Rhodium-catalyzed direct alkylation of benzylic amines using alkyl bromides

Article abstract of DOI:10.1007/s00706-018-2305-9

Within this contribution, the development and substrate scope evaluation of a direct alkylation protocol of the C(sp³)–H bond of benzylic amines using alkyl bromides is reported. This pyridine-directed method is initiated by elimination of the alkyl bromide to a terminal olefin, which is then the true alkylating agent. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-018-2305-9

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-018-2305-9
ORIGINAL PAPER
Rhodium‑catalyzed direct alkylation of benzylic amines using alkyl
bromides
Martin Anschuber1 · Robert Pollice2 · Michael Schnürch1
Received: 29 August 2018 / Accepted: 25 September 2018
© The Author(s) 2018
Abstract
Within this contribution, the development and substrate scope evaluation of a direct alkylation protocol of the C(sp3)–H
bond of benzylic amines using alkyl bromides is reported. This pyridine-directed method is initiated by elimination of the
alkyl bromide to a terminal olefn, which is then the true alkylating agent.
Graphical abstract
Keywords C–H activation · C–H functionalization · Directing group · Catalysis
Introduction
are the most frequently applied alkyl source [7]. However,
it has to be mentioned that literature examples often limit
themselves to functional group-substituted or long-chain
alkenes to avoid working with gaseous reagents. We have
shown, previously, that gaseous alkenes can be replaced by
quaternary ammonium salts, which deliver olefns in-situ via
Hofmann elimination (Scheme 1) [8].
Direct C–H functionalization via metal catalysis is emerging
as one of the most frequently investigated methods in recent
years. This can be deduced from the large number of contri-
butions published almost on a daily basis, and the number
of review articles summarizing various aspects of the feld
[1–4]. The largest part of research is dedicated to functional
group directed C–H functionalization reactions. By now lit-
erally, all of the most frequently occurring functional groups
have been used as a directing group, at least in a small set of
examples [5, 6]. Regarding the transformations which have
been reported, the variety has increased in recent years, as
well. Besides arylation, alkylation, and alkenylation reac-
tions, also more and more C-heteroatom bond forming reac-
tions are disclosed. Regarding alkylation reactions, olefns
This is a very convenient protocol, since all these salts are
easy-to-handle solids. Even though the quaternary ammo-
nium salts of interest are cheap reagents, the question was
raised whether alkyl halides can be used as olefn replace-
ment, as well, since ammonium salts are typically prepared
from alkyl halides and ammonia. If so, for introduction of
short alkyl chains gaseous reagents could be replaced by
liquid ones, which would still be more convenient than using
their gaseous counterparts. We have previously investigated
such a transformation briefy, and found that the reaction
actually proceeds via the initial elimination to the olefn,
which is then the true alkylating agent [9]. However, we then
focused on mechanistic investigations of the alkylation pro-
tocol using hex-1-ene and did not investigate the substrate
scope of the alkyl bromide protocol [10].
* Michael Schnürch
michael.schnuerch@tuwien.ac.at
1
Institute of Applied Synthetic Chemistry, TU Wien,
Getreidemarkt 9/163, 1060 Vienna, Austria
In the literature, alkyl halides are known to be suitable
alkyl sources for direct alkylation reactions; however, in
2
Laboratorium für Organische Chemie, ETH Zürich,
Vladimir-Prelog-Weg 2, 8093 Zurich, Switzerland
Vol.:(0123456789)
1 3

M. Anschuber et al.
Scheme 1
Scheme 2
Scheme 3
none of the examples, a prior elimination to an olefn is
considered [11–16]. For most of them, such a mechanistic
pathway can be excluded, since alkyl halide substrates which
cannot give elimination to an olefn are amongst the reported
examples (e.g., benzyl halides or iodomethane). However,
among the reported examples, there is one contribution in
which there is a high probability that initial elimination
might precede the actual alkylation [17]. In this contribution,
all alkyl halide examples allow the initial olefn formation,
and additionally, shortcomings of the transformation could
be explained, as well, since, e.g., benzylic and allylic halides
failed to give the desired products (Scheme 2).
source (Table 1, entry 1). Hence, further optimization was
necessary. First, we did two experiments, once increas-
ing and once decreasing the amount of KOH. Decreas-
ing the amount of the base to 0.5 equivalents had a det-
rimental efect and the yield was cut half to 6% (Table 1,
entry 2). Also the threefold amount of base led only to a
slightly increased yield of 16% (Table 1, entry 3). Next,
the temperature was increased to 160 °C. However, also
in this case, the efect was not dramatic and 22% of 6 were
obtained (Table 1, entry 4). In a next step, we prolonged
the reaction time, frst to 46 h, then to 70 h. The resulting
yields were 36% and 41%, respectively.
Within this contribution, we report on the development
and substrate scope evaluation of an alkylation protocol
using alkyl bromides initially eliminating to the correspond-
ing terminal olefns before direct alkylation takes place
(Scheme 3).
The fnal step in the optimization was substituting KOH
by K2CO3 and, at the same time, increasing the amount to
4.5 equivalents. The isolated yield of this reaction was 50%.
Unfortunately, all other optimization experiments did not
lead to a higher yield. Compared to our previously published
quaternary ammonium salt protocol, this corresponds to an
about 10–20% lower yield.
Results and discussion
It has to be mentioned that this transformation is limited
to the application of alkyl bromides, since alkyl chlorides
did not react at all, and alkyl iodides give N-alkylation
instead of the desired C-alkylation.
Before turning towards the substrate scope evaluation,
we wanted to revisit the reaction optimization briefy. We
started using the reaction conditions of our previously
reported Rh(I)-catalyzed alkylation protocol [8] with 1
as substrate and 1-bromohexane instead of a quaternary
ammonium salt, since these conditions were quite success-
ful in Hofmann elimination. The frst result was not very
satisfactory, delivering only 12% yield of the desired prod-
uct 6, showing that the conditions for the previous proto-
col could not be applied when alkyl halides are the alkyl
With the fnal conditions in hand, we started investi-
gating the substrate scope with respect to alkyl bromides.
First, we used diferent alkyl halides with a carbon chain
length up to C22 (Scheme 4, products 2–14).
Bromoethane gave an isolated yield of only 25% of 2.
However, to synthesize 2, N(Et4)Br can be used giving
68% yield [8]. Using longer alkyl bromides gave much
better results, i.e., yields typically around 50%. Especially,
1 3

Rhodium-catalyzed direct alkylation of benzylic amines using alkyl bromides
Table 1 Selected screening results for alkylation of 1 using n-hexyl bromide
Experiment
Base
Eq. base
Catalyst/5 mol%
Temperature/°C
Time/h
Yield/%
1
2
3
4
5
6
7
KOH
KOH
KOH
KOH
KOH
KOH
K2CO3
1.0
0.5
3.0
3.0
3.0
3.0
4.5
[RhCl(cod)]2
[RhCl(cod)]2
[RhCl(cod)]2
[RhCl(cod)]2
[RhCl(cod)]2
[RhCl(cod)]2
[RhCl(cod)]2
140
140
140
160
160
160
160
22
22
22
22
46
70
22
12
6
16
22
36
41
50
alkyl chains from C3 to C6 and C10 to C12 gave basically
the same isolated yield, i.e., they were within experimental
error (Scheme 4, compounds 3–6, 9–11, 50–60%). Inter-
estingly, 1-bromoheptyl and 1-bromooctyl gave a slightly
lower yield (7, 38% and 8, 42%), the reason for that being
currently unclear. To go to the extreme, we also tested
1-bromodocosane (C22, product 12, 31%) and observed
that an alkyl bromide with such a long alkyl chain is still
a potential substrate for this kind of reaction delivering the
fnal product in 31% yield.
hypothesized that other alkylation reactions using olefns
should be accessible to our protocol as long as the moieties
of the substrates do not deactivate or destroy the catalyst.
However, it turned out that alkyl bromides eliminating to
substituted allylic and vinylic compounds were not toler-
ated giving either no or very low conversion (Scheme 5).
In cases where the formed olefn is further away from
the functional group, the reaction worked again as dem-
onstrated by the reaction of ethyl 4-bromobutanoate and
ethyl 5-bromopentanoate, which delivered the respective
products in 57% and 35% yield, respectively (Scheme 6,
compounds 18 and 19).
In addition to linear primary bromoalkanes, other alkyl
bromides were tested, as well. Secondary linear alkyl bro-
mides such as 2-bromopropane and 2-bromobutane gave
the same product as their primary isomers although in
considerably lower yield. This is due to the fact that the
initial elimination to the corresponding olefn in case of
2-bromopropane seems to be slower, and in case of 2-bro-
mobutane, it can additionally deliver two diferent olefns,
of which only the terminal one can react, but the internal
one is the more stable one. Using cyclohexyl bromide as
substrate which can only deliver an internal olefn, no con-
version was detected at all.
