Microwave-mediated synthesis of N-methyliminodiacetic acid (MIDA) boronates

Article abstract of DOI:10.1016/j.tet.2014.09.044

A library of over 20, mainly aryl or heteroaryl, N-methyliminodiacetic acid (MIDA) boronates have been synthesised. A rapid microwave-mediated (MW) method (5-10 min) has been developed using polyethylene glycol 300 (PEG 300) as solvent. However, acetonitr

Full text of DOI:10.1016/j.tet.2014.09.044

Tetrahedron xxx (2014) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-mediated synthesis of N-methyliminodiacetic acid
(MIDA) boronates
,
Adam J. Close a, Paul Kemmitt b, Matthew K. Emmerson a, John Spencer a
*
a Dept of Chemistry, School of Life Sciences, University of Sussex, Falmer, BN1 9QJ, UK
b AstraZeneca, Mereside Alderley Park, Macclesfield, SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2014
Received in revised form 3 September 2014
Accepted 15 September 2014
Available online xxx
A library of over 20, mainly aryl or heteroaryl, N-methyliminodiacetic acid (MIDA) boronates have been
synthesised. A rapid microwave-mediated (MW) method (5e10 min) has been developed using poly-
ethylene glycol 300 (PEG 300) as solvent. However, acetonitrile (MeCN) and dimethylformamide (DMF)
were found to be alternative solvents, the latter especially for 2-substituted aryl boronic acids.
Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
Keywords:
Boron chemistry
Microwaves
Green chemistry
1. Introduction
as in various functional group interconversions on arenes. Exam-
ples of the latter include oxidations under Jones or Swern condi-
The twelve Principles Of Green Chemistry, encompassing inter
alia, atom economy, less hazardous chemical syntheses, safer sol-
vent use, improved energy efficiency and the use of renewable
feedstocks, are invaluable guidelines for evaluating the greenness
in the design and implementation of any new process or
technology.1e3
Burke’s group has pioneered MIDA boronate chemistry, showing
these compounds to be orthogonal to boronic acids in Suzu-
kieMiyaura (SM) reactions. By virtue of an sp3 hybridised boron,
MIDA boronates, Fig. 1,4 are less prone to transmetallation, exem-
plified by the selective cross-coupling of bromophenyl MIDA bor-
onates with p-tolylboronic acid, affording biaryl-MIDA boronates,
under anhydrous conditions.5
tions or the cycloisomerisation of arylethynyl MIDA boronates.11,12
These allow for greener, multistep telescopic reactions with an in
situ cleavage of the MIDA boronate, enabling a second coupling,
minimising workeup and solvent usage in these one-pot processes.
This is desirable in medicinal chemistry as the deployment of faster
reaction times, fewer reaction steps and lower solvent volumes is
desirable.13 MIDA boronates are crystalline solids that are air stable
and silica-gel column-compatible14 and may also be used as ‘han-
dles’ to enhance the stability of otherwise unstable boronic
acids.15e18
Due to their advantageous attributes, many MIDA boronates are,
not surprisingly, commercially available.19 Current methods of
MIDA boronate synthesis include (Fig. 2); (i) metallation to form an
organolithium or Grignard reagent, followed by borylation with
trimethyl or triisopropyl-borate to form the corresponding boro-
nate followed by in situ esterification with MIDA in dimethylsuf-
oxide (DMSO). (ii) Electrophilic arene borylation followed by an
overnight MIDA esterification with the bis-trimethylsilyl ester of
MIDA, the disodium salt of MIDA or MIDA alone. (iii) MIDA esteri-
fication of a boronic acid with 4-methylmorpholine-2,6-dione
(MIDA anhydride). (iv) Esterification of a boronic acid with MIDA
in DMSO/benzene or toluene via an 8 h azeotropic removal of water
with a Dean Stark trap. (v) Esterification of a boronic acid with
MIDA in DMF at 85 ꢀC for 18 h, hitherto deemed to be the method of
choice.20e23
Fig. 1. sp2 versus sp3 boronic acids and derivatives in cross-couplings.
The scope of MIDA boronates as protecting groups has been
underlined in other related coupling reactions, e.g., Negishi, Heck,
Sonogashira, Stille and BuchwaldeHartwig amination,6e10 as well
Many current synthetic methods towards MIDA boronates re-
quire a multistep process, large solvent volume or an extensive
* Corresponding author. Fax: þ44 (0)1273 876687; e-mail address: j.spencer@
sussex.ac.uk (J. Spencer).
http://dx.doi.org/10.1016/j.tet.2014.09.044
0040-4020/Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
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A.J. Close et al. / Tetrahedron xxx (2014) 1e7
Table 1 shows that, apart from water (entry 3), DMSO gave the
poorest results out of the solvents trialled, and reactions mixtures
tended to blacken, with dimethylsulphide odour detected (entries
4, 5). This was more noticeable when molecular sieves were used as
they are known to be Lewis acidic and could increase de-
composition (entry 5) and large amounts of impurities in the crude
NMR were observed.27 It is notable that dry DMF was the best
solvent (entry 6). We concluded that small amounts of water in
reagent grade DMF (entry 7) may lead to in situ MIDA ester cleavage
due to possible (basic) dimethylamine generation.28 The result
employing acetonitrile (entry 1), although comparable to that of
entry 6, was deemed to be the most promising, due to the reduced
toxicity and lower boiling point of this solvent.29,30 Interestingly,
the use of molecular sieves (entry 2) did not push the reaction to
completion.
To test the reaction scope, we next synthesised a small library of
MIDA boronates using the initial solvent of choice, acetonitrile, and
employing a short, 5 min, reaction hold time, see Table 2 (general
method A, orange highlight). Yields, in general, were good to ex-
cellent, e.g., 2a, 2c, 2o and the reaction showed good functional
group tolerance. A simple alkyl MIDA boronate 2m was formed in
near quantitative yield. However, 2b was formed in a low yield, for
unknown reasons, and one other notable exception is compound
2p, which we were unable to synthesise. We hypothesised the lack
of reaction may at least be partly due to the presence of two ortho
substituents flanking the boronic acid functionality and that
a higher boiling point solvent and/or extended reaction times
might enable this reaction.
