Ion-Pair-Directed Borylation of Aromatic Phosphonium Salts

Article abstract of DOI:10.1021/acs.joc.9b00878

Control of positional selectivity in C-H activation reactions remains a challenge for synthetic chemists. Noncovalent catalysis has the potential to be a powerful strategy to address this challenge. As a part of our ongoing investigations into the use of ion-pairing interactions in site-selective catalysis, we demonstrate that several classes of aromatic phosphonium salts undergo iridium-catalyzed C-H borylation with a high selectivity for the arene meta position. This is achieved using a bifunctional bipyridine ligand bearing a pendant sulfonate group, which had previously been successful for borylation of aromatic ammonium salts. In this case, the phosphonium salts give a higher meta selectivity than the corresponding ammonium salts. We propose that the high selectivity occurs due to an attractive electrostatic interaction between the substrate and the ligand in the transition state for borylation.

Full text of DOI:10.1021/acs.joc.9b00878

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Ion Pair-Directed Borylation of Aromatic Phosphonium Salts
Bernadette Lee, Madalina T. Mihai, Violeta Stojalnikova, and Robert J Phipps
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 May 2019
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The Journal of Organic Chemistry
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Ion Pair-Directed Borylation of Aromatic Phosphonium Salts
Bernadette Lee, Madalina T. Mihai, Violeta Stojalnikova and Robert J. Phipps*
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Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Supporting Information Placeholder
R
P
n
R
R
H
Ir
PMe3
OTs
O
S
PMe3
OTs
n
n
O
O
PinB
N
BPin
N
BPin
n = 0,1,2
BPin
n = 0,1,2
Ion pair-directed C-H borylation of
phosphonium salts
ABSTRACT: Control of positional selectivity in C-H activation reactions remains a challenge for synthetic chemists. Non-covalent
catalysis has the potential to be a powerful strategy to address this challenge. As part of our ongoing investigations into the use of
ion-pairing interactions in site-selective catalysis, we demonstrate that several classes of aromatic phosphonium salts undergo iridium-
catalyzed C-H borylation with high selectivity for the arene meta position. This is achieved using a bifunctional bipyridine ligand
bearing a pendant sulfonate group which had previously been successful for borylation of aromatic ammonium salts. In this case, the
phosphonium salts give higher meta-selectivity than the corresponding ammonium salts. We propose that the high selectivity occurs
due to an attractive electrostatic interaction between substrate and ligand in the transition state for borylation.
The direct functionalization of arene C-H bonds using transition
metal catalysis constitutes a highly effective method for
elaboration of aromatic compounds. Numerous advances have
been made, particularly over the last two decades. It is notable
however that the majority of these advances result in selective
reaction at the arene ortho position, as a consequence of
proximity to a directing group. Strategies that are able to reach
further to the more remote meta and para positions are less
common and as a consequence these positions are typically
more difficult to access.1
sulfonate group which we hypothesized may engage in
attractive electrostatic interactions with quaternary
a
ammonium moiety in the substrate, directing C-H borylation to
occur at the arene meta position. Gratifyingly, high meta-
selectivity was obtained with a variety of chain lengths between
the quaternary ammonium group and the arene, despite initial
concerns that substantial substrate flexibility may be
incompatible with the relatively low directionality of ion-
pairing interactions. However, in these studies we only
examined quaternary ammonium salts as cationic groups on the
substrates.
We and others have recently been exploring strategies which
exploit a temporary non-covalent interaction between substrate
and ligand to guide the reactive transition metal to a particular
position in the selectivity-determining transition state for C-H
bond functionalization.2, This approach builds on previous
advances for controlling regioselectivity in reactions including
aliphatic C-H activation,3 hydroformylation4 and others. We
have been particularly interested in applying this idea to control
regioselectivity in arene C-H functionalization via C-H
borylation, which has been investigated by a number of
groups.5,6,7 Specifically, we were curious to explore a scenario
in which the catalyst engages in ion-pairing interactions with
the substrate, as this is far rarer than using hydrogen bonding
and relatively unexplored.8 In our previous work, we developed
Phosphonium salts have number of important chemical
applications, including as phase transfer catalysts, ionic liquids,
and lipophilic cations. They can be transformed into reactive
intermediates upon deprotonation to form ylides, as widely used
in the Wittig reaction and variants.10,11 Several recent studies
have shown that certain phosphonium salts can also be used in
cross coupling reactions.12 Hence, we were keen to explore
whether our ion-pair directed method for controlling
regioselectivity in C-H borylation would be compatible with
arenes bearing a phosphonium group, in order to demonstrate
greater generality of the approach.
We began our studies with trifluoromethyl-substituted benzyl
trimethyl phosphonium salt 3a, possessing a tosylate counterion
(Table 1). An initial evaluation with standard borylation ligand
an anionic bipyridine ligand (1) for application in iridium-
9
catalyzed C-H borylation.
This ligand bears a pendant
o
dtbpy gave no conversion in THF at 50 C (entry 1), but we
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found that switching to a more reactive tmphen ligand gave Scheme 1. Synthesis of benzyl phosphonium salts 2 and 3
Page 2 of 13
1
2
3
4
5
6
7
8
high conversion to a mixture of meta and para isomers with
poor selectivity, as expected (entry 2). We were happy to see
that using our sulfonate ligand 1 in place of tmphen, good
conversion was obtained with 7:1 meta:para selectivity, in line
with our hypothesis (entry 3). Under the same conditions, the
same phosphonium cation but bearing bromide as the
counteranion (2a) gave no conversion, presumably due to the
very poor solubility of the starting material (entry 4), hence we
continued optimization using 3a. An evaluation of solvents
revealed that in 1,4-dioxane the meta selectivity was greatly
improved (>20:1) and with full conversion (entry 5). Selectivity
was reasonably tolerant to solvent variation (entries 6-8)
although non-polar solvents were not suitable, likely due to
solubility issues (entry 9). A control borylation of 3a in dioxane
with tmphen revealed a slight bias towards para selectivity,
highlighting the dramatic effect that our anionic ligand 1 has on
this substrate’s intrinsic selectivity towards C-H borylation
(entry 10).
+
+
Br
R
Br
Me3P
Me3P
OTs
PMe3
AgOTs
R
R
R
MeCN, rt
CHCl3, rt
R
% Yield
% Yield
2-CF3 (2a)
96
84
76
77
84
96
58
97
2-CF3 (3a)
96
96
93
81
73
98
95
90
3b
2-Cl (
2-Br (
2-Me (
)
)
(2b
2-Cl
)
)
3c
9
2c
2-Br (
2-Me (
3d
)
2d
)
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3e
3-F (
H (
)
a
2e
3-F (
)
3f
)
2f
3g
3h
H (
2-I (
3-I (
)
2-I (
3-I (
)
)
2g
2h
)
)
a Prepared as the chloride rather than bromide salt
We first examined the 2-chloro substituted salt and found that
this also gave high meta selectivity using ligand 1 (Scheme 2,
4b). Similarly to the CF3-substituted substrate, the use of
tmphen gave some bias towards para selectivity, in this case
3.3:1 para:meta (see values in parenthesis). A bromo-
substituted variant also worked very well, giving 17:1 m:p
selectivity (4c). In the case of the electron donating methyl
substituent, a higher catalyst loading of 6 mol% Ir was required
for good conversion, and this substrate too gave high selectivity
(4d). The small size of fluorine resulted in substrate 4e giving a
mixture of isomers under borylation with tmphen, but with
ligand 1, only the meta-borylated isomer was observed (>20:1).
Finally, an unsubstituted benzylphosphonium salt also
performed well (4f). In this case, it was not possible to stop at
mono borylation and so three equivalents of B2Pin2 were used
to obtain the di-metaborylated product in good yield. The iodo-
substituted phosphonium salts 3g and 3h unfortunately were
found to give no conversion either with tmphen or ligand 1.
Interestingly, the triarylbenzylphosphonium salt 3i was also
found to give no reaction with either ligand. It should be
mentioned that in many cases small amounts of starting material
were still present at the end of the reaction and these were
impossible to separate from the borylated products as the salts
were not purifiable on silica and had to be precipitated. The
yields quoted have been adjusted to reflect this based on the
molar mass of starting material (see Experimental section).
Table 1. Evaluation of ligand 1 on benzylphosphonium salt
3a.
CF3
1.5 mol% [Ir(COD)OMe]2
3.0 mol% Ligand
CF3
PMe3
PMe3
X
1.5 equiv. B2Pin2
Solvent, 50 °C, 18 h
X
PinB
4a
X = Ts,
3a
X = Ts,
X = Br, not formed
2a
X = Br,
tBu
tBu
Bu4N+
SO3
-
N
N
N
N
N
N
dtbpy
1
tmphen
X
Ligand
Solvent
meta:
paraa
--
%
Entry
Conv.b
1
2
3
4
5
6
7
8
9
10
OTs dtbpy
THF
0
OTs tmphen
THF
1 : 1.3
7 : 1
--
91
93
0
OTs
Br
1
1
1
1
1
1
1
THF
THF
OTs
OTs
OTs
OTs
OTs
Dioxane
CH2Cl2
CH3CN
MTBE
>20 : 1
>20 : 1
12 : 1
7 : 1
--
100
77
92
32
0
Scheme 2. Scope of substituents on benzylphosphonium
salts 3
Cyclohexane
Dioxane
OTs tmphen
1 : 1.6
100
a
1
Meta:para ratios are taken from analysis of crude H NMR
b
spectra.
Determined by 1H NMR with reference to 1,2-
dimethoxyethane internal standard.
With optimal conditions in hand, we proceeded to evaluate the
scope of the transformation. The substrates could be
synthesized very readily from substituted benzyl bromides by
benzylation of trimethylphosphine, followed by anion exchange
with silver tosylate, both steps proceeding with generally high
yields (Scheme 1). Whilst the use of silver is not ideal from a
cost standpoint, it is also possible to access these tosylate salts
from benyl tosylates (see Scheme 3).
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The Journal of Organic Chemistry
+
+
We next sought to vary the carbon chain of the phosphonium
1.5 mol% [Ir(COD)OMe]2
Me3P
OTs
Me3P
OTs
1
2
3
4
5
6
7
8
1
3.0 mol% ligand
salt to evaluate whether selectivity would be maintained if it is
either extended or reduced. We were pleased to find that
trifluoromethyl-substituted phenethyl phosphonium salt 7a
gave >20:1 m:p selectivity in good yield (Scheme 4a). In
contrast, control borylation of this substrate with tmphen as
ligand gave 1:2 m:p. Whilst we did explore substituents apart
from CF3 in this class, we found that less electron-withdrawing
substituents typically gave only moderate conversions and so
these were not further pursued due to the challenges of
separating product from unreacted starting material (vide
supra). Phenyltrimethyl phosphonium tosylate (7b) gave
excellent meta-selectivity, resulting in dimeta borylated product
8b (Scheme 4b). These results provide encouragement that
phosphonium salts are likely to be tolerant of a range of chain
lengths, as we had previously seen with the corresponding
ammonium salts which gave meta-selectivity with both 2- and
3- carbon linker lengths.9
4
3
1.5 equiv. B2Pin2
Dioxane, 50 °C, 16 h
R
R
BPin
+
+
+
Me3P
OTs
Me3P
Me3P
OTs
OTs
Cl
Br
F3C
4a
4b
4c
BPin
BPin
BPin
9
a
1:
89% yield , >20:1 m:p
1:
1:
73% yield, 17:1 m:p
(tmphen: 1:3.5 m:p)
70% yield, >20:1 m:p
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(tmphen: 1:3.3 m:p)
(tmphen: 1:1.6 m:p)
+
+
+
Me3P
OTs
Me3P
OTs
Me3P
OTs
4d
4e
BPin
68% yield, >20:1 m:p
4f
BPin
PinB
F
BPin
b
c
1:
1:
1:
69% yield , >20:1 m:p
(tmphen: complex)
89% yield , 18:1 m:p
(tmphen: 1:1.3 m:p)
(tmphen: 1:1.3 m:p)
Scheme 4. Borylation of longer chain phosphonium salt 7a
and phenyltrimethyl phosphonium tosylate (7b)
+
+
+
Me3P
OTs
(p-Tol)3P
Me3P
OTs
OTs
1.5 mol% [Ir(COD)OMe]2
Cl
I
CF3
4g
4h
BPin
no reaction
4i
BPin
CF3
1
3.0 mol% ligand
PMe3
OTs
PMe3
OTs
I
BPin
2.0 equiv. B2Pin2
Dioxane, 70 °C, 20 h
(a)
1:
no reaction
(tmphen :no reaction)
1:
1:
no reaction
(tmphen :no reaction)
8a
7a
BPin
(tmphen :no reaction)
80% yield, >20:1 m:p
(tmphen: 1:2 m:p)
a 1H NMR yield with reference to an internal standard quoted
b
due to decomposition during purification.
