An easy route to (hetero)arylboronic acids

Article abstract of DOI:10.1002/chem.201402487

An unprecedented spontaneous reactivity between diazonium salts and diboronic acid has been unveiled, leading to a versatile arylboronic acid synthesis directly from (hetero)arylamines. This fast reaction (35 min overall) tolerates a wide range of functional groups and is carried out under very mild conditions. The radical nature of the reaction mechanism has been investigated.

Full text of DOI:10.1002/chem.201402487

DOI: 10.1002/chem.201402487
Communication
&
Synthetic Methods
An Easy Route to (Hetero)arylboronic Acids
William Erb, Akila Hellal, Mathieu Albini, Jacques Rouden, and Jꢀrꢁme Blanchet*[a]
Abstract: An unprecedented spontaneous reactivity be-
tween diazonium salts and diboronic acid has been un-
veiled, leading to a versatile arylboronic acid synthesis di-
rectly from (hetero)arylamines. This fast reaction (35 min
overall) tolerates a wide range of functional groups and is
carried out under very mild conditions. The radical nature
of the reaction mechanism has been investigated.
Arylboronic acids are important building blocks that have
found a widespread utility during the last two decades in vari-
ous palladium-, copper-, or nickel-catalyzed cross-coupling re-
actions (Suzuki–Miyaura and Chan–Lam couplings) and in the
Petasis borono-Mannich reaction.[1] The unique stability, low
toxicity, and easy handling of arylboronic acids make them an
Scheme 1. Borylations using aminoborane and diboron reagents.
appealing class of user- and environment-friendly building
blocks. Additionally, the catalytic properties[2] and biological ac-
tivities[3] of these compounds has received broad interest from
the scientific community.
et al.[8] and Pucheault et al.,[12] previous methodologies yield
a less-reactive pinacolate ester, which then requires an addi-
tional step to deliver the reactive boronic acid.[13] Moreover,
Since the isolation of the first boronic acid by Frankland and
Duppa in 1860[4] the preparation of boronic acids has attracted
a lot of attention because, unlike the analogous carboxylic
acids, boronic acids are abiotic compounds. For over a century,
the synthesis of boronic acids mainly relied on the trapping of
ArLi or ArMgX[2,5] with a trialkyl borate, followed by acidic hy-
drolysis. Although straightforward, this approach is limited by
poor functional-group tolerance, which results from the use of
strongly basic and nucleophilic organometallic species.
[8c]
the poor atom economy associated with the use of B2pin2
should lead to the investigation of its replacement with
a more simple boron source when possible. Interestingly,
when used as a halide surrogate,[14a] diazonium salts were
found to undergo borylation without the assistance of palladi-
um species, leading to the first examples of catalyst-free bory-
lation.[14b–c] Accordingly, the development of a new methodolo-
gy that is able to directly deliver boronic acids from simple
and inexpensive starting materials is attractive.
This area of research was rejuvenated with the seminal con-
tribution by Miyaura et al.,[6] introducing palladium-catalyzed
borylation of aryl halides with B2pin2 (pin=pinacol). This
method was later refined by Murata et al., Buchwald and Bill-
ingsley,[7] and Molander et al.[8] by using HBpin and B2(OH)4 as
boron reagents (Scheme 1). Although the substrate compatibil-
ity was broadened, the competitive formation of homocoupled
products needed to be dealt with. Recently, CÀH bond activa-
tion[9] and electrophilic borylation[10] have been reported. How-
ever, the steric or electronic bias required to govern the regio-
selectivity are still limiting factors.[11] It is important to point
out that with the exception of the methods by Molander
We have recently initiated a research program dedicated to
the design of original chiral Brønsted acids for asymmetric cat-
alysis.[15] One method involves a Suzuki arylation as the key
step to develop steric hindrance around the acidic site, but re-
quired large quantities of boronic acids. Because it is reasona-
ble to avoid cryogenic/anhydrous conditions and high-cost
palladium catalysts we reported thereafter a new methodolo-
gy, inspired by the recently reported palladium-catalyzed bory-
lation, using diboronic acid (B2(OH)4, 2). Our original plan was
to combine Molander’s strategy by using widely available Pd/C
species to promote the borylation of aryl diazonium salts.[16]
In the first attempt, diazonium salt 1a was introduced to
a methanol solution of diboronic acid 2, at room temperature
in the presence of palladium adsorbed on charcoal. A rapid
gas evolution was observed, attributed to a fast palladium oxi-
dative insertion.[17] However, a test reaction revealed a similar
reactivity in the absence of palladium species.[18] After only
a few minutes, the homogeneous reaction mixture turned to
[a] Dr. W. Erb, A. Hellal, M. Albini, Prof. J. Rouden, Dr. J. Blanchet
Laboratoire de Chimie Moleculaire et Thio-organique
ENSICAEN, Universite de Caen
6 boulevard du Marechal Juin, 14050 Caen (France)
E-mail: jerome.blanchet@ensicaen.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402487.
