Palladium-Catalysed Cross-Coupling of Benzylammonium Salts with Boronic Acids under Mild Conditions

Article abstract of DOI:10.1055/s-0036-1588548

Herein, we give a full account of the development of the palladium-catalysed cross-coupling of benzylammonium salts with boronic acids. A range of benzylamine-derived quaternary ammonium salts can be coupled with boronic acids under relatively mild conditions. Our optimization has identified ligands that can be used to chemoselectively cross-couple at the ammonium in the presence of chlorides. We demonstrate that intramolecular palladium-catalysed C-H activation is also a viable pathway for the putative benzyl-Pd(II) intermediate obtained upon oxidative addition and have optimised this to obtain fluorene in good yield.

Full text of DOI:10.1055/s-0036-1588548

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–J
paper
A
en
P. L. Türtscher et al.
Paper
Synthesis
Palladium-Catalysed Cross-Coupling of Benzylammonium Salts
with Boronic Acids under Mild Conditions
Paul L. Türtscher
R2
X
Me3N
Holly J. Davis
Pd-Catalysed
Cross Coupling
Robert J. Phipps*
(HO)2B
R1
R2
R1
+
Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, UK
rjp71@cam.ac.uk
Diarylmethanes
Published as part of the Bürgenstock Special Section
2017 Future Stars in Organic Chemistry
If R1 = 2-Ph
X
Me3N
H
Pd-Catalysed
C–H Activation
Fluorene
Received: 15.06.2017
Accepted after revision: 20.07.2017
Published online: 23.08.2017
gant nickel-catalysed cross-couplings of benzylamine-
derived ammonium salts have been reported with aryl
boronic acids to give diarylmethanes,5g,6 with B2Pin2 to give
benzylic boronates,5i,7 and with CO2 to give carboxylic
acids8 (Scheme 1, a). Notably, Watson and co-workers were
able to carry out these couplings stereospecifically from
chiral ammonium salts, which proceeded with inversion of
configuration.6,7b Until our recent work, to our knowledge,
DOI: 10.1055/s-0036-1588548; Art ID: ss-2017-z0402-op
Abstract Herein, we give a full account of the development of the
palladium-catalysed cross-coupling of benzylammonium salts with bo-
ronic acids. A range of benzylamine-derived quaternary ammonium
salts can be coupled with boronic acids under relatively mild conditions.
Our optimization has identified ligands that can be used to chemoselec-
tively cross-couple at the ammonium in the presence of chlorides. We
demonstrate that intramolecular palladium-catalysed C–H activation is
also a viable pathway for the putative benzyl-Pd(II) intermediate ob-
tained upon oxidative addition and have optimised this to obtain fluo-
rene in good yield.
only
a single example of palladium-catalysed cross-
coupling of benzylamine-derived ammonium salts had
been reported; that is in a Heck type reaction with alkenes
(Scheme 1, b).9 We recently reported the ion-pair directed
C–H borylation of benzylamine-derived quaternary ammo-
nium salts, which delivered high levels of meta selectivity
by using a novel anionic bipyridine ligand.10 To probe the
elaboration of the ammonium salt products of our boryla-
tion reaction, we wished to cross-couple benzylamine-
derived ammonium salts with multiple functional handles,
including chlorides. Watson and co-workers noted that
with their Ni-catalysed method, cross coupling occurred at
both the ammonium group and chloride functionality.6 Ac-
cordingly, we sought an alternative method and showed an
example of palladium-catalysed coupling of the benzyl am-
monium functionality with boronic acids, which allowed us
to cross-couple in the presence of the chloride (Scheme 1,
c). In the present paper we give a full account of our studies
on this reaction (Scheme 1, d).11 We also disclose the palla-
dium-catalysed C–H activation of an ortho-phenyl substi-
tuted ammonium salt to form fluorene, which we discov-
ered during the course of these studies (Scheme 1, e).
Key words cross-coupling, ammonium salts, palladium catalysis, di-
arylmethanes, fluorenes
Quaternary ammonium functionality occurs commonly
in a wide range of compounds that are used for many appli-
cations.1 It is most frequently employed to promote aque-
ous solubility or to interact with an anionic partner through
ion pairing. It is less often utilised as a reactive functional
group, but is nevertheless known to engage in a number of
useful reaction types, most prominently in Hofmann elimi-
nation2 and sigmatropic rearrangements such as the
Stevens3 and Sommelet–Hauser4 rearrangements. Quater-
nary ammonium salts have also been investigated to a less-
er extent in the context of transition-metal-catalysed cross-
coupling, where they would represent a useful functional
handle for oxidative addition due to their ease of access
through simple methylation of amines. Whilst the cross-
coupling of aniline-derived ammonium salts has been quite
well explored,5 until recently there have been far fewer
methods applicable to benzylaniline-derived ammonium
salts. The diarylmethanes that would result from such cou-
plings are a commonly encountered motif in pharmaceuti-
cals and natural products. Very recently a number of ele-
We chose benzyltrimethylammonium tosylate (1a) as
our initial optimisation substrate and evaluated a number
of ligands using KF as base at 60 °C. Of the ligands surveyed,
we found that L4 (Xantphos), L6 and XPhos gave the highest
yields of product (Table 1, entries 1–12). We subsequently
tested L4 and XPhos at lower temperatures and found that
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

B
P. L. Türtscher et al.
Paper
Synthesis
Table 1 Optimisation of the Cross-Coupling Reaction on Substrate 1a
Previous Work on Cross Coupling of Quaternised Benzylamines:
(a) Using nickel catalysis:
MeO
OTs
OTs
Ar
2.5 mol% Pd(OAc)2
5 mol% Ligand
Me3N
Me3N
PinB
ArB(OH)2
B2Pin2
(HO)2B
x equiv base
Ni Catalysis
Ni Catalysis
+
THF, T (°C)
OMe
Watson, 2016
Shi, 2016
Itami, 2015
Watson, 2013
Watson, 2014
1a
2a
(b) Single example using palladium catalysis:
PPh2
PPh2
n = 1, L1 (dppe)
n = 2, L2 (dppp)
n = 3, L3 (dppb)
Ph2P
PR2
PPh2
R
O
n
Br
Me3N
R
L6
PR2
O
Pd Catalysis
PPh2
R = Ph, L4 (XantPhos)
R = tBu, L5
Fe
Zhang, 1995
Ph2P
Our previous work:
L7
(c) Example of palladium-catalysed coupling with boronic acids (ref 10):
Entry
Ligand
Base
Temp (°C)
Yield 2a (%)a
MeO
OTs
1
2
L1
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
60
60
60
60
60
60
60
60
60
60
60
60
50
40
50
40
50
50
50
50
50
50
0
Me3N
5 mol% Pd(OAc)2
10 mol% XantPhos
L2
10
63
92
0
Cl
Cl
+
3
L3
3 equiv KF
MeO
4
L4
THF, 80 °C
5
L5
B(OH)2
73%
6
L6
93
33
88
85
29
0
This work:
7
L7
(d) Full description of optimisation and scope of cross-coupling reaction
8
XPhos
SPhos
PPh3
X
Ar
Me3N
R
9
10
11
12
13
14
15
16
17
18
19
20
21
22
ArB(OH)2
R
P(oTol)3
(S)-BINAP
L4
Pd Catalysis
18
87
47
98 (82)
93
94 (82)
0
(e) Example of C–H activation of ortho-aryl benzyl ammonium salt to form a fluorene:
X
Me3N
H
Pd-catalysed
C–H Activation
L4
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
K3PO4
Scheme 1
K2CO3
Na2CO3
Cs2CO3
CsOAc
CsF
27
97
33
93
XPhos appeared to be the more reactive, still giving good
yields at only 40 °C (entries 13–16). A base screen using
XPhos at 50 °C revealed that K3PO4 is also a highly effective
base (entry 17). Among carbonate bases, only Cs2CO3 was
viable (entries 18–20) and CsF proved to be similar to KF
(entry 22).
a Determined by 1H NMR analysis with reference to an internal standard.
