Aryl bromides and aryl chlorides for the direct arylation of benzylic amines mediated by ruthenium(II)

Article abstract of DOI:10.1002/ejoc.201300004

The ruthenium(II)-catalyzed sp³ C-H bond arylation of benzylic amines with aryl halides is reported. In the present method, aryl iodides and, more importantly, also the cheaper aryl bromides and aryl chlorides can be applied as aryl sources. Additionally, the method does not require elaborate manipulations in a glove box and can be carried out in simple screw cap vials. Potassium pivalate proved to be beneficial for the transformation with aryl bromides or iodides as aryl source, but was not required for aryl chlorides. In the latter case, the addition of PPh₃ led to high conversion. 3-Methyl and 3-phenyl pyridine were established as directing groups, and the substituent in the 3-position represents a key structural feature for high conversion. The directing group can be cleaved after the transformation, which allows access to diarylmethylamines. Mechanistic studies were carried out and critically compared to mechanistic reports of related transformations.. Copyright

Full text of DOI:10.1002/ejoc.201300004

FULL PAPER
DOI: 10.1002/ejoc.201300004
Aryl Bromides and Aryl Chlorides for the Direct Arylation of Benzylic Amines
Mediated by Ruthenium(II)
Navid Dastbaravardeh,[a] Michael Schnürch,*[a] and Marko D. Mihovilovic[a]
Keywords: Homogeneous catalysis / C–H activation / Cleavage reactions / Reaction mechanisms / Isotope effects
The ruthenium(II)-catalyzed sp3 C–H bond arylation of benz-
ylic amines with aryl halides is reported. In the present
method, aryl iodides and, more importantly, also the cheaper
aryl bromides and aryl chlorides can be applied as aryl
sources. Additionally, the method does not require elaborate
manipulations in a glove box and can be carried out in simple
screw cap vials. Potassium pivalate proved to be beneficial
for the transformation with aryl bromides or iodides as aryl
source, but was not required for aryl chlorides. In the latter
case, the addition of PPh3 led to high conversion. 3-Methyl
and 3-phenyl pyridine were established as directing groups,
and the substituent in the 3-position represents a key struc-
tural feature for high conversion. The directing group can
be cleaved after the transformation, which allows access to
diarylmethylamines. Mechanistic studies were carried out
and critically compared to mechanistic reports of related
transformations.
Regioselective direct arylations are difficult to achieve
because the arene reagents often contain several nonequiva-
lent C–H bonds that can react with the metal center at a
similar rate. This selectivity problem usually furnishes unde-
sired side products. The electronic properties of the sub-
strate can control the position of C–H bond cleavage.[3]
These electronic properties can be difficult to override and
limit the scope of reagents. There are several approaches to
overcome this problem and the most common strategy for
conducting regioselective direct arylations involves the use
of substrates containing directing groups. Ligating substitu-
ents can direct the metal center to cleave a specific C–H
bond to form a five- or six-membered metallacycle.[4] De-
spite the success in this area, there are relatively few studies
on the direct functionalization of sp3 carbon centers.[5]
We recently reported a Ru0-catalyzed chelation-assisted
method for the direct arylation of benzylic amines.[6] Our
preliminary studies in this area focused on the identification
of an appropriate directing group. Notably, we found that
3-substituted pyridine displayed the best activity owing to
the steric properties of this group. However, this protocol
was limited to boronic acid esters, and other aryl sources,
most importantly aryl halides, were not tolerated. Hence,
we were interested in the investigation of alternative meth-
ods suitable for aryl halides, and we developed a RuII-cata-
lyzed method that enabled the use of aryl bromides and
aryl iodides as arylation reagents.[7] Aryl chlorides were not
suitable for this kind of transformation. Within the present
contribution, we describe the expansion of substrate scope
of our previously reported method and disclose a new syn-
thetic procedure, which also enables the use of aryl chlor-
ides. Mechanistic investigations indicated that the two pro-
tocols proceed by different mechanistic pathways.
Introduction
Carbon–carbon bond formation is a central part of many
chemical syntheses, and nowadays there is a vast number of
ways for the formation of this kind of bond. Transition-
metal catalyzed cross-coupling reactions are one of the
most frequently applied methods for the creation of new C–
C bonds.[1] However, the required organometallic nucleo-
philic reagents, particularly those that are functionalized,
are often not commercially available or are relatively ex-
pensive. One way to overcome this problem is to introduce
new functional groups directly through transformation of
C–H bonds, which unlocks opportunities for markedly dif-
ferent synthetic strategies. Thus, transition-metal-catalyzed
functionalization of hydrocarbons is one of the most fre-
quently investigated but also one of the most challenging
topics in modern organic synthesis.[2] The development of
new synthetic methods and innovations in these types of
reactions will profoundly improve overall synthetic effi-
ciency. The possibility of direct formation of a new carbon–
carbon bond by C–H bond transformation is a highly at-
tractive strategy in covalent synthesis, owing to the ubiqui-
tous nature of C–H bonds in organic substances and the
high atom economy of the process.
[a] Institute of Applied Synthetic Chemistry, Vienna University of
Technology,
Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Fax: +43-1-58801-9163616
E-mail: michael.schnuerch@tuwien.ac.at
Homepage: http://www.ias.tuwien.ac.at/mdm/mschnuerch.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300004.
Re-use of this article is permitted in accordance with the Terms
and Conditions set out at http://onlinelibrary.wiley.com/journal/
10.1002/(ISSN)1099-0690/homepage/2046_onlineopen.html
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Direct Arylation of Benzylic Amines Mediated by Ruthenium(II)
Table 1. Optimization studies for the direct arylation of benzylic
amine 1a[a]
Results and Discussion
.
The initial inspiration for the development of an aryl-
ation protocol that uses aryl halides came from a publica-
tion of Ackermann and co-workers who reported a ruthe-
nium-catalyzed cyclometalation method for the direct aryl-
ation of sp2 carbon centers with aryl halides.[8] [RuCl2(p-
cymene)]2 is a frequently used catalyst for the direct func-
tionalization of unactivated sp2 C–H bonds and a variety
of catalytic reactions have been developed during recent
years.[9] We envisaged that this method would also be appli-
cable to our benzylic system, although direct sp3 arylation
was unprecedented with this catalyst at that time. We initi-
ated our optimization studies with 1 equiv. of N-benzyl-3-
methylpyridin-2-amine (1a), 1.5 equiv. of bromobenzene,
2.5 mol-% of [RuCl2(p-cymene)]2, and 3 equiv. of K2CO3 in
2 mL of toluene. The reaction mixture was stirred for 24 h
at 140 °C. Under these conditions, the desired product 3a
was formed (Table 1, Entry 1), but only in 34% yield. Inter-
estingly, we could also detect the corresponding dehydroge-
nated imine derivative 4 as a major side product, although
the reaction was performed under an inert atmosphere in
the absence of an oxidant. We also tested other catalysts
known to undergo C–H activation in combination with dif-
ferent additives (Table 1, Entries 2–7).[10] Products 3a and
4a were detected simultaneously in reactions that gave note-
worthy conversions (Table 1, Entries 1–3), however in dif-
ferent amounts. The ratio of amine to imine product was
obviously dependant on the reaction conditions, in particu-
Entry Catalyst
Ligand
X
Conv.[b] 3a/4[c] Yield
of 3a[d]
1
[RuCl2(p-cymene)]2
–
–
–
–
–
–
–
Br
Br
Br
Br
Br
Br
Br
59
28
47
8
4.0
3.5
2.4
–
34
2
3
4
5
6
7
RuCl3·(H2O)n
RuCl2(PPh3)3
[RhCl(cod)]2
[RhCl(C2H4)]2
[RhCp*Cl2]2
Rh4(CO)12
17
27
5
8
–
4
6
–
4
0
–
0
8
[RuCl2(p-cymene)]2 KOPiv Br
98
0
6.0
–
75
0
9
RuCl3·(H2O)n
KOPiv Br
KOPiv Br
10
11
12
13
14
15
RuCl2(PPh3)3
[RuCl2(p-cymene)]2 PPh3
RuCl3·(H2O)n
RuCl2(PPh3)3
[RuCl2(p-cymene)]2 KOPiv Cl
[RuCl2(p-cymene)]2 KOPiv
0
–
0
Br
Br
Br
85
0
4.6
–
51
0
PPh3
PPh3
37
8
2.2
–
20
4
I
88
30
57
[a] Reaction conditions: 1a (0.5 mmol), PhX (0.75 mmol), catalyst
(2.5 mol-%), KOPiv (30 mol-%) or PPh3 (5 mol-%), K2CO3
(1.5 mmol), and PhMe (2 mL). [b] Conversion determined by GC
analysis with respect to 1a. [c] Ratio based on GC analysis. [d]
Yield determined by GC analysis with respect to 1a (dodecane as
internal standard).
lar on the catalyst species. Amongst the investigated com- phenyl substituent at the 3-position of pyridine 1b showed
plexes, the initially used [RuCl2(p-cymene)]2 showed the slightly better yields at a higher temperature (150 °C, see
best activity and also the highest amine-to-imine ratio. In a Table 2, Entries 23–33). By employing this bulky group,
first series of experiments, we tested whether additives such even the electron-withdrawing 4-MeCO substituent in the
as potassium pivalate (KOPiv) and PPh3 showed beneficial aryl donor was converted with 41% yield (Table 2, En-
effects on the yields and also if they suppressed imine for- try 31).
mation. The addition of carboxylates can facilitate C–H
Next, we were interested in the influence of the electronic
bond activation by promoting a concerted metalation de- effects of functional groups incorporated into the benzylic
protonation (CMD) mechanism.[11] Indeed, the addition of group. Thus, we varied the benzylic group of our starting
KOPiv led to a significant higher yield of 75% (Table 1, material and performed the reaction under the above out-
Entry 8). PPh3 also increased the activity of the catalyst, lined standard conditions. To exclude steric effects, func-
but we decided to continue with KOPiv owing to its slightly tional groups were only installed at the para position. The
better performance. Bromo- and iodobenzene showed good results are in accordance with those with the ruthenium(0)
conversion but chlorobenzene was not suitable for this series and indicate that electron-neutral groups perform
method.