Double catalyst
loadings used, reaction at 70 °C. c 3 eq. B2Pin2 used.
1.5 mol% [Ir(COD)OMe]2
OTs
OTs
PMe3
PMe3
1
3.0 mol% ligand
Borylation of a pyridine-derived phosphonium salt was next
examined to evaluate whether selectivity between the 4- and 5-
positions could be obtained. In this case, the counterion
exchange according to the previous substrate synthesis using
silver failed in the presence of the basic pyridine. So an
alternative approach was taken via the intermediate tosylate,
which allows substrates to be accessed from benzyl alcohols.
This approach can be advantageous for some substrates as it
installs tosylate directly as the counteranion (Scheme 3, a). For
the pyridine substrate 5a, it was quite challenging to prevent
over borylation to 6c, but by stopping the reaction after 1 h,
useful amounts of 6a, the product of borylation at C4, could be
obtained and the C4:C5 ratio was 10:1 (corresponding to the
m:p ratio in non-heteroarenes). In contrast, with tmphen the
C4:C5 ratio was ~1:1 (Scheme 3, b).
(b)
8b
3.0 equiv. B2Pin2
Dioxane, 50 °C, 20 h
7b
PinB
BPin
80% yield, >20:1 m:p
Finally, we demonstrate the meta-selective borylation of 3b on
1.0 mmol scale and telescope this with conversion of the BPin
to a hydroxyl group followed be reduction of the phosphonium
functionality with lithium aluminium hydride (Scheme 5).13
This example of further elaboration highlights the potential of
our method for the rapid access to complex arene building
blocks.
Scheme 5. Larger scale reaction and elaboration of product
Scheme 3. Synthesis and borylation of pyridylphosphonium
salt 5a
OTs
PMe3
OTs
PMe3
LiAlH4
Cl
Cl
+
Cl
a) As above
Me3P
N
HO
N
OTs
TsO
N
THF, 60 °C
1 h
b) H2O2,
NaHCO3
OH
OH
PMe3
9
a)
TsCl
77%
3b
1.0 mmol scale
46% yield over three steps
(single purification)
MeCN, rt,
84%
5a
+
+
+
+
OTs
Me3P
Me3P
OTs
Me3P
Me3P
OTs
OTs
1.5 mol% [Ir(COD)OMe]2
3.0 mol% ligand
In summary, we have demonstrated that aromatic
phosphonium salts are compatible with our previously reported
sulfonate ligand 1 to enable C-H borylation to be directed to the
arene meta position. The selectivities are in general very high
and we envisage that this study provides further evidence of the
utility of ion pairing interactions in the design of new catalyst
scaffolds for site-selective functionalization.
1
b)
N
N
N
N
1.5 equiv. B2Pin2
Dioxane, 50 °C, 1 h
PinB
BPin
BPin
BPin
5a
6a
48
26
6b
6c
5
1
With
With
:
5
Yield by 1H-NMR
tmphen
:
34
0
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Page 4 of 13
reduced pressure, and the salt precipitated with CHCl3 and Et2O
EXPERIMENTAL SECTION
1
2
3
4
5
6
7
8
(approximately 1:10 ratio of CHCl3:Et2O). The salt was
collected by filtration, washed with Et2O and dried in vacuo to
yield the title compound as a white powder (1.58 g, 5.0 mmol,
96%). 1H NMR (600 MHz, CDCl3) δ 7.85 (dd, J = 7.7, 2.2 Hz,
1H), 7.72 (d, J = 7.9 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.49 (t,
J = 7.7 Hz, 1H), 4.37 (d, J = 16.7 Hz, 2H), 2.24 (d, J = 14.2 Hz,
9H); 13C{1H} NMR (151 MHz, CDCl3) δ 133.0 (d, 3JC–P = 4.7
Materials and Methods. All reagents, unless otherwise stated,
were used as supplied from commercial sources without further
purification. CH2Cl2, THF and Et2O were purified by
distillation on site under inert atmosphere via the following
processes: THF and Et2O were pre-dried over sodium wire then
distilled from calcium hydride and lithium aluminium hydride.
CH2Cl2 and n-hexane were distilled from calcium hydride.
5
2
3
Hz), 128.9 (d, JC–P = 3.8 Hz), 128.8 (qd, JC–F = 29.8 Hz, JC–
1H NMR spectra were recorded on a 600 MHz Bruker Avance
DRX-600 spectrometer, 500 MHz Bruker DCH Cryoprobe or
400 MHz QNP Cryoprobe. Chemical shifts are reported in parts
per million (ppm) and the spectra are calibrated to the resonance
resulting from incomplete deuteration of the solvent (CDCl3:
7.26 ppm, CD3OD: 3.31 ppm, (CD3)2SO: 2.50 ppm). 13C NMR
spectra were recorded on the same spectrometers with complete
proton decoupling. Chemical shifts are reported in ppm with the
solvent resonance as the internal standard (13CDCl3: 77.16 ppm,
t; 13CD3OD: 49.00 ppm, sept; DMSO-d6: 39.51 ppm, s). Data
are reported as follows: chemical shift δ/ppm, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, br = broad, m =
multiplet or combinations thereof; 13C signals are singlets
unless otherwise stated), coupling constants J in Hz, integration
P = 5.7 Hz), 127.3–127.1 (m), 126.9 (dq, 3JC–F = 1.6 Hz, 2JC–P
=
9
1
4
9.0 Hz), 123.9 (qd, JC–F = 273.8 Hz, JC–P = 1.5 Hz), 27.9 (d,
1JC–P = 51.1 Hz), 9.2 (d, 1JC–P = 54.3 Hz); 19F NMR (376 MHz,
CDCl3) δ −58.81; 31P NMR (243 MHz, CDCl3) δ 28.29. HRMS
m/z (ESI+) [M – Br]+ calculated for [C11H15F3P]+ 235.0858,
found 235.0849;
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Trimethyl(2-(trifluoromethyl)benzyl)phosphonium
4-
methylbenzenesulfonate (3a):
Followed
GP1,
used
trimethyl(2-
(trifluoromethyl)benzyl)phosphonium bromide (0.53 g,
1.7 mmol), silver p-toluenesulfonate (0.53 g, 1.9 mmol, 1.1 eq.)
and chloroform (5 ml). The title compound was obtained as a
1
1
(1H only). H-COSY, HSQC, HMBC and NOESY were used
white solid (0.66 g, 1.6 mmol, 96%). H NMR (600 MHz,
where appropriate to facilitate structural determination. The
CDCl3) δ 7.73 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.66
(d, J = 7.7 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.4 Hz,
1H), 7.12 (d, J = 7.9 Hz, 2H), 4.06 (d, J = 16.8 Hz, 2H), 2.31 (s,
3H), 2.08 (d, J = 14.4 Hz, 9H); 13C{1H} NMR (151 MHz,
CDCl3) δ 143.6, 139.4, 133.2 (d, 3JC–P = 4.8 Hz), 133.0 (d, 4JC–
P = 2.3 Hz), 128.9 (qd, 2JC–F = 30.2 Hz, 3JC–P = 5.7 Hz), 128.72,
128.65 (d, 5JC–P = 3.5 Hz), 127.3 (qd, 3JC–F = 1.7 Hz, 2JC–P = 8.7
carbon attached to boron was generally not observed by 13C
1
spectroscopy due to quadrupolar relaxation. H NMR signals
are reported to 2 decimal places and 13C signals to 1 decimal
place (2 decimals places if the peaks are not distinguishable
with only 1 decimal place). 19F NMR spectra were recorded on
a 400 MHz Bruker Avance III HD Spectrometer, and 19F signals
are reported to 2 decimal places. 31P NMR spectra were
recorded on a 600 MHz Bruker Avance DRX-600 spectrometer
or a 400 MHz Bruker Avance III HD Spectrometer, and 31P
signals are reported to 2 decimal places.
1
4
Hz), 127.1 (m), 125.8, 124.0 (qd, JC–F = 273.3 Hz, JC–P = 1.6
Hz), 27.7 (d, 1JC–P = 50.3 Hz), 21.3, 8.4 (d, 1JC–P = 54.1 Hz); 19F
NMR (376 MHz, CDCl3) δ −58.86; 31P NMR (243 MHz,
CDCl3) δ 29.07; HRMS m/z (ESI+) [M – OTs]+ calculated for
[C11H15F3P]+ 235.0858, found 235.0853;
High Resolution Mass Spectra (HRMS) were recorded on a
Waters Micromass LCT Premier TOF spectrometer using a
positive electrospray ionization (ESI+). Measured values are
reported to 4 decimal places are within ±5 ppm of the calculated
value. The calculated values are based on the most abundant
isotope.
(2-Chlorobenzyl)trimethylphosphonium bromide (2b):
To a solution of 2-chlorobenzyl bromide (0.65 ml, 5 mmol) in
acetonitrile (10 ml) was added a 1.0 M solution of
trimethylphosphine in THF (5.5 ml, 5.5 mmol, 1.1 eq.)
dropwise. The reaction mixture was stirred at room temperature
for 1 h under an argon atmosphere. The solvent was then
removed, and the salt precipitated with Et2O. The salt was
collected by filtration, washed with Et2O and dried in vacuo to
yield the title compound as a white powder (1.18 g, 4.2 mmol,
84%). 1H NMR (600 MHz, CDCl3) δ 7.74–7.72 (m, 1H), 7.40–
7.39 (m, 1H), 7.26-7.29 (m, 2H), 4.32 (d, J = 16.2 Hz, 2H), 2.21
(d, J = 14.2 Hz, 9H); 13C{1H} NMR (151 MHz, CDCl3) δ 133.9
(d, 3JC–P = 6.2 Hz), 132.7 (d, 3JC–P = 5.0 Hz), 130.3 (d, 5JC–P = 3.3
Infrared (IR) spectroscopy was performed using a Perkin Elmer
Spectrum One FT infra-red spectrophotometer sampling
accessory, scanning from 4000–600 cm−1. IR absorption
maxima (νmax) are reported in wavenumbers (cm−1).
General procedure for the synthesis of phosphonium 4-
methylbenzenesulfonates (GP1). The corresponding
phosphonium bromide (or chloride) salt and silver p-
toluenesulfonate (1.1 eq.) were dissolved in CHCl3. The
reaction mixture was stirred at room temperature for 30 min,
then filtered through MgSO4. The filtrate was collected, and the
solvent was removed under reduced pressure to afford the
product.
4
4
Hz), 130.1 (d, JC–P = 3.9 Hz), 128.0 (d, JC–P = 3.5 Hz), 126.9
(d, 2JC–P = 9.3 Hz), 28.1 (d, 1JC–P = 50.1 Hz), 9.1 (d, 1JC–P = 54.0
Hz); 31P NMR (243 MHz, CDCl3) δ 28.82. HRMS m/z (ESI+)
[M – Br]+ calculated for [C10H15ClP]+ 201.0594, found
201.0587.
