Developing a Bench-Scale Green Diboration Reaction toward Industrial Application

Article abstract of DOI:10.1055/s-0036-1590912

We report a new methodology for the organocatalytic diboration reaction using inexpensive, sustainable, nontoxic, commercially available halogen salts. This is an educative manuscript for the transformation of laboratory scale reactions into a sustainable approach of appeal to industry.

Full text of DOI:10.1055/s-0036-1590912

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
special topic
A
en
A. Farre et al.
Special Topic
Synthesis
Developing a Bench-Scale Green Diboration Reaction toward
Industrial Application
Albert Farrea
Rachel Briggsa
Bcat
Bcat
Bcat
Bcat
Cristina Pubill-Ulldemolins*b
Amadeu Bonet*a,c
MePPh3I (10 mol%)
NaI (10 mol%)
B2cat2 (1.05 equiv)
B2cat2 (1.05 equiv)
anhyd THF, 14 h, 70 °C
toluene/H2O, 14 h, 70 °C
85% NMR yield
83% isolated yield as alcohol
81% NMR yield
a Department of Chemistry, University of Hull, Cottingham
Road, Hull, HU6 7RX, UK
77% isolated yield as alcohol
b School of Chemistry, University of St Andrews, St Andrews,
KY16 9ST, UK
c Synkotech Biocompatible Materials S.L., Av. Paisos Catalans
18, 43007 Tarragona, Catalonia, Spain
amadeu.bonet@synkotechbio.com
‘Small changes are powerful’ quoting Captain Lettuce
Dedicated to Prof. Maria Elena Fernandez and Prof. Carles Bo,
our scientific parents
Published as part of the Special Topic Modern Strategies for Borylation in Synthesis
Received: 12.08.2017
Accepted after revision: 28.08.2017
Published online: 10.10.2017
recently developed an organocatalytic method which uses
amines to activate the diboron reagent.2v Amines are a soft-
er Lewis base than alkoxides or carbenes and, therefore, are
unable to engage with the most-used diboron reagent
bis(pinacolato)diboron (B2pin2); however, amines can en-
gage with the more Lewis acidic bis(catecholato)diboron
(B2cat2). Thus, amines activate the B2cat2 reagent, generat-
ing an sp2–sp3 adduct which smoothly reacts with olefins
providing high yields in the diboration reaction. This meth-
od offers the advantage of broad substrate scope while
overcoming some functional and protecting group limita-
tions of previously established methodologies.2v
DOI: 10.1055/s-0036-1590912; Art ID: ss-2017-e0524-op
Abstract We report a new methodology for the organocatalytic dibo-
ration reaction using inexpensive, sustainable, nontoxic, commercially
available halogen salts. This is an educative manuscript for the transfor-
mation of laboratory scale reactions into a sustainable approach of ap-
peal to industry.
Key words green chemistry, organocatalysis, boron chemistry, ate
complexes
Organoboron compounds offer a versatile synthetic
platform for efficient access to a wide range of functional-
ities and are commonly applied in the synthesis of new ac-
tive pharmaceutical ingredients.1 Currently, many research
groups have been focussing on the development of transi-
tion-metal-free methodologies for the introduction of bo-
ron functionality into organic moieties.2 In general, these
methodologies use a Lewis base that coordinates to a dibo-
ron reagent generating an sp2 nucleophilic boron species
which can react with organic functionalities.3 These meth-
odologies are a step forward in terms of sustainability in
comparison with the traditional transition-metal catalysis
and they can be classified as stoichiometric, using organo-
lithiums,2m,u thioethers2m and fluoride salts,2k or catalytic,
using alkoxides,2d–h,2n,s,t carbenes2a–c and amines.2v
Among these transition-metal-free methods, use of the
salts has a great potential due to their availability, low price
and low toxicity. However, current methodologies for the
activation of the diboron reagent are limited to the use of
stoichiometric fluoride salts.2k Fluoride salts could be diffi-
cult to handle due to their highly hygroscopic nature and
have some limitations in terms of protecting group compat-
ibility, such as with silyl ethers. In our laboratory, we have
Building upon our previous experience,2v we envisaged
that use of the more Lewis acidic diboron reagent, B2cat2,
can allow the development of a catalytic methodology with
less expensive, milder and more readily available halogen
salts than fluoride. Halogen salts, especially quaternary
salts, have been used as phase-transfer catalysts for de-
cades, providing a powerful and sustainable strategy for or-
ganic synthesis, which can substitute others methods in-
volving toxic and expensive transition-metal catalysts.4 Our
reaction of choice was the diboration reaction due to its in-
herently high atom economy. Recently, organocatalytic
methodologies have been demonstrated as being advanta-
geous over transition-metal approaches, offering a broader
substrate scope, a higher degree of selectivity and greater
protecting and functional group tolerance. However, cur-
rent enantioselective organocatalytic strategies provide ei-
ther low enantioselectivities or a narrow substrate scope.2f,o
Therefore, there is a need to develop a new organocatalytic
enantioselective version of the reaction. In this context, the
successful use of a variety of halogen salts as a catalyst will
generate a more sustainable activation of the diboron re-
agents and will be amenable to potential new borylation
asymmetric methodologies using chiral cations.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
