Para-Selective C-H Borylation of Common Arene Building Blocks Enabled by Ion-Pairing with a Bulky Countercation

Article abstract of DOI:10.1021/jacs.9b07267

The selective functionalization of C-H bonds at the arene para position is highly challenging using transition metal catalysis. Iridium-catalyzed borylation has emerged as a leading technique for arene functionalization, but there are only a handful of strategies for para-selective borylation, which operate on specific substrate classes and use bespoke ligands or catalysts. We describe a remarkably general protocol which results in para-selectivity on some of the most common arene building blocks (anilines, benzylamines, phenols, benzyl alcohols) and uses standard borylation ligands. Our strategy hinges upon the facile conversion of the substrates into sulfate or sulfamate salts, wherein the anionic arene component is paired with a tetrabutylammonium cation. We hypothesize that the bulk of this cation disfavors meta-C-H borylation, thereby promoting the challenging para-selective reaction.

Full text of DOI:10.1021/jacs.9b07267

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Communication
Para-Selective C-H Borylation of Common Arene Building
Blocks Enabled by Ion-Pairing with a Bulky Countercation
Madalina T. Mihai, Benjamin D. Williams, and Robert J Phipps
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07267 • Publication Date (Web): 05 Aug 2019
Downloaded from pubs.acs.org on August 5, 2019
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Para-Selective C-H Borylation of Common Arene Building Blocks
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Madalina T. Mihai, Benjamin D. Williams and Robert J. Phipps*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom.
Supporting Information Placeholder
remote position due to steric interactions.16 Most recently,
ABSTRACT: The selective functionalization of C-H bonds at the
Chattopadhyay and co-workers disclosed an ‘L-shaped’ bipyridine
ligand proposed to direct borylation to the para position by virtue
of interaction between the potassium salt of the ligand and an ester
in the substrate.17
arene para position is highly challenging using transition metal ca-
talysis. Iridium-catalyzed borylation has emerged as a leading tech-
nique for arene functionalization, but there are only a handful of
strategies for para-selective borylation, which operate on specific
substrate classes and use bespoke ligands or catalysts. We describe
a remarkably general protocol which results in para-selectivity on
some of the most common arene building blocks (anilines, benzyl-
amines, phenols, benzyl alcohols) and uses standard borylation lig-
ands. Our strategy hinges upon the facile conversion of the sub-
strates into sulfate or sulfamate salts, wherein the anionic arene
component is paired with a tetrabutylammonium cation. We hy-
pothesize that the bulk of this cation disfavors meta-C-H boryla-
tion, thereby promoting the challenging para-selective reaction.
Despite the inventiveness of these approaches, two aspects
limit wider application. Firstly, they are restricted to relatively
narrow substrate classes. Secondly, they require bespoke or non-
commercially available ligands or catalysts, presenting a barrier to
those looking to use “off-the-shelf” reagents, such as end-users in
the pharmaceutical industry. At the outset of this work, we sought
to develop a general and practical strategy that would enable para-
selective borylation of a range of common substrate classes using
readily available catalysts and ligands. We have previously utilized
attractive ion-pairing interactions between catalyst and substrate to
direct the iridium metal to the arene meta position (Figure 1b).12c,
12f, 12h We were concerned that adopting a similar strategy to target
the para isomer would be very challenging due to the distance that
the ligand would be required to reach. A design able to achieve this
would likely have a complex, extended structure necessitating
lengthy synthesis and reduced practical utility. We envisaged an
alternative ion-pairing strategy in which the counterion of the
substrate does not deliver the reactive catalyst, but is
unfunctionalised and bulky, acting as a ‘steric shield’ to obstruct
borylation at the meta position, thereby resulting in para selectivity
with standard ‘off-the-shelf’ borylation catalysts (Figure 1c).
