N-heterocyclic carbene based ruthenium complexes for selective β-C(sp3)-H functionalization of N-fused saturated cyclic amines

Article abstract of DOI:10.1016/j.tet.2018.12.049

Herein, a series of new ruthenium(II) complexes with the general molecular formula [RuCl₂(arene)(NHC)], (arene = η⁶-p-cymene, NHC = N-heterocyclic carbene) were synthesized from in situ prepared silver(I)-NHCs by the transmetallation method. These complexes were fully characterized by analytical and spectral methods. Ruthenium(II) complexes were tested as promising catalyst for selective β-C(sp³)-H functionalization of N-methylpiperidine with various aldehydes through hydrogen transfers in presence of external acidic additive. These eco-friendly cross-dehydrogenative couplings enable the production of C(3)-alkylated N-methylpiperidine derivatives without enamines with only carbon dioxide and water as benign by-product.

Full text of DOI:10.1016/j.tet.2018.12.049

Accepted Manuscript
3
N-heterocyclic carbene based ruthenium complexes for selective β-C(sp )-H
functionalization of N-fused saturated cyclic amines
Nazan Kaloğlu
PII:
S0040-4020(18)31539-4
https://doi.org/10.1016/j.tet.2018.12.049
TET 30035
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 September 2018
Revised Date: 20 December 2018
Accepted Date: 21 December 2018
Please cite this article as: Kaloğlu N, N-heterocyclic carbene based ruthenium complexes for selective
3
β-C(sp )-H functionalization of N-fused saturated cyclic amines, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2018.12.049.
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ACCEPTED MANUSCRIPT
Graphical Abstract
N-Heterocyclic carbene based ruthenium
complexes for selective β-C(sp3)-H
functionalization of N-fused saturated cyclic
amines
Nazan Kaloğlua
aİnönü University, Faculty of Science and Arts, Department of Chemistry, 44280 Malatya, Turkey

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
N-Heterocyclic carbene based ruthenium complexes for selective β-C(sp3)-H
functionalization of N-fused saturated cyclic amines
Nazan Kaloğlua,
aİnönü University, Faculty of Science and Arts, Department of Chemistry, 44280 Malatya, Turkey
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein, a series of new ruthenium(II) complexes with the general molecular formula
[RuCl2(arene)(NHC)], (arene = η6-p-cymene, NHC = N-heterocyclic carbene) were synthesized
from in situ prepared silver(I)-NHCs by the transmetallation method. These complexes were
fully characterized by analytical and spectral methods. Ruthenium(II) complexes were tested as
promising catalyst for selective β-C(sp3)-H functionalization of N-methylpiperidine with various
aldehydes through hydrogen transfers in presence of external acidic additive. These eco-friendly
cross-dehydrogenative couplings enable the production of C(3)-alkylated N-methylpiperidine
derivatives without enamines with only carbon dioxide and water as benign by-product.
Available online
Keywords:
N-Heterocyclic carbene
Ruthenium
Cyclic amine
Catalysis
2009 Elsevier Ltd. All rights reserved
.
β-alkylation
———
Corresponding author. Tel.: +90-422-377-3871; e-mail: nzntemelli@hotmail.com

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
by β-C(sp3)–H functionalization of saturated cyclic amines with
aldehydes catalyzed by (arene)ruthenium(II) complexes
containing phosphino sulfonate as chelating ligands.24 Then,
Gaunt and co-workers have reported the transformation of
aliphatic amines to β-lactams enabled by palladium catalyzed β-
C–H carbonylation,25 and followed by Yu and co-workers have
described a directing group-assisted palladium catalyzed β-
C(sp3)–H arylation of saturated cyclic amines.26
Cyclic amines are ubiquitous scaffolds in many natural
products, biologically active compounds, and functional
materials.1-3 Considering the importance of these compounds,
eco-friendly preparation of them still represents a challenging
task for chemists.4-6 In particular, various pharmaceutically
relevant natural and synthetic molecules are functionalized cyclic
amines with varied ring sizes. Selected examples of the bioactive
cyclic amine derivatives are presented in Fig. 1.7-9
Over the two past decades, N-heterocyclic carbenes (NHCs)
have become ubiquitous ligands for homogeneous catalysis,27 and
transiton-metal complexes containing NHC ligands have been
widely used in organometallic chemistry as an alternative to well
known phosphine ligands for the synthesis of homogeneous
catalysts.28 Up to now, many examples of ruthenium-catalyzed β-
C(sp3)-H functionalization of saturated cyclic amines involving
hydrogen transfers have been reported.29,30 But, very few
examples of the about the use of NHC ligands in related
transformations are known.31 In this connection, we have
reported first example of ruthenium-NHC catalyzed β-C(sp3)-H
functionalization of N-fused saturated cyclic amines with
aldehydes through hydrogen transfers in presence of external
acidic additive in 2015.32
Fig. 1. Selected examples of biologically active cyclic amines.
