First selective direct mono-arylation of piperidines using ruthenium-catalyzed C-H activation

Article abstract of DOI:10.1007/s00706-013-0947-1

A Ru-catalyzed mono-arylation in α-position of saturated cyclic amines is reported employing a C-H activation protocol. Substitution of the pyridine directing group with a bulky group, e.g., trifluoromethyl in the 3-position, proved to be crucial to avoid bis-arylation. This highly selective transformation can be performed with different amines and arylboronate esters. Additionally, the directing group can be cleaved, taking advantage of an unprecedented detrifluoromethylation reaction.

Full text of DOI:10.1007/s00706-013-0947-1

Monatsh Chem (2013) 144:539–552
DOI 10.1007/s00706-013-0947-1
ORIGINAL PAPER
First selective direct mono-arylation of piperidines using
ruthenium-catalyzed C–H activation
•
Maria C. Schwarz Navid Dastbaravardeh
•
•
•
Karl Kirchner Michael Schnu¨rch
Marko D. Mihovilovic
Received: 4 January 2013 / Accepted: 10 February 2013 / Published online: 3 April 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract A Ru-catalyzed mono-arylation in a-position of
saturated cyclic amines is reported employing a C–H
activation protocol. Substitution of the pyridine directing
group with a bulky group, e.g., trifluoromethyl in the
3-position, proved to be crucial to avoid bis-arylation. This
highly selective transformation can be performed with
different amines and arylboronate esters. Additionally, the
directing group can be cleaved, taking advantage of an
unprecedented detrifluoromethylation reaction.
nitrogen is of special interest, since it provides an efficient
pathway towards a valuable building block that is tedious
to obtain via other methods [34].
Due to the importance of a-arylated cyclic amines,
several groups have undertaken efforts to develop direct
arylation methods towards these compounds. Sames and
coworkers reported the first direct a-arylation via C–H
activation of saturated cyclic amines, primarily pyrrol-
idines, using a ruthenium catalyst and arylboronate esters
as coupling partner (Scheme 1, upper part) [35]. A cyclic
imine was used as a directing group, and the presence of a
ketone proved to be essential for this reaction. In 2010, the
group of Maes published a ruthenium-catalyzed, pyridine-
directed C–H activation of piperidine derivatives in the
presence of an alcohol, again involving arylboronate esters
as coupling partners (Scheme 1, lower part) [36].
Keywords Catalysis Á Heterocycles Á C–H activation Á
Metal carbonyls Á Arylation Á Detrifluoromethylation
Introduction
Transition-metal-catalyzed C–H activation has become an
important tool for organic chemists in recent years [1–8].
Activation of sp2 C–H groups is already well established
[9–17], and though transition-metal-catalyzed sp3 C–H
activation is more difficult, there are also various recently
reported examples [18–31]. This approach offers an
appealing method towards more efficient synthetic path-
ways with fewer steps, since pre-activation of carbons with
functional groups can be avoided.
Both of these methods have one notable limitation; i.e., no
selective mono-arylation could be achieved. In one case the
second a-position was blocked to avoid bis-arylation (Sames’
protocol); in the other case a mixture of mono- and bis-ary-
lated products was obtained (Maes’ protocol). Bis-arylation
not only decreases the yield of the mono-arylated compound
but also leads to difficult separation due to similar properties
of mono- and bis-arylated compounds. The best yield for
selective mono-arylation reported to date was published by
Maes with 49 % [arylation of (pyridin-2-yl)piperidine with
3-(trifluoromethyl)phenyl boronic acid ester] [36]. Herein, we
report on selective mono-arylation of saturated cyclic amines
achieved using a specially designed directing group.
a-Substituted saturated N-heterocycles can be found in
natural products such as alkaloids, as well as in drug
compounds [32, 33]. Hence, utilization of the sp3 C–H
bond for C–C bond-forming reactions in a-position to the
M. C. Schwarz Á N. Dastbaravardeh Á K. Kirchner Á
M. Schnu¨rch (&) Á M. D. Mihovilovic
Results and discussion
Institute of Applied Synthetic Chemistry, Vienna University
of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
e-mail: michael.schnuerch@tuwien.ac.at
Bis-arylation occurs due to a low energy barrier for rotation
of the directing group around the C–N bond as observed for
123

540
M. C. Schwarz et al.
Scheme 1
O
Sames:
B Ar
Ru3(CO)12
Pinacolone
R
Ar
R
O
or
O
N
N
+
150 °C, 4-19 h
N
N
B Ar
O
Maes:
Ru3(CO)12
3-Ethyl-3-pentanol
O
O
N
N
Ar
Ar
N
Ar
+
B Ar
+
Reflux, 24 h
N
N
N
Scheme 2
H
Ar
N
H
R
N
H
H
N
[Ru]
[Ru] H
Ar-X
R
R
N
N
N
R = H: free rotation possible
R = bulky group: free rotation hampered
[Ru]
Ar
Ar
H
N
Ar
H
N
H
Ar
H
N
H [Ru]
N
N
N
only possible if R is small enough, e.g. H
pyridine or the cyclic imine. Free rotation therefore allows
insertion of the catalyst into both C–H bonds after com-
plexation of the catalyst to the nitrogen of pyridine
(Scheme 2). For this reason, it was envisioned to install a
bulky group in 3-position of the pyridine directing group to
hamper this free rotation, subsequently avoiding a second
arylation step. The trifluoromethyl group was chosen for
several reasons: (i) similar directing groups have already
been successfully applied in direct arylation reactions
[37–39]; (ii) it gave better results as compared with the
simpler CH3 group (typically *10 % better conversion);
(iii) only mono-arylated product was obtained in the initial
screening; and (iv) it is easy to install in good yields.
In most cases the directing group was installed by simple
nucleophilic aromatic substitution (Table 1). Therefore,
2-chloro-3-(triflouromethyl)pyridine (1) was reacted with
saturated amine 2, adding K2CO3 and using acetonitrile as a
solvent. Except 3b (Table 1, entry 2) and 3k (Table 1,
entry 11), all products could be obtained in excellent yields.
Theratherlowyieldof3b isprobablyduetosterichindranceof
the methyl group adjacent to the piperidine nitrogen. Though
3k showed conversion of 74 %, only 37 % of pure product
could be isolated, which can be attributed to significant vola-
tility of the product leading to losses upon solvent evaporation.
Having a series of starting materials in hand, the
direct arylation reaction was optimized. Initially, the C–H
123

First selective direct mono-arylation of piperidines using ruthenium-catalyzed C–H activation
541
Table 1 Synthesis of substrates
for direct arylation
R
R
N
Cl
N
F3C
K2CO
F3C
3 (3equiv.)
N
+
3 equiv. 2
Acetonitrile
1
3
Entry
1
Amine
t /h
24
T /°C
Product
Yield /%
79d
F
C
3
2aHN
Reflux
180
N
N
3a
F
C
3
HN
2
3
0.5
1.5
26b,c
N
N
2b
2c
3b
3c
F
C
3
HN
180
87c
N
N
C
F
3
4
5
1
180
100
90c
75e
87e
84d
86d
83d
64c
2dHN
N
N
3d
F
C
3
Et
COO
2eHN
22.5
22.5
48
N
Et
COO
N
3e
F
C
3
HN
6
100
N
Ph
2f
N
Ph
3f
F
C
3
2gHN
7
Reflux
Reflux
Reflux
180
N
N
3g
F
C
F
3
HN
8
65
N
2h
N
C
3h
3
2iHN
2jHN
2k
N
9
65
N
F
N
N
a
3i
Reaction conditions: 1
C
(1 equiv.), saturated amine 2
(2 equiv.), K2CO3 (2 equiv.),
acetonitrile
3
O
10
1.5
N
C
O
N
3j
b
3 equiv. saturated amine
F
c
3
Microwave heating
d
N
37bc
Round-bottom flask, reflux
conditions
N
11
2
180
H
N
e
3k
Closed vial, heating block
activation was performed with Ru3(CO)12 as catalyst and
1,3-propanediol derived boronic esters as the aryl donor,
similar to previous literature examples [35, 36] and being
easily prepared from the corresponding boronic acids [40].
As we observed also deborylation besides the desired ary-
lation reaction, an excess of 4 equiv. of arylboronate ester
was used. Maes reported that addition of an alcohol (e.g.,
2,2-dimethylpropane-1,3-diol) was beneficial in his piperi-
dine arylation protocol, since the alcohol should scavenge a
diol–borane species formed after transmetallation [36].
Hence, we also tried addition of 2,2-dimethylpropane-1,3-
diol. The reaction was performed in a reaction vial with a
123