Isolated yield given in parentheses for selected experiments.
At this point, we also conducted an investigation into
the effect of ligands on the cross coupling of 2-chloro am-
monium salt 1b as we wished to establish a protocol in
which chloro-containing substrates could be selectively
cross coupled at the ammonium moiety (Table 2). The abili-
ty to accomplish this would offer some complementarity to
the Ni-catalysed coupling methods in which chloride-
containing substrates are incompatible.6 Our survey re-
vealed that XPhos gives very low yields of the desired prod-
uct (entry 8), with the majority of coupling occurring at the
chloride. However, L4 (Xantphos), which had been the sec-
ond most active ligand in optimisation on 1a, gave no cou-
pling at the chloride and an excellent yield of desired prod-
uct 2b (entry 4). In this case, heating to 60 °C was found to
be necessary (entry 11). This emphasises how important
appropriate ligand choice is to accomplish chemoselectivity
in more complex substrates.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

C
P. L. Türtscher et al.
Paper
Synthesis
Table 2 Optimisation of the Cross-Coupling Reaction on Chloride-
Containing Substrate 1b
trimethylammonium, as
a
piperidine variant reacts
smoothly. In cases such as 2i, where the yield was low, the
mass balance typically comprised unreacted starting mate-
rial.
MeO
OTs
Me3N
2.5 mol% Pd(OAc)2
5 mol% ligand
3 equiv KF
MeO
Cl (HO)2B
Cl
+
2.5 mol% Pd(OAc)2
5 mol% XPhos
3 equiv K3PO4 or KF
NMe3
X
THF, Temp (°C)
OMe
(HO)2B
1b
2b
+
R
THF, 50 °C
R
OMe
2
Yield 2b (%)a
1
Entry
Ligand
Temp (°C)
1
2
L1
60
60
60
60
60
60
60
60
60
60
50
23
28
87
93 (90)
0
NMe3
OTs
NMe3
Br
NMe3
Br
NMe3
L2
F3C
Me
Ph
F
CF3
OTs
3
L3
4
L4
2c, 85%
2d, 78%
2e, 75%
2f, 83%
5
L5
6
L6
86
55
4
NMe3
OTs
NMe3
OTs
NMe3
OTs
NMe3
7
L7
MeO
OTs
S
8
XPhos
SPhos
(S)-BINAP
L4
F
9
19
5
10
11
2g, 72%
2h, 54%*
2i, 40%
2j, 77%
NMe3
Br
28
Br-
NMe3
a Determined by 1H NMR analysis with reference to an internal standard.
Isolated yield given in parentheses for selected experiments.
N
OTs
Ph
2a, 66%
With optimised conditions in hand on the ammonium
tosylate salt 1a, we sought to examine the tolerance of the
counterion of the ammonium salt and were pleased to find
the reaction was general, with common counteranions such
as halides and tetrafluoroborate all being compatible
(Scheme 2).
CO2Me
2k, 89%
2l, 80%
Scheme 3 Scope of the coupling reaction with respect to the ammoni-
um salt
We next demonstrated that a representative selection of
boronic acids are compatible in the cross-coupling with
benzyltrimethylammonium bromide (Scheme 4). We found
that a 4-pyridylboronic acid gave no conversion under these
conditions but have not carried out extensive optimisation
on this substrate at this stage.
MeO
X
Me3N
2.5 mol% Pd(OAc)2
5 mol% XPhos
3 equiv K3PO4
(HO)2B
+
THF, 50 °C
OMe
1
2a
X = OTs, 82%*
X = BF4, 85%*
X = Cl, 80%
X = Br, 82%
NMe3
Br
R
2.5 mol% Pd(OAc)2
5 mol% XPhos
3 equiv K3PO4 or KF
*KF used in place of K3PO4 in this case
(HO)2B
R
+
Scheme 2 Evaluation of counteranion of ammonium salt
THF, 50 °C
2
1
We next examined the scope of the coupling with re-
spect to the benzylammonium salt component and investi-
gated a range of substituted aromatic and heteroaromatic
salts (Scheme 3, starting materials shown in table for clari-
ty). For a selection of examples, we found that ortho, meta
and para substitution is tolerated. Furthermore, a heterocy-
clic thiophene ammonium salt could be coupled in good
yield. For the ortho-substituted compounds we often found
that the bromide salts gave better yields than the corre-
sponding tosylates, suggesting potentially higher reactivity.
We also show that the ammonium salt does not have to be a
OMe Me
CO2Et
2a
2m
2n
2o
K3PO4: 46%a
K3PO4: 65%
KF: 82%
K3PO4: 74%
Scheme 4 Selection of boronic acids tested in cross coupling. a Com-
prises an inseparable mixture of 3:1 2n/homocoupled boronic acid
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

D
P. L. Türtscher et al.
Paper
Synthesis
R2
O
NMe3
OTs
NMe3
2.5 mol% Pd(OAc)2
5 mol% Xantphos
MeO
(HO)2B
(a)
X
3 equiv K3PO4 or KF
R1
+
R1
THF, 50 or 60 °C
R2
MeO
O
2.5 mol% Pd(OAc)2
5 mol% Xphos
R = OMe or Cl
X = OTs or Br
(R)-3
3 equiv K3PO4
+
THF, 80 °C
MeO
MeO
Cl
MeO
(HO)2B
53%
rac-4
OMe
OMe
Cl
Cl
2b
2p
2q
2r
Cl
NMe3
OTs
2.5 mol% Pd(OAc)2
5 mol% Xphos
3 equiv K3PO4
(b)
(HO)2B
Cl
KF, 60 °C
90%
KF, 60 °C
78%
K3PO4, 50 °C
69%
K3PO4, 50 °C
62%
+
OMe
THF, 50 °C
<5% cross coupling,
elimination major byproduct
Scheme 5 Evaluation of chloride-containing substrates using Xantphos
as ligand
Scheme 6 Evaluation of cross-coupling of an α-chiral ammonium salt
under our conditions
We were keen to examine substrates that contain a
chloride on either the ammonium salt or the boronic acid to
be able to demonstrate orthogonality between the chloride
and the ammonium. Based on our previous ligand optimis-
ation (Table 2), we selected Xantphos and found that a
number of chloride-containing ammonium salts and a chlo-
ride-containing boronic acid give good to excellent yields in
the coupling, under mild conditions (Scheme 5). This leaves
the chloride functionality intact for further cross-coupling.
Given the elegant work of Watson and co-workers in
which stereospecific coupling was found to occur under
Nickel catalysis,6 we were keen to evaluate whether stereo-
chemical information is retained with our palladium-
catalysed protocol. By using an elevated temperature of
80 °C, we were able to obtain a moderate yield of coupled
product 4 (Scheme 6a). However, HPLC analysis showed
that this was racemic. The enantiopurity of the starting am-
monium salt 3, obtained by methylation of phenylglycine
methyl ester, was confirmed by 1H NMR analysis after anion
exchange with BINPHAT.12 Therefore, we can conclude that
the stereochemical information was lost during the course
of the cross-coupling process in this case. Unfortunately, we
were not able to obtain more than 5% yield of the corre-
sponding α-methyl substrate under our conditions and thus
were not able to determine whether this substrate would
retain its stereochemical fidelity (Scheme 6b). In this case,
the major by-product was the result of elimination to the
styrene and a range of ligands were tested for this substrate
with no success.
the boronic acid. Indeed, a literature search revealed that 2-
phenylbenzyl halides undergo a similar C–H activation pro-
cess under Pd(II)-catalysis.13
OMe
Ph
Br
NMe3
2.5 mol%
Pd(OAc)2
5 mol% XPhos
Ph
(HO)2B
+
2e
75%
+
3 equiv KF
THF, 50 °C
OMe
1e
5
9%
Scheme 7 Fluorene side-product observed in coupling of 1e
Fluorene derivatives are valuable structural motifs with
various applications in chemistry and materials science,14
and the ability to access them via C–H activation from ben-
zylamine building blocks would be a potentially new and
useful route to access them. Furthermore, we have shown
in our previous work that it is possible to cross-couple at
the ortho position in the presence of the benzyl ammonium
functionality.10 This leads to the possibility of a tandem
cross-coupling/C–H activation process for fluorene synthe-
sis. In an effort to increase the yield, we undertook optimis-
ation in the absence of the boronic acid (Table 3). Evaluation
of bases showed that Cs2CO3 is by far the best (entries 1–6),
although the yield of fluorene was still only moderate. Re-
ducing the equivalents of base was detrimental (entry 7), as
was increasing the temperature to 100 °C (entries 8 and 9).
