Ion Pair-Directed Regiocontrol in Transition-Metal Catalysis: A Meta-Selective C-H Borylation of Aromatic Quaternary Ammonium Salts

Article abstract of DOI:10.1021/jacs.6b08164

The use of noncovalent interactions to direct transition-metal catalysis is a potentially powerful yet relatively underexplored strategy, with most investigations thus far focusing on using hydrogen bonds as the controlling element. We have developed an ion pair-directed approach to controlling regioselectivity in the iridium-catalyzed borylation of two classes of aromatic quaternary ammonium salts, leading to versatile meta-borylated products. By examining a range of substituted substrates, this provides complex, functionalized aromatic scaffolds amenable to rapid diversification and more broadly demonstrates the viability of ion-pairing for control of regiochemistry in transition-metal catalysis.

Full text of DOI:10.1021/jacs.6b08164

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Communication
Ion Pair-Directed Regiocontrol in Transition Metal Catalysis: A Meta-
Selective C–H Borylation of Aromatic Quaternary Ammonium Salts
Holly Jane Davis, Madalina Mihai, and Robert J Phipps
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b08164 • Publication Date (Web): 14 Sep 2016
Downloaded from http://pubs.acs.org on September 15, 2016
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Journal of the American Chemical Society
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Ion Pair-Directed Regiocontrol in Transition Metal Catalysis: A Meta-
Selective C–H Borylation of Aromatic Quaternary Ammonium Salts
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Holly J. Davis, Madalina T. Mihai and Robert J. Phipps*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom.
Supporting Information Placeholder
ideal forum to test our ion-pairing approach. Iridium-
ABSTRACT: The use of non-covalent interactions to direct
catalyzed C–H borylation stands apart in that regioselectivity
is largely controlled by sterics, as opposed to electronics or
proximity.7 Consequently, it is very powerful for functionali-
zation of 1,3-disubstituted arenes. However, monosubstituted
or 1,2-disubstituted arenes generally give inseparable mix-
tures of isomers (eq. 3), unless a particular substituent can
direct either ortho6c,8 or meta,9 or a bulky ligand favor pa-
ra.10,11 In particular, accessing the meta position is desirable
due to the relative paucity of methods to access this position,
despite much recent interest.5,9,12 To address this, we sought
to investigate cationic arene substrates in iridium-catalyzed
borylation, anticipating that the charged center would be
able to ion pair with an anionic bifunctional ligand (eq. 4).
Quaternary ammonium salts are readily accessed and many
methods exist for their elaboration in sp2, sp3 and
transition metal catalysis is a potentially powerful yet rela-
tively underexplored strategy, with most investigations thus
far focusing on using hydrogen bonds as the controlling ele-
ment. We have developed an ion pair-directed approach to
controlling regioselectivity in the iridium-catalyzed boryla-
tion of two classes of aromatic quaternary ammonium salts,
leading to versatile meta-borylated products. By examining a
range of substituted substrates, this provides complex, func-
tionalized aromatic scaffolds amenable to rapid diversifica-
tion and more broadly demonstrates the viability of ion-
pairing for control of regiochemistry in transition metal ca-
talysis.
The use of non-covalent interactions to direct transition
metal catalysis is a potentially powerful yet relatively under-
explored strategy, particularly for addressing issues of regi-
oselectivity in synthetic chemistry. Alongside hydrogen
bonds, ion-pairing interactions have emerged as a powerful
tool for control of enantioselectivity,1 but an equally im-
portant aspect in which careful control is required is regiose-
lectivity. Important advances have demonstrated that multi-
ple hydrogen bonds are able to provide precise molecular
recognition in particular situations,2 delivering regioselectivi-
ty in reactions such as site-selective oxygenation of sp3 C–H
bonds,3 regioselective hydroformylation of unsaturated car-
boxylic acids4 and most recently, regioselective arene boryla-
tion,5 amongst others (eq. 1).6 In contrast to this, ion-pairing
interactions have not been explored in the context of ad-
dressing regioselectivity challenges. If, however, a single elec-
trostatic interaction could be successfully employed to posi-
tion a reactive metal center via dynamic ion exchange, this
could help to reduce the need for a synthetically elaborate
‘receptor’ portion of the catalyst, potentially increasing both
practicality and generality (eq. 2). It is possible that per-
ceived lack of directionality of ion pairs when compared with
single and particularly multiple hydrogen bonds has inhibit-
ed their investigation thus far. In this Communication we
demonstrate ion-pairing to be a viable approach to address
issues of regiocontrol in the iridium-catalyzed borylation of
aromatic C-H bonds.
