Meta -Selective C-H functionalisation of aryl boronic acids directed by a MIDA-derived boronate ester

Article abstract of DOI:10.1039/d0sc00230e

N-Methyliminodiacetic acid (MIDA) boronates are boronic acid derivatives which are stable to reduction, oxidation and transmetalation. This has led to their widespread use as boronic acid protecting groups (PGs) and in iterative cross-couplings. We describe herein the development of a novel MIDA derivative that acts in a dual manner, as a protecting group and a directing group (DG) for meta C(sp²)-H functionalisation of arylboronic acids. Palladium catalysed C-H alkenylations, acetoxylations and arylations are possible, at room temperature and under aerobic conditions. Deprotection to reveal the functionalised boronic acids is rapid and allows for full recovery of the DG. The technique allows the facile diversification of aryl boronic acids and their subsequent use in a range of reactions or in iterative processes.

Full text of DOI:10.1039/d0sc00230e

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DOI: 10.1039/D0SC00230E
ARTICLE
Meta-Selective C–H Functionalisation of Aryl
Boronic Acids Directed by a MIDA-Derived Boronate
Received 00th January 20xx,
Accepted 00th January 20xx
Ester
Alexander F. Williams,a Andrew J.P. White,a Alan C. Spivey*a and Christopher J. Cordier*a,b
DOI: 10.1039/x0xx00000x
N-Methyliminodiacetic acid (MIDA) boronates are boronic acid derivatives which are stable to reduction, oxidation and
transmetalation. This has led to their widespread use as boronic acid protecting groups (PGs) and in iterative cross-couplings.
We describe herein the development of a novel MIDA derivative that acts in a dual manner, as a protecting group and a
directing group (DG) for meta C(sp2)–H functionalisation of arylboronic acids. Palladium catalysed C–H alkenylations,
acetoxylations and arylations are possible, at room temperature and under aerobic conditions. Deprotection to reveal the
functionalised boronic acids is rapid and allows for full recovery of the DG. The technique allows the facile diversification of
aryl boronic acids and their subsequent use in a range of reactions or in iterative processes.
Introduction
In recent years, directed C–H functionalisation has rapidly
progressed from a new concept to an indispensable synthetic
technique.1 Directing groups (DGs) have emerged as powerful tools
to achieve these transformations, often over-riding the inherent
steric or electronic bias of the substrate.2 While numerous methods
for the directed ortho C(sp2)–H functionalisation of aryl systems have
been developed, directed, meta-selective processes remain
relatively underexplored.3 The distal nature of the meta C–H bond,
its proximity to the ortho and para positions and often unfavourable
electronic properties pose unique challenges. In 2012, Yu was able to
address these challenges with the seminal design of U-shaped DGs
for the meta alkenylation of hydrocinnamic acid and toluene
derivatives.4
Numerous DG designs have since been developed, expanding on
Yu’s work.3d,5 However, the DGs are often bespoke for a particular
substitution process, require stepwise syntheses and attachment via
functional groups (FGs) which are themselves non-ideal for
subsequent derivatisation (e.g. amides).6 Consequently, the
synthetic versatility of the DGs is limited. A single, more general,
meta-selective DG, tethered via a synthetically versatile FG would
reduce the current need for many individually bespoke systems
(Scheme 1).
a.Department of Chemistry
Imperial College London
White City Campus, Molecular Sciences Research Hub, 80 Wood Lane, London,
W12 0BZ, UK
a.c.spivey@imperial.ac.uk
b.Present address: Grow Biotech
Rothamsted Enterprise, West Common, Harpenden, Hertfordshire, AL5 2JQ, UK
chris.cordier@growbiotech.com
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Scheme 1. A comparison between previously developed, bespoke
meta-DGs and a general boron-tethered meta-DG.
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We identified the boronic acid FG as an attractive foundation for
Journal Name
We describe herein the development of a novel MVIDieAw AdrteicrlievOatnilivnee
such a meta-selective DG. Boronic acids are ubiquitous in organic for the meta selective C(sp2)–H functionaDlisOaIt:i1o0n.10o3f9/aDr0ySl Cb0o0r2o3n0iEc
synthesis, with a wealth of transformations available for their acids. The MIDA-DG is simple to attach and remove, with
derivatisation.7,8 Their propensity to undergo transmetalation quantitative recovery possible. The DG enables Pd-catalysed C–H
precludes their direct use in metal catalysed C–H functionalisations functionalisation of aryl boronic acids, at room temperature and
however.9,10 Selective transition metal insertion into the desired, under aerobic conditions, with retention of the boronic acid FG. On
comparatively inert, C–H bond over the C–B bond must therefore be deprotection, the functionalised boronic acids can be derivatised
engineered to allow boronic acids to be exploited as the foundation into numerous other FGs using established boronic acid chemistry.
of the envisioned DG.
Lastly, we demonstrate the utility of MIDA-DG boronates by using
iterative C–H functionalisation/cross-coupling procedures to access
diverse polysubstituted aromatic systems.
Such selectivity has been demonstrated by Suginome et al., who
developed anthranilamide (aam) and 2-(1H-pyrazole-3-yl)aniline
(pza) boronate DGs which enable ortho-directed C–H
When considering the design of a MIDA-tethered DG, two general
functionalisations.11 Using these DGs, selective C–H silylations, principles were identified: that MIDA boronates are unstable
alkynylations and borylations are possible using iridium, ruthenium towards strongly basic reagents and nucleophilic solvents,12b and
or rhodium catalysts, with retention of the protected boronic acid that electron-withdrawing groups adjacent to the B–N bond were
FGs.
N-Methyliminodiacetic acid (MIDA) boronate esters, popularised
by Burke et al., similarly suppress B→M transmetalation, allowing
anticipated to weaken the strength of this interaction, causing the
MIDA ligand to become more labile.
Consequently, DG design focused on a cyanophenol moiety,
the selective Suzuki–Miyaura coupling of boronic acids in the attached via an O-alkyl linker to the nitrogen of the iminodiacetic
presence of masked MIDA boronates, under anhydrous conditions.12 acid.
This reactivity profile, combined with their ease of introduction and
The aryl ether linkage was anticipated to impart a minimal
deprotection, and the fact that N-tethered moieties are held in
detrimental effect on the MIDA B–N bond, while allowing for a
enforced proximity to the parent boronic acid by the rigid bicyclic
system, make the MIDA boronate an attractive scaffold upon which
to base a DG.13
cyclophane-like macrocyclic transition state to be accessed.3d,4
A number of DGs were synthesised and screened using conditions
based on those reported for meta C–H alkenylation (Fig. 1).3d,4,5
Product formation was initially observed with the simple 2-
cyanophenol based system 2, as well as ethyl cinnamate 1, formed
after deprotection and oxidative Heck coupling. Changes to the 2-
cyanophenol motif, investigating sterically biasing the direction of
the nitrile DG (3 and 4), increasing its Lewis basicity (5), or varying
the nitrile position (6) did not lead to improved performance.
However, increasing the length of the linker from ethyl to propyl (7)
resulted in a doubling of the yield and a concomitant drop in
formation of by-product 1.
Fig. 1. Screening of DG designs against C–H alkenylation conditions.
1
Reactions performed on 0.05 mmol scale, yields calculated using H
a
NMR against a CH2Br2 internal standard. HFIP (0.1 M), AgOAc (1.0
eq.), 50 °C used with 7, resulting in 46% yield as a mixture of 32%
meta (7a), 6% para, 5% di meta-meta and 3% di meta-para isomers.
2 | J. Name., 2012, 00, 1-3
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Scheme 2. MIDA-DG 8 allows protection of boronic acids,
ARTICLE
A 3 × 3 array was devised to investigate the reaction scope,
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functionalisation via C–H insertion and is simple to deprotect with incorporating
electron-donating
to DOeI:le10ct.1r0o3n9-/wDi0tShCd0ra0w23in0Eg
quantitative recovery.
substituents in the ortho, meta and para positions (Fig. 2, left). Yields
varied from 33% to 79%, with electron-withdrawing ester groups
Fig. 2. The scope of the C–H alkenylation reaction. Reactions (16a-18a) requiring longer reaction times. Ortho substituents gave a
performed on 0.3 mmol scale, isolated yields. aAc-Val-OH (40 mol%), more complex mixture of regioisomers, as the meta positions are no
40 °C used. bReaction time 48 h. c Average yield of 4 and 3 mmol scale longer equivalent or blocked. It appears that electron-withdrawing
reactions. d1.2 eq. of alkene used. e2.0 eq. alkene used, reaction time groups strengthen the PG ability of the MIDA-DG, while the opposite
48 h. fReported yield is over 2 steps following synthesis of the pinacol was true for electron-donating substituents, especially the para-
boronate ester.
methoxy analogue (12a), where significant degradation occurred.
This may reflect donation of electron density weakening the B–N
dative bond. The regioselectivity could be increased by employing a
more sterically encumbered Ac-Val-OH ligand in place of Ac-Gly-OH
(14ab).
Switching solvent to HFIP,
a privileged solvent in C–H
functionalisation protocols,14,15 and lowering temperature to 50 °C,
led to a further increase in yield (Fig. 1, 7a), along with the formation
of para and di-functionalised products. A design of experiment (DOE)
approach was taken to optimise the conditions (see SI). The
Other functionalised aryl boronic acids were also investigated.
optimisation process led to the surprising discovery that Bromo (19a and 20a) and fluoro (21a) substitutents are tolerated
functionalisation occurred at room temperature, which is unusual for under the conditions, with selective C–H functionalisation occurring
a transition metal catalysed C–H functionalisation process (Scheme in preference to oxidative insertion. The alkenylated products
2 middle).6u
provide interesting handles for further SNAr or cross-coupling
chemistry. 2-Napthylboronic acid (22a) gave two regioisomers at the
4- and 8-positions, with the former being the major product. 3,5-
Dimethyl analogue 23a gave a good yield of the para product
selectively. The reaction is amenable to scale-up to gram scale (7ac),
with quantitative recovery of the DG after further functionalisations
(see Scheme 4).
The MIDA-DG boronate 7 can easily be accessed from the MIDA-
DG 8 simply by heating with phenylboronic acid (Scheme 2). All
MIDA-DG boronates synthesised thus far have been bench-stable,
free-flowing solids, stable for extended periods (>6 months) and to
column chromatography using silica gel. Lastly, the MIDA-DG salt 8 is
fully recoverable and reusable after deprotection. An unmodified
phenylboronic acid MIDA ester was submitted to the optimised
The scope of the alkene coupling partner was next investigated
conditions, yielding no alkenylated product and indicating the (Fig. 2, right). Ketone (7b), nitrile (7g), sulfone (7h) and aldehyde (7i),
necessity of the directing motif for achieving reactivity (see SI).
FGs were all suitable alkene activating groups. Competition between
the acrylonitrile and the MIDA-DG 7 for catalyst co-ordination led to
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extended reaction times. A cyclic alkene was tolerated, yielding only
one alkene regioisomer (7e). A 1,1-heterodisubstituted alkene
featuring a diphenylamide was successful (7f), demonstrating the
tolerance of secondary amide FGs and that fewer equivalents of
alkene can be utilised. N,N-dimethylacrylamide, styrene (7j) and
diethyl vinylphosphonate were unreactive under the standard
conditions.
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DOI: 10.1039/D0SC00230E
Scheme 3. i. Pd(OAc)2 (40 mol%), Ac-Gly-OH (40 mol%), 4-
methylphenylboronic acid pinacol ester (2.0 eq.), Ag2CO3 (2.0 eq.),
Cs2CO3 (2.0 eq.), HFIP (0.1 M), rt, 18 h, 52% ii. Pinacol (1.0 eq.), K3PO4
(3.0 eq.), H2O, THF, DCM, rt, 18 h, 62%.
The success of the MIDA-DG in achieving C–H alkenylations and
acetoxylations, led us to perform a brief screen of C–H arylation
conditions.16 Gratifyingly, the transformation was successful,
allowing access to biphenyl product 24 via the selective C–H coupling
of one organoboron species in the presence of another.
Removal of the DG is facile and can be performed using NaOH, or
K3PO4, with quantitative recovery of the MIDA-DG 8 (Scheme 4,
top).17
The deprotected boronic acid can subsequently be used in
numerous transformations (Scheme 4). Suzuki–Miyaura (→26),
Chan-Lam (→30) and Rh-catalysed conjugate addition reactions
(→28) all proceeded well. A chemoselective oxidation using N,N-
dimethylaniline-N-oxide (→29) and a fluorination reaction (→27)
also achieved good yields over the two-steps. The telescoped
deprotection–functionalisation procedure allows access to a broad
range of motifs, including those that would be difficult to access via
alternative methods.
Burke et al. were able to develop an automated iterative synthesis
platform using the unusual properties of MIDA boronates on silica.12e
Pleasingly, MIDA-DG boronates display similar properties, allowing
for their facile purification using the ‘catch and release’ method.
Reaction mixtures can be loaded directly onto silica and washed with
Et2O to remove organic by-products, while the MIDA-DG-containing
components remain ‘caught’. After washing, MIDA-DG boronates
can be selectively ‘released’ using a more polar solvent.
Fig. 3. Scope of the C–H acetoxylation reaction. Reactions were
performed on
a
0.2 mmol scale, isolated yields. aReactions
performed at room temperature. bReaction performed at room
temperature, for 18 h, on 0.9 mmol scale cReaction time 48 h.
In all cases, the alkenylated products were converted to the
pinacol esters using
a one-pot procedure (see SI), allowing
unambiguous characterisation of products.
Nitrile DGs have shown activity in C(sp2)–H acetoxylations, using a
suitable oxidant to access a putative PdIV intermediate.5 Building
upon this, meta selective C–H acetoxylations were successfully
achieved using PhI(OAc)2 as oxidant. Using a 3-methylboronic acid
MIDA-DG ester 14 model system, a DOE approach was again applied
to optimise the reaction conditions (see SI). The scope of the reaction
was then investigated using the same 3 × 3 grid to assess the effects
of sterics and electronics on yield and regioselectivity (Fig. 3).
Electron-donating groups (10b-12b) again resulted in increased
degradation – lowering the reaction temperature from 40 °C to room
temperature reduced this and led to an increase in yield. Increased
sensitivity to steric bulk was observed relative to the alkenylation
reactions particularly with methyl substituents (13b-15b), potentially
due to the involvement of a sterically encumbered hexacoordinate
PdIV intermediate. The rate was also reduced when using electron-
withdrawing groups (16b-18b) and full conversions were not
achieved. With the phenylboronic acid MIDA-DG ester 7, 70% yield
(6:1 meta:para) was obtained (see SI).
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H functionalisation are operationally simple and useVcieowmArmticelerOcinalilnlye
available reagents. Removal of the DG is fast, mild and provides
DOI: 10.1039/D0SC00230E
access to synthetically useful aryl boronic acids with quantitative
recovery of the MIDA-DG 8. Finally, the technique enables iterative
C–H functionalisation/cross-coupling pathways, with the potential
for future automation. Studies to expand the breadth of
transformations possible with the MIDA-DG 8 are underway.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We acknowledge financial support from Imperial College London, the
EPSRC (PhD Studentship, A.F.W.), and the Royal Society for a
University Research Fellowship (C.J.C.). We thank Dr Li-Jie Cheng for
early prototype work, Alexander Dudnik for helpful discussions
during the concept stage, Ben Deadman for assistance performing
DOE optimisation and Peter Haycock for NMR assistance.
Notes and references
1
2
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Scheme 4. Deprotection and derivatisation of C–H functionalised
aryl MIDA-DG boronate. The boronic acid was used directly after
deprotection without purification. All yields given are over two steps.
3
For selected reviews on meta selective C–H functionalisations
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a
procedure allows access to 1,3,5-trisubstituted aromatic systems.
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b
4
5
In this manner, an iterative C–H functionalisation/cross-coupling
procedure was envisaged, enabling access to poly-substituted
aromatic systems, in just three catalytic steps using the ‘catch and
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accessed using this method. Importantly, the procedures appear to
be amenable to automation using the platform developed by Burke.
6
Conclusions
In conclusion, a new MIDA derivative 8 has been developed which
condenses to aryl boronic acids, enabling their meta-selective C–H
functionalisation at room temperature. Installation of the DG and C–
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DOI: 10.1039/D0SC00230E
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8
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Page 7 of 7
Chemical Science
HO
OH
View Article Online
DOI: 10.1039/D0SC00230E
O
N
O
O
O
O
DG
B(
)
MeCN
NaOH
O
B
O
N
O
CN
H
N
H
FG = aryl, OH, F, NR2 etc...
FG
DG
B(
)
DG
B(
)
C-H
PhB(OH)2
functionalisation
meta
functionalisation
R
R
H
R = alkenyl, OAc, aryl
R = alkenyl, OAc, aryl
An N-methyliminodiacetic acid derivative allows the meta-C–H functionalisation of boronic acids,
acting simultaneously as a directing and protecting group.