We envisaged that the ubiquitous tetrabutylammonium cation
may consitute an ideal ‘steric shield’; the alkyl chains project
outwards at all angles from the tetrahedral nitrogen, occupying a
large area. This bulky cation could be paired with a variety of
common arene building blocks (anilines, benzylamines, phenols,
benzyl alcohols) which can all be rendered temporarily anionic in
a single simple step through conversion to the corresponding
sulfate (X=O) or sulfamate (X=N) salts (Figure 1d). Herein, we
demonstrate the realization of this approach, which we believe
represents the most general strategy for para-selective borylation
developed to date and indeed provides complementarity to existing
strategies. In contrast to our earlier work, the key ion-pairing
interaction in this system is not being exploited in an attractive
sense between substrate and catalyst, but rather to temporarily
anchor the ‘steric shield’ to the substrate. The resulting repulsive
steric interactions with the incoming catalyst thereby guide the
latter to the remote position that would be the most challenging to
reach using a strategy invoking attractive catalyst-substrate
interactions.
Use of transition metals to catalytically functionalize arene C-H
bonds has undergone tremendous development. Whilst most
advances have dealt with ortho-selective functionalization, the last
decade has seen many advances in meta-selective reactions.1 Many
of these approaches have been based on templates or ligands with
extended architectures, or on strategies which proceed via
metalation at the ortho position. Considering this, it is not
surprising that methods to direct transition metals to the para
position remain rather fewer, given the greater distance from
existing functionality.2 Although SEAr mechanisms give the para
isomer when electrophiles react with electron rich arenes, it is
uncommon for transition metals to perform C-H bond
functionalization via SEAr mechanisms.3 Exceptions are several
examples using gold catalysis4 and a smaller number of examples
using high-valent copper5 or palladium6. Yet such selectively
metallated intermediates are extremely versatile and new methods
to access them are urgently required.7,8
Iridium-catalyzed borylation has emerged to become one of
the most versatile and intensively used of modern arene
functionalization methods.9,10 Whilst regioselectivity is typically
determined by steric considerations, numerous modifications can
direct borylation to the ortho position11 and, to a lesser extent, the
meta position.12 In contrast, there are only three instances where
para-selective iridium catalyzed C-H borylation has been achieved
(Figure 1a).13,14 Saito, Segawa and Itami used a bulky, chiral
phosphine ligand to create
a highly sterically congested
environment at iridium.15 However, high para-selectivity was
limited to substrates possessing a very bulky substituent, and 1,2-
disubstituted arenes were unselective. Nakao and co-workers used
a bulky Lewis acid catalyst to complex aromatic amides, both
activating the substrate and forcing borylation to occur at the most
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notable given the incompatibility of many other C-H activation
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methods with iodide substituents. Arenes bearing trifluoromethoxy
(3e) and difluoromethoxy (3g) substituents are also compatible, as
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Scheme 1. a) Initial results. (b), (c) Control reactions.
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is the difluorinated 3h. Interestingly, the para selectivity was
slightly reduced with a resonance withdrawing substituent (2-CN,
3f), in-line with the precedent that this substituent has a small para-
directing (relative to itself) electronic effect in borylation.19 Sub-
strates bearing electron-donating substituents (isopropyl, methoxy)
gave low conversion, albeit with excellent para-selectivity (see SI).
Given the ubiquity of benzylamines as aromatic building
blocks, we next sought to test our strategy on benzylamine-derived
sulfamates. As with the aniline variant, these tetrabutylammonium
salts are easily synthesized from cheap materials. This class proved
highly amenable, in most cases giving >20:1 regioselectivity
(Scheme 2B) A range of useful halide substituents was tolerated,
including Cl (7a), Br (7b), I (7c) and F (7g). Trifluoromethyl (7d),
trifluoromethoxy (7e) and difluoromethoxy (7f) substituted vari-
ants also performed well. A methoxy-substituted variant gave ex-
cellent selectivity but with poor conversion (7h). It was necessary
to derivatize the free amine products to enable purification on sil-
ica; isolated yields are following borylation/hydrolysis/trifluoroa-
cetylation.
Figure 1. Previous para-selective Ir-catalyzed borylation ap-
proaches and that taken in this work.