For 2d, 2h and 2o similar yields were achieved when the re-
actions were run on a small (1 mmol) or large (gram) scale. How-
ever, for the high scale reactions, some technical adjustments were
required; for example, a 5 mmol scale reaction in a 35 mL CEM
microwave vial often gave rise to increased pressurisation, due to
a reduction in relative head space in the closed system. In order to
resolve this, a like-for-like mmol mLꢁ1 ratio (to the original 1 mmol
conditions) was implemented, enabling the same relative head
space. Hence, a 1 mmol scale reaction was conducted in a 10 mL vial
whereas a 3.5 mmol scale reaction was performed in a 35 mL vial.
Given that we had no access to 50 mL microwave vials, we ran
5 mmol scale reactions under open vessel microwave conditions.
Next, we turned our attention to DMF as solvent and increased
the reaction time to 10 min, as a rapid screen showed 5 min to lead
to incomplete reactions (Table 2 general method B, red highlight).
Gratifyingly, 2p was now formed in 62% yield and a series of 2-
substituted aryl and heteroaryl MIDA boronates were syn-
thesised, mostly in moderate to good yields. Relatively poor yields
were recorded for the 2-phenol derivative 2v and the chloropyr-
idine 2t whereas 2y was not formed at all. Reaction optimisation
studies, beyond the scope of the current work, may lead to im-
proved yields. On increasing the scale of these conditions we
found, comparable or slightly lower yields for 2p, 2s and 2w. Due to
the higher boiling point of DMF, compared with acetonitrile, it
allowed us to work on a larger 5 mmol scale in a closed vessel, and
even an open vessel on a 10 mmol scale in the case of 2s. We also
note an acceptable 44% yield for the somewhat elusive benzalde-
hyde derivative 2q.23
Fig. 2. MIDA arylboronate synthesis.
period of heating. Given the above, the increasing numbers of green
processes employing MIDA boronates would be far more attractive
were a general, scalable, efficient process for preparing the starting
material available. Herein, we describe our efforts aimed at re-
ducing reaction times and solvent usage. Moreover, the use of mi-
crowave chemistry24e26 for enabling quick, more efficient reactions
was anticipated to be advantageous in the synthesis MIDA boro-
nates 2 from their boronic acid precursors.
2. Results and discussion
We wished to form the MIDA ester of 4-fluoro-3-formyl boronic
acid 1i using the standard literature method of choice. However, we
were frustrated with the reaction times involved and, hence, ex-
amined the use of microwave-mediated methods. Hence, a rapid
screen of (minimal volume) solvent and potential additives was
performed to ascertain the best conditions. This method was par-
ticularly propitious for screens employing small volumes of deu-
terated NMR solvents such that, upon cooling, the reaction mixture
was transferred directly to an NMR tube then spectrometer for
inspection. Employing 1 equiv of MIDA, a microwave-mediated
route using a short hold time of 5 min was attempted and results
are summarised in Table 1.
Table 1
Rapid solvent screen for test reaction
Entry
Solvent/additive
% Conversiona
Having considerably improved upon conventional reaction
times for MIDA boronate synthesis using microwave chemistry, our
next iteration needed to address the issues of solvent suitability.
PEG 300 was considered as a worthy candidate solvent as it has
similar properties to DMSO, in terms of polarity and hydrogen bond
acceptor properties, as highlighted by Jessop, in two KamleteTaft
plots of common solvents.31 It also has the desired green solvent
properties, viz. negligible vapour pressure, low flammability, re-
duced environmental damage adding to the advantage of a com-
plete toxicity report and it is approved by the FDA for human
1
2
3
4
5
6
7
8
Acetonitrile-d3
95
93
5b
60
0
97
72
69b
ꢀ
Acetonitrile-d3þ3 A molecular sieves
Water
DMSO-d6
ꢀ
DMSO-d6þ4 A molecular sieves
DMF dry
DMF reagent grade
PEG 300
a
Calculated from 1H NMR integration of crude mixture.
Isolated yield.
b
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A.J. Close et al. / Tetrahedron xxx (2014) 1e7
3
Table 2
Isolated yields (%) for MIDA boronates
consumption.32 Finally, we already found it to be suitable for mi-
crowave-mediated MIDA boronate synthesis (entry 8, Table 1).
Hence, yields in PEG 300 were generally good but, again, some
technical adjustments were necessary at the start. The higher vis-
cosity of the medium led to difficulty in stirring the reaction during
microwave irradiation, sometimes leading to overheating by up to
40 ꢀC. This was averted by limiting the maximum power on the
microwave’s dynamic setting to 40 W. A few trends need to be
outlined (Table 2 general method C, green highlight); yields for 2-
substituted MIDA boronates tend to be lower than those obtained
in DMF, e.g., the poorer yields for 2s (51% vs 97%), 2u (60% vs 83%) or
the significantly lower yields for 2p (14% vs 62%), 2q (9% vs 44%) in
PEG 300 signify that DMF would be a solvent of choice in their
synthesis. In PEG 300 comparable yields for the synthesis of 2h
were obtained when performed on a low to multigram scale and an
isolated yield of 82% for 2t was observed. The low vapour pressure
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4
A.J. Close et al. / Tetrahedron xxx (2014) 1e7
of PEG 300 made scale up easy and we no longer experienced
a limitation in vial size, as noted for acetonitrile (vide supra).
Product 2h was easily made in an open vessel MW reaction on
a 10 mmol scale and the work up procedure using PEG 300 proved
easy; precipitation of the pure MIDA boronate product, after cool-
ing, was achieved using water. After collection by filtration the
product was washed with minimal water to remove any residual
solvent.
