Mechanistic investigations and substrate scope evaluation of ruthenium-catalyzed direct sp3 arylation of benzylic positions directed by 3-substituted pyridines

Article abstract of DOI:10.1021/jo302547q

A highly efficient direct arylation process of benzylic amines with arylboronates was developed that employs Ru catalysis. The arylation takes place with greatest efficiency at the benzylic sp³ carbon. If the distance to the activating aryl ring is increased, arylation is still possible but the yield drops significantly. Efficiency of the CH activation was found to be significantly increased by use of 3-substituted pyridines as directing groups, which can be removed after the transformation in high yield. Calculation of the energy profile of different rotamers of the substrate revealed that presence of a substituent in the 3-position favors a conformation with the CH₂ group adopting a position in closer proximity to the directing group and facilitating C-H insertion. This operationally simple reaction can be carried out in argon atmosphere as well as in air and under neutral reaction conditions, displaying a remarkable functional group tolerance. Mechanistic studies were carried out and critically compared to mechanistic reports of related transformations.

Full text of DOI:10.1021/jo302547q

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Article
Mechanistic Investigations and Substrate Scope
Evaluation of Ruthenium-Catalyzed Direct sp3 Arylation
of Benzylic Positions Directed by 3-Substituted Pyridines
Navid Dastbaravardeh, Karl Kirchner, Michael Schnürch, and Marko D. Mihovilovic
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo302547q • Publication Date (Web): 13 Dec 2012
Downloaded from http://pubs.acs.org on December 17, 2012
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The Journal of Organic Chemistry
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Mechanistic Investigations and Substrate Scope Evaluation of Ruthenium-Catalyzed Direct sp3
Arylation of Benzylic Positions Directed by 3-Substituted Pyridines
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Navid Dastbaravardeh,† Karl Kirchner,† Michael Schnürch,*,† and Marko D. Mihovilovic†
† Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163ꢀOC,
1060 Vienna, Austria
* michael.schnuerch@tuwien.ac.at
ABSTRACT: A highly efficient direct arylation process of benzylic amines with arylboronates was
developed employing Ruꢀcatalysis. The arylation takes place with greatest efficiency at the benzylic sp3
carbon. If the distance to the activating aryl ring is increased arylation is still possible but the yield
drops significantly. Efficiency of the CHꢀactivation was found to be significantly increased using 3ꢀ
substituted pyridines as directing groups which can be removed after the transformation in high yield.
Calculation of the energy profile of different rotamers of the substrate revealed that presence of a
substituent in 3ꢀposition favors a conformation with the CH2ꢀgroup adopting a position in closer
proximity to the directing group and facilitating C–H insertion. This operationally simple reaction can
be carried out in argon atmosphere as well as in air and under neutral reaction conditions displaying a
remarkable functional group tolerance. Mechanistic studies were carried out and critically compared to
mechanistic reports of related transformations.
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INTRODUCTION
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The efficient synthesis of complex organic molecules is a permanent challenge for synthetic chemists.
The available portfolio of chemical transformations allows for the synthesis of almost any molecule,
however, the introduction of functional groups or substituents in a specific position often requires multiꢀ
step synthesis which naturally lowers atom efficiency. Additionally, purification of the intermediates is
time consuming and resource intensive and yields over several steps are often rather low. Therefore, one
of the most important quests for synthetic chemists is the development of new, more efficient and direct
transformations which allow the elimination of synthetic detours. In this regard, the direct catalytic
cleavage of C–H bonds is highly attractive and one of the most investigated but also most challenging
topics in modern organic synthesis.1 Much effort is put in realizing such C–H activation reactions since
it would increase the atom efficiency of transformations and, therefore, is in consent with the principles
of green chemistry.
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Within the last years, the field of transition metal catalyzed C–H activation reactions is rapidly
expanding and the commitment of research groups all around the world afforded many interesting
results in this area. However, most of the developed methods are focused on the direct functionalization
of sp2 C–H bonds.2 The more challenging direct functionalization of sp3 C–H bonds is a highly
attractive process since regioselective functionalization of such sp3 C–H bonds still requires multiꢀstep
sequences in many cases in order to address a specific C–H bond without compromising others.3
Cyclometalation is among the proposed solutions to achieve C–H bond activation by transitionꢀmetal
complexes utilizing nearby heteroatoms as directing/coordinating groups.4 Again, many chelation
assisted functionalizations have been reported in context of sp2 C–H bond activation but only few
involve sp3 C–H bonds.5 One of the first chelation assisted transformations of sp3 C–H bonds was
described by the group of Jun in 1998.6 A few years later, Kakiuchi and Chatani demonstrated in their
pioneering work the arylation of aromatic ketones with arylboronates.7 Afterwards, Sames and
coworkers published the arylation of pyrrolidines and piperidine directed by a cyclic imine (Figure 1,
A),8 followed by the discovery of Maes and coworkers where they showed a pyridine directed arylation
of piperidine derivatives (Figure 1, B).9 However, the last two methods were limited to cyclic amines.
The limitation to saturated Nꢀheterocycles is probably related to the preferred geometrical alignment of
such systems where the directing group is excellently positioned to activate the CH2 group adjacent to
the heteroatom. In acyclic systems such a conformational lock is not possible; therefore, the directing
group and positions to be activated rather arrange in a way of greatest distance to minimize energy.
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The Journal of Organic Chemistry
Hence, in order to successfully achieve a direct substitution via C–H activation, provisions have to be
undertaken in order to bring the directing group and the C–H bond to be functionalized in close enough
proximity. We reported recently the direct arylation of acyclic sp3 C–H bonds adjacent to a free NH
group with various arenes via cyclometalation with Ru3(CO)12.10
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Figure 1. Direct Arylation of sp3 C–H bonds adjacent to nitrogen.
RESULTS AND DISCUSSION
We started our project with investigating the role of the directing group. Therefore, we synthesized
different benzylic amines and tested them under the specific conditions described by Sames and coꢀ
workers (Scheme 1). We tested different heterocyclicꢀ, (sulfon)amideꢀ, and carbamate directing groups,
but only pyridine showed low activity. All the other directing groups, including the carbonyl of the Boc
carbamate and pivaloyl moiety, were not suitable for this protocol.
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Scheme 1 Investigated directing groups for the Ru-catalyzed C–H arylation protocol.
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Hence, we focused on pyridine as suitable directing group. However, intensive screening of the
conditions afforded no higher conversion until we discovered that the installation of a substituent in 3ꢀ
position of pyridine enhanced the conversion significantly, which was describe in our previously
published study containing preliminary results (Scheme 2).10 The crucial role of the substituent in 3ꢀ
position was also described by Jun and coꢀworkers.11 When carrying out the direct arylation with 4a, a
much higher conversion (85%) could be achieved compared to the reaction with 1a. We hypothesized
that the installation of a sterically demanding group in 3ꢀposition of the pyridine ring forces the benzyl
group into a position where the metal and the CH2 group are in much closer proximity, which facilitates
the C–H insertion of the metal, significantly. This Ru(0)ꢀcatalyzed arylation of benzylic amines with
arylboronates works most efficiently (but it is not limited to) when benzylic C–H bonds are arylated.
Notably, this operationally simple method does not require the proximity of a heteroatom. In subsequent
work we could develop a method for the reaction with aryl halides as well by using a Ru(II) catalyst
using the same directing group.12
Within this contribution we report on a systematic evaluation of directing groups, substrate scope
exploration and mechanistic investigations of the Ru(0) catalyzed direct arylation process.