542
M. C. Schwarz et al.
septum cap and an attached argon balloon to ‘‘release’’
hydrogen which should be formed according to the mech-
anism proposed by Maes. The reaction was carried out in
o-xylene as solvent at 135 °C for 36 h. With those condi-
tions (Table 2, entry 1) conversion of 53 % could be
achieved. Changing the nature or amount of alcohol had no
significant influence on the reaction outcome. In the Maes
protocol, 1 equiv. of alcohol was used [36]. In our case it did
not make any difference whether we used 0.5 or 1 equiv. of
alcohol additive. Increasing the catalyst loading did not
improve the yield either. Also, longer reaction times did not
increase the yield (data not shown). It turned out that, after a
significant amount of screened reaction conditions, the only
modification that could increase the yield significantly was
to add a metal salt as co-catalyst. Table 2 presents a selec-
tion of metal salts applied. Addition of PdCl2 (entries 2–4),
FeCl2 (entries 5–7), FeCl3 (entries 8–10), CuCl2Á2H2O
(entries 11–13), and CuSO4Á5H2O (entries 14–16) led to
improved conversion, with 2 mol% CuSO4Á5H2O giving the
best gas chromatography (GC) yield of 70 %. It can only be
speculated that the metal salt may help to keep the catalyst
in the required oxidation state, but evidence for this is
lacking. To investigate the role of CuSO4Á5H2O and to
exclude that CuSO4Á5H2O alone could serve as a catalyst in
this transformation, the reaction was carried out in the
absence of Ru3(CO)12; as expected, no formation of the
product could be observed.
A slight increase of the temperature to 140 °C still gave
the same conversion, but the reaction time could be
decreased to 24 h. Further increasing the temperature was
not beneficial and lower conversions were obtained, which
most likely can be attributed to catalyst decomposition.
Since the kind of alcohol had no influence on the yield,
0.5 equiv. of 1,3-propanediol was used instead of 2,2-
dimethylpropane-1,3-diol. This change was conducted as the
1,3-propanediol derived boronate was much easier to sepa-
rate from the product in the workup process and the nature of
the boronic ester had no significant influence on the substrate
conversion. At this point it could be argued that the avoid-
ance of bis-arylation is no advantage over existing protocols,
Table 2 Optimization of the reaction conditionsa
Ru3(CO)12 (7 mol%)
cocatalyst
O
O
N
B
N
+
4
F3C
F3C
2,2-Dimethylpropane-1,3-diol
(0.5 equiv.),
N
N
o-xylene, 135 °C, 36 h
3a
5a
4a
Entry
Co-catalyst
Mol%
Conversion/%b
GC yield/%c
1
–
–
1
3
5
1
2
5
1
2
5
1
2
5
1
2
5
53
53
70
65
72
75
75
73
77
71
77
72
69
74
82
87
39
43
54
49
54
61
63
58
58
49
63
61
43
59
70
69
2
PdCl2
PdCl2
PdCl2
FeCl2
FeCl2
FeCl2
FeCl3
FeCl3
FeCl3
3
4
5
6
7
8
9
10
11
12
13
14
15
16
a
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuSO4Á5H2O
CuSO4Á5H2O
CuSO4Á5H2O
Reaction conditions: 3a (0.5 mmol), 5a (2 mmol), Ru3(CO)12 (7 mol%), co-catalyst, 2,2-dimethylpropane-1,3-diol (0.25 mmol), 0.5 cm3 o-
xylene, 135 °C, stirred for 36 h under argon conditions in an open vial
b
Conversion based on GC analysis with respect to 3a and 4a (dodecane as internal standard)
c
Yield determined by GC analysis with respect to 4a (dodecane as internal standard) using a calibration curve
123

First selective direct mono-arylation of piperidines using ruthenium-catalyzed C–H activation
543
Table 3 Scope of mono-arylations with different arylboronate esters 5a
Ru3(CO)12 (7 mol%)
N
Ar
N
·
CuSO4 5H2O (2 mol%)
+
4 O
O
B
F3C
F3C
1,3-Propanediol (0.5 equiv.),
o-xylene, 140 °C, 24 h
N
N
Ar
3a
5
4
Entry
Ar
Product
Yield/%b
1
C6H5
4a
4b
4c
4d
4e
4f
60
47
50
43
34
16c
40
n.i.
n.i.
49
39
n.i.
2
4-Me-C6H4
3
4-t-Bu-C6H4
4-F-C6H4
4
5
4-Cl-C6H4
6
4-MeO-C6H4
4-CF3-C6H4
4-CN-C6H4
4-NO2-C6H4
3-Me-C6H4
3-Cl-C6H4
7
4g
4h
4i
8
9
10
11
12
a
4j
4k
4l
2-Me-C6H4
Reaction conditions: 3a (0.5 mmol), 5 (2 mmol), Ru3(CO)12 (7 mol%), CuSO4Á5H2O (2 mol%), 1,3-propanediol (0.25 mmol), 0.5 cm3
o-xylene, 140 °C, stirred for 24 h under argon conditions in an open vial
b
Isolated yield after flash column chromatography; those examples with low or no conversion were not isolated (n.i.)
c
Bis-arylated product was obtained in addition; additional purification by preparative TLC
since instead of having to separate mono-arylated from
bis-arylated compound, the mono-arylated compound now
has to be separated from starting material due to incom-
plete conversion. However, separation of substrate from
mono-arylated product is very facile, whereas separation of
mono- and bis-arylated products is very difficult.
lower and electron-withdrawing coordinating substituents to
give no conversion was already observed by us in the pre-
viously reported direct arylation of benzylamines [37–39].
The result for the p-methoxy substituent was surprising
(Table 3, entry 6). Compound 4f could be isolated with yield
of only 16 %, because to some extent also the bis-arylated
product was formed. This was the only case where bis-ary-
lation was observed for piperidine, when employing a
substituted pyridine directing group. To separate the two
compounds, preparative thin-layer chromatography (TLC)
had to be performed additionally after flash column chro-
matography. This accounts for the low yield and shows the
isolation problems with unselective reactions. A pure frac-
tion of bis-arylated product could actually not be obtained.
The mono-arylated product 4f seems to promote the second
arylation step. This hypothesis was tested by subjecting
isolated 4f to the arylation conditions. Indeed, formation of
the bis-arylated compound could be observed by GC–mass
spectrometry (MS), albeit only in small amounts (*10 %).
The scope of the reaction was also investigated
regarding different saturated amines (Table 4). In the case
of 2-methyl-substituted piperidine 3b (Table 4, entry 1),
the conversion dropped, as expected, to only 36 % due to
steric hindrance. When the arylation was conducted on
With the optimized conditions in hand, we explored the
scope of the reaction. For piperidine, different aryl groups
were introduced and the results are shown in Table 3. The
best result could be achieved for the unsubstituted phenyl
group, yielding 60 % of the desired product 4a (Table 3,
entry 1). Also in the presence of electron-donating alkyl
groups as substituents in para- or meta-position, yields in
the range of 50 % were obtained for 4b, 4c, and 4j
(Table 3, entries 2, 3, 10). The presence of a substituent in
ortho-position decreased the conversion dramatically, most
likely due to steric hindrance (Table 3, entry 12, 4l). Boro-
nic acid esters bearing electron-withdrawing groups gave
lower yields (Table 3, entries 4, 5, 7, 11). Nitrogen-con-
taining electron-withdrawing groups such as nitro or cyano
were not tolerated (Table 3, entries 8, 9). This may be due to
complexation of the catalyst at these functional groups,
making the catalyst unavailable for the desired transforma-
tion. The trend for electron-withdrawing substituents to give
123