Compatibility issues with the attempted MIDA protection of 2-
heterocyclic boronic acids, which are of particular interest for
slow release couplings, were encountered.18 Test reactions were
carried out on N-Boc-pyrrole-2-boronic acid, 2-furanylboronic acid
and 2-thienylboronic acid, but 1H NMR inspection of the crude
material in these three cases showed a large amount of impurities,
and these were not pursued any further.
performed using a 30 min method in water/acetonitrile with 0.1%
formic acid (5 min at 5%, 5e95% over 20 min, 5 min at 95%) with the
UV set to 254 nm. High-resolution mass spectrometry (HRMS) was
done either internally or by the National Mass Spectrometry Fa-
cility, University of Swansea on an LTQ Orbitrap XL. A number of the
products described below are commercially available or known,
e.g., in patents. In these cases, 1H, 13C, HRMS and % purity data are
presented since in many cases these data are not published. For
compounds that appear to be novel, more analytical data are pre-
sented including 11B NMR.
3.2. General procedure for MIDA boronate formation with
acetonitrile (general method A)
The boronic acid (1 mmol) was added to a 10 mL microwave vial
equipped with a magnetic stirrer, and then acetonitrile (1 mL) was
added, followed by methyliminodiacetic acid (MIDA) (147 mg,
1 mmol). The Teflon cap was added and the reaction mixture was
heated using the dynamic heating method, with the maximum
power set to 300 W, max pressure 250 psi, max temperature 130 ꢀC,
high stirring throughout and power max turned off. This method
was used to hold the reaction mixture at 130 ꢀC for 5 min. After
cooling, the magnetic stirrer was retrieved and the acetonitrile was
removed under reduced pressure giving a crude white powder. This
crude material was first triturated via sonication with deionised
water (5 mL), cooled in an ice bath and collected by filtration and
washed withcold water (5 mL). This solid was then further triturated
with diethyl ether (5 mL), cooled in an ice bath, collected by filtration
and washed with diethyl ether (5 mL) giving pure product as a white
precipitate (if not otherwise quoted), which was air dried.
Finally, we have checked the applicability of this MIDA forming
reaction with other boron-containing precursors and selected
dichlorophenylborane 3n as a precursor (Table 3). The latter, being
highly reactive, was not suitable for use in the aprotic solvent, PEG
300, (entry 1) and best yields were obtained in DMF (entry 3), which
are comparable to those obtained using phenylboronic acid (entry 5).
Table 3
Dichlorophenylborane as a precursor to the MIDA analogue 2n
Entry
Solvent
Method
Isolated yield (%)
1
2
3
PEG 300
MeCN dry
DMF dry
DMF dry
PEG 300
5 min MW heating 130 ꢀC
5 min MW heating 130 ꢀC
5 min MW heating 130 ꢀC
24 h rt
0
39
63
12
55
Notes: The 3.5 mmol scale reaction was done using a 35 mL
microwave vial, with the same heating profile.
4
5a
5 min MW heating 130 ꢀC
3.3. General procedure for MIDA boronate formation with
DMF (general method B)
a
Entry 2n, Table 2, (from PhB(OH)2), for comparison.
The boronic acid (1 mmol) was added to a 10 mL microwave vial
equipped with a magnetic stirrer, followed by methyliminodiacetic
acid (MIDA) (1 mmol) and dry DMF (1 mL) was added to the vial.
The Teflon cap was added and the reaction mixture was heated
using the dynamic heating method, with max power set to 300 W,
max pressure 300 psi, max temperature 130 ꢀC, high stirring
throughout and power max turned off. This method was used to
hold the reaction mixture at 130 ꢀC for 10 min.
After cooling, the DMF was removed under reduced pressure
giving crude yellow oil. The latter was triturated via sonication with
deionised water (5 mL), cooled in an ice bath and collected by fil-
tration and washed with cold water (5 mL). This solid was then
further triturated with diethyl ether (5 mL), cooled in an ice bath,
collected by filtration and washed with diethyl ether (5 mL) then air
dried giving pure product as a white precipitate.
3. Conclusion
A rapid microwave-mediated synthesis of a library of MIDA
boronates has been developed. In many cases this reaction is high
yielding, uses minimal solvent and reaction times, can be per-
formed on a multigram scale and is tolerant of a range of functional
groups. At best, performed in PEG 300 as solvent, this protocol
should now represent the method of choice for the synthesis of
synthetically important MIDA boronates and used in the synthesis
of bioactive compounds. Results in this respect will be reported in
due course. We have also found that this reaction can be used with
a dichlorophenylborane precursor. Moreover, full characterisation
data for these products, many of which are commercially available,
are provided.
3.1. General experimental methods
3.4. General procedure for MIDA boronate formation with
PEG 300 (general method C)
Solvents and reagents were purchased from commercial sup-
pliers and used without further purification. Boronic acids were
typically purchased, and used as such, from Sigma Aldrich or Boron
Molecular. Reactions were heated using a CEM discovery micro-
wave fitted with an explorer unit ensure a ventilated fumehood
with the sash lowered is used as these reactions are under high
pressure and temperature. NMR spectra were recorded on a Varian
500 MHz or 400 MHz spectrometer. Chemical shifts are reported in
parts per million (ppm) and are referenced to the residual solvent
peak or to TMS used as an internal standard; note that in some
The boronic acid (1 mmol) was added to a 10 mL microwave vial
equipped with a magnetic stirrer, and then PEG 300 (1 mL) was
added followed by methyliminodiacetic acid (MIDA) (147 mg,
1 mmol). The Teflon cap was added and the reaction was heated
using the dynamic heating method, with max power set to 40 W,
max pressure 250 psi, max temperature 130 ꢀC, high stirring
throughout and power max turned off. This method was used to
hold the reaction mixture at 130 ꢀC for 5 min.