heteroatom cross coupling,13 reduction,14 conversion to boro-
nate esters13d,15, partners for C–H activation,16 displacement
with 18F17 and [1,2] and [2,3] rearrangement chemistry18
amongst others. In approaching the design of a suitable ion-
pairing ligand, we began by elaborating an example of the
Arguably the most common problem of regioselectivity is
encountered in functionalization of arenes, making this an
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basic transition state for iridium-catalyzed borylation, as
protected amine is also compatible (2h). Meta-fluoro sub-
calculated by Singleton, Maleczka, Smith and coworkers.6c,19
By modifying the structure to append a sulfonate-bearing
tether onto the bipyridine backbone, a productive ion-
pairing interaction appears plausible with a quaternized ben-
zylamine substrate undergoing C–H oxidative addition at the
meta-position (eq. 4). On alkylammonium salts the positive
charge is spread over the methyl/methylene units directly
adjacent to the nitrogen20 and thus it is possible that less
conventional interactions such as C-H-O hydrogen bonds
could provide directionality at close proximity.21 We synthe-
sized anionic bipyridine ligand L1 in only two steps from
inexpensive, commercial material.22 Using quaternized 2-
chlorobenzylamine (1a) as a test substrate, conventional lig-
and dtbpy gave poor levels of selectivity in both THF and
cyclohexane (Table 1, entries 1 and 2), although in THF a
small preference for the para position was observed. Pleas-
ingly, using L1 instead of dtbpy gave 10:1 selectivity for the
meta position (entry 3). A ligand with a longer linker (L2),
and isomers where the linker extends from the 4-position (L3
and L4) all gave poorer selectivity (entries 4 to 6) and L1 gave
very low conversion in cyclohexane, even at 70 °C (entry 7).
strate 2i gives high selectivity with L1 and an ortho-fluoro
results in diborylation via initial borylation at the 5-position
(2j). Substrates 2k and 2l demonstrate that our ion-pairing
ligand is able to ‘reach past’ ortho-fluoro substituents in both
cases to impart high selectivity in the first borylation. Indeed,
in 2l borylation occurs preferentially adjacent to the fluorine
(meta) rather than in the less hindered para-position. In all
cases poor selectivity was observed with standard borylation
ligand dtbpy. The products were isolated by precipitation
from ether, except in several cases where the products de-
composed upon isolation – in these few cases, yields were
determined by NMR with reference to an internal standard.
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Scheme 1. Substrate scope for ion pair-directed
borylation of quaternized benzylamine derivatives.a,b
Table 1. Evaluation of ligands on substrate 1a
Entry
Solvent
Ligand
T
Conv.a meta:paraa,
1
Cyclohexane
THF
dtbpy
dtbpy
L1
L2
L3
50
50
50
50
50
50
70
24
98
96
100
100
100
<5
1.1: 1
1 : 2.4
10 : 1
3.5 : 1
1.8 : 1
1.1 : 1
--
2
3
4
5
6
7
THF
THF
THF
THF
L4
L1
a
Typically: Substrate (0.25 mmol), B2Pin2 (0.375 mmol), [Ir(COD)OMe]2 (1.5
Cyclohexane
b
mol%), ligand (3 mol%), solvent (0.2 M), 50 °C to 70 °C (See SI for details).
aDetermined by 1H-NMR analysis with reference to an internal standard.