A. Farre et al.
Special Topic
Synthesis
Herein, we present the development of a green dibora-
tion reaction using simple halogen salts and have explored
for the first time the use of quaternary ammonium salts
with a different counteranion in the diboration reaction.
We decided to study the catalytic potential of chloride, bro-
mide and iodide salts due to their superior stability, avail-
ability and lower price compared with their fluoride ana-
logues. Our initial reaction conditions involved the use of
anhydrous THF and a low catalyst loading (10 mol%) under
inert atmosphere (Table 1). With styrene (1a) as a model
substrate, and after stirring the reaction mixture overnight
at reflux, we were pleased to observe the selective forma-
tion of the desired diborated product 2a–Bcat. Although all
the tested salts provided catalytic activity, the iodide salt,
TBAI, showed the highest activity with a 76% NMR yield af-
ter 14 hours (Table 1, entries 1 and 2 vs 3). It is worth not-
ing that the iodide salt is the least expensive ammonium
salt of the series, making the process economically more vi-
able.5 After several other iodide salts were tested (see the
Supporting Information), it was established that use of the
phosphonium salt, MePPh3I, resulted in an increased reac-
tivity with NMR yields up to 81% (Table 1, entry 4). As pre-
viously observed, when soft Lewis bases like amines are
used, the alkylic diboronic esters, B2pin2 and bis(neopentyl
glycolato)diboron (B2neop2), remained unreactive under
the same reaction conditions.
action conditions. Olefins 1g and 1h reacted in a similar
manner independently of being terminal or internal, and
cyclic or acyclic. Diboration of this type of substrate provid-
ed synthetically useful yields up to 86% (2h, Scheme 1).
1) MePPh3I (10%)
OH
B2cat2 (1.05 equiv)
anhyd THF, 70 °C, 14 h
OH
R
R
2) H2O2/NaOH
or
2a–h
1a–h
2) pinacol (6 equiv)
Et3N
OH
Bpin
Bpin
OH
OH
OH
R
2a–Bpin 74%a
2e 55%
2a R = H 77%
2b R = p-OMe 80%
2c R = p-F 78%
2d R = m-Me 75%
OH
OH
OH
OH
OH
OH
2h 86%
2f 49%
2g 82%
Conditions: substrate (0.5 mmol), salt (0.05 mmol), B2cat2 (0.525 mmol),
solvent (2 mL), 70 °C, 14 h. Oxidation: H2O2/NaOH.
a Transesterification: pinacol (6 equiv), Et3N.
Scheme 1 Initial substrate scope
At this point, we realised the potential of the use of in-
expensive and sustainable salts in the diboration reaction.
Encouraged by these results, we aimed to develop what
could be one of the greenest borylation methodologies re-
ported so far. Since boron compounds are widely used in
fine industry, with 40% of the new drug candidates being
synthesised using Suzuki–Miyaura cross-coupling,6 we de-
cided to further optimise the reaction conditions using the
toolkit recently reported by Clark and co-workers.7 Such a
toolkit allows the evaluation of synthetic methods of inter-
est to the pharmaceutical industry toward their optimisa-
tion into a more green and sustainable process.
With our encouraging preliminary results, we next fo-
cussed on tailoring the reactions to improve the sustain-
ability that can be beneficial for the fine chemical industry.