Scheme 2. Ru-catalyzed Arylation of sp3 C–H Bond.
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The Journal of Organic Chemistry
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Having identified the presence of a bulky group in 3ꢀposition as key element of the directing group, we
tested which other groups in 3ꢀposition would be tolerated and give similar results as compared to the
methyl group in 4a. Therefore, substrates carrying chlorine (4b), CF3 (4c), and phenyl (4d) in 3ꢀposition
were prepared. The 3ꢀphenyl substrate 4d could be efficiently prepared from 4b via SuzukiꢀMiyaura
crossꢀcoupling (Scheme 3).13 In the case of chlorine conversion to the product was detected but only to
an extent of ~10% (Table 1, entry 2). Trifluoromethyl was also a suitable bulky group and an improved
yield of 78% was obtained (Table 1, entry 4). The phenyl group gave even better results and 90% yield
of product was obtained (Table 1, entry 5). This indicates that the size of the bulky group in 3ꢀposition
has an influence on the effectiveness of the arylation process. It has to be mentioned that the overall
process of benzylamine attachment, phenyl introduction and finally direct arylation to 5d is very
efficient and gave 80% overall yield over 3 steps (Scheme 3).
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The reaction was further optimized regarding the aryl source, revealing that the 1,3ꢀpropanediol boron
ester 6 gave the best result.10 This ester is also most convenient in the reaction workup since it can be
hydrolyzed easily to the boronic acid facilitating chromatographic purification of the product.
Table 1 Influence of the substituent in 3-position of pyridine on the direct arylation process.a
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entry
4
R
5
convb
9
yield
n.i.c
n.i.c
64
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1
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4
H
1a
4b
4a
4c
4d
3a
5b
5a
5c
5d
Cl
10
CH3
CF3
Ph
85
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a
Reaction conditions: 4 (0.5 mmol), 6a (0.75 mmol), Ru3(CO)12 (5 mol%) and
b
pinacolone (0.5 mL). Conversion based on GC analysis with respect to 4
(dodecane as internal standard). cn.i. = not isolated.
Scheme 3. Sequential Coupling of 2,3-dichloropyridine (7) to the arylated product (5d).
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The Journal of Organic Chemistry
Taking into account the mandatory features of a suitable directing group, we expected Nꢀsubstituted
benzimidazole 9 to perform in similar way as 4a due to the analogous geometry of the directing group
compared to 3ꢀmethylpyridꢀ2ꢀyl. Indeed, this group showed activity, albeit with comparatively lower
conversion and yield (Scheme 4). The lower conversion can be rationalized by the differences in
geometry of a fiveꢀ compared to a sixꢀmembered ring; this leads to less interference of the Nꢀmethyl
group with the CH2 group to be arylated as compared to the methyl group in 4a and the benzylic
position. Hence the energy difference between the two conformers will be lower and the “right”
conformer is less preferred resulting in lower conversion and yield.
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Scheme 4. Ru-catalyzed Arylation of 9.
Hence, 3ꢀsubstituted pyridines were chosen as directing groups for further investigations. Such directing
groups can be introduced easily via BuchwaldꢀHartwigꢀamination, starting from commercially available
2ꢀchloroꢀ3ꢀsubstituted pyridine derivatives and benzylic amines (see supporting information). This
operationally simple, high yielding reaction provides an applicable entry to the starting materials.
With the optimized conditions in hands we wanted to investigate the scope and limitations of the
presented transformation. This catalytic method was found compatible with arene donors carrying a
variety of different functional groups. Using 3ꢀmethyl substituted pyridine as directing group, simple
phenylboronic acid ester gave a good yield of 64% (Table 2, entry 1). Sterically demanding aryls (2ꢀMe,
1ꢀnaphthyl) were not tolerated and led to unsatisfactory yields (Table 2, entries 2 & 3), but meta (3ꢀMe,
3ꢀCl) and para substituents showed good reactivity (Table 2, entries 4 & 5). Aryls containing electronꢀ
donating alkyl substituents (Me, tꢀBu) gave also good yields (Table 2, entries 6 & 7) but 4ꢀmethoxy
substitution led to a decreased yield of 39% (Table 2, entry 8). Also a 4ꢀfluoro substituent was well
tolerated (Table 2, entry 9), however 4ꢀCl (33%) and 4ꢀCF3 (41%) led to significantly lower yields
(Table 2, entries 10 & 11), indicating that electron withdrawing substituents are unfavorable. Still,
halides are tolerated and can be used for further manipulations, e.g. cross coupling reactions. Strong
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electron withdrawing substituents were not tolerated (Table 2, entries 12ꢀ14). Also heterocyclic boronic
esters were inefficient (Table 2, entries 15 & 16).
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We replaced the 3ꢀmethyl group by the 3ꢀtrifluoromethyl group in order to test whetherstereoelectronic
effects of the 3ꢀsubstituent had an influence on the reaction outcome. Interestingly, the 3ꢀtrifluoromethyl
group showed even better yields but required also a higher reaction temperature (Table 2, entries 17ꢀ21).
For instance, the yield could be increased from 64% to 78% for Ph (Table 2, entry 1 vs. entry 17) and
from 62% to 77% for 4ꢀMeꢀPh (Table 2, entry 2 vs. entry 18). In one case, namely 4ꢀfluoro substituted
boronic acid ester, the yield was lower in the CF3 case as compared to the CH3 case (Table 2, entry 9 vs
21).
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Additionally, we tested the phenyl group as even more bulky substituent in 3ꢀposition. Indeed, the
arylation yield could be significantly increased when changing the group in 3ꢀposition of the pyridine
directing group to the phenyl group (Table 2, entries 22ꢀ28). The yield could be increased in almost all
the cases (e.g. 64% entry 1 ꢀ 90% entry 22 for Ph, 64% entry 7 ꢀ 96 % entry 24 for 4ꢀtBuꢀPh). Even
the more problematic electron withdrawing substituents gave now better yields (e.g. 33% entry 10 ꢀ
64% entry 24 for 4ꢀClꢀPh, 52% entry 28 for 4ꢀAcꢀPh). However, as expected, strong coordinating
substituents such as NO2 and CN showed again no conversion at all (Table 2, entries 29 & 30).
Table 2. Ru (0)-catalyzed arylation of pyridine derivatives.a
entry
4
R
Ar
5
convb yield
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2
3
Me
Me
Me
Ph
86
55
8
64
4a
4a
4a
5a
5e
5f
2ꢀMeꢀPh
1ꢀNaph
n.i.c,d
n.i.c
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The Journal of Organic Chemistry
4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CF3
CF3
CF3
CF3
CF3
Ph
3ꢀMeꢀPh
3ꢀClꢀPh
4ꢀMeꢀPh
4ꢀtꢀBuꢀPh
4ꢀOMeꢀPh
4ꢀFꢀPh
87
59
88
87
50
89
49
61
11
0
61
38
62
64
39
66
33
41
n.i.c
0
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4c
4c
4c
4c
4c
4d
4d
4d
5g
5h
5i
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2
3
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5
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8
5
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7
5j
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8
5k
5l
9
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24
4ꢀClꢀPh
4ꢀCF3ꢀPh
4ꢀAcꢀPh
4ꢀNO2ꢀPh
4ꢀCNꢀPh
3ꢀpyridyl
2ꢀthienyl
Phe
5m
5n
5o
5p
5q
5r
5s
0
0
0
0
0
0
90
92
84
76
65
100
100
100
78
77
70
61
51
90
85
96
5c
5t
4ꢀMeꢀPhe
4ꢀtꢀBuꢀPhe
4ꢀOMeꢀPhe
4ꢀFꢀPhe
5u
5v
5w
5d
5x
5y
Phe
Ph
4ꢀMeꢀPhe
4ꢀtꢀBuꢀPhe
Ph
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25
26
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29
30
Ph
4ꢀFꢀPhe
100
87
65
89
0
72
64
31
52
0
4d
4d
4d
4d
4d
4d
5z
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
4ꢀClꢀPhe
4ꢀCF3ꢀPhe
4ꢀAcꢀPhe
4ꢀ NO2ꢀPhe
4ꢀCNꢀPhe
5aa
5ab
5ac
5ad
5ae
9
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0
0
a Reaction conditions: 4 (0.5 mmol), 6 (0.75 mmol), Ru3(CO)12 (5
b
mol%) and pinacolone (0.5 mL). Conversion based on GC analysis
c
with respect to 4 (dodecane as internal standard). n.i. = not isolated.