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a deep-blue color with the release of nitrogen at a regular
rate. Pleasingly, in both cases desired boronic acid 3a was ob-
tained with encouraging 40–46% yields.
Table 1. Optimization of the borylation reaction.
Thus, we decided to study this new catalyst-free borylation
of 1a by the systematic evaluation of each reaction parameter.
The choice of solvent significantly influenced the borylation
yield (Table 1, entries 1–7), with DMF being the optimal reac-
tion medium, presumably due to the low solubility of 2 in
other solvents, with exception of DMSO and MeOH.
The nature of the counter anion of the diazonium salt was
then tested, with similar results for tetrafluoroborate, hexa-
fluorophosphate, and trifluoroacetate anions. For practical rea-
sons, tetrafluoroborate was chosen for the rest of this study.
We also briefly investigated the reagent ratio and the reaction
temperature, the latter having a minimal effect on the yield of
the reaction (Table 1, entries 11–14). Conveniently, the optimal
conditions involved using a two-fold excess of diacid 2 in re-
agent-grade DMF, at room temperature under air, for only
15 min (after this time, monitoring of the reaction by FTIR
showed no signal at 2250 cmÀ1, characteristic of the presence
of diazonium).
Entry
X
Ratio (1a/2)
Solvent, T [8C]
Yield [%][a]
1
2
3
4
5
6
7
9
10
11
12
13
14
BF4
BF4
BF4
BF4
BF4
BF4
BF4
PF6
CF3CO2
BF4
BF4
BF4
BF4
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1.2
1:3
DMF, RT
DMSO, RT
MeOH, RT
MeCN, RT
THF, RT
acetone, RT
water, RT
DMF, RT
DMF, RT
DMF, 0
62 (66)[b]
29
46
26
22
18
25
(65)[b]
60
49
57
49
65
DMF, 40
DMF, RT
DMF, RT
[a] Isolated yield. [b] 1H NMR yield with 1,3,5-trimethoxybenzene as an in-
ternal standard.
The scope of the borylation
reaction of various diazonium
salts was next examined under
Table 2. Scope of the borylation.
the
optimized
conditions
(Table 2, conditions A). Diazoni-
um species substituted at the
para-position gave moderate to
good yields (Table 2, entries 3–
11). These new borylation condi-
tions were compatible with vari-
ous functional groups, such as
ketones (entry 3), halogen atoms
(entries 4–7), nitro and nitrile
groups (entries 8 and 9), and
TMS-protected alkynes and tert-
butyl carbonates (entries 10 and
11). Significantly, a gram-scale re-
action afforded boronic acid 1a
with a yield of 48% (entry 1).
Entry
Product
Yield from 1[a,b] [%]
Yield from 4[c,f] [%][a]
1
2
3a
3b
62, 48[d]
58
77, 70[d]
71
3
3c
52
49
4
3d
3e
3 f
3g
3h
3i
50
60
58
42
43
42
57
73
53
61
39
76
76
n.d.
5
meta-Substituted substrates
behaved similarly. Interestingly,
a 3-benzoic acid derivative af-
forded a 39% yield without pro-
tection of the acid functionality,
6
7
8
whereas the
corresponding
methyl ester afforded 50% yield
(entries 15 and 16). ortho-Substi-
tuted substrates were found to
be more challenging, with yields
ranging from 26 to 36% (en-
tries 19–21). In these cases, ex-
tensive reduction of the diazoni-
um salt was observed. Finally,
various heterocycles, such as 3-
quinoline, 4-coumarin, 4-chro-
manone, 5-indole, and 5-benzo-
9
10
3j
11
12
3k
3l
56
53
n.d.