In the present article, we now described the synthesis and
characterization of new benzimidazolium halides as NHC ligands
(1a f) and their corresponding new ruthenium complexes 2a-f.
These complexes were tested as promising catalyst for selective
β-C(sp3)-H functionalization of N-methylpiperidine with various
aldehydes as electrophile in the presence of external acidic
additive based on hydrogen transfers (Fig. 2). All ruthenium
complexes were showed regioselective alkylation at the C(3)
position of N-methylpiperidine via sequential dehydrogenation
under non-oxidative conditions, C-C bond formation, and final
transfer hydrogenation to produce C(3)-alkylated N-
methylpiperidine.
Traditional methods to preparation of cyclic amines involve
substitution reactions employing environmentally harmful alkyl
halides10-13 or reductive aminations using stoichiometric reducing
agents.14,15 These processes are wasteful and not atom
economical. In the past decades, C-H bond functionalization
involving activation of inert C-H bonds to allow direct C-C
coupling has attracted considerable attention for the sythesis of
amines.16 This process minimizes the reaction steps and therefore
the number of purification processes and the production of
wastes and full fills the criteria of sustainability and green
chemistry. Although C(sp3)-H functionalization of saturated
cyclic amines provides an important tool for the synthesis of
various nitrogen containing derivatives including N-heterocycles,
there are still many challenge for the C(sp3)-H functionalization
of them.17
cat. (
)
[Ru]
2aꢀf
R
RCHO
N
N
Selective ꢀalkylation
Me
Me
OMe
MeO
Several functionalization at the α-position of saturated cyclic
amines have been reported involving either activation of the α-
C(sp3)-H bond via formal oxidative addition to a transition
metal18 or oxidation by various types of oxidant into iminium
intermediates followed by reaction with a nucleophile.19 But as
the β-C(sp3)-H bond of unfunctionalized saturated cyclic amines
is inert, their preparation requires multi step synthesis.20 The first
example of β-C(sp3)-H functionalization of cyclic amine was
performed upon oxidation in the presence of oxygen and
platinum catalyst, followed by Michael addition leading to C(3)-
substituted enamines, but with no additional hydrogenation.21
One approach to perform C(sp3)-H functionalization involves as
the first step the in situ generation of reactive enamines via
C(sp3)-H activation and dehydrogenation as already shown in the
presence of iridium22 and cobalt catalysts.23 Recently, the group
of Bruneau has reported an extremely interesting and amazingly
efficient reaction that allows for the formation of a new C-C bond
Cl
Cl
N
Cl
N
N
N
N
Ru
Ru
Cl
Ru
N
Cl
Cl
MeO
MeO
OMe
OMe
2c
2a
2b
MeO
Cl
N
Cl
Cl
N
N
N
N
Ru
Ru
Ru
N
Cl
Cl
Cl
MeO
2d
2f
2e
Fig. 2. Ruthenium catalyzed selective β-alkylation of N-
methylpiperidine with aldehydes.

3
2. Results and discussion
also evidenced by their IR spectra, which showed CN bond
ACCEPTED MANUSCRIPT
absorption at 1559, 1557, 1555 and 1563 cm-1 for the respective
2.1. Preparation of Benzimidazolium Halides
CN bond vibrations of 1b, 1c, 1e and 1f.
The benzimidazolium chlorides 1a33 and 1d34 were
obtained as previously described in the literature. The
benzimidazolium halides 1b, 1c, 1e and 1f were prepared by
reacting N-(alkyl)-benzimidazole with various alkyl halides in
DMF at 80 °C for 36 h. Benzimidazolium halides 1b, 1c, 1e and
1f are air and moisture stable both in the solid state and in
solution. The structures of the these compounds were determined
by their characteristic spectroscopic data and elemental analyses.
In the 13C NMR spectra of 1b, 1c, 1e and 1f compounds, the
characteristic signals of the C(2) carbon (NCHN) were detected
as typical singlets at 143.7, 143.7, 143.4 and 143.3 ppm,
2.2. Preparation of Ruthenium Complexes
The ruthenium(II) complexes 2a–f were obtained in 41–86 %
yields by transmetalation of the corresponding silver(I)-NHC
adducts and [RuCl2(p-cymene)]2. The air and moisture-stable
ruthenium complexes are brown in colour and soluble in
common chlorinated organic solvents. They are found to be
diamagnetic and they were fully characterised by elemental
1
analysis, H and 13C NMR, and IR spectroscopy. Their IR data
each show a band at 1403, 1407, 1415, 1401, 1413 and 1410 cm–1
(v(NCN)) and their 13C NMR spectra each display a singlets at
189.8, 191.5, 190.6, 191.9, 191.3 and 189.9 ppm (NCHN), two
evidences of the formationof a Ru–carbene bond.36 The new
compounds were prepared according to general reaction pathway
depicted in Scheme 1. The analytical data are in good agreement
with the compositions proposed for all the novel compounds we
prepared, and are summarized in the Table 1.