best (Table 3, Entry 4).[6] However, this method gives better
Subsequently, the scope of pyridine-substituted benzyl- results with electron-withdrawing substituents than with
amines 1 to react with aryl bromide and iodide derivatives electron-donating substituents, which is contrary to the ru-
was examined. This catalytic method showed a similar be- thenium(0) method.[6] We could not detect any decarboxyl-
havior to our previously reported ruthenium(0)-catalyzed ation with starting material 1h (Table 3, Entry 7), as was the
method with respect to the steric and electronic properties case within the ruthenium(0) method.[6]
of the aryl donor species. Sterically demanding ortho-substi-
Competition experiments between differently substituted
tuted aryls (2-Me 18% and 1-naphthyl 14%; Table 2, En- starting materials were carried out to validate the results
tries 3 and 4) gave significantly lower conversions, but meta- presented in Table 3. We used an equimolar mixture of un-
substituted aryls showed good conversions and yields (3- substituted and para-substituted starting material with our
Me 55%, 3-OMe 60%, 3-Cl 37%; Table 2, Entries 5–7). optimized reaction conditions; this mixture was treated
Electron-neutral or -donating aryl groups (Table 2, En- with 1 equiv. of bromobenzene, a decreased amount of aryl
tries 8–13) could be applied with the best results, whereas source in comparison to previous experiments to ensure in-
strong electron-withdrawing or coordinating substituents complete conversion of both substrates. Only then does the
(Table 2, Entries 17–22) were much less tolerated. The obtained product distribution give meaningful results,
Eur. J. Org. Chem. 2013, 2878–2890
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Table 2. Scope of arylation of benzylic amine 1.[a]
Table 3. Influence of the substituent on the benzylic group for the
Ru-catalyzed direct arylation.[a]
Entry
1
R
X
Ar
3
Conv.[b] Yield
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
C6H5 Br
C6H5 Br
C6H5 Br
C6H5 Br
C6H5 Br
C6H5 Br
C6H5 Br
C6H5 Br
C6H5 Br
C6H5 Br
C6H5 Br
Br
I
C6H5
C6H5
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3j
3k
3l
3l
3m
3n
3o
3p
3q
3r
96
100
18
14
98
97
60
98
96
98
95
98
94
92
97
98
72
15
0
69
48
n.i.[c]
n.i.[c]
55
60
37
65
64
67
63
61
50
61
55
51
33
n.i.[c]
–
Entry
1
Y
3
Conv.[b]
Yield
1
2
3
4
5
6
7
1c
1d
1e
1a
1f
1g
1h
OMe
OiPr
Me
H
F
CF3
CO2Me
3j
3ae
3g
3a
3l
3af
3ag
49
75
77
96
85
97
88
28
43
48
69
59
57
57
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
Br
Br
I
Br
Br
Br
Br
Br
Br
Br
2-Me-C6H4
1-naphthyl
3-Me-C6H4
3-MeO-C6H4
3-Cl-C6H4
4-Me-C6H4
4-tBu-C6H4
4-nBu-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-Me2N-C6H4
4-F-C6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
[a] Reaction conditions: 1 (0.5 mmol), PhBr (0.75 mmol), [RuCl2(p-
cymene)]2 (2.5 mol-%), KOPiv (30 mol-%), K2CO3 (1.5 mmol), and
PhMe (2 mL). [b] Conversion determined by GC analysis with re-
spect to 1.
[d]
4-F-C6H4
4-Cl-C6H4
Table 4. Competitive experiments for the Ru-catalyzed direct aryl-
ation reaction.[a]
4-EtO2C-C6H4
4-MeOC-C6H4
4-O2N-C6H4
4-NC-C6H4
3-pyridyl
0
0
0
–
–
–
2-thienyl
3s
3t
[e]
C6H5
98
97
95
97
98
97
81
64
65
0
70
68
64
67
72
69
59
42
41
–
[e]
3-Me-C6H4
3-MeO-C6H4
4-Me-C6H4
4-tBu-C6H4
4-nBu-C6H4
4-Cl-C6H4
4-EtO2C-C6H4
4-MeOC-C6H4
4-O2N-C6H4
3u
3v
3w
3x
3y
3z
3aa
3ab
3ac
3ad
[e]
[e]
[e]
[e]
[e]
[e]
e]
[e]
[e]
4-NC-C6H4
0
–
Entry
Y
H/Y[b]
[a] Reaction conditions: 1 (0.5 mmol), ArX (0.75 mmol), [RuCl2(p-
cymene)]2 (2.5 mol-%), KOPiv (30 mol-%), K2CO3 (1.5 mmol), and
PhMe (2 mL). [b] Conversion determined by GC analysis with re-
spect to 1. [c] n.i. = not isolated. [d] 130 °C. [e] 150 °C.
1
2
3
4
5
6
OMe
OiPr
Me
2
1.3
1.1
1.1
0.9
1.8
F
CF3
CO2Me
which are shown in Table 4. Weak electron-withdrawing
substituents such as F or CF3 (Table 4, Entries 4 and 5)
react faster than strong electron-donating and -withdrawing
groups (Table 4, Entries 1, 2, and 6). These findings corro-
borate the results shown in Table 3, and the overall per-
formance of the systems is complementary to the results
with Ru0 catalysis.[6]
[a] Reaction conditions: 1a (0.5 mmol), substituted amine
(0.5 mmol), PhBr (0.5 mmol), [RuCl2(p-cymene)]2 (2.5 mol-%),
KOPiv (30 mol-%), K2CO3 (1.5 mmol), and PhMe (2 mL). [b] Ra-
tio determined by GC analysis.
The last experiments inspired us to test whether a free
In the next step, we wanted to investigate the role of the NH group is essential for this transformation. We per-
nitrogen atom adjacent to the C–H bond. Therefore, we formed the reaction with the NMe-benzylic amine 7a
substituted the nitrogen atom with a CH2 group (5) or oxy- (Scheme 1). In contrast to the ruthenium(0) system, only
gen atom (6). In the ruthenium(0) protocol, the presence of the free amines showed any conversion, and all other sub-
an oxygen center was detrimental, but CH2 gave a good strates were not tolerated. Hence, we conclude that the free
yield. In the ruthenium(II) protocol, both substituents were amine function is essential for the ruthenium(II)-catalyzed
not suitable for this transformation, which indicates that the transformation. This conclusion is also supported by the
ruthenium(II) mechanism is completely different from the findings presented in Scheme 2. Tetrahydroisoquinoline
ruthenium(0) mechanism and requires a nitrogen atom in (THIQ) substrates 7b and 7c did not show any conversion.
this position (Scheme 1).
Hence, the predominant geometry of substrate 7a, which
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Direct Arylation of Benzylic Amines Mediated by Ruthenium(II)
We were also interested in a comparison of the rate of
both the arylation of amine 1a and of imine 12. To this end,
we performed kinetic studies for both derivatives. We found
that the rate of arylation of imine 12 was in the same range
as that of the arylation of amine 1a. This could either be
coincidental or be due to a fast (not rate determining) for-
mation of imine 12 from amine 1a. In the latter case, the
reduction of 4 to 3a also has to be fast (i.e., not rate de-
termining). Alternatively, 4 could be formed after arylation
from 3a by metal-catalyzed dhydrogenation; this could be
tested by submitting 1a and 3a to the reaction conditions
in the absence of bromobenzene. Interestingly, in both cases
only trace amounts of the corresponding imines were
formed. Evidently, the aryl halide is also involved in the
dehydrogenation process. Based on these results, we cannot
determine whether the arylation takes place on the amine
Scheme 1. Direct arylation of 5, 6, and 7a.
disfavors arylation, can be excluded as the reason for sub-
strate 7a to fail in this reaction. If this were the case, com-
pounds 7b and 7c would react at least to some extent.
Scheme 2. Direct arylation of N-substituted THIQ.
One explanation for the mandatory presence of a free
NH group could be that the mechanism does not proceed
by direct sp3 C–H insertion of the metal center but rather
by dehydrogenation of the amine to the corresponding im-
ine. The imine formed can further react in a subsequent
arylation step to form imine product 4, which is most likely
in equilibrium with the desired product. This equilibrium
explains the detection of imine 4 in the reaction. We con-
ducted an experiment with the already dehydrogenated
benzylic imine 12 to investigate this hypothesis. As ex-
pected, we isolated the imine compound 4 (67% yield,
Scheme 3). The fact that 4 was not reduced to 3 in this
experiment suggests that the hydrogen required for re-
duction originates from a [RuH2] species. This species is
produced by the dehydrogenation of 11 to form 12. It seems
that [RuH2] stays closely associated with 4 and immediately
induces the reduction to 3. Furthermore, Jun and co-
workers have shown that 12 can be arylated with Ru3-
(CO)12 and phenyl boronic acid ester.[12]
Scheme 4. Kinetic measurements for the ruthenium(II)-catalyzed
direct arylation of 1a and 12.
Scheme 3. Hypothesis for imine formation and ruthenium(II)-catalyzed direct arylation of 12.
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FULL PAPER
or imine compound; at this stage of our studies we favor probable mechanism involves the carboxylatoruthenium(II)
mechanisms that do not include imine formation complex 14, which is formed from [RuCl2(p-cymene)]2 in
(Scheme 4).
the presence of KOPiv. This complex undergoes cyclo-
Finally, we performed the reaction under different atmo- metalation with 1 to form intermediate 15. Subsequent
spheres as this could provide mechanistic information. We CMD via transition state 16 delivers the ruthenium(II)
have found the catalyst to be stable under air in the ruthe- complex 17, followed by oxidative addition of the aryl hal-
nium(0) protocol and that it performs even better under ide to the ruthenium(IV) species 18. Final reductive elimi-
a H2 atmosphere.[6] In the ruthenium(II) case, the catalyst nation yields product 3, and the ruthenium(II) complex 14
performs slightly worse under air and significantly worse is regenerated; complex 14 can now reenter the next cata-
under hydrogen (Table 5, Entries 2 and 4). Eventually, H2 lytic cycle (Scheme 5).
partially transforms the catalyst to an inactive species. Al-
ternatively, the oxidation of the amine to the imine might
be hindered under a H2 atmosphere if the reaction proceeds
by initial imine formation and arylation thereof. Further-
more, the reaction does not proceed under CO, which can
be attributed to the strong binding character of the CO li-
gand (Table 5, Entry 3), which leads to catalyst inactivation.
The reaction can be carried out under microwave irradia-
tion, which significantly decreases the reaction time from
24 h to 2.5 h with similar yield.
Table 5. Ru-catalyzed arylation of 1a under different atmo-
spheres.[a]
Entry
Atmosphere
Conv.[b]
3a/4[c]
Yield[d]
1
2
3
4
5
argon
air
96
79
0
53
92
6.0
4.0
–
8.3
5.1
75 (69)[e]
56
0
37
66
CO
H2
argon (microwave)[f]
[a] Reaction conditions: 1a (0.5 mmol), PhBr (0.75 mmol),
[RuCl2(p-cymene)]2 (2.5 mol-%), KOPiv (30 mol-%), K2CO3
(1.5 mmol), and PhMe (2 mL). [b] Conversion determined by GC
analysis with respect to 1a. [c] Ratio determined by GC. [d] Yield
determined by GC analysis with respect to 1a (dodecane as internal
standard). [e] Number in parentheses is yield of 3a. [f] Microwave
conditions: 180 °C for 2.5 h.
We also performed kinetic isotope effect (KIE) experi-
ments to determine whether the C–H activation step is rate-
limiting. A KIE of 1.3 was found, which indicates that C–
H insertion of the metal center is not the rate-determining
step in this reaction, as otherwise a much higher KIE would
Scheme 5. Proposed mechanism for the ruthenium(II)-catalyzed re-
action.