73
13
3m
59
67
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Initial attempts using the tet-
rafluoroborate salts yielded en-
couraging, albeit moderate,
yields (50%). Owing to the low
solubility of 1 and 2 in water,
slower reaction rates were ob-
served, even if a co-solvent was
used. However, on switching to
water-soluble diazonium chlo-
ride salts, the borylation was
found to be more effective.
Table 2. (Continued)
Entry
14
Product
Yield from 1[a,b] [%]
Yield from 4[c,f] [%][a]
3n
3o
3p
38
64
Significantly improved results
were obtained by using this
new one-pot procedure with
aniline derivatives, even on
a gram scale (Table 2, entry 1),
and this procedure displayed
a similar broad functional-group
tolerance. Indeed, in most cases,
the two-step protocol afforded
a global yield superior to the
borylation of the pure isolated
diazonium species (Table 2, en-
tries 1, 2, 4, 6, 8, 9, 12–16, 19–
21, 23, and 26). Owing to acidic
aqueous diazotization and work
up, acid-sensitive substrates
were not tested (Table 2, en-
tries 10 and 11). Interestingly,
substantially increased yields
were achieved in the presence
of a nitro, nitrile, or carboxylic
acid group (Table 2, entries 8, 9,
14, and 15), and in the presence
of sterically demanding ortho
substituents (Table 2, entries 19–
21). Finally, a thiophene deriva-
tive gave a 42% yield, whereas
the borylation of the isolated di-
azonium salts was found to be
unsuccessful (Table 2, entry 27).
Borylation reactions involv-
ing aryl diazonium salts are gen-
erally suggested to proceed
through a radical mechanism, al-
though a hypothetic ionic pro-
cess can not be completely
ruled out.[9b] Accordingly, we set
up a number of experiments to
investigate the present boryla-
15
16
39
50
53
66
17
18
3q
3r
70
38
63
21
19
20
21
3s
3t
3u
36
26
31
63
70
59
22
23
3v
37[e]
58[e]
32
61
3w
24
3x
70[e]
n.d.
25
26
27
3y
35[e]
49[e]
0
11
71
42
3z
3za
[a] Isolated yield after short silica gel chromatography. [b] Conditions A: 1, 2 (2.0 equiv), DMF (0.15m). [c] Con-
ditions B: 1) 4, NaNO2 (1.2 equiv), aq HCl, 08C, 15 min. 2) 2 (2.0 equiv), NaOAc (2.0 equiv), H2O, RT, 20 min.
[d] Gram-scale reaction. [e] 3 equiv of 2 was used at RT. [f] Isolated yield after sorbitol extractive workup [%].
furan diazonium species yielded the corresponding boronic
acids with 35–70% yield (entries 22–26).
tion mechanism. Firstly, we found that the borylation was ef-
fective in the dark and in the absence of oxygen, and was not
improved by radical promoters, such as ferrocene[12] or CuI
(Table 3, entries 2–5). This finding clearly indicates that if a radi-
Concerned with the potential hazards associated with the
handling of diazonium salts, we investigated the possibility of
carrying out the reaction directly from anilines. Amongst the
various diazotization methods available, we selected the use of
sodium nitrite in acidic aqueous media for simplicity.
C
cal mechanism operates, the ArN2 radical is readily generated.
Thereafter, the reaction was attempted in the presence of vari-
ous known radical traps.[20] Puzzlingly, a three-fold excess of
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of tetrahydroxydiboron resulted in an atom-economic synthe-
sis, which is able to directly deliver reactive boronic acids. The
possibility to avoid the isolation of the diazonium salt inter-
mediates, by conducting the whole diazotization/borylation se-
quence in water, made this approach very appealing for fur-
ther developments and should ease an eventual scaling up of
the process. Finally, some insight into the reaction mechanism
has been obtained from various experiments, suggesting a radi-
cal pathway and ruling out the alternative anionic nucleophilic
substitution. This new borylation reaction is expected to signif-
icantly facilitate general access to versatile arylboronic acids.