Trimethyl(2-(trifluoromethyl)benzyl)phosphonium
(2a):
bromide
(2-Chlorobenzyl)trimethylphosphonium
4-
methylbenzenesulfonate (3b):
To a solution of 2-(trifluoromethyl)benzyl bromide (1.25 g, 5.2
mmol) in acetonitrile (10 ml) was added a 1.0 M solution of
trimethylphosphine in toluene (5.8 ml, 5.8 mmol, 1.1 eq.). The
reaction mixture was stirred at room temperature for 1 h under
an argon atmosphere. The solvent was then removed under
Followed GP1, used (2-chlorobenzyl)trimethylphosphonium
bromide (0.56 g, 2 mmol), silver p-toluenesulfonate (0.61 g, 2.2
mmol, 1.1 eq.) and chloroform (5 ml). The title compound was
obtained as a white solid (0.72 g, 1.9 mmol, 96%). 1H NMR
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The Journal of Organic Chemistry
(600 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.54–7.52 (m,
(d, 4JC–P = 4.0 Hz), 126.7 (m), 27.8 (d, 1JC–P = 49.4 Hz), 20.7 (d,
1
4JC–P = 1.3 Hz), 8.8 (d, JC–P = 54.1 Hz); 31P NMR (243 MHz,
1
2
3
4
5
6
7
8
1H), 7.39 (d, J = 7.4 Hz, 1H), 7.28–7.22 (m, 2H), 7.14 (d, J =
7.9 Hz, 2H), 4.04 (d, J = 16.4 Hz, 2H), 2.32 (s, 3H), 2.08 (d, J
= 14.4 Hz, 9H); 13C{1H} NMR (151 MHz, CDCl3) δ 143.6,
139.5, 133.8 (d, 3JC–P = 6.1 Hz), 132.8 (d, 3JC–P = 4.9 Hz), 130.2
CDCl3) δ 28.25. HRMS m/z (ESI+) [M – Br]+ calculated for
[C11H18P]+ 181.1141, found 181.1137
5
4
(d, JC–P = 3.3 Hz), 129.9 (d, JC–P = 3.9 Hz), 128.8, 128.0 (d,
Trimethyl(2-methylbenzyl)phosphonium
4-
4JC–P = 3.5 Hz), 127.3 (d, 2JC–P = 9.3 Hz), 125.8, 27.8 (d, 1JC–P
=
methylbenzenesulfonate (3d):
49.8 Hz), 21.3, 8.2 (d, JC–P = 53.8 Hz); 31P NMR (243 MHz,
CDCl3) δ 29.51; HRMS m/z (ESI+) [M – OTs]+ calculated for
[C10H15ClP]+ 201.0594, found 201.0596;
1
Followed GP1, used trimethyl(2-methylbenzyl)phosphonium
bromide (0.52 g, 2 mmol), silver p-toluenesulfonate (0.61 g, 2.2
mmol, 1.1 eq.) and chloroform (5 ml). The title compound was
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
obtained as a white solid (0.57 g, 1.6 mmol, 81%). H NMR
(2-Bromobenzyl)trimethylphosphonium bromide (2c):
(600 MHz, CDCl3) δ 7.77 (d, J = 8.1 Hz, 2H), 7.22–7.19 (m,
3H), 7.15–7.14 (m, 3H), 3.95 (d, J = 16.4 Hz, 2H), 2.33 (s, 3H),
2.31 (d, J = 1.3 Hz, 3H), 2.06 (d, J = 14.3 Hz, 9H);
13C{1H} NMR (151 MHz, CDCl3) δ 143.7, 139.4, 137.0 (d, 3JC–
P = 5.7 Hz), 131.4 (d, 5JC–P = 3.4 Hz), 131.2 (d, 3JC–P = 4.9 Hz),
128.7, 128.3 (d, 4JC–P = 4.0 Hz), 127.1 (d, 2JC–P = 9.0 Hz), 126.7
(d, 4JC–P = 3.6 Hz), 125.8, 27.4 (d, 1JC–P = 49.1 Hz), 21.3, 20.2
(d, 4JC–P = 1.4 Hz), 8.0 (d, 1JC–P = 54.0 Hz); 31P NMR (243 MHz,
CDCl3) δ 28.85; HRMS m/z (ESI+) [M – OTs]+ calculated for
[C11H18P]+ 181.1141, found 181.1134;
To a solution of 2-bromobenzyl bromide (1.25 g, 5 mmol) in
acetonitrile (10 ml) was added a 1.0 M solution of
trimethylphosphine in THF (5.5 ml, 5.5 mmol, 1.1 eq.)
dropwise. The reaction mixture was stirred at room temperature
for 15 min under an argon atmosphere, with the product being
observed to precipitate from solution. The reaction mixture was
then filtered, and the solids washed with Et2O then dried in
vacuo to yield the title compound as a white powder (1.24 g, 3.8
1
mmol, 76%). H NMR (600 MHz, CDCl3) δ 7.77–7.75 (m, 1H),
7.61 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.22 (tt, J =
7.7, 2.1 Hz, 1H), 4.37 (d, J = 16.2 Hz, 2H), 2.25 (d, J = 14.2 Hz,
9H); 13C{1H} NMR (151 MHz, CDCl3) δ 133.7 (d, 4JC–P = 3.2
Hz), 132.7 (d, 3JC–P = 4.9 Hz), 130.3 (d, 4JC–P = 3.9 Hz), 128.7
(3-fluorobenzyl)trimethylphosphonium chloride (2e):
To a solution of 3-fluorobenzyl chloride (0.60 ml, 5 mmol) in
acetonitrile (10 ml) was added a 1.0 M solution of
trimethylphosphine in THF (5.5 ml, 5.5 mmol, 1.1 eq.)
dropwise. The reaction mixture was stirred at 60 °C for 6 h, then
at room temperature for 16 h, under an argon atmosphere. The
solvent was then removed, and the salt precipitated with Et2O.
The salt was collected by filtration, washed with Et2O and dried
in vacuo to yield the title compound as a white powder (0.92 g,
2
5
3
(d, JC–P = 9.2 Hz), 128.6 (d, JC–P = 3.6 Hz), 124.5 (d, JC–P
=
6.5 Hz), 30.5 (d, JC–P = 50.0 Hz), 9.1 (d, JC–P = 54.0 Hz); 31P
NMR (243 MHz, CDCl3) δ 28.80. HRMS m/z (ESI+) [M – Br]+
calculated for [C10H15BrP]+ 245.0089, found 245.0082;
1
1
(2-bromobenzyl)trimethylphosphonium
4-
methylbenzenesulfonate (3c):
1
4.2 mmol, 84%). H NMR (400 MHz, DMSO-d6) δ 7.50–7.44
Followed GP1, used (2-bromobenzyl)trimethylphosphonium
bromide (0.65 g, 2 mmol), silver p-toluenesulfonate (0.61 g, 2.2
mmol, 1.1 eq.) and chloroform (5 ml). The title compound was
(m, 1H), 7.24–7.17 (m, 3H), 3.90 (d, J = 17.2 Hz, 2H), 1.83 (d,
J = 14.8 Hz, 9H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.3
3
(dd, 1JC–F = 244.2 Hz, 4JC–P = 3.9 Hz), 132.4 (dd, JC–F = 8.5 Hz,
1
obtained as a white solid (0.78 g, 1.9 mmol, 93%). H NMR
2JC–P = 8.5 Hz), 131.2 (dd, 3JC–F = 8.9 Hz, 4JC–P = 3.6 Hz), 126.2
(dd, 4JC–F = 3.0 Hz, 3JC–P = 5.5 Hz), 116.8 (dd, 2JC–F = 22.3 Hz,
3JC–P = 5.2 Hz), 114.9 (dd, 2JC–F = 21.2 Hz, 5JC–P = 3.9 Hz), 29.2
(600 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2H), 7.59–7.56 (m,
1H), 7.30 (t, J = 7.5 Hz, 2H), 7.18 (tt, J = 7.8, 2.1 Hz, 1H), 7.14–
7.13 (d, J = 7.9 Hz, 2H), 4.10 (d, J = 16.3 Hz, 2H), 2.33 (s, 3H),
2.12 (d, J = 14.3 Hz, 9H); 13C{1H} NMR (151 MHz, CDCl3) δ
143.6, 139.5, 133.6 (d, 4JC–P = 3.3 Hz), 132.7 (d, 3JC–P = 4.8 Hz),
130.1 (d, 4JC–P = 3.9 Hz), 129.1 (d, 2JC–P = 9.2 Hz), 128.8, 128.6
(d, 5JC–P = 3.5 Hz), 125.8, 124.5 (d, 3JC–P = 6.4 Hz), 30.3 (d, 1JC–P
= 49.7 Hz), 21.3, 8.3 (d, 1JC–P = 53.8 Hz); 31P NMR (243 MHz,
CDCl3) δ 29.32; HRMS m/z (ESI+) [M – OTs]+ calculated for
[C10H15BrP]+ 245.0089, found 245.0086;
1
1
(d, JC–P = 49.1 Hz), 7.1 (d, JC–P = 54.0 Hz); 19F NMR (376
MHz, DMSO-d6) δ −113.08 (d, 5JF–P = 2.7 Hz); 31P NMR (243
MHz, DMSO-d6) δ 28.11. HRMS m/z (ESI+) [M – Br]+
calculated for [C10H15FP]+ 185.0890, found 185.0882
(3-fluorobenzyl)trimethylphosphonium
4-
methylbenzenesulfonate (3e):
Followed GP1, used (3-fluorobenzyl)trimethylphosphonium
chloride (0.44 g, 2 mmol), silver p-toluenesulfonate (0.61 g, 2.2
mmol, 1.1 eq.) and chloroform (10 ml). Stirred at room
temperature for 3 h rather than 30 min. The title compound was
obtained as an off-white solid (0.52 g, 1.5 mmol, 73%) that
turned reddish in colour over time. 1H NMR (400 MHz,
DMSO-d6) δ 7.51 (d, J = 8.1 Hz, 2H), 7.49–7.43 (m, 1H), 7.24–
7.17 (m, 3H), 7.12 (d, J = 8.0 Hz, 2H), 3.81 (d, J = 17.1 Hz,
2H), 2.29 (s, 3H), 1.80 (d, J = 14.8 Hz, 9H); 13C{1H} NMR
(101 MHz, DMSO-d6) δ 162.3 (dd, 1JC–F = 244.9 Hz, 4JC–P = 3.8
Trimethyl(2-methylbenzyl)phosphonium bromide (2d):
To a solution of 2-methylbenzyl bromide (0.67 ml, 5 mmol) in
acetonitrile (10 ml) was added a 1.0 M solution of
trimethylphosphine in THF (5.5 ml, 5.5 mmol, 1.1 eq.)