Furthermore, we changed the substitution pattern at the
ortho-, meta-, and para-position of the benzyl group of
our starting material. Substrate 15 is bearing an o-methyl
group, 16 is bearing an m-methoxy group, and 17 is bear-
ing a p-trifuoromethyl group. The rationale behind using
these groups is to fnd out whether the reaction is infu-
enced by sterically demanding groups, as well as both
electron donating and withdrawing groups.
These substrates were tested in n-butylation and
n-decylation reactions, respectively, to demonstrate the
utility of our protocol to introduce both a short and a long
alkyl chain. As can be seen in Scheme 6 (compounds
20–25), again, the same range of yields was obtained
(47–62%), apart from one reaction (vide infra). It was
observed that the methyl group at the benzylic ortho-
position decreased the yield compared to the unsubsti-
tuted starting compound 1 (Scheme 6, compounds 22 and
23). This can be rationalized using steric arguments. The
decrease in yield is much more dramatic in case of 1-bro-
modecane as coupling partner as compared to 1-bromobu-
tane, which again hints towards a steric efect.
The reaction with 1-bromo-3-methylbutane as branched
alkyl bromide delivered the product 13 in quite good
yield of 55% (Scheme 4). In addition, the alkylation
with 1-bromo-2-phenylethane, which delivers styrene
upon elimination, worked with an acceptable yield of 14
(Scheme 3, 43%). These two substrates are not accessible
for this reaction via quaternary ammonium salts.
Next, it was tested whether the developed alkylation
protocol is limited to unsubstituted alkyl halides, since
utility and acceptance of the protocol would depend
largely on the possibility of general applicability. It was
1 3

M. Anschuber et al.
Scheme 4
A m-methoxy group gave good yields of 56% in both
cases (Scheme 6, compounds 20 and 21). In addition, an
electron-withdrawing substituent such as a p-CF3 group
seems to have no impact on the isolated yield, since 50% of
24 and 62% of 25 were obtained, respectively.
Finally, it has to be mentioned that the cleavage of the
directing group is possible following a strategy that has
proven to be successful in the literature [18] and in our lab
[19–21].
1 3

Rhodium-catalyzed direct alkylation of benzylic amines using alkyl bromides
Scheme 5
Scheme 6
quaternary ammonium salts [8]. Linear and unsubstituted
alkyl bromides give the best results and examples up to a
C22 chain length were reported. Functional group toler-
ance on the amine substrate was good, but limitations were
observed when substituted alkyl bromides were used. If
elimination to an allylic or vinylic olefn would need to
Conclusion
We demonstrated that alkyl bromides can be used as ole-
fn precursors in the direct alkylation of C(sp3)–H bonds
of benzylic amines. The reaction works with slightly
lower efciency as the previously disclosed protocol using
1 3

M. Anschuber et al.
with hybrid ion trap and high-resolution time-of-fight–mass
spectrometry (LC–IT–TOF–MS) in only positive-ion detec-
tion mode with the recording of standard (MS) and tandem
(MS/MS) spectra.
General procedure A for C–H activation reactions
to compounds 2–14 and 18–25
Solid starting materials (except the catalyst) were placed in
an oven-dried 8 cm3 glass vial with a solid top screw cap
and a magnetic stirring bar. The vial was transferred into
the glovebox under argon. Catalyst, liquid starting materials,
solvent, and dodecane (as internal standard) were added in
the glovebox. Finally, the vial was closed and the reaction
mixture was heated in a heating block for the desired time
at the desired temperature.
Fig. 1 Scheme for assigning NMR signals
occur, the reaction is inefcient. In addition, not many func-
tional groups were tolerated. However, carboxylic acid esters
work well. This gives a handle for further elaboration of the
obtained products. Finally, cleavage of the directing group is
possible, as well, an important feature in DG-assisted C–H
functionalization.
General work‑up procedure B for C–H activation
reactions towards compounds 2–14 and 18–25
After cooling the reaction mixture to room temperature,
the solid material was removed by fltration using a Pasteur
pipette with cotton and Hyfo. The residue was washed with
CH2Cl2. The combined organic fltrate was concentrated
under reduced pressure. The resulting crude residue was
purifed by fash column chromatography (LP/EtOAc).
Experimental
In general, unless noted otherwise, chemicals were pur-
chased from commercial suppliers and used without fur-
ther purifcation. Cyclooctadiene rhodium chloride dimer
[RhCl(cod)]2 was handled in the glovebox under argon. Dry
and degassed toluene was stored over molecular sieves in the
glovebox under argon. Other dry solvents were obtained by
passing pre-dried material through a cartridge-containing
activated alumina (solvent dispensing system) and stored
under nitrogen atmosphere until usage.
General procedure C for precursor synthesis (1,
15–17)
Solid starting materials were placed in a 100 cm3 3-necked-
fask, evacuated, and fushed with argon three times. Then,
the liquid starting materials and, fnally, toluene were added
through the septum with a syringe. The mixture was heated
at 130 °C (oil bath temperature) maintaining the argon
atmosphere with a balloon. The reaction was stopped after
18 h (TLC). After cooling to r.t., the solid material was
removed by fltration and washed with CH2Cl2. The com-
bined organic layers were evaporated and the resulting crude
product was purifed by fash column chromatography (LP/
EtOAc) starting with 5% EtOAc to 10% EtOAc over the
course of 20 min. Then, fash column chromatography was
continued with 10% EtOAc. Drying under reduced pressure
delivered the pure product.
1H NMR, 13C NMR, and HSQC spectra were recorded
on a Bruker Avance 400; chemical shifts are reported in
ppm, using Me4Si as internal standard. NMR signals were
assigned according to Fig. 1. GC–MS was performed on
a Thermo Trace 1300 GC/MS ISQ LT (quadrupole, EI+)
with a TR-5 capillary column (7 m × 0.32 mm, 0.25 μm
flm, achiral). Temperature program: Start at 100 °C (hold
2 min), 35 °C/min, and 300 °C (hold 4 min). GC spectra
were recorded on a Thermo Focus GC using a BGB-5 capil-
lary column (30 m×0.32 mm, 1.0 μm flm, achiral) with the
following oven temperature program: Start at 100 °C (hold
2 min), 35 °C/min, 300 °C (hold 4 min). For TLC aluminum,
backed silica gel 60 with fuorescence indicator F254 was
used. Column chromatography was performed on Silica 60
from Merck (40–63 μm). Flash chromatography was carried
out on a Büchi Sepacore™ MPLC system. Melting points
were determined on an automated melting point system
(Büchi Melting Point B-545). High-resolution mass spec-
trometry (HRMS) for the literature-unknown compounds
was performed by liquid chromatography in combination
N‑Benzyl‑3‑methylpyridin‑2‑amine (1) In a 100 cm3 three-
necked-flask, were placed 67 mg Pd(OAc)2 (0.3 mmol,
0.02 eq.), 187 mg rac. BINAP (0.3 mmol, 0.02 eq.), and
7.214 g K2CO3 (52.5 mmol, 3.5 eq.), and the fask was evac-
uated and fushed with argon three times. Then, 1.63 cm3
2-chloro-3-methylpyridine (15 mmol, 1 eq.), 1.97 cm3
freshly distilled benzylamine (18 mmol, 1.2 eq.), and,
fnally, 38 cm3 toluene were added through the septum with
1 3

Rhodium-catalyzed direct alkylation of benzylic amines using alkyl bromides
a syringe. The mixture was heated to 130 °C maintaining the
argon atmosphere with a balloon. The reaction was stopped
after 18 h (TLC). After cooling to r.t. the solid material was
removed by fltration and washed with 150 cm3 CH2Cl2. The
combined organic layers were evaporated and the resulting
crude product was purifed by fash column chromatography
(LP/EtOAc) starting with 5% EtOAc to 10% EtOAc over the
course of 20 min. Then, fash column chromatography was
continued with 10% EtOAc. Drying under reduced pressure
delivered 2.55 g (86%) 1 as beige solid. Analytical data are
in accordance to the literature [22].
layers were evaporated and the resulting crude product was
purifed by fash column chromatography (LP/EtOAc, 45 g
SiO2, fowrate 30 cm3/min) using a gradient which varies the
solvents from 0% to 5% EtOAc within 45 min. The product
was dried under reduced pressure and 4 was isolated in 56%
(71 mg) yield as pale yellowish oil. Analytical data are in
accordance to the literature [8].