After cooling, the mixture was added to water (9 mL). This
mixture was stirred forming a white precipitate, then cooled in an
ice bath allowing flocculation, then collected by filtration and
cases the CeB bond is not detectable in the 13C NMR.25 LCMS were
ꢀ
ran with a 5
m
m C18 110 A column. Percentage purities were
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A.J. Close et al. / Tetrahedron xxx (2014) 1e7
5
washed with cold water (5 mL). The precipitate was allowed to
dried in an oven set to 100 ꢀC, giving pure product as a white
precipitate (if not otherwise quoted).
Notes: The 5 mmol scale reaction was performed using a 35 mL
microwave vial and the 10 mmol scale was carried out using
a 100 mL round bottomed flask with a small air condenser attached
with the open vessel attenuator installed. The heating parameters
were kept the same but the hold time was changed to 7.5 min for
the 5 mmol scale and 10 min for the 10 mmol scale reactions.
Yield: 227 mg (87%). CAS number 1257650-77-3. 1H NMR (500 MHz,
acetonitrile-d3)
10.04 (s, 1H), 7.89 (d, J¼8.0 Hz, 2H), 7.72 (d,
J¼8.0 Hz, 2H), 4.10 (d, J¼17.1 Hz, 2H), 3.93 (d, J¼17.1 Hz, 2H), 2.52 (s,
3H). 13C NMR (126 MHz, DMSO-d6)
193.4,169.2,136.5,133.1,128.5,
62.0, 47.7. 11B NMR (128 MHz, DMSO-d6)
10.82. LCMS purity >99%
(UV), ret. time¼11.76 min. HRMS-ESI (m/z) found 284.0699, calcd
d
d
d
10
for [C
H
BNO5Na]þ 284.0701.
12 12
3.4.7. 3-Bromophenyl MIDA boronate 2g. Made following general
method A. Yield: 274 mg (88%). Made following general method C.
Yield: 218 mg (70%). CAS number 943552-25-8. 1H NMR (500 MHz,
3.4.1. 3-Hydroxyphenyl MIDA boronate 2a. Made following general
method A. Yield: 199 mg (80%). CAS number 1257724-90-5. 1H NMR
acetonitrile-d3)
7.37e7.33 (m, 1H), 4.07 (d, J¼17.1 Hz, 2H), 3.91 (d, J¼17.1 Hz, 2H),
2.53 (s, 3H). 13C NMR (126 MHz, acetonitrile-d3)
169.3, 136.2,
133.2, 132.3, 131.0, 123.4, 63.0, 48.7. 11B NMR (128 MHz, Acetoni-
trile-d3)
d 7.65 (s, 1H), 7.63e7.59 (m, 1H), 7.53e7.48 (m, 1H),
(500 MHz, DMSO-d6)
d
9.26 (s,1H), 7.25 (d, J¼8.0 Hz,1H), 6.96e6.90
(m, 2H), 6.84 (d, J¼8.0 Hz, 1H), 4.40 (d, J¼17.1 Hz, 2H), 4.18 (d,
d
J¼17.1 Hz, 2H), 2.58 (s, 3H). 13C NMR (126 MHz, DMSO-d6)
d 169.3,
156.7, 128.8, 122.9, 119.0, 115.8, 61.7, 47.5. 11B NMR (128 MHz,
d
11.31. LCMS purity >99% (UV), ret. time¼16.73 min.
10
DMSO-d6)
d
11.68. LCMS purity >99% (UV), ret. time¼11.61 min.
HRMS-ESI (m/z) found 333.9851, calcd for [C H
BBrNO4Na]þ
11 11
10
HRMS-ESI (m/z) found 250.0878, calcd for [C
H
BNO5H]þ
333.9857.
11 12
250.0881.
3.4.8. 4-Bromophenyl MIDA boronate 2h. Made following general
method A. Yield: 278 mg (1 mmol scale, 89%), 861 mg (3.5 mmol
scale, 79%). Made following general method C. CAS number
943552-04-3.
3.4.2. 4-Hydroxyphenyl MIDA boronate 2b. Made following general
method A. Yield: 87 mg (35%). CAS number 1312788-59-2. 1H NMR
(500 MHz, acetonitrile-d3)
(d, J¼8.0 Hz, 2H), 4.02 (d, J¼17.1 Hz, 2H), 3.84 (d, J¼17.1 Hz, 2H), 2.48
(s, 3H). 13C NMR (100 MHz, acetonitrile-d3)
169.6, 159.0, 135.0,
115.9, 62.7, 48.4. 11B NMR (128 MHz, acetonitrile-d3)
11.60. LCMS
purity >99% (UV), ret. time¼11.14 min. HRMS-ESI (m/z) found
d
7.33 (d, J¼8.0 Hz, 2H), 6.93 (s, 1H), 6.82
Yield: 259 mg (1 mmol scale, 83%), 1.127 g (5 mmol scale, 72%),
d
2.551 g (10 mmol scale, 82%). 1H NMR (500 MHz, acetonitrile-d3)
d
d
7.55 (d, J¼8.0 Hz, 2H), 7.42 (d, J¼8.0 Hz, 2H), 4.07 (d, J¼17 Hz, 2H),
3.89 (d, J¼17 Hz, 2H), 2.51 (s, 3H). 13C NMR (126 MHz, acetonitrile-
10
272.0700, calcd for [C
H
BNO5Na]þ 272.0701.
d3)
tonitrile-d3)
d
169.4, 135.6, 132.0, 124.4, 62.9, 48.6. 11B NMR (128 MHz, ace-
11 12
d
11.24. LCMS purity >99% (UV), ret. time¼16.87 min.
10
3.4.3. 3-Acetamidophenyl MIDA boronate 2c. Made following gen-
eral method A. Yield: 230 mg (1 mmol scale, 79%), 861 mg
(3.5 mmol scale, 85%) as a pink precipitate. Made following general
method C. Yield: 223 mg (77%) as a pink precipitate. 1H NMR
HRMS-ESI (m/z) found 333.9857, calcd for [C H
BBrNO4Na]þ
11 11
333.9857.
3.4.9. 4-Fluoro-3-formylphenyl MIDA boronate 2i. Made following
general method A. Yield: 226 mg (81%).