dropwise. The reaction mixture was stirred at room temperature
for 1 h under an argon atmosphere, with the product being
observed to precipitate from solution. The reaction mixture was
then filtered, and the solids washed with Et2O then dried in
vacuo to yield the title compound as a white powder (1.01 g,
3.9 mmol, 77%). 1H NMR (600 MHz, CDCl3) δ 7.37 (dd, J =
7.6, 2.7 Hz, 1H), 7.24 (m, 2H), 7.21–7.19 (m, 1H), 4.20 (d, J =
16.3 Hz, 2H), 2.43 (d, J = 1.4 Hz, 3H), 2.21 (d, J = 14.2 Hz,
9H); 13C{1H} NMR (151 MHz, CDCl3) δ 137.0 (d, 3JC–P = 5.7
3
2
Hz), 145.7, 137.8, 132.3 (dd, JC–F = 8.7 Hz, JC–P = 8.7 Hz),
131.2 (dd, 3JC–F = 8.7 Hz, 4JC–P = 3.6 Hz), 128.2, 126.2 (dd, 4JC–F
= 3.0 Hz, 3JC–P = 5.3 Hz), 125.6, 116.8 (dd, 2JC–F = 22.2 Hz, 3JC–P
= 5.4 Hz), 115.0 (dd, 2JC–F = 21.1 Hz, 5JC–P = 4.0 Hz), 29.1 (d,
1JC–P = 48.9 Hz), 20.9, 7.0 (d, 1JC–P = 54.0 Hz); 19F NMR (376
MHz, DMSO-d6) δ −113.02 (d, 5JF–P = 2.7 Hz); 31P NMR (243
5
3
Hz), 131.5 (d, JC–P = 3.4 Hz), 131.2 (d, JC–P = 5.0 Hz), 128.5
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The Journal of Organic Chemistry
Page 6 of 13
MHz, DMSO-d6) δ 28.07; HRMS m/z (ESI+) [M – OTs]+
Followed GP1, used (2-iodobenzyl)trimethylphosphonium
calculated for [C10H15FP]+ 185.0890, found 185.0887;
bromide (0.75 g, 2 mmol), silver p-toluenesulfonate (0.61 g, 2.2
mmol, 1.1 eq.) and chloroform (10 ml). The title compound was
1
2
3
4
5
6
7
8
1
obtained as a white solid (0.90 g, 1.9 mmol, 95%). H NMR
Benzyltrimethylphosphonium bromide (2f):
(600 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.1
Hz, 2H), 7.53 (dt, J = 7.8, 2.3 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H),
7.13 (d, J = 7.9 Hz, 2H), 7.00 (tt, J = 8.0, 1.8 Hz, 1H), 4.11 (d,
J = 16.2 Hz, 2H), 2.32 (s, 3H), 2.13 (d, J = 14.4 Hz, 9H);
13C{1H} NMR (151 MHz, CDCl3) δ 143.8, 140.4 (d, 4JC–P = 3.1
Hz), 139.4, 132.9 (d, 2JC–P = 9.1 Hz), 131.7 (d, 3JC–P = 4.8 Hz),
130.1 (d, 4JC–P = 3.8 Hz), 129.4 (d, 5JC–P = 3.6 Hz), 128.7, 125.8,
100.8 (d, 3JC–P = 6.8 Hz), 34.8 (d, 1JC–P = 49.3 Hz), 21.3, 8.5 (d,
1JC–P = 53.7 Hz); 31P NMR (243 MHz, CDCl3) δ 29.76; HRMS
m/z (ESI+) [M – OTs]+ calculated for [C10H15IP]+ 292.9951,
found 292.9943;
To a solution of benzyl bromide (1.2 ml, 10 mmol) in
acetonitrile (20 ml) was added
a 1.0 M solution of
trimethylphosphine in toluene (11 ml, 11 mmol, 1.1 eq.)
dropwise. The reaction mixture was stirred at room temperature
for 1 h under an argon atmosphere, with the product being
observed to precipitate from solution. The reaction mixture was
cooled on ice, then filtered, and the solids washed with Et2O
then dried in vacuo to yield the title compound as a white
powder (2.36 g, 9.6 mmol, 96%). 1H NMR (600 MHz,
CDCl3) δ 7.43–7.41 (m, 2H), 7.38–7.34 (m, 3H), 4.27 (d,
J = 16.1 Hz, 2H), 2.16 (d, J = 14.1 Hz, 9H); 13C{1H} NMR (151
MHz, CDCl3) δ 130.1 (d, 3JC–P = 5.4 Hz), 129.5 (d, 4JC–P = 3.5
Hz), 128.5 (d, 5JC–P = 4.0 Hz), 128.2 (d, 2JC–P = 9.2 Hz), 30.6 (d,
1JC–P = 49.6 Hz), 8.5 (d, 1JC–P = 54.8 Hz); 31P NMR (243 MHz,
CDCl3) δ 26.32. HRMS m/z (ESI+) [M – Br]+ calculated for
[C10H16P]+ 167.0984, found 167.0978;
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3-iodobenzyl)trimethylphosphonium bromide (2h):
To a solution of 3-iodobenzyl bromide (0.30 g, 1 mmol) in
acetonitrile (2 ml) was added
a 1.0 M solution of
trimethylphosphine in toluene (1.1 ml, 1.1 mmol, 1.1 eq.)
dropwise. The reaction mixture was stirred at room temperature
for 1.5 h under an argon atmosphere, with the product being
observed to precipitate from solution. The reaction mixture was
then filtered, and the solids washed with Et2O then dried in
vacuo to yield the title compound as a white powder (0.36 g,
mmol, 0.97 mmol, 97%). 1H NMR (600 MHz, CD3OD) δ 7.79–
7.77 (m, 2H), 7.39–7.37 (m, 1H), 7.24–7.21 (m, 1H), 3.76 (d, J
= 16.3 Hz, 2H), 1.87 (d, J = 14.3 Hz, 9H); 13C{1H} NMR (151
MHz, CD3OD) δ 138.5 (d, 3JC–P = 5.4 Hz), 137.4 (d, 5JC–P = 3.9
Hz), 131.0 (d, 2JC–P = 9.0 Hz), 130.8 (d, 4JC–P = 3.5 Hz), 129.0
(d, 3JC–P = 5.0 Hz), 94.3 (d, 4JC–P = 4.1 Hz), 29.2 (d, 1JC–P = 49.8
Benzyltrimethylphosphonium 4-methylbenzenesulfonate (3f):
Followed GP1, used benzyltrimethylphosphonium bromide
(0.99 g, 4 mmol), silver p-toluenesulfonate (1.23 g, 4.4 mmol,
1.1 eq.) and chloroform (10 ml). Stirred at room temperature for
1.5 h rather than 30 min. The title compound was obtained as a
1
white solid (1.32 g, 3.9 mmol, 98%). H NMR (600 MHz,
CDCl3) δ 7.77 (d, J = 8.1 Hz, 2H), 7.27–7.26 (m, 3H), 7.23–
7.21 (m, 2H), 7.14 (d, J = 8.0 Hz, 2H), 3.93 (d, J = 16.4 Hz,
2H), 2.32 (s, 3H), 1.95 (d, J = 14.3 Hz, 9H); 13C{1H} NMR
3
1
Hz), 6.3 (d, JC–P = 55.2 Hz); 31P NMR (243 MHz, CD3OD)
(151 MHz, CDCl3) δ 143.8, 139.4, 130.2 (d, JC–P = 5.3 Hz),
4
2
δ 27.25. HRMS m/z (ESI+) [M – Br]+ calculated for [C10H15IP]+
129.2 (d, JC–P = 3.5 Hz), 128.81, 128.75 (d, JC–P = 9.2 Hz),
128.1 (d, 5JC–P = 3.9 Hz), 125.8, 29.9 (d, 1JC–P = 49.0 Hz), 21.3,
7.4 (d, 1JC–P = 54.5 Hz); 31P NMR (243 MHz, CDCl3) δ 27.16;
HRMS m/z (ESI+) [M – OTs]+ calculated for [C10H16P]+
167.0984, found 167.0982;
292.9951, found 292.9938;
(3-iodobenzyl)trimethylphosphonium
4-
methylbenzenesulfonate (3h):
Followed GP1, used (3-iodobenzyl)trimethylphosphonium
bromide (0.25 g, 0.67 mmol), silver p-toluenesulfonate (0.22 g,
0.8 mmol, 1.2 eq.) and chloroform (15 ml). The title compound
(2-iodobenzyl)trimethylphosphonium bromide (2g):
To a solution of 2-iodobenzyl bromide (1.48 g, 5 mmol) in
1
acetonitrile (10 ml) was added
a 1.0 M solution of
was obtained as a white solid (0.28 g, 0.60 mmol, 90%). H
trimethylphosphine in toluene (11 ml, 11 mmol, 2.2 eq.)
dropwise. The reaction mixture was stirred at room temperature
for 3 h under an argon atmosphere. The solvent was removed,
and the salt was precipitated with CHCl3 and Et2O
(approximately 1:5 ratio of CHCl3:Et2O). The salt was collected
by filtration, washed with Et2O and dried in vacuo to yield the
title compound as a white powder (1.09 g, 2.9 mmol, 58%). 1H
NMR (600 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.74 (dt, J
= 7.8, 2.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.06 (tt, J = 7.8, 2.0
Hz, 1H), 4.41 (d, J = 16.1 Hz, 2H), 2.28 (d, J = 14.1 Hz, 9H);
NMR (400 MHz, DMSO-d6) δ 7.73–7.69 (m, 2H), 7.47–7.44
(m, 2H), 7.32–7.29 (m, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.10–7.08
(m, 2H), 3.69 (d, J = 16.9 Hz, 2H), 2.26 (s, 3H), 1.76 (d, J =
14.7 Hz, 9H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 145.9,
138.2 (d, 3JC–P = 5.3 Hz), 137.6, 136.7 (d, 5JC–P = 3.8 Hz), 132.1
2
4
3
(d, JC–P = 9.0 Hz), 131.2 (d, JC–P = 3.3 Hz), 129.3 (d, JC–P
=
=
5.1 Hz), 128.1, 125.5, 95.6 (d, 4JC–P = 4.0 Hz), 28.9 (d, 1JC–P
48.8 Hz), 20.8, 7.0 (d, JC–P = 54.0 Hz); 31P NMR (243 MHz,
DMSO-d6) δ 27.86; HRMS m/z (ESI+) [M – OTs]+ calculated
for [C10H15IP]+ 292.9951, found 292.9938;
1
4
13C{1H} NMR (101 MHz, CDCl3) δ 140.6 (d, JC–P = 3.2 Hz),
132.4 (d, 2JC–P = 9.2 Hz), 131.8 (d, 3JC–P = 4.9 Hz), 130.4 (d, 4JC–
P = 3.9 Hz), 129.5 (d, 5JC–P = 3.6 Hz), 101.0 (d, 3JC–P = 6.9 Hz),
35.0 (d, 1JC–P = 49.9 Hz), 9.4 (d, 1JC–P = 54.0 Hz); 31P NMR (243
MHz, CDCl3) δ 28.90. HRMS m/z (ESI+) [M – Br]+ calculated
for [C10H15IP]+ 292.9951, found 292.9940;
(2-chlorobenzyl)tri-p-tolylphosphonium
4-
methylbenzenesulfonate (3i):
A solution of 2-chlorobenzyl bromide (0.25 ml, 2 mmol) and
tri(p-tolyl)phosphine (0.85 g, 2.8 mmol, 1.4 eq.) in acetonitrile
(10 ml) was stirred at 50 °C for 30 h under an argon atmosphere.
The solvent was then removed, and the crude product was used
directly in the next step. The crude product and silver
p-toluenesulfonate (0.61 g, 2.2 mmol, 1.1 eq.) were dissolved
in chloroform (10 ml), then stirred at room temperature for 2 h.
(2-iodobenzyl)trimethylphosphonium
4-
methylbenzenesulfonate (3g):
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The Journal of Organic Chemistry
Filtration through MgSO4 and removal of the solvent under
3H), 2.13 (d, J = 14.5 Hz, 9H); 13C{1H} NMR (151 MHz,
2
4
1
2
3
4
5
6
7
8
reduced pressure yielded the crude product as a yellow solid,
which darkened to a grey solid overnight and was then purified
by flash column chromatography on silica gel (5% MeOH in
CH2Cl2). NMR analysis of the product showed that not all of
the product was present as the tosylate, thus the ion exchange
reaction was repeated. Filtration through MgSO4 and removal
of solvent under reduced pressure yielded the title compound as
CDCl3) δ 151.1 (d, JC–P = 9.4 Hz), 149.3 (d, JC–P = 1.9 Hz),
3
143.9, 139.2, 137.6, 128.6, 125.9, 125.7 (d, JC–P = 7.3 Hz),
122.8 (d, 5JC–P = 2.3 Hz), 32.2 (d, 1JC–P = 53.1 Hz), 21.3, 8.9 (d,
1JC–P = 54.9 Hz); 31P NMR (243 MHz, CDCl3) δ 27.46; HRMS
m/z (ESI+) [M – OTs]+ calculated for [C9H15NP]+ 168.0937,
found 168.0932;
1
a yellow solid (0.52 g, 0.87 mmol, 44% over two steps). H
Trimethyl(2-(trifluoromethyl)phenethyl)phosphonium
4-
NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.1 Hz, 2H), 7.48 (dd, J
= 12.5, 8.0 Hz, 6H), 7.44 (dt, J = 7.9, 2.3 Hz, 1H), 7.38 (dd, J =
8.1, 3.5 Hz, 6H), 7.20–7.14 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H),
7.01 (d, J = 7.9 Hz, 2H), 5.15 (d, J = 14.4 Hz, 2H), 2.46 (s, 9H),
2.28 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 146.1 (d, 4JC–P
= 3.0 Hz), 144.6, 138.2, 135.7 (d, 3JC–P = 6.3 Hz), 134.1 (d, 3JC–P
= 10.3 Hz), 133.4 (d, 3JC–P = 4.8 Hz), 130.8 (d, 2JC–P = 13.0 Hz),
129.7 (d, 4JC–P = 3.9 Hz), 129.4 (d, 5JC–P = 3.2 Hz), 128.1, 127.7
methylbenzenesulfonate (7a)
9
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2-(trifluoromethyl)phenethyl 4-methylbenzenesulfonate was
synthesized according to a published procedure as a colourless
oil (3.33 g, 7.94 mmol, 53%).9b 2-(Trifluoromethyl)phenethyl
4-methylbenzenesulfonate (3.33 g, 7.94 mmol) was added to a
microwave vial and the vial was sealed, evacuated and
backfilled with argon. Acetonitrile (1 M) was added, followed
by trimethylphosphine (9.5 ml, 1.2 equiv., 1 M solution in
toluene). The resulting reaction mixture was stirred at 80 °C for
24 hours. The solvent was removed under reduced pressure,
then Et2O was added and the title phosphonium salt was isolated
by filtration as a white solid (2.90 g, 6.91 mmol, 87%).