To this end, each factor of the reaction was optimised by
following the Clark toolkit using the First Pass (for benchtop
reactions); these findings are summarised within the next
paragraphs, where each reaction factor is described.
Table 1 Preliminary Results for the Halogen Salt Catalysed Diboration
Reactiona
salt (10 mol%)
B2cat2 (1.05 equiv)
Bcat
anhyd THF, 70 °C, 14 h
Bcat
1a
2a–Bcat
Entry
Catalyst
NMR yield (%)
1
2
3
4
TBACl
TBABr
TBAI
26
31
76
81
MePPh3I
a Reaction conditions: styrene (0.5 mmol), halogenated salt (0.05 mmol),
B2cat2 (0.525 mmol), THF (2 mL), 70 °C, 14 h. The reactions were carried
out in duplicate and the reported NMR yields are the average of them.
1,3,5-Trimethoxybenzene was used as internal standard.
With the optimised reaction conditions in hand, we ex-
plored the substrate scope of the reaction (Scheme 1).
While disubstituted vinylarenes 1e and 1f provided only
moderate yields, we were glad to observe that terminal vi-
nylarenes 1a–d delivered yields up to 80%. It is important to
highlight that the reactivity of terminal vinylarenes is not
affected by the electronic or the steric properties of the
ring. Furthermore, we were pleased to observe that nonac-
tivated alkenes successfully engaged under the present re-
Catalyst: We initially relied on the widely used quater-
nary salt catalysts for the activation of the diboron reagent,
B2cat2, but the high molecular weight results in a lower
atom economy and mass intensity of the reaction. To ad-
dress this limitation, we used inorganic salts containing
smaller cations, such as lithium, sodium, magnesium or po-
tassium. These salts have a lower molecular weight than the
organic ammonium or phosphonium salts, thus increasing
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A. Farre et al.
Special Topic
Synthesis
the sustainability of the overall process. In order to ensure
that the salt was the real catalyst, only trace metal basis
quality salts were used in this study.
Amongst the inorganic salts screened using our stan-
dard reaction conditions (Table 2, entries 1 and 2), LiI pro-
vided an interesting 65% NMR yield of the diborated prod-
uct; the other salts showed a poor performance due to their
very low solubility in anhydrous THF.
Table 2 Optimisation Resultsa
salt (10 mol%)
B2cat2 (1.05 equiv)
solvent, 70 °C, 14 h
Bcat
Bcat
1a
2a–Bcat
Entry
Solvent
Salt (10 mol%)
NMR yield (%)
Solvent: The solvent is a key factor in developing a sus-
tainable methodology because it constitutes a large per-
centage of the mass intensity. It is recognised that, during
pharmaceutical process development, solvent selection is
key in determining the sustainability of future commercial
production methods. Recent benchmarking has demon-
strated that solvents contribute ~50% of materials used in
the manufacture of bulk active pharmaceutical ingredi-
ents.8 Safety, health and environmental aspects need to be
taken into account when a solvent is considered for a reac-
tion.9 THF is not preferred because of high water solubility,
a low flash point and the potential generation of peroxides.
Taking into account the low solubility of inorganic salts in
organic solvents, we considered using water which will eas-
ily solubilise such salts. Water is the solvent in which chem-
ical reactions are performed in nature, and it is inexpensive,
safe and environmentally benign.10 Milli-Q quality, de-
gassed water was used in this study.
In order to identify greener reaction conditions/ap-
proach, we tested the catalysis by a number of inorganic
salts in water, and compared them with the use of organic
salts. The inorganic salts performed better than the organic
salts (Table 2, entries 3 and 4 vs 5–7). However, the NMR
yields only reached a moderate level, up to 60% using NaI in
water, which is far from the 81% yield obtained in anhy-
drous THF (Table 1, entry 4).
1
2
anhyd THF
anhyd THF
H2O
LiI
65
0
NaI
3
MePPh3I
TBAI
LiI
50
40
50
60
52
85
84
50
54
44
4
H2O
5
H2O
6
H2O
NaI
7
H2O
KI
8
toluene/H2Ob
hexane/H2Ob
CH2Cl2/H2Ob
EtOAc/H2Ob
toluene/H2Ob
NaI
9
NaI
10
11
12
NaI
NaI
NaCl
a Reaction conditions: styrene (0.5 mmol), salt (0.05 mmol), B2cat2 (0.525
mmol), solvent (2 mL), 70 °C, 14 h. The reactions were carried out in dupli-
cate and the reported NMR yields are the average of the two. 1,3,5-Trimeth-
oxybenzene was used as internal standard.
b 1:1 mixture.
generated waste in the reaction is reduced and the biphasic
character of the resulting reaction mixture potentially al-
lows recycling of the catalyst or a setup for a flow approach.