(500 MHz, DMSO-d6)
d 9.87 (s, 1H), 7.79e7.74 (m, 1H), 7.46 (s, 1H),
7.31e7.24 (m,1H), 7.12e7.06 (m,1H), 4.33 (d, J¼17.2 Hz, 2H), 4.09 (d,
Made following general method C. Yield: 193 mg (69%). 1H NMR
4
J¼17.2 Hz, 2H), 2.49 (s, 3H), 2.02 (s, 3H). 13C NMR (126 MHz, DMSO-
(500 MHz, acetonitrile-d3)
d
10.30 (s, 1H), 7.96 (dd, JFH¼7.4,
3
4
4
d6)
d
169.2, 168.1, 138.7, 128.0, 127.0, 122.9, 119.7, 61.6, 47.5, 23.9. 11
B
4JHH¼2.0 Hz, 1H), 7.82 (ddd, JHH¼8.3, JFH¼5.6, JHH¼2.0 Hz, 1H),
7.27 (dd, 3JFH¼11.0, 3JHH¼8.3 Hz, 1H), 4.10 (d, J¼17.2 Hz, 2H), 3.93 (d,
J¼17.2 Hz, 2H), 2.54 (s, 3H). 13C NMR (126 MHz, acetonitrile-d3)
NMR (128 MHz, DMSO-d6)
d 11.34. LCMS purity >99% (UV), ret.
time¼11.76 min. HRMS-FTMS (m/z) found 290.1180, calcd for
10
3
1
[C
H
BN2O5H]þ 290.1183.
d
187.9 (d, JFC¼6.0 Hz), 168.3, 165.0 (d, JFC¼260 Hz), 140.9 (d,
3 2
13 15
3JFC¼9 Hz), 134.0 (d, JFC¼2 Hz), 123.7 (d, JFC¼8.0 Hz), 116.1 (d,
3.4.4. 4-Acetamidophenyl MIDA boronate 2d. Made following gen-
eral method A. Yield: 232 mg (1 mmol scale, 80%), 768 mg
(3.5 mmol scale, 76%) as a brown crystalline solid. Made following
general method C. Yield: 252 mg (1 mmol scale, 87%) as a brown
2JFC¼20 Hz), 62.1, 47.7. 19F NMR (376 MHz, acetonitrile-d3)
d
ꢁ110.85
(ddd, J¼12.2, 7.7, 5.1 Hz). 11B NMR (128 MHz, acetonitrile-d3)
d
10.6.
LCMS purity 96% (UV), ret. time¼14.10 min. HRMS-ESI (m/z) found
10
302.0607, calcd for [C
H
BFNO5Na]þ 302.0607.
12 11
crystalline solid. 1H NMR (500 MHz, DMSO-d6)
d 9.90 (s, 1H), 7.55
(d, J¼8.0 Hz, 2H), 7.34 (d, J¼8.0 Hz, 2H), 4.30 (d, J¼17.2 Hz, 2H), 4.08
3.4.10. 3-Fluoro-4-formylphenyl MIDA boronate 2j. Made following
general method A. Yield: 235 mg (84%).
(d, J¼17.2 Hz, 2H), 2.48 (s, 3H), 2.04 (s, 3H). 13C NMR (126 MHz,
DMSO-d6)
(128 MHz, DMSO-d6)
¼11.37 min HRMS-FTMS (m/z) found 290.1181, calcd for
d
169.3, 168.2, 139.9, 132.8, 118.2, 61.7, 47.5, 24.0. 11B NMR
Made following general method C. Yield: 204 mg (73%). 1H NMR
3
d
10.36. LCMS purity >99% (UV), ret. time-
(500 MHz, acetonitrile-d3)
d
10.34 (s, 1H), 7.87 (appt, JHH,4JFH
3
3
J¼7.5 Hz, 1H), 7.49 (d, JHH¼7.5 Hz, 1H), 7.43 (d, JFH¼11.4 Hz, 1H),
10
[C
H
BN2O5H]þ 290.1183.
4.15 (d, J¼17.2 Hz, 2H), 3.98 (d, J¼17.2 Hz, 2H), 2.59 (s, 3H). 13C NMR
13 15
3
(126 MHz, acetonitrile-d3)
d
188.7 (d, JFC¼6.0 Hz), 169.2, 164.9 (d,
3.4.5. 3-Formylphenyl MIDA boronate 2e. Made following general
method A. Yield: 200 mg (76%). Made following general method C.
Yield: 264 mg (51%). CAS number 1257642-72-0. 1H NMR (500 MHz,
1JFC¼258.0 Hz), 129.8, (d, 3JFC¼4.0 Hz), 129.4, 125.7 (d, 2JFC¼9.0 Hz),
121.3 (d, 2JFC¼19.0 Hz), 63.2, 48.7. 19F NMR (376 MHz, acetonitrile-
d3)
d
ꢁ112.46 (dd, J¼11.7, 7.3 Hz). LCMS purity 94% (UV), ret.
DMSO-d6)
d
10.04 (s, 1H), 8.0 (s, 1H), 7.91 (d, J¼7.5 Hz, 1H), 7.78 (d,
time¼14.24 min. 11B NMR (128 MHz, acetonitrile-d3)
d 10.6. HRMS-
10
J¼7.5 Hz, 1H), 7.60 (appt, J¼7.5 Hz, 1H), 4.37 (d, J¼17.2 Hz, 2H), 4.17
ESI (m/z) found 302.0605, calcd for [C
H
BFNO5Na]þ 302.0607.