dCould not be isolated because of side products. e150 °C.
After exploring the substrate scope of the boronic acid ester coupling partner, the influence of
substituents on the benzylic position was investigated exercising different electronic effects. Model
substrates were synthesized carrying different substituents in the para position of the benzylic
substituent and these precursors were submitted to the optimized conditions using phenylboronic acid
ester 6a as coupling partner. In general, it appears that the reaction is very sensitive to the electronic
properties of the benzylic amine. Strong electron donating (Table 3, entries 1 & 2) and withdrawing
(Table 3, entries 6 & 7) substituents diminished the conversion. Best results could again be achieved
with weak electron donating or withdrawing substituents (Table 3, entries 3ꢀ5). In the case of the methyl
ester substrate 4j, we could also detect decarboxylated compound 5a as side product. Even though
Ru3(CO)12 has been used in decarboxylative coupling reactions,14 this was unexpected since a directing
group is lacking to bring the catalyst in proximity to the ester functionality and the pyridine is too far
away in order to act as directing group for the decarboxylation process.
Table 3. Competitive experiments for the Ru(0)-catalyzed reaction.a
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entry 4
R
X
Y
5
convb yield
1
Me
Me
Me
Me
Me
Me
Mec
Me
Me
CF3
Phc
Phc
Phc
Phc
Phc
OiPr
OMe
Me
H
H
35
58
99
86
73
24
43
69
48
95
98
88
76
71
47
25
32
76
64
44
15
26
50
33
80
90
73
67
60
33
4e
5af
5k
2
H
4f
3
H
4g
4a
4h
4i
5i
4
H
5a
5
F
H
5l
6
CF3
CO2Me
Me
Me
Me
Me
Me
Me
Me
Me
H
5n
7
H
4j
5ag
5ah
5ai
5t
8
Cl
CF3
H
4g
4g
4k
4m
4m
4m
4m
4m
9
10
11
12
13
14
15
H
5x
Me
tꢀBu
F
5aj
5ak
5al
5am
CF3
a Reaction conditions: 4 (0.5 mmol), 6 (0.75 mmol), Ru3(CO)12 (5 mol%) and
b
pinacolone (0.5 mL). Conversion based on GC analysis with respect to 4
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(dodecane as internal standard). c150 °C.
1
2
3
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7
8
9
Since the pꢀmethyl substrate 4g gave the best conversion and yield so far, a series of reactions was
performed with substrates 4g, 4k and 4m , all carrying a this pꢀmethylbenzyl substituent and different
blocking groups in 3 position of pyridine. In the introduction of the phenyl substituent a significantly
higher yield was obtained using 4g as substrate (Table 3, entry 3, 76%) as compared to 4a (Table 2,
entry 1, 64%). In cases where 4a gave low conversions and yield (Table 2 entries 10 & 11) the
difference compared to 4g as substrate was negligible (Table 3, entries 8 & 9). Having pꢀmethylbenzyl
substituted substrates with either trifluoromethyl (4k) or phenyl (4m) as bulky group in 3ꢀposition of
pyridine (Table 3, entries 10 & 11) the yields were almost identical to substrates 4c and 4d. Substrate
4m was also reacted with different aryl donors (Table 3, entries 12ꢀ15). The trend of decrease of
conversion from electron donating to withdrawing substituents is again similar to the previous observed
results.
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In order to investigate the relative reactivity of differently substituted starting materials, we performed a
series of intermolecular competition experiments. For this purpose 1 equivalent each of two different
starting materials and 1 equivalent of phenylboronic acid ester 6a were reacted under standard
conditions (Scheme 5). The reaction was monitored via GC and also the product distribution was
determined using GC analysis. The obtained results indicate that substrates with electron neutral or
weakly donating substituents react fastest which also goes in line with the finding that those starting
materials also give the highest yields. The 4ꢀmethyl substituted starting material 4g reacts in the same
rate as unsubstituted 4a (Scheme 5, H:X = 1). The substrates carrying electron donating (4e & 4f) and
electron withdrawing substituents (4h & 4i) react comparatively slower. In the case of the methyl ester
4j we observed again decarboxylation to 5a as side reaction. Hence, the high H:X ratio of 5.3 does not
correlate to the difference in reaction rate in this case.
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Scheme 5. Competitive experiments for the Ru(0)-catalyzed reaction.a
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Finally, we investigated if the reaction is limited to C–H bonds adjacent to nitrogen. We found that the
NH group can be replaced by a CH2 group as in 11 which even gives an improved yield in the arylation
step (Scheme 6, 75% yield of 14). However, extending the reaction time to 36h was required.
Interestingly, the reaction did not work by replacing the NH with oxygen (Scheme 6, 12 to 15).
Furthermore, the transformation also works with nonꢀbenzylic sp3 C–H bonds as in 13, however with
again longer reaction time and lower yield (Scheme 6, 39% of 16). Overall this suggests that an adjacent
NH has a significantly lower activating influence (if any) on the CH2 group as compared to the adjacent
phenyl group.
Scheme 6. The direct transformation of C–H bond adjacent to the CH2 (11) group and the non
benzylic C–H bond (13).
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To strengthen our hypothesis that a bulky group in position 3 of pyridine favors the desired
conformation of the substrate, we calculated the structures of two stable rotamers of Nꢀbenzylꢀ3ꢀ
methylpyridineꢀ2ꢀamine 4a and Nꢀbenzylpyridineꢀ2ꢀamine 1a and the corresponding transition states for
their interconversion by means of DFT calculations (Gaussian 03/PBE1PBE, see supporting
information).15 The energy profiles, optimized structures, and transition states obtained are presented in
figure 2 (the results for the Nꢀbenzylpyridineꢀ2ꢀamine 1a system are given in parenthesis). The methyl
substituent in the 3ꢀposition of the pyridine moiety stabilizes rotamer A over rotamer B by 4.4 kcal/mol,
while in the case of parent amine the energies of both rotamers are essentially the same differing merely
by 0.5 kcal/mol. The energy barriers for the interconversion of A to B via a rotation by 180o around the
C–N bond is slightly higher in the case of Nꢀbenzylꢀ3ꢀmethylpyridineꢀ2ꢀamine 4a by 1.6 kcal/mol.
Accordingly, chelate assisted C–H bond activation at the benzylic C–H bonds by transition metals is
facilitated in the case of the Nꢀbenzylꢀ3ꢀmethylpyridineꢀ2ꢀamine 4a and most likely generally by
derivatives with bulky substituents in the 3ꢀposition.
