78–3.74 (t, J = 6 Hz,
2 H), 2.90–2.82 (m, J = 6 Hz, 2 H).
1H NMR (300 MHz, DMSO-d6): δ = 7.09–7.04 (dd, J = 6, 2 Hz, 2 H),
6.77–6.69 (m, 2 H), 5.97 (br s, 2 H), 3.67–3.62 (m, 8 H), 2.94–2.84 (m,
J = 6 Hz, 2 H).
11B NMR (100 MHz, DMSO-d6): δ = 3.5.
11B NMR (100 MHz, DMSO-d6): δ = 4.2.
13C NMR (75 MHz, DMSO-d6): δ = 133.5, 132.1, 130.4, 127.0, 129.7,
13C NMR (75 MHz, DMSO-d6): δ = 162.3, 134.1, 127.0, 120.1, 109.8,
128.3, 63.1, 41.
62.8, 55.3, 41.6.
Di-2-naphthylborinic Acid 2-Aminoethyl Ester (11i)
B,B-(4-Methylphenyl)-(4-methoxyphenyl)borinic Acid 2-Amino-
ethyl Ester (11bc)
[CAS Reg. No. 515157-62-7]
[CAS Reg. No. 7294-53-3]
Following general procedure A using DIPAB 1a (574 mg) gave 11i
(1.431 g, 88%) as a brown solid.
To a suspension of magnesium (3.3 equiv, 16.5 mmol) in a solution of
DIPAB (1.5 equiv, 7.5 mmol) in anhydrous THF (40 mL), at r.t., was
added 4-bromoanisole (1 equiv, 5 mmol, 631 μL). The mixture was let
for 4 h at r.t. under stirring. 4-Bromotoluene (1.2 equiv, 6 mmol, 740
μL) was added and the mixture was heated at 40 °C under stirring for
12 h, then cooled at 0 °C and quenched with 3 M aq HCl solution (25
mL). The mixture was stirred for 45 min at r.t. To this solution was
added H2O (20 mL) and Et2O (20 mL) and the organic phase was sepa-
rated. The aqueous phase was then extracted with CH2Cl2 (6 × 30 mL).
The combined organic phases were dried over anhydrous Na2SO4, fil-
tered and concentrated under reduced pressure to afford the crude
borinic acid as a light yellow powder. The residue was dissolved in
Et2O (20 mL) and ethanolamine (1.2 equiv) was added. The resulting
crystals were filtered, washed with pentane and dried under vacuum
to yield the pure 2-aminoethyl borinate.
1H NMR (300 MHz, DMSO-d6): δ = 7.94 (s, 2 H), 7.77–7.74 (m, 4 H),
7.70–7.63 (m, 4 H), 7.41–7.32 (m, 4 H), 6.34 (br s, 2 H), 3.89–3.85 (t,
J = 6 Hz, 2 H), 2.97–2.89 (m, J = 6 Hz, 2 H).
11B NMR (100 MHz, DMSO-d6): δ = 5.6.
13C NMR (75 MHz, DMSO-d6): δ = 133.3, 132.3, 131.3, 130.2, 127.9,
127.7, 125.9, 125.3, 124.7, 63.6, 42.0.
Di-3,4-xylylborinic Acid 2-Aminoethyl Ester (11j)
[CAS Reg. No. 99269-70-2]
Following general procedure A using DIPAB 1a (575 mg) gave 11j
(1.250 g, 89%) as a white solid.
1H NMR (300 MHz, DMSO-d6): δ = 7.13 (s, 2 H), 7.09–7.06 (d, J = 9 Hz,
2 H), 6.90–6.87 (d, J = 9 Hz, 2 H), 5.89 (br s, 2 H), 3.75–3.70 (t, J = 6 Hz,
2 H), 2.83–2.75 (m, J = 6 Hz, 2 H), 2.15–2.13 (m, 12 H).
1H NMR (300 MHz, DMSO-d6): δ = 7.26 (m, 4 H), 6.94 (d, J = 7.5 Hz, 2
H), 6.71 (d, J = 8.4, 1.8 Hz, 2 H), 5.89 (bt, 2 H), 3.74 (t, J = 6.1 Hz, 2 H),
3.67 (s, 3 H), 2.80 (m, J = 6.1 Hz, 2 H), 2.21 (s, 3 H).
11B NMR (100 MHz, DMSO-d6): δ = 4.9.
13C NMR (75 MHz, DMSO-d6): δ = 133.9, 133.5, 132.4, 129.6, 128.3,
11B NMR (96 MHz, DMSO-d6): δ = 5.19.
62.8, 41.7, 20.1, 19.7.
13C NMR (100 MHz, DMSO-d6): δ = 157.3, 133.3, 132.6, 131.6, 127.3,
112.3, 62.4, 54.6, 41.3, 20.9.
B,B-Bis(4-fluorophenyl)borinic Acid 2-Aminoethyl Ester (11k)
[CAS Reg. No. 176913-70-5]
Acknowledgment
Following general procedure A using DIPAB 1a (575 mg) gave 11k
(871 mg, 80%) as a pale yellow solid.
1H NMR (300 MHz, DMSO-d6): δ = 7.40–7.36 (t, J = 6 Hz, 4 H), 6.98–
6.92 t, J = 9 Hz, 4 H), 6.11 (br s, 2 H), 3.77 (t, J = 6 Hz, 2 H), 2.84 (m, J =
6 Hz, 2 H).
This work was funded by the Université de Bordeaux and the CNRS.
Supporting Information
11B NMR (100 MHz, CDCl3): δ = 3.9.
Supporting information for this article is available online at
13C NMR (75 MHz, CDCl3): δ = 163.0, 159.8, 133.6, 113.5, 62.9, 41.8.
http://dx.doi.org/10.1055/s-0036-1588345.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

I
J. Richard et al.
Feature
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I