544
M. C. Schwarz et al.
Table 4 Scope of mono-
arylations with different
saturated cyclic amines 3a
Ru3(CO)12 (7 mol%)
CuSO4·5H2O (2 mol%)
O
O
N
N
B
+
4
F3C
F3C
1,3-Propanediol (0.5 equiv.),
o-xylene, 140 °C, 24 h,
open vial, Ar
N
N
3
5a
6-15
Entry
Heterocycle
Product
Yield/%b
N
1
2
6
n.i.
n.i.
3b
N
7
3c
N
3
4
8
9
28
25
3d
N
N
COOEt
3e
5
10
34
a
Reaction conditions: 3
(0.5 mmol), 5a (2 mmol),
Ru3(CO)12 (7 mol%),
3f
6
7
8
11
12
49c
n.i.
n.i.
N
3g
CuSO4Á5H2O (2 mol%), 1,3-
propanediol (0.25 mmol),
0.5 cm3 o-xylene, 140 °C,
stirred for 24 h under argon
conditions in an open vial
N
3h
b
N
N
O
13
14
15
Isolated yield after flash
3i
column chromatography; those
examples with low or no
conversion were not isolated
(n.i.)
N
9
n.i.
n.i.
3j
N
c
10
Bis-arylated product was
obtained in addition
3k
3-methyl-substituted piperidine 3c (entry 2), four isomers
could be observed on GC–MS, which indicated that, in
addition to the expected 2,5-substituted compound, also a
2,3-substituted compound was synthesized, both in cis and
trans conformation. Not surprisingly, the isomers could not
be separated by flash column chromatography. Overall, the
yield was 30 %. For 4-substituted piperidines (Table 4,
entries 3–5), yields between 25 and 34 % were obtained. In
(3i), and morpholine (3j) substrates (Table 4, entries 7–9)
gave only low conversion, and the corresponding products
were not isolated. The loss of reactivity for 3i and 3j may
be explained by complexation of the catalyst to the het-
eroatoms. The only open-chain saturated amine (Table 4,
entry 10) showed nearly no conversion at all.
As the reaction does not seem to be very tolerant
regarding different rings, it was hypothesized that a specific
geometry seems to be essential. Therefore, energy-mini-
mization calculations were conducted for 3a, 3b, 3c, 3d,
3g, 3i, and 3j. The six-membered rings, except for the
2-substituted piperidine 3b, all have rather similar geom-
etry according to the calculations. As shown in Fig. 1 for
3a, they all have a slightly twisted boat conformation at the
piperidine core. Especially the piperidine ring of 3a and the
4-substituted piperidine ring of 3d show very similar
properties, and therefore the difference in yield could not
be explained by the calculated geometries of these starting
materials. A more conclusive result could have been
obtained by calculating the corresponding Ru complexes
1
all cases only one isomer was observed and isolated. H
nuclear magnetic resonance (NMR) signal patterns and
coupling constants revealed that the aryl group in 8 is cis to
the methyl group in 4-position. The products of the other
reactions were assigned as the cis-isomers by analogy.
Compared with piperidine, pyrrolidine 3g (Table 4,
entry 6) showed higher conversion, but due to the different
geometry of the ring, the trifluoromethyl group was not as
effective in preventing bis-arylation (mono:bis = 1:0.35
on GC–MS). The mono-arylated compound 11 was
obtained in 49 % yield, but the bis-arylated product could
not be obtained in pure form. Azepane (3h), piperazine
123

First selective direct mono-arylation of piperidines using ruthenium-catalyzed C–H activation
545
Both 16 (as crude material) and 17 were subjected to the
cleavage conditions of NH2NH2/AcOH (2.5/0.7 M in
EtOH) at 120 °C for 2 h in a closed vial, but only the
reaction of 17 gave the desired product 2-phenylpiperidine
1
(18) as detected by GC–MS and H NMR of the crude
product after basic extraction. Also other reaction param-
eters (changing the acid to trifluoroacetic acid, increasing
the reaction time or temperature) to cleave the reduced
directing group from 16 did not lead to formation of 18.
Still, a new cleavage protocol was developed as shown in
Scheme 3, providing the desired product 18 in 47 % yield.
Hence, our deprotection protocol is competitive to the
previously published removal procedure of the unsubsti-
tuted pyridine directing group, which was also cleaved in
47 % overall yield [36].
Fig. 1 Optimized PBE1PBE geometry of the equilibrium structure
of 3a
We propose the following mechanism for cleavage of
the trifluoromethyl group (Scheme 4): Substrate 16 reacts
with a free O–H group at the surface of silica gel to form
17, and the triflouromethyl group is bound to silica gel.
Next, water present in silica gel hydrolyzes the newly
formed O–CF3 bond and trifluoromethanol is released,
which then decomposes to carbonyl difluoride and hydro-
gen fluoride rapidly. This decomposition is described in the
literature [41] to occur already at -20 °C, leading to gas-
eous compounds which can then not be detected using
standard analytic techniques. The formation of gaseous
compounds is supported by infrared (IR) analysis of the
remaining silica gel after the deprotection, where no bands
specific for C–F bonds were detected.
formed during the reaction. However, since the nature of
the active catalyst species is not known entirely, no such
calculations could be conducted.
Finally, cleavage of the directing group was investi-
gated. Initially, it was attempted to cleave the directing
group via a method reported by Maes and coworkers [36].
They subjected the mono-arylated product (2-phenyl-1-
pyridin-2-yl)piperidine to Pd-catalyzed hydrogenation
(Pd/C, 1 atm H2, HCl, i-PrOH) and subsequent NH2NH2/
AcOH treatment, which had already been used by Sames
and coworkers [35], to cleave the pyrroline directing group.
The same conditions were applied to 2-phenyl-1-(3-tri-
fluoromethylpyridin-2-yl)piperidine (4a), but the reported
protocol was not successful. It turned out that hydrogena-
tion using Pd/C as catalyst was not working in presence of
the CF3 group on pyridine. On changing the hydrogenation
catalyst to PtO2 hydrate, almost pure intermediate 16 was
obtained after basic extraction. For further purification, the
crude product was dissolved in CH2Cl2 and silica gel was
added before the solvent was evaporated. This procedure
was undertaken to subject the compound to column chro-
matography as solid. Interestingly, not only the desired
product 2-phenyl-1-[3-(trifluoromethyl)-3,4,5,6-tetrahydro-
pyridin-2-yl]piperidine (16) could be obtained in yield of
12 % after purification, but also the product 17 lacking the
trifluoromethyl group was isolated, in fact at much higher
yield of 47 %. Obviously, this compound was generated
during column chromatography, as it was not detected by
GC–MS or 1H NMR of the crude product. Hence, intentional
formation of 17 from 16 was attempted. Crude 16 was diluted
in CH2Cl2 and stirred in the presence of approximately
fivefold weight of silica gel in a closed vial at 50 °C. After
2.5 h, GC–MS showed full conversion to 2-phenyl-
1-(3,4,5,6-tetrahydropyridin-2-yl)piperidine (17). To the
best of our knowledge, this interesting detrifluoromethyla-
tion mediated by silica gel is unprecedented in the literature.
In conclusion, saturated cyclic amines could be mono-
arylated in a-position by selective transition-metal-catalyzed
C–H activation. Best results were obtained for piperidine. A
number of different arylboronate esters were accepted in this
reaction. For substituted piperidines the yields decreased and
further dropped for all other saturated amines, with the
exception of pyrrolidine. In this case, however, the different
ring geometry led to some bis-arylation. Still, since purifi-
cation problems between mono- and bis-arylated compounds
can be avoided, the protocol offers significant potential in the
synthesis of mono-arylated piperidines. For cleavage of the
directing group, a modified protocol was developed, resulting
in good yield. This interesting method takes advantage of an
unprecedented CF3 cleavage under very mild conditions.
Further exploration of the detrifluoromethylation may be of
significant interest to the synthetic community and will be
conducted in the near future.
Experimental
Unless otherwise noted chemicals were purchased
from commercial suppliers and were used without further
purification. Flash column chromatography was performed
123

546
M. C. Schwarz et al.
Scheme 3
PtO2 hydrate (5 mol%),
H2 (1 atm), HCl, iPrOH
N
N
F3C
F3C
RT, 14 h
N
N
16
4a
Silica gel
DCM,
50 °C, 2.5 h,
closed vial
NH2NH2.H2O
AcOH, i-PrOH
N
N
H
120 °C, 2.5 h
N
Overall yield 47%
17
18
Scheme 4
i
i
H
S O S O
i
i
H
S O S O
N
N
N
O
O
i
O
O
i
+
F
3C
i
H
S O S O
i F
S O S O C
3
N
16
17
+
H
2O
-
+
H
F
O C
3
i
i
H
H
S O S O
-
~
O
O
i
20 °
C
i
S O S O
=
O
+
F
C
HF
2
on silica gel 60 from Merck (40–63 lm), using a Sepacore
medium pressure liquid chromatography (MPLC) system
from Bu¨chi equipped with an ultraviolet (UV) light
detector. TLC analysis was done with precoated aluminum-
backed plates (silica gel 60 F254, Merck). Preparative
TLC was performed on 20 9 20 cm, 1,000 lm thin-layer
chromatography plates. Signals were visualized with UV
light (254 nm). GC analyses were conducted on a Trace
GC (Thermo Finnigan) using a BGB-5 (30 m 9 0.32 mm
i.d., 1.0 lm film thickness) polysiloxane (5 % diphenyl-,
95 % dimethylpolysiloxane) capillary column. The oven
temperature program was 100 °C (2 min)/18 °C per min/
280 °C (5 min). GC–MS analyses were conducted on a
DSQ II GC–MS with Focus GC (Thermo Scientific), using
a BGB-5 (30 m 9 0.25 mm i.d., 0.25 lm film thickness)
polysiloxane (5 % diphenyl-, 95 % dimethylpolysiloxane)
capillary column. The oven temperature program was
100 °C (2 min)/18 °C per min/280 °C (3 min), unlike
otherwise stated. Source and transfer line were set at 250
and 280 °C, respectively.
High-resolution mass spectroscopy measurements were
carried out by E. Rosenberg at the Institute for Chemical
123