1
respectively. The H NMR signals of the C(2)-H protons were
observed as sharp singlets at chemical shifts of 12.12, 11.88,
11.72 and 10.53 ppm, respectively, for 1b, 1c, 1e and 1f further
supporting the assigned structures. These NMR values are in line
with those found for other benzimidazolium halides of the
literature.35 The formation of the benzimidazolium halides was
Scheme 1. Synthesis of benzimidazolium halides (1a-f) and ruthenium(II) complexes (2a-f).
Table 1
Physical and spectroscopic properties of new compounds.
Compound
Molecular Formula
Isolated yield
(%)
M.p.
(oC)
v(CN)
H(2) 1H NMR
(ppm)
C(2) 13C NMR
(ppm)
(cm-1)
1a
1c
1e
1f
C22H21N2OCl
78
87
91
90
73
86
75
67
41
74
201-203
144-145
129-130
232-233
262-263
186-187
193-194
>350
1559
1557
1555
1563
1403
1407
1415
1401
1413
1410
12.12
143.7
143.7
143.4
143.3
189.8
191.5
190.6
191.9
191.3
189.9
C23H23N2OCl
11.88
C26H29BrN2O
11.72
C34H45BrN2
10.53
2a
2b
2c
2d
2e
2f
C31H40Cl2N2O3Ru
C32H34Cl2N2ORu
C33H36Cl2N2ORu
C33H36Cl2N2O2Ru
C36H42Cl2N2ORu
C44H58Cl2N2Ru
-
-
-
-
-
-
229-230
294-295
and selective functionalization keeping intact the methyl group is
attractive. However, during β-alkylation, the competitive
formation of exo and endo-cyclic iminium would result in
undesired demethylation reaction through the attack of
nucleophile on the resulting exo-cyclic iminium.32 A plausible
mechanism is depicted for give point to the role of camphor
sulfonic acid (CSA) in Scheme 2.
2.3. Optimization of the Reaction Conditions for β-Alkylation
With these well-defined complexes in hand, we next
undertook their preliminary evaluation in oxidant free C(sp3)-H
bond functionalization of saturated cyclic amines in the presence
of electrophile. On the other hand, N-methylated amines
represent an interesting class of biologically active compounds

4
Tetrahedron
For this purpose we decided to evaluate the challenging N-
ACCEPTED MANUSCRIPT
methylpiperidine material which can easily undergo hydrolysis of
the methyl group under hydrogen transfer conditions. The
screening of our new ruthenium complexes 2a, 2b and 2f was
performed in toluene with benzaldehyde, in the presence of 2.5
mol% ruthenium complex at 150 ◦C for 16 h (Table 2, Eq. 1). The
addition of formic acid at the end of the reaction ensure complete
conversion of the (C3)-alkylated enamine to the corresponding
amines (Table 2, entries 1-5).
Scheme 2. Proposed general pathway for the ruthenium catalyzed
hydrogen transfer processes for the C(3)-alkylation of N-
methylpiperidine.
Table 2
Influence of the reaction conditions for ruthenium(II) catalyzed alkylation of N-methylpiperidine.a
1)
cat. (2.5 mol%)
[Ru]
CSA (5ꢀ10 mol%)
CHO
2) HCO2H (1ꢀ2 equiv.)
Toluene, 150 oC, 16 h
(Eq. 1)
N
N
N
Me
Me
Me
3a
4
Entry
[Ru]
2f
CSA (mol%)
5 mol%
HCO2H (equiv.)
Ratio (3a/4)
65/35
Yieldb (%)
1
2
3
4
5
1.5
1.5
2.0
2.0
2.0
85
2f
10 mol%
10 mol%
10 mol%
10 mol%
75/25
80
92 (85)c
2f
100/0
2a
100/0
88
2b
100/0
85
a Reactions conditions: [Ru] cat. (2.5 mol%), N-methylpiperidine (1.5 mmol), benzaldehyde (1.0 mmol), toluene (1 mL), 150 °C, 16 h.
b GC yields were calculated with respect to aldehyde from the results of GC spectrometry.
c Isolated yields were shown in parentheses.
Firstly, we examined the reactivity of precatalyst 2f in the
presence of 5 mol% CSA along with of formic acid (1.5 eq.)