3‑Methyl‑N‑(1‑phenylhexyl)pyridin‑2‑amine (5) The reac-
tion was carried out according to general procedure A with
100 mg 1 (0.50 mmol, 1 eq.), 225 mg 1-bromopentane
(1.50 mmol, 3 eq.), 311 mg K2CO3 (2.25 mmol, 4.5 eq.),
and 12 mg [RhCl(cod)]2 (0.025 mmol, 0.05 eq.) in 2 cm3 dry
and degassed toluene. The reaction mixture was heated for
22 h at 160 °C. The general work-up procedure B for C–H
activation reactions was followed. The combined organic
layers were evaporated and the resulting crude product was
purifed by fash column chromatography (LP/EtOAc, 45 g
SiO2, fowrate 30 cm3/min) starting with pure LP for 10 min.
Then, the fash column chromatography was continued using
a gradient which varies the solvents from 0% to 10% EtOAc
within 45 min. The product was dried under reduced pres-
sure and 5 was isolated in 35% (46 mg) yield as pale yellow-
ish oil. Analytical data are in accordance to the literature [8].
3‑Methyl‑N‑(1‑phenylpropyl)pyridin‑2‑amine (2) The
reaction was carried out according to general procedure A
with 100 mg 1 (0.50 mmol, 1 eq.), 163 mg 1-bromoethane
(1.50 mmol, 3 eq.), 311 mg K2CO3 (2.25 mmol, 4.5 eq.), and
12 mg [RhCl(cod)]2 (0.025 mmol, 0.05 eq.) in 2 cm3 dry and
degassed toluene. The reaction mixture was heated for 22 h
at 160 °C. The general work-up procedure B for C–H activa-
tion reactions was followed. The combined organic layers
were evaporated and the resulting crude product was puri-
fed by fash column chromatography (LP/EtOAc, 45 g SiO2,
fowrate 30 cm3/min) starting with pure LP for 10 min and
then continuing using a gradient which varies the solvents
from 0% to 5% EtOAc within 45 min. The product was dried
under reduced pressure and 2 was isolated in 25% (29 mg)
yield as yellow oil. Analytical data are in accordance to the
literature [19].
3‑Methyl‑N‑(1‑phenylheptyl)pyridin‑2‑amine (6) The reac-
tion was carried out according to general procedure A
with 100 mg 1 (0.50 mmol, 1 eq.), 248 mg 1-bromohexane
(1.50 mmol, 3 eq.), 311 mg K2CO3 (2.25 mmol, 4.5 eq.),
and 12 mg [RhCl(cod)]2 (0.025 mmol, 0.05 eq.) in 2 cm3 dry
and degassed toluene. The reaction mixture was heated for
22 h at 160 °C. The general work-up procedure B for C–H
activation reactions was followed. The combined organic
layers were evaporated and the resulting crude product was
purifed by fash column chromatography (LP/EtOAc, 45 g
SiO2, fowrate 30 cm3/min) starting with pure LP for 10 min.
Then, the fash column chromatography was continued using
a gradient which varies the solvents from 0% to 10% EtOAc
within 45 min. The product was dried under reduced pres-
sure and 6 was isolated in 40% (56 mg) yield as pale yellow-
ish oil. Analytical data are in accordance to the literature [8].
3‑Methyl‑N‑(1‑phenylbutyl)pyridin‑2‑amine (3) The reac-
tion was carried out according to general procedure A with
100 mg 1 (0.50 mmol, 1 eq.), 184 mg 2-bromopropane
(1.50 mmol, 3 eq.), 311 mg K2CO3 (2.25 mmol, 4.5 eq.),
and 12 mg [RhCl(cod)]2 (0.025 mmol, 0.05 eq.) in 2 cm3 dry
and degassed toluene. The reaction mixture was heated for
22 h at 160 °C. The general work-up procedure B for C–H
activation reactions was followed. The combined organic
layers were evaporated and the resulting crude product was
purifed by fash column chromatography (LP/EtOAc, 45 g
SiO2, fowrate 30 cm3/min) using a gradient which varies the
solvents from 0% to 5% EtOAc within 45 min. Drying under
reduced pressure delivered 3 in 32% (39 mg) yield. TLC:
Rf =0.74 (LP/EtOAc 10:1); analytical data are in accordance
to the literature [8].
3‑Methyl‑N‑(1‑phenyloctyl)pyridin‑2‑amine (7, C20H28N2) The
reaction was carried out according to general procedure A
with 100 mg 1 (0.50 mmol, 1 eq.), 269 mg 1-bromoheptane
(1.50 mmol, 3 eq.), 311 mg K2CO3 (2.25 mmol, 4.5 eq.),
and 12 mg [RhCl(cod)]2 (0.025 mmol, 0.05 eq.) in 2 cm3 dry
and degassed toluene. The reaction mixture was heated for
22 h at 160 °C. The general work-up procedure B for C–H
activation reactions was followed. The combined organic
layers were evaporated and the resulting crude product was
purifed by fash column chromatography (LP/EtOAc, 45 g
SiO2, fowrate 30 cm3/min) starting with pure LP for 5 min.
3‑Methyl‑N‑(1‑phenylpentyl)pyridin‑2‑amine (4) The reac-
tion was carried out according to general procedure A
with 100 mg 1 (0.50 mmol, 1 eq.), 206 mg 1-bromobutane
(1.50 mmol, 3 eq.), 311 mg K2CO3 (2.25 mmol, 4.5 eq.),
and 12 mg [RhCl(cod)]2 (0.025 mmol, 0.05 eq.) in 2 cm3 dry
and degassed toluene. The reaction mixture was heated for
22 h at 160 °C. The general work-up procedure B for C–H
activation reactions was followed. The combined organic
1 3

M. Anschuber et al.
Then, the fash column chromatography was continued using
a gradient which varies the solvents from 0% to 5% EtOAc
within 1 h. Drying under reduced pressure delivered 7 in 38%
(57 mg) yield as yellow oil. TLC: Rf =0.59 (LP/EtOAc 10:1);
1H NMR (400 MHz, CDCl3): δ=0.86 (t, J=14.6, 9.8 Hz,
3H, C[9]–H3), 1.14–1.38 (m, 10H, C[4–8]–H2), 1.87 (ddd,
J=22.3, 9.6, 6.8 Hz, 1H, C[3]–H), 2.12 (s, 3H, C[7a]–H3),
4.37 (d, J=7.6 Hz, 1H, N–H), 5.24 (d, J=7.3 Hz, 1H, C[2]–
H), 6.47 (dd, J=7.1, 5.1 Hz, 1H, C[5a]–H), 7.15–7.25 (m,
2H, C[4a; 4b]–H), 7.27–7.41 (m, 4H, C[2b; 3b; 5b; 6b]–H),
7.95 (dd, J = 5.0, 1.8 Hz, 1H, C[6a]–H) ppm; 13C NMR
(101 MHz, CDCl3): δ=14.1 (q, C[9]), 17.1 (q, C[7a]), 22.7
(t, C[8]), 26.4 (t, C[7]), 29.2 (t, C[6]), 29.6 (t, C[5]), 31.8 (t,
C[4]), 37.6 (t, C[3]), 54.6 (d, C[2]), 112.5 (d, C[5a]), 116.2
(s, C[3a]), 126.5 (d, C[2b; 6b]), 126.7 (d, C[4b]), 128.4
(d, C[3b; 5b]), 136.7 (d, C[4a]), 144.6 (s, C[1b]), 145.6,
(d, C[6a]), 156.2 (s, C[2a]) ppm; GC–MS: retention time:
7.86 min; main fragments: m/z (%)=296 (M+, 11), 211 (19),
197 (100), 108 (22), 91 (21), 65 (11).
26.4 (t, C[7]), 29.3 (t, C[5]), 29.5 (t, C[8, 9]), 29.6 (t, C[4a;
4b]), 31.9 (t, C[11]), 37.6 (t, C[3]), 54.6 (d, C[2]), 112.5
(d, C[5a]), 116.1 (s, C[3a]), 126.5 (d, C[2b; 6b]), 126.7 (d,
C[4b]), 128.1 (d, C[3b; 5b]), 136.8 (d, C[4a]), 144.6 (s,
C[1b]), 145.8 (d, C[6a]), 156.2 (s, C[2a]) ppm; GC–MS:
retention time: 8.73 min; main fragments: m/z (%) = 338
(M+, 8), 211 (20), 197 (100), 108 (23), 91 (18), 65 (7).
3‑Methyl‑N‑(1‑phenyldodecyl)pyridin‑2‑amine (10,
C24H36N2) The reaction was carried out according to gen-
eral procedure A with 100 mg 1 (0.50 mmol, 1 eq.), 353 mg
1-bromoundecane (1.50 mmol, 3 eq.), 311 mg K2CO3
(2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2 (0.025 mmol,
0.05 eq.) in 2 cm3 dry and degassed toluene. The reaction
mixture was heated for 22 h at 160 °C. The general work-
up procedure B for C–H activation reactions was followed
starting with pure LP for 10 min. Then, the fash column
chromatography was continued using a gradient which var-
ies the solvents from 0% to 5% EtOAc within 1 h. Drying
under reduced pressure delivered 10 in 60% (106 mg) yield.