First selective direct mono-arylation of piperidines using ruthenium-catalyzed C–H activation
547
1-(3-Trifluoromethylpyridin-2-yl)piperidine
(3a, C11H13F3N2)
Technologies and Analytics, Vienna University of Tech-
nology. All samples were analyzed by liquid chromato-
graphy (LC)-ion trap (IT)-time of flight (TOF)-MS with
electrospray (ES) ionization and atmospheric-pressure
chemical ionization (APCI) in positive ion detection mode,
recording only MS(1) spectra. The exact mass was used to
calculate the elemental composition of the analytes from
the quasimolecular ion [M ? H]? for the evaluation.
Instrumental parameters: Shimadzu Prominence HPLC,
consisting of: solvent degassing unit (DGU-20 A3), binary
gradient pump (29 LC-20AD), auto-injector (SIL-20A),
column oven (CTO-20AC), control module (CBM-20A),
and diode array detector (SPD-M20A). Chromatography:
column: Phenomenex Kinetex ODS(3), 30 9 4.6 mm,
2.6 lm core–shell particles, operated at 40 °C; gradient:
0 min: 70 % A, 30 % B (1 min); linear gradient to 5 min to
10 % A, 90 % B (hold until 10 min); at 10.01 min back to
70 % A, 30 % B (hold until 12.0 min); A: H2O (0.1 % v/v
HCOOH), B: acetonitrile (0.1 % v/v HCOOH); flow:
0.5 cm3/min; injection volume: 0.5 mm3. MS parameters:
MS parameters as in autotune. Data recorded with detector
value at autotune value. Scan range: 100–1,000 amu for
MS (PI) detection. ES ionization: curved desolvation line
(CDL) temperature: 200 °C, heating block temperature:
200 °C.
Prepared according to general procedure A starting from
3.630 g 1 (20 mmol) and 3.406 g piperidine (2a, 40 mmol,
2 equiv.) using 40 cm3 acetonitrile. Conditions: round-
bottom flask with reflux condenser, reflux, 24 h. Yield:
79 % (3.634 g); colorless oil; 1H NMR (CDCl3,
200 MHz): d = 1.51–1.75 (m, 6H), 3.20–3.25 (m, 4H),
6.92 (dd, J = 7.7 Hz, 4.7 Hz, 1H), 7.83 (dd, J = 7.7 Hz,
1.7 Hz, 1H), 8.40 (br d, J = 3.7 Hz, 1H) ppm; 13C NMR
(CDCl3, 50 MHz): d = 24.4, 26.0, 51.9, 116.1, 116.6 (q,
J = 31.3 Hz), 124.1 (q, J = 272.4 Hz), 137.2 (q,
J = 5.1 Hz), 150.9, 160.5 ppm; HR-MS: [M ? H]?
m/z (predicted) = 307.1417, m/z (measured) = 307.1409.
2-Methyl-1-[3-(trifluoromethyl)pyridin-2-yl]piperidine
(3b, C12H15F3N2)
Prepared according to general procedure A starting from
363 mg 1 (2 mmol) and 594 mg 2-methylpiperidine (2b,
6 mmol, 3 equiv.) using 4 cm3 acetonitrile. Conditions:
microwave, 180 °C, 3.5 h. Yield: 26 % (128.3 mg);
slightly yellow oil; 1H NMR (CDCl3, 200 MHz):
d = 0.84 (d, 3H, J = 6.2 Hz), 1.33–1.84 (m, 6H),
2.74–2.86 (m, 1H), 2.99–3.09 (m, 1H), 3.36–3.52 (m,
1H), 7.12 (dd, J = 7.8 Hz, 4.8 Hz, 1H), 7.97 (dd,
J = 7.8 Hz, 1.9 Hz, 1H), 8.57 (dd, J = 4.7 Hz, 1.2 Hz,
1H) ppm; 13C NMR (CDCl3, 50 MHz): d = 19.3, 23.7,
26.0, 33.8, 53.6, 54.2, 119.0, 122.3 (q, J = 30.6 Hz), 123.5
(q, J = 272.4 Hz), 136.2 (q, J = 5.1 Hz), 151.6,
162.9 ppm; HR-MS: [M ? H]? m/z (predicted) =
245.1260, m/z (measured) = 245.1257.
Melting points were recorded using a Kofler-type Leica
Galen III micro hot-stage microscope. Microwave reac-
tions were performed on
a BIOTAGE Initiator 60
microwave unit. The reported times are hold times. NMR
spectra were recorded from CDCl3 solutions on a Bruker
AC 200 (200 MHz) or a Bruker DRX 400 (400 MHz)
spectrometer (as indicated), using the solvent peak [CDCl3:
d = 7.26 ppm (1H), d = 77.16 ppm (13C)] and tetrameth-
ylsilane (TMS) as reference. 13C spectra were run in
proton-decoupled mode, and in addition some spectra were
also recorded as distortionless enhanced polarization
transfer (DEPT) or attached proton test (APT).
3-Methyl-1-[3-(trifluoromethyl)pyridin-2-yl]piperidine
(3c, C12H15F3N2)
Prepared according to general procedure A starting from
363 mg 1 (2 mmol) and 396 mg 3-methylpiperidine (2c,
4 mmol, 2 equiv.) using 4 cm3 acetonitrile. Conditions:
microwave, 180 °C, 1.5 h. Yield: 87 % (423.6 mg); col-
1
orless oil; H NMR (CDCl3, 200 MHz): d = 0.92 (d, 3H,
General procedure A
J = 6.4 Hz), 0.97–1.17 (m, 1H), 1.59–1.89 (m, 4H), 2.53
(dd, J = 12.2 Hz, 10.2 Hz, 1H), 2.75–2.88 (m, 1H),
3.48–3.57 (m, 2H), 6.92 (dd, J = 7.7 Hz, 4.8 Hz, 1H),
7.83 (dd, J = 7.7 Hz, 1.8 Hz, 1H), 8.41 (dd, J = 4.7 Hz,
1.3 Hz, 1H) ppm; 13C NMR (CDCl3, 50 MHz): d = 19.2,
25.4, 31.1, 33.0, 51.6, 58.5, 116.1, 116.5 (q, J = 31.2 Hz),
124.1 (q, J = 272.4 Hz), 137.2 (q, J = 5.1 Hz), 150.9,
160.3 ppm; HR-MS: [M ? H]? m/z (predicted) =
245.1260, m/z (measured) = 245.1252.
2-Chloro-3-(trifluoromethyl)pyridine (1, 1 equiv.), amine 2
(2 or 3 equiv.), K2CO3 (2 equiv.), and acetonitrile were
placed in a microwave vial, a round-bottom flask with a
reflux condenser, or a closed 8-cm3 vial, all equipped with
a magnetic stirring bar (see respective compound for the
reaction vessel used). The reaction mixture was heated,
either in the microwave reactor or conventionally, and
monitored by TLC and GC–MS. When reaction control
showed full consumption of the starting material or no
further progress, the mixture was cooled to room temper-
ature and filtered, and the solvent was evaporated. The
residue was purified by silica gel flash column chroma-
tography to give the desired product 3.
4-Methyl-1-[3-(trifluoromethyl)pyridin-2-yl]piperidine
(3d, C12H15F3N2)
Prepared according to general procedure A starting from
363 mg 1 (2 mmol) and 396 mg 4-methylpiperidine (2d,
4 mmol, 2 equiv.) using 4 cm3 acetonitrile. Conditions:
123