Additionally, we were also interested in the expansion of
be expected.[13] This result is in contrast to the previously the arylation reaction to aryl chlorides. These precursors
observed Ru3(CO)12/phenylboronic acid ester protocol, showed very little conversion under the standard conditions
which displays a KIE of 3.3.[6] Consequently, we also car- developed for aryl bromides and iodides. Further fine tun-
ried out an intramolecular competition experiment. Here, ing of the protocol was attempted to make this compound
the KIE was found to be 1, which is again in contrast to class also accessible for direct sp3 arylation. The reactions
the Ru3(CO)12 protocol (KIE = 0.43) and indicates again of aryl chlorides have already been the target of catalyst
that C–H insertion is not rate-determining and is most development in cross-coupling chemistry because they are
likely also irreversible. As experiments to form imine 12 less expensive than aryl bromides and more derivatives are
from substrate 1a failed, we hypothesize that the mecha- commercially available.[14] In the field of direct arylations
nism does not include imine formation prior to arylation. of sp3 C–H bonds, only a few examples have been reported
However, at present only a speculative discussion of the re- that take advantage of aryl chlorides, usually in combina-
action mechanism is possible, which is in line with the work tion with Pd catalysts.[15] We started our screening with our
of Ackermann[11b] and Jutand and Dixneuf.[11c] The most initial conditions and changed the ligand in a first series of
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Direct Arylation of Benzylic Amines Mediated by Ruthenium(II)
experiments. A low yield of 12% was achieved in the ab- than 2.9 (Table 6, Entry 10) which is significantly lower
sence of carboxylate (Table 6, Entry 1), whereas only 4% than that obtained with aryl bromides (6.0, Table 1, En-
yield was detected in the presence of carboxylate (Table 6, try 8). In the ruthenium(0) reaction, we found the dissoci-
Entries 2 and 3). Next, we tested different kinds of phos- ated hydrogen to be successfully scavenged by the ketone
phane ligands as Oi and co-workers had already demon- with concomitant reduction to the alcohol.[6] Hence, we hy-
strated their favorable effect on the [RuCl2(p-cymene)]2 cat- pothesized the possibility of a reverse pathway: the addition
alyst system.[16] In these cases, an increased yield for all in- of an alcohol should deliver the required hydrogen, which
vestigated phosphanes (Table 6, Entries 4–12) was ob- might reduce the imine in situ (Scheme 6).
served. The best result was obtained when using simple
PPh3, however in this case a 38% GC yield (Table 6, Entry
4) could not be surpassed. Other electron-rich, electron-
poor, or sterically-demanding phosphanes also showed an
enhancement of GC yield but were less effective (Table 6,
Entries 5–12). The addition of bidentate BINAP ligand de-
creased the conversion (Table 6, Entry 13). The N-heterocy-
clic carbene (NHC) ligand IMes·HCl did not show a signifi-
cant positive effect (Table 6, Entry 14). Hence, we decided
to continue optimization with PPh3 as ligand. One main
Scheme 6. Role of secondary alcohol.
problem for the transformation of aryl chlorides has been
the high concomitant imine formation. This imine forma-
We were pleased to discover that the addition of second-
tion can be explained by ruthenium-catalyzed dehydrogena-
ary alcohols led to a high amine-to-imine ratio (Table 6,
tion of the product.[17] Unfortunately, when using aryl
Entries 15–18). Cyclohexanol was more effective (38%,
Table 6, Entry 18) than other alcohols such as iPrOH and
chlorides we could not get a better amine-to-imine ratio
3-pentanol (Table 6, Entries 15 and 16). Although this addi-
tive did not improve the overall transformation (cf. Table 6,
Entry 4), its presence led to the exclusive formation of
Table 6. Optimization studies for the direct arylation of benzylic
amine 1a with aryl chlorides.[a]
amine product 3a. Notably, we could detect the correspond-
ing cyclohexanone by GC–MS analysis. Finally, conducting
the reaction at 160 °C for 30 h (with o-xylene as solvent)
furnished 70% yield of product 3a (Table 6, Entry 19).
Furthermore, this catalytic system is not restricted to hal-
ides, and triflates were also accepted, which was not the
case in the presence of KOPiv (tosylates were in both cases
not tolerated, Scheme 7). Unfortunately, the GC yield was
Entry Ligand
Additive
Conv.[b] 3a/4[c]
Yield of
only modest, and the procedure requires additional optimi-
zation for synthetic utilization.
3a[d]
1
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
34
8
1.8
–
12
4
4
38
32
33
19
28
30
26
23
29
4
11
12
18
2
3
4
KOPiv
AdCO2K
PPh3
7
–
81
64
61
50
60
62
51
56
66
9
1.9
2.3
2.5
1.6
1.5
2.1
2.9
1.4
5
6
7
8
P(o-Tol)3
P(4-OMe-Ph)3
P(4-Cl-Ph)3
P(Cy)3
9
XPhos
JohnPhos
RuPhos
DavePhos
BINAP
IMes·HCl
PPh3
PPh3
PPh3
PPh3
PPh3
10
11
12
13
14
15
16
17
18
19
1.5
2.6
Scheme 7. Direct arylation of 1a with aryl triflate and tosylate.
45
17
26
9
0.8
iPrOH
3-pentanol
cyclopentanol
cyclohexanol 49
cyclohexanol 93
Ͼ 100[e]
Ͼ 100[e]
Ͼ 100[e]
Ͼ 100[e]
12
The corresponding aryl chlorides showed analogous sub-
strate scope to the bromide/iodide protocol, albeit the reac-
tion conditions are harsher (Table 7, Entries 1–5). In this
case, the reaction is obviously again sensitive to electron-
withdrawing substituents (Table 7, Entries 6 and 7). Inter-
estingly, phenyl-substituted pyridine precursor 1b showed
lower conversion for this specific method (Table 7, En-
tries 8–16). We assume that the more bulky phenyl substitu-
ent is less tolerated by the in-situ-formed complex in this
case.
6
38
79 (70)[f][g]
[a] Reaction conditions: 1a (0.5 mmol), PhCl (1.5 mmol), [RuCl2(p-
cymene)]2 (5 mol-%), ligand (10 mol-%), additive (0.5 mmol),
K2CO3 (1.5 mmol), and PhMe (2 mL). [b] Conversion determined
by GC analysis with respect to 1a. [c] Ratio based on GC analysis.
[d] Yield determined by GC analysis with respect to 1a (dodecane
as internal standard). [e] No 4 detected. [f] 160 °C for 30 h in o-
xylene. [g] Number in parentheses is yield of 3a.
Eur. J. Org. Chem. 2013, 2878–2890
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2883

N. Dastbaravardeh, M. Schnürch, M. D. Mihovilovic
FULL PAPER
Table 7. Scope of arylation of benzylic amine 1 with aryl chlor- clusively the H-containing product. This proves that KIE
ides.[a]
studies are not possible for the aryl chloride protocol.
Entry
1
R
Ar
3
Conv.[b]
Yield
Scheme 8. KIE control experiment with 19.
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
Me
Me
Me
Me
Me
Me
Me
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3a
3d
3g
3j
3l
3af
3ag
3t
3u
3v
3w
3x
3y
3ab
3ah
3ac
93
95
93
88
76
79
23
60
68
72
58
69
55
38
16
0
70
72
79
64
56
3-Me-C6H4
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-F3C-C6H4
4-MeO2C-C6H4
C6H5
3-Me-C6H4
3-MeO-C6H4
4-Me-C6H4
4-tBu-C6H4
4-nBu-C6H4
4-MeCO-C6H4
4-MeO2C-C6H4
4-O2N-C6H4
Conclusions
Acyclic sp3 C–H bonds adjacent to a free N–H group
were readily arylated by cyclometalation by employing
[RuCl2(p-cymene)]2 and carboxylates with aryl bromides
and iodides. Improvements in the conversion in the pres-
ence of carboxylates can be explained by a CMD mecha-
nism. Furthermore, the protocol was expanded to cheaper
aryl chlorides by using phosphanes as ligands and second-
ary alcohols as the hydrogen source. The synthetic utility of
this approach was demonstrated by the synthesis of various
arylated benzylic amines. A wide range of substituents were
used in the reaction, and moderate-to-good yields were
achieved. The electronic nature of the substituents affects
the electron density of the benzylic C–H bond, which has a
significant impact on the C–H functionalization rate. Elec-
tron-withdrawing and coordinating substituents inhibited
the reaction. A free N–H group was mandatory for the aryl-
ation, which indicates that imine formation is a crucial step
in this reaction. KIE experiments of the RuII protocol re-
vealed that the oxidative addition step is not the rate-de-
termining step for aryl bromides and aryl iodides. For the
aryl chloride protocol, no KIE measurements could be un-
dertaken owing to a competing H–D exchange. The estab-
lishment of these conditions should provide a valuable
starting point for subsequent examinations of direct aryl-
ation in C–C bond synthesis and may facilitate the discov-
ery of other new cross-coupling partners in this type of
chemistry.
30
n.i.[c]
48
9
58
61
39
55
10
11
12
13
14
15
16
47
n.i.[c]
n.i.[c]
0
[a] Reaction conditions: 1 (0.5 mmol), ArCl (1.5 mmol), [RuCl2(p-
cymene)]2 (5 mol-%), PPh3 (10 mol-%), cyclohexanol (0.5 mmol),
K2CO3 (1.5 mmol), and PhMe (2 mL). [b] Conversion determined
by GC analysis with respect to 1. [c] n.i. = not isolated.
Notably, the corresponding imine starting material 12
was not converted under these conditions, which indicates
that the arylation process occurs directly on the C–H bond
of the starting material 1a, and the imine compound 4 is
subsequently formed from amine product 3a by dehydroge-
nation. The mechanism of the [RuCl2(p-cymene)PPh3] cata-
lyst is obviously not exactly the same as for the [Ru(p-
cymene)(OPiv)2] complex (the lack of carboxylate allows no
CMD mechanism). Finally, we also wanted to conduct
intermolecular and intramolecular KIE experiments with
the [RuCl2(p-cymene)]2/PPh3/chlorobenzene/cyclohexanol
system to obtain more information about the mechanism
of the reaction. However, we observed a high ruthenium-
catalyzed H/D exchange of the substrates under these con-
ditions. In an intermolecular competition experiment, only
an arylated product that contained hydrogen atoms but not
deuterium atoms was detected. The same result was found
in the intramolecular competition experiment. This would
Experimental Section
General Methods: All reactions were carried out under argon, un-
less otherwise mentioned. Argon was purified by passage through
Drierite. Unless otherwise noted, chemicals were purchased from
mean that only the C–D bond is broken, which is highly commercial suppliers and were used without further purification.
HRMS for literature unknown compounds were analyzed by hy-
brid ion trap/time-of-flight MS coupled with liquid chromatog-
raphy (LC-IT-TOF-MS) in positive ion detection mode with the
recording of MS and MS/MS spectra. NMR spectra were recorded
in CDCl3 with TMS as internal standard and chemical shifts are
reported in ppm. GC–MS runs were performed with a standard
capillary column (BGB 5, 30 mϫ0.32 mm i.d.). Microwave reac-
tions were performed with a BIOTAGE Initiator sixty microwave
unit (max pressure 20 bar, IR temperature sensor). Analytical data
for all new compounds are given below. Compounds 12[18] and 19[6]
unlikely. We also isolated the substrates from these experi-
ments, which also contained only hydrogen atoms and no
deuterium atoms. Most likely, the exchange is caused by the
cyclohexanol present in the reaction mixture. Performing
the reaction with deuterated cyclohexanol instead would
also not give a meaningful result as in this case H/D ex-
change has to be expected and, hence, the measured values
would also be misleading. As a control experiment, we sub-
jected only the deuterated starting material 19 to the reac-
tion conditions (Scheme 8). This experiment delivered ex- were prepared according to the literature procedures.