12 11
(d, J¼17.2 Hz, 2H), 2.53 (s, 3H). 13C NMR (126 MHz, DMSO-d6)
d
193.5, 169.2, 138.6, 135.5, 133.9, 129.8, 128.4, 62.0, 47.7. 11B NMR
3.4.11. 2-Fluoropyridin-5-yl MIDA boronate 2k. Made following
general method A. Yield: 152 mg (60%). Made following general
method C. Yield: 121 mg (48%). 1H NMR (500 MHz, DMSO-d6)
(128 MHz, DMSO-d6)
d
11.31. LCMS purity UV¼98%, ret. time-
¼13.45 min. HRMS-ESI (m/z) found 284.0701, calcd for
10
[C
H
BNO5Na]þ 284.0701.
d 8.26e8.23 (m, 1H), 8.03e7.97 (m, 1H), 7.17e7.13 (m, 1H), 4.36 (d,
12 12
J¼17.2 Hz, 2H), 4.16 (d, J¼17.2 Hz, 2H), 2.58 (s, 3H). 13C NMR
1
3.4.6. 4-Formylphenyl MIDA boronate 2f. Made following general
method A. Yield: 264 mg (99%). Made following general method C.
(100 MHz, DMSO-d6)
d
169.0, 164.0 (d, JFC¼236.2 Hz), 151.6 (d,
3JFC¼14.1 Hz), 146.4 (d, JFC¼7.6 Hz), 108.7 (d, JFC¼35.8 Hz), 62.0,
3
2
Please cite this article in press as: Close, A. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.044

6
A.J. Close et al. / Tetrahedron xxx (2014) 1e7
47.7. 19F NMR (376 MHz, DMSO-d6)
d
ꢁ68.77 (d, J¼9.0 Hz). 11B NMR
2H), 4.14 (d, J¼17.8, 2H), 4.14 (d, J¼17.8, 2H), 2.68 (s, 3H). 13C NMR
(126 MHz, acetonitrile-d3): 196.8, 169.9, 142.1, 136.8, 135.2, 134.0,
130.7, 65.7, 50.0. 11B NMR (128 MHz, acetonitrile-d3): 11.83. LCMS
(128 MHz, DMSO-d6)
d 11.16. LCMS purity >99% (UV), ret. time-
¼12.13 min. HRMS-ESI (m/z) found 253.0789, calcd for
10
[C
H
BN2O4H]þ 253.0790.
purity ꢂ99% (UV), ret. time¼12.94 min. HRMS-FTMS (m/z) found
10 10
10
262.0880, calcd for [C
H
BNO5H]þ 262.0881.
12 12
3.4.12. 3-Fluorophenyl MIDA boronate 2l. Made following general
method A. Yield: 231 mg (92%). Made following general method C.
Yield: 171 mg (68%). CAS number 1313614-50-4. 1H NMR (500 MHz,
3.4.18. 2-Bromophenyl MIDA boronate 2r. Made following general
method B. Yield: 224 mg (72%). Made following general method C.
Yield: 218 mg (70%). CAS number 1257649-57-2. 1H NMR (500 MHz,
DMSO-d6)
d
7.44e7.38 (m, 1H), 7.26 (d, J¼7.3 Hz, 1H), 7.23e7.12 (m,
2H), 4.34 (d, J¼17.2 Hz, 2H), 4.14 (d, J¼17.2 Hz, 2H), 2.53 (s, 3H). 13
C
acetonitrile-d3):
d
7.67 (d, J¼7.4 Hz, 1H), 7.62 (d, J¼7.8 Hz, 1H), 7.39
NMR (126 MHz, DMSO-d6)
d
169.2, 162.0 (d, 1JFC¼244.0 Hz), 129.8
(dd, J¼7.4 Hz, 7.5 Hz, 1H), 7.30 (dd, J¼7.8, 7.5 Hz, 1H), 4.13 (d,
J¼17.3 Hz, 2H), 4.03 (d, J¼17.3 Hz, 2H), 2.71 (s, 3H). 13C NMR
(126 MHz, acetonitrile-d3): 169.5, 137.4, 134.6, 132.4, 128.7, 128.0,
65.3, 49.6. 11B NMR (128 MHz, acetonitrile-d3): 11.60. LCMS purity
(d, 3JFC¼7.3 Hz), 128.3 (d, 4JFC¼2.6 Hz), 118.6 (d, 2JFC¼18.7 Hz), 115.6
(d, 2JFC¼20.8 Hz), 61.9, 47.6. 19F NMR (376 MHz, DMSO-d6)
d
ꢁ114.11
(td, J¼9.6, 5.8 Hz). 11B NMR (128 MHz, DMSO-d6)
d 10.69. LCMS
purity >99% (UV), ret. time¼15.22 min. HRMS-FTMS (m/z) found
ꢂ99% (UV), ret. time¼15.44 min. HRMS-FTMS (m/z) found
10
274.0664, calcd for [C11H11O4NBFNa]þ 274.0664.
333.9862, calcd for [C
H
BBrNO4Na]þ 333.9857.
11 11
3.4.13. Methyl MIDA boronate 2m. Made following general method
A. Yield: 171 mg (99%). Made following general method C. Yield:
87 mg (51%). CAS number 1104637-40-2. 1H NMR (500 MHz, ace-
3.4.19. 2-Methoxyphenyl MIDA boronate 2s. Made following gen-
eral method B. Yield: 254 mg (97%), 1144 mg (5 mmol scale, 87%),
2420 mg (10 mmol scale, 92%). Made following general method C.
Yield: 134 mg (51%). CAS number 1257737-05-5. 1H NMR (500 MHz,
tonitrile-d3)
d
3.92 (d, J¼17.0 Hz, 2H), 3.78 (d, J¼17.0 Hz, 2H), 2.84 (s,
3H), 0.10 (s, 3H). 13C NMR (126 MHz, acetonitrile-d3)
d
169.1, 62.6,
acetonitrile-d3):
d
7.56 (dd, J¼7.2, 1.9 Hz, 1H), 7.39 (ddd, J¼8.2, 7.2,
46.9. 11B NMR (128 MHz, acetonitrile-d3)
d
13.37. HRMS-ESI (m/z)
1.9 Hz, 1H), 6.97 (m, 2H), 4.06 (d, J¼17.0 Hz, 2H), 3.95 (d, J¼17.0 Hz,
2H), 3.77 (s, 3H), 2.61 (s, 3H). 13C NMR (126 MHz, DMSO-d6): 169.2,
162.0, 133.9, 130.7, 120.2, 110.3, 63.2, 54.8, 47.2. 11B NMR (128 MHz,
10
found 194.0594, calcd for [C6H BNO4Na]þ 194.0595.