548
M. C. Schwarz et al.
microwave, 180 °C, 1 h. Yield: 90 % (440.6 mg); color-
less oil; H NMR (CDCl3, 200 MHz): d = 0.99 (d, 3H,
1.7 Hz, 1H), 8.27 (dd, J = 4.4 Hz, 1.2 Hz, 1H) ppm; 13C
NMR (CDCl3, 50 MHz): d = 25.6, 49.5 (q, J = 3.2 Hz),
108.6 (q, J = 32.2 Hz), 110.9, 124.5 (q, J = 271.2 Hz),
136.9 (q, J = 6.2 Hz), 150.6, 154.9 ppm; HR-MS:
[M ? H]? m/z (predicted) = 217.0947, m/z (measured) =
217.0945.
1
J = 6.1 Hz), 1.25–1.75 (m, 5H), 2.83–2.95 (m, 2H),
3.57–3.63 (m, 2H), 6.92 (dd, J = 7.7 Hz, 4.8 Hz, 1H),
7.83 (dd, J = 7.8 Hz, 1.8 Hz, 1H), 8.40 (br d, J = 3.6 Hz,
1H) ppm; 13C NMR (CDCl3, 50 MHz): d = 21.9, 30.9,
34.3, 51.3, 116.1, 116.6 (q, J = 31.4 Hz), 124.1 (q,
J = 272.4 Hz), 137.2 (q, J = 5.0 Hz), 150.8, 160.4 ppm;
HR-MS: [M ? H]? m/z (predicted) = 245.1260, m/z
(measured) = 245.1250.
1-[3-(trifluoromethyl)pyridin-2-yl]hexahydroazepine
(3h, C12H15F3N2)
Prepared according to general procedure A starting from
1.452 g 1 (8 mmol) and 1.584 g hexahydroazepine (2h,
16 mmol, 2 equiv.) using 16 cm3 acetonitrile. Conditions:
round-bottom flask with reflux condenser, reflux, 65 h.
Ethyl 1-[3-(trifluoromethyl)pyridin-2-yl]piperidine-4-
carboxylate (3e, C14H17F3N2O2)
1
Prepared according to general procedure A starting from
363 mg 1 (2 mmol) and 628 mg ethyl piperidine-4-car-
boxylate (2c, 4 mmol, 2 equiv.) using 4 cm3 acetonitrile.
Conditions: closed vial, 100 °C, 22.5 h. Yield: 75 %
(454.5 mg); slightly yellow oil; 1H NMR (CDCl3,
200 MHz): d = 1.28 (t, 3H, J = 7.1 Hz), 1.25–1.75
(m, 4H), 2.40–2.55 (m, 1H), 2.89–3.03 (m, 2H),
3.54–3.63 (m, 2H), 7.13 (q, 2H, J = 7.1 Hz), 6.98 (dd,
J = 7.7 Hz, 4.8 Hz, 1H), 7.85 (dd, J = 7.8 Hz, 1.8 Hz,
1H), 8.42 (dd, J = 4.6 Hz, 1.4 Hz, 1H) ppm; 13C NMR
(CDCl3, 50 MHz): d = 13.9, 28.0, 40.9, 50.3, 60.1, 116.6,
117.0 (q, J = 31.4 Hz), 123.6 (q, J = 272.6 Hz), 136.9 (q,
J = 5.0 Hz), 150.7, 159.9, 174.6 ppm; HR-MS: [M ? H]?
m/z (predicted) = 303.1316, m/z (measured) = 303.1307.
Yield: 86 % (1.6728 g); colorless oil; H NMR (CDCl3,
200 MHz): d = 1.54–1.66 (m, 4H), 1.76–1.89 (m, 4H),
3.57 (t, J = 5.6 Hz, 4H), 6.72 (dd, J = 7.7 Hz, 4.6 Hz,
1H), 7.77 (dd, J = 7.8 Hz, 1.8 Hz, 1H), 8.29 (dd,
J = 4.3 Hz, 1.3 Hz, 1H) ppm; 13C NMR (CDCl3,
200 MHz): d = 27.6, 28.4, 51.9 (q, J = 2.2 Hz), 111.3
(q, J = 31.7 Hz), 116.3, 124.4 (q, J = 271.7 Hz), 137.5 (q,
J = 5.7 Hz), 150.1, 158.8 ppm; HR-MS: [M ? H]?
m/z (predicted) = 245.1260, m/z (measured) = 245.1250.
1-Methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
(3i, C11H14F3N3)
Prepared according to general procedure A starting from
1.452 g 1 (8 mmol) and 1.600 g 1-methylpiperazine (2i,
16 mmol, 2 equiv.) using 16 cm3 acetonitrile. Conditions:
round-bottom flask with reflux condenser, reflux, 65 h.
Yield: 83 % (1.632 g); slightly yellow oil; 1H NMR
(CDCl3, 200 MHz): d = 2.35 (s, 3H), 2.56 (t,
J = 4.8 Hz, 4H), 3.35 (t, J = 4.8 Hz, 4H), 6.95 (dd,
J = 7.7 Hz, 4.8 Hz, 1H), 7.84 (dd, J = 7.8 Hz, 1.5 Hz,
1H), 8.41 (br d, J = 4.8 Hz, 1H) ppm; 13C NMR (CDCl3,
50 MHz): d = 46.1, 50.4, 55.1, 116.3 (q, J = 31.5 Hz),
116.4, 124.0 (q, J = 272.6 Hz), 137.2 (q, J = 5.1 Hz),
150.9, 159.4 ppm; HR-MS: [M ? H]? m/z (predicted) =
246.1213, m/z (measured) = 246.1200.
4-Benzyl-1-[3-(trifluoromethyl)pyridin-2-yl]piperidine
(3f, C18H19F3N2)
Prepared according to general procedure A starting from
363 mg 1 (2 mmol) and 700 mg 4-benzylpiperidine (2f,
4 mmol, 2 equiv.) using 4 cm3 acetonitrile. Conditions:
closed vial, 100 °C, 22.5 h. Yield: 87 % (556 mg); slightly
yellow solid; m.p.: 56–59 °C; 1H NMR (CDCl3,
200 MHz): d = 1.32–1.76 (m, 5H), 2.60 (d, 2H,
J = 6.6 Hz), 2.78–2.90 (m, 2H), 3.57–3.64 (m, 2H), 6.92
(dd, J = 7.7 Hz, 4.8 Hz, 1H), 7.16–7.34 (m, 5H), 7.82 (dd,
J = 7.7 Hz, 1.8 Hz, 1H), 8.39 (dd, J = 4.6 Hz, 1.5 Hz,
1H) ppm; 13C NMR (CDCl3, 50 MHz): d = 32.3, 38.0,
43.3, 51.2, 116.3, 116.6 (q, J = 31.4 Hz), 124.1 (q,
J = 272.5 Hz), 128.2, 129.1, 137.2 (q, J = 5.1 Hz),
140.6, 150.9, 160.2 ppm; HR-MS: [M ? H]? m/z (pre-
dicted) = 321.1573, m/z (measured) = 321.1559.
1-[3-(trifluoromethyl)pyridin-2-yl]morpholine
(3j, C10H11F3N2O)
Prepared according to general procedure A starting from
182 mg 1 (1 mmol) and 174 mg morpholine (2j, 2 mmol,
2 equiv.) using 2 cm3 acetonitrile. Conditions: microwave,
1
180 °C, 1.5 h. Yield: 63 % (147.3 mg); colorless oil; H
1-[3-(trifluoromethyl)pyridin-2-yl]pyrrolidine
(3g, C10H11F3N2)
NMR (CDCl3, 200 MHz): d = 3.29 (t, J = 4.6 Hz, 4H),
3.84 (t, J = 4.6 Hz, 4H), 7.01 (dd, J = 7.8 Hz, 4.8 Hz,
1H), 7.89 (dd, J = 7.8 Hz, 1.7 Hz, 1H), 8.44 (br d,
J = 4.3 Hz, 1H) ppm; 13C NMR (CDCl3, 50 MHz):
d = 51.1, 66.9, 117.0 (q, J = 31.5 Hz), 117.1, 123.9 (q,
J = 272.5 Hz), 137.2 (q, J = 5.1 Hz), 151.1, 159.5 ppm;
HR-MS: [M ? H]? m/z (predicted) = 233.0896, m/z
(measured) = 233.0888.
Prepared according to general procedure A starting from
1.089 g 1 (6 mmol) and 853 mg pyrrolidine (2g, 12 mmol,
2 equiv.) using 12 cm3 acetonitrile. Conditions: round-
bottom flask with reflux condenser, reflux, 48 h. Yield:
84 % (1.0884 g); colorless oil; 1H NMR (CDCl3,
200 MHz): d = 1.88–2.01 (m, 4H), 3.56–3.62 (m, 4H),
6.62 (dd, J = 7.7 Hz, 4.7 Hz, 1H), 7.78 (dd, J = 7.8 Hz,
123