(HCO2H). In this case, formation of the expected β-alkylated
product 3a occured but side formation of the disusbstituted β-
alkylated product reached a 65:35 ratio of 3a:4 (Table 2, entry 1).
To overcome the undesired formation of the dialkylated product
4 we next examined the influence of the CSA amount. Thus,
higher the catalytic loading of CSA to 10 mol% diminished side
dialkylation reaching complete conversion and 75:25 ratio of
3a:4 (Table 2, entry 2). Comparing entries 1 and 2, the positive
effect of CSA as additive was confirmed. Another strategy to
reduce side dialkylation involved the use of a large excess of
HCO2H (2.0 eq.) to give a ratio up to 100:0 (Table 2, entry 3).
The influence of the ruthenium complex was next investigated.
Notably, complete conversions were obtained in the presence of
catalytic amount of complex 2a and 2b and the best ratio was
observed in the presence of complex 2a bearing two sterically
hindered benzylic side arms (Table 2, entries 4 compared to 5).
The chemical characterizations of the products were made by
NMR spectroscopy. The conversions were based on the N-
methylpiperidine by GC. We our best reaction conditions in
hands, we next evaluated the scope of the transformation with
various aldehydes.
2.4. β-Alkylation of N-Methylpiperidine with Various Aldehydes
The scope of the selective C(3) alkylation reaction,
starting from various aldehydes and N-methylpiperidine has been
examined (Table 3, Eq. 2). N-Methylpiperidine was smoothly
converted to the desired products with various aliphatic and
aromatic aldehydes between 59-85% isolated yield (Table 3,
entries 1-36). Indifferently aldehydes bearing electron-
withdrawing such as chloro group or electron-releasing such as
methyl group were successfully engaged in this reaction. The
reaction appeared to be quite general and good results were
obtained from the reaction of N-methylpiperidine with p-
methylbenzaldehyde yielding up to 87% of product 3b. The
coupling of N-methylpiperidine with an electron-poor aromatic
aldehydes such as 4-chlorobenzaldehyde and α-naphthaldehyde
also nicely, yields at between 65–78% and 55-75% (Table 3,
entries 13–18 and 19-24). More importantly, the reaction was not
limited to aromatic aldehydes, and aliphatic aldehydes such as
octanal and cyclohekzanal provided good yields (Table 3, entries
25-36). When the reaction of N-methylpiperidine with an
electron-rich aliphatic aldehydes such as octanal and cyclohexyl
aldehyde was investigated, yields at between 80–95% and 90-
100% (Table 3, entries 25–30 and 31-36).

5
In conclusion, selective C(3) alkylation of N-
methylpiperidine involving activation of C(sp3)-H bond via
hydrogen transfer was efficiently catalyzed by ruthenium
complex 2f. We attributed these performance differences to well-
accordance electronic and steric properties of the NHC ligands.
We believe that in the presence of electron-donor and sterically
ACCEPTED MANUSCRIPT
hindered NHC ligands bearing 3,5-di-tert-butylbenzyl
substituent, hydrogen transfer step more readily takes place and
this is might be a key step.
Table 3
Ruthenium(II) catalyzed β-alkylation of N-methylpiperidine by using various aldehydes.a
Entry
1
RCHO
[Ru]
2a
2b
2c
2d
2e
2f
Product
Yieldb (%)
88
2
85
3
80
4
76
5
90
6
92 (85)c
87 (76)c
80
7
2a
2b
2c
2d
2e
2f
8
9
75
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
70
82
84
2a
2b
2c
2d
2e
2f
76
75
68
65
70
78 (69)c
2a
2b
2c
2d
2e
2f
70
65
62
55
69
75 (59)c
2a
2b
2c
2d
2e
2f
89
86
80
82
90
95 (75)c
2a
2b
2c
2d
2e
2f
99
95
90
91
95
100 (85)c
a Reaction conditions: [Ru] cat. (2a-f) (2.5 mol%), N-methylpiperidine (1.5 mmol), aldehyde (1.0 mmol), toluene (1 mL), 150 °C, 16 h.
b GC yields were calculated with respect to aldehyde from the results of GC spectrometry.
c Isolated yields were shown in parentheses.

6
Tetrahedron
3. Conclusion
4.2. General Procedure for the Preparation of Benzimidazolium
ACCEPTED MANUSCRIPT
Halides (1a-f)
In summary, we have prepared
a
series of new
A
dimethylformamide (5 mL) solution of N-(alkyl)-
benzimidazolium halides and their corresponding new
ruthenium(II) complexes. All new compounds were characterized
using different spectroscopic and analytical techniques.