Table 3. Effect of additives on the borylation efficiency.
Entry
Additive [(mol%)]
Yield [%][c]
1
2
3
4
5
6
7
8
–
62
59
63
65
61
34
36
6[d]
none, in the dark
none, inert atmosphere
ferrocene (1)
CuI (5)
BHT[a] (300)
nBu3SnH (300)
TEMPO[b] (100)
[a] BHT=3,5-di-tert-butyl-4-hydroxytoluene.
[b] TEMPO=(2,2,6,6-Tetra-
Experimental Section
methyl-piperidin-1-yl)oxyl. [c] Isolated yield. [d] 1H NMR yield with 1,3,5-
trimethoxybenzene as an internal standard.
General procedure
HCl (37% in water, 208.0 mL, 2.5 mmol, 2.5 equiv) was added to
a suspension of aniline (1.0 mmol, 1.0 equiv) in water (1.0 mL) at
room temperature and the reaction mixture was stirred for 1 min
before being cooled to 08C. A solution of NaNO2 (82.9 mg,
1.2 mmol, 1.2 equiv) in water (0.5 mL) was added dropwise with
a syringe, which was washed with water (0.3 mL) and the reaction
mixture was stirred for 15 min at 08C. Tetrahydroxydiboron
(179.3 mg, 2.0 mmol, 2.0 equiv), NaOAc (164.0 mg, 2.0 mmol,
2.0 equiv), and water (6.0 mL) were added to the reaction mixture,
which was warmed to room temperature and stirred for 20 min.
EtOAc (20 mL) and saturated K2CO3 were added to the reaction
mixture until pHꢀ8. This mixture was extracted with sorbitol/
Na2CO3 (1m solution in water, 2ꢃ10 mL, 5 min of stirring). The
combined aqueous layers were washed with EtOAc (10 mL) and
then acidified until pH 1 with HCl (6m). The aqueous layer was ex-
tracted with EtOAc (4ꢃ10 mL), the combined organic layers were
washed with water (2ꢃ5 mL), brine (5 mL), dried over magnesium
sulphate, filtered, and concentrated under vacuum to give the de-
sired product.
BHT or nBu3SnH failed to fully suppress the borylation, al-
though a drop of yield was noticed (Table 3, entries 6 and 7).
However, a stoichiometric quantity of TEMPO readily altered
the efficiency of the reaction and only 6% of boronic acid 3a
was detected (Table 3, entry 8).
When testing the radical internal trap 1aa (Scheme 2),
a moderate, but significant, 17% of boronic acid 3aa was iso-
lated. This finding, along with the results shown above, favor
a radical pathway for this borylation.[21] However, a competition
experiment between a methoxy- (1a) and nitro- (1g) substitut-
ed diazonium salt, in the presence of one equivalent of dibor-
onic acid 2, led to a higher reactivity of the electron-rich sub-
strate (Scheme 2), consistent with an ionic aromatic SN1 substi-
tution pathway. Nevertheless, the viability of the reaction in
protic solvents, and the absence of phenols as side products,
render an elusive aryl cation intermediate unlikely.
Acknowledgements
ANR (NeoACat) and Rꢀgion Basse-Normandie are gratefully ac-
knowledged for a fellowship to W.E.
Keywords: aromatics
· diazo compounds · heterocyclic
compounds · pseudohalogens · radicals
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Received: March 5, 2014
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COMMUNICATION
&
Synthetic Methods
W. Erb, A. Hellal, M. Albini, J. Rouden,
J. Blanchet*
&& – &&
An Easy Route to (Hetero)arylboronic
Acids
The simpler the better! A very simple
synthesis of (hetero)arylboronic acids is
reported (see scheme). This approach
features an unprecedented, spontane-
ous, and fast reactivity of diazonium
salts in the presence of diboronic acid,
and accommodates a range of function-
al groups. Consequently, a versatile one-
pot borylation of anilines is reported.
The radical nature of the reaction mech-
anism has been investigated.
&
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