First selective direct mono-arylation of piperidines using ruthenium-catalyzed C–H activation
549
N-Ethyl-N-[3-(trifluoromethyl)pyridin-2-yl]ethanamine
(3k, C10H13F3N2)
2-(p-Tolyl)-1-[3-(trifluoromethyl)pyridin-2-yl]piperidine
(4b, C18H19F3N2)
Prepared according to general procedure A starting from
363 mg 1 (2 mmol) and 439 mg N-ethylethanamine (2k,
6 mmol, 3 equiv.) using 4 cm3 acetonitrile. Conditions:
microwave, 180 °C, 2 h. Yield: 37 % (160.8 mg); slightly
Yield: 47 % (84.8 mg); slightly yellow solid; m.p.:
61–63 °C; 1H NMR (CDCl3, 400 MHz): d = 1.52–1.57
(m, 1H), 1.71–1.90 (m, 5H), 2.17 (s, 3H), 2.76 (ddd,
J = 11.5 Hz, 11.5 Hz, 2.5 Hz, 1H), 3.30–3.34 (m, 1H),
4.43 (dd, J = 10.1 Hz, 2.8 Hz, 1H), 6.88–6.91 (m, 3H),
7.19 (d, J = 7.9 Hz, 2H), 7.75 (dd, J = 7.8 Hz, 1.7 Hz,
1H), 8.34 (dd, J = 4.8 Hz, 1.5 Hz, 1H) ppm; 13C NMR
(CDCl3, 100 MHz): d = 21.0, 24.9, 26.1, 35.6, 56.7, 64.0,
118.9, 121.6 (q, J = 30.9 Hz), 123.5 (q, J = 272.7 Hz,),
127.6, 127.8, 135.6, 136.3 (q, J = 5.2 Hz), 141.3,
151.1, 162.7 ppm; HR-MS: [M ? H]? m/z (predicted) =
321.1557, m/z (measured) = 321.1564.
1
yellow oil; H NMR (CDCl3, 200 MHz): d = 1.09 (t, 6H,
J = 7.1 Hz), 3.30 (q, 4H, J = 7.1 Hz), 6.93 (dd,
J = 7.8 Hz, 4.7 Hz, 1H), 7.85 (dd, J = 7.8 Hz, 1.8 Hz,
1H), 8.42 (dd, J = 4.6 Hz, 1.2 Hz, 1H) ppm; 13C NMR
(CDCl3, 50 MHz): d = 12.8, 46.1, 116.1, 117.6 (q,
J = 31.1 Hz), 124.0 (q, J = 272.2 Hz), 137.0 (q,
J = 5.3 Hz), 150.6, 159.9 ppm; HR-MS: [M ? H]?
m/z (predicted) = 219.1104, m/z (measured) = 219.1009.
2-(4-tert-Butylphenyl)-1-[3-(trifluoromethyl)pyridin-2-yl]-
piperidine (4c, C21H25F3N2)
General procedure B
Yield: 50 % (90.7 mg); colorless solid; m.p.: 93–96 °C; 1H
NMR (CDCl3, 200 MHz): d = 1.20 (s, 9H), 1.51–1.90 (m,
6H), 2.75–2.87 (m, 1H), 3.28–3.39 (m, 1H), 4.46–4.53 (m,
1H), 6.89 (dd, J = 7.7 Hz, 4.9 Hz, 1H), 7.09–7.24 (m, 4H),
7.76 (br d, J = 6.7 Hz, 1H), 8.34 (br d, J = 3.6 Hz,
1H) ppm; 13C NMR (CDCl3, 50 MHz): d = 24.6, 26.1,
31.3, 34.2, 35.3, 56.2, 63.6, 115.5, 121.2 (q, J = 30.8 Hz),
123.6 (q, J = 272.7 Hz), 124.5, 127.4, 136.3 (q,
J = 5.2 Hz), 141.0, 148.7, 151.1, 162.5 ppm; HR-MS:
[M ? H]? m/z (predicted) = 363.2043, m/z (measured) =
263.2036.
An 8-cm3 vial with a magnetic stirring bar and a screw cap
with septum was charged with saturated cyclic amine 3
(0.5 mmol, 1 equiv.), arylboronate ester 5 (2 mmol,
4 equiv.), 22 mg Ru3(CO)12 (0.035 mmol, 7 mol%),
19 mg 1,3-propanediol (0.25 mmol, 0.5 equiv.), and
2.5 mg CuSO4Á5H2O (0.01 mmol, 2 mol%). The vial was
evacuated and flushed with argon three times, and 0.5 cm3
o-xylene was added via syringe. Then, the vial was
equipped with a balloon filled with argon, which was
attached to a needle and plunged through the septum. The
mixture was heated to 140 °C for 24 h in a heating block
with a reflux condenser block on top. The reaction mixture
was cooled to room temperature, and 2 cm3 EtOAc and
2 cm3 water were added to the reaction solution and agi-
tated. The mixture was extracted three times with EtOAc.
To achieve better phase separation, brine was added if
necessary. The combined organic layers were dried over
Na2SO4 and filtered, and the solvent was evaporated. The
residue was purified by silica gel flash chromatography to
give 4.
2-(4-Fluorophenyl)-1-[3-(trifluoromethyl)pyridin-2-yl]-
piperidine (4d, C17H16F4N2)
Yield: 43 % (68.9 mg); slightly yellow solid; m.p.:
70–72 °C; 1H NMR (CDCl3, 200 MHz): d = 1.46–1.94
(m, 6H), 2.75 (ddd, J = 11.2 Hz, 11.2 Hz, 3.1 Hz, 1H),
3.28–3.38 (m, 1H), 4.43 (dd, J = 9.7 Hz, 3.3 Hz, 1H),
6.73–6.83 (m, 2H), 6.95 (dd, J = 7.8 Hz, 4.8 Hz, 1H),
7.23–7.30 (m, 2H), 7.78 (dd, J = 7.8 Hz, 1.6 Hz, 1H), 8.35
(dd, J = 4.7 Hz, 1.4 Hz, 1H) ppm; 13C NMR (CDCl3,
50 MHz): d = 24.8, 26.0, 35.6, 56.8, 63.6, 114.4 (d,
J = 21.4 Hz), 119.2, 121.9 (q, J = 30.8 Hz), 123.4 (q,
J = 272.7 Hz), 129.4 (d, J = 7.7 Hz), 136.2 (q,
J = 5.3 Hz), 140.0 (d, J = 3.2 Hz), 151.1, 161.2 (d,
J = 243.7 Hz), 162.5 ppm; HR-MS: [M ? H]? m/z (pre-
dicted) = 325.1322, m/z (measured) = 325.1317.
2-Phenyl-1-[3-(trifluoromethyl)pyridin-2-yl]piperidine
(4a, C17H17F3N2)
Yield: 60 % (91.1 mg); colorless solid; m.p.: 92–94 °C; 1H
NMR (CDCl3, 400 MHz): d = 1.52–1.61 (m, 1H),
1.72–1.90 (m, 5H), 2.77 (ddd, J = 11.5 Hz, 11.5 Hz,
1.7 Hz, 1H), 3.32–3.36 (m, 1H), 4.46 (br d, J = 10.0 Hz,
1H), 6.89 (dd, J = 7.2 Hz, 5.0 Hz, 1H), 6.98–7.02 (m, 1H),
7.09 (t, J = 7.6 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.75
(dd, J = 7.8 Hz, 1.4 Hz, 1H), 8.32 (br d, J = 4.7 Hz,
1H) ppm; 13C NMR (CDCl3, 100 MHz): d = 24.9, 26.1,
35.6, 56.7, 64.3, 118.9, 121.7 (q, J = 30.9 Hz), 123.5 (q,
J = 272.6 Hz), 126.2, 127.7, 127.9, 136.3 (q, J = 5.2 Hz),
144.3, 151.1, 162.5 ppm; HR-MS: [M ? H]? m/z (pre-
dicted) = 307.1417, m/z (measured) = 307.1409.
2-(4-Chlorophenyl)-1-[3-(trifluoromethyl)pyridin-2-yl]-
piperidine (4e, C17H16ClF3N2)
1
Yield: 34 % (58.0 mg); colorless oil; H NMR (CDCl3,
400 MHz): d = 1.48–1.60 (m, 1H), 1.72–1.91 (m, 5H),
2.73 (ddd, J = 11.6 Hz, 11.6 Hz, 2.5 Hz, 1H), 3.31–3.36
(m, 1H), 4.42 (dd, J = 10.8 Hz, 2.5 Hz, 1H), 6.94 (dd,
J = 7.7 Hz, 4.9 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 7.24
(d, J = 8.5 Hz, 2H), 7.78 (dd, J = 7.8 Hz, 1.7 Hz, 1H),
8.34 (dd, J = 4.7 Hz, 1.5 Hz, 1H) ppm; 13C NMR (CDCl3,
123