2884 Eur. J. Org. Chem. 2013, 2878–2890
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Direct Arylation of Benzylic Amines Mediated by Ruthenium(II)
General Procedure I for the Preparation of Benzylic Amines: The 2-
choloro-3-substituted pyridine (1 equiv.), amine (1.2 equiv.),
K2CO3 (3.5 equiv.), Pd(OAc)2 (2 mol-%), and BINAP (2 mol-%)
were placed in an oven-dried 6 mL vial with septum screw cap and
a magnetic stirring bar. The vial was evacuated and flushed with
argon (three times). Dry toluene was added to the reaction mixture,
and the vial was closed with a fully covered solid Teflon®-lined cap.
The reaction vial was then heated in a reaction block at 130 °C for
16 h. The suspension was cooled to room temp., and the solid ma-
terial was removed by filtration and washed with CH2Cl2 (10 mL).
The combined organic layers were evaporated, and the resulting
crude product was purified by flash column chromatography (PE/
EtOAc = 10:1).
idine (128 mg, 1 mmol, 1 equiv.), benzylamine (128 mg, 1.2 mmol,
1.2 equiv.), K2CO3 (483 mg, 3.5 mmol, 3.5 equiv.), Pd(OAc)2 (4 mg,
0.02 mmol, 2 mol-%), and BINAP (12 mg, 0.02 mmol, 2 mol-%) in
dry toluene (2.5 mL). Colorless solid (182 mg, 92% yield); m.p. 48–
49 °C. 1H NMR (CDCl3, 200 MHz): δ = 2.09 (s, 3 H), 4.36 (s, 1
H), 4.70 (d, J = 5.3 Hz, 2 H), 6.57 (dd, J = 7.1, 5.1 Hz, 1 H), 7.23–
7.43 (m, 6 H), 8.06 (dd, J = 5.0, 1.3 Hz, 1 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 17.1, 45.9, 113.0, 116.6, 127.3, 128.0, 128.7,
136.9, 140.1, 145.6, 156.8 ppm.
N-Benzyl-3-chloropyridin-2-amine:[20] The reaction was carried out
according to general procedure
I with 2,3-dichloropyridine
(148 mg, 1 mmol, 1 equiv.), benzylamine (128 mg, 1.2 mmol,
1.2 equiv.), K2CO3 (483 mg, 3.5 mmol, 3.5 equiv.), Pd(OAc)2 (4 mg,
0.02 mmol, 2 mol-%), and BINAP (12 mg, 0.02 mmol, 2 mol-%) in
dry toluene (2.5 mL). Yellow oil (200 mg, 91% yield). 1H NMR
(CDCl3, 200 MHz): δ = 4.68 (d, J = 5.6 Hz, 2 H), 5.26 (s, 1 H),
6.54 (dd, J = 7.6, 4.9 Hz, 1 H), 7.23–7.39 (m, 5 H), 7.45 (dd, J =
7.6, 1.6 Hz, 1 H) 8.04 (dd, J = 4.9, 1.6 Hz, 1 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 45.6, 113.2, 115.4, 127.4, 127.8, 128.7, 136.2,
139.4, 146.2, 154.0 ppm.
General Procedure II for the Preparation of Tertiary Amines: The
2-bromo-3-substituted pyridine (1 equiv.), amine (1.4 equiv.), Na-
OtBu (2 equiv.), bis(dibenzylideneacetone)palladium [Pd2(dba)2,
2 mol-%], and DPPP [1,3-bis(diphenylphosphanyl)propane, 2 mol-
%] were placed in an oven-dried 6 mL vial with a septum screw cap
and a magnetic stirring bar. The vial was evacuated and flushed
with argon (three times). Dry toluene was added to the reaction
mixture, and the vial was closed with a fully covered solid Teflon®-
lined cap. The reaction vial was then heated in a reaction block at
75 °C for 16 h. The suspension was cooled to room temp., and the
solid material was removed by filtration and washed with CH2Cl2
(10 mL). The combined organic layers were evaporated, and the
resulting crude product was purified by flash column chromatog-
raphy (PE/EtOAc = 15:1/10:1).
N-Benzyl-3-phenylpyridin-2-amine (1b):[21] The reaction was carried
out according to general procedure I with N-benzyl-3-chloropyr-
idin-2-amine obtained from the above protocol (219 mg, 1 mmol,
1 equiv.), phenylboronic acid (366 mg, 3 mmol, 3 equiv.), K2CO3
(276 mg, 2 mmol, 2 equiv.), Pd(OAc)2 (4 mg, 0.02 mmol, 2 mol-%),
and
2-dicyclohexylphosphanyl-2Ј,4Ј,6Ј-triisopropylbiphenyl
General Procedure III for the C–H Activation Reaction with Aryl
Bromides: [RuCl2(p-cymene)]2 (2.5 mol-%) and KOPiv (30 mol-%)
were placed in an oven-dried 6 mL vial with a septum screw cap
and a magnetic stirring bar. The vial was evacuated and flushed
with argon (three times). Dry toluene (2 mL) was added, and the
reaction mixture was stirred at room temp. for 30 min. Sub-
(DCPTPB, 10 mg, 0.02 mmol, 2 mol-%) in dry toluene (2.5 mL).
Colorless solid (255 mg, 98% yield); m.p. 58–60 °C. 1H NMR
(CDCl3, 200 MHz): δ = 4.64 (d, J = 5.6 Hz, 2 H), 4.88 (s, 1 H),
6.66 (dd, J = 7.2, 5.1 Hz, 1 H), 7.18–7.42 (m, 11 H), 8.14 (dd, J =
4.9, 1.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 45.6,
113.1, 122.4, 127.1, 127.5, 127.9, 128.6, 129.0, 129.3, 137.2, 138.0,
sequently, the pyridine derivative (0.5 mmol, 1 equiv.), aryl bromide 140.0, 147.2, 155.5 ppm. HRMS: calcd. for C18H16N2 [M + H]+
(0.75 mmol, 1.5 equiv.), and K2CO3 (1.5 mmol, 3 equiv.) were
added to the mixture. The vial was again evacuated, flushed with
argon, closed with a fully covered solid Teflon®-lined cap, and
heated in a reaction block at 140–150 °C for 24 h. The suspension
was cooled to room temp. and filtered through a short pad of Ce-
lite, which was further washed with CH2Cl2 (2ϫ 5 mL). The com-
bined organic layers were concentrated in vacuo, and the remaining
residue was purified by flash column chromatography (PE/EtOAc
= 49:1) and dried under high vacuum. Compounds 3a–3ah and 4
were prepared according to this procedure.
261.1386; found 261.1390.
N-(4-Methoxybenzyl)-3-methylpyridin-2-amine (1c):[21] The reaction
was carried out according to general procedure I with 2-chloro-3-
methylpyridine (128 mg, 1 mmol, 1 equiv.), 4-methoxybenzylamine
(164 mg, 1.2 mmol, 1.2 equiv.), K2CO3 (414 mg, 3 mmol, 3 equiv.),
Pd(OAc)2 (4 mg, 0.02 mmol, 2 mol-%), and BINAP (12 mg,
0.02 mmol, 2 mol-%) in dry toluene (2.5 mL). Yellow oil (183 mg,
1
80% yield). H NMR (CDCl3, 200 MHz): δ = 2.07 (s, 3 H), 3.80
(s, 3 H), 4.30 (s, 1 H), 4.61 (d, J = 5.2 Hz, 2 H), 6.55 (dd, J = 7.1,
5.1 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 2 H), 7.21–7.34 (m, 3 H), 8.06
(dd, J = 4.9, 1.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ =
17.1, 45.4, 55.4, 112.9, 114.1, 116.6, 129.3, 132.1, 136.9, 145.5,
156.8, 158.9 ppm. HRMS: calcd. for C14H16N2O [M + H]+
229.1335; found 229.1338.
General Procedure IV for the C–H Activation Reaction with Aryl
Chlorides: [RuCl2(p-cymene)]2 (0.025 mmol, 5 mol-%) and PPh3
(0.05 mmol, 10 mol-%) were placed in an oven-dried 6 mL vial with
a septum screw cap and a magnetic stirring bar. The vial was evacu-
ated and flushed with argon (3ϫ). Dry o-xylene (2 mL) was added,
and the reaction mixture was stirred at room temp. for 30 min.
Subsequently, the pyridine derivative (0.5 mmol, 1 equiv.), aryl
chloride (1.5 mmol, 3 equiv.), cyclohexanol (0.5 mmol, 1 equiv.),
and K2CO3 (1.5 mmol, 3 equiv.) were added to the mixture. The
vial was again evacuated and flushed with argon, closed with a fully
covered solid Teflon®-lined cap, and heated in a reaction block at
160 °C for 30 h. The suspension was cooled to room temp. and
then filtered through a short pad of Celite, which was further
washed with DCM (2ϫ 5 mL). The combined organic layers were
concentrated in vacuo, and the remaining residue was purified by
flash column chromatography (PE/EtOAc = 49:1) and dried under
high vacuum.
N-(4-Isopropoxybenzyl)-3-methylpyridin-2-amine (1d):[21] The reac-
tion was carried out according to general procedure I with 2-
chloro-3-methylpyridine (128 mg, 1 mmol, 1 equiv.), (4-isopropoxy-
phenyl)methanamine (198 mg, 1.2 mmol, 1.2 equiv.), K2CO3
(483 mg, 3.5 mmol, 3.5 equiv.), Pd(OAc)2 (4 mg, 0.02 mmol, 2 mol-
%), and BINAP (12 mg, 0.02 mmol, 2 mol-%) in dry toluene
(2.5 mL). Colorless oil (185 mg, 72% yield). 1H NMR (CDCl3,
200 MHz): δ = 1.33 (d, J = 6.0 Hz, 6 H), 2.06 (s, 3 H), 4.27 (s, 1
H), 4.51 (sep, J = 6.0 Hz, 1 H), 4.59 (d, J = 5.2 Hz, 2 H), 6.54 (dd,
J = 7.1, 5.1 Hz, 1 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.20–7.32 (m, 3 H),
8.05 (dd, J = 5.1, 1.3 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ
= 17.1, 21.2, 45.5, 70.0, 112.9, 116.0, 116.6, 129.3, 131.9, 136.9,
145.6, 156.8, 157.3 ppm. HRMS: calcd. for C16H20N2O [M + H]+
257.1648; found 257.1642.