4
2
(d, JC–P = 3.6 Hz), 126.5 (d, JC–P = 9.1 Hz), 126.2, 114.4 (d,
1JC–P = 88.5 Hz), 27.8 (d, 1JC–P = 50.3 Hz), 21.8 (d, 5JC–P = 1.4
Hz), 21.2; 31P NMR (243 MHz, CDCl3) δ 21.71; HRMS m/z
(ESI+) [M – OTs]+ calculated for [C28H27ClP]+ 429.1533, found
429.1522;
1H NMR (600 MHz, Methanol-d4) δ 7.68-7.70 (m, 3H), 7.61 (t,
J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz,
1H), 7.21 (d, J = 8.0 Hz, 2H), 3.04-3.10 (m, 2H), 2.49-2.54 (m,
2H), 2.35 (s, 3H), 1.94 (d, 2JPH = 14.6 Hz, 9H); 13C{1H} NMR
(150 MHz, Methanol-d4) δ 142.3, 140.2, 137.9 (dd, J = 17.4, 1.5
Hz), 132.6, 131.2, 128.4, 127.6 (q, 2JCF = 29.5 Hz), 127.2, 125.8
Trimethyl(pyridin-2-ylmethyl)phosphonium
4-
methylbenzenesulfonate (5a):
Powdered potassium hydroxide (0.88 g, 15.68 mmol) was
added to a vigorously stirred solution of 2-pyridinemethanol
(1.0 ml, 10.36 mmol) in THF (50 ml) at 0 °C. The reaction
mixture was stirred for 15 min, then p-toluenesulfonyl chloride
(2.56 g, 13.43 mmol) was added. The reaction mixture was then
stirred for a further 18 h at room temperature. The reaction
mixture was quenched with NaHCO3 and the THF was removed
under reduced pressure. The product was then extracted with
ethyl acetate (3 × 40 ml), dried with MgSO4 and concentrated
under reduced pressure to give a dark red oil. Purification by
flash column chromatography on silica gel (20% EtOAc in pet.
ether 40–60) afforded the title compound as an orange solid
(2.11 g, 8.01 mmol, 77%). 1H NMR (600 MHz, CDCl3) δ 8.51
(d, J = 4.6 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.70 (td, J = 7.9,
1.8 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H),
7.23 (dd, J = 8.0, 5.2 Hz, 1H), 5.14 (s, 2H), 2.44 (s, 3H);
13C{1H} NMR (151 MHz, CDCl3) δ 153.7, 149.3, 145.1, 137.0,
132.7, 129.9, 128.1, 123.4, 122.0, 71.7, 21.6. Data are in good
agreement with those reported in the literature.9a To a solution
of pyridin-2-ylmethyl 4-methylbenzenesulfonate (1.32 g, 5.01
mmol) in acetonitrile (10 ml) was added a 1.0 M solution of
trimethylphosphine in toluene (5.5 ml, 5.5 mmol, 1.1 eq.)
dropwise. The reaction mixture was stirred at room temperature
for 16 h under an argon atmosphere. The solvent was removed,
and the salt was precipitated with CHCl3 and Et2O
(approximately 1:5 ratio of CHCl3:Et2O). This was followed by
filtration through a pad of MgSO4 and elution of the salts with
CHCl3. Removal of solvent under reduced pressure and drying
in vacuo afforded the crude product as a red oil. This was
dissolved in CH2Cl2 and filtered through an Agilent SampliQ
amino cartridge to remove any acids. The solvent was removed
under reduced pressure. The precipitation step (with CHCl3 and
Et2O) was repeated to afford the title compound as an orange
powder (1.43 g, 4.21 mmol, 84%). Note that the purification
step to remove acid is essential – the borylation reaction does
3
1
(q, JCF = 5.7 Hz), 125.5, 124.7 (q, JCF = 272.9 Hz), 24.8 (d,
1JCP = 50.6 Hz), 23.9 (d, 2JCP = 2.0 Hz), 19.9, 6.2 (d, 1JCP = 54.6
Hz); 31P NMR (243 MHz, MeOD-d4) δ 27.33; HRMS (ESI+):
calculated for [C12H17PF3]+ 249.1014, found 249.1020.
General procedure for iridium-catalysed borylation (GP2).
The reactions were carried out in 4 ml 15 × 45 mm crimp top
vials. The substrate (0.25 mmol), ligand 1 (3 mol%), B2Pin2
(1.5 equiv.) and [Ir(COD)OMe]2 (1.5 mol%) were weighed and
added to the vial, which was then sealed, evacuated and
backfilled with argon. 1,4-dioxane was then added for a final
substrate concentration of 0.2 M. The reaction mixture was
stirred and heated in deep-welled heating blocks (IKA DB 5.2)
for a specified amount of time, at a specified temperature,
followed by removal of solvent and analysis of the crude
1
reaction mixture by H NMR. Purification was generally by
precipitation with Et2O.
Calculation of yield in borylation reactions. In some cases,
small amounts of starting material remained in the reactions,
which were inseperable from the borylated products. The
following procedure was then used to determine the yield of the
borylated products.The ratio of borylated products to starting
material was determined by NMR analysis, using the NMR of
the isolated product. This ratio was used to calculate an average
molecular weight in order to determine the mmols of product
obtained, such that an overall yield could be obtained. The yield
of the borylated products was then obtained by multiplying the
overall yield by the fraction of borylated products present.
Assignment of meta and para products. When possible, the
coupling patterns in the aromatic region were used to assign the
respective isomers. Otherwise, assignments were done using
information from 2D NMR experiments (COSY, HSQC,
HMBC, NOESY). Data for the para product was usually
obtained from the tmphen control experiments by subtracting
1
not work in the presence of trace acid. H NMR (600 MHz,
CDCl3) δ 8.48 (d, J = 4.3 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.66
(td, J = 8.0, 1.2 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.23–7.21 (m,
1H), 7.14 (d, J = 7.9 Hz, 2H), 4.15 (d, J = 15.8 Hz, 2H), 2.33 (s,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 13
the signals for the meta product and starting material from the
spectra.
1JC–P = 54.1 Hz); 19F NMR (376 MHz, CDCl3) δ −57.75; 31P
NMR (162 MHz, CDCl3) δ 29.19.
1
2
3
4
5
6
7
8
9
trimethyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-
(trifluoromethyl)benzyl)phosphonium
methylbenzenesulfonate (4a)
(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
4-
yl)benzyl)trimethylphosphonium
4-methylbenzenesulfonate
(4b)
With sulfonate ligand 1 (0.1 mmol scale):
With sulfonate ligand 1:
Followed
GP2,
used
trimethyl(2-
4-
Followed GP2, used (2-chlorobenzyl)trimethylphosphonium 4-
methylbenzenesulfonate (3b) (93 mg, 0.25 mmol), B2Pin2 (95
mg, 0.375 mmol, 1.5 eq.), [Ir(COD)OMe]2 (2.5 mg,
0.00375 mmol, 0.015 eq.), 1 (3.8 mg, 0.0075 mmol, 0.03 eq.)
and 1,4-dioxane (1.25 ml). The reaction mixture was stirred for
(trifluoromethyl)benzyl)phosphonium
methylbenzenesulfonate (3a) (40.8 mg, 0.1 mmol), B2Pin2 (38
mg, 0.15 mmol, 1.5 eq.), [Ir(COD)OMe]2 (1 mg, 0.0015 mmol,
0.015 eq.), 1 (1.5 mg, 0.003 mmol, 0.03 eq.) and 1,4-dioxane
(0.5 ml). The reaction mixture was stirred for 16 h at 50 °C.
Analysis of the crude 1H NMR with 1,2-dimethoxyethane as the
internal standard showed >20:1 meta:para borylation, in 89%
NMR yield.
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32
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48
49
50
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52
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56
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59
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1
16 h at 50 °C. Analysis of crude H NMR showed >20:1
meta:para borylation. The solvent was removed, and the salts
precipitated with Et2O. This was followed by filtration through
a pad of MgSO4 and elution of the salts with CH2Cl2. Removal
of solvent under reduced pressure and drying in vacuo afforded
the title compounds (83:3:14 meta:para:SM) as a light orange
powder (99 mg, 0.18 mmol borylated products, 70%, >20:1
meta:para).
With sulfonate ligand 1 (0.25 mmol scale):
Followed
GP2,
used
trimethyl(2-
4-
(trifluoromethyl)benzyl)phosphonium
methylbenzenesulfonate (3a) (102 mg, 0.25 mmol), B2Pin2 (95
mg, 0.375 mmol, 1.5 eq.), [Ir(COD)OMe]2 (2.5 mg, 0.00375
mmol, 0.015 eq.), 1 (3.8 mg, 0.0075 mmol, 0.03 eq.) and 1,4-
dioxane (1.25 ml). The reaction mixture was stirred for 16 h at
50 °C. Analysis of the crude 1H NMR with 1,2-
dimethoxyethane as the internal standard showed 6.5:1
meta:para borylation, in 93% NMR yield. The meta product
decomposed upon attempted isolation by precipitation with
Et2O, therefore the crude NMR data was used in order to
characterise the meta product.
4a: 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.6 Hz, 1H), 7.72
(d, J = 8.0 Hz, 2H), 7.72 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.06
(d, J = 7.9 Hz, 2H), 3.90 (d, J = 16.4 Hz, 2H), 2.25 (s, 3H), 2.04
(d, J = 14.4 Hz, 9H), 1.31 (s, 12H); 13C{1H} NMR (101 MHz,
CDCl3) δ 143.6, 139.2, 137.8 (d, 3JC–P = 4.8 Hz), 134.8 (d, 5JC–
P = 3.3 Hz), 130.9 (qd, 2JC–F = 29.8 Hz, 3JC–P = 5.9 Hz), 128.6,
1
4b: H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 8.1 Hz, 2H),
7.72–7.70 (m, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 8.0 Hz,
2H), 3.97 (d, J = 16.0 Hz, 2H), 2.32 (s, 3H), 2.13 (d, J = 14.3
Hz, 9H), 1.34 (s, 12H); 13C{1H} NMR (101 MHz, CDCl3) δ
143.7, 139.3, 137.9 (d, 3JC–P = 4.8 Hz), 137.1 (d, 3JC–P = 6.0 Hz),
136.3 (d, 5JC–P = 3.8 Hz), 129.9 (d, 4JC–P = 3.0 Hz), 128.7, 126.5
(d, 2JC–P = 9.1 Hz), 125.9, 84.5, 28.4 (d, 1JC–P = 49.8 Hz), 24.9,
1
21.3, 8.4 (d, JC–P = 54.0 Hz); 31P NMR (243 MHz, CDCl3) δ
29.17; HRMS m/z (ESI+) [M – OTs]+ calculated for
[C16H26BClO2P]+ 327.1447, found 327.1443;
With tmphen:
Followed GP2, used (2-chlorobenzyl)trimethylphosphonium 4-
methylbenzenesulfonate (3b) (93 mg, 0.25 mmol), B2Pin2 (95
mg, 0.375 mmol, 1.5 eq.), [Ir(COD)OMe]2 (2.5 mg,
0.00375 mmol, 0.015 eq.), tmphen (1.8 mg, 0.0075 mmol, 0.03
eq.) and 1,4-dioxane. The reaction mixture was stirred for 16 h
at 50 °C. Analysis of crude 1H NMR showed 1:3.3:1.5
meta:para:starting material. The solvent was removed, and the
salts precipitated with Et2O. This was followed by filtration
through a pad of MgSO4 and elution of the salts with CH2Cl2.