Whilst switching the solvent to dioxane or 1,2-dime-
thoxyethane (DME) did not significantly improve matters
(entries 10–13), it was found that doubling the catalyst/
ligand loading was key (entries 14 and 15); the best yield
Finally, in our scope studies, we had observed an inter-
esting side product that was produced in 9% yield in the
cross-coupling of 2-phenylbenzylammonium salt 1e
(Scheme 7). This was determined to be fluorene (5) and
most likely arises through C–H activation onto the ortho-
phenyl ring being competitive with transmetallation with
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

E
P. L. Türtscher et al.
Paper
Synthesis
could be achieved at 90 °C with a moderate three equiva-
lents of base (entry 16). Use of DME as solvent together
with (S)-BINAP as ligand gave comparable results (entries
17 and 18).13
All reagents were used as supplied from commercial sources without
further purification. Cross-coupling reactions were carried out in 4
mL 15 × 45mm crimp-top vials, which were purged with argon. Vials
were heated in welled heating blocks. 1H NMR spectra were recorded
with a 600 MHz Bruker Avance 600 BBI spectrometer. Chemical shifts
are reported in parts per million (ppm) and the spectra are calibrated
to the resonance resulting from incomplete deuteration of solvents.
13C NMR spectra were recorded with a 600 MHz Bruker Avance 600
BBI spectrometer or 500 MHz DCH Cryoprobe spectrometer with
complete proton decoupling. Chemical shifts are reported in ppm and
calibrated to the solvent resonance resulting from incomplete deuter-
ation. Data are reported as follows: chemical shift in ppm, multiplici-
ty (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or
combinations of them; 13C signals are singlets unless otherwise stat-
ed), coupling constants J in Hz, integration (only for 1H spectra). 19F
NMR spectra were recorded with a 400 MHz Avance III HD Smart
Probe spectrometer. Analytical thin-layer chromatography was per-
formed using precoated Merck glass-backed silica gel plates (Silicagel
60 F254). Visualisation was by ultraviolet fluorescence (254nm) and
staining the plates with cerium ammonium molybdate (CAM). Flash
column chromatography was performed using silica gel 60 (0.040–
0.063 μm).
Table 3 Optimisation of Intramolecular C–H Activation to form Fluo-
rine (5)
NMe3
2.5 mol% Pd(OAc)2
5 mol% ligand
Br
base
solvent, T (°C)
1e
5
Entry Ligand
Base (equiv)
Temp (°C) Solvent
Yield 2a (%)a
1
2
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
(S)-BINAP
XPhos
XPhos
XPhos
(S)-BINAP
(S)-BINAP
KF (5)
80
80
THF
0
NMe3 (5)
THF
0
3
K3PO4 (5)
Na2CO3 (5)
NaHCO3 (5)
Cs2CO3 (5)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (3)
80
THF
12
0
4
80
THF
5
80
THF
0
Synthesis of Ammonium Salts
6
80
THF
50
23
8
The preparations of 1a, 1b, 1c, 1d, 1h and 1i were reported previous-
7
80
THF
ly.10
8
100
100
100
100
100
100
80
THF
9
THF
21
24
33
1
Preparation of Ammonium Tosylate Salts; General Procedure A
A flask was charged with NaHCO3, which was suspended in either
MeOH or MeCN. The specified benzylamine was added, followed by
methyl toluenesulfonate. After stirring the reaction at r.t. overnight,
the solvent was removed and the precipitate was filtered off and
washed with CH2Cl2. The combined filtrate and washings were con-
centrated under reduced pressure, redissolved in a minimum amount
of CH2Cl2 and the product was precipitated by addition of Et2O. The
precipitate was collected by filtration and washed with further Et2O.
If further purification was necessary, it is stated accordingly.
10
11
12
13
14b
15b
16b
17b
18b
dioxane
dioxane
DME
DME
THF
35
46
54
64 (41)
63 (61)
46
90
THF
90
THF
90
DME
DME
Preparation of Ammonium Bromide Salts; General Procedure B
90
Trimethylamine was added to a solution of a benzylbromide in MeCN
and the resulting mixture was stirred at r.t. for 1 h. The volatiles were
evaporated and the remaining precipitate was collected by filtration
and washed with Et2O.
a Determined by 1H NMR analysis with reference to an internal standard.
Isolated yield given in parentheses for selected experiments.
b Pd(OAc)2 (5.0 mol%) and ligand (10 mol%) used.
In summary, we have described in detail our studies on
the development of the palladium-catalysed coupling of
benzyl ammonium salts and boronic acids under mild con-
ditions. We have shown that a variety of substrates are
compatible and that, with appropriate ligand choice,
chemoselectivity can be obtained between reaction at the
ammonium functionality and reaction at a chloride on the
arene. This offers an advantage over the related Ni-
catalysed processes in which chlorides are not tolerated. In
addition, we have found that palladium-catalysed C–H acti-
vation can occur if an aromatic ring is present at the ortho-
position of the benzylammonium salt, demonstrating an-
other productive pathway for the putative benzyl-Pd(II) in-
termediate other than transmetallation.
1-([1,1′-Biphenyl]-2-yl)-N,N,N-trimethylmethanaminium Bro-
mide (1e)
Prepared according to General Procedure B with 2-(bromomethyl)-
1,1′-biphenyl (0.73 mL, 4 mmol, 1 equiv) and trimethylamine (6 mL,
1 M in THF, 6 mmol, 1.5 equiv) in MeCN (4 mL).
Yield: 1.169 g (3.8 mmol, 95%); white solid.
1H NMR (600 MHz, d6-DMSO): δ = 7.74 (dd, J = 7.7, 1.3 Hz, 1 H), 7.62
(td, J = 7.5, 1.4 Hz, 1 H), 7.57–7.44 (m, 4 H), 7.47–7.37 (m, 4 H), 4.68 (s,
2 H), 2.76 (s, 9 H).
13C NMR (151 MHz, d6-DMSO): δ = 144.55, 139.95, 134.64, 131.48,
130.67, 129.48, 128.87, 127.69, 127.67, 125.35, 64.79, 52.00.
HRMS: m/z [M]+ calcd for [C16H20N]+: 226.1596; found: 226.1597.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

F
P. L. Türtscher et al.
Paper
Synthesis
1-(2-Fluoro-6-(trifluoromethyl)phenyl)-N,N,N-trimethylmethan-
13C NMR (151 MHz, MeOD-d4): δ = 166.2, 133.0, 132.5, 132.1, 129.7,
aminium Tosylate (1f)
68.2, 52.0, 51.6.
Data in agreement with the reported values.15
Trimethylamine (1.28 mL, 5.4 mmol, 4.2 M in ethanol) was added to a
solution of 2-fluoro-6-(trifluoromethyl)benzyl bromide (700 mg, 2.72
mmol) in acetonitrile and the solution was stirred at r.t. for 1 h. The
volatiles were evaporated under reduced pressure, the residue was
dissolved in CH2Cl2 and Et2O was slowly added. The precipitated bro-
mide salt was collected by filtration (840 mg, 2.65 mmol, 98%). This
salt (632 mg, 2 mmol) was dissolved in chloroform and AgOTs (837
mmol, 3 mmol) was added. The resulting reaction mixture was
stirred for 30 min, then filtered through a bed of Celite. The solvent
was removed under reduced pressure to afford the tosylate salt 1f.