N-Benzyl-3-methylpyridin-2-amine (1a):[19] The reaction was carried
out according to general procedure I with 2-chloro-3-methylpyr-
Eur. J. Org. Chem. 2013, 2878–2890
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2885

N. Dastbaravardeh, M. Schnürch, M. D. Mihovilovic
FULL PAPER
3-Methyl-N-(4-methylbenzyl)pyridin-2-amine (1e):[21] The reaction
was carried out according to general procedure I with 2-chloro-
3-methylpyridine (128 mg, 1 mmol, 1 equiv.), 4-methylbenzylamine
(145 mg, 1.2 mmol, 1.2 equiv.), K2CO3 (414 mg, 3 mmol, 3 equiv.),
Pd(OAc)2 (4 mg, 0.02 mmol, 2 mol-%), and BINAP (12 mg,
0.02 mmol, 2 mol-%) in dry toluene (2.5 mL). Colorless solid
(188 mg, 88% yield); m.p. 46–47 °C. 1H NMR (CDCl3, 200 MHz):
δ = 2.01 (s, 3 H), 2.30 (s, 3 H), 4.26 (s, 1 H), 4.59 (d, J = 5.2 Hz,
2 H), 6.50 (dd, J = 7.1, 5.1 Hz, 1 H), 7.08–7.26 (m, 5 H), 8.00 (dd,
J = 5.0, 1.3 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 17.1,
21.2, 45.8, 112.9, 116.6, 128.0, 129.4, 136.8, 136.9, 137.0, 145.5,
156.8 ppm. HRMS: calcd. for C14H16N2 [M + H]+ 213.1386; found
213.1380.
(m, 11 H), 7.89 (dd, J = 5.0, 1.3 Hz, 1 H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 17.2, 58.6, 113.2, 116.4, 127.1, 127.7, 128.6, 137.0,
143.6, 145.7, 155.8 ppm.
3-Methyl-N-[phenyl(m-tolyl)methyl]pyridin-2-amine (3d):[21] The re-
action was carried out according to general procedure III with 1a
(99 mg, 0.5 mmol, 1 equiv.), 1-bromo-3-methylbenzene (128 mg,
0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg, 0.0125 mmol,
2.5 mol-%), KOPiv (21 mg, 0.15 mmol, 30 mol-%), and K2CO3
(207 mg, 1.5 mmol, 3 equiv.) in dry toluene (2 mL). Colorless oil
(79 mg, 55% yield). 1H NMR (CDCl3, 200 MHz): δ = 2.11 (s, 3
H), 2.29 (s, 3 H), 4.63 (d, J = 7.2 Hz, 1 H), 6.46–6.52 (m, 2 H),
7.01–7.34 (m, 10 H), 7.95 (dd, J = 5.0, 1.2 Hz, 1 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 17.2, 21.6, 58.5, 113.1, 116.4, 124.7, 127.0,
127.6, 127.9, 128.5, 128.6, 129.3, 137.0, 138.2, 143.6, 143.7, 145.8,
155.8 ppm. HRMS: calcd. for C20H20N2 [M + H]+ 289.1699; found
289.1679.
N-(4-Fluorobenzyl)-3-methylpyridin-2-amine (1f):[21] The reaction
was carried out according to general procedure I with 2-chloro-3-
methylpyridine (128 mg, 1 mmol, 1 equiv.), (4-fluorophenyl)-
methanamine (150 mg, 1.2 mmol, 1.2 equiv.), K2CO3 (483 mg,
3.5 mmol, 3.5 equiv.), Pd(OAc)2 (4 mg, 0.02 mmol, 2 mol-%), and
BINAP (12 mg, 0.02 mmol, 2 mol-%) in dry toluene (2.5 mL). Col-
N-[(3-Methoxyphenyl)(phenyl)methyl]-3-methylpyridin-2-amine (3e):
The reaction was carried out according to general procedure III
with 1a (99 mg, 0.5 mmol, 1 equiv.), 1-bromo-3-methoxybenzene
(140 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%) and KOPiv (21 mg, 0.15 mmol, 30 mol-
%) in dry toluene (2 mL). Colorless oil (91 mg, 60% yield). 1H
NMR (CDCl3, 200 MHz): δ = 2.12 (s, 3 H), 3.73 (s, 3 H), 4.65 (d,
J = 7.5 Hz, 1 H), 6.48–6.54 (m, 2 H), 6.74–6.80 (m, 1 H), 6.89–
6.93 (m, 2 H), 7.18–7.37 (m, 7 H), 7.96 (dd, J = 5.0, 1.2 Hz, 1 H)
ppm. 13C NMR (CDCl3, 50 MHz): δ = 17.1, 55.2, 58.5, 112.1,
113.2, 113.7, 116.4, 120.0, 127.1, 127.6, 128.6, 129.6, 137.0, 143.5,
145.3, 145.7, 155.7, 159.8 ppm. HRMS: calcd. for C20H20N2O [M
+ H]+ 305.1648; found 305.1637.
1
orless oil (158 mg, 73% yield). H NMR (CDCl3, 200 MHz): δ =
2.08 (s, 3 H), 4.36 (s, 1 H), 4.65 (d, J = 5.4 Hz, 2 H), 6.56 (dd, J =
7.1, 5.1 Hz, 1 H), 6.96–7.05 (m, 2 H), 7.21–7.37 (m, 3 H), 8.03 (dd,
J = 5.0, 1.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 17.1,
45.1, 113.2, 115.5 (d, JC,F = 21.3 Hz), 116.6, 129.5 (d, JC,F
=
8.0 Hz), 135.9 (d, JC,F = 3.1 Hz), 137.1, 145.6, 156.6, 162.2 (d, JC,F
= 244.9 Hz) ppm. HRMS: calcd. for C13H13FN2 [M + H]+
217.1136; found 217.1128.
3-Methyl-N-[4-(trifluoromethyl)benzyl]pyridin-2-amine (1g):[21] The
reaction was carried out according to general procedure I with 2-
chloro-3-methylpyridine (128 mg, 1 mmol, 1 equiv.), [4-(trifluoro-
methyl)phenyl]methanamine (210 mg, 1.2 mmol, 1.2 equiv.),
K2CO3 (483 mg, 3.5 mmol, 3.5 equiv.), Pd(OAc)2 (4 mg,
0.02 mmol, 2 mol-%), and BINAP (12 mg, 0.02 mmol, 2 mol-%) in
dry toluene (2.5 mL). Colorless solid (195 mg, 73% yield); m.p. 54–
55 °C. 1H NMR (CDCl3, 200 MHz): δ = 2.14 (s, 3 H), 4.50 (s, 1
H), 4.78 (d, J = 5.7 Hz, 2 H), 6.58 (dd, J = 7.1, 5.1 Hz, 1 H), 7.25–
7.29 (m, 1 H), 7.53 (d, J = 9.7 Hz, 4 H), 8.03 (dd, J = 5.0, 1.2 Hz,
1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 17.1, 45.2, 113.5,
116.7, 124.4 (q, JC,F = 271.9 Hz), 125.6 (q, JC,F = 3.9 Hz), 127.9,
129.4 (q, JC,F = 32.3 Hz), 137.2, 144.6, 145.6, 156.4 ppm. HRMS:
calcd. for C14H13F3N2 [M + H]+ 267.1104; found 267.1099.
N-[(3-Chlorophenyl)(phenyl)methyl]-3-methylpyridin-2-amine (3f):[21]
The reaction was carried out according to general procedure III
with 1a (99 mg, 0.5 mmol, 1 equiv.), 1-bromo-3-chlorobenzene
(143 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%), KOPiv (21 mg, 0.15 mmol, 30 mol-%),
and K2CO3 (207 mg, 1.5 mmol, 3 equiv.) in dry toluene (2 mL).
1
Colorless oil (58 mg, 37% yield). H NMR (CDCl3, 200 MHz): δ
= 2.13 (s, 3 H), 4.59 (d, J = 6.6 Hz, 1 H), 6.46–6.57 (m, 2 H), 7.19–
7.32 (m, 10 H), 7.95 (dd, J = 5.0, 1.3 Hz, 1 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 17.2, 58.3, 113.6, 116.6, 125.8, 127.3, 127.5,
127.6, 127.8, 128.9, 129.8, 134.5, 137.2, 143.0, 145.7, 155.6 ppm.
HRMS: calcd. for C19H17ClN2 [M
309.1138.
+
H]+ 309.1153; found
Methyl 4-{[(3-Methylpyridin-2-yl)amino]methyl}benzoate (1h):[21]
The reaction was carried out according to general procedure I with
2-chloro-3-methylpyridine (128 mg, 1 mmol, 1 equiv.), methyl 4-
(aminomethyl)benzoate (198 mg, 1.2 mmol, 1.2 equiv.), K2CO3
(414 mg, 3 mmol, 3 equiv.), Pd(OAc)2 (4 mg, 0.02 mmol, 2 mol-%),
and BINAP (12 mg, 0.02 mmol, 2 mol-%) in dry toluene (2.5 mL).
Colorless solid (223 mg, 87% yield); m.p. 122–123 °C. 1H NMR
(CDCl3, 200 MHz): δ = 2.12 (s, 3 H), 3.90 (s, 3 H), 4.48 (s, 1 H),
4.77 (d, J = 5.7 Hz, 2 H), 6.56 (dd, J = 7.1, 5.1 Hz, 1 H), 7.23–7.27
(m, 1 H), 7.43 (d, J = 8.2 Hz, 2 H), 7.97–8.02 (m, 3 H) ppm. 13C
NMR (CDCl3, 50 MHz): δ = 17.1, 45.3, 52.2, 113.3, 116.6, 127.5,
129.0, 130.0, 137.1, 145.6, 145.8, 156.5, 167.1 ppm. HRMS: calcd.
for C15H16N2O2 [M + H]+ 257.1285; found 257.1296.
3-Methyl-N-[phenyl(p-tolyl)methyl]pyridin-2-amine (3g):[21] The re-
action was carried out according to general procedure III with 1a
(99 mg, 0.5 mmol, 1 equiv.), 1-bromo-4-methylbenzene (128 mg,
0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg, 0.0125 mmol,
2.5 mol-%), KOPiv (21 mg, 0.15 mmol, 30 mol-%), and K2CO3
(207 mg, 1.5 mmol, 3 equiv.) in dry toluene (2 mL). Colorless solid
(94 mg, 65% yield); m.p. 103–105 °C. 1H NMR (CDCl3,
200 MHz): δ = 2.13 (s, 3 H), 2.32 (s, 3 H), 4.64 (d, J = 6.8 Hz, 1
H), 6.46–6.54 (m, 2 H), 7.09–7.32 (m, 10 H), 7.96 (dd, J = 5.0,
1.3 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 17.2, 21.2,
58.3, 113.1, 116.4, 127.0, 127.6, 127.7, 128.6, 129.3, 136.8, 137.0,
140.7, 143.7, 145.8, 155.8 ppm. HRMS: calcd. for C20H20N2 [M +
H]+ 289.1699; found 289.1699.