1
3‑Methyl‑N‑(1‑phenylnonyl)pyridin‑2‑amine (8) The reac-
tion was carried out according to general procedure A
with 100 mg 1 (0.50 mmol, 1 eq.), 290 mg 1-bromooctane
(1.50 mmol, 3 eq.), 311 mg K2CO3 (2.25 mmol, 4.5 eq.), and
12 mg [RhCl(cod)]2 (0.025 mmol, 0.05 eq.) in 2 cm3 dry and
degassed toluene. The reaction mixture was heated for 22 h
at 160 °C. The general work-up procedure B for C–H activa-
tion reactions was followed starting with pure LP for 10 min.
Then, the fash column chromatography was continued using
a gradient which varies the solvents from 0% to 5% EtOAc
within 1 h. Drying under reduced pressure delivered 8 in
42% (65 mg) yield as yellow oil. TLC: Rf =0.51 (LP/EtOAc
10:1); analytical data are in accordance to the literature [8].
TLC: Rf = 0.55 (LP/EtOAc 10:1); H NMR (400 MHz,
CDCl3): δ=0.93 (s, 3H, C[13]–H3), 1.28 (s, 18H, C[4–12]–
H2), 1.81–2.03 (m, 2H, C[3]–H2), 2.15 (s, 3H, C[7a]–H3),
4.43 (s, 1H, N–H), 5.30 (q, J=7.1 Hz, 1H, C[2]–H), 6.50
(dd, J=7.1, 5.1 Hz, 1H, C[5a]–H), 7.19–7.30 (m, 2H, C[4a;
4b]–H)), 7.30–7.45 (m, 4H, C[2b; 3b; 5b; 6b]–H), 8.00 (dd,
J = 5.0, 1.9 Hz, 1H, C[6a]–H) ppm; 13C NMR (101 MHz,
CDCl3): δ=14.2 (q, C[13]), 17.1 (q, C[7a]), 29.6 (t, C[5–
10]), 32.0 (t, C[11]), 37. 6 (t, C[3]), 54.7 (d, C[2]), 112.5
(d, C[5a]), 116.2 (s, C[3a]), 126.5 (d, C[2b; 6b]), 126.7 (d,
C[4b]), 128. 4 (d, C[3b; 5b]), 136.8 (d, C[4a]), 144.6 (s,
C[1b]), 145.5 (d, C[6a]), 156.2 (s, C[2a]) ppm; GC–MS:
retention time: 8.73 min; main fragments: m/z (%) = 352
(M+, 8), 211 (19), 197 (100), 108 (23), 91 (19), 65 (7);
HRMS: m/z calculated for C24H36N2 ([M+H]+) 353.2957,
found 353.2972; Δ=5.93 ppm.
3‑Methyl‑N‑(1‑phenylundecyl)pyridin‑2‑amine (9,
C23H34N2) The reaction was carried out according to
general procedure A with 100 mg 1 (0.50 mmol, 1 eq.),
332 mg 1-bromodecane (1.50 mmol, 3 eq.), 311 mg K2CO3
(2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2 (0.025 mmol,
0.05 eq.) in 2 cm3 dry and degassed toluene. The reaction
mixture was heated for 22 h at 160 °C. The general work-
up procedure B for C–H activation reactions was followed
using a gradient which varies the solvents from 0% to 5%
EtOAc within 1 h. Drying under reduced pressure deliv-
ered 9 in 56% (65 mg) yield. TLC: Rf = 0.57 (LP/EtOAc
10:1); 1H NMR (400 MHz, CDCl3): δ=0.88 (t, J=6.8 Hz,
3H, C[12]–H3), 1.10–1.48 (m, 16H, C[4–11]–H2), 1.77–
1.98 (m, 2H, C[3]–H2), 2.12 (s, 3H, C[7a]–H3), 4.37 (d,
J=7.4 Hz, 1H, N–H), 5.24 (q, J=7.1 Hz, 1H, C[2]–H), 6.47
(dd, J=7.1, 5.0 Hz, 1H, C[5a]–H), 7.15–7.27 (m, 2H, C[4a;
4b]–H), 7.27–7.44 (m, 4H, C[2b; 3b; 5b; 6b]–H), 7.96 (dd,
J = 5.1, 1.8 Hz, 1H, C[6a]–H) ppm; 13C NMR (101 MHz,
CDCl3): δ=14.1 (q, C[12]), 17.1 (q, C[7a]), 22.7 (t, C[6]),
3‑Methyl‑N‑(1‑phenyltridecyl)pyridin‑2‑amine (11,
C25H38N2) The reaction was carried out according to
general procedure A with 100 mg 1 (0.50 mmol, 1 eq.),
374 mg 1-bromododecane (1.50 mmol, 3 eq.), 311 mg
K2CO3 (2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2
(0.025 mmol, 0.05 eq.) in 2 cm3 dry and degassed tolu-
ene. The reaction mixture was heated for 22 h at 160 °C.
The general work-up procedure B for C–H activation reac-
tions was followed using frst 5 min pure LP and continu-
ing using a gradient which varies the solvents from 0% to
5% EtOAc within 1 h. Drying delivered 24 in 56% (96 mg)
yield as pale yellowish oil. TLC: Rf =0.9 (LP/EtOAc 10:1);
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3H,
C[14]–H3), 1.21–1.36 (m, 20H, C[4–13]–H2), 1.78–1.97 (m,
2H, C[3]–H2), 2.12 (s, 3H, C[7a]–H3), 4.41 (s, 1H, N–H),
5.26 (q, J=7.3 Hz, 1H, C[2]–H), 6.47 (dd, J=7.1, 5.1 Hz,
1 3

Rhodium-catalyzed direct alkylation of benzylic amines using alkyl bromides
1H, C–[5a]–H), 7.18–7.25 (m, 2H, C[4a; 4b]–H), 7.31 (t,
solvents from 0% to 5% EtOAc within 45 min. Drying under
J=7.5 Hz, 2H, C[2b; 6b]–H, 7.37 (d, J=7.5 Hz, 2H, C[3b;
reduced pressure delivered 13 in 55% (90 mg) yield as pale
5b]–H), 7.95 (dd, J=5.1, 1.7 Hz, 1H, C[6a]–H) ppm; 13
C
yellowish oil. TLC: Rf = 0.67 (LP/EtOAc 10:1); H NMR
1
NMR (101 MHz, CDCl3): δ = 14.14 (q, C[14]), 17.09 (q,
C[7a]), 22.71 (t, C[13]), 26.35 (t, C[12]), 29.31–29.75 (m)
(t, C[5–11]), 31.94 (t, C[4]), 37.55 (t, C[3]), 54.72 (d, C[2]),
112.50 (d C[5a]), 126.53 (d, C[3b; 5b]), 126.73 (d, C[4b]),
128.39 (d, C[2b; 6b]), 136.91 (d, C[4a]), 144.43 (s, C[1b])
ppm; GC–MS: retention time: 9.22 min; main fragments:
m/z (%) = 366 (M+, 8), 267 (1), 211 (19), 197 (100), 108
(26), 91 (18), 65 (6); HRMS: m/z calculated for C25H38N2
([M+H]+) 367.3114, found 367.3119; ∆=3.14 ppm.
(400 MHz, CDCl3): δ=0.87 (dd, J=6.6, 3.5 Hz, 6H, C[6,
7]–H3), 1.09–1.39 (m, 2H, C[3]–H2), 1.58 (dp, J = 13.3,
6.7 Hz, 1H, C[5]–H), 1.73–2.00 (m, 2H, C[4]–H2), 2.12
(s, 3H, C[7a]–H3), 4.39 (d, J = 7.5 Hz, 1H, N–H), 5.23
(q, J=7.2 Hz, 1H, C[2]–H), 6.47 (dd, J=7.1, 5.1 Hz, 1H,
C[5a]–H), 7.14–7.25 (m, 2H, C[4a; 4b]–H), 7.27–7.42 (m,
4H, C[2b; 3b; 5b; 6b]–H), 7.95 (dd, J = 6.0, 1.8 Hz, 1H,
C[6a]–H) ppm; 13C NMR (101 MHz, CDCl3): δ=17.2 (q,
C[6, 7]), 22.7 (q, C[7a]), 28.2 (d, C[5]), 35.4 (t, C[4]), 35.6
(t, C[3]), 55.0 (d, C[2]), 112.6 (d, C[5a]), 116.4 (s, C[3a]),
126.7 (d, C[2b; 6b]), 126.9 (d, C[4b]), 128.5 (d, C[3b; 5b]),
137.0 (d, C[4a]), 144.6 (s, C[1b]), 145.5 (d, C[6a]), 156.2
(s, C[2a]) ppm; GC–MS: retention time: 9.97 min; main
fragments: m/z (%)=268 (M+, 6), 211 (17), 197 (100), 108
(30), 91 (20).