10
3.4.14. Phenyl MIDA boronate 2n. Made following general method
A. Yield: 123 mg (53%). Made following general method C. Yield:
128 mg (55%). Made following modified general method B (PhBCl2
(Sigma Aldrich)) was first added dropwise to stirred MIDA in DMF
in microwave vial (CAUTION, HCl evolution!) Yield: 147 mg (63%).
CAS number 109737-57-7. 1H NMR (500 MHz, acetonitrile-d3)
acetonitrile-d3): 7.66. LCMS purity ꢂ99% (UV), ret. time¼14.76 min.
BNO5Na]þ
10
HRMS-FTMS (m/z) found 286.0860, calcd for [C
H
12 14
286.0857.
3.4.20. 2-Chloro-3-pyridyl MIDA boronate 2t. Made following gen-
eral method B. Yield: 67 mg (25%). Made following general method
C. Yield: 220 mg (82%). CAS number 1309676-59-2. 1H NMR
d
7.53e7.47 (m, 2H), 7.44e7.36 (m, 3H), 4.06 (d, J¼17.1 Hz, 2H), 3.88
(d, J¼17.1 Hz, 2H), 2.49 (s, 3H). 13C NMR (100 MHz, acetonitrile-d3)
(500 MHz, acetonitrile-d3):
d
8.39 (dd, J¼4.7, 1.8 Hz, 1H), 8.11 (dd,
d
169.6, 133.4, 130.3, 128.9, 62.8, 48.5. 11B NMR (128 MHz, aceto-
J¼1.8, 7.4 Hz, 1H), 7.35 (dd, J¼7.4, 4.7 Hz, 1H), 4.16 (d, J¼17.3 Hz, 2H),
4.05 (d, J¼17.3 Hz, 2H), 2.75 (s, 3H). 13C NMR (126 MHz, acetonitrile-
d3): 169.3, 151.6, 146.6, 123.5, 111.0, 65.2, 49.3. 11B NMR (128 MHz,
nitrile-d3)
d
10.64. LCMS purity >99% (UV), ret. time¼14.38 min.
10
HRMS-ESI (m/z) found 256.0750, calcd for [C
H
BNO4Na]þ
11 12
256.0752.
acetonitrile-d3): 11.01. LCMS purity ꢂ99% (UV), ret. time¼11.43 min.
10
HRMS-FTMS (m/z) found 291.0309, calcd for [C
H
BClN2O4Na]þ
10 10
3.4.15. (E)-Styryl MIDA boronate 2o. Made following general
method A. Yield: 135 mg (52%), 480 mg (3.5 mmol scale, 53%). Made
following general method C. Yield: 75 mg (29%). CAS number
291.0314.
3.4.21. 2,4-Dimethoxypyrimidine-5-MIDA boronate 2u. Made fol-
lowing general method B. Yield: 245 mg (83%). Made following
general method C. Yield: 177 mg (60%). 1H NMR (500 MHz, aceto-
1152427-93-4. 1H NMR (400 MHz, DMSO-d6)
d 7.52e7.47 (m, 2H),
7.39e7.32 (m, 2H), 7.29e7.24 (m, 1H), 6.83 (d, J¼18.2 Hz, 1H), 6.28
(d, J¼18.2 Hz, 1H), 4.25 (d, J¼17.0 Hz, 2H), 4.04 (d, J¼17.0 Hz, 2H),
nitrile-d3):
d
8.38 (s,1H), 4.08 (d, J¼17.0 Hz, 2H), 3.95 (s, 3H), 3.94 (d,
2.81 (s, 3H). 13C NMR (101 MHz, DMSO)
d
169.0, 141.0, 137.8, 128.5,
J¼17.0 Hz, 2H), 3.91 (s, 3H), 2.66 (s, 3H). 13C NMR (126 MHz, ace-
127.8, 126.4, 61.3, 46.7, 39.5. 11B NMR (128 MHz, acetonitrile-d3)
10.54. LCMS purity ꢂ99% (UV), ret. time¼1.75 min. HRMS-FTMS
tonitrile-d3): d 174.8, 169.3, 167.9, 164.9, 111.0, 64.0, 55.2, 54.3, 48.2.
d
11B NMR (128 MHz, acetonitrile-d3):
ret. time¼10.34 min. HRMS-FTMS (m/z) found 296.1046, calcd for
d 11.24. LCMS purity 97% (UV),
10
(m/z) found 328.9971, calcd for [C
H
11 10
BBrFNO4H]þ 328.9979.
10
[C
H
BN3O6H]þ 296.1048.
11 14
3.4.16. 2-Bromo-6-fluorophenyl MIDA boronate 2p. Made following
general method B. Yield: 205 mg (62%), 924 mg (5 mmol scale, 56%).
Made following general method C. Yield: 46 mg (14%). CAS number
3.4.22. 2-Hydroxyphenyl MIDA boronate 2v. Made following gen-
eral method B. Yield: 105 mg (1 mmol scale, 42%). 1H NMR
1257650-76-2. 1H NMR (500 MHz, DMSO-d6)
d
7.49 (d, 3JHH¼8.0 Hz,
(500 MHz, DMSO-d6):
d
9.53 (s, 1H), 7.38 (dd, J¼7.3, 1.6 Hz, 1H), 7.17
1H), 7.36 (dd, 3JHH¼8.0, 8.2 Hz, 1H), 7.19 (dd, 3JFH¼10.9, 3JHH¼8.2 Hz,
(ddd, J¼7.9, 7.3, 1.6 Hz, 1H), 6.80e6.73 (m, 2H), 4.32 (d, J¼17.0 Hz,
2H), 4.03 (d, J¼17.0 Hz, 2H), 2.63 (s, 3H). 13C NMR (126 MHz, DMSO-
d6): 169.3, 160.0, 134.0, 130.2, 118.7, 114.6, 63.1, 47.1. 11B NMR
(128 MHz, DMSO-d6): 11.80. LCMS purity ꢂ99% (UV), Ret.