550
M. C. Schwarz et al.
100 MHz): d = 24.8, 26.0, 35.6, 56.9, 63.7, 119.2, 121.8
(q, J = 30.9 Hz), 123.4 (q, J = 272.7 Hz), 127.9, 129.3,
131.7, 136.3 (q, J = 5.2 Hz), 142.9, 151.2, 162.3 ppm;
HR-MS: [M ? H]? m/z (predicted) = 341.1027, m/z
(measured) = 341.1035.
2-(3-Chlorophenyl)-1-[3-(trifluoromethyl)pyridin-2-yl]-
piperidine (4k, C17H16ClF3N2)
Yield: 39 % (66.6 mg); colorless solid; m.p.: 82–84 °C; 1H
NMR (CDCl3, 200 MHz): d = 1.45–1.92 (m, 6H), 2.72
(ddd, J = 11.2 Hz, 11.2 Hz, 3.1 Hz, 1H), 3.29–3.39 (m,
1H), 4.45 (dd, J = 10.1 Hz, 2.5 Hz, 1H), 6.92–7.06 (m,
3H), 7.15–7.26 (m, 1H), 7.33 (br s, 1H), 7.80 (dd,
J = 7.8 Hz, 1.4 Hz, 1H), 8.35 (dd, J = 4.8 Hz, 1.2 Hz,
1H) ppm; 13C NMR (CDCl3, 100 MHz): d = 24.7, 26.0,
35.5, 56.8, 63.8, 119.2, 121.7 (q, J = 30.9 Hz), 123.5 (q,
J = 272.6 Hz), 126.1, 126.4, 128.1, 129.0, 133.5, 136.4 (q,
J = 5.1 Hz), 146.5, 151.2, 162.2 ppm; HR-MS: [M ? H]?
m/z (predicted) = 341.1027, m/z (measured) = 341.1017.
2-(4-Methoxyphenyl)-1-[3-(trifluoromethyl)pyridin-2-yl]-
piperidine (4f, C18H19F3N2O)
Yield: 16 % (26.5 mg); slightly yellow solid; m.p.:
69–72 °C; 1H NMR (CDCl3, 200 MHz): d = 1.46–1.91
(m, 6H), 2.76 (ddd, J = 11.3 Hz, 11.3 Hz, 3.1 Hz, 1H),
3.26–3.36 (m, 1H), 3.68 (s, 3H), 4.40 (dd, J = 9.1 Hz,
3.8 Hz, 1H), 6.64 (d, J = 8.6 Hz, 2H), 6.93 (dd,
J = 7.8 Hz, 4.8 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 7.77
(dd, J = 7.8 Hz, 1.6 Hz, 1H), 8.36 (br d, J = 3.8 Hz,
1H) ppm; 13C NMR (CDCl3, 50 MHz): d = 24.9, 26.1,
35.5, 55.0, 56.7, 63.6, 113.0, 119.0, 121.8 (q,
J = 30.8 Hz), 123.5 (q, J = 272.7 Hz), 129.1, 136.2 (qd,
3J = 5.2 Hz), 136.4, 151.1, 157.8, 162.7 ppm; HR-MS:
[M ? H]? m/z (predicted) = 337.1522, m/z (measured) =
337.1515.
4-Methyl-2-phenyl-1-[3-(trifluoromethyl)pyridin-2-yl]-
piperidine (8, C18H19F3N2)
Yield: 28 % (44.4 mg); colorless solid; m.p.: 106–108 °C;
1H NMR (CDCl3, 400 MHz): d = 1.00 (d, J = 6.2 Hz, 3H),
1.44–1.61 (m, 2H), 1.68–1.78 (m, 2H), 1.84–1.89 (m, 1H),
2.75 (ddd, J = 11.9 Hz, 11.9 Hz, 1.8 Hz, 1H), 3.43 (ddd,
J = 11.7 Hz, 11.7 Hz, 3.1 Hz, 1H), 4.42 (dd, J = 11.5 Hz,
1.9 Hz, 1H), 6.92 (dd, J = 7.6 Hz, 4.9 Hz, 1H), 7.06–7.10
(m, 1H), 7.08 (br dd, J = 7.5 Hz, 7.5 Hz, 2H), 7.30 (br d,
J = 7.5 Hz, 2H), 7.76 (dd, J = 7.8 Hz, 1.6 Hz, 1H), 8.33
(dd, J = 4.7 Hz, 1.4 Hz, 1H) ppm; 13C NMR (CDCl3,
100 MHz): d = 22.0, 31.7, 34.5, 44.7, 57.0, 64.4, 119.3,
122.3 (q, J = 30.6 Hz), 123.4 (q, J = 272.9 Hz), 126.2,
127.7, 127.9, 136.2 (q, J = 5.1 Hz), 144.4, 151.1,
162.7 ppm; HR-MS: [M ? H]? m/z (predicted) =
321.1573, m/z (measured) = 321.1565.
2-(4-Trifluoromethylphenyl)-1-[3-(trifluoromethyl)pyridin-
2-yl]piperidine (4g, C18H16F6N2)
Yield: 40 % (74.9 mg); slightly yellow solid; m.p.:
60–62 °C; 1H NMR (CDCl3, 400 MHz): d = 1.53–1.62
(m, 1H), 1.73–1.93 (m, 5H), 2.74 (ddd, J = 11.6 Hz,
11.6 Hz, 2.5 Hz, 1H), 3.35–3.40 (m, 1H), 4.53 (dd,
J = 10.9 Hz, 2.4 Hz, 1H), 6.95 (dd, J = 7.7 Hz, 4.9 Hz,
1H), 7.35 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H),
7.80 (dd, J = 7.8 Hz, 1.7 Hz, 1H), 8.32 (dd, J = 4.8 Hz,
1.4 Hz, 1H) ppm; 13C NMR (CDCl3, 100 MHz): d = 24.7,
26.0, 35.6, 56.9, 64.0, 119.3, 121.7 (q, J = 30.9 Hz),
123.4 (q, J = 272.8 Hz), 124.2 (q, J = 271.8 Hz),
124.8 (q, J = 3.8 Hz), 128.1, 128.4 (q, J = 32.3 Hz),
136.5 (q, J = 5.2 Hz), 148.6, 151.1, 162.0 ppm; HR-MS:
[M ? H]? m/z (predicted) = 375.1290, m/z (measured) =
375.1280.
Ethyl 2-phenyl-1-[3-(trifluoromethyl)pyridin-2-yl]-
piperidine-4-carboxylate (9, C20H21F3N2O2)
Yield: 25 % (47.6 mg); slightly yellow solid; m.p.:
74–76 °C; 1H NMR (CDCl3, 200 MHz): d = 1.25 (t,
J = 7.1 Hz, 3H), 1.86–2.21 (m, 4H), 2.55–2.84 (m, 2H),
3.43 (ddd, J = 11.7 Hz, 11.7 Hz, 3.4 Hz, 1H), 4.14 (q,
J = 7.1 Hz, 2H), 4.46 (dd, J = 11.3 Hz, 2.4 Hz, 1H),
6.92–7.14 (m, 3H), 7.29–7.34 (m, 2H), 7.78 (dd,
J = 7.8 Hz, 1.5 Hz, 1H), 8.34 (dd, J = 4.5 Hz, 1.2 Hz,
1H) ppm; 13C NMR (CDCl3, 100 MHz): d = 14.2, 28.5,
37.9, 42.2, 56.0, 63.8, 119.7, 122.4 (q, J = 31.0 Hz), 123.4
(q, J = 272.8 Hz), 126.6, 127.8, 128.0, 136.3 (q,
J = 5.1 Hz), 141.2, 151.1, 162.1 ppm; HR-MS: [M ? H]?
m/z (predicted) = 379.1628, m/z (measured) = 379.1629.
2-(m-Tolyl)-1-[3-(trifluoromethyl)pyridin-2-yl]piperidine
(4j, C18H19F3N2)
Yield: 49 % (78.8 mg) colorless solid; m.p.: 80–82 °C; 1H
NMR (CDCl3, 200 MHz): d = 1.47–1.88 (m, 6H), 2.19 (s,
3H), 2.73 (ddd, J = 11.3 Hz, 11.3 Hz, 2.9 Hz, 1H),
3.27–3.38 (m, 1H), 4.43 (dd, J = 9.3 Hz, 3.3 Hz, 1H),
6.79–7.16 (m, 5H), 7.75 (dd, J = 7.8 Hz, 1.6 Hz, 1H), 8.33
(dd, J = 4.8 Hz, 1.3 Hz, 1H) ppm; 13C NMR (CDCl3,
50 MHz): d = 21.3, 24.8, 26.1, 35.6, 56.7, 64.2, 118.9,
121.6 (q, J = 30.9 Hz), 123.5 (q, J = 272.7 Hz), 124.9,
126.9, 127.5, 128.6, 136.3 (q, J = 5.2 Hz), 137.1, 144.3,
151.1, 162.6 ppm; HR-MS: [M ? H]? m/z (predicted) =
321.1573, m/z (measured) = 321.1569.
4-Benzyl-2-phenyl-1-[3-(trifluoromethyl)pyridin-2-yl]-
piperidine (10, C24H23F3N2)
Yield: 34 % (67.8 mg); slightly yellow gum; 1H NMR
(CDCl3, 200 MHz): d = 1.46–1.93 (m, 5H), 2.59–2.76 (m,
2H), 3.35 (ddd, J = 11.7 Hz, 11.7 Hz, 3.2 Hz, 1H), 4.39
(bd, J = 9.8 Hz, 1H), 6.87–7.31 (m, 11H), 7.75 (dd,
J = 7.8 Hz, 1.6 Hz, 1H), 8.31 (dd, J = 4.7 Hz, 1.3 Hz,
123