3‑Methyl‑N‑(1‑phenyltricosyl)pyridin‑2‑amine (12,
C35H58N2) The reaction was carried out according to gen-
eral procedure A with 100 mg 1 (0.50 mmol, 1 eq.), 584 mg
1-bromodocosane (1.50 mmol, 3 eq.), 311 mg K2CO3
(2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2 (0.025 mmol,
0.05 eq.) in 2 cm3 dry and degassed toluene. The reaction
mixture was heated for 22 h at 160 °C. The general work-up
procedure B for C–H activation reactions was followed using
a gradient which varies the solvents from 0% to 20% EtOAc
within 45 min. Upon recrystallisation, the pure product was
isolated in 31% (80 mg) yield as white crystals. M.p.: 47.5–
47.6 °C; TLC: Rf =0.8 (LP/EtOAc 5:1); 1H NMR (400 MHz,
CDCl3): δ=0.88 (t, J=6.7 Hz, 3H, C[24]–H3),), 1.19–1.33
(m, 40H, C[4–23]–H2), 1.80–1.90 (m, 2H, C[3]–H2), 2.13
(s, 3H, C[7a]–H3), 4.52 (s, 1H, N–H), 5.32 (s, 1H, C[2]–H),
6.49 (dd, J=7.1, 5.2 Hz, 1H, C[5a]–H), 7.18–7.25 (m, 2H,
C[4a; 4b]–H), 7.31 (t, J =7.5 Hz, 2H, C[2b; 6b]–H), 7.39
(d, J=7.5 Hz, 2H, C[3b; 5b]–H), 7.95 (dd, J=5.2, 1.7 Hz,
1H, C[6a]–H) ppm; 13C NMR (101 MHz, CDCl3): δ=14.1
(q, C[24]), 17.1 (q, C[7a]), 22.7 (t, C[23]), 26.3 (t, C[4]),
29.81–29.32 (m) (t, C[5–21]), 31.9 (t, C[22]), 37.6 (t, C[3]),
55.0 (d, C[2]), 112.5 (d, C[5a]), 126.5 (d, C[3b; 5b]), 126.9
(d, C[4b]), 128.5 (d, C[2b; 6b]) ppm; LC–MS: retention
time: 2.28 min; main fragments: m/z (%)=507.40 ([M+H]+,
100), 508.4 (40), 509.4 (7), 493.4 (18), 322.2 (16), 314.2
(10), 282.2 (28).
N‑(1,3‑Diphenylpropyl)‑3‑methylpyridin‑2‑amine (14,
C21H22N2) The reaction was carried out according to gen-
eral procedure A with 100 mg 1 (0.50 mmol, 1 eq.), 278 mg
(2-bromoethyl)benzene (1.50 mmol, 3 eq.), 311 mg K2CO3
(2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2 (0.025 mmol,
0.05 eq.) in 2 cm3 dry and degassed toluene. The reaction
mixture was heated for 22 h at 160 °C. The general work-up
procedure B for C–H activation reactions was followed. The
combined organic layers were evaporated and the resulting
crude product was purifed by fash column chromatogra-
phy (LP/EtOAc, 45 g SiO2, fowrate 30 cm3/min) starting
with pure LP for 10 min. Then, the fash column chroma-
tography was continued using a gradient which varies the
solvents from 0% to 5% EtOAc within 45 min. Drying under
reduced pressure delivered 14 in 23% (36 mg) yield as pale
1
yellowish oil. TLC: Rf = 0.46 (LP/EtOAc 10:1); H NMR
(400 MHz, CDCl3): δ=1.95 (s, 3H, C[7a]–H3), 1.96–2.28
(m, 2H, C[4]–H), 2.70 (dddd, J=51.9, 14.0, 9.8, 6.0 Hz, 2H,
C[3]–H2), 4.27–4.34 (m, 1H, N–H), 5.30 (q, J=7.1 Hz, 1H,
C[2]–H), 6.40 (dd, J=7.1, 5.1 Hz, 1H, C[5a]–H), 7.04–7.28
(m, 9H, C[2b; 3b; 5b; 6b; 2c–6c]–H), 7.28–7.36 (m, 2H,
C[4a; 4b]–H), 7.88 (dd, J=5.2, 1.8 Hz, 1H, C[6a]–H) ppm;
13C NMR (101 MHz, CDCl3): δ = 17.0 (q, C[7]), 32.8 (t,
C[4]), 38.9 (t, C[3]), 54.7 (d, C[2]), 112.7 (s, C[3a]), 116.4
(d, C[5a]), 125.9 (d, C[2b; 6b]), 126.6 (d, C[4b]), 127.0 (d,
C[3b; 5b]), 127.7 (d, C[4c]), 128.5 (d, C[3c; 5c]), 128.6
(d, C[2c; 6c]), 136.9 (d, C[4a]), 142.1 (s, C[1c]), 144.1 (s,
C[1b]), 145.4 (d, C[6a]), 156.0 (s, C[2a]) ppm; GC–MS:
retention time: 8.50 min; main fragments: m/z (%) = 302
(M+, 9), 211 (85), 197 (100), 108 (20), 91 (52), 65 (30).
3‑Methyl‑N‑(4‑methyl‑1‑phenylpentyl)pyridin‑2‑amine (13,
C18H24N2) The reaction was carried out according to general
procedure A with 100 mg 1 (0.50 mmol, 1 eq.), 227 mg
1-bromo-3-methylbutane (1.50 mmol, 3 eq.), 311 mg K2CO3
(2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2 (0.025 mmol,
0.05 eq.) in 2 cm3 dry and degassed toluene. The reaction
mixture was heated for 22 h at 160 °C. The general work-up
procedure B for C–H activation reactions was followed. The
combined organic layers were evaporated and the resulting
crude product was purifed by fash column chromatogra-
phy (LP/EtOAc, 45 g SiO2, fowrate 30 cm3/min) starting
with pure LP for 10 min. Then, the fash column chroma-
tography was continued using a gradient which varies the
3‑Methyl‑N‑(2‑methylbenzyl)pyridin‑2‑amine (15,
C14H16N2) The reaction was carried out according to gen-
eral procedure C with 67 mg Pd(OAc)2 (0.3 mmol, 0.02
1 3

M. Anschuber et al.
equiv.), 187 mg rac. BINAP (0.3 mmol, 0.02 equiv.), 7.26 g
K2CO3 (52.5 mmol, 3.5 equiv.), 1.91 g 2-chloro-3-methyl-
pyridine (15 mmol, 1 equiv.), 2.18 g 2-methylbenzylamine
(18 mmol, 1.2 equiv.), and 38 cm3 toluene. The yield of
the thereby prepared yellow crystals is 73% (2.34 g). TLC:
general work-up procedure B for C–H activation reactions
was followed. The combined organic layers were evaporated
and the resulting crude product was purifed by fash column
chromatography (LP/EtOAc, 9 g SiO2, fowrate 15 cm3/min)
using a gradient which varies the solvents from 0% to 5%
EtOAc within 45 min. Drying under reduced pressure deliv-
ered 18 in 26% (41 mg) yield as dark yellowish oil. TLC:
1
Rf = 0.2 (LP/EtOAc 10:1); H NMR (400 MHz, CDCl3):
δ = 2.07 (s, 3H, C[7a]–H3), 2.39 (s, 3H, C[7b]–H3), 4.20
(s, 1H, N[1]–H), 4.66 (d, J = 4.9 Hz, 2H, C[2]–H2), 6.57
(dd, J=7.0, 5.2 Hz, 1H, C[5a]–H), 7.20 (m, 3H, C[4a; 2b;
4b]), 7.25 (d, J = 6.6 Hz, 1H, C[3b]), 7.34 (d, J = 6.6 Hz,
1H, C[5b]), 8.07 (d, J=4.2 Hz, 1H, C[6a]) ppm; 13C NMR
(101 MHz, CDCl3): δ=17.1 (q, C[7a]), 19.2 (q, C[7b]), 44.3
(t, C[2]), 112.9 (d, C[5a]), 116.7 (s, C[3a]), 126.2 (d, C[2b]),
127.6 (d, C[4b]), 128.8 (d, C[5b]), 130.6 (d, C[4a]), 136.9 (s,
C[2b]), 137.0 (d, C[3b]), 137.6 (s, C[1b]) 145.4 (d, C[6a]),
156.7 (s, C[2a]) ppm.