N-Benzhydryl-3-methylpyridin-2-amine (3a):[12] The reaction was
carried out according to general procedure III with 1a (99 mg,
0.5 mmol, 1 equiv.), bromobenzene (118 mg, 0.75 mmol,
1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg, 0.0125 mmol, 2.5 mol-%),
N-{[4-(tert-Butyl)phenyl](phenyl)methyl}-3-methylpyridin-2-amine
(3h):[21] The reaction was carried out according to general pro-
cedure III with 1a (99 mg, 0.5 mmol, 1 equiv.), 1-bromo-4-(tert-bu-
KOPiv (21 mg, 0.15 mmol, 30 mol-%), and K2CO3 (207 mg, tyl)benzene (160 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2
1.5 mmol, 3 equiv.) in dry toluene (2 mL). Colorless solid (95 mg,
69% yield); m.p. 91–93 °C. H NMR (CDCl3, 200 MHz): δ = 2.07
(s, 3 H), 4.60 (d, J = 6.8 Hz, 1 H), 6.42–6.48 (m, 2 H), 7.12–7.29
(7.6 mg, 0.0125 mmol, 2.5 mol-%), KOPiv (21 mg, 0.15 mmol,
30 mol-%), and K2CO3 (207 mg, 1.5 mmol, 3 equiv.) in dry toluene
(2 mL). Colorless solid (106 mg, 64% yield); m.p. 120–122 °C. H
1
1
2886
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2878–2890

Direct Arylation of Benzylic Amines Mediated by Ruthenium(II)
NMR (CDCl3, 200 MHz): δ = 1.29 (s, 9 H), 2.13 (s, 3 H), 4.66 (d,
J = 6.8 Hz, 1 H), 6.48–6.53 (m, 2 H), 7.20–7.34 (m, 10 H), 7.96
(7.6 mg, 0.0125 mmol, 2.5 mol-%), and KOPiv (21 mg, 0.15 mmol,
30 mol-%) in dry toluene (2 mL). Colorless oil (79 mg, 51% yield).
(dd, J = 5.0, 1.3 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 1H NMR (CDCl3, 200 MHz): δ = 2.12 (s, 3 H), 4.59 (d, J = 6.6 Hz,
17.3, 31.5, 34.6, 58.2, 113.1, 116.4, 125.6, 127.0, 127.4, 127.6, 128.5,
137.0, 140.6, 143.7, 145.8, 150.0, 155.9 ppm. HRMS: calcd. for
C23H26N2 [M + H]+ 331.2169; found 331.2178.
1 H), 6.45–6.55 (m, 2 H), 7.21–7.32 (m, 10 H), 7.94 (dd, J = 5.0,
1.3 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 17.1, 58.2,
113.5, 116.5, 127.5, 127.8, 128.7, 128.8, 129.0, 132.7, 137.1, 142.1,
143.2, 145.7, 155.6 ppm. HRMS: calcd. for C19H17ClN2 [M + H]+
309.1153; found 309.1138.
N-[(4-Butylphenyl)(phenyl)methyl]-3-methylpyridin-2-amine (3i):
The reaction was carried out according to general procedure III
with 1a (99 mg, 0.5 mmol, 1 equiv.), 1-bromo-4-butylbenzene
(160 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%), and KOPiv (21 mg, 0.15 mmol, 30 mol-
%) in dry toluene (2 mL). Colorless oil (111 mg, 67% yield). 1H
NMR (CDCl3, 200 MHz): δ = 0.89 (t, J = 7.2 Hz, 3 H), 1.23–1.63
(m, 2 H), 1.48–1.63 (m, 2 H), 2.08 (s, 3 H), 2.55 (t, J = 7.7 Hz, 2
H), 4.62 (d, J = 7.0 Hz, 1 H), 6.43–6.50 (m, 2 H), 7.06–7.33 (m, 10
H), 7.93 (dd, J = 5.0, 1.3 Hz, 1 H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 14.1, 17.2, 22.5, 33.7, 35.4, 58.3, 113.1, 116.4, 127.0,
127.5, 127.6, 128.5, 128.6, 137.0, 140.9, 141.7, 143.8, 145.8, 155.9
ppm. HRMS: calcd. for C23H26N2 [M + H]+ 331.2169; found
331.2156.
Ethyl
4-{[(3-Methylpyridin-2-yl)amino](phenyl)methyl}benzoate
(3n): The reaction was carried out according to general procedure
III with 1a (99 mg, 0.5 mmol, 1 equiv.), ethyl 4-bromobenzoate
(172 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%), and KOPiv (21 mg, 0.15 mmol, 30 mol-
%) in dry toluene (2 mL). Colorless oil (57 mg, 33% yield). 1H
NMR (CDCl3, 200 MHz): δ = 1.37 (t, J = 7.1 Hz, 3 H), 2.15 (s, 3
H), 4.36 (q, J = 7.1 Hz, 2 H), 4.66 (d, J = 6.6 Hz, 1 H), 6.51–6.57
(m, 2 H), 7.23–7.35 (m, 6 H), 7.42 (d, J = 8.1 Hz, 2 H), 7.94–8.02
(m, 3 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 14.4, 17.1, 58.7,
60.9, 113.5, 116.6, 127.4, 127.6, 127.9, 128.8, 129.3, 129.9, 137.1,
143.0, 145.7, 148.7, 155.6, 166.6 ppm. HRMS: calcd. for
C22H22N2O2 [M + H]+ 347.1754; found 347.1737.
N-[(4-Methoxyphenyl)(phenyl)methyl]-3-methylpyridin-2-amine
(3j):[21] The reaction was carried out according to general procedure
III with 1a (99 mg, 0.5 mmol, 1 equiv.), 1-bromo-4-methoxyben-
zene (140 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%), and KOPiv (21 mg, 0.15 mmol, 30 mol-
%) in dry toluene (2 mL). Colorless solid (96 mg, 63% yield); m.p.
N-Benzhydryl-3-phenylpyridin-2-amine (3t):[21] The reaction was
carried out according to general procedure III with 1b (130 mg,
0.5 mmol, 1 equiv.), bromobenzene (118 mg, 0.75 mmol,
1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg, 0.0125 mmol, 2.5 mol-%),
KOPiv (21 mg, 0.15 mmol, 30 mol-%), and K2CO3 (207 mg,
1.5 mmol, 3 equiv.) in dry toluene (2 mL). Colorless solid (118 mg,
1
59–61 °C. H NMR (CDCl3, 200 MHz): δ = 2.14 (s, 3 H), 3.79 (s,
3 H), 4.63 (d, J = 6.5 Hz, 1 H), 6.46–6.55 (m, 2 H), 6.82–6.89 (m,
2 H), 7.22–7.36 (m, 8 H), 7.97 (dd, J = 5.0, 1.3 Hz, 1 H) ppm. 13C
NMR (CDCl3, 50 MHz): δ = 17.2, 55.4, 58.0, 113.2, 114.0, 116.4,
127.0, 127.6, 128.6, 128.9, 135.8, 137.0, 143.8, 145.8, 155.8, 158.7
ppm. HRMS: calcd. for C20H20N2O [M + H]+ 305.1648; found
305.1655.
1
70% yield); m.p. 90–92 °C. H NMR (CDCl3, 200 MHz): δ = 5.18
(d, J = 7.4 Hz, 1 H), 6.51 (d, J = 7.5 Hz, 1 H), 6.64 (dd, J = 7.2,
5.0 Hz, 1 H), 7.14–7.44 (m, 16 H), 8.08 (dd, J = 5.0, 1.8 Hz, 1 H)
ppm. 13C NMR (CDCl3, 50 MHz): δ = 58.5, 113.5, 122.4, 127.1,
127.5, 128.0, 128.6, 128.9, 129.4, 137.4, 138.1, 143.5, 147.4, 154.6
ppm. HRMS: calcd. for C24H20N2 [M + H]+ 337.1699; found
337.1713.
N-{[4-(Dimethylamino)phenyl](phenyl)methyl}-3-methylpyridin-2-
amine (3k): The reaction was carried out according to general pro-
cedure III with 1a (99 mg, 0.5 mmol, 1 equiv.), 4-bromo-N,N-di-
methylaniline (150 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2
(7.6 mg, 0.0125 mmol, 2.5 mol-%), and KOPiv (21 mg, 0.15 mmol,
30 mol-%) in dry toluene (2 mL). Yellow oil (79 mg, 50% yield).
1H NMR (CDCl3, 200 MHz): δ = 2.10 (s, 3 H), 2.90 (s, 6 H), 4.62
(d, J = 6.8 Hz, 1 H), 6.41–6.51 (m, 2 H), 6.64–6.69 (m, 2 H), 7.13–
7.35 (m, 8 H), 7.95 (dd, J = 5.0, 1.3 Hz, 1 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 17.2, 40.7, 58.0, 112.7, 112.9, 116.4, 126.7,
127.4, 128.4, 128.7, 131.6, 136.9, 144.0, 145.7, 149.8, 155.9 ppm.
HRMS: calcd. for C21H23N3 [M + H]+ 318.1965; found 318.1955.
3-Phenyl-N-[phenyl(m-tolyl)methyl]pyridin-2-amine (3u): The reac-
tion was carried out according to general procedure III with 1b
(130 mg, 0.5 mmol, 1 equiv.), 1-bromo-3-methylbenzene (128 mg,
0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg, 0.0125 mmol,
2.5 mol-%), KOPiv (21 mg, 0.15 mmol, 30 mol-%), and K2CO3
(207 mg, 1.5 mmol, 3 equiv.) in dry toluene (2 mL). Colorless oil
1
(119 mg, 68% yield). H NMR (CDCl3, 200 MHz): δ = 2.25 (s, 3
H), 5.18 (d, J = 7.5 Hz, 1 H), 6.49 (d, J = 7.5 Hz, 1 H), 6.61 (dd,
J = 7.2, 5.0 Hz, 1 H), 6.97–7.42 (m, 15 H), 8.08 (dd, J = 5.0, 1.8 Hz,
1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 21.6, 58.6, 113.3,
122.3, 124.5, 127.0, 127.5, 127.8, 127.9, 128.3, 128.4, 128.5, 128.9,
129.3, 137.3, 138.0, 138.1, 143.4, 143.6, 147.4, 154.6 ppm. HRMS:
calcd. for C25H22N2 [M + H]+ 351.1856; found 351.1847.
N-[(4-Fluorophenyl)(phenyl)methyl]-3-methylpyridin-2-amine (3l):[21]
The reaction was carried out according to general procedure III
with 1a (99 mg, 0.5 mmol, 1 equiv.), 1-bromo-4-fluorobenzene
(131 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%), and KOPiv (21 mg, 0.15 mmol, 30 mol-
%) in dry toluene (2 mL). Colorless solid (89 mg, 61% yield); m.p.
N-[(3-Methoxyphenyl)(phenyl)methyl]-3-phenylpyridin-2-amine (3v):
The reaction was carried out according to general procedure III
with 1b (130 mg, 0.5 mmol, 1 equiv.), 1-bromo-3-methoxybenzene
(140 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%), KOPiv (21 mg, 0.15 mmol, 30 mol-%),
and K2CO3 (207 mg, 1.5 mmol, 3 equiv.) in dry toluene (2 mL).
1
101–103 °C. H NMR (CDCl3, 200 MHz): δ = 2.07 (s, 3 H), 4.55
(d, J = 6.7 Hz, 1 H), 6.42–6.50 (m, 2 H), 6.86–6.97 (m, 2 H), 7.16–
7.26 (m, 8 H), 7.90 (dd, J = 5.0, 1.3 Hz, 1 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 17.2, 58.0, 113.4, 115.4 (d, J = 21.3 Hz),
116.5, 127.3, 127.7, 128.7, 129.2 (d, J = 8.1 Hz), 137.2, 139.3 (d, J
= 3.1 Hz), 143.4, 145.7, 155.6, 161.9 (d, J = 245.0 Hz) ppm.
HRMS: calcd. for C19H17N2F [M + H]+ 293.1449; found 293.1448.