Ruthenium complexes were tested as promising catalyst for
selective β-C(sp3)-H functionalization of N-methylpiperidine
with various aldehydes as electrophile in the presence of external
acidic additive based on hydrogen transfers. The catalytic
systems generated from ruthenium complexes were very efficient
at 2.5 mol% catalyst loading for selective β-C(sp3)-H
functionalization of N-methylpiperidine with various aldehydes.
The ruthenium complexes were all found to be suitable catalysts
for this study. This catalytic reaction makes possible the selective
introduction of a variety of substituents arising from aldehydes at
the C(3) position. Further studies to extend this methodology and
effort to establish the detailed mechanism are in progress.
benzimidazole (5.0 mmol) and alkyl halide (5.0 mmol) was
stirred at 80 °C for 24 h. After completion of the reaction, the
solvent was removed by vacuum and Et2O (15 mL) was added to
obtain a white crystalline solid, which was filtered off. The solid
was washed with Et2O (3×10 mL) and dried under vacuum. The
crude product was recrystallized from EtOH/Et2O mixture (1:2,
v/v) and dried under vacuum.
4.2.1.
chloride (1a)
1-(n-Butyl)-3-(3,4,5-trimethoxybenzyl)benzimidazolium
This benzimidazolium chloride was synthesized according to
published procedure.33
4.2.2. 1-(4-Methoxybenzyl)-3-(benzyl)benzimidazolium chloride
(1b)
4. Experimental
(1.42 g, yield 78%); 1H NMR (300 MHz, CDCl3, 25 oC, TMS): δ
(ppm) = 3.68 (s, 3H, CH2C6H4(OCH3)-4); 5.74 (s, 2H, CH2C6H5);
5.80 (s, 2H, CH2C6H4(OCH3)-4); 6.79 and 7.27 (d, J = 7.3 Hz,
4H, arom. CH, CH2C6H4(OCH3)-4); 7.40-7.56 (m, 9H, arom. CH,
NC6H4N and CH2C6H5); 12.12 (s, 1H, NCHN). 13C NMR (75
4.1. General Methods
All reactions performed to prepare the benzimidazolium
halides and their ruthenium complexes were carried out under
argon in flame-dried glassware using standard Schlenk
techniques. Chemicals and solvents were purchased from Sigma-
Aldrich and Merck. Dichloromethane, dimethylformamide,
toluene and diethyl ether were of anhydrous quality and were
used as received. The solvents used were purified by distillation
over the drying agents indicated and were transferred under
argon. All reagents were purchased from commercial sources and
used without further purification. Microanalyses were performed
by İnönü University Scientific and Technological Research
Center (Malatya, Turkey). IR spectra were recorded on ATR
(Attenuated Total Reflection) sampling accessory in the range of
400-4000 cm-1 with Perkin Elmer Spectrum 100
Spectrophotometer. Melting points were measures in open
capillary tubes with an Electrothermal-9200 melting points
apparatus. Routine 1H NMR and 13C NMR spectra were recorded
using a Bruker UltraShield 300, Bruker AscendTM 400 Avance III
HD and Bruker Avance 600 AMX spectrometer operating at 300,
400 and 600 MHz for 1H NMR, and at 75, 100 and 150 MHz for
13C NMR in CDCl3 with tetramethylsilane (TMS) as an internal
reference. The NMR studies were carried out in high-quality 5
mm NMR tubes. Chemical shifts (δ) and coupling constants (J)
are reported in ppm and in Hz, respectively. NMR multiplicities
are abbreviated as follows: s = singlet, d = doublet, t = triplet, q =
o
MHz, CDCl3, 25 C, TMS): δ (ppm) = 51.1 (CH2C6H5); 51.5
(CH2C6H4(OCH3)-4); 55.3 (CH2C6H4(OCH3)-4); 113.7, 113.8,
114.7, 124.7, 126.9, 127.0, 128.3, 129.2, 129.4, 130.0, 131.3,
160.1 (arom. Cs, NC6H4N, CH2C6H5 and CH2C6H4(OCH3)-4);
143.7 (NCHN). Elemental analysis calcd. (%) for C22H21ClN2O
(Mr = 364.87 g.mol-1): C 72.42, H 5.80, N 7.68; found (%): C
72.42, H 5.81, N 7.69.
4.2.3. 1-(3-Methoxybenzyl)-3-(4-methylbenzyl)benzimidazolium
chloride (1c)
(1.64 g, yield 87%); 1H NMR (300 MHz, CDCl3, 25 oC, TMS): δ
(ppm)
= 2.30 (s, 3H, CH2C6H4(CH3)-4); 3.79 (s, 3H,
CH2C6H4(OCH3)-3); 5.84 (s, 2H, CH2C6H4(CH3)-4); 5.86 (s, 2H,
CH2C6H4(OCH3)-3); 6.86 and 7.04 (d, J = 6.6 Hz, 2H, arom. CH,
CH2C6H4(OCH3)-3); 7.10 (s, 1H, arom. CH, CH2C6H4(OCH3)-3);
7.16 and 7.40 (d, J = 7.8 Hz, 4H, arom. CH, CH2C6H4(CH3)-4);
7.27 (dd, J = 14.5, 6.6 Hz, 1H, arom. CH, CH2C6H4(OCH3)-3);
7.47-7.60 (m, 4H, arom. CH, NC6H4N); 11.88 (s, 1H, NCHN).