Yields shown are isolated except where shown in parenthesis (NMR yields with
reference to internal standard). Isomeric ratios are meta:para taken from
analysis of crude 1H-NMR spectra.
Control experiments with two non-cationic surrogates for 1a
gave poor selectivity with L1, demonstrating the importance
of the positive charge on the substrate and supporting the
ion pairing hypothesis (eq. 5).22 Also, the addition of varying
amounts of Bu4NOTs to the borylation of 1a using L1 lead to
some decrease in the meta-selectivity, potentially due to the
excess Bu4N+ displacing the substrate as ligand counterion
and a subsequent increase in non-directed borylation.22
We next investigated whether aniline-derived quaternary
ammonium salts may exhibit similar trends (Scheme 2).
Whilst we were concerned that moving the arene one carbon
closer to the ammonium group could disrupt the selectivity,
basic modelling suggested that this substrate class also
looked viable according to our hypothesis, since there are a
number of different ways in which the cationic substrate and
anionic ligand can plausibly associate. In the event, anionic
ligand L1 again proved to be a powerful meta-director and
provided good to excellent selectivity in most cases, far supe-
rior to analogues L2-L4.22 As before, the scope was found to
be broad with respect to functionality tolerated with electron
withdrawing (4a-4c), donating (4d-4f), halogens (4a) and
aromatic groups (4g).23 Heterocyclic substrates (4h and 4i)
had a propensity for diborylation due to the reduced steric
demand of the aliphatic ring, although 4h could be stopped
at the mono. Several fluorine-containing substrates under-
went selective borylation using L1 (4j and 4k). Furthermore,
With regard to scope of the transformation (Scheme 1), a
variety of substituents are tolerated in the ortho position
including halogens (2a–2c), electron withdrawing (2d and
2e) and electron donating (2f and 2g) groups. A Boc-
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Journal of the American Chemical Society
borylation to give 4a could be carried out efficiently on gram
We examined a selection of derivatives without arene sub-
1
2
3
4
5
6
7
8
scale. We also investigated aromatic heterocyclic substrates
(Scheme 3). 2-Substituted pyridines generally give mixtures
upon borylation and with dtbpy, pyridyl ammonium salts 5a
and 5b gave non-selective 5- and 4,6-diborylation.24 In the
latter case, borylation at C4 occurs initially but is followed by
a facile second borylation at C6.24b Using L1 in both cases
leads to very high selectivity for the 4,6-diborylated product,
indicating high levels of regiocontrol over C4 vs C5 boryla-
tion. Free NH indoles are established to undergo initial
borylation at the 2-position, followed by a second directed
borylation at the C7 position due to a directing effect of the
N-heteroatom.24a,25 On substrate 5c, the 2,7 diborylated iso-
mer was the predominant product with dtbpy. Despite the
innate substrate-direction to C7, L1 was able to significantly
affect the regiochemical outcome and a roughly equal
amount of C2,6 and C2,7 diborylated isomers were obtained.
stituents which all resulted in symmetrical diborylation with
>20:1 selectivity in all cases using L1 (Scheme 4).26 As well as
unsubstituted versions of earlier substrates (2m and 4l), this
includes a substrate quaternized with butyl groups (2n),
benzylammonium salts with α-substitution (2o and 2p) and a
glycine-derived ammonium salt (2q). We also demonstrate
application to the meta-selective diborylation of the antimi-
crobial surfactant benzthionium chloride (2r).
9
Scheme 4. Diborylation of Unsubstituted Arenes
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OTs
OTs
Bu3N
2n
PinB
Me3N
2m
OTs
NMe3
4l
Bpin
Bpin
BPin
PinB
L1 THF:
BPin
>20:1, 92%
dtbpy, THF: 3.3:1 (82%)
L1, THF: >20:1, 86%
dtbpy, THF: 1.3:1 (95%)
L1 THF:
,
>20:1, 80%
dtbpy, THF: 5.3:1 (88%)
,
OTs
OTs
Me
Me
CO2Me
Me3N
Me
EtO2C
N
Me3N
2p
OTs
Scheme 2. Substrate scope for ion pair-directed
borylation of quaternized aniline derivatives.