1
Rf = 0.16 (LP/EtOAc 10:1); H NMR (400 MHz, CDCl3):
δ=1.05–1.25 (m, 3H, C[9]–H3), 1.46–1.95 (m, 4H, C[3, 4]–
H2), 2.02 (s, 3H, C[7a]–H3), 2.11–2.35 (m, 2H, C[5]–H2),
4.01 (q, J=7.1 Hz, 2H, C[8]–H2), 4.38 (d, J=7.7 Hz, 1H,
N–H), 5.19 (q, J=7.1 Hz, 1H, C[2]–H), 6.38 (dd, J=7.1,
5.1 Hz, 1H, C[5a]–H), 7.07–7.15 (m, 2H, C[4a; 4b]–H),
7.17–7.37 (m, 4H, C[2b; 3b; 5b; 6b]–H), 7.85 (dd, J=5.2,
1.7 Hz, 1H, C[6a]–H) ppm; 13C NMR (101 MHz, CDCl3):
δ = 14.3 (q, C[9]), 17.1 (q, C[7a]), 21.8 (t, C[3]), 34.0 (t,
C[4]), 36.7 (t, C[5]), 54.3 (d, C[2]), 60.3 (d, C[8]), 112.7
(d, C[5a]), 116.4 (s, C[3a]), 126.5 (d, C[2b; 6b]), 126.9 (d,
C[4b]), 128.5 (d, C[3b; 5b]), 136.9 (d, C[4a]), 144.0 (s,
C[1b]), 145.4 (d, C[6a]), 156.1 (s, C[2a]), 173.5 (s, C[6])
ppm; GC–MS: retention time: 8.10 min; main fragments:
m/z (%)=312 (M+, 16), 267 (10), 211 (42), 197 (100), 117
(10), 108 (25), 91 (15), 65 (16).
N‑(3‑Methoxybenzyl)‑3‑methylpyridin‑2‑amine (16,
C14H16N2O) The reaction was carried out according to gen-
eral procedure C with 29 mg Pd(OAc)2 (0.13 mmol, 0.02
equiv.), 77 mg rac. BINAP (0.12 mmol, 0.02 equiv.), 2.93 g
K2CO3 (21.2 mmol, 3.5 equiv.), 0.78 g 2-chloro-3-methyl-
pyridine (6.1 mmol, 1 equiv.), 1.0 g 3-methoxybenzylamine
(7.3 mmol, 1.2 equiv.), and 30 cm3 toluene. The yield of
the thereby prepared white solid is 64% (0.41 g). 1H NMR
(400 MHz, CDCl3): δ=2.10 (s, 3H, C[7a]–H3), 3.80 (s, 3H,
C[8b]–H3), 4.42 (s, 1H, N[1]–H), 4.68 (d, J=5.2 Hz, 2H,
C[2]–H2), 6.56 (dd, J=7.0, 5.2 Hz, 1H, C[2b]–H), 6.83 (dd,
J=8.2, 2.1 Hz, 1H, C[4b]–H), 7.03–6.92 (m, 2H, C[5a; 6b]),
7.33–7.19 (m, 2H, C[4a; 5b]), 8.05 (d, J=6.0 Hz, 1H, C[6a])
ppm; 13C NMR (101 MHz, CDCl3): δ=17.0 (q, C[7a]), 45.9
(q, C[8b]), 55.2 (d, C[2]), 112.6 (d, C[2b]), 113.0 (d, C[4b]),
113.5 (d, C[5a]), 116.7 (s, C[3a]), 120.1 (d, C[6b]), 129.6 (d,
C[5b]), 137.0 (d, C[4a]), 141.6 (s, C[1b]), 145.25 (d, C[6a]),
156.6 (s, C[3b]), 159.86 (s, C[3a]) ppm.
Ethyl 6‑[(3‑methylpyridin‑2‑yl)amino]‑6‑phenylhexanoate
(19, C20H26N2O2) The reaction was carried out according
to general procedure A with 100 mg 1 (0.50 mmol, 1 eq.),
314 mg ethyl 5-bromopentanoate (1.50 mmol, 3 eq.), 311 mg
K2CO3 (2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2
(0.025 mmol, 0.05 eq.) in 2 cm3 dry and degassed tolu-
ene. The reaction mixture was heated for 22 h at 160 °C.
The general work-up procedure B for C–H activation reac-
tions was followed using a gradient which varies the sol-
vents from 0% to 10% EtOAc within 45 min. Drying under
reduced pressure delivered 19 in 35% (56 mg) yield. TLC:
1
Rf = 0.16 (LP/EtOAc 10:1); H NMR (400 MHz, CDCl3):
3‑Methyl‑N‑[4‑(trifluoromethyl)benzyl]pyridin‑2‑amine
(17) [20] The reaction was carried out according to general
procedure C with 67 mg Pd(OAc)2 (0.3 mmol, 0.02 equiv.),
187 mg rac. BINAP (0.3 mmol, 0.02 equiv.), 7.26 g K2CO3
(52.5 mmol, 3.5 equiv.), 1.91 g 2-chloro-3-methylpyridine
(15 mmol, 1 equiv.), 3.15 g 4-(trifuoromethyl)benzylamine
(18 mmol, 1.2 equiv.), and 38 cm3 toluene. The yield of the
thereby prepared yellow crystals is 81% (3.24 g).
δ = 1.13 (t, J = 7.1 Hz, 3H, C[10]–H3), 1.17–1.47 (m, 2H,
C[4]–H2), 1.58 (p, J=7.6 Hz, 2H, C[5]–H2), 1.70–1.95 (m,
2H, C[3]–H2), 2.02 (s, 3H, C[7a]–H3), 2.19 (t, J=7.5 Hz,
2H, C[6]–H2), 4.09 (q, J= 7.1 Hz, 2H, C[9]–H2), 4.39 (d,
J=7.8 Hz, 1H, N–H), 5.26 (q, J=7.3 Hz, 1H, C[2]–H), 6.47
(dd, J=7.1, 5.1 Hz, 1H, C[5a]–H), 7.15–7.24 (m, 2H, C[4a;
4b]–H), 7.27–7.44 (m, 4H, C[2b; 3b; 5b; 6b]–H), 7.95 (dd,
J = 5.2, 1.8 Hz, 1H, C[6a]–H) ppm; 13C NMR (101 MHz,
CDCl3): δ=14.2 (q, C[10]), 17.1 (q, C[7a]), 24.9 (t, C[5]),
25. 9 (t, C[4]), 34.2 (t, C[3]), 37.0 (t, C[6]), 54.6 (d, C[2]),
60.2 (t, C[9]), 112.6 (d, C[5a]), 116.4 (s, C[3a]), 126.5 (d,
C[2b; 6b]), 126. 9 (d, C[4b]), 128. 5 (d, C[3b; 5b]), 137.0 (d,
C[4a]), 144.1 (d, C[6a]), 155.9 (s, C[2a]), 173. 7 (s, C[7])
ppm; GC–MS: retention time: 8.41 min; main fragments:
m/z (%) = 326 (M+, 12), 281 (9), 197 (100), 108 (20), 91
(19), 65 (10).
Ethyl 5‑[(3‑methylpyridin‑2‑yl)amino]‑5‑phenylpentanoate
(18, C19H24N2O2) The reaction was carried out according
to general procedure A with 100 mg 1 (0.50 mmol, 1 eq.),
293 mg ethyl 4-bromobutyrate (1.50 mmol, 3 eq.), 311 mg
K2CO3 (2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2
(0.025 mmol, 0.05 eq.) in 2 cm3 dry and degassed toluene.
