meta-Selective C?H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand

Article abstract of DOI:10.1002/anie.201708967

Selective functionalization at the meta position of arenes remains a significant challenge. In this work, we demonstrate that a single anionic bipyridine ligand bearing a remote sulfonate group enables selective iridium-catalyzed borylation of a range of common amine-containing aromatic molecules at the arene meta position. We propose that this selectivity is the result of a key hydrogen bonding interaction between the substrate and catalyst. The scope of this meta-selective borylation is demonstrated on amides derived from benzylamines, phenethylamines and phenylpropylamines; amine-containing building blocks of great utility in many applications.

Full text of DOI:10.1002/anie.201708967

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Meta Selective C-H Borylation of Benzylamine, Phenethylamine
and Phenylpropylamine-Derived Amides Enabled by a Single
Anionic Ligand
Authors: Holly J Davis, Georgi R Genov, and Robert Phipps
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708967
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10.1002/anie.201708967
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Meta Selective C-H Borylation of Benzylamine, Phenethylamine
and Phenylpropylamine-Derived Amides Enabled by a Single
Anionic Ligand
Holly J. Davis, Georgi R. Genov and Robert J. Phipps*
9e]
Abstract: Selective functionalization at the meta position of arenes
remains a significant challenge. In this work, we demonstrate that a
single anionic bipyridine ligand bearing a remote sulfonate group
enables selective iridium-catalyzed borylation of a range of common
amine-containing aromatic molecules at the arene meta position. We
propose that this selectivity is the result of a key hydrogen bonding
interaction between the substrate and catalyst. The scope of this meta
selective borylation is demonstrated on amides derived from
benzylamines, phenethylamines and phenylpropylamines; amine-
containing building blocks of great utility in many applications.
ortho-borylation of aniline derivatives[9d,
(Figure 1a) and by
Kuninobu, Kanai and co-workers for meta selective borylation of
arenes bearing carbonyl and phosphoryl groups (Figure 1b).[10a]
We have recently disclosed a bipyridine ligand bearing a distal
anionic sulfonate group to direct iridium-catalyzed borylation to
the arene meta position in two classes of aromatic quaternary
ammonium salts, by virtue of a putative ion-pairing interaction
between the active catalyst and cationic substrate (Figure 1c).[10c]
Herein, we report that this same anionic ligand scaffold is highly
proficient as a hydrogen bond acceptor to direct borylation to the
meta position in a range of aromatic substrates bearing amide
hydrogen
bond
donors.
Effective
on
benzylamine,
The employment of non-covalent interactions to direct transition
metal catalysis is a strategy of great potential but remains
relatively underexplored, particularly for addressing issues of
regioselectivity and site-selectivity.[1],[2] A commonly encountered
regioselectivity choice arises during the functionalization of
phenethylamine and phenylpropylamine-derived amides, our
method delivers versatile, multifunctional arenes with broad
potential applicability in pharmaceuticals and materials chemistry.
aromatic rings.
In electrophilic aromatic substitution,
regioselectivity is determined largely by the electronic
predisposition of the substrate, while proximity to a directing group
is the determining factor in directed ortho-metalation chemistry
and many catalytic arene C-H functionalizations.[3] The
application of C-H functionalization strategies to distal positions is
more challenging[4],[5] and we believe that the design of catalytic
systems which incorporate attractive non-covalent interactions
constitutes a powerful strategy to address these challenges.[1c]
Iridium-catalyzed C–H borylation has evolved into
a
uniquely powerful arene functionalization method that operates
under mild conditions, is highly tolerant of functionality and
delivers boronate esters that can be readily transformed into a
variety of common groups.[6] Perhaps most interesting is the
regioselectivity of this process, which is largely controlled by steric
considerations.[6a, 7] Whilst highly effective for borylation of 1,3-
disubstituted arenes, isomeric mixtures are typically obtained
when borylation is applied to monosubstituted and unsymmetrical
1,2-disubstituted arenes, limiting broader application. There have
been a number of developments in ortho-selective borylation,[8],[9]
but much fewer achieve meta-[10] or para-selectivity.[11] The
productive harnessing of non-covalent interactions has played a
crucial role in several recent advances.[9i, 11b] This includes ‘outer
sphere’ hydrogen bond-directed approaches such as those
developed by Singleton, Maleczka, Smith and co-workers for
Figure 1. Selected examples of the use hydrogen bonds to control
regioselectivity in iridium-catalyzed C-H borylation.