13C NMR (75 MHz, CDCl3, 25 oC, TMS): δ (ppm) = 21.2
(CH2C6H4(CH3)-4);
51.4
(CH2C6H4(CH3)-4);
51.5
(CH2C6H4(OCH3)-3); 55.6 (CH2C6H4(OCH3)-3); 113.8, 113.9,
114.9, 120.3, 127.0, 127.1, 128.3, 129.7, 130.0, 130.4, 131.4,
131.5, 134.3, 139.2, 160.3 (arom. Cs, NC6H4N, CH2C6H4(CH3)-4
and CH2C6H4(OCH3)-3); 143.7 (NCHN). Elemental analysis
calcd. (%) for C23H23N2OCl (Mr = 378.90 g.mol-1): C 72.91, H
6.12, N 7.39; found (%): C 72.98, H 6.20, N 7.47.
1
quartet, pent = pentet, hext = hextet, m = multiplet. H NMR
spectra are referenced to residual protiated solvents (δ = 7.26
ppm for CDCl3), 13C chemical shifts are reported relative to
deuteriated solvents (δ = 77.16 ppm for CDCl3). The catalytic
solutions were analysed with an Agilent 6890N GC and
Schimadzu 2010 Plus GC-MS system by GC-FID (Flame
Ionization Dedector) with an HP-5 column of 30 m length, 0.32
mm diameter, and 0.25 ꢀm film thickness.
4.2.4. 1-(3-Methoxybenzyl)-3-(4-methoxybenzyl)benzimidazolium
chloride (1d)
This benzimidazolium chloride was synthesized according to
published procedure.34

7
4.2.5. 1-(4-Methoxybenzyl)-3-(4-tert-butylbenzyl)benzimidazol-
ium bromide (1e)
(0.482 g, yield 73%) 1H NMR (300 MHz, CDCl3, 25 oC, TMS):
ACCEPTED MANUSCRIPT
δ (ppm) = 1.04 (t, J = 7.3 Hz, 3H, CH2CH2CH2CH3); 1.28 (d, J =
6.9 Hz, 6H, CH(CH3)2 of p-cymene); 1.65 (m, 2H,
CH2CH2CH2CH3); 2.02 (s, 3H, CH3 of p-cymene); 1.92-1.94 and
2.23-2.25 (m, 2H, CH2CH2CH2CH3); 2.98 (hept, J = 6.9 Hz, 1H,
CH(CH3)2 of p-cymene); 3.73 and 3.85 (s, 9H, CH2C6H2(OCH3)3-
3,4,5); 4.39-4.41 and 5.00-5.02 (m, 2H, CH2CH2CH2CH3); 5.05-
5.09 (m, 2H, CH2C6H2(OCH3)3-3,4,5); 5.38-5.48, 5.83-5.89 and
6.16-6.29 (m, 4H, arom. CH of p-cymene); 6.40 (s, 2H, arom.
CH, CH2C6H2(OCH3)3-3,4,5); 7.10-7.20 (m, 2H, arom. CH of
benzimidazole, NC6H4N); 7.26-7.31 (m, 1H, arom. CH of
benzimidazole, NC6H4N); 7.49 (d, J = 8.1 Hz, 1H, arom. CH of
benzimidazole, NC6H4N); 7.26-7.31 (m, 1H, arom. CH of
benzimidazole, NC6H4N) ppm. 13C NMR (75 MHz, CDCl3, 25
(2.11 g, yield 91%); 1H NMR (400 MHz, CDCl3, 25 oC, TMS): δ
(ppm) = 1.18 (s, 9H, CH2C6H4(C(CH3)3)-4); 3.68 (s, 3H,
CH2C6H4(OCH3)-4); 5.75 (s, 4H, CH2C6H4(C(CH3)3)-4 and
CH2C6H4(OCH3)-4); 6.80 and 7.29 (d, J = 8.3 Hz, 4H, arom. CH,
CH2C6H4(OCH3)-4); 7.36 (d, J = 8.2 Hz, 2H, arom. CH,
CH2C6H2(C(CH3)3)-4); 7.40-7.44 and 7.52-7.55 (m, 6H, arom.
CH, NC6H4N and CH2C6H2(C(CH3)3)-4); 11.72 (s, 1H, NCHN).