We began by converting 2-chloroaniline (1a) to the corre-
sponding tetrabutylammonium sulfamate salt 2a by treatment with
chlorosulfonic acid followed by cation exchange using Bu4NHSO4
(Scheme 1a). To our delight, iridium-catalyzed borylation of 2a un-
der standard conditions with dtbpy as ligand resulted in >20:1 se-
lectivity for the para isomer. Simply treating the crude reaction
mixture with HCl in methanol revealed the parent aniline, which
give 85% yield of para-borylated aniline 3 over two steps and only
a single purification procedure. A similar outcome was achieved
for the electronically different 2-trifluoromethylaniline (Scheme
1a, 1b to 3b). In contrast, direct borylation of parent anilines 1a and
1b results in m:p ratios of 1:3.9 and 1:1 respectively (Scheme 1b).
The moderate para selectivity in direct borylation of 1a echoes a
similar observation made by Krska, Maleczka, Smith and co-work-
ers, the origins of which are not obvious.18 Accordingly, we exam-
ined 4a and 4b, control substrates much closer in electronic nature
to 2a and 2b, and found both of these give poor selectivity (Scheme
1c). This outcome suggests that the high para selectivity obtained
with sulfamate salts 2a and 2b does not have electronic origins and
that the salt formation and association with the tetrabutylammo-
nium cation are crucial factors.
Encouraged by the effectiveness of the strategy thus far, we next
extrapolated this to the ubiquitous oxygen-containing building
blocks, phenols and benzyl alcohols.20 The tetrabutylammonium
sulfate salts of these compounds are also easily obtained and
cleaved. Gratifyingly, high para-selectivity was observed for a
number of ortho-substituted phenol-derived sulfate salts, encom-
passing Cl (9a), Br (9b), I (9c), CF3 (9d), OCF3 (9e), iPr (9f) and a
difluorinated analogue (9h) (Scheme 2C). Control borylations on
2-chlorophenol and on a 2-chlorophenol sulfate ester gave poor se-
1
lectivity.21 Interestingly, selectivity (by crude H-NMR analysis
With these initial results in hand, we next examined a selection
of 2-substituted anilines and were pleased to find that the high lev-
els of para selectivity were observed for a range of useful building
blocks (Scheme 2A). Bromide and iodide substituents were well
tolerated (3c, 3d),both giving >20:1 para selectivity. The latter is
following borylation) was somewhat reduced compared with the
aniline-derived sulfamates. Particularly, substrates possessing con-
jugatively withdrawing groups such as nitro (9g) exhibited only
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Scheme 2. Scope of para C-H borylation of aniline (A), benzylamine (B), phenol (C) and benzyl alcohol (D) derivatives, and
aryl and benzylsulfonates (E).a,b
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a Typically: Substrate (0.25 mmol), B2Pin2 (0.25-0.5 mmol), [Ir(COD)OMe]2 (1.5-2.5 mol%), dtbpy (3-5 mol%), 1,4-dioxane (0.33-0.5 M), 70 °C (See SI for full details). b Isomeric
ratios are para:meta taken from analysis of crude 1H-NMR spectra after borylation, unless otherwise stated. Yields shown are isolated and typically include meta and para isomers
which are generally inseparable. cSelectivity assessed after HCl step. dSelectivity assessed after TFA protection step. eTmphen used instead of dtbpy. fOxidized to corresponding
phenol for isolation.
moderate para-selectivity. This is likely due to the substituent elec-
tronic influence on the desired para selectivity (vide supra).
Remarkably, the extension to a fourth common substrate class,
benzyl alcohols, was well tolerated (Scheme 2D, 11a-11h). As in
the phenol-derived sulfates, regioselectivity was adversely affected
by resonance withdrawing groups (11h), but positively reinforced
by resonance donors (11f). These results suggest that in substrate
classes when the para-directing influence from the associated cat-
ion is weaker, substituents electronic effects can have greater im-
pact on selectivity.
followed by cation exchange. Furthermore, through treatment with
POCl3, both sulfonates can be easily converted to sulfonyl chlo-
rides, valuable precursors to sulfonamides. Both of these substrate
classes result in para-selective borylation, in line with our hypoth-
esis. Aryl sulfonates bearing ortho Cl (13a), Br (13b), CF3 (13c)
and OCF3 (13d) gave excellent para-selectivity, as did the analo-
gously-substituted benzyl sulfonates (13e-13h). Following boryla-
tion, the crude borylated sulfonates were either converted through
to the corresponding piperidine sulfonamides (13a-13d) or were
isolated as sulfonyl chlorides (13e-13h).