Removal of solvent under reduced pressure and drying in vacuo
afforded the title compounds (15:50:35 meta:para:SM) as a
brown solid (108 mg, 0.15 mmol borylated products, 62%, 1:3.3
meta:para).
2
1
126.9 (d, JC–P = 8.3 Hz), 126.4 (m), 125.9, 123.8 (q, JC–F
=
273.8 Hz), 84.7, 28.0 (d, 1JC–P = 49.6 Hz), 24.8, 21.2, 8.4 (d, 1JC–
P = 54.1 Hz); 19F NMR (376 MHz, CDCl3) δ −58.43; 31P NMR
(162 MHz, CDCl3) δ 29.13; HRMS m/z (ESI+) [M – OTs]+
calculated for [C17H26BF3O2P]+ 361.1710, found 361.1706;
With tmphen (0.25 mmol scale):
Followed
GP2,
used
trimethyl(2-
4-
(trifluoromethyl)benzyl)phosphonium
methylbenzenesulfonate (3a) (102 mg, 0.25 mmol), B2Pin2 (95
mg, 0.375 mmol, 1.5 eq.), [Ir(COD)OMe]2 (2.5 mg, 0.00375
mmol, 0.015 eq.), tmphen (1.8 mg, 0.0075 mmol, 0.03 eq.) and
1,4-dioxane (1.25 ml). The reaction mixture was stirred for 16
h at 50 °C. Analysis of the crude 1H NMR with 1,2-
dimethoxyethane as the internal standard showed 1:1.6
meta:para borylation, in 90% NMR yield. It was observed that
it was possible to isolate the para product by precipitation by
Et2O, while the meta product decomposed.
para product: 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.88
(d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.55 (dd, J = 7.7,
2.5 Hz, 1H), 7.06 (d, J = 7.9 Hz, 2H), 4.01 (d, J = 17.0 Hz, 2H),
2.25 (s, 3H), 2.02 (d, J = 14.4 Hz, 9H), 1.30 (s, 12H); 13C{1H}
NMR (101 MHz, CDCl3) δ 143.5, 139.3, 138.9 (br s), 133.0
(m), 132.3 (d, 3JC–P = 4.8 Hz), 130.2 (d, 2JC–P = 9.0 Hz), 128.6,
128.2 (dq, 2JC–F = 29.5 Hz, 3JC–P = 5.6 Hz), 125.8, 124.1 (q, 1JC–F
= 273.9 Hz), 84.5, 27.9 (d, 1JC–P = 49.4 Hz), 24.8, 21.2, 8.3 (d,
para product: 1H NMR (600 MHz, CDCl3) δ 7.81 (s, 1H), 7.75
(d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.48–7.47 (m, 1H),
7.12 (d, J = 8.0 Hz, 2H), 4.06 (d, J = 16.7 Hz, 2H), 2.32 (s, 3H),
2.07 (d, J = 14.5 Hz, 9H), 1.34 (s, 12H); 13C{1H} NMR (101
4
MHz, CDCl3) δ 143.7, 139.4, 136.2 (d, JC–P = 3.1 Hz), 133.9
3
3
4
(d, JC–P = 6.3 Hz), 133.7 (d, JC–P = 6.1 Hz), 132.1 (d, JC–P
=
2
4.9 Hz), 130.0 (d, JC–P = 9.3 Hz), 128.7, 125.8, 84.4, 28.2 (d,
1JC–P = 49.4 Hz), 24.9, 21.3, 8.3 (d, 1JC–P = 53.8 Hz); 31P NMR
(243 MHz, CDCl3) δ 29.54.
(2-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzyl)trimethylphosphonium
4-methylbenzenesulfonate
(4c)
With sulfonate ligand 1:
Followed GP2, used (2-bromobenzyl)trimethylphosphonium 4-
methylbenzenesulfonate (3c) (104 mg, 0.25 mmol), B2Pin2 (95
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Page 9 of 13
The Journal of Organic Chemistry
mg, 0.375 mmol, 1.5 eq.), [Ir(COD)OMe]2 (2.5 mg,
0.00375 mmol, 0.015 eq.), 1 (3.8 mg, 0.0075 mmol, 0.03 eq.)
4d: 1H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 8.2 Hz, 2H), 7.64
1
2
3
4
5
6
7
8
(d, J = 7.6 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 7.6
Hz, 1H), 7.13 (d, J = 7.9 Hz, 2H), 3.81 (d, J = 16.0 Hz, 2H),
2.35 (s, 3H), 2.32 (s, 3H), 2.06 (d, J = 14.3 Hz, 9H), 1.33 (s,
12H); 13C{1H}NMR (101 MHz, CDCl3) δ 143.9, 140.8 (d, 3JC–
and 1,4-dioxane (1.25 ml). The reaction mixture was stirred for
1
16 h at 50 °C. Analysis of crude H NMR showed >20:1
meta:para borylation. The solvent was removed, and the salts
precipitated with Et2O. This was followed by filtration through
a pad of MgSO4 and elution of the salts with CH2Cl2. Removal
of solvent under reduced pressure and drying in vacuo afforded
the title compounds (85:5:10 meta:para:SM) as a foamy
orange-brown solid (107 mg, 0.18 mmol borylated products,
73%, 17:1 meta:para).
3
5
= 5.5 Hz), 139.2, 136.8 (d, JC–P = 5.0 Hz), 134.8 (d, JC–P
=
P
4
2
3.7 Hz), 131.1 (d, JC–P = 3.1 Hz), 128.7, 126.6 (d, JC–P = 8.9
Hz), 125.9, 84.0, 27.8 (d, 1JC–P = 49.1 Hz), 24.9, 21.3, 20.5, 8.1
(d, JC–P = 54.0 Hz); 31P NMR (243 MHz, CDCl3) δ 28.79;
1
HRMS m/z (ESI+) [M – OTs]+ calculated for [C17H29BO2P]+
9
307.1993, found 307.1988;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
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44
45
46
47
48
49
50
51
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60
4c: 1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 8.1 Hz, 2H), 7.69
(d, J = 1.6 Hz, 1H), 7.62–7.57 (m, 2H), 7.13 (d, J = 7.9 Hz, 2H),
3.98 (d, J = 15.9 Hz, 2H), 2.31 (s, 3H), 2.12 (d, J = 14.3 Hz,
9H), 1.34 (s, 12H); 13C{1H} NMR (101 MHz, CDCl3) δ 143.7,
139.3, 137.7 (d, 3JC–P = 4.9 Hz), 136.3 (d, 5JC–P = 3.3 Hz), 133.3
With tmphen with 3 mol% [Ir(COD)OMe]2 at 70 °C:
Followed GP2, used trimethyl(2-methylbenzyl)phosphonium
4-methylbenzenesulfonate (3d) (88 mg, 0.25 mmol), B2Pin2
(127 mg, 0.5 mmol, 2 eq.), [Ir(COD)OMe]2 (5.0 mg, 0.0075
mmol, 0.03 eq.), tmphen (3.6 mg, 0.015 mmol, 0.06 eq.) and
1,4-dioxane (1.25 ml). The reaction mixture was stirred for 16
h at 70 °C. Analysis of crude 1H NMR showed 1:1.4 meta:para
borylation.The solvent was removed, and the salts precipitated
with Et2O. This was followed by filtration through a pad of
MgSO4 and elution of the salts with CH2Cl2. Removal of solvent
under reduced pressure and drying in vacuo afforded the title
compounds (30:42:28 meta:para:SM) as a brown solid (104
mg, 0.17 mmol borylated products, 68%, 1:1.3 meta:para).
4
2
(d, JC–P = 3.2 Hz), 128.7, 128.6 (d, JC–P = 9.0 Hz), 128.2 (d,
1
3JC–P = 6.3 Hz), 125.9, 84.5, 30.9 (d, JC–P = 49.4 Hz), 24.9,
1
21.3, 8.5 (d, JC–P = 53.8 Hz); 31P NMR (243 MHz, CDCl3) δ
29.02; HRMS m/z (ESI+) [M – OTs]+ calculated for
[C16H26BBrO2P]+ 371.0941, found 371.0931;
With tmphen:
Followed GP2, used (2-bromobenzyl)trimethylphosphonium 4-
methylbenzenesulfonate (3c) (104 mg, 0.25 mmol), B2Pin2 (95
mg, 0.375 mmol, 1.5 eq.), [Ir(COD)OMe]2 (2.5 mg,
0.00375 mmol, 0.015 eq.), tmphen (1.8 mg, 0.0075 mmol, 0.03
eq.) and 1,4-dioxane (1.25 ml). The reaction mixture was stirred
1
para product: H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 8.1
Hz, 2H), 7.63 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.19–7.17 (m,
1H), 7.13 (d, J = 7.9 Hz, 2H), 3.95 (d, J = 16.7 Hz, 2H), 2.32 (s,
3H), 2.30 (s, 3H), 2.03 (d, J = 14.3 Hz, 9H), 1.34 (s, 12H);
13C{1H} NMR (101 MHz, CDCl3) δ 143.9, 139.3, 137.7 (d, 4JC–P
1
for 16 h at 50 °C. Analysis of crude H NMR showed 1:3.5
meta:para borylation.The solvent was removed, and the salts
precipitated with Et2O. This was followed by filtration through
a pad of MgSO4 and elution of the salts with CH2Cl2. Removal
of solvent under reduced pressure and drying in vacuo afforded
the title compounds (19:67:14 meta:para:SM) as an orange
powder (121 mg, 0.20 mmol borylated products, 79%, 1:3.5
meta:para).
3
4
= 3.3 Hz), 136.4 (d, JC–P = 5.7 Hz), 132.8 (d, JC–P = 3.4 Hz),
130.5 (d, 3JC–P = 4.7 Hz), 130.4 (d, 2JC–P = 9.1 Hz), 128.7, 125.8,
84.0, 27.7 (d, 1JC–P = 49.0 Hz), 24.9, 21.3, 19.9, 8.0 (d, 1JC–P
53.9 Hz); 31P NMR (243 MHz, CDCl3) δ 29.12.
=
(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
para product : 1H NMR (600 MHz, CDCl3) δ 8.01 (s, 1H), 7.77
(d, J = 8.1 Hz, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.52–7.51 (m, 1H),
7.14 (d, J = 8.0 Hz, 2H), 4.13 (d, J = 16.5 Hz, 2H), 2.33 (s, 3H),
2.12 (d, J = 14.2 Hz, 9H), 1.34 (s, 12H); 13C{1H} NMR (101
yl)benzyl)trimethylphosphonium
4-methylbenzenesulfonate
(4e)
With sulfonate ligand 1:
4
Followed GP2, used (3-fluorobenzyl)trimethylphosphonium 4-
methylbenzenesulfonate (3e) (89 mg, 0.25 mmol), B2Pin2 (95
mg, 0.375 mmol, 1.5 eq.), [Ir(COD)OMe]2 (2.5 mg,
0.00375 mmol, 0.015 eq.), 1 (3.8 mg, 0.0075 mmol, 0.03 eq.)
and 1,4-dioxane (1.25 ml). The reaction mixture was stirred for
MHz, CDCl3) δ 143.7, 139.5 (d, JC–P = 3.1 Hz), 139.3, 134.5
4
3
2
(d, JC–P = 3.4 Hz), 132.0 (d, JC–P = 4.8 Hz), 131.9 (d, JC–P
=
3
9.3 Hz), 128.7, 125.8, 124.4 (d, JC–P = 6.4 Hz), 84.5, 30.7 (d,
1JC–P = 49.7 Hz), 24.9, 21.3, 8.4 (d, 1JC–P = 53.7 Hz); 31P NMR
(243 MHz, CDCl3) δ 29.64.