13C NMR (100 MHz, CDCl3, 25 oC, TMS): δ (ppm) = 31.2
(CH2C6H4(C(CH3)3)-4); 34.6 (CH2C6H4(C(CH3)3)-4); 51.1
(CH2C6H4(C(CH3)3)-4);
51.2
(CH2C6H4(OCH3)-4);
55.3
(CH2C6H4(OCH3)-4); 113.8, 114.7, 124.8, 126.3, 127.0, 128.1,
129.8, 130.0, 130.1, 131.3, 131.4, 152.3, 160.1 (arom. Cs,
NC6H4N, CH2C6H4(C(CH3)3)-4 and CH2C6H4(OCH3)-4); 143.4
(NCHN). Elemental analysis calcd. (%) for C26H29BrN2O (Mr =
465.44 g.mol-1): C 67.10, H 6.28, N 6.02; found (%): C 67.12, H
6.31, N 6.04.
oC,
(CH3C6H4(CH(CH3)2)-4);
TMS):
δ
=
14.0
20.4
(CH2CH2CH2CH3);
(CH2CH2CH2CH3);
18.7
21.6
(CH3C6H4(CH(CH3)2)-4); 30.7 (CH3C6H4(CH(CH3)2)-4); 32.4
(CH2CH2CH2CH3); 50.2 (CH2CH2CH2CH3); 53.0 and 53.5
(CH2C6H2(OCH3)3-3,4,5); 56.3 and 61.0 (CH2C6H2(OCH3)3-
3,4,5); 83.5, 84.4, 85.2 and 86.9 (s, arom Cs of p-cymene); 99.2,
103.7, 109.2, 110.9, 111.8, 122.9, 123.0, 133.1, 135.1, 135.8,
153.6 (arom. Cs, NC6H4N and CH2C6H2(OCH3)3-3,4,5); 189.8
(Ru-Ccarbene). Elemental analysis calcd (%) for C31H40Cl2N2O3Ru
(Mr = 660.64 g.mol-1): C 56.36, H 6.10, N 4.24; found (%): C
56.40, H 6.12, N 4.25.
4.2.6. 1-(2,3,4,5,6-Pentamethylbenzyl)-3-(3,5-di-tert-butylbenzyl)
benzimidazolium bromide (1f)
(2.527 g, yield 90%) 1H NMR (300 MHz, CDCl3, 25 oC, TMS): δ
(ppm) = 1.26 (s, 18H, CH2C6H3(C(CH3)3)-3,5); 2.25, 2.29 and
2.31 (s, 15H, CH2C6(CH3)5-2,3,4,5,6); 5.85 (s, 2H,
CH2C6H3(C(CH3)3)-3,5); 5.90 (s, 2H, CH2C6(CH3)5-2,3,4,5,6);
7.15 (d, J = 1.6 Hz, 1H, arom. CH, CH2C6H3(C(CH3)3)-3,5); 7.37
(d, J = 1.5 Hz, 2H, arom. CH, CH2C6H3(C(CH3)3)-3,5); 7.46-7.57
(m, 3H, arom. CH of benzimidazole, NC6H4N); 7.61-7.64 (m,
1H, arom. CH of benzimidazole, NC6H4N); 10.53 (s, 1H, NCHN)
4.3.2. Dichloro-[1-(4-methoxybenzyl)-3-(benzyl)benzimidazole-2-
ylidene](p-cymene)ruthenium(II) (2b)
(0.545 g, yield 86%); 1H NMR (600 MHz, CDCl3, 25 C, TMS):
o
δ (ppm) = 1.20 (d, J = 6.9 Hz, 6H, CH(CH3)2 of p-cymene); 1.91
(s, 3H, CH3 of p-cymene); 2.77 (h, J = 6.9 Hz, 1H, CH(CH3)2 of
p-cymene); 3.80 (s, 3H, CH2C6H4(OCH3)-4); 5.07 (d, J = 5.9 Hz,
2H, CH2C6H5); 5.37 (d, J = 5.8 Hz, 2H, CH2C6H4(OCH3)-4); 5.85
(t, J = 14.7 Hz, 2H, arom. CH of p-cymene); 6.35 and 6.55 (d, J =
16.8 Hz, 2H, arom. CH of p-cymene); 6.87-7.37 (m, 13H, arom.
o
ppm. 13C NMR (75 MHz, CDCl3, 25 C, TMS): δ = 17.0, 17.1
and 17.3 (CH2C6(CH3)5-2,3,4,5,6); 31.3 (CH2C6H3(C(CH3)3)-
3,5); 34.9 (CH2C6H3(C(CH3)3)-3,5); 48.2 (CH2C6(CH3)5-
2,3,4,5,6); 52.1 (CH2C6H3(C(CH3)3)-3,5); 113.6, 113.7, 121.9,
122.9, 125.1, 126.8, 127.0, 131.6, 131.7, 132.7, 133.5, 134.0,
152.0 (arom. Cs, NC6H4N, CH2C6(CH3)5-2,3,4,5,6 and
CH2C6H3(C(CH3)3)-3,5); 143.3 (NCHN). Elemental analysis
calcd (%) for C34H45BrN2 (Mr = 561.65 g.mol-1): C 72.71, H
8.08, N 4.99; found (%): C 72.84, H 8.11, N 5.04.