1
Colorless oil (117 mg, 64% yield). H NMR (CDCl3, 200 MHz): δ
= 3.70 (s, 3 H), 5.18 (d, J = 7.5 Hz, 1 H), 6.48 (d, J = 7.5 Hz, 1
H), 6.63 (dd, J = 7.3, 5.0 Hz, 1 H), 6.70–6.85 (m, 3 H), 7.13–7.43
(m, 12 H), 8.08 (dd, J = 5.0, 1.8 Hz, 1 H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 55.2, 58.6, 112.3, 113.3, 113.4, 119.9, 122.4, 127.1,
127.5, 127.9, 128.6, 128.9, 129.3, 129.6, 137.3, 138.0, 143.3, 145.1,
147.4, 154.5, 159.8 ppm. HRMS: calcd. for C25H22N2O [M + H]+
367.1805; found 367.1794.
N-[(4-Chlorophenyl)(phenyl)methyl]-3-methylpyridin-2-amine
(3m):[21] The reaction was carried out according to general pro-
cedure III with 1a (99 mg, 0.5 mmol, 1 equiv.), 1-bromo-4-chloro-
benzene (143 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2
Eur. J. Org. Chem. 2013, 2878–2890
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2887

N. Dastbaravardeh, M. Schnürch, M. D. Mihovilovic
FULL PAPER
3-Phenyl-N-[phenyl(p-tolyl)methyl]pyridin-2-amine (3w):[21] The re-
action was carried out according to general procedure III with 1b
and K2CO3 (207 mg, 1.5 mmol, 3 equiv.) in dry toluene (2 mL).
Colorless oil (86 mg, 42% yield). H NMR (CDCl3, 200 MHz): δ
1
(130 mg, 0.5 mmol, 1 equiv.), 1-bromo-4-methylbenzene (128 mg, = 1.35 (t, J = 7.1 Hz, 3 H), 4.33 (q, J = 7.1 Hz, 2 H), 5.17 (d, J =
0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg, 0.0125 mmol, 7.2 Hz, 1 H), 6.53 (d, J = 7.2 Hz, 1 H), 6.66 (dd, J = 7.2, 5.0 Hz,
2.5 mol-%), KOPiv (21 mg, 0.15 mmol, 30 mol-%), and K2CO3 1 H), 7.16–7.45 (m, 13 H), 7.96 (d, J = 8.3 Hz, 2 H), 8.06 (dd, J =
(207 mg, 1.5 mmol, 3 equiv.) in dry toluene (2 mL). Colorless oil
(117 mg, 67% yield). H NMR (CDCl3, 200 MHz): δ = 2.29 (s, 3
5.0, 1.8 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 14.4, 58.7,
60.9, 113.7, 122.5, 127.3, 127.4, 127.6, 128.0, 128.8, 128.9, 129.2,
1
H), 5.17 (d, J = 7.4 Hz, 1 H), 6.47 (d, J = 7.5 Hz, 1 H), 6.63 (dd, 129.4, 129.9, 137.4, 137.9, 142.7, 147.3, 148.6, 154.3, 166.6 ppm.
J = 7.2, 5.0 Hz, 1 H), 7.04–7.44 (m, 15 H), 8.08 (dd, J = 5.0, 1.8 Hz,
1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 21.2, 58.4, 113.3,
122.3, 126.9, 127.4, 127.5, 127.9, 128.5, 129.0, 129.3, 129.4, 136.6,
137.3, 138.1, 140.5, 143.6, 147.4, 154.6 ppm. HRMS: calcd. for
C25H22N2 [M + H]+ 351.1856; found 351.1873.
HRMS: calcd. for C27H24N2O2 [M + H]+ 409.1911; found
409.1907.
1-(4-{Phenyl[(3-phenylpyridin-2-yl)amino]methyl}phenyl)ethanone
(3ab):[21] The reaction was carried out according to general pro-
cedure III with 1b (130 mg, 0.5 mmol, 1 equiv.), 1-(4-bromophen-
yl)ethanone (149 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2
(7.6 mg, 0.0125 mmol, 2.5 mol-%), KOPiv (21 mg, 0.15 mmol,
30 mol-%), and K2CO3 (207 mg, 1.5 mmol, 3 equiv.) in dry toluene
(2 mL). Colorless oil (77 mg, 41 % yield). 1H NMR (CDCl3,
200 MHz): δ = 2.53 (s, 3 H), 5.18 (d, J = 7.1 Hz, 1 H), 6.52 (d, J
= 7.1 Hz, 1 H), 6.66 (dd, J = 7.2, 5.0 Hz, 1 H), 7.19–7.44 (m, 13
H), 7.87 (d, J = 8.2 Hz, 2 H), 8.06 (dd, J = 5.0, 1.7 Hz, 1 H) ppm.
13C NMR (CDCl3, 50 MHz): δ = 26.7, 58.7, 113.7, 122.4, 127.4,
127.5, 127.6, 128.0, 128.7, 128.8, 128.9, 129.4, 135.9, 137.4, 137.8,
142.6, 147.3, 149.0, 154.3, 197.8 ppm. HRMS: calcd. for
C26H22N2O [M + H]+ 379.1805; found 379.1799.
N-{[4-(tert-Butyl)phenyl](phenyl)methyl}-3-phenylpyridin-2-amine
(3x):[21] The reaction was carried out according to general pro-
cedure III with 1b (130 mg, 0.5 mmol, 1 equiv.), 1-bromo-4-(tert-
butyl)benzene (160 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2
(7.6 mg, 0.0125 mmol, 2.5 mol-%), KOPiv (21 mg, 0.15 mmol,
30 mol-%), and K2CO3 (207 mg, 1.5 mmol, 3 equiv.) in dry toluene
(2 mL). Colorless solid (141 mg, 72% yield); m.p. 74–76 °C. 1H
NMR (CDCl3, 200 MHz): δ = 1.27 (s, 9 H), 5.20 (d, J = 7.5 Hz, 1
H), 6.50 (d, J = 7.6 Hz, 1 H), 6.62 (dd, J = 7.2, 5.0 Hz, 1 H), 7.12–
7.44 (m, 15 H), 8.08 (dd, J = 5.0, 1.8 Hz, 1 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 31.5, 34.5, 58.2, 113.2, 122.3, 125.5, 126.9,
127.2, 127.5, 127.9, 128.5, 129.0, 129.4, 137.3, 138.1, 140.4, 143.7,
147.4, 149.8, 154.6 ppm (one phenyl-carbon resonance is overlap-
ping). HRMS: calcd. for C28H28N2 [M + H]+ 393.2325; found
393.2349.
N-[(4-Isopropoxyphenyl)(phenyl)methyl]-3-methylpyridin-2-amine
(3ae): The reaction was carried out according to general procedure
III with 1d (128 mg, 0.5 mmol, 1 equiv.), bromobenzene (118 mg,
0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg, 0.0125 mmol,
2.5 mol-%), KOPiv (21 mg, 0.15 mmol, 30 mol-%), and K2CO3
(207 mg, 1.5 mmol, 3 equiv.) in dry toluene (2 mL). Colorless oil
(71 mg, 43% yield). 1H NMR (CDCl3, 200 MHz): δ = 1.30 (d, J =
6.0 Hz, 6 H), 2.11 (s, 3 H), 4.49 (sep, J = 6.0 Hz, 1 H), 4.61 (d, J
= 7.0 Hz, 1 H), 6.44–6.52 (m, 2 H), 6.77–6.85 (m, 2 H), 7.17–7.34
(m, 8 H), 7.95 (dd, J = 5.0, 1.3 Hz, 1 H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 17.2, 22.2, 58.0, 69.9, 113.1, 115.8, 116.4, 126.9,
127.5, 128.5, 128.9, 135.6, 137.0, 143.8, 145.8, 155.8, 157.0 ppm.
HRMS calcd. for C22H24N2O [M + H]+ 333.1961; found 333.1963.
N-[(4-Butylphenyl)(phenyl)methyl]-3-phenylpyridin-2-amine
(3y):
The reaction was carried out according to general procedure III
with 1b (130 mg, 0.5 mmol, 1 equiv.), 1-bromo-4-butylbenzene
(160 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%), KOPiv (21 mg, 0.15 mmol, 30 mol-%),
and K2CO3 (207 mg, 1.5 mmol, 3 equiv.) in dry toluene (2 mL).
1
Colorless oil (135 mg, 69% yield). H NMR (CDCl3, 200 MHz): δ
= 0.89 (t, J = 7.2 Hz, 3 H), 1.23–1.40 (m, 2 H), 1.47–1.62 (m, 2
H), 2.54 (t, J = 7.7 Hz, 2 H), 5.18 (d, J = 7.5 Hz, 1 H), 6.50 (d, J
= 7.5 Hz, 1 H), 6.61 (dd, J = 7.2, 5.0 Hz, 1 H), 7.04–7.42 (m, 15 H),
8.07 (dd, J = 5.0, 1.8 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ
= 14.1, 22.5, 33.6, 35.4, 58.4, 113.2, 122.3, 126.9, 127.4, 127.5,
127.9, 128.5, 128.6, 128.9, 129.3, 137.3, 138.1, 140.7, 141.6, 143.7,
147.4, 154.6 ppm. HRMS: calcd. for C28H28N2 [M + H]+ 393.2325;
found393.2323.
3-Methyl-N-{phenyl[4-(trifluoromethyl)phenyl]methyl}pyridin-2-
amine (3af):[21] The reaction was carried out according to general
procedure III with 1g (133 mg, 0.5 mmol, 1 equiv.), bromobenzene
(118 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%), KOPiv (21 mg, 0.15 mmol, 30 mol-%),
and K2CO3 (207 mg, 1.5 mmol, 3 equiv.) in dry toluene (2 mL).
Colorless solid (97 mg, 57% yield); m.p. 56–58 °C. 1H NMR
(CDCl3, 200 MHz): δ = 2.17 (s, 3 H), 4.65 (d, J = 6.3 Hz, 1 H),
6.54–6.60 (m, 2 H), 7.26–7.60 (m, 10 H), 7.97 (dd, J = 5.0, 1.3 Hz,
1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 17.1, 58.6, 113.7,
116.6, 124.4 (q, J = 272.7 Hz), 125.5 (q, J = 3.8 Hz), 127.7, 127.8,
127.9, 128.9, 129.2 (q, J = 32.3 Hz), 137.2, 142.9, 145.7, 147.6,
155.5 ppm. HRMS: calcd. for C20H17F3N2 [M + H]+ 343.1417;
found 343.1433.
N-[(4-Chlorophenyl)(phenyl)methyl]-3-phenylpyridin-2-amine (3z):[21]
The reaction was carried out according to general procedure III
with 1b (130 mg, 0.5 mmol, 1 equiv.), 1-bromo-4-chlorobenzene
(143 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%), KOPiv (21 mg, 0.15 mmol, 30 mol-%),
and K2CO3 (207 mg, 1.5 mmol, 3 equiv.) in dry toluene (2 mL).
1
Colorless oil (109 mg, 59% yield). H NMR (CDCl3, 200 MHz): δ
= 5.12 (d, J = 7.2 Hz, 1 H), 6.47 (d, J = 7.3 Hz, 1 H), 6.64 (dd, J
= 7.2, 5.0 Hz, 1 H), 7.15–7.42 (m, 15 H), 8.07 (dd, J = 5.0, 1.8 Hz,
1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 58.2, 113.6, 122.4,
127.3, 127.5, 128.0, 128.6, 128.7, 128.9, 129.4, 132.7, 137.4, 137.9,
142.0, 142.9, 147.3, 154.3 (one phenyl-carbon resonance is overlap-
ping) ppm. HRMS: calcd. for C24H19N2Cl [M + H]+ 371.1310;
found 371.1294.