2q
2o
PinB
L1 THF:
BPin
>20:1, 96%
PinB
L1 THF:
BPin
>20:1, 97%
PinB
L1 THF:
BPin
OTs
OTf
NMe3
Cl
OTf
NMe3
CF3
NMe3
,
,
>20:1, 52%
,
CO2Et
dtbpy, THF: 5:1 (94%)
dtbpy, THF: 3.2:1 (99%)
dtbpy, THF: 5:1 (92%)
4c
4a
4b
PinB
PinB
PinB
Cl-
N+
PinB
L1, THF:
L1, THF:
L1, THF:
O
O
Hyamine 1622
(Benzthionium Chloride)
8:1, 88%
9:1, 90%
7:1, (91%)
dtbpy, THF: 1:2, 91%
dtbpy, THF: 1:1.2, 88%
dtbpy, THF: 1:1, (98%)
2r
L1 THF:
,
>20:1, 60%
Topical antimicrobial agent
OTs
NMe3
OTs
OTs
NMe3
Et
NMe3
dtbpy, THF: 3.2:1 (97%)
BPin
OMe
Me
4f
4d
4e
To demonstrate the utility of our products, which contain up
to three orthogonal handles for cross-coupling, we carried
out a borylation/Suzuki coupling of 1a, and used this as the
basis for two subsequent palladium-catalyzed cross couplings
in an iterative manner (Scheme 5). Notably, we discovered
that in compound 8, the ammonium functionality can be
selectively coupled with a boronic acid in the presence of the
chloride, using Pd(OAc)2/Xantphos (8 to 10). Conversely,
using XPhos selectively couples the chloride and leaves the
ammonium untouched (8 to 9). This ligand-controlled
chemoselectivity using palladium catalysis is significant as
previously only nickel catalysis has been used in coupling of
benzyl ammonium salts with boronic acids, a protocol not
tolerant of halide functionality, limiting application to se-
quential couplings.13f This discovery, together with the exten-
sive cross-coupling literature,13 provides ample opportunity
for rapid diversification of the versatile aromatic structures
accessible using this ligand-directed approach to borylation.
Furthermore, the ammonium handle can be readily cleaved
by hydrogenation, if desired (9 to 12).
PinB
PinB
PinB
L1, THF: 8:1, 85%
L1, THF: 14:1, 93%
L1, THF: 4:1, 75%
dtbpy, THF: 1.7:1, (21%)
dtbpy, THF: 1.4:1, 87%
dtbpy, THF: 1:1.2, 95%
OTs
N+
OTs
N+
NMe3
OTs
O
4g
4i
4h
PinB
L1, THF:
PinB
BPin
PinB
L1, THF:
L1, THF:
9:1, 79%
dtbpy, THF: 1:1, 86%
>20:1, 80%
dtbpy, THF: 2.7:1, (67%)
20:1, 89%
dtbpy, THF: 1.4:1, 73%
OTs
NMe3
NMe3
OTs
F
4j
4k
PinB
F
PinB
BPin
L1, THF: >20:1, 81%
L1, THF: >20:1, 87%
dtbpy, THF: 5:1, 87%
dtbpy, THF: 2:1, 87%
Scheme 3. Borylation of Aromatic Heterocycles
BPin
PinB
OTs
NMe3
OTs
NMe3
OTs
NMe3
N
N
PinB
N
6a
5a
7a
L1, THF:
:
:
1
1.4
>20
1*
dtbpy
, THF:
Scheme 5. Application to Iterative Cross-Coupling
*Mixture of C4 borylated and C4,6 diborylated
BPin
Ion pair
directed
borylation
OTs
OTs
PinB
Me3N
Me3N
R
OMe
OTf
OTf
OTf
Pd(OAc)2
XPhos
Cl
Cl
N
6b
NMe3
N
5b
NMe3
PinB
N
7b
NMe3
then
ArBr
Pd(dba)2
ArB(OH)2
74%
L1, THF:
:
:
1
1
>20
2.1
1a
8
P(oTol)3
dtbpy
, THF:
OTs
9, R = Me3N
61%
H2, Pd/C
93%
NMe3
NMe
NMe3
3 OTs
OTs
OTs
BPin
12,
R = H
CO2Et
MeO
MeO
BPin
N
N
N
H
Pd(OAc)2
XantPhos
Pd(OAc)2
XPhos
PinB
H
H
Cl
5c
6c
7c
BPin
:
:
L1, THF:
dtbpy
1.1
10
1
1
ArB(OH)2
ArB(OH)2
, THF:
11
10
73%
77%
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M.; Plattner, D. L.; Staples, R. J.; Maligres, P. E.; Krska, S. W.; Malec-