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Figure 2. Energy profile (PBE1PBE) for the interconversion of the stable N-benzyl-3-
methylpyridine-2-amine 4a rotamers A and B via rotation about the C–N bond. The numbers in
parenthesis refer to parent N-benzylpyridine-2-amine 1a. The energy values (in kcal mol-1) are
referred to the more stable rotamer A.
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So far only substrates with a free NH group were tested (with the exception of 11 & 12). Now it was
tried to introduce a second substituent on the amino nitrogen and to see whether such substituents would
be tolerated. Using compound 17 as starting material which carries an Nꢀmethyl group but lacks the
pyridine methyl group gave very low conversion of 8% (Table 4, entry 3). Furthermore, compound 18
led also to a decreased conversion of only 17% (Table 4, entry 4). Other substituents on the amine
nitrogen such as acetyl, pivalyl, or benzoyl (substrates 19-24 in the experimental section) did not give
any conversion no matter whether the methyl group in 3ꢀposition of pyridine was present or not.
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Table 4 The direct arylation of N-substituted benzylic amines.
entry sm
R1
R2
convb
1
2
3
4
H
H
9
1a
4a
17
18
Me
H
H
86
8
Me
Me
Me
17
aReaction conditions: Benzylic amine (0.5
mmol), 6a (0.75 mmol), Ru3(CO)12 (5
mol%) and pinacolone (0.5
mL).
bConversion determined by GC analysis with
respect to benzylic amine.
Further DFT calculations showed that the NꢀMe substitution leads to a decreased energy difference
between rotamer B, which has the preferred conformation for the C–H insertion of the metal, over
rotamer A (Figure 3). As shown in figure 2, rotamer B of Nꢀbenzylꢀ3ꢀmethylpyridineꢀ2ꢀamine 4a is
stabilized by 4.4 kcal/mol over rotamer A. After Nꢀmethylation, rotamer B of NꢀbenzylꢀNꢀ3ꢀ
dimethylpyridinꢀ2ꢀamine 18 shows only 0.2 kcal/mol stability of over A (the stability of rotamer B of
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compound 17 over rotamer A was 0.9 kcal/mol). We hypothesize that this decreased stability causes a
lower energy barrier for the rotation of the benzylic amine around the N–C bond which hinders the
metal to insert into the C–H bond. This calculation explains the lower conversion (17%) of 18 compared
to the unsubstituted compound 4a (86%).
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Figure 3 Energy profile (PBE1PBE) for the interconversion of the stable 17 and 18 rotamers A
and B via rotation around the C–N bond. The energy values (in kcal mol-1) are referred to the
more stable rotamer A.
On cyclic tetrahydroisoquinoline substrates 25 and 26 which have of course a locked conformation in
which the CH2 group has to point towards the pyridine nitrogen, the reaction also worked but with
moderate conversion (Scheme 7). However, this example shows that the 3ꢀmethyl group has only the
function to favor the conformation which can be arylated. Since 27 and 28 are formed in the same yield
essentially, other than steric influences of the 3ꢀmethyl group can be excluded.
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Scheme 7. The direct arylation of N-substituted tetrahydroisoquinoline 25 and 26.
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After having established the substrate scope of the transformation we set out to investigate the
mechanism of this arylation process. For similar reactions, two different mechanisms were proposed by
the groups of Sames8 and Maes.9
So far, all reactions were carried out under an argon atmosphere with pinacolone as solvent (Table 5,
entry 1). Sames argued that the ketone was important to form an intermediate metalꢀalkoxy complex
which can then undergo transmetalation. Maes on the other hand reported that an alcohol as solvent is
important to trap a formed alkylꢀborate species upon concomitant formation of hydrogen. Hence, we
investigated the effect of different solvents and atmospheres to check if one of these two mechanisms is
operable in our case.
The nature of ketone seems to be irrelevant since all investigated ketones gave similar conversions and
yield (Table 5, entries 1ꢀ4). In case of acetone a 1:1 mixture with dioxane had to be used in order to
reach the required temperature. In terms of operational simplicity, we tested whether the reaction could
also be carried out in air, i.e. if the catalyst is stable under air at such elevated temperatures.
Gratifyingly, we found that the conversion remained in a similar range under air and also the yield was
within experimental error (Table 5, entry 5). We also carried out the reaction under an atmosphere of
CO and H2. As expected, CO as strong coordinating ligand led to a decreased catalyst activity (Table 5,
entry 6). The group of Maes suggested that the Ru(II) hydride species obtained after C–H insertion
undergoes transmetalation with the boronic ester directly leading to a pinacolborane species.9 Since this
pinacolborane could poison the catalyst, they suggest trapping it with an alcohol to give a boronate and
H2. Indeed they were able to detect H2 via Raman spectroscopy supporting their mechanistic suggestion.
We hypothesized that an atmosphere of H2 should decrease the conversion and yield if the reaction
proceeds via this mechanism since trapping of the borane species might be hampered. Interestingly, the
reaction worked even better under hydrogen, suggesting that either no hydrogen is produced in the
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current transformation or it has no detrimental influence on the arylation (Table 5, entry 7). Regarding
the solvent, pinacolone can be replaced by 3ꢀethylꢀ3ꢀpentanol, albeit the yield was lower (Table 5, entry
8). Hence, it can be excluded that in case of pinacolone as ketone, a reduction to the corresponding
alcohol is the initial step of the reaction. If that would be the case, the yield using 3ꢀethylꢀ3ꢀpentanol as
solvent should be significantly higher, in the range of the yields obtained using ketones as solvents. The
improved result under H2 atmosphere cannot be explained at this point. It could be possible that under
H2 atmosphere a more reactive catalytic species is formed but evidence for that is lacking.
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We also tested whether pinacolborane (HBpin) indeed hampers the reaction by poisoning the catalyst by
performing the reaction in the presence of 1 equivalent HBpin. Maes speculated that such a
pinacolborane species could poison the catalyst eventually by oxidative addition9 and the reaction
should actually be shut down almost completely when such a great excess of HBpin is present. We
observed that the conversion indeed decreased to 75 % in comparison to the 95 % without the HBpin.
However, even with a large excess of HBpin with respect to the catalyst, the conversion is still high.
This result indicates that HBpin eventually produced in the reaction is not poisoning the catalyst and the
decrease of conversion in the control experiment could be explained by other reasons (e.g. dilution,
change of the internal temperature, etc.).
Table 5. Screening of Conditions.a
entry
atmosphere
solvent
convb
yieldc
1
argon
pinacolone
86
69 (64)f
2
3
4
5
argon
argon
argon
air
acetone/dioxane (1:1)
cyclohexanone
acetophenone
82
83
80
91
62
61
61
pinacolone
73 (61)f
6
7
8
9
CO
pinacolone
65
97
96
99
43
H2
pinacolone
93 (91)f
45
argond
argone
3ꢀethylꢀ3ꢀpentanol
pinacolone
59 (53)f
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a
Reaction conditions: 4a (0.5 mmol), 6a (0.75 mmol), Ru3(CO)12 (5
1
b
2
3
4
5
6
7
8
mol%) and pinacolone (0.5 mL). Conversion based on GC analysis with
c
respect to 4a (dodecane as internal standard). Yield determined by GC
d
analysis with respect to 4a (dodecane as internal standard). The reaction
was performed in a vial with septum and argon balloon. e ꢁW Reaction: 170
9
10
11
f
°C for 2.5 h. Number in parentheses is yield of 5a.