A flow approach is recommended in the toolkit as a greener
option than a batch setup. Specifically, the use of microre-
actors allows precise control over the interfacial area pro-
viding an increase in yield and productivity in phase-trans-
fer-catalysed reactions.12 However, the generation of a flow
method or the recycling of the catalyst for this reaction falls
outside the scope of this study.
In our context, toluene, hexane, dichloromethane and
ethyl acetate fit in the solvent scope. Apolar, hydrocarbon-
type solvents, toluene and hexane, provided high yields, up
to 85% (Table 2, entries 8 and 9). In contrast, polar solvents
provided only moderate results, up to 54% yield (Table 2,
entries 10 and 11). Based on these results, toluene, which is
more environmentally friendly than hexane, was our choice
as the optimal solvent. Under the optimal reaction condi-
tions, we achieved a synthetically useful 85% yield with 10
mol% NaI in toluene/water as a solvent mixture (Table 2, en-
try 8). This system provides a higher yield than the previous
reaction conditions involving a phosphonium salt in THF
(Table 1 and Scheme 1), with a greener setup. Interestingly,
NaCl provides a notable 44% yield (Table 2, entry 12), giving
room for future optimisation using these household goods.
Due to their environmental and safety benignness, different
Water is not a common solvent for borylation reactions
because it is a noninnocent solvent which can interact with
the empty p orbital of the boron atom. However, there are
some examples of borylations in aqueous systems using
B2(OH)4 or using the more stable B2pin2.11
In our case, the higher Lewis acidity of B2cat2 makes it
prone to decomposition under aqueous conditions. The co-
ordinating nature of water could promote the dissociation
of the catechol ligand (partially or totally). The nature of the
catechol is key to enhance the Lewis acidity of the diboron-
ic ester and, without it, the anion is unable to activate the
empty p orbital of the diboron reagent. Also, we observed
that the B2cat2 remained mostly insoluble during the reac-
tion, which will definitely decrease the reaction rate.
In order to increase the solubility of the B2cat2 and min-
imise the potential decomposition, we exploited the use of
a mixture (1:1 ratio) of different organic solvents in water
(Table 2, entries 8–11). Our choice would be an inexpensive,
readily available solvent insoluble in water. In this way, the
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A. Farre et al.
Special Topic
Synthesis
alcohols were tested either as a unique solvent or a combi-
nation with other solvents; however, none of these reac-
tions provided the desired product.
RME value up to 10% (Equation 2). We believe that the RME
number could be increased upon further optimisation on
such a higher scale. However, this optimisation falls outside
the current study.
Yield, Atom Economy and Reaction Mass Efficiency: 1H
NMR yields were determined using an internal standard, af-
ter the reactions were quenched. The borylated catechol
product is sensitive to silica gel; therefore, it cannot be iso-
lated using column chromatography without being deriva-
tised. Common derivatisation methods are oxidation, trans-
esterification, homologation or cross-coupling.1 These deri-
salt (10 mol%)
Bcat
B2cat2 (1.01 equiv)
Bcat
toluene (4.5 mL)
H2O (4.5 mL)
70 °C, 14 h
NMR yield 61%
5 mmol
1a
2a–Bcat
vatisations can be performed in
a tandem fashion.
Scheme 2 Diboration reaction on a 5-mmol scale
Oxidation and transesterification are straightforward and
quantitative, and the isolated yields of the corresponding
alcohol and the pinacol derivatives are comparable with the
obtained NMR yields (Table 1, entry 4 vs Scheme 1, 2a and
2a–Bpin). However, standard procedure transformations of
boronic esters are not sustainable and need further work to
improve these methodologies. Although we are currently
working in this area, this part of the study falls outside the
scope of the current manuscript.