The reaction mixture was heated for 22 h at 160 °C. The
1 3

Rhodium-catalyzed direct alkylation of benzylic amines using alkyl bromides
N‑[1‑(3‑Methoxyphenyl)pentyl]‑3‑methylpyridin‑2‑amine
(20, C18H24N2O) The reaction was carried out according to
general procedure A with 114 mg 16 (0.50 mmol, 1 eq.),
206 mg 1-bromobutane (1.50 mmol, 3 eq.), 311 mg K2CO3
(2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2 (0.025 mmol,
0.05 eq.) in 2 cm3 dry and degassed toluene. The reaction
mixture was heated for 22 h at 160 °C. The general work-up
procedure B for C–H activation reactions was followed using
a gradient which varies the solvents from 0% to 10% EtOAc
within 45 min. Drying under reduced pressure delivered 20
in 56% (80 mg) yield. TLC: Rf =0.42 (LP/EtOAc 10:1); 1H
NMR (400 MHz, CDCl3): δ=0.90 (t, J=7.0 Hz, 3H, C[6]–
H3), 1.24–1.52 (m, 4H, C[3, 5]–H2), 1.89 (tdt, J=16.4, 9.6,
4.5 Hz, 2H, C[4]–H2), 1.89 (tdt, J=16.4, 9.6, 4.5 Hz, 2H,
C[19]–H2), 2.14 (s, 3H, C[7a]–H3), 3.82 (s, 3H, C[8b]–H3),
4.42 (s, 1H, N–H), 5.26 (q, J=7.5 Hz, 1H, C[2]–H), 6.50
(dd, J=7.1, 5.1 Hz, 1H, C[4b]–H), 6.78 (ddd, J=8.1, 2.6,
1.1 Hz, 1H, C[5a]–H), 6.93–7.03 (m, 2H, C[2b; 6b]–H),
7.18–7.30 (m, 2H, C[4a; 4b]–H), 7.98 (dd, J=5.1, 1.8 Hz,
1H, C[6a]–H) ppm; 13C NMR (101 MHz, CDCl3): δ=14.0
(q, C[6]), 17.1 (q, C[7a]), 22.7 (t, C[4]), 28.5 (t, C[3]), 54.7
(d, C[2]), 55.2 (q, C[8b]), 111.8 (d, C[2b]), 112.6 (d, C[4b]),
112.7 (d, C[5b]), 116. 5 (s, C[3a]), 118.9 (d, C[6b]), 129.4
(d, C[5a]), 137.1 (d, C[4a]), 145.0 (d, C[6a]), 146.2 (s,
C[1b]), 155.9 (s, C[3b]), 159. 7 (s, C[2a]) ppm; GC–MS:
retention time: 8.41 min; main fragments: m/z (%) = 326
(M+, 12), 281 (9), 197 (100), 108 (20), 91 (19), 65 (10).
retention time: 9.48 min; main fragments: m/z (%) = 368
(M+, 9), 241 (21), 227 (100), 207 (6), 108 (26), 91 (6) 65 (5).
3‑Methyl‑N‑[1‑(o‑tolyl)pentyl]pyridin‑2‑amine (22,
C18H24N2) The reaction was carried out according to general
procedure A with 100 mg 15 (0.47 mmol, 1 eq.), 206 mg
1-bromobutane (1.50 mmol, 3.2 eq.), 311 mg K2CO3
(2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2 (0.025 mmol,
0.05 eq.) in 2 cm3 dry and degassed toluene. The reaction
mixture was heated for 22 h at 160 °C. The general work-up
procedure B for C–H activation reactions was followed using
a gradient which varies the solvents from 0% to 5% EtOAc
within 1 h. Thereafter, a gradient that varies the solvents
from 5% to 10% EtOAc was applied. Drying delivered 22 in
47% (60 mg) yield as colorless oil. TLC: Rf =0.6 (LP/EtOAc
10:1); 1H NMR (400 MHz, CDCl3): δ=0.87 (t, J=7.0 Hz,
3H, C[6]–H3), 1.19–1.46 (m, 4H, C[4, 5]–H2), 1.74–1.99 (m,
2H, C[3]–H2), 2.11 (s, 3H, C[7a]–H3), 2.32 (s, 3H, C[7b]–
H3), 4.39 (s, 1H, (m, 1H, N–H)), 5.22 (q, J = 7.5 Hz, 1H,
C[2]–H), 6.47 (dd, J=7.1, 5.1 Hz, 1H, C[5a]–H), 7.12 (d,
J=7.8 Hz, 2H, C[4a;4b]), 7.23–7.16 (m, 1H, C[2b]), 7.27
(d, J=8.1 Hz, 2H, C[3b; 5b]), 7.96 (dd, J=5.1, 1.8 Hz, 1H,
C[6a]–H) ppm; 13C NMR (101 MHz, CDCl3): δ=14.1 (q,
C[12]), 17.2 (q, C[7a]), 21.2 (t, C[7b], 22.8 (t, C[4]), 28.7
(t, C[5]), 37.3 (t, C[3]), 54.5 (d, C[2]), 112.5 (d, C[5a]),
116.4 (s, C[3a]), 126.6 (d, C[2b]), 129.2 (d, C[4b]), 136.6 (d,
C[4a]), 137.0 (d, C[3b]), 141.6 (s, C[1b]), 156.2 (d, C[5b])
ppm; GC–MS: retention time: 8.88 min; main fragments:
m/z (%)=352 (M+, 5), 225 (8), 211 (100), 108 (19), 92 (22)
65 (4).
N‑[1‑(3‑Methoxyphenyl)undecyl]‑3‑methylpyridin‑2‑amine
(21, C24H36N2O) The reaction was carried out according to
general procedure A with 114 mg 16 (0.50 mmol, 1 eq.),
332 mg 1-bromodecane (1.50 mmol, 3 eq.), 311 mg K2CO3
(2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2 (0.025 mmol,
0.05 eq.) in 2 cm3 dry and degassed toluene. The reaction
mixture was heated for 22 h at 160 °C. The general work-up
procedure B for C–H activation reactions was followed using
a gradient which varies the solvents from 0% to 5% EtOAc
within 45 min. Drying under reduced pressure delivered 21
in 56% (102 mg) yield. TLC: Rf =0.65 (LP/EtOAc 10:1); 1H
NMR (400 MHz, CDCl3): δ=0.91 (t, J=6.9 Hz, 3H, C[12]–
H3), 1.19–1.51 (m, 16H, C[4–11]–H2), 1.81–1.97 (m, 2H,
C[3]–H2), 2.15 (s, 3H, C[7a]–H3), 3.82 (s, 3H, C[8b]–H3),
4.41–4.48 (m, 1H, N–H), 5.27 (q, J = 7.3 Hz, 1H, C[2]–
H), 6.51 (dd, J=7.1, 5.1 Hz, 1H, C[5a]–H), 6.75–6.83 (m,
1H, C[4b]–H), 6.94–7.04 (m, 2H, C[5b; 6b]–H), 7.25 (q,
J=7.5 Hz, 2H, C[2b; 4a]–H), 7.99 (dd, J=5.2, 1.8 Hz, 1H,
C[6a]–H) ppm; 13C NMR (101 MHz, CDCl3): δ=14.1 (q,
C[12]), 17.1 (q, C[7a]), 22.7 (t, C[11]), 26.4 (t, C[4]), 29.31
(t, C[5]), 29.60 (t, C[6–9]), 31.9 (t, C[10]), 37.5 (t, C[3]),
54.7 (d, C[2]), 55.2 (q, C[8b]), 111. 8 (d, C[6b]), 112.5 (d,
C[4b]), 112.6 (d, C[5a]), 116.4 (s, C[3a]), 118.8 (d, C[2b]),
129. 4 (d, C[5a]), 137.6 (d, C[4a]), 145.3 (s, C[1b]), 146.2
(d, C[6a]), 156.6 (s, C[5b]), 159.7 (s, C[2a]) ppm; GC–MS:
3‑Methyl‑N‑[1‑(o‑tolyl)undecyl]pyridin‑2‑amine (23,
C24H36N2) The reaction was carried out according to gen-
eral procedure A with 106 mg 17 (0.50 mmol, 1 eq.),
332 mg 1-bromodecane (1.50 mmol, 3 eq.), 311 mg K2CO3
(2.25 mmol, 4.5 eq.), and 12 mg [RhCl(cod)]2 (0.025 mmol,
0.05 eq.) in 2 cm3 dry and degassed toluene. The reaction
mixture was heated for 22 h at 160 °C. The general work-up
procedure B for C–H activation reactions was followed using
a gradient which varies the solvents from 0% to 5% EtOAc
within 45 min. Drying under reduced pressure delivered 23
1
in 25% (44 mg) yield. TLC: Rf = 0.8 (LP/EtOAc 5:1); H
NMR (400 MHz, CDCl3): δ = 0.92–0.86 (m, 3H, C[12]–
H3), 1.39–1.20 (m, 16H, C[4–11]–H2), 1.97–1.75 (m, 2H,
C[3]–H2), 2.10 (s, 3H, C[7a]–H3), 2.50 (s, 3H, C[7b]–H3),
4.53–4.30 (m, 1H, N–H), 5.49 (q, J = 6.4 Hz, 1H, C[2]–
H), 6.47 (dd, J=7.1, 5.1 Hz, 1H, C[5a]–H), 7.23–7.08 (m,
4H, C[2b–5b]–H), 7.36–7.30 (m, 1H, C[4a]–H), 7.97 (dd,
J = 5.2, 1.8 Hz, 1H, C[6a]–H) ppm; 13C NMR (101 MHz,
CDCl3): δ=14.2 (q, C[12]), 17.1 (q, C[7a]), 19.6 (q, C[7b]),
22.7 (t, C[11]), 26.5 (t, C[9]), 29.47 (t, C[8]), 29.56 (t, C[7]),
29.63 (t, C[5]), 29.73 (t, C[6]), 31.9 (t, C[4]), 34.5 (t, C[10]),
36.8 (t, C[3]), 51.0 (d, C[2]), 112.4 (s, C[6b]), 116.1 (s,
1 3

M. Anschuber et al.
C[3a]), 124. 8 (d, C[5a]), 126.1 (d, C[4b]), 126.5 (d, C[2b]),
130.5 (d, C[3b]), 136.2 (d, C[4a]), 142.8 (s, C[1b]), 145.4
(d, C[6a]), 156.0 (d, C[5b]), 174.0 (s, C[2a]) ppm; GC–MS:
retention time: 8.88 min; main fragments: m/z (%) = 352
(M+, 5), 225 (8), 211 (100), 108 (19), 92 (22) 65 (4).