We have developed a readily accessed, anionic ligand that
engages in a substrate-catalyst ion-pairing interaction to
enable meta-selective borylation of two distinct classes of
aromatic quaternary ammonium salts. The use of non-
covalent interactions to control regioselectivity in transition
metal catalysis is an area of great potential. This study
demonstrates the viability of ion-pairing as a powerful tool
for the development of new regioselective transformations.
zka, R. E.; Smith, M. R. J. Am. Chem. Soc. 2014, 136, 14345; (d)
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ASSOCIATED CONTENT
Supporting Information
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(11) For rhodium catalysed silylation of less sterically defined
arenes, see: Cheng, C.; Hartwig, J. F. Science 2014, 343, 853.
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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 the EPSRC and Pfizer for a CASE student-
ship (H.J.D.), AstraZeneca for
a studentship (M.T.M.)
through the AZ-Cambridge PhD Program, the Royal Society
for a University Research Fellowship (R.J.P.), the EPSRC and
EPSRC UK National Mass Spectrometry Facility at Swansea
University and Dr Andrew Bond for X-ray crystallography.
We thank Professors Steven V. Ley and Matthew J. Gaunt for
support and useful discussions, and Dr David Blakemore
(Pfizer) and Dr Alan D. Brown for useful discussion.
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(22) See Supporting Information for full details.
(23) Due to requirements of synthetic accessibility, some sub-
strates were used as their triflate salts.
(24) (a) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura,
N. Tetrahedron Lett. 2002, 43, 5649; (b) Sadler, S. A.; Tajuddin, H.;
Mkhalid, I. A. I.; Batsanov, A. S.; Albesa-Jove, D.; Cheung, M. S.;
Maxwell, A. C.; Shukla, L.; Roberts, B.; Blakemore, D. C.; Lin, Z.;
Marder, T. B.; Steel, P. G. Org. Biomol. Chem. 2014, 12, 7318.
(25) (a) Ishiyama, T.; Takagi, J.; Yonekawa, Y.; Hartwig, J. F.;
Miyaura, N. Adv. Synth. Catal. 2003, 345, 1103; (b) Paul, S.; Chotana,
G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E.; Smith, M. R. J. Am.
Chem. Soc. 2006, 128, 15552.
(26) Interestingly, several of these substrates gave higher than ex-
pected meta selectivity with dtbpy in THF (2o, 2p and 4l). Switching
to cyclohexane with dtbpy as ligand gave unexpectedly high meta
selectivity for these compounds, albeit in generally low conversion to
mixtures of mono and diborylated compounds. The substrates in
Schemes 1-3 were found to give poor selectivity using
dtbpy/cyclohexane, demonstrating that this unusual effect was not
general and restricted to substrates with no arene substituents. For
further details and screening of 1a and 1m against a range of bipyri-
dine ligands in cyclohexane to probe this, see supporting infor-
mation.
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