It seems that the mechanism described by the Maes group is either not operable in this case or at least
not the preferred one for this particular transformation. Seemingly, the arylation proceeds rather via the
mechanism suggested by Sames and coworkers in our case.8 Notably, the reaction is also feasible under
microwave irradiation (Table 5, entry 9) which shortens the reaction time significantly (2.5 h instead of
24 h) with only a slight decrease in yield (59% ꢁw vs. 64% conventional heating).
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60
Since an H2 atmosphere was found to improve the yield in our standard reaction we investigated
whether this can be generalized to other boronic esters. As already shown in Table 5, the yield in the
reaction of 4a with boronic ester 6a improved from 64% to 91% under H2 atmosphere (Table 6, entries
1 & 2). Also in the case of 4ꢀmethylphenylboronic ester the yield improved significantly from 62% to
83% (Table 6, entries 3 & 4). However, other boronic esters, such as 4ꢀmethoxy or 4ꢀtrifluoromethyl
substituted once (Table 6, entries 5ꢀ8) performed worse. Due to this discrepancy the reaction under
argon atmosphere is the more reliable choice.
Table 6. Ru(0)-catalyzed arylation of 4a under argon and hydrogen.a
entry
Ar
atmosphere
argon
H2
5
convb
86
yield
64
1
2
3
4
5
6
Ph
5a
5a
5f
5f
5h
5h
Ph
97
91
4ꢀMeꢀPh
4ꢀMeꢀPh
4ꢀOMeꢀPh
4ꢀOMeꢀPh
argon
H2
88
62
98
83
argon
H2
50
39
23
n.i.c
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7
8
4ꢀCF3ꢀPh
4ꢀCF3ꢀPh
argon
H2
61
65
41
35
5k
5k
1
2
3
4
5
6
7
8
a Reaction conditions: 4a (0.5 mmol), 6a (0.75 mmol), Ru3(CO)12 (5 mol%) and
pinacolone (0.5 mL). b Conversion based on GC analysis with respect to 4a
(dodecane as internal standard). cn.i. = not isolated.
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Kinetic isotope effect (KIE) studies were carried out for interꢀ and intramolecular experiments to gain
additional mechanistic insight. The KIE was found to be kH/kD=3.3 for the intermolecular experiment
using starting material 4a and its deuterated counterpart 29. However, this primary isotope effect does
not provide evidence whether or not C–H bond cleavage occurs during the rate determining step of the
reaction.16 Interestingly, the intramolecular KIE using substrate 30 was found to be kH/kD=0.43, which
can be explained by a reversible C–H activation step (also termed inverse equilibrium isotope effect).17
Naturally, the CꢀH bond is preferentially broken over the CꢀD bond. However, the RꢀRuꢀD intermediate
is more stable as compared to the RꢀRuꢀH species. Hence, the reverse reaction for RꢀRuꢀD is slower and
this intermediate can be accumulated (kꢀ1H > kꢀ1D). Obviously the subsequent step in the catalytic cycle
is significantly slower (i.e. rate determining) and due to the much higher concentration of RꢀRuꢀD in the
reaction mixture, this species is converted further more often resulting in the observed inverse
equilibrium isotope effect. These results demonstrate that the C–H activation step is not the rate
determining step otherwise a reversed KIE would not be observed. The energy diagram in Scheme 8
shows qualitatively the energy profile of this reaction until the proposed Ruꢀalkoxy complex (no
detailed DFT calculations were carried out since there is not known enough about the nature of the
intermediate Ruꢀcomplexes).
Scheme 8. Competitive Deuterium-Labeling Experiment.
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Mechanistic Proposal (Scheme 9). In agreement to the work of Kakiuchi, Chatani and Murai7 we
propose the following mechanism: In the first step, the Ru(0) complex is coordinating to the pyridine
nitrogen before CꢀH insertion to 31 takes place. The ketone reacts with this intermediate complex via
hydride transfer and forms a metalꢀalkoxy (Ru–OR) species 33 which facilitates the transmetalation
with Ar–B(OR)2. Therefore, the ketone works as hydrogen and boron scavenger simultaneously. We
could detect the formed alcohol species by GCꢀMS. The reductive elimination delivers finally product 5
and regenerates the catalyst.
Scheme 9. Proposed mechanism.
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Potentially also imine formation from the amine substrate and subsequent sp2 arylation via nucleophilic
attack of the boronic acid ester could be possible. However, we excluded this possibility due to several
reasons. First of all, the reaction also works when the NH is substituted for a CH2 group where imine
formation is not possible. Also when analyzing the reaction mixtures no imine was detected in any case
(GCꢀMS analysis) neither from the substrate nor from the product. This is in contrast to our previously
reported Ru(II) catalyzed arylation protocol12 where we detected the arylated imine in most cases.
Additionally, the reaction also proceeds in H2 atmosphere where imine formation is for sure disfavored.
Also the tetrahydroisoquinoline substrates 25 and 26 give the product. In these cases no imine but only
an iminium cation could be formed. Hence, we excluded the possibility intermediate imine formation
and subsequent arylation.
Very recently, a reductive deprotection protocol for the pyridine directing group was reported.9 In this
example the pyridine ring was first reduced (Pd/C/H2) to the corresponding cyclic imine before it was
cleaved by hydrazine and acetic acid as reported previously.8 Due to the initial reduction step it was
expected that this protocol would not be suitable for our systems since rather “benzylic deprotection”
will occur leading to diphenylmethane as well as 3ꢀmethylpyridineꢀ2ꢀamine. Indeed, the benzylic
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product 5a delivered only diphenylmethane as expected. Therefore, we adopted a strategy recently
reported by Studer and coꢀworkers:18 Initially the amino group of 5a is BOC protected before Nꢀ
methylation of the pyridyl group. A final hydrolysis of the pyridinium salt delivers the Boc protected
diphenylmethanamine in high yield (84 % overall). The Bocꢀprotected compounds can be used in
further reactions or deprotected by well established protocols.19
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Scheme 10 Cleavage of the directing group.
CONCLUSION
In conclusion, benzylic amines were readily arylated with various arenes via cyclometalation with
Ru3(CO)12. 3ꢀSubstituted pyridine emerged to be a useful directing group for this transformation.
Various bulky groups (CH3, CF3, Ph) were applied and usually led to the desired products in good yield.
Only chlorine was inefficient being eventually not bulky enough. The free NH group seems to be crucial
for this reaction but could also be replaced by CH2 without decrease in yield. The reaction seems to be
sensitive towards the electronically and sterically nature of the substituents on the aryl donor and the
benzylic amine. This operationally simple reaction can be performed under air and showed even better
activity under H2 atmosphere in selected examples. Finally, removal of the directing group was
successfully demonstrated. The performed mechanistic investigations support the mechanism proposed
by Kakiuchi et al.7 which is also supported by the group of Sames.8
EXPERIMENTAL SECTION
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General Methods. All reactions were carried out under argon, unless otherwise mentioned. Argon was
purified by passage through Drierite. Unless otherwise noted, chemicals were purchased from
commercial suppliers and used without further purification. Microwave reactions were performed on a
BIOTAGE InitiatorTM sixty microwave unit (max pressure 20 bar, IR temperature sensor). HRꢀMS for
literature unknown compounds were analyzed by LCꢀITꢀTOFꢀMS in only 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. GCꢀMS runs were performed using a standard
capillary column BGB 5 (30m x 0.32 mm ID).