As stated previously, one of the reasons to study the di-
boration reaction is its intrinsic complete atom economy:
all the atoms of both reagents combine to form the desired
product.13 In order to progress further, we decided to calcu-
late the reaction mass efficiency (RME). This metric is ob-
tained when the mass of the isolated product is compared
against the total mass of the reactants and is widely used to
compare mass efficiency between methods.14 As boronic
esters are common intermediates in organic synthesis and
they can be used without the necessity of isolation,2o,15 we
calculated the RME directly from the obtained NMR yield
(Equation 1).
Equation 2 RME of 5-mmol reaction
Price and Availability: NaI has a molecular weight 2.69
times smaller than that of MePPh3I, and both salts are com-
mercially available in large quantities from different re-
sellers. Considering a 100 g bottle, one mole of MePPh3I is
6.5 times more expensive than NaI.16 This number becomes
even more favourable for NaI when bigger quantities are
compared.
Also, the use of toluene/water instead of anhydrous THF
reduces the overall cost as there is no need to dry the or-
ganic solvent.
Energy: We performed our reactions at 70 °C, which are
considered mild reaction conditions by the industry.17
However, 70 °C is the boiling point temperature when THF
was used as a solvent. From the industrial point of view,
boiling point temperature reactions require six times more
energy than using 5 °C below the boiling point. The tolu-
ene/water reaction conditions (Table 2, entry 8) are far from
boiling point temperatures, making the process much more
energetically efficient.
Workup: Evaluation of the reaction outcome by NMR
yield is sustainable as simple evaporation of the solvent at
mild temperature is involved. After such a simple process,
the desired product is pure enough to continue with the
corresponding derivatisations. Therefore, if this diboration
reaction is performed at the industrial level, the subsequent
reaction can continue in a tandem fashion.
Equation 1 RME of 0.5 mmol reaction
Substrate Scope: At this point, with the newly opti-
mised green reaction conditions in hand, we explored the
substrate scope of the reaction. Vinylarenes 1a–c, 3a–g pro-
vided synthetically useful yields, independently of the elec-
tronic and steric properties and substitution on the ring,
with isolated yields up to 95% (Scheme 3). The method can
engage with nonactivated alkenes 1g, 3h and 3i to obtain
the corresponding diols 2g, 4h and 4i in synthetically useful
isolated yields, up to 89%. In contrast with previous meth-
As small-scale reactions usually obtain a low RME value
due to the high impact of the solvent weight relative to the
reagent weights, we decided to scale up our diboration re-
action. In a 5-mmol scale reaction, we were able to reduce
the solvent amount by more than half (4.5 mL of each sol-
vent) and also the excess B2cat2 to 1.01 equivalents (Scheme
2). Although the yield of the reaction decreased notably
(from 85% to 61%), we were successful in increasing the
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E
A. Farre et al.
Special Topic
Synthesis
odologies, the presence of a protic solvent does not pro-
mote the formation of hydroborate byproducts. In addition,
the reactivity is not affected by the geometry of internal
alkenes. The reaction is completely diastereospecific, with
hol-containing substrates remain unreactive under our op-
timised reaction conditions. Silicon protecting groups can
be used, but the deprotected alcohol product is obtained af-
ter derivatisation of the catechol diboronic ester.
1
only a single diastereoisomer observed by H NMR spec-
Mechanistic Studies: We have performed NMR studies
along with theoretical calculations to elucidate the role of
the anion in the reaction and to propose a plausible mecha-
nism for the herein developed diboration method.2v,19
However, due to solubility issues, no interaction signals
troscopy. Unfortunately, trisubstituted olefins provided
only low to moderate yields. Thus, they were not included
in the present sustainable study.
between the B2cat2 and the iodide could be found in the 11
B
1) NaI (10 mol%)
B2cat2 (1.05 equiv)
NMR spectra when stoichiometric experiments were per-
formed in either THF, water or toluene/water (see the Sup-
porting Information for further details).
DFT Calculations: We selected iodide as the catalyst
along with styrene, as a combination of both provided high
yields of the diborated product under the optimised reac-
tion conditions.