N,N,N-Trimethyl-1-(naphthalen-2-yl)methanaminium Bromide
(1l)16
Prepared according to General Procedure B with 2-(bromometh-
yl)naphthalene (442 mg, 2 mmol, 1 equiv) and trimethylamine (3 mL,
1 M in THF, 3 mmol, 1.5 equiv) in MeCN (4 mL).
Yield: 486 mg (1.7 mmol, 87%); white solid.
1H NMR (600 MHz, MeOD-d4): δ = 8.15 (s, 1 H), 8.06–7.95 (m, 3 H),
7.66–7.58 (m, 3 H), 4.73 (s, 2 H), 3.18 (s, 9 H).
Yield: 572 mg (1.4 mmol, 70%); white solid.
13C NMR (151 MHz, MeOD-d4): δ = 134.0, 133.2, 133.0, 128.7, 128.6,
128.1, 127.5, 127.4, 126.7, 125.0, 69.2, 51.9.
Data in agreement with the reported values.16
1H NMR (600 MHz, CDCl3): δ = 7.68–7.63 (m, 3 H), 7.59 (d, J = 7.9 Hz,
1 H), 7.43 (t, J = 8.8 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 2 H), 4.81 (s, 2 H), 3.29
(s, 9 H), 2.25 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 162.5 (d, 1JC–F = 254 Hz), 143.8, 139.2,
3
3
133.9 (d, JC–F = 10 Hz), 132.5 (dq, JC–F/2JC–F = 1, 32 Hz), 128.6, 125.7,
1-(4-Chlorophenyl)-N,N,N-trimethylmethanaminium 4-Methyl-
benzenesulfonate (1p)
124.2 (dq, 4JC–F/3JC–F = 6, 3 Hz), 123.0 (q, 1JC–F = 271 Hz), 121.0 (d, 2JC–F
24 Hz), 113.9 (d, 2JC–F = 16 Hz), 59.6, 54.2, 21.2.
HRMS: m/z [M]+ calcd for [C11H14NF4]+: 263.1057; found: 263.1056.
=
Prepared according to General Procedure A with 4-chlorobenzylamine
(0.48 mL, 4.0 mmol, 1 equiv), NaHCO3 (3.36 g, 40 mmol, 10 equiv) and
methyl toluenesulfonate (3.0 mL, 20 mmol, 5 equiv) in MeOH (14 mL).
N,N,N-Trimethyl-1-(p-tolyl)methanaminium Tosylate (1g)
Yield: 1.216 g (3.4 mmol, 85%); white powder.
1H NMR (600 MHz, CDCl3): δ = 7.76 (d, J = 8.0 Hz, 2 H), 7.45 (d, J =
8.4 Hz, 2 H), 7.29 (d, J = 8.4 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 4.79 (s,
2 H), 3.22 (s, 9 H), 2.33 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 143.3, 139.8, 136.9, 134.5, 129.3,
128.9, 126.2, 125.7, 67.7, 52.3, 21.3.
To a solution of the corresponding bromide salt (244 mg, 1.0 mmol) in
CHCl3 (5 mL) was added AgOTs (418 mg, 1.5 mmol) and the mixture
was stirred at r.t. for 30 min. After this time, the mixture was filtered
through a thin pad of Celite and the solvent was evaporated to give
the title compound.
Yield: 170 mg (0.51 mmol, 51%); white solid.
HRMS: m/z [M]+ calcd for [C10H15NCl]+: 184.0888; found: 184.0886.
1H NMR (600 MHz, CDCl3): δ = 7.74 (d, J = 8.0 Hz, 2 H), 7.27 (d, J =
8.0 Hz, 2 H), 7.09 (d, J = 8.0 Hz, 2 H), 7.07 (d, J = 8.0 Hz, 2 H), 4.55 (s,
2 H), 3.12 (s, 9 H), 2.30 (s, 3 H), 2.28 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 143.6, 140.5, 139.5, 132.9, 129.6,
128.8, 125.8, 124.7, 68.7, 52.1, 21.28, 21.27.
1-(2,5-Dichlorophenyl)-N,N,N-trimethylmethanaminium Methyl-
benzenesulfonate (1r)
Prepared according to General Procedure A with 2,5-dichlorobenzyl-
amine (1.0 g, 5.7 mmol, 1 equiv), NaHCO3 (4.7 g, 57 mmol, 10 equiv)
and methyl toluenesulfonate (4.3 mL, 28.5 mmol, 5 equiv) in MeOH
(20 mL).
HRMS: m/z [M]+ calcd for [C11H18N]+: 164.1434; found: 164.1432.
N,N,N-Trimethyl-1-(thiophen-2-yl)methanaminium Tosylate (1j)
Yield: 2.1 g (5.4 mmol, 94%); white powder.
1H NMR (600 MHz, MeOD-d4): δ = 7.79 (d, J = 2.3 Hz, 1 H), 7.75 (d, J =
8.0 Hz, 2 H), 7.63 (d, J = 8.5 Hz, 1 H), 7.60 (dd, J = 8.5, 2.3 Hz, 1 H), 7.25
(d, J = 8.0 Hz, 2 H), 4.71 (s, 2 H), 3.21 (s, 9 H), 2.38 (s, 3 H).
Prepared according to General Procedure A with thiophen-2-ylmeth-
anamine (0.51 mL, 5.0 mmol, 1 equiv), NaHCO3 (4.2 g, 50 mmol, 10
equiv) and methyl toluenesulfonate (4.7 mL, 25 mmol, 5 equiv) in
MeOH (10 mL).
13C NMR (151 MHz, MeOD-d4): δ = 144.0, 141.9, 136.6, 136.5, 134.8,
Yield: 1.34 g (4.1 mmol, 82%); white powder.
134.0, 133.6, 130.1, 129.3, 127.2, 66.4, 54.0, 21.6.
1H NMR (600 MHz, d6-DMSO): δ = 7.81 (d, J = 5.1 Hz, 1 H), 7.52 (d, J =
8.0 Hz, 2 H), 7.40 (d, J = 3.2 Hz, 1 H), 7.18 (dd, J = 3.7, 5.0 Hz, 1 H), 7.12
(d, J = 7.9 Hz, 2 H), 4.81 (s, 2 H), 3.05 (s, 9 H), 2.28 (s, 3 H).
HRMS: m/z [M]+ calcd for [C10H14NCl2]+: 218.0498; found: 218.0488.
(R)-2-Methoxy-N,N,N-trimethyl-2-oxo-1-phenylethan-1-amini-
um 4-Methylbenzenesulfonate (3)
13C NMR (151 MHz, d6-DMSO): δ = 146.0, 138.2, 134.7, 131.1, 129.4,
128.6, 128.3, 125.9, 62.1, 51.9, 21.2.
HRMS: m/z [M]+ calcd for [C8H14NS]+: 156.0841; found: 156.0841.
Prepared according to General Procedure A with methyl (R)-2-amino-
2-phenylacetate hydrochloride (807 mg, 4.0 mmol, 1 equiv), NaHCO3
(3.36 g, 40 mmol, 10 equiv) and methyl toluenesulfonate (3 mL, 20
mmol, 5 equiv) in MeCN (14 mL). For further purification, the crude
material was dissolved in H2O (20 mL) and washed with CH2Cl2
(3 × 20 mL) and Et2O (3 × 20 mL). H2O was removed under reduced
pressure, yielding 1p as an oil (647 mg, 1.7 mmol, 43%). The enantio-
purity was determined by dissolving 1p (5 mg) and S-BINPHAT (15
mg) in CH2Cl2/acetone (2 mL, 1:1) and stirring for 5 min.
1-(4-(Methoxycarbonyl)phenyl)-N,N,N-trimethylmethanamini-
um Bromide (1k)15
Prepared according to General Procedure B with methyl 4-(bro-
momethyl)benzoate (458 mg, 2 mmol, 1 equiv) and trimethylamine
(3 mL, 1 M in THF, 3 mmol, 1.5 equiv) in MeCN (8 mL).