13C NMR (101 MHz, CDCl3): δ=14.1 (q, C[12]), 17.0 (q,
C[7a]), 22.7 (t, C[11]), 26.3 (t, C[10]), 29.3 (t, C[8]), 29.5 (t,
C[6, 7]), 29.6 (t, C[5, 9]), 31.9 (t, C[4]), 37.6 (t, C[3]), 54.6
(d, C[2]), 113.0 (d, C[5a]), 122.9 (s, C[7b]), 125.3 (d, C[3b;
5b]), 126.8 (d, C[2b; 6b]), 128.7 (s, C[3a]), 129.1 (s, C[4b]),
137.8 (d, C[4a]), 145.0, (s, C[1b]), 148.8 (d, C[6a]), 155.5
(s, C[2a]) ppm; GC–MS: retention time: 8.52 min; main
fragments: m/z (%)=406 (M+, 11), 279 (34), 265 (100), 159
(8), 108 (64), 92 (30) 65 (11).
3‑Methyl‑N‑[1‑[4‑(trifluoromethyl)phenyl]pentyl]pyri‑
din‑2‑amine (24, C18H21F3N2) The reaction was carried
out according to general procedure A with 133 mg 17
(0.50 mmol, 1 eq.), 206 mg 1-bromobutane (1.50 mmol,
3 eq.), 311 mg K2CO3 (2.25 mmol, 4.5 eq.), and 12 mg
[RhCl(cod)]2 (0.025 mmol, 0.05 eq.) in 2 cm3 dry and
degassed toluene. The reaction mixture was heated for 22 h
at 160 °C. The general work-up procedure B for C–H acti-
vation reactions was followed using a gradient which varies
the solvents from 0% to 5% EtOAc within 45 min. Dry-
ing under reduced pressure delivered 24 in 50% (81 mg)
yield as pale yellowish oil. TLC: Rf =0.41 (LP/EtOAc 10:1);
1H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 6.9 Hz, 3H,
C[6]–H3), 1.18–1.49 (m, 4H, C[4, 5]–H2), 1.77–1.96 (m,
2H, C[3]–H2), 2.16 (s, 3H, C[7a]–H3), 4.48 (s, 1H, N–H),
5.31 (p, J=7.4 Hz, 1H, C[2]–H), 6.50 (dd, J=7.1, 5.1 Hz,
1H, C[5a]–H), 7.23 (d, J = 7.1 Hz, 1H, C[4a]–H), 7.49
(d, J=8.2 Hz, 2H, C[2b; 6b]–H), 7.55 (d, J =8.1 Hz, 2H,
C[3b; 5b]–H), 7.91 (dd, J=5.1, 1.8 Hz, 1H, C[6a]–H) ppm;
13C NMR (101 MHz, CDCl3): δ = 14.1 (q, C[6]), 17.2 (q,
C[7a]), 22.7 (t, C[5]), 28.6 (t, C[4]), 37.5 (t, C[3]), 54.7 (d,
C[2]), 113.1 (d, C[5a]), 116.6 (s, C[3a]), 123.1 (s, C[7b]),
125.5, (d, C[3b; 5b]), 126.9 (d, C[2b; 6b]), 129.3 (s, C[6b]),
137.4 (d, C[4a]), 147.3 (s, C[1b]), 148.8 (d, C[6a]), 155.5
(s, C[2a]) ppm; GC–MS: retention time: 6.94 min; main
fragments: m/z (%)=322 (M+, 18), 265 (100), 159 (11), 108
(41), 92 (46) 65 (24).
Acknowledgements Open access funding provided by TU Wien
(TUW).
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution 4.0 International License (http://creativeco
mmons.org/licenses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate
credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
References
1. Shang R, Ilies L, Nakamura E (2017) Chem Rev 117:9086
2. Xue X-S, Ji P, Zhou B, Cheng J-P (2017) Chem Rev 117:8622
3. Gensch T, Hopkinson MN, Glorius F, Wencel-Delord J (2016)
Chem Soc Rev 45:2900
4. Ma W, Gandeepan P, Li J, Ackermann L (2017) Org Chem Front
4:1435
5. Chen Z, Wang B, Zhang J, Yu W, Liu Z, Zhang Y (2015) Org
Chem Front 2:1107
6. Sambiagio C, Schönbauer D, Blieck R, Dao-Huy T, Pototschnig
G, Schaaf P, Wiesinger T, Zia MF, Wencel-Delord J, Besset T,
Maes BUW, Schnürch M (2018) Chem Soc Rev 47:6603
7. Dong Z, Ren Z, Thompson SJ, Xu Y, Dong G (2017) Chem Rev
117:9333
8. Spettel M, Pollice R, Schnürch M (2017) Org Lett 19:4287
9. Pollice R, Dastbaravardeh N, Marquise N, Mihovilovic MD,
Schnürch M (2015) ACS Catal 5:587
3‑Methyl‑N‑[1‑[4‑(trifluoromethyl)phenyl]undecyl]pyri‑
din‑2‑amine (25, C24H33F3N2) The reaction was carried
out according to general procedure A with 133 mg 17
(0.50 mmol, 1 eq.), 332 mg 1-bromodecane (1.50 mmol,
3 eq.), 311 mg K2CO3 (2.25 mmol, 4.5 eq.), and 12 mg
[RhCl(cod)]2 (0.025 mmol, 0.05 eq.) in 2 cm3 dry and
degassed toluene. The reaction mixture was heated for 22 h
at 160 °C. The general work-up procedure B for C–H acti-
vation reactions was followed using a gradient which varies
the solvents from 0% to 5% EtOAc within 45 min. Dry-
ing under reduced pressure delivered 25 in 62% (126 mg)
yield. TLC: Rf =0.79 (LP/EtOAc 10:1); 1H NMR (400 MHz,
CDCl3): δ=0.87 (t, J=6.8 Hz, 3H, C[12]–H3), 1.19–1.39
(m, 16H, C[7–11]–H2), 1.78–1.94 (m, 2H, C[3]–H2), 2.16
(s, 3H, C[7a]–H3), 4.47 (d, J = 7.0 Hz, 1H, N–H), 5.30
(q, J = 7.2 Hz, 1H, C[2]–H), 6.50 (dd, J = 7.1, 5.2 Hz,
1H, C[6a]–H), 7.23 (d, J = 7.1 Hz, 1H, C[4a]–H), 7.48
(d, J=8.1 Hz, 2H, C[2b; 6b]–H), 7.55 (d, J =8.1 Hz, 2H,
C[3b; 5b]–H), 7.91 (dd, J=5.1, 1.7 Hz, 1H, C[6a]–H) ppm;
10. Pollice R, Schnürch M (2015) J Org Chem 80:8268
11. Zhu R-Y, He J, Wang X-C, Yu J-Q (2014) J Am Chem Soc
136:13194
12. Gao K, Yoshikai N (2013) J Am Chem Soc 135:9279
13. Chen K, Shi B-F (2014) Angew Chem Int Ed 53:11950
14. Aihara Y, Chatani N (2013) J Am Chem Soc 135:5308
15. Song W, Lackner S, Ackermann L (2014) Angew Chem Int Ed
53:2477
16. Monks BM, Fruchey ER, Cook SP (2014) Angew Chem Int Ed
53:11065
17. Wu X, Zhao Y, Ge H (2014) J Am Chem Soc 136:1789
18. Jana CK, Grimme S, Studer A (2009) Chem Eur J 15:9078
19. Dastbaravardeh N, Schnürch M, Mihovilovic MD (2012) Org Lett
14:1930
20. Dastbaravardeh N, Kirchner K, Schnürch M, Mihovilovic MD
(2013) J Org Chem 78:658
21. Schnürch M (2015) Arkivoc 212
22. Chatani N, Asaumi T, Yorimitsu S, Ikeda T, Kakiuchi F, Murai S
(2001) J Am Chem Soc 123:10935
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