3
CH, NC6H4N, CH2C6H5 and CH2C6H4(OCH3)-4). C NMR (150
MHz, CDCl3, 25 oC, TMS):
δ
(ppm)
(CH3C6H4(CH(CH3)2)-4); 22.6 (CH3C6H4(CH(CH3)2)-4); 31,0
(CH3C6H4(CH(CH3)2)-4); 52.7 (CH2C6H5); 53.0
=
18.4
(CH2C6H4(OCH3)-4); 55.4 (CH2C6H4(OCH3)-4); 84.3, 84.4, 85.6,
85.7 (arom Cs of p-cymene); 97.3, 108.4, 111.6, 111.7, 111.8,
114.3, 123.0, 123.1, 126.0, 127.3, 129.4, 135.5, 135.6, 137.5,
158.9 (arom. Cs, NC6H4N, CH2C6H5 and CH2C6H4(OCH3)-4);
191.5 (Ru-Ccarbene). Elemental analysis calcd. (%) for
C32H34Cl2N2ORu (Mr = 634.61 g.mol-1): C 60.56, H 5.40, N 4.41;
found (%): C 60.59, H 5.46, N 4.47.
4.3. General Procedure for the Preparation of the Ruthenium
Complexes (2a-f)
A solution of benzimidazolium halide (1.0 mmol), Ag2O (0.5
mmol), and activated 4 Å molecular sieves in anhydrous CH2Cl2
(20 mL) was stirred room temperature for 20 h in the dark
conditions. The reaction mixture was filtered through Celite, and
the solvent was removed under reduced pressure. The in situ
prepared silver(I)-NHC complex was reacted with [RuCl2(p-
cymene)]2 dimer (0.5 mmol), and the mixture was allowed to stir
for 4 h at room temperature. The solution was filtered through
Celite, and the solvent was removed under vacuum to afford the
product as a red-brown powder. The crude product was washed
with Et2O (3×5 mL), dried under vacuum and recrystallized from
CH2Cl2/Et2O (1:2, v/v).
4.3.3.
Dichloro-[1-(3-methoxybenzyl)-3-(4-methylbenzyl)benz-
imidazole-2-ylidene](p-cymene)ruthenium(II) (2c)
o
(0.486 g, yield 75%); 1H NMR (600 MHz, CDCl3, 25 C, TMS):
δ (ppm) = 1.11 (d, J = 6.9 Hz, 6H, CH(CH3)2 of p-cymene); 1.83
(s, 3H, CH3 of p-cymene); 2.27 (s, 3H, CH2C6H4(CH3)-4); 2.66
(h, J = 6.9 Hz, 1H, CH(CH3)2 of p-cymene); 3.70 (s, 3H,
CH2C6H4(OCH3)-3); 5.03 (d, J = 5.2 Hz, 2H, CH2C6H4(CH3)-4);
5.29 (d, J = 5.6 Hz, 2H, CH2C6H4(OCH3)-3); 5.68 (t, J = 19.2 Hz,
2H, arom. CH of p-cymene); 6.42 and 6.51 (d, J = 16.8 Hz, 2H,
arom. CH of p-cymene); 6.58-7.21 (m, 12H, arom. CH, NC6H4N,
4.3.1. Dichloro-[1-(n-butyl)-3-(3,4,5-trimethoxybenzyl)benzimid-
azol-2-ylidene](p-cymene)ruthenium(II) (2a)

8
Tetrahedron
CH2C6H4(CH3)-4 and CH2C6H4(OCH3)-3). 13C NMR (150
calcd. (%) for C36H42Cl2N2ORu (Mr = 690.72 g.mol-1): C 62.60,
ACCEPTED MANUSCRIPT
MHz, CDCl3, 25 oC, TMS):
(CH3C6H4(CH(CH3)2)-4);
δ
(ppm)
=
17.3
21.5
H 6.13, N 4.06; found (%): C 62.63, H 6.15, N 4.06.
20.8
(CH2C6H4(CH3)-4);
4.3.6. Dichloro-[1-(2,3,4,5,6-pentamethylbenzyl)-3-(3,5-di-tert-
butylbenzyl)benzimidazol-