Yield: 534 mg (1.9 mmol, 93%); solid.
1H NMR (600 MHz, MeOD-d4): δ = 8.19–8.14 (m, 2 H), 7.75–7.70 (m,
2 H), 4.65 (s, 2 H), 3.94 (s, 3 H), 3.16 (s, 9 H).
After removing the solvent, the 1H NMR (600 MHz, CDCl3) spectra
showed only one ammonium peak, conforming the enantiopurity of
the product. A portion (533 mg) of the obtained oil was additionally
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

G
P. L. Türtscher et al.
Paper
Synthesis
washed twice with Et2O, decanting the washing off and dissolved in a
minimum amount of CH2Cl2. A white solid (330 mg) was obtained by
addition of Et2O, collected by filtration and washed with Et2O.
1H NMR (600 MHz, CDCl3): δ = 7.81–7.76 (m, 2 H), 7.61 (d, J = 7.5 Hz,
2 H), 7.55–7.48 (m, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.14 (d, J = 7.9 Hz,
2 H), 6.09 (s, 1 H), 3.70 (s, 3 H), 3.45 (s, 9 H), 2.32 (s, 3 H).
Yield: 45 mg (0.17 mmol, 85%).
1H NMR (600 MHz, CDCl3): δ = 7.67 (dd, J = 7.9, 1.3 Hz, 1 H), 7.43 (td,
J = 7.6, 1.3 Hz, 1 H), 7.30 (t, J = 7.6 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 1 H),
7.11–7.06 (m, 2 H), 6.89–6.83 (m, 2 H), 4.14 (s, 2 H), 3.80 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.1, 140.0, 131.8, 131.7, 131.5,
2
3
130.1, 128.5 (q, JC–F = 29.7 Hz), 126.0, 125.7 (q, JC–F = 5.8 Hz), 124.5
13C NMR (151 MHz, CDCl3): δ = 167.4, 143.3, 139.6, 131.6, 129.7,
(q, 1JC–F = 273.9 Hz), 113.9, 55.2, 36.8 (q, 4JC–F = 2.2 Hz).
128.8, 126.8, 125.9, 74.6, 53.5, 51.8, 21.4.
HRMS: m/z [M]+ calcd for [C12H18NO2]+: 208.1338; found: 208.1336.
19F NMR (376 MHz, CDCl3): δ = –59.6.
Data in agreement with reported values.19
Palladium-Catalysed Cross-Coupling; General Procedure
1-(4-Methoxybenzyl)-2-methylbenzene (2d)17
The desired amount of substrate, boronic acid (3 equiv), base (3
equiv), Pd(OAc)2 (2.5 mol%) and ligand (5 mol%) were weighed out as
solids, the vial was sealed and purged with argon, then solvent was
added and the vial was purged again. The reactions were run for 14 h
at the specified temperature. The crude material was filtered through
a pad of Celite and washed three times with CHCl3. The solvent was
removed under reduced pressure, an internal standard was added and
Obtained by following the general procedure using 1d (Br) (49 mg, 0.2
mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), KF (35
mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Purification by silica gel chro-
matography (20%, CH2Cl2/petroleum ether) gave 2d.
Yield: 33 mg (0.16 mmol, 78%).
1H NMR (600 MHz, CDCl3): δ = 7.19–7.12 (m, 3 H), 7.12–7.02 (m, 3 H),
1
the reaction was analysed by H NMR spectroscopy. For purification,
6.85–6.80 (m, 2 H), 3.93 (s, 2 H), 3.79 (s, 3 H), 2.25 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 157.8, 139.3, 136.5, 132.4, 130.2,
129.7, 129.6, 126.3, 125.9, 113.7, 55.2, 38.5, 19.6.
the analysed mixture was concentrated, the product extracted with
Et2O and filtered through anhydrous MgSO4 and further purified by
flash column chromatography.
Data in agreement with reported values.17
1-Benzyl-4-methoxybenzene (2a)17
Obtained by following the general procedure using 1a (OTs) (78 mg,
0.2 mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), K3PO4
(127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol), in THF (0.4 mL) at 50 °C. Purification by silica gel
chromatography (20% CH2Cl2/petroleum ether) gave 2a.
2-(4-Methoxybenzyl)-1,1′-biphenyl (2e)20
Obtained by following the general procedure using 1e (Br) (61 mg, 0.2
mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), KF (35
mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Purification by silica gel chro-
matography (20%, CH2Cl2/petroleum ether) gave 2e.
Yield: 33 mg (0.16 mmol, 82%).
1H NMR (600 MHz, CDCl3): δ = 7.30 (t, J = 7.6 Hz, 2 H), 7.24–7.17 (m,
3 H), 7.13 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 3.94 (s, 2 H), 3.80
(s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.0, 141.7, 133.3, 129.9, 128.9,
128.5, 126.1, 114.0, 55.3, 41.1.
Yield: 41 mg (0.15 mmol, 75%).
1H NMR (600 MHz, CDCl3): δ = 7.41–7.35 (m, 2 H), 7.37–7.31 (m, 1 H),
7.34–7.24 (m, 5 H), 7.22 (dd, J = 6.7, 1.8 Hz, 1 H), 6.93–6.88 (m, 2 H),
6.80–6.74 (m, 2 H), 3.91 (s, 2 H), 3.78 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 157.7, 142.1, 141.6, 138.6, 133.5,
130.1, 130.0, 129.7, 129.2, 128.0, 127.4, 126.8, 126.0, 113.5, 55.2, 38.1.
Data in agreement with reported values.17
Data in agreement with reported values.20
1-Chloro-2-(4-methoxybenzyl)benzene (2b)18
Obtained by following the general procedure using 1-(2-chlorophe-
nyl)-N,N,N-trimethylmethanaminium tosylate (36 mg, 0.1 mmol),
(4-methoxyphenyl)boronic acid (46 mg, 0.3 mmol), KF (17 mg,
0.3 mmol), Pd(OAc)2 (0.6 mg, 2.5 × 10–3 mmol), Xantphos (2.9 mg,
5 × 10–3 mmol) in THF (0.2 mL) at 60 °C. Purification by silica gel chro-
matography (25 to 40% CH2Cl2/petroleum ether) gave 2b.
1-Fluoro-2-(4-methoxybenzyl)-3-(trifluoromethyl)benzene (2f)
Obtained by following the general procedure using 1f (OTs) (82 mg,
0.2 mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), KF (35
mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Purification by silica gel chro-
matography (20%, CH2Cl2/petroleum ether) gave 2f.
Yield: 21 mg (0.09 mmol, 90%).
1H NMR (600 MHz, CDCl3): δ = 7.37 (dd, J = 7.5, 1.7 Hz, 1 H), 7.23–7.10
(m, 5 H), 6.87–6.81 (m, 2 H), 4.05 (s, 2 H), 3.79 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.2, 139.2, 134.2, 131.6, 131.0,
130.0, 129.6, 127.6, 126.9, 114.0, 55.3, 38.4.
Data in agreement with reported values.18
Yield: 47 mg (0.17 mmol, 83%).
1H NMR (600 MHz, CDCl3): δ = 7.50 (d, J = 7.8 Hz, 1 H), 7.38–7.31 (m,
1 H), 7.29–7.22 (m, 1 H), 7.07 (d, J = 8.3 Hz, 2 H), 6.84–6.78 (m, 2 H),
4.14 (s, 2 H), 3.77 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 162.1 (d, 1JC–F = 248 Hz), 158.1, 131.1,
130.9 (dq, 3JC–F/2JC–F = 4, 30 Hz), 129.2, 128.2 (d, 3JC–F = 9 Hz), 127.3 (d,
2JC–F = 17.6 Hz), 123.9 (dq, 4JC–F/1JC–F = 4, 274 Hz), 121.9 (dq, 4JC–F/3JC–F
=
1-(4-Methoxybenzyl)-2-(trifluoromethyl)benzene (2c)19
4, 6 Hz), 119.3 (d, JC–F = 23 Hz), 113.8, 55.3, 30.6 (dq, JC–F/4JC–F = 4,
2
3
2 Hz).
Obtained by following the general procedure using 1c (OTs) (78 mg,
0.2 mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), KF (35
mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol), in THF (0.4 mL) at 50 °C. Purification by silica gel
chromatography (20% CH2Cl2/petroleum ether) gave 2c.