We envisioned a mechanism for this organocatalytic di-
boration reaction (Figure 1) in which iodide anion activates
the diboron reagent, B2cat2, in line with the previously re-
ported mechanistic proposal by Fernández, Bo and co-
workers.2e
toluene/H2O, 70 °C, 14 h
2) H2O2/NaOH
OH
OH
R
R
or
2a–c,g
4a–q
1a–c,g
3a–q
2) pinacol (6 equiv)
Et3N
OH
2a R = H
83%
80%
74%
95%
81%
73%
90%
75%
89%
80%
2b R = p-OMe
2c R = p-F
4a R = p-Me
4b R = p-Cl
4c R = m-Me
4d R = m-F
4e R = o-Me
4f R = o-F
4g naphthyl
OH
R
OH
OH
OH
Similarly to their study, we identified two transition
states (TS1 and TS2) that lead to the formation of the de-
sired diborated product. TS1 in which the nucleophilic sp2
moiety of the in situ formed B2cat2·I– adduct interacts with
the unsubstituted carbon of the styrene (most electrophilic
carbon) is the most energetically demanding and thus rate
determining for the reaction. Electronic factors play a key
role in facilitating this demanding nucleophilic attack, as
suggested by the difference in energy of approximately 6.5
kcal·mol–1 higher for propylene (see the Supporting Infor-
mation). This phenomenon is in agreement with our exper-
imental results, since vinylarenes provided slightly better
yields than the nonactivated olefins. It is noteworthy to
mention that, in contrast to previous organocatalytic re-
ports, although electronic factors stabilise TS1, the compet-
itive hydroboration reaction is not promoted under our de-
veloped current reaction conditions.2e Overall, the reaction
is exothermic before the iodide catalyst is regenerated.
Importantly, we were able to locate a transition state in-
cluding Na cation, along with computation of its corre-
sponding B2cat2 adduct. Formation of the neutral Na[B2cat2I]
adduct is energetically favoured, as is the generation of its
anionic analogue B2cat2·I– [ΔE = –15.6 (ΔG = –8.7) and
ΔE = –19.8 (ΔG = –9.5) kcal·mol–1, respectively; see gas-
phase calculations in the Supporting Information]. In addi-
tion, we found that the energy barrier for its nucleophilic
addition to ethylene is slightly lower than for B2cat2·I–, by
about 3.0 kcal·mol–1.
OH
OH
OH
4i 78%
2g 89%
4h 82%
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
OCb
4l 69%a,b
OBn
CN
OAc
4j 75%a
4k 70%a
Bpin
Bpin
Bpin
Bpin
Br
Bpin
O
4m 70%a
4n 65%a
4o 83%a
Conditions: substrate (0.5 mmol), salt (0.05 mmol), B2cat2 (0.525 mmol),
solvent (2 mL), 70 °C, 14 h. Oxidation: H2O2/NaOH.
a Transesterification: pinacol (6 equiv), Et3N.
b Cb = C(O)N-i-Pr2
Scheme 3 Substrate scope
After this broad general scope, we next explored the
functional and protecting group compatibility of our meth-
odology (Scheme 3). To our delight, we observed that our
sustainable method tolerated alcohol protecting groups like
acetyl, 4j, or benzyl, 4k, with isolated yields up to 75%. In-
terestingly, the carbamate group, 4l, which can be further
functionalised using established lithiation–borylation
methodology, resulted in a synthetically useful yield of
69%.18 On the other hand, ketones, which provided only
moderate yields with our amine methodology,2v engaged
perfectly under the optimised reaction conditions (e.g., giv-
ing 4m). Cyano- and halo-substituted alkenes, which pro-
vide a handle to access other groups such as amines or
cross-coupling products, delivered good isolated yields, up
to 83% (4n, 4o). Unfortunately, not all functional and pro-
tective groups are compatible with this methodology. Alco-
In conclusion, we have reported a new methodology for
the diboration reaction using inexpensive, sustainable, non-
toxic, commercially available halogen salts. We have opti-
mised and designed this methodology to suit all the re-
quirements of the pharmaceutical industry. Our mechanis-
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F
A. Farre et al.
Special Topic
Synthesis
Figure 1 Suggested catalytic cycle. Electronic energy (kcal·mol–1) and Gibbs free energy (kcal·mol–1; in parentheses) computed at the M06 level of
theory,20,21 relative to B2cat2·I– adduct plus styrene.
tic studies have elucidated the role of the halide anion and
we have proposed a plausible catalytic cycle. In conjunc-
tion, this work not only provides a greener and more sus-
tainable diboration approach, but also opens the door to
further studies aimed at the design and execution of an en-
antioselective version of the herein reported halogen salt
catalysed diboration using chiral cations.