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General procedure I for the preparation of benzylic amines. The 2ꢀChloroꢀ3ꢀsubstituted pyridine (1
equiv), amine (1.2 equiv), K2CO3 (3.5 equiv) Pd(OAc)2 (2 mol%) and BINAP (2 mol%) were placed in
an ovenꢀdried 6 mLꢀvial with septum screw cap and a magnetic stirring bar. The vial was evacuated and
flushed with argon (three times). After adding dry toluene to the reaction mixture, 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. After cooling to r.t., the solid material was removed by filtration and washed with 10 mL of
CH2Cl2. The combined organic layers were evaporated and the resulting crude product was purified by
flash column chromatography (PE:EtOAc = 10:1).
General procedure II for the C–H activation reaction. The pyridine derivative (0.5 mmol, 1 equiv),
arylboronic acid ester (0.75 mmol, 1.5 equiv) and Ru3(CO)12 (0.025 mmol, 5 mol%) were placed in an
ovenꢀdried 6 mLꢀvial with septum screw cap and a magnetic stirring bar. The vial was evacuated and
flushed with argon (three times). After adding 0.5 mL of dry pinacolone to the reaction mixture, the vial
was closed with a fully covered solid teflon lined cap. The reaction vial was then heated in a reaction
block at 140 °C for 24ꢀ36 h. After cooling to r.t., 2 mL of EtOAc and 2 mL of water were added to the
reaction mixture and stirred for 5 min at r.t. The reaction mixture was extracted with EtOAc (three
times). The combined organic layers were dried over Na2SO4, filtrated and concentrated under reduced
pressure. The resulting crude product was purified by flash column chromatography (PE:EtOAc = 49:1)
and dried under high vacuum.
General procedure III for the preparation of tertiary amines. The 2ꢀBromoꢀ3ꢀsubstituted pyridine
(1 equiv), amine (1.4 equiv), NaOtBu (2 equiv), Pd2(dba)2 (2 mol%) and DPPP (1,3ꢀ
Bis(diphenylphosphino)propan, 2 mol%) were placed in an ovenꢀdried 6 mLꢀvial with septum screw cap
and a magnetic stirring bar. The vial was evacuated and flushed with argon (three times). After adding
dry toluene to the reaction mixture, the vial was closed with a fully covered solid Teflon lined cap. The
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reaction vial was then heated in a reaction block at 75 °C for 16 h. After cooling to r.t., the solid
material was removed by filtration and washed with 10mL of CH2Cl2. The combined organic layers
were evaporated and the resulting crude product was purified by flash column chromatography
(PE:EtOAc = 15:1/10:1).
1
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3
4
5
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7
8
9
General procedure IV for the preparation of the amides. A 3M solution of CH3MgCl in THF (1.2
equiv) was added dropwise to a solution of Nꢀbenzylꢀpyridinꢀ2ꢀamine (1 equiv) in dry THF (5 mL) at
r.t., and the mixture was stirred for 10 min at that temperature. The acyl chloride (3 equiv) was
dissolved in 2 mL THF and then added slowly to the solution. The stirring was continued at r.t. for 1 h
(or full conversion, monitored by TLC). Then the reaction was quenched with H2O, and the resulting
solution was extracted with Et2O (3 x 5 mL). The combined organic layers were washed with NaHCO3
(2x), brine (2x), dried over Na2SO4, filtered, and concentrated in vacuo.
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N-Benzyl-3-methylpyridin-2-amine (4a): 2ꢀChloroꢀ3ꢀmethylpyridine (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 2.5 mL of dry toluene. The reaction
was carried out according to the general procedure I. The analytical data are in accordance with the
1
20
literature. Colorless solid (182 mg, 92% yield); mp 48ꢀ49 °C; H NMR (CDCl3, 200 MHz) δ 2.09 (s,
3H), 4.36 (s, 1H), 4.70 (d, J = 5.3 Hz, 2H), 6.57 (dd, J = 7.1, 5.1 Hz, 1H), 7.23ꢀ7.43 (m, 6H), 8.06 (dd, J
13
= 5.0, 1.3 Hz, 1H); C 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.
N-Benzyl-3-chloropyridin-2-amine (4b): 2,3ꢀDichloropyridine (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 2.5 mL of dry toluene. The reaction
was carried out according to the general procedure I. The analytical data are in accordance with the
1
21
literature. Yellow oil (200 mg, 91% yield); H NMR (CDCl3, 200 MHz) δ 4.68 (d, J = 5.6 Hz, 2H),
5.26 (s, 1H), 6.54 (dd, J = 7.6, 4.9 Hz, 1H), 7.23ꢀ7.39 (m, 5H), 7.45 (dd, J = 7.6, 1.6 Hz, 1H) 8.04 (dd, J
= 4.9, 1.6 Hz, 1H); 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.
N-Benzyl-3-(trifluoromethyl)pyridin-2-amine (4c): 2ꢀChloroꢀ3ꢀ(trifluoromethyl)pyridine (182 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 2.5 mL of dry
toluene. The reaction was carried out according to the general procedure I. Colorless oil (238 mg, 95%
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1
yield); H NMR (CDCl3, 200 MHz) δ 4.66 (d, J = 5.3 Hz, 2H), 5.11 (s, 1H), 6.56 (dd, J = 7.5, 5.0 Hz,
1
2
3
13
1H), 7.16ꢀ7.28 (m, 5H), 7.59 (dd, J = 7.6, 0.8 Hz, 1H), 8.20 (d, J = 4.4 Hz, 1H); C NMR (CDCl3, 50
MHz) δ 45.4, 108.7 (q, J = 31.3 Hz), 118.8, 124.6 (q, J = 271.5 Hz) 127.4, 127.6, 128.8, 135.1 (q, J =
4
5
6
7
5.1 Hz), 139.2, 151.9, 154.4. HRMS calculated for C13H11F3N2
253.0955.
+
: [M+H]
+
253.0947, found [M+H]
+
8
9
N-Benzyl-3-phenylpyridin-2-amine (4d): NꢀBenzylꢀ3ꢀchloropyridinꢀ2ꢀamine 4c 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 2ꢀdicyclohexylꢀphosphinoꢀ2',4',6'ꢀ
triisopropylbiphenyl DCPTPB (10 mg, 0.02 mmol, 2 mol%) in 2.5 mL of dry toluene. The reaction was
10
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45
46
47
48
49
50
51
52
53
54
55
56
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58
59
60
1
carried out according to the general procedure I. Colorless solid (255 mg, 98% yield); mp 58ꢀ60 °C; H
NMR (CDCl3, 200 MHz) δ 4.64 (d, J = 5.6 Hz, 2H), 4.88 (s, 1H), 6.66 (dd, J = 7.2, 5.1 Hz, 1H), 7.18ꢀ
7.42 (m, 11H), 8.14 (dd, J = 4.9, 1.5 Hz, 1H); 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, 140.0, 147.2, 155.5. HRMS calculated for C18H16N2
+
:
[M+H] 261.1386, found [M+H] 261.1390.