19F NMR (376 MHz, CDCl3): δ = –58.8, –112.3.
HRMS: m/z [M]+ calcd for [C15H12F4O]+: 284.0824; found: 284.0823.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

H
P. L. Türtscher et al.
Paper
Synthesis
1-Methoxy-4-(4-methylbenzyl)benzene (2g)17
Data in agreement with reported values.17
Obtained by following the general procedure using 1g (OTs) (67 mg,
0.2 mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), K3PO4
(127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Purification by silica gel chro-
matography (25%, CH2Cl2/petroleum ether) gave 2g.
Methyl 4-(4-Methoxybenzyl)benzoate (2k)21
Obtained by following the general procedure using 1k (Br) (58 mg, 0.2
mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), K3PO4
(127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8
mg, 1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Purification by silica gel
chromatography (4% up to 8% EtOAc/petroleum ether) gave 2n.
Yield: 31 mg (0.14 mmol, 72%).
1H NMR (600 MHz, CDCl3): δ = 7.14–7.06 (m, 6 H), 6.87–6.81 (m,
Yield: 46 mg (0.18 mmol, 89%).
2 H), 3.90 (s, 2 H), 3.79 (s, 3 H), 2.33 (s, 3 H).
1H NMR (600 MHz, CDCl3): δ = 7.96 (d, J = 8.3 Hz, 2 H), 7.24 (d, J =
8.4 Hz, 2 H), 7.09 (d, J = 8.7 Hz, 2 H), 6.85 (d, J = 8.7 Hz, 2 H), 3.97 (s,
2 H), 3.90 (s, 3 H), 3.79 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.0, 138.6, 135.5, 133.6, 129.9,
129.2, 128.8, 113.9, 55.3, 40.7, 21.1.
Data in agreement with reported values.17
13C NMR (151 MHz, CDCl3): δ = 167.2, 158.3, 147.1, 132.3, 130.0,
129.9, 128.9, 128.1, 114.1, 55.4, 52.1, 41.1.
Data in agreement with reported values.21
1-Methoxy-2-(4-methoxybenzyl)benzene (2h)6
Obtained by following the general procedure using 1h (OTs) (70 mg,
0.2 mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), K3PO4
(127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol) in THF (0.4 mL) at 80 °C. Purification by silica gel chro-
matography (first run with 25% up to 40% CH2Cl2/petroleum ether,
second run with 10% Et2O/petroleum ether) gave 2h.
2-(4-Methoxybenzyl)naphthalene (2l)6
Obtained by following the general procedure using 1l (56 mg, 0.2
mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), K3PO4
(127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Analysis of crude 1H NMR
showed 82% yield; purification by silica gel chromatography (25%,
CH2Cl2/petroleum) gave 2l.
Yield: 25 mg (0.11 mmol, 54%).
1H NMR (600 MHz, CDCl3): δ = 7.19 (td, J = 7.8, 1.8 Hz, 1 H), 7.17–7.11
(m, 2 H), 7.06 (dd, J = 7.2, 1.7 Hz, 1 H), 6.91–6.84 (m, 2 H), 6.85–6.79
(m, 2 H), 3.92 (s, 2 H), 3.83 (s, 3 H), 3.78 (s, 3 H).
Yield: 40 mg (0.16 mmol, 80%).
1H NMR (600 MHz, CDCl3 ): δ = 7.85–7.76 (m, 3 H), 7.67–7.63 (m, 1 H),
7.46 (dqd, J = 8.2, 6.8, 1.5 Hz, 2 H), 7.34 (dd, J = 8.4, 1.8 Hz, 1 H), 7.18
(d, J = 8.6 Hz, 2 H), 6.91–6.85 (m, 2 H), 4.12 (s, 2 H), 3.81 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.15, 139.19, 133.74, 133.21,
132.18, 130.09, 128.17, 127.74, 127.71, 127.67, 127.03, 126.07,
125.42, 114.04, 55.38, 41.34.
13C NMR (151 MHz, CDCl3): δ = 157.8, 157.4, 133.2, 130.2, 130.2,
130.0, 127.4, 120.5, 113.8, 110.5, 55.4, 55.3, 35.0.
Data in agreement with reported values.6
1-Fluoro-3-(4-methoxybenzyl)benzene (2i)17
Obtained by following the general procedure using 1i (OTs) (68 mg,
0.2 mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), K3PO4
(127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8
mg, 1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Purification by silica gel
chromatography (25%, CH2Cl2/petroleum ether) gave 2i.
Data in agreement with reported values.6
1-Benzyl-2-methylbenzene (2m)22
Obtained by following the general procedure using 1a (OTs) (64 mg,
0.2 mmol), (2-methylphenyl)boronic acid (82 mg, 0.6 mmol), K3PO4
(127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Purification by silica gel chro-
matography (1% up to 3% EtOAc/petroleum ether) gave 2m (contain-
ing ca. 5% homocoupled boronic acid impurity).
Yield: 17 mg (0.08 mmol, 40%).
1H NMR (600 MHz, CDCl3): δ = 7.23 (td, J = 7.9, 6.0 Hz, 1 H), 7.13–7.08
(m, 2 H), 6.98–6.93 (m, 1 H), 6.91–6.82 (m, 4 H), 3.92 (s, 2 H), 3.79 (s,
3 H).
13C NMR (151 MHz, CDCl3): δ = 163.1 (d, 1JC–F = 245.5 Hz), 158.2, 144.3
Yield: 27 mg (74%); colourless oil.
1H NMR (600 MHz, CDCl3): δ = 7.31–7.23 (m, 2 H), 7.22–7.09 (m, 7 H),
4.00 (s, 2 H), 2.26 (s, 3 H).
(d, 3JC–F = 7.2 Hz), 132.5, 130.0, 129.9 (d, 3JC–F = 8.3 Hz), 124.5 (d, 4JC–F
=
2.8 Hz), 115.7 (d, 2JC–F = 21.1 Hz), 114.1, 113.0 (d, 2JC–F = 21.1 Hz), 55.4,
40.88 (d, 4JC–F = 1.8 Hz).
13C NMR (151 MHz, CDCl3): δ = 140.5, 139.0, 136.7, 130.4, 130.0,
Data in agreement with reported values.17
128.8, 128.5, 126.5, 126.1, 126.0, 39.5, 19.82.
2-(4-Methoxybenzyl)thiophene (2j)17
Data in agreement with reported values.22
Obtained by following the general procedure using 1j (OTs) (66 mg,
0.2 mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), K3PO4
(127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Purification by silica gel chro-
matography (25% up to 40% CH2Cl2/petroleum ether) gave 2j.
2-Benzylnaphthalene (2n)
Obtained by following the general procedure using 1a (OTs) (64 mg,
0.2 mmol), naphthalen-2-ylboronic acid (103 mg, 0.6 mmol), K3PO4
(127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Purification by silica gel chro-
matography (2% up to 5% EtOAc/petroleum ether) gave a mixture of
2n and the homocoupled boronic acid in a 3:1 ratio.
Yield: 31 mg (0.15 mmol, 77%).
1H NMR (600 MHz, CDCl3): δ = 7.20–7.17 (m, 2 H), 7.15 (dd, J = 5.1,
1.2 Hz, 1 H), 6.93 (dd, J = 5.1, 3.4 Hz, 1 H), 6.90–6.84 (m, 2 H), 6.80 (dq,
J = 3.4, 1.1 Hz, 1 H), 4.12 (s, 2 H), 3.81 (s, 3 H).
Yield: 28 mg (0.12 mmol, both homo- and cross-coupled products,
46%).