degassed Milli-Q water (1 mL) were added and the mixture was
stirred for 5 min. After this time, an alkene (0.5 mmol) was added un-
der argon. Then, the mixture was warmed to 70 °C and stirred for 14
h. After this time, the Schlenk tube was cooled to r.t. and the volatiles
were removed. THF (2 mL) was added and the mixture was cooled to
0 °C, and 3 M NaOH (2 mL) and 30% H2O2 (1 mL) were added dropwise
to the solution which was stirred for 4 h at r.t. The reaction was then
quenched with saturated aqueous Na2S2O3 (2 mL). The mixture was
extracted with EtOAc (3 × 25 mL). The organic layers were then dried
over anhydrous MgSO4 and filtered, and the solvent was removed by
rotary evaporation. The crude material was purified by silica gel chro-
matography.
Styrene and substrates containing stabiliser were filtered through sil-
ica gel before used. All other fine chemicals were used directly with-
out purification, unless mentioned. Anhydrous solvents were pur-
chased from Acros and used directly or dried by standard methods.
Non-anhydrous solvents were degassed by bubbling argon for 30 min.
All air- and water-sensitive reactions were carried out in flame-dried
glassware under argon atmosphere using standard Schlenk manifold
techniques. 1H and 13C NMR spectra were acquired at various field
strengths as indicated and were referenced to CHCl3 (7.27 and 77.0
1-Phenylethane-1,2-diol
Following the general procedure with styrene (0.5-mmol scale), 1-
phenylethane-1,2-diol (57 mg, 83%) was obtained as a white solid;
Rf = 0.19 (EtOAc/n-hexane, 1:1).
1H NMR (400 MHz, CDCl3): δ = 7.38 (m, 5 H), 4.86 (dd, J = 8.2, 3.5 Hz, 1
H), 3.79 (dd, J = 11.3, 3.6 Hz, 1 H), 3.69 (dd, J = 11.2, 8.2 Hz, 1 H), 1.90
(br, 2 H).
1
ppm for 1H and 13C NMR, respectively) or TMS (0.00 ppm for H and
13C NMR). 1H NMR coupling constants are reported in hertz and refer
to apparent multiplicities and not true coupling constants. Data are
reported as follows: chemical shift, multiplicity (standard abbrevia-
tions) and integration. 11B NMR spectra were recorded with complete
proton decoupling using BF3·OEt2 (0.0 ppm) as an external standard.
Aluminum-backed plates precoated (0.25 mm) with Merck silica gel
60 F254 were used for analytical TLC. Compounds were visualised by
exposure to UV light or by dipping the plates in KMnO4 stain followed
by heating. Flash column chromatography was performed using Fluo-
rochem silica gel 60 (40–63 μm).
13C NMR (100 MHz, CDCl3): δ = 140.56, 128.66, 128.15, 126.15, 74.78,
68.19.
Data are in accordance with the literature. (see Supporting Informa-
tion).
Acknowledgment
A.B. would like to thank the University of Hull for the starting grant
that supported this research. A.F. would like to thank the EU for an
Erasmus+ grant and a University of Hull fellowship. We thank
AllyChem for the gift of diboranes. C.P.-U. would like to thank Dr.
Rebecca Goss and Dr. Herbert Fruchtl for their support and H2020-
MSCA-IF-2014 (Grant no. 659399) for funding.
Catalytic Diboration/Oxidation; General Procedure
An oven-dried Schlenk tube equipped with a stir bar was charged
with bis(catecholato)diboron (125 mg, 0.525 mmol) and NaI (7.5 mg,
0.05 mmol) under an inert atmosphere. Degassed toluene (1 mL) and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
A. Farre et al.
Special Topic
Synthesis
Supporting Information
M. E., Ed.; American Chemical Society: Washington D.C., 1997.
(e) Liu, S.; Kumatabara, Y.; Shirakawa, S. Green Chem. 2016, 18,
331.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590912.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(5) Price obtained from the Sigma Aldrich website (22/09/2016) for
a 100 g bottle: TBAF·H2O £233.50, TBACl £164.50, TBABr £55.00,
TBAI £28.40.
(6) McMurry, J. E. Organic Chemistry with Biological Applications;
Cengage Learning: Stanford USA, 2015, 394.
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