1
16 h at 50 °C. Analysis of crude H NMR showed >20:1
meta:para borylation. The solvent was removed, and the salts
precipitated with Et2O. This was followed by filtration through
a pad of MgSO4 and elution of the salts with CHCl3. Removal
of solvent under reduced pressure and drying in vacuo afforded
the meta product and starting material (84:16 meta:SM, para
isomer was not detected) as a light orange solid (93 mg, 0.17
mmol borylated products, 68%, >20:1 meta:para).
Trimethyl(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzyl)phosphonium
4-
methylbenzenesulfonate (4d)
With sulfonate ligand 1 with 3 mol% [Ir(COD)OMe]2 at 70 °C:
Followed GP2, used trimethyl(2-methylbenzyl)phosphonium
4-methylbenzenesulfonate (3d) (88 mg, 0.25 mmol), B2Pin2
(127 mg, 0.5 mmol, 2 eq.), [Ir(COD)OMe]2 (5.0 mg, 0.0075
mmol, 0.03 eq.), 1 (7.6 mg, 0.015 mmol, 0.06 eq.) and 1,4-
dioxane (1.25 ml). The reaction mixture was stirred for 16 h at
1
4e: H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 8.1 Hz, 2H),
7.44–7.42 (m, 1H), 7.35 (s, 1H), 7.22–7.20 (m, 1H), 7.17 (d, J
= 8.1 Hz, 2H), 3.94 (d, J = 16.3 Hz, 2H), 2.33 (s, 3H), 2.03 (d,
J = 14.3 Hz, 9H), 1.34 (s, 12H); 13C{1H} NMR (101 MHz,
1
70 °C. Analysis of crude H NMR showed 18:1 meta:para
1
4
borylation. The solvent was removed, and the salts precipitated
with Et2O. This was followed by filtration through a pad of
MgSO4 and elution of the salts with CH2Cl2. Removal of solvent
under reduced pressure and drying in vacuo afforded the title
compounds (90:5:5 meta:para:SM) as an orange solid (111 mg,
0.22 mmol borylated products, 89%, 18:1 meta:para).
CDCl3) δ 162.7 (dd, JC–F = 249.7 Hz, JC–P = 3.7 Hz), 143.7,
139.5, 131.3 (dd, 4JC–F = 3.0 Hz, 3JC–P = 5.3 Hz), 130.6 (dd, 3JC–F
= 7.6 Hz, 2JC–P = 9.1 Hz), 128.8, 125.8, 121.2 (dd, 2JC–F = 18.5
Hz, 5JC–P = 3.1 Hz), 120.2 (dd, 2JC–F = 23.0 Hz, 3JC–P = 5.4 Hz),
1
1
84.4, 30.0 (d, JC–P = 48.5 Hz), 24.9, 21.3, 7.8 (d, JC–P = 54.5
Hz); 19F NMR (376 MHz, CDCl3) δ −112.56; 31P NMR (243
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MHz, CDCl3) δ 27.53; HRMS m/z (ESI+) [M – OTs]+
with Et2O. This was followed by filtration through a pad of
calculated for [C16H26BFO2P]+ 311.1742, found 311.1736;
With tmphen:
MgSO4 and elution of the salts with CHCl3. Removal of solvent
under reduced pressure and drying in vacuo afforded a dark
brown solid. NMR analysis revealed that this was a complex
mixture of products (presumably a mixture of starting material
and meta, dimeta and para products).
1
2
3
4
5
6
7
8
Followed GP2, used (3-fluorobenzyl)trimethylphosphonium 4-
methylbenzenesulfonate (3e) (89 mg, 0.25 mmol), B2Pin2 (95
mg, 0.375 mmol, 1.5 eq.), [Ir(COD)OMe]2 (2.5 mg,
0.00375 mmol, 0.015 eq.), tmphen (1.8 mg, 0.0075 mmol, 0.03
eq.) and 1,4-dioxane (1.25 ml). The reaction mixture was stirred
for 16 h at 50 °C. Analysis of crude 1H NMR showed 1:1.3:2.6
meta:para:starting material. The solvent was removed, and the
salts precipitated with Et2O. This was followed by filtration
through a pad of MgSO4 and elution of the salts with CHCl3.
Removal of solvent under reduced pressure and drying in vacuo
afforded the title compounds (20:26:54 meta:para:SM) as a
brown solid (84 mg, 0.09 mmol borylated products, 37%, 1:1.3
meta:para).
Trimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)pyridin-2-yl)methyl)phosphonium 4-methylbenzenesulfonate
(6a) :
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With sulfonate ligand 1:
Followed
GP2,
used
trimethyl(pyridin-2-
ylmethyl)phosphonium 4-methylbenzenesulfonate (5a) (85 mg,
0.25 mmol), B2Pin2 (95 mg, 0.375 mmol, 1.5 eq.),
[Ir(COD)OMe]2 (2.5 mg, 0.00375 mmol, 0.015 eq.), 1 (3.8 mg,
0.0075 mmol, 0.03 eq.) and 1,4-dioxane (1.25 ml). The reaction
1
para product: H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 8.0
1
mixture was stirred for 1 h at 50 °C. Analysis of the crude H
Hz, 2H), 7.64 (t, J = 6.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.03
(d, J = 7.0 Hz, 1H), 6.93 (d, J = 9.1 Hz, 1H), 4.02 (d, J = 16.9
Hz, 2H), 2.33 (s, 3H), 1.97 (d, J = 14.4 Hz, 9H), 1.35 (s, 12H);
13C{1H} NMR (101 MHz, CDCl3) δ 167.2 (dd, 1JC–F = 253.0 Hz,
NMR with 1,2-dimethoxyethane as the internal standard
showed 10:1 C4:C5 borylation, in 53% NMR yield (NMR yield
used in this case due to possible contamination by the dimeta
product). For isolation of the product, the solvent was removed.
The resultant brown oil was washed with Et2O (add Et2O,
decant off the Et2O, repeat 10–15 times to remove most of the
residual B2Pin2). Drying in vacuo afforded the title compounds
as an orange powder initially, which became a brown oil upon
standing.
4JC–P = 4.0 Hz), 143.7, 139.6, 137.7 (dd, 3JC–F = 8.6 Hz, 4JC–P
=
3.7 Hz), 134.7 (dd, 3JC–F = 9.2 Hz, 2JC–P = 9.2 Hz), 128.9, 125.8,
125.6 (dd, 4JC–F = 4.4 Hz, 3JC–P = 4.4 Hz), 116.9 (dd, 2JC–F = 23.6
Hz, 3JC–P = 5.5 Hz), 84.1, 29.6 (d, 1JC–P = 49.2 Hz), 24.8, 21.3,
7.5 (d, 1JC–P = 54.4 Hz); 19F NMR (376 MHz, CDCl3) δ −101.74
(d, 5JF–P = 2.9 Hz); 31P NMR (243 MHz, CDCl3) δ 27.84.
1
6a: H NMR (400 MHz, CDCl3) δ 8.49 (dd, J = 4.8, 1.0 Hz,
1H), 7.77 (d, J = 8.1 Hz, 2H), 7.65 (s, 1H), 7.56–7.55 (m, 1H),
7.12 (d, J = 7.9 Hz, 2H), 4.01 (d, J = 15.4 Hz, 2H), 2.31 (s, 3H),
2.14 (d, J = 14.6 Hz, 9H), 1.34 (s, 12H); 13C{1H} NMR (101
MHz, CDCl3) δ 150.3 (d, 2JC–P = 8.9 Hz), 148.8 (d, 4JC–P = 1.1
(3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzyl)trimethylphosphonium 4-methylbenzenesulfonate (4f)
With sulfonate ligand L1:
Hz), 143.7, 139.2, 129.9 (d, 3JC–P = 7.6 Hz), 128.7, 127.9 (d, 5JC–
Followed GP2, used benzyltrimethylphosphonium 4-
methylbenzenesulfonate (3f) (85 mg, 0.25 mmol), B2Pin2 (190
mg, 0.75 mmol, 3.0 eq.), [Ir(COD)OMe]2 (2.5 mg, 0.00375
mmol, 0.015 eq.), 1 (3.8 mg, 0.0075 mmol, 0.03 eq.) and 1,4-
dioxane (1.25 ml). The reaction mixture was stirred for 16 h at
1
= 1.7 Hz), 125.9, 84.8, 32.4 (d, JC–P = 54.2 Hz), 24.9, 21.3,
P
9.2 (d, 1JC–P = 55.1 Hz); 31P NMR (162 MHz, CDCl3) δ 27.36;
HRMS m/z (ESI+) [M – OTs]+ calculated for [C15H26BNO2P]+
294.1789, found 294.1777;
1
Note: The peaks partially overlap with the SM in the 1H NMR
spectrum
50 °C. Analysis of crude H NMR showed >20:1 dimeta:para
borylation.The solvent was removed, and the salts precipitated
with Et2O. This was followed by filtration through a pad of
MgSO4 and elution of the salts with CHCl3. Removal of solvent
under reduced pressure and drying in vacuo afforded the title
compound (contaminated with <10% mono meta product) as a
light orange solid (111 mg, 0.17 mmol diborylated product,
69%, >20:1 dimeta+monometa:para)
With tmphen:
Followed
GP2,
used
trimethyl(pyridin-2-
ylmethyl)phosphonium 4-methylbenzenesulfonate (5a) (85 mg,
0.25 mmol), B2Pin2 (95 mg, 0.375 mmol, 1.5 eq.),
[Ir(COD)OMe]2 (2.5 mg, 0.00375 mmol, 0.015 eq.), tmphen
(1.8 mg, 0.0075 mmol, 0.03 eq.) and 1,4-dioxane (1.25 ml). The
reaction mixture was stirred for 1 h at 50 °C. Analysis of the
crude 1H NMR with 1,2-dimethoxyethane as the internal
standard showed 1:1.3 C4:C5 borylation, in 60% NMR yield.
For isolation of the product, the solvent was removed. The
resultant brown oil was washed with Et2O. Drying in vacuo
afforded the title compounds as an orange powder initially. This
powder became a brown oil upon standing.
4f: 1H NMR (600 MHz, CDCl3) δ 8.22 (s, 1H), 7.81 (d, J = 8.1
Hz, 2H), 7.69 (d, J = 1.9 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 3.73
(d, J = 15.7 Hz, 2H), 2.31 (s, 3H), 2.04 (d, J = 14.3 Hz, 9H),
1.33 (s, 24H); 13C{1H} NMR (151 MHz, CDCl3) δ 143.7, 141.2
(d, 5JC–P = 3.5 Hz), 139.2, 138.6 (d, 3JC–P = 5.2 Hz), 128.7, 127.2
(d, 2JC–P = 8.9 Hz), 125.9, 84.1, 30.8 (d, 1JC–P = 49.2 Hz), 24.9,
1
21.3, 7.8 (d, JC–P = 54.6 Hz); 31P NMR (243 MHz, CDCl3)
26.98; HRMS m/z (ESI+) [M – OTs]+ calculated for
C5 product: 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 7.96
(d, J = 7.7 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 7.7
Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 4.07 (d, J = 16.0 Hz, 2H),
2.29 (s, 3H), 2.05 (d, J = 14.6 Hz, 9H), 1.33 (s, 12H); 13C{1H}
NMR (101 MHz, CDCl3) δ 155.1 (d, 4JC–P = 1.7 Hz), 153.5 (d,
2JC–P = 9.2 Hz), 143.7, 143.6, 139.4, 128.7, 125.8, 124.7 (d, 3JC–P
[C22H38B2O4P]+ 419.2688, found 419.2685;
With tmphen:
Followed GP2, used benzyltrimethylphosphonium 4-
methylbenzenesulfonate (3f) (85 mg, 0.25 mmol), B2Pin2 (190
mg, 0.75 mmol, 3.0 eq.), [Ir(COD)OMe]2 (2.5 mg, 0.00375
mmol, 0.015 eq.), tmphen (1.8 mg, 0.0075 mmol, 0.03 eq.) and
1,4-dioxane (1.25 ml). The reaction mixture was stirred for 16
h at 50 °C. The solvent was removed, and the salts precipitated
4
= 7.1 Hz), 84.4, 32.4 (d, JC–P = 52.8 Hz), 24.9, 21.3, 8.8 (d,
4JC–P = 54.9 Hz); 31P NMR (162 MHz, CDCl3) δ 27.58.