13C NMR (151 MHz, CDCl3): δ = 158.3, 144.8, 132.7, 129.7, 126.9,
124.9, 123.9, 114.0, 55.3, 35.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

I
P. L. Türtscher et al.
Paper
Synthesis
Compound 2l
13C NMR (151 MHz, CDCl3): δ = 140.5, 139.6, 131.9, 130.2, 128.8,
1H NMR (600 MHz, CDCl3): δ = 7.83–7.75 (m, 3 H), 7.65 (d, J = 1.8 Hz,
1 H), 7.45 (ddd, J = 8.2, 6.8, 1.5 Hz, 2 H), 7.36–7.28 (m, 3 H), 7.28–7.20
(m, 3 H), 4.16 (s, 2 H).
128.6, 128.5, 126.3, 41.2.
Data in agreement the reported values.26
13C NMR (151 MHz, CDCl3): δ = 141.1, 138.7, 133.7, 132.2, 129.1,
1,4-Dichloro-2-(4-methoxybenzyl)benzene (2r)
128.6, 128.2, 127.7, 127.7, 127.6, 127.2, 126.2, 126.1, 125.4, 42.2.
Data in agreement with reported values.6
Obtained by following the general procedure using 1r (OTs) (78 mg,
0.2 mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), K3PO4
(127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xantphos (5.8
mg, 1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Purification by silica gel
chromatography (25% CH2Cl2/petroleum ether) gave 2r.
Homocoupled Impurity
1H NMR (600 MHz, CDCl3): δ = 8.19 (d, J = 1.7 Hz, 2 H), 7.98 (d, J =
8.5 Hz, 2 H), 7.96 (d, J = 7.4 Hz, 2 H), 7.91 (dd, J = 8.4, 1.8 Hz, 4 H), 7.53
(dqd, J = 8.2, 6.9, 1.4 Hz, 4 H).
Yield: 33 mg (0.12 mmol, 62%).
1H NMR (600 MHz, CDCl3): δ = 7.29 (d, J = 8.5 Hz, 1 H), 7.16–7.08 (m,
13C NMR (151 MHz, CDCl3): δ = 138.5, 133.8, 132.8, 128.6, 128.3,
127.8, 126.5, 126.2, 126.1, 125.8.
4 H), 6.89–6.83 (m, 2 H), 4.00 (s, 2 H), 3.80 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.4, 141.0, 132.7, 132.4, 130.7,
Data in agreement with reported values.23
130.6, 130.6, 130.1, 127.7, 114.2, 55.3, 38.3.
HRMS: m/z [M] calcd for [C14H12Cl2O]: 266.0265; found: 266.0253.
Ethyl 3-Benzylbenzoate (2o)24
Methyl 2-(4-Methoxyphenyl)-2-phenylacetate (4)27
Obtained by following the general procedure using 1a (OTs) (64 mg,
0.2 mmol), 3-ethoxycarbonylphenylboronic acid (116 mg, 0.6 mmol),
K3PO4 (127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), XPhos
(4.8 mg, 1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Purification by silica
gel chromatography (5% EtOAc in petroleum ether then a further pu-
rification with 30% to 50% CH2Cl2/petroleum ether) yielded 2o.
Obtained by following the general procedure using 3 (76 mg, 0.2
mmol), (4-methoxyphenyl)boronic acid (91 mg, 0.6 mmol), K3PO4
(127 mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xphos (4.8 mg,
1 × 10–2 mmol) in THF (0.4 mL) at 80 °C. Purification by silica gel chro-
matography (3% up to 5% EtOAc/petroleum ether) gave 5 (27 mg, 0.11
mmol, 53%). Chiral HPLC analysis (Chiralcel OD Column; 1 mL/min;
0.5% iPrOH/hexane; tR = 18.64 min and 19.95 min) of the product
showed a racemic mixture was obtained.
1H NMR (600 MHz, CDCl3): δ = 7.36–7.27 (m, 4 H), 7.30–7.21 (m, 3 H),
6.89–6.83 (m, 2 H), 4.99 (s, 1 H), 3.79 (s, 3 H), 3.74 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 173.3, 158.9, 139.1, 130.8, 129.8,
128.7, 128.5, 127.3, 114.1, 56.3, 55.3, 52.4.
Yield: 31 mg (0.13 mmol, 65%); colourless oil.
1H NMR (600 MHz, CDCl3): δ = 7.93 (br s, 1 H), 7.91 (dt, J = 6.9, 1.4 Hz,
1 H), 7.39–7.35 (m, 2 H), 7.31 (t, J = 7.6 Hz, 2 H), 7.24–7.20 (m, 3 H),
4.38 (q, J = 7.2 Hz, 2 H), 4.05 (s, 2 H), 1.40 (t, J = 7.2 Hz, 3 H).
13C NMR (151 MHz, CDCl3): δ = 166.7, 141.4, 140.5, 133.4, 130.7,
130.0, 128.9, 128.6, 128.5, 127.4, 126.3, 60.9, 41.7, 14.3.
Data in agreement with reported values.24
Data in agreement with reported values.27
1-Chloro-4-(4-methoxybenzyl)benzene (2p)25
Fluorene (5)28
Obtained by following the general procedure using 1p (OTs) (36 mg,
0.1 mmol), (4-methoxyphenyl)boronic acid (46 mg, 0.3 mmol), KF (17
mg, 0.3 mmol), Pd(OAc)2 (0.6 mg, 2.5 × 10–3 mmol), Xantphos (2.9 mg,
5 × 10–3 mmol) in THF (0.2 mL) at 60 °C. Purification by silica gel chro-
matography (25% CH2Cl2/petroleum ether) gave 2p.
Obtained by following the general procedure (excluding boronic acid)
using 1e (61 mg, 0.2 mmol, 1 equiv), Cs2CO3 (196 mg, 0.6 mmol, 2
equiv), Pd(OAc)2 (2.2 mg, 1 × 10–2 mmol, 5 mol%), Xphos (9.6 mg,
2 × 10–2 mmol, 10 mol%) in THF (0.4 mL) at 90 °C. Purification by silica
gel chromatography (2% CH2Cl2/petroleum ether) gave 5.
Yield: 18 mg (0.08 mmol, 78%).
1H NMR (600 MHz, CDCl3): δ = 7.26–7.21 (m, 2 H), 7.13–7.05 (m, 4 H),
6.86–6.81 (m, 2 H), 3.89 (s, 2 H), 3.79 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 158.2, 140.1, 132.7, 131.9, 130.2,
129.9, 128.6, 114.1, 55.4, 40.4.
Data in agreement with reported values.25
Yield: 14 mg (0.08 mmol, 41%).
1H NMR (600 MHz, CDCl3): δ = 7.81 (d, J = 7.6 Hz, 2 H), 7.56 (d, J =
7.4 Hz, 2 H), 7.39 (td, J = 7.4, 1.0 Hz, 2 H), 7.32 (td, J = 7.4, 1.1 Hz, 2 H),
3.92 (s, 2 H).
13C NMR (151 MHz, CDCl3): δ = 143.3, 141.8, 126.8, 126.8, 125.1,
120.0, 37.0.
Data in agreement with reported values.28
1-Benzyl-4-chlorobenzene (2q)26
Obtained by following the general procedure using 1a (Br) (46 mg, 0.2
mmol), (4-chlorophenyl)boronic acid (78 mg, 0.5 mmol), K3PO4 (127
mg, 0.6 mmol), Pd(OAc)2 (1.1 mg, 5 × 10–3 mmol), Xantphos (5.8 mg,
1 × 10–2 mmol) in THF (0.4 mL) at 50 °C. Analysis of crude 1H NMR
showed 94% yield, purification by silica gel chromatography (1%
CH2Cl2/hexane) gave 2q.
Funding Information
We are grateful to the Engineering and Physical Sciences Research
Council (EPSRC, Grant Number EP/N005422/1) and Pfizer for a CASE
studentship (H.J.D.), the EPSRC and the Royal Society for a University
Research Fellowship (R.J.P.). P.L.T. thanks the Swiss-European Mobility
Yield: 28 mg (0.14 mmol, 69%).