At the outset of our studies, we envisioned that an
appropriately designed bipyridine ligand bearing a remote
hydrogen bond accepting group may enable the meta selective
borylation of arenes bearing hydrogen bond donors. If successful,
this would represent an electronically inverted strategy to that of
Kuninobu and Kanai and may provide a complementary scope of
compatible substrates. We already possessed four bipyridine
ligands that bear a sulfonate group from our previous study on
ion-pair directed borylation (1a, 1b, 1i and 1j). In addition to the
sulfonate group, we targeted three neutral hydrogen bond
acceptor groups: amide, phosphonate and sulfoxide, for
comparison. This resulted in a library of 16 bifunctional bipyridine
[*]
Holly J. Davis, Georgi R. Genov, Dr. Robert J. Phipps
Department of Chemistry,
University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, UK
E-mail: rjp71@cam.ac.uk
Supporting information for this article is given via a link at the end of
the document.
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benzylamine-derived substrate 2a.[14] In both cases, the use of the
standard borylation ligand 4,4-di-tert-butylbipyridine (dtbpy)
resulted in poor regiocontrol.[6c]
In evaluation of the scope of the transformation we found that
a
range of trifluoroacetylated benzylamine (Table 1a),
phenethylamine (Table 1b) and phenylpropylamine (Table 1c)
derived amides were borylated with good to excellent
regioselectivity for the meta position using ligand 1a. In all cases,
poor selectivity was obtained in the control reaction with dtbpy.
Electron withdrawing groups such as trifluoromethyl (3a, 5a, 7a)
and esters (3g, 5g, 7g) are tolerated, as are halides including
bromides (5f, 7c), chlorides (3d, 5h, 7d) and even iodide (5d).
Electron donating alkyl groups do not affect the selectivity (3b, 5i,
7i), although substrates bearing
a 2-methoxy substituent
underwent non-selective borylation using 1a (3c, 5j, 7j). Several
studies have shown that alkoxy groups exhibit a small but
significant electronic meta-directing effect in borylation, which
could go some way to accounting for this.[15] A substrate bearing
an unprotected hydroxyl group likely undergoes in situ O-
9e]
borylation (3f).[9d,
Unsubstituted arenes lead to meta-
diborylated products (3h, 5l, 7b) and, in the case of 3i, a methyl
substituent in the benzylic position is tolerated. Fluorine is
sufficiently small to allow borylation at the adjacent position and
this could be controlled on monofluorinated (3e, 3j, 5e, 7e, 7f) and
difluorinated (7h) arenes. Our ligand-directed approach was also
effective on pyridine substrates from all three classes (Table 1d).
In these cases, borylation was favored at the 4-position whilst
dtbpy gave mixtures of borylation at the 4- and 5- positions.
We anticipated that there would come a point where further
increasing the flexibility of the substrate would have a negative
impact on the borylation regioselectivity as the entropic price for
achieving an organized transition state becomes prohibitively high.
This point is reached with substrates bearing chains longer than
three carbons; despite screening all four sulfonate ligands poor
regioselectivity was observed.[13]
With regard to the fact that a single ligand is compatible with
three different classes of amine, we speculate that the sulfonate
group, with its negative charge distributed across all three oxygen
atoms, represents a relatively diffuse area of high electron density
at a fixed distance from the iridium metal centre. Thus, it seems
reasonable that as long as a given substrate is able to achieve a
low-energy conformation that will allow a productive hydrogen
bond to form in the borylation transition state then this may
plausibly lead to meta-selective borylation. To probe this
hypothesis, we evaluated several substrates which possess
restricted conformational freedom to assess the impact on
regioselectivity (Figure 3a). For aminoindane-derived substrate
11, in which rotation about all but the C-N bond is impossible, very
poor regioselectivity was obtained. Further support for the
importance of a productive hydrogen bonding interaction between
catalyst and substrate was obtained in the borylation of the cis
and trans isomers of 12. For the cis isomer, in which the amino
group occupies an axial position, poor regioselectivity was
obtained whilst the trans isomer gave far better regiocontrol. This
can be rationalized by deducing that the lowest energy
conformation of cis-12 is likely to involve the N-H (rather than the
trifluoroacetyl group) projecting across the cyclohexane ring,
away from the arene, in order to avoid unfavourable 1,3-diaxial
interactions that would arise in the alternative conformation. This
Figure 2. Initial evaluation and optimization studies.