Methyl 4-{[(3-Methylpyridin-2-yl)amino] (phenyl)methyl}benzoate
(3ag):[21] The reaction was carried out according to general pro-
cedure III with 1h (128 mg, 0.5 mmol, 1 equiv.), bromobenzene
(118 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%), and KOPiv (21 mg, 0.15 mmol, 30 mol-
%) in dry toluene (2 mL). Colorless oil (95 mg, 57% yield). 1H
NMR (CDCl3, 200 MHz): δ = 2.13 (s, 3 H), 3.86 (s, 3 H), 4.65 (d,
J = 6.6 Hz, 1 H), 6.49–6.55 (m, 2 H), 7.21–7.33 (m, 6 H), 7.41 (d,
J = 8.2 Hz, 2 H), 7.92–7.99 (m, 3 H) ppm. 13C NMR (CDCl3,
Ethyl 4-{Phenyl[(3-phenylpyridin-2-yl)amino]methyl}benzoate (3aa):
The reaction was carried out according to general procedure III
with 1b (130 mg, 0.5 mmol, 1 equiv.), ethyl 4-bromobenzoate
(172 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-cymene)]2 (7.6 mg,
0.0125 mmol, 2.5 mol-%), KOPiv (21 mg, 0.15 mmol, 30 mol-%), 50 MHz): δ = 17.1, 52.1, 58.7, 113.5, 116.5, 127.4, 127.5, 127.9,
2888
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2878–2890

Direct Arylation of Benzylic Amines Mediated by Ruthenium(II)
128.8, 129.9, 137.1, 142.9, 145.7, 148.8, 155.5, 167.1 ppm. HRMS:
calcd. for C21H20N2O2 [M + H]+ 333.1598; found 333.1587.
methanamine (169 mg, 1.4 mmol, 1.4 equiv.), NaOtBu (192 mg,
2 mmol, 2 equiv.), Pd2(dba)3 (18 mg, 0.02 mmol, 2 mol-%), and
DPPP (16 mg, 0.04 mmol, 4 mol-%) in dry toluene (4 mL). Color-
less oil (186 mg, 88% yield). 1H NMR (CDCl3, 200 MHz): δ = 2.32
(s, 3 H), 2.75 (s, 3 H), 4.33 (s, 2 H), 6.82 (dd, J = 7.3, 4.9 Hz, 1 H),
7.24–7.40 (m, 6 H), 8.16 (dd, J = 4.8, 1.5 Hz, 1 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 19.0, 39.1, 57.8, 117.4, 124.5, 126.9, 128.0,
128.4, 139.3, 139.5, 145.2, 162.6 ppm. HRMS: calcd. for C14H16N2
[M + H]+ 213.1386; found 213.1385.
N-(Diphenylmethylene)-3-methylpyridin-2-amine (4):[7] The reaction
was carried out according to general procedure III with N-benzyl-
idene-3-methylpyridin-2-amine (12, 98 mg, 0.5 mmol, 1 equiv.), 1-
bromobenzene (118 mg, 0.75 mmol, 1.5 equiv.), [RuCl2(p-
cymene)]2 (7.6 mg, 0.0125 mmol, 2.5 mol-%), and KOPiv (21 mg,
0.15 mmol, 30 mo l%) in dry toluene (2 mL). Yellow oil (91 mg,
67% yield); The analytical data are in accordance with the litera-
ture values.[12] 1H NMR (CDCl3, 200 MHz): δ = 2.08 (s, 3 H), 6.76
(dd, J = 7.4, 4.9 Hz, 1 H), 7.20–7.42 (m, 9 H), 7.82 (d, J = 6.5 Hz,
2 H), 8.09 (d, J = 4.8 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz):
δ = 17.5, 118.8, 122.8, 127.8, 128.1, 128.9, 129.7, 138.1, 145.7,
162.3, 169.4 ppm.
3-Methyl-2-(phenylethynyl)pyridine:[22] 2-Bromo-3-methylpyridine
(172 mg, 1 mmol, 1 equiv.), phenylacetylene (122 mg, 1.2 mmol,
1.2 equiv.), pyrrolidine (142 mg, 2 mmol, 2 equiv.), PdCl2 (4 mg,
0.02 mmol, 2 mol-%), PPh3 (10 mg, 0.04 mmol, 4 mol-%), and de-
gassed water (2 mL) were placed in an oven-dried 6 mL vial with
a Teflon cap and a magnetic stirring bar. The reaction vial was
then heated in a reaction block at 120 °C for 3 h. The reaction
mixture was cooled to room temp. and extracted with diethyl ether
(4ϫ 5 mL). The combined organic layers were dried with Na2SO4,
filtered, and concentrated. The residue was purified by flash
chromatography (PE/EtOAc = 9:1) to give the pure product as a
red oil (139 mg, 72% yield). 1H NMR (CDCl3, 200 MHz): δ = 2.52
(s, 3 H), 7.15 (dd, J = 7.7, 4.8 Hz, 1 H), 7.33–7.40 (m, 3 H), 7.51–
7.63 (m, 3 H), 8.45 (dd, J = 4.7, 1.0 Hz, 1 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 19.6, 87.6, 93.2, 122.6, 122.8, 128.5, 129.0,
132.1, 136.0, 137.1, 143.2, 147.5 ppm.
3-Methyl-2-phenethylpyridine (5):[23] 3-Methyl-2-(phenylethynyl)-
pyridine (193 mg, 1 mmol, 1 equiv.), triethylamine (253 mg,
2.5 mmol, 2.5 equiv.), 10% palladium on carbon (30 mg), and
EtOH (30 mL) were charged in a round-bottomed flask. The reac-
tion mixture was stirred at room temperature under H2 at atmo-
spheric pressure for 16 h. The solvent was removed under reduced
pressure, and the residue dissolved in Et2O (25 mL). The solid ma-
terial was removed by filtration. The organic layer was washed with
saturated NaHCO3 and then brine, dried with Na2SO4, filtered,
and concentrated. Pale yellow oil (196 mg, 99% yield). 1H NMR
(CDCl3, 200 MHz): δ = 2.23 (s, 3 H), 3.02–3.10 (m, 4 H) 7.05 (dd,
J = 7.6, 4.8 Hz, 1 H), 7.19–7.42 (m, 6 H), 8.42 (d, J = 3.7 Hz, 1
H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 18.8, 35.1, 37.5, 121.4,
126.0, 128.5, 128.6, 131.3, 137.7, 142.1, 146.8, 159.6 ppm.
2-(Pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (7b):[25] The reaction
was carried out according to general procedure II with 2-bromo-
pyridine (158 mg, 1 mmol, 1 equiv.), 1,2,3,4-tetrahydroisoquinoline
(186 mg, 1.4 mmol, 1.4 equiv.), NaOtBu (192 mg, 2 mmol,
2 equiv.), Pd2(dba)3 (18 mg, 0.02 mmol, 2 mol-%), and DPPP
(16 mg, 0.04 mmol, 4 mol-%) in dry toluene (4 mL). Colorless solid
(199 mg, 95% yield); m.p. 47–49 °C. 1H NMR (CDCl3, 200 MHz):
δ = 2.98 (t, J = 5.9 Hz, 2 H), 3.86 (t, J = 5.9 Hz, 2 H), 4.72 (s, 2
H), 6.59–6.71 (m, 2 H), 7.21 (q, J = 3.1 Hz, 4 H), 7.46–7.55 (m, 1
H), 8.25 (dd, J = 4.9, 1.2 Hz, 1 H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 29.1, 42.6, 47.2, 106.7, 112.6, 126.3, 126.5, 126.7,
128.5, 134.5, 135.5, 137.5, 148.1, 158.8 ppm.
2-(3-Methylpyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (7c):[21] The
reaction was carried out according to general procedure II with 2-
bromo-3-methylpyridine (172 mg, 1 mmol, 1 equiv.), 1,2,3,4-tetra-
hydroisoquinoline (186 mg, 1.4 mmol, 1.4 equiv.), NaOtBu
(192 mg, 2 mmol, 2 equiv.), Pd2(dba)3 (18 mg, 0.02 mmol, 2 mol-
%), and DPPP (16 mg, 0.04 mmol, 4 mol-%) in dry toluene (4 mL).
1
Yellow oil (203 mg, 91% yield). H NMR (CDCl3, 200 MHz): δ =
2.35 (s, 3 H), 3.07 (t, J = 5.8 Hz, 2 H), 3.41 (t, J = 5.8 Hz, 2 H),
4.45 (s, 2 H), 6.88 (dd, J = 7.3, 4.9 Hz, 1 H), 7.19 (s, 4 H), 7.42–
7.46 (m, 1 H), 8.22 (dd, J = 4.8, 1.8 Hz, 1 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 18.5, 29.9, 48.5, 51.6, 117.8, 124.9, 125.9,
126.2, 126.9, 128.9, 134.6, 135.4, 139.4, 145.3, 161.9 ppm. HRMS:
calcd. for C15H16N2 [M + H]+ 225.1386; found 225.1378.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details and spectra.
Acknowledgments
We acknowledge the Austrian Science Foundation (FWF) (project
number P21202-N17) for financial support of this work.
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2-(Benzyloxy)-3-methylpyridine (6):[24] 2-Chloro-3-methylpyridine
(128 mg, 1 mmol, 1 equiv.), phenylmethanol (140 mg, 1.3 mmol,
1.3 equiv.), KOtBu (224 mg, 2 mmol, 2 equiv.), and dioxane (5 mL)
were charged in a round-bottomed flask. The reaction mixture was
heated to reflux for 24 h. The solution was cooled to room temp.,
and H2O (2 mL) was added. The aqueous phase was extracted with
EtOAc (3ϫ 5 mL). The combined organic layer was washed with
saturated NaHCO3 and then brine, dried with Na2SO4, filtered,
and concentrated. The residue was purified by flash chromatog-
raphy (PE/EtOAc = 19:1) to give the pure product. Colorless oil
1
(140 mg, 70% yield). H NMR (CDCl3, 200 MHz): δ = 2.26 (s, 3
H), 5.44 (s, 2 H), 6.82 (dd, J = 7.1, 5.1 Hz, 1 H), 7.31–7.52 (m, 6 H),
8.03 (dd, J = 5.0, 1.3 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ
= 16.0, 67.3, 116.9, 121.1, 127.6, 127.7, 128.5, 138.0, 138.7, 144.1,
162.0 ppm.
N-Benzyl-N,3-dimethylpyridin-2-amine (7a):[21] The reaction was
carried out according to general procedure II with 2-bromo-3-
methylpyridine (172 mg, 1 mmol, 1 equiv.), N-methyl-1-phenyl-
Eur. J. Org. Chem. 2013, 2878–2890
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2889

N. Dastbaravardeh, M. Schnürch, M. D. Mihovilovic
FULL PAPER
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Received: January 2, 2013
Published Online: March 22, 2013
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