+
+
N-(4-Isopropoxybenzyl)-3-methylpyridin-2-amine (4e): 2ꢀChloroꢀ3ꢀmethylpyridine (128 mg, 1
mmol, 1 equiv), (4ꢀisopropoxyphenyl)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 2.5 mL of dry toluene. The reaction was carried out according to the general procedure I. Colorless
1
oil (185 mg, 72% yield); H NMR (CDCl3, 200 MHz) δ 1.33 (d, J = 6.0 Hz, 6H), 2.06 (s, 3H), 4.27 (s,
1H), 4.51 (sep, J = 6.0 Hz, 1H), 4.59 (d, J = 5.2 Hz, 2H), 6.54 (dd, J = 7.1, 5.1 Hz, 1H), 6.86 (d, J = 8.6
13
Hz, 2H), 7.20ꢀ7.32 (m, 3H), 8.05 (dd, J = 5.1, 1.3 Hz, 1H).; C 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. HRMS calculated for
C16H20N2O
+
: [M+H]
+
257.1648, found [M+H] 257.1642.
+
N-(4-Methoxybenzyl)-3-methylpyridin-2-amine (4f): 2ꢀChloroꢀ3ꢀmethylpyridine (128 mg, 1 mmol, 1
equiv), 4ꢀmethoxybenzylamine (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 2.5 mL of dry
toluene. The reaction was carried out according to the general procedure I. Yellow oil (183 mg, 80%
1
yield); H NMR (CDCl3, 200 MHz) δ 2.07 (s, 3H), 3.80 (s, 3H), 4.30 (s, 1H), 4.61 (d, J = 5.2 Hz, 2H),
6.55 (dd, J = 7.1, 5.1 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 7.21ꢀ7.34 (m, 3H), 8.06 (dd, J = 4.9, 1.0 Hz,
13
1H); C 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. HRMS calculated for C14H16N2O
+: [M+H]
+
229.1335, found [M+H] 229.1338.
+
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3-Methyl-N-(4-methylbenzyl)pyridin-2-amine (4g): 2ꢀChloroꢀ3ꢀmethylpyridine (128 mg, 1 mmol, 1
equiv), 4ꢀmethylbenzylamine (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 2.5 mL of dry
toluene. The reaction was carried out according to the general procedure I. Colorless solid (188 mg,
88% yield); mp 46ꢀ47 °C; 1H NMR (CDCl3, 200 MHz) δ 2.01 (s, 3H), 2.30 (s, 3H), 4.26 (s, 1H), 4.59 (d,
1
2
3
4
5
6
7
8
13
9
J = 5.2 Hz, 2H), 6.50 (dd, J = 7.1, 5.1 Hz, 1H), 7.08ꢀ7.26 (m, 5H), 8.00 (dd, J = 5.0, 1.3 Hz, 1H); C
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48
49
50
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59
60
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.
HRMS calculated for C14H16N2
+
: [M+H]
+
213.1386, found [M+H] 213.1380.
+
N-(4-Fluorobenzyl)-3-methylpyridin-2-amine (4h): 2ꢀChloroꢀ3ꢀmethylpyridine (128 mg, 1 mmol, 1
equiv), (4ꢀfluorophenyl)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 2.5 mL of
dry toluene. The reaction was carried out according to the general procedure I. Colorless oil (158 mg,
73% yield); 1H NMR (CDCl3, 200 MHz) δ 2.08 (s, 3H), 4.36 (s, 1H), 4.65 (d, J = 5.4 Hz, 2H), 6.56 (dd,
13
J = 7.1, 5.1 Hz, 1H), 6.96ꢀ7.05 (m, 2H), 7.21ꢀ7.37 (m, 3H), 8.03 (dd, J = 5.0, 1.2 Hz, 1H); C NMR
(CDCl3, 50 MHz) δ 17.1, 45.1, 113.2, 115.5 (d, JCF = 21.3 Hz), 116.6, 129.5 (d, JCF = 8.0 Hz), 135.9 (d,
JCF = 3.1 Hz), 137.1, 145.6, 156.6, 162.2 (d, JCF = 244.9 Hz). HRMS calculated for C13H13FN2
[M+H] 217.1136, found [M+H] 217.1128.
+:
+
+
3-Methyl-N-(4-(trifluoromethyl)benzyl)pyridin-2-amine (4i): 2ꢀChloroꢀ3ꢀmethylpyridine (128 mg, 1
mmol, 1 equiv), (4ꢀ(trifluoromethyl)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 2.5 mL of dry toluene. The reaction was carried out according to the general procedure I.
1
Colorless solid (195 mg, 73% yield); mp 54ꢀ55 °C; H NMR (CDCl3, 200 MHz) δ 2.14 (s, 3H), 4.50 (s,
1H), 4.78 (d, J = 5.7 Hz, 2H), 6.58 (dd, J = 7.1, 5.1 Hz, 1H), 7.25ꢀ7.29 (m, 1H), 7.53 (d, J = 9.7 Hz,
13
4H), 8.03 (dd, J = 5.0, 1.2 Hz, 1H).; C NMR (CDCl3, 50 MHz) δ 17.1, 45.2, 113.5, 116.7, 124.4 (q,
JCF = 271.9 Hz), 125.6 (q, JCF = 3.9 Hz), 127.9, 129.4 (q, JCF = 32.3 Hz), 137.2, 144.6, 145.6, 156.4.
HRMS calculated for C14H13F3N2
+
: [M+H]
+
267.1104, found [M+H] 267.1099.
+
Methyl 4-(((3-methylpyridin-2-yl)amino)methyl)benzoate (4j): 2ꢀChloroꢀ3ꢀmethylpyridine (128 mg,
1 mmol, 1 equiv), methyl 4ꢀ(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 2.5
mL of dry toluene. The reaction was carried out according to the general procedure I. Colorless solid
1
(223 mg, 87% yield); mp 122ꢀ123 °C; H NMR (CDCl3, 200 MHz) δ 2.12 (s, 3H), 3.90 (s, 3H), 4.48 (s,
1H), 4.77 (d, J = 5.7 Hz, 2H), 6.56 (dd, J = 7.1, 5.1 Hz, 1H), 7.23ꢀ7.27 (m, 1H), 7.43 (d, J = 8.2 Hz,
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2H), 7.97ꢀ8.02 (m, 3H); 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. HRMS calculated for C15H16N2O2 : [M+H] 257.1285, found
[M+H] 257.1296.
1
2
3
4
+
+
+
5
N-(4-Methylbenzyl)-3-(trifluoromethyl)pyridin-2-amine (4k): 2ꢀChloroꢀ3ꢀ(trifluoromethyl)pyridine
(182 mg, 1 mmol, 1 equiv), methylbenzylamine (145 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
2.5 mL of dry toluene. The reaction was carried out according to the general procedure I. Colorless oil
(260 mg, 98% yield); 1H NMR (CDCl3, 200 MHz) δ 2.33 (s, 3H), 4.67 (d, J = 5.2 Hz, 2H), 5.13 (s, 1H),
6.62 (dd, J = 7.5, 5.0 Hz, 1H), 7.12ꢀ7.26 (m, 4H), 7.65 (dd, J = 7.6, 0.8 Hz, 1H), 8.27 (d, J = 4.4 Hz,
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1H); C NMR (CDCl3, 50 MHz) δ 21.2, 45.2, 108.6 (q, J = 31.3 Hz), 111.6, 124.6 (q, J = 271.5 Hz)
127.6, 129.4, 135.1 (q, J = 5.1 Hz), 136.1, 137.0, 151.8, 154.5. HRMS calculated for C14H13F3N2
[M+H] 267.1104, found [M+H] 267.1093.