1H NMR (600 MHz, CDCl3): δ = 7.31 (t, J = 7.5 Hz, 2 H), 7.27 (d, J =
8.0 Hz, 2 H), 7.23 (t, J = 7.5 Hz, 1 H), 7.18 (d, J = 7.5 Hz, 2 H), 7.13 (d, J =
8.0 Hz, 2 H), 3.97 (s, 2 H).
Programme for Traineeships for funding his stay in Cambridge.
E
n
gn
i
e
enri
g
a
n
d
P
h
ycsai
l
Secinces
Research
C
o
u
n
lc
i
E(
P
N/0
0
5
4
2
2
1/
)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

J
P. L. Türtscher et al.
Paper
Synthesis
Acknowledgment
(9) Yi, P.; Zhuangyu, Z.; Hongwen, H. Synthesis 1995, 245.
(10) Davis, H. J.; Mihai, M. T.; Phipps, R. J. J. Am. Chem. Soc. 2016, 138,
12759.
We thank the EPSRC UK National Mass Spectrometry Facility at Swan-
sea University as well as Professors Steven V. Ley and Matthew J.
Gaunt for support and useful discussions. Also thanks to Dr David
Blakemore (Pfizer) and Dr Alan D. Brown for useful discussion. We are
grateful to Madalina T. Mihai for donation of some ammonium salts
used in this study. R.J.P. is very grateful to the organizing committee
of the 2016 Bürgenstock conference for a JSP fellowship.
(11) During the preparation of this manuscript, Zhao and co-workers
reported a similar cross-coupling reaction, see: Wang, T.; Yang,
S.; Xu, S.; Han, C.; Guo, G.; Zhao, J. RSC Adv. 2017, 7, 15805. Dis-
appointingly, our own previous contribution was not acknowl-
edged, despite our paper being referenced in another context. A
notable advantage of our protocol is that ligand optimisation
allows the reactions to be carried out at 50 °C rather than
100 °C.
(12) Lacour, J.; Vial, L.; Herse, C. Org. Lett. 2002, 4, 1351.
(13) (a) Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130,
16158. (b) Hwang, S. J.; Kim, H. J.; Chang, S. Org. Lett. 2009, 11,
4588.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588548.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(14) (a) Amatatsu, Y. J. Phys. Chem. A 2011, 115, 13611. (b) Conyard,
J.; Addison, K.; Heisler, I. A.; Cnossen, A.; Browne, W. R.; Feringa,
B. L.; Meech, S. R. Nat. Chem. 2012, 4, 547. (c) Knaapila, M.;
Bright, D. W.; Nehls, B. S.; Garamus, V. M.; Almásy, L.; Schweins,
R.; Scherf, U.; Monkman, A. P. Macromolecules 2011, 44, 6453.
(d) Thangthong, A. m.; Prachumrak, N.; Namuangruk, S.;
Jungsuttiwong, S.; Keawin, T.; Sudyoadsuk, T.; Promarak, V. Eur.
J. Org. Chem. 2012, 5263. (e) Fleckenstein, C. A.; Plenio, H. Chem.
Eur. J. 2007, 13, 2701.
(15) Loe-Mie, F.; Marchand, G.; Berthier, J.; Sarrut, N.; Pucheault, M.;
Blanchard-Desce, M.; Vinet, F.; Vaultier, M. Angew. Chem. Int. Ed.
2010, 49, 424.
(16) Liu, Y.; Fang, R.; Tan, X.; Wang, Z.; Zhang, X. Chem. Eur. J. 2012,
18, 15650.
(17) Zhang, J.; Lu, G.; Xu, J.; Sun, H.; Shen, Q. Org. Lett. 2016, 18, 2860.
(18) Quinio, P.; Benischke, A. D.; Moyeux, A.; Cahiez, G.; Knochel, P.
Synlett 2015, 26, 514.
(19) Endo, K.; Ishioka, T.; Ohkubo, T.; Shibata, T. J. Org. Chem. 2012,
77, 7223.
(20) Kuwano, R.; Yokogi, M. Chem. Commun. 2005, 5899.
(21) Rao, M. L. N.; Dhanorkar, R. J. RSC Adv. 2014, 4, 13134.
(22) Zhang, P.; Xu, J.; Gao, Y.; Li, X.; Tang, G.; Zhao, Y. Synlett 2014,
25, 2928.
(23) Nakamura, K.; Tobisu, M.; Chatani, N. Org. Lett. 2015, 17, 6142.
(24) Pal, S.; Chowdhury, S.; Rozwadowski, E.; Auffrant, A.; Gosmini,
C. Adv. Synth. Catal. 2016, 358, 2431.
References
(1) Zhang, C.; Cui, F.; Zeng, G.-m.; Jiang, M.; Yang, Z.-z.; Yu, Z.-g.;
Zhu, M.-y.; Shen, L.-q. Science of The Total Environment 2015,
518–519, 352.
(2) Cope, A. C.; Trumbull, E. R. Olefins from Amines: The Hofmann
Elimination Reaction and Amine Oxide Pyrolysis, In Organic Reac-
tions; John Wiley & Sons, Inc: Weinheim, 2004.
(3) (a) Tayama, E.; Kimura, H. Angew. Chem. Int. Ed. 2007, 46, 8869.
(b) Biswas, B.; Singleton, D. A. J. Am. Chem. Soc. 2015, 137,
14244.
(4) (a) Sweeney, J. B. Chem. Soc. Rev. 2009, 38, 1027. (b) Pine, S. H.
The Base-Promoted Rearrangements of Quaternary Ammonium
Salts, In Organic Reactions; John Wiley & Sons, Inc: Weinheim,
2004.
(5) (a) Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125,
6046. (b) Reeves, J. T.; Fandrick, D. R.; Tan, Z.; Song, J. J.; Lee, H.;
Yee, N. K.; Senanayake, C. H. Org. Lett. 2010, 12, 4388. (c) Xie, L.-
G.; Wang, Z.-X. Angew. Chem. Int. Ed. 2011, 50, 4901. (d) Zhang,
X.-Q.; Wang, Z.-X. J. Org. Chem. 2012, 77, 3658. (e) Guo, W.-J.;
Wang, Z.-X. Tetrahedron 2013, 69, 9580. (f) Zhang, X.-Q.; Wang,
Z.-X. Org. Biomol. Chem. 2014, 12, 1448. (g) Zhang, H.; Hagihara,
S.; Itami, K. Chem. Eur. J. 2015, 21, 16796. (h) Zhu, F.; Tao, J.-L.;
Wang, Z.-X. Org. Lett. 2015, 17, 4926. (i) Hu, J.; Sun, H.; Cai, W.;
Pu, X.; Zhang, Y.; Shi, Z. J. Org. Chem. 2016, 81, 14.
(6) Maity, P.; Shacklady-McAtee, D. M.; Yap, G. P. A.; Sirianni, E. R.;
Watson, M. P. J. Am. Chem. Soc. 2013, 135, 280.
(7) (a) Shacklady-McAtee, D. M.; Roberts, K. M.; Basch, C. H.; Song,
Y.-G.; Watson, M. P. Tetrahedron 2014, 70, 4257. (b) Basch, C. H.;
Cobb, K. M.; Watson, M. P. Org. Lett. 2016, 18, 136.
(25) Huang, R.; Zhang, X.; Pan, J.; Li, J.; Shen, H.; Ling, X.; Xiong, Y.
Tetrahedron 2015, 71, 1540.
(26) Schäfer, G.; Bode, J. W. Angew. Chem. Int. Ed. 2011, 50, 10913.
(27) Ghorai, J.; Anbarasan, P. J. Org. Chem. 2015, 80, 3455.
(28) Shi, G.; Chen, D.; Jiang, H.; Zhang, Y.; Zhang, Y. Org. Lett. 2016,
18, 2958.
(8) Moragas, T.; Gaydou, M.; Martin, R. Angew. Chem. Int. Ed. 2016,
55, 5053.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J