First selective direct mono-arylation of piperidines using ruthenium-catalyzed C–H activation
551
1H) ppm; 13C NMR (CDCl3, 100 MHz): d = 32.4, 38.8,
42.5, 43.4, 56.8, 64.3, 119.4, 122.3 (q, J = 30.8 Hz), 123.5
(q, J = 272.7 Hz), 125.9, 126.3, 127.7, 128.0, 128.3,
129.2, 136.2 (q, J = 5.1 Hz), 140.5, 144.2, 151.1,
162.5 ppm; HR-MS: [M ? H]? m/z (predicted) = 397.
1886, m/z (measured) = 397.1888.
5 mol%), evacuated, and flushed with nitrogen three times.
Then, 2.5 cm3 i-PrOH was added with a syringe through a
septum, and the mixture was stirred at RT. After some
minutes, a solution of 153 mg 4a (0.5 mmol, 1 equiv.) in
2.5 cm3 i-PrOH and 0.5 cm3 2 N HCl was added to the
catalyst with a syringe. The flask was flushed with hydrogen
two times, and a hydrogen balloon was attached. The
reaction mixture was then stirred at RT for 14 h and filtered
through a pad of CeliteÒ, and the solvent was evaporated.
The residue was taken up in 1 N NaOH solution and
subsequently extracted with CH2Cl2 three times. The
combined organic layers were dried over Na2SO4, filtered,
and evaporated to dryness. The crude product 16 was then
diluted in 2.5 cm3 CH2Cl2 and stirred in the presence of
700 mg silica gel in a closed vial at 50 °C for 2.5 h. The
crude intermediate 17 was eluted from the silica gel with a
mixture of EtOAc and Et3N (15:1, then 1:1), evaporated to
dryness, and then treated with 2.5 cm3 NH2NH2/AcOH
(2.5 M/0.7 M in EtOH) at 120 °C for 2 h in a closed
microwave vial under nitrogen atmosphere. Again the
solvent was evaporated, and the residue was brought in
2 N NaOH solution and subsequently extracted with Et2O
three times. Evaporation to dryness yielded the crude
product. This was further purified by silica gel flash column
chromatography, affording 37.9 mg (47 %) 18 as colorless
gum. NMR spectra were found to be in accordance with the
ones described in reference [36].
2-Phenyl-1-[3-(trifluoromethyl)pyridin-2-yl]pyrrolidine
(11, C16H15F3N2)
Yield: 49 % (72.2 mg); slightly yellow solid; m.p.:
81–84 °C; 1H NMR (CDCl3, 400 MHz): d = 1.82–2.07
(m, 3H), 2.37–2.42 (m, 1H), 3.57–3.61 (m, 1H), 3.92–3.98
(m, 1H), 5.54 (dd, J = 7.8 Hz, 7.8 Hz, 1H), 6.61 (dd,
J = 7.7 Hz, 4.7 Hz, 1H), 7.13–7.16 (m, 1H), 7.24 (t,
J = 7.5 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.74 (dd,
J = 7.7 Hz, 1.2 Hz, 1H), 8.32 (br d, J = 4.4 Hz,
1H) ppm; 13C NMR (CDCl3, 100 MHz): d = 26.0, 35.9,
52.5 (q, 5J = 5.2 Hz), 63.1, 111.1 (q, J = 30.9 Hz), 112.6,
123.2 (q, J = 271.7 Hz), 126.1, 126.3, 128.2, 136.9 (q,
J = 5.7 Hz), 144.9, 150.4, 155.5 ppm; HR-MS: [M ? H]?
m/z (predicted) = 293.1260, m/z (measured) = 293.1249.
2-Phenyl-1-(3,4,5,6-tetrahydropyridin-2-yl)piperidine
(17, C16H22N2)
PtO2Áaq (16.3 mg, 0.072 mmol, 5 mol%) was placed in a
three-necked 25-cm3 flask equipped with a magnetic stirrer.
Theflaskwasevacuatedandflushedwithnitrogenthreetimes,
and then 7.2 cm3 i-PrOH was added with a syringe through a
septum. After stirring the mixture at room temperature (RT)
for some minutes, a solution of 441 mg 4a (1.44 mmol,
1 equiv.) in 7.2 cm3 i-PrOH and 1.4 cm3 2 N HCl was added
to the catalyst with a syringe. The flask was flushed with
hydrogen two times, and a hydrogen balloon was attached.
The reaction mixture was then stirred at RT for 14 h and
filtered through a pad of CeliteÒ, and the solvent was
evaporated. The residue was taken up in 1 N NaOH solution
and subsequently extracted with CH2Cl2 three times. The
combinedorganiclayersweredriedoverNa2SO4, filtered, and
evaporated to dryness. The crude product was then diluted in
5 cm3 CH2Cl2 andstirredinthepresenceof1.6 gsilicagelina
closed vial at 50 °C for 2.5 h. Afterwards, the crude product
wasdirectlyrotatedontothe silicagelandpurifiedbysilicagel
flash column chromatography. Yield: 72 % (252 mg); color-
Computational details
All calculations were performed using the Gaussian09
software package on the Phoenix Linux Cluster of the
Vienna University of Technology [42]. The geometry and
energy of the model compounds were optimized at the
PBE1PBE level [43–45] with the 6-31G** basis set
employed for all atoms [46–52]. All geometries were
optimized without symmetry constraints. Frequency cal-
culations were performed to confirm the nature of the
stationary points, yielding no imaginary frequencies.
Acknowledgments We acknowledge the Austrian Science Foun-
dation (FWF, project P21202-N17) for financial support of this work.
1
less oil; H NMR (CDCl3, 200 MHz): d = 1.36–2.41 (m,
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
12H), 2.75–2.87 (m, 1H), 3.43–3.66 (m, 2H), 4.12 (br d,
J = 13.3 Hz, 1H), 5.36 (br s, 1H), 7.16–7.36 (m, 5H) ppm;
13C NMR (CDCl3, 200 MHz): d = 19.7, 21.0, 22.6, 24.8,
25.5, 29.0, 40.0, 47.2, 52.8, 126.1, 126.7, 128.5, 141.6,
155.7 ppm; HR-MS: [M ? H]? m/z (predicted) = 243.1856,
m/z (measured) = 243.1846.
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