Finally, to further reinforce the generality and practicality of our
strategy for the selective synthesis of complex, multifunctional
building blocks, we targeted aryl sulfonates and benzyl sulfonates,
substrates which inherently bear a negative charge (Scheme 2E).
The former are readily accessed from commercially available aryl
sulfonyl chlorides by treatment with tetrabutylammonium hydrox-
ide, and the latter by the action of sodium sulfite on benzyl halides,
At the outset we advanced the tentative hypothesis that the bulk of
the associated tetrabutylammonium cation may occupy sufficient
space around the arene such that borylation at the normally acces-
sible meta positions becomes disfavored (Figure 1C). To probe this
hypothesis, we synthesized the 2-Cl member of the first four sub-
strate classes with the smaller tetraethylammonium cation (synthe-
sis of the tetramethyl variant for all members proved problematic)
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to gauge the impact on selectivity (Scheme 3a). These experiments
In conclusion, we have developed a general method for the
para-selective C-H borylation of a broad range of the most useful
arene building blocks encompassing anilines, benzylamines, phe-
nols and benzyl alcohols as well as several classes of arenesul-
fonate, valuable precursors to sulfonamides. Our method produces
a variety of complex trisubstituted arene cores typically with three
functional handles for further elaboration that in many cases would
require numerous steps to obtain by other methods. We provide ev-
idence to suggest that this is due to ion-pairing of a bulky tetrabu-
tylammonium cation with the substrate, which is rendered tempo-
rarily anionic. The bulky cation blocks the meta position, promot-
ing borylation at the most remote and typically most challenging
para position. Our approach provides a practical and general solu-
tion to the challenge of para-selective C-H borylation and demon-
strates a new strategy for the utilization of ion-pairing interactions
in catalysis.
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showed that for three of the four classes, para selectivity was sig-
nificantly reduced, in line with our hypothesis (in the fourth, selec-
tivity remained excellent at >20:1). We next selected the benzyl
sulfonate substrate class to carry out a complete evaluation of se-
quential modulation of cation size on a single substrate. These ex-
periments showed a clear and consistent trend to higher para-selec-
tivity as the cation grows larger (Scheme 3b).
Scheme 3. Experiments to probe origin of selectivity.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*rjp71@cam.ac.uk
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
We are grateful to AstraZeneca for a PhD studentship through the
AZ-Cambridge PhD program (M.T.M.), the Cambridge Trust and
Sidney Sussex College, Cambridge for a PhD studentship
(B.D.W.), the Royal Society for a University Research Fellowship
(R.J.P.), the EPSRC (EP/N005422/1) and the ERC (StG 757381).
We thank the EPSRC UK National Mass Spectrometry Facility at
Swansea University. We thank Dr. Andrew Bond acquiring and
solving the X-ray data. Thanks to Iain Cumming (AstraZeneca) for
useful discussion.
Finally, in order to visualize the steric effect of the associated
tetrabutylammonium cation, we were able to obtain X-ray struc-
tures of the starting materials for three substrate classes (Figure 2).
These give a visual impression of the bulk provided by the cation
and support our central tenet that it could feasibly act as a non-co-
valent ‘shield’ to block the arene meta-position. Accordingly, one
might expect that removal of the ortho substituent incorporated into
all substrates thus far may reduce para-selectivity as both meta po-
sitions would be open to borylation and the cation would not be
able to block both at any one time. Indeed, this is the case; the para
selectivity was drastically reduced for all unsubstituted variants
providing further support for our hypothesis.21 We also extended
the chain length of all three classes of substrate as the 2-Cl variant
but found that with two methylenes between the arene and the ani-
onic group, selectivity was reduced to around 3:1 p:m, presumably
due to the much greater flexibility.21
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Lan, Y.; Zhao, Y., Ruthenium(II)-Catalyzed C−H Difluoromethylation of
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