1H), 4.42 (d, J¼17.3 Hz, 2H), 4.16 (d, J¼17.3 Hz, 2H), 2.72 (s, 3H). 13
C
NMR (126 MHz, DMSO-d6)
d
168.6, 166.5 (d, 1JCF¼248.0 Hz), 132.6
(d, 3JFC¼11 Hz),130.5 (d, 4JFC¼3.0 Hz),127.8 (d, 3JFC¼9.0 Hz),115.2 (d,
2JFC¼27.0 Hz), 63.0, 47.9. 19F NMR (376 MHz, DMSO-d6)
d
ꢁ97.67
time¼12.76 min. HRMS-FTMS (m/z) found 272.0702, calcd for
10
(dd, J¼10.9, 6.3 Hz). 11B NMR (128 MHz, DMSO-d6)
d
10.6. LCMS
[C
H
BNO5Na]þ 272.0701.
11 12
purity ꢂ99% (UV), ret. time¼15.42 min. HRMS-FTMS (m/z) found
10
328.9971, calcd for [C
H
BBrFNO4H]þ 328.9979.
3.4.23. 2-Fluorophenyl MIDA boronate 2w. Following general
method B. Yield: 208 mg (83%), 991 mg (5 mmol scale, 79%). 1H
NMR (500 MHz, acetonitrile-d3): 7.59 (dd, J¼7.4 Hz, 1H), 7.49e7.41
(m, 1H), 7.22 (dd, J¼7.4 Hz, 1H), 7.08 (dd, J¼10.4, 8.4 Hz, 1H), 4.12 (d,
J¼17.1 Hz, 2H), 3.95 (d, J¼17.1 Hz, 2H), 2.64 (s, 3H). 13C NMR
(126 MHz, DMSO-d6): 168.9, 165.5 (d, J¼241.1 Hz), 134.7 (d,
11 10
3.4.17. 2-Formylphenyl MIDA boronate 2q. Following general
method B. Yield: 116 mg (44%), CAS number 1257651-51e6. Fol-
lowing general method C. Yield: 23 mg (9%). 1H NMR (500 MHz,
acetonitrile-d3):
d 10.11 (s, 1H), 7.93 (m, 1H), 7.80 (m, 1H), 7.66 (m,
Please cite this article in press as: Close, A. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.044

A.J. Close et al. / Tetrahedron xxx (2014) 1e7
7
J¼9.2 Hz), 131.6 (d, J¼8.7 Hz), 124.1 (d, J¼2.7 Hz), 114.9 (d,
References and notes
J¼24.8 Hz), 62.4 (d, J¼2.2 Hz), 47.5. 19F NMR (376 MHz, DMSO-d6):
ꢁ107.45 (m). 11B NMR (128 MHz, acetonitrile-d3): 10.48. LCMS
1. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford Uni-
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purity ꢂ99% (UV), ret. time¼14.72 min. HRMS-FTMS (m/z) found
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274.0661, calcd for [C
H
BFNO4Na]þ 274.0657.
11 11
3.4.24. 2,6-Dichlorophenyl MIDA boronate 2x. Following general
method B. Yield: 104 mg (35%). 1H NMR (500 MHz, acetonitrile-d3):
d
7.40 (m, 1H), 7.34e7.29 (m, 2H), 4.15 (d, J¼17.4 Hz, 2H), 4.01 (d,
J¼17.4 Hz, 2H), 2.83 (s, 3H). 13C NMR (126 MHz, acetonitrile-d3):
d
169.2, 142.0, 132.4, 130.9, 65.4, 49.7. 11B NMR (128 MHz, acetoni-
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49, 5574e5577.
trile-d3);
d
11.36. LCMS purity ꢂ99% (UV), ret. Time¼15.56 min.
10
HRMS-FTMS (m/z) found 323.9967, calcd for [C
H
BCl2NO4Na]þ
11 10
323.9972.
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3.4.25. 4-Methoxyphenyl MIDA boronate 2z. Made following gen-
eral method C. Yield: 184 mg (70%). CAS number 1257739-11-9. 1H
NMR (500 MHz, acetonitrile-d3)
J¼8.5 Hz, 2H), 4.03 (d, J¼17.1 Hz, 2H), 3.86 (d, J¼17.1 Hz, 2H), 3.80 (s,
3H), 2.49 (s, 3H). 13C NMR (126 MHz, acetonitrile-d3)
169.6, 161.8,
134.9, 114.5, 62.7, 55.8, 48.4. 11B NMR (128 MHz, acetonitrile-d3)
d
7.42 (d, J¼8.6 Hz, 2H), 6.94 (d,
d
17. Isley, N.; Gallou, F.; Lipshutz, B. H. J. Am. Chem. Soc. 2013, 135, 17707e17710.
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d
11.56. LCMS purity >99% (UV), ret. time¼14.36 min. HRMS-ESI (m/
10
z) found 286.0869, calcd for [C
H
BNO5Na]þ 286.0857.
12 14
20. Bagutski, V.; Del Grosso, A. J. Am. Chem. Soc. 2013, 135, 474e487.
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Acknowledgements
AstraZeneca and the University of Sussex are acknowledged for
funding (A.J.C.). SMSdrug.net is acknowledged for providing fund-
ing for networking. We would also like to express our gratitude to
the EPSRC UK National Mass Spectrometry Facility (Swansea Uni-
versity) and Dr. Alaa Abdul-Sada (University of Sussex) for per-
forming mass spectrometry measurements.
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ꢁ
ꢁ ꢂ
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compounds are available. Supplementary data associated with this
article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2014.09.044.
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Please cite this article in press as: Close, A. J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.044