+:
+
+
3-Chloro-N-(4-methylbenzyl)pyridin-2-amine (4l): 2,3ꢀDichloropyridine (148 mg, 1 mmol, 1 equiv),
4ꢀmethylbenzylamine (145 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 2.5 mL of dry toluene. The
1
reaction was carried out according to the general procedure I. Colorless oil (201 mg, 86% yield); H
NMR (CDCl3, 200 MHz) δ 2.35 (s, 3H), 4.65 (d, J = 5.4 Hz, 2H), 5.23 (s, 1H), 6.54 (dd, J = 7.6, 4.9 Hz,
1H), 7.14ꢀ.30 (m, 4H), 7.45 (dd, J = 7.6, 1.6 Hz, 1H) 8.04 (dd, J = 4.9, 1.6 Hz, 1H); 13C NMR (CDCl3,
50 MHz) δ 21.2, 45.4, 113.1, 115.4, 127.8, 129.4, 136.1, 136.3, 137.0, 146.2, 154.0. HRMS calculated
for C13H13ClN2
+
: [M+H]
+
233.0840, found [M+H] 233.0849.
+
N-(4-Methylbenzyl)-3-phenylpyridin-2-amine (4m): 3ꢀChloroꢀNꢀ(4ꢀmethylbenzyl)pyridinꢀ2ꢀamine 4l
from the above protocol (233 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 2ꢀdicyclohexylꢀ
phosphinoꢀ2',4',6'ꢀtriisopropylbiphenyl DCPTPB (10 mg, 0.02 mmol, 2 mol%) in 2.5 mL of dry toluene.
The reaction was carried out according to the general procedure I. Colorless solid (230 mg, 84% yield);
1
mp 68ꢀ69 °C; H NMR (CDCl3, 200 MHz) δ 2.33 (s, 3H), 4.62 (d, J = 5.4 Hz, 2H), 4.87 (s, 1H), 6.69
(dd, J = 7.2, 5.1 Hz, 1H), 7.10ꢀ7.45 (m, 10H), 8.18 (dd, J = 5.0, 1.8 Hz, 1H); 13C NMR (CDCl3, 50
MHz) δ 21.2, 45.5, 113.0, 122.4, 127.6, 127.9, 129.0, 129.3, 136.7, 136.9, 137.2, 138.1, 147.2, 155.5
(one phenylꢀcarbon is overlapping). HRMS calculated for C19H18N2
275.1556.
+: [M+H]
+
275.1543, found [M+H]
+
N-Benzhydryl-3-methylpyridin-2-amine (5a): NꢀBenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine 4a (99 mg, 0.5
mmol, 1 equiv), 2ꢀphenylꢀ1,3,2ꢀdioxaborinane (122 mg, 0.75 mmol, 1.5 equiv), and Ru3(CO)12 (16 mg,
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0.025 mmol, 5 mol%) in 0.5 mL of dry pinacolone. The reaction was carried out according to the
general procedure II. The analytical data are in accordance with the literature.4b Colorless solid (88 mg,
1
2
3
4
5
6
1
64% yield); mp 91ꢀ93 °C; H NMR (CDCl3, 200 MHz) δ 2.07 (s, 3H), 4.60 (d, J = 6.8 Hz, 1H), 6.42ꢀ
13
6.48 (m, 2H), 7.12ꢀ7.29 (m, 11H), 7.89 (dd, J = 5.0, 1.3 Hz, 1H); C NMR (CDCl3, 50 MHz) δ 17.2,
7
8
58.6, 113.2, 116.4, 127.1, 127.7, 128.6, 137.0, 143.6, 145.7, 155.8.
9
N-Benzhydryl-3-(trifluoromethyl)pyridin-2-amine (5c): NꢀBenzylꢀ3ꢀ(trifluoromethyl)pyridinꢀ2ꢀ
amine 4c (126 mg, 0.5 mmol, 1 equiv), 2ꢀphenylꢀ1,3,2ꢀdioxaborinane (122 mg, 0.75 mmol, 1.5 equiv),
and Ru3(CO)12 (16 mg, 0.025 mmol, 5 mol%) in 0.5 mL of dry pinacolone. The reaction was carried out
according to the general procedure II. Colorless oil (128 mg, 78% yield); 1H NMR (CDCl3, 200 MHz) δ
5.45 (d, J = 6.7 Hz, 1H), 6.54ꢀ6.63 (m, 2H), 7.19ꢀ7.32 (m, 10H), 7.66 (d, J = 7.3 Hz, 1H), 8.19 (d, J =
10
11
12
13
14
15
16
17
18
19
20
21
22
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41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
4.6, 1H); C NMR (CDCl3, 50 MHz) δ 58.5, 108.8 (q, J = 31.2 Hz), 112.1, 124.6 (q, J = 271.3 Hz)
127.4, 127.6, 128.8, 135.1 (q, J = 5.1 Hz), 142.7, 151.9, 153.6. HRMS calculated for C19H15F3N2
[M+H] 329.1260, found [M+H] 329.1271.
+
:
+
+
N-Benzhydryl-3-phenylpyridin-2-amine (5d): NꢀBenzylꢀ3ꢀphenylpyridinꢀ2ꢀamine 4d (130 mg, 0.5
mmol, 1 equiv), 2ꢀphenylꢀ1,3,2ꢀdioxaborinane (122 mg, 0.75 mmol, 1.5 equiv), and Ru3(CO)12 (16 mg,
0.025 mmol, 5 mol%) in 0.5 mL of dry pinacolone. The reaction was carried out according to the
general procedure II for 36 h. Colorless solid (151 mg, 90% yield); mp 90ꢀ92 °C; 1H NMR (CDCl3, 200
MHz) δ 5.18 (d, J = 7.4 Hz, 1H), 6.51 (d, J = 7.5 Hz, 1H), 6.64 (dd, J = 7.2, 5.0 Hz, 1H), 7.14ꢀ7.44 (m,
13
16H), 8.08 (dd, J = 5.0, 1.8 Hz, 1H); C 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. HRMS calculated for C24H20N2
337.1699, found [M+H] 337.1713.
+
: [M+H]
+
+
3-Methyl-N-(phenyl(m-tolyl)methyl)pyridin-2-amine (5g): NꢀBenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine 4a
(99 mg, 0.5 mmol, 1 equiv), 2ꢀ(mꢀTolyl)ꢀ1,3,2ꢀdioxaborinane (132 mg, 0.75 mmol, 1.5 equiv), and
Ru3(CO)12 (16 mg, 0.025 mmol, 5 mol%) in 0.5 mL of dry pinacolone. The reaction was carried out
1
according to the general procedure II. Colorless oil (88 mg, 61% yield); H NMR (CDCl3, 200 MHz) δ
2.11 (s, 3H), 2.29 (s, 3H), 4.63 (d, J = 7.2 Hz, 1H), 6.46ꢀ6.52 (m, 2H), 7.01ꢀ7.34 (m, 10H), 7.95 (dd, J =
5.0, 1.2 Hz, 1H); 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. HRMS calculated for C20H20N2
+
:
[M+H] 289.1699, found [M+H] 289.1679.
+
+
N-((3-chlorophenyl)(phenyl)methyl)-3-methylpyridin-2-amine (5h): NꢀBenzylꢀ3ꢀmethylpyridinꢀ2ꢀ
amine 4a (99 mg, 0.5 mmol, 1 equiv), 2ꢀ(2ꢀchlorophenyl)ꢀ1,3,2ꢀdioxaborinane (147 mg, 0.75 mmol, 1.5
equiv), and Ru3(CO)12 (16 mg, 0.025 mmol, 5 mol%) in 0.5 mL of dry pinacolone. The reaction was
29
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