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The Journal of Organic Chemistry
Trimethyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-
δ 22.47; HRMS (ESI+): calculated for [M-OTs]+ [C9H14P]+
153.0828, found 153.0827.
1
trifluoromethyl)phenethyl)
phosphonium
4-
2
3
4
5
6
7
8
9
methylbenzenesulfonate (8a)
3,5-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
With sulfonate ligand 1 (0.25 mmol scale):
yl)phenyl)trimethylphosphonium
4-methylbenzenesulfonate
Following general procedure GP2 using 7a (105.1 mg, 0.25
mmol), B2Pin2 (127.0 mg, 0.50 mmol), [Ir(COD)OMe]2 (2.5
mg, 0.00375 mmol) and 1 (3.8 mg, 0.0075 mmol) in dioxane
(1.25 mL). Stirred in vial at 70 °C for 20 hours. Analysis of
(8b)
Following general procedure GP2 using 7b (81 mg, 0.25
mmol), B2Pin2 (190 mg, 0.75 mmol), Ir(COD)OMe]2 (2.5 mg,
0.00375 mmol) and 1 (3.8 mg, 0.0075 mmol) in dioxane (1.25
mL). Stirred in vial at 50 °C for 20 hours. Analysis of crude 1H
NMR showed >20:1 dimeta:other borylation products.
Purification by evaporation of solvent and addition of ether,
followed by filtration and drying in vacuo gave the title
compound as a light brown solid (115 mg, 0.20 mmol, 80%).
1
crude H NMR showed a 26:1:2 ratio of meta:para:starting
material (26:1 meta:para borylation). Purification by
evaporation of solvent and addition of ether, followed by
filtration and drying in vacuo gave the title compound as a light
brown solid (109.2 mg, 0.200 mmol, 80%), as a mixture of
42:1:2.3 ratio of meta:para:starting material.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.06 (d, J = 12.9
Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 2.41
(d, J = 14.4 Hz, 9H), 2.30 (s, 3H), 1.34 (s, 24H); 13C{1H} NMR
(101 MHz, CDCl3) δ 146.6 (d, 4JC-P = 2.8 Hz), 143.8, 138.9,
138.3 (d, 2JC-P = 9.8 Hz), 128.5, 125.9, 121.4 (d, 1JC-P = 83.3
Hz), 84.7, 24.9, 21.3, 9.8 (d, 1JC-P = 56.1 Hz); 31P (162 MHz,
CDCl3) δ 22.34; HRMS (ESI+): calculated for [M-OTs]+
[C21H36B2O4P]+ 405.2532, found 405.2542.
8a: 1H NMR (600 MHz, Methanol-d4) δ 7.91 (s, 1H), 7.81 (d, J
= 7.9 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H),
7.19 (d, J = 8.1 Hz, 2H), 3.06-3.08 (m, 2H), 2.48-2.51 (m, 2H),
2
2.34 (s, 3H), 1.95 (d, JPH = 14.6 Hz, 9H), 1.36 (s, 12H);
13C{1H} NMR (150 MHz, Methanol-d4) δ 142.4, 140.1, 137.10,
137.12 (d, J = 17.0 Hz), 133.2, 130.0 (q, 2JCF = 29.9 Hz), 128.4,
125.5, 125.2 (q, 3JCF = 5.6 Hz), 124.5 (q, 1JCF = 273 Hz), 84.3,
24.8 (d, 1JCP = 50.8 Hz), 23.8, 23.7, 19.9, 6.2 (d, 1JCP = 54.7 Hz);
31P NMR (243 MHz, Methanol-d4) δ 27.31; HRMS (ESI+):
calculated for [M-OTs]+ [C18H28BF3O2P]+ 375.1872, found
375.1879.
4-chloro-3-methylphenol (9)
Followed GP2, used (2-chlorobenzyl)trimethylphosphonium 4-
methylbenzenesulfonate (3b) (372.8 mg, 1.0 mmol), B2Pin2
(381 mg, 1.5 mmol), [Ir(COD)OMe]2 (10 mg, 0.015 mmol), 1
(15.2 mg, 0.03 mmol) and 1,4-dioxane (5 ml). The reaction
mixture was stirred for 16 h at 50 °C. Analysis of crude 1H NMR
showed >20:1 meta:para borylation. The solvent was removed
then the residue was dissolved in THF (8.25 ml) and methanol
(8.25 ml). NaHCO3 (1.05 g, 12.5 equiv.) was added and the
mixture was cooled to 0 °C before dropwise addition of H2O2
(3 ml, 30% in water, ~26 mmol). The resulting reaction mixture
was stirred at room temperature for 1 hour, then filtcered
through Celite and the filtrate was concentrated under reduced
pressure and dried under high vacuum. The residue was
dissolved in dry THF (5 ml) under an argon atmosphere and
cooled to 0 °C. A solution of lithium aluminium hydride (2 ml,
1M in THF, 2 mmol) was added dropwise, then heated to 60 °C
for 1 hour. The reaction was cooled to 0 °C and quenched by
addition of water, then acidified using 1M HCl and extracted
with CH2Cl2. The organic layer was dried over MgSO4 and
purified by column chromatography on silica gel (5% EtOAc in
pet ether 40-60) to afford 9 as a white solid (65 mg, 0.46 mmol,
46% over 3 steps).
With tmphen ligand (0.25 mmol scale)
Following general procedure GP2 using 7a (105.1 mg, 0.25
mmol), B2Pin2 (127.0 mg, 0.50 mmol), [Ir(COD)OMe]2 (2.5
mg, 0.00375 mmol) and tmphen (2.0 mg, 0.0075 mmol) in
dioxane (1.25 mL). Stirred in vial at 70 °C for 20 hours.
Analysis of crude 1H NMR showed a 1:2:1 ratio of
meta:para:starting material. A small sample was triturated with
diethyl ether in order to characterise the para isomer. This
contained 4:1:3 para:meta:starting material.
Para 1H NMR (600 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.92 (d,
J = 7.9 Hz, 1H), 7.67-7.70 (m, 3H), 7.18 (d, J = 8.0 Hz, 2H),
3.04-3.10 (m, 2H), 2.44-2.54 (m, 2H), 2.33 (s, 3H), 1.93 (d, J =
15.0 Hz, 9H), 1.36 (s, 12H); 13C{1H}NMR (150 MHz,
Methanol-d4) δ 142.4, 141.0 (d, J = 17.2 Hz), 140.2, 138.5,
3
131.6 (q, JCF = 5.5 Hz), 130.7, 128.4, 127.2 (q, J = 29.5 Hz),
124.5 (q, 1JCF = 273 Hz) 125.5, 84.3, 24.4 (d, 1JCP = 50.4 Hz),
23.8, 23.7, 19.9, 6.2 (d, 1JCP = 54.6 Hz).
Trimethyl(phenyl)phosphonium 4-methylbenzenesulfonate (7b)
Dimethylphenylphosphine (0.71 ml, 5 mmol) was dissolved in
methanol (10 ml), then methyl p-toluenesulfonate (1.37 ml, 6
mmol) was added and the resulting reaction mixture was stirred
at room temperature for 16 hours. The crude was concentrated
(to about 1 ml), then diethyl ether (20 ml) was added and the
resulting precipitate was collected by filtration and washed with
more diethyl ether to afford the title product as a white solid
(1.58 g, 4.87 mmol, 97%).
1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.5 Hz, 1H), 6.71
(d, J = 2.8 Hz, 1H), 6.61 (dd, J = 8.6, 3.0 Hz, 1H), 5.14 (br, 1H),
2.31 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 153.9, 137.4,
129.8, 126.0, 117.8, 114.1, 20.1; HRMS (ESI+): calculated for
[M-H]- [C7H6ClO]- 141.0113, found 141.0110.
1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 13.1, 7.3 Hz, 2H),
7.68 (d, J = 8.0 Hz, 2H), 7.58 (dd, J = 7.3, 1.2 Hz, 1H), 7.45
(dd, J = 7.9, 3.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 2.36 (d, J =
14.6 Hz, 9H), 2.30 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
144.0, 139.1, 133.9 (d, 4JC-P = 3.0 Hz), 131.0 (d, 2JC-P = 10.4
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website. Contains 1H NMR and 13C NMR spectra for
all compounds.
Hz), 129.8 (d, 3JC-P = 12.5 Hz), 128.6, 125.9, 122.3 (d, 1JC-P
85.5 Hz), 21.3, 9.6 (d, 1JC-P = 55.8 Hz); 31P (162 MHz, CDCl3)
=
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Hartwig, J. F., Regioselectivity of the borylation of alkanes and arenes.
AUTHOR INFORMATION
Chem. Soc. Rev. 2011, 40, 1992-2002; (g) Ros, A.; Fernandez, R.;
Lassaletta, J. M., Functional group directed C-H borylation. Chem. Soc.
Rev. 2014, 43, 3229-3243.
1
2
Corresponding Author
* rjp71@cam.ac.uk
3
4
5
6
7
8
9
6. (a) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.;
Singleton, D. A.; Maleczka, R. E.; Smith, M. R., Outer-Sphere
Direction in Iridium C–H Borylation. J. Am. Chem. Soc. 2012, 134,
11350-11353; (b) Preshlock, S. M.; Plattner, D. L.; Maligres, P. E.;
Krska, S. W.; Maleczka, R. E.; Smith, M. R., A Traceless Directing
Group for C-H Borylation. Angew. Chem. Int. Ed. 2013, 52, 12915-
12919; (c) Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M., A meta-
selective C–H borylation directed by a secondary interaction between
ligand and substrate. Nat. Chem. 2015, 7, 712-717; (d) Chattopadhyay,
B.; Dannatt, J. E.; Andujar-De Sanctis, I. L.; Gore, K. A.; Maleczka, R.
E.; Singleton, D. A.; Smith, M. R., Ir-Catalyzed ortho-Borylation of
Phenols Directed by Substrate–Ligand Electrostatic Interactions: A
Combined Experimental/in Silico Strategy for Optimizing Weak
Interactions. J. Am. Chem. Soc. 2017, 139, 7864-7871; (e) Hoque, M.
E.; Bisht, R.; Haldar, C.; Chattopadhyay, B., Noncovalent Interactions
in Ir-Catalyzed C–H Activation: L-Shaped Ligand for Para-Selective
Borylation of Aromatic Esters. J. Am. Chem. Soc. 2017, 139, 7745-
7748; (f) Davis, H. J.; Genov, G. R.; Phipps, R. J., meta-Selective C−H
ACKNOWLEDGMENT
We are grateful to AstraZeneca for a PhD studentship through the
AZ-Cambridge PhD program (M.T.M.), the Royal Society for a
University Research Fellowship (R.J.P.), the EPSRC
(EP/N005422/1) and the ERC (StG 757381). We are very grateful
to Dr. Holly J. Davis for performing initial experiments. We thank
the EPSRC UK National Mass Spectrometry Facility at Swansea
University as well as Professors Steven V. Ley and Matthew J.
Gaunt for support and useful discussions.
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