ligands with the hydrogen bond acceptor extending from the 5-
(1a-h) or 4- (1i-p) position, combined with either one or two
methylene units between the bipyridine and the hydrogen bond
acceptor (Figure 2a). These were tested in the borylation of 2a
and the outcome was that only ligand 1a, which was optimal in
our ion pair-directed approach, resulted in good meta selectivity
(8:1 m:p).[12] Of the others, none gave greater than a 2.6:1 m:p
ratio. We investigated alternative N-protecting groups and
although an N-mesyl protected substrate gave similarly high
selectivity, we elected to proceed with trifluoroacetyl for its ease
of deprotection (Figure 2b).[13] Additionally, borylation of 2a at
room temperature increased selectivity to 13:1. A variety of
solvents were compatible with the borylation and THF was found
to give the best balance between selectivity and conversion.[13] In
order to evaluate the generality of ligand 1a for the borylation of
substrates bearing different chain lengths between the amide and
arene, we synthesized and tested the two- and three- carbon
analogues of 2a (Figure 2c). Excellent meta-selectivity was
achieved in both cases using ligand 1a despite the much
increased flexibility in the chain when compared with
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Table 1. Scope of the hydrogen bond-directed meta selective borylation. [a], [b]
[a] Typically: Substrate (0.25 mmol), B2Pin2 (0.375-1.0 mmol), [Ir(COD)OMe]2 (1.5 mol%), 1a (3 mol%), THF (0.2 M), rt to 70 °C (See SI for details). [b]Isomeric
ratios are meta:para taken from analysis of crude 1H-NMR spectra; yields shown are isolated unless otherwise indicated and include meta and para isomers
which are generally inseparable. [c] NMR yield quoted due to decomposition on silica gel. [d]Product isolated as mixture of mono- and diborylated compounds
likely precludes productive hydrogen-bonding interactions with
the catalyst in the transition state. Conversely, trans-12 is likely to
substituent syn to the N-H bond. Therefore, any hydrogen
bonding interaction in the transition state would have to overcome
significant catalyst-substrate steric interactions (inset).
have far more conformational freedom and
a favourable
substrate-ligand interaction may be easily achievable. We also
investigated the borylation of anilides and found that acetanilide
gave a good 12:1 m:p ratio (Figure 3b). However, introducing an
ortho-substituent resulted in disappointing regioselectivity. This
can be rationalized by considering that the acetyl group will
occupy a position anti to the ortho substituent, placing the
To provide quantitative evidence for the proposed ligand-
substrate hydrogen bonding interaction, we investigated the
extent of interaction between amide substrate 2h and ligand 1a in
various solvents (Figure 3c). NMR titrations showed that even in
polar MeCN, significant association is seen.[16] Background
titrations of 5,5’-dimethylbipyridine against 2h showed negligible
interaction, demonstrating that the sulfonate group is responsible
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for support and useful discussion. Thanks to Prof. Chris A. Hunter
and Dr David Blakemore (Pfizer) and Dr Alan D. Brown for useful
discussion.
Keywords: hydrogen bonding • C-H activation • regioselectivity •
homogeneous catalysis • noncovalent interactions
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ligand 1a, emphasizing the importance of the N-H in order to
achieve high levels of regiocontrol and providing support for the
crucial role of hydrogen bonding (Figure 3d).
In conclusion, we have developed a method for the meta-
selective borylation of benzylamine, phenethylamine and
phenylpropylamine derivatives, using a single anionic bipyridine
ligand. This ligand, previously successful in ‘ion-pairing mode’ has
been found to be highly effectively in ‘hydrogen-bond accepting
mode’ and underlines the general nature of this strategy and
ligand scaffold for regioselective borylation. Our method provides
valuable and practical access to pharmaceutically relevant
scaffolds bearing complex substitution patterns and more broadly
highlights the potential of harnessing non-covalent interactions to
exert regiocontrol in C-H activation chemistry.
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Acknowledgements
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We are grateful to the EPSRC and Pfizer for a CASE studentship
(H.J.D.), the EPSRC (EP/N005422/1, G.R.G.) and the Royal
Society for a University Research Fellowship (R.J.P.). We thank
the EPSRC UK National Mass Spectrometry Facility at Swansea
University and Professors Steven V. Ley and Matthew J. Gaunt
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[13] See Supporting Information for full details.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
A bipyridine ligand incorporating a
remote anionic sulfonate group directs
iridium-catalyzed borylation to the
meta-position on a range of amide-
containing arenes. This is thought to
occur through use of a hydrogen
bonding interaction to correctly
position the iridium metal centre in the
crucial C-H activation.
Holly J. Davis, Georgi R. Genov and
Robert J. Phipps*
Page No. – Page No.
Meta Selective C-H Borylation of
Benzylamine, Phenethylamine and
Phenylpropylamine-Derived Amides
Enabled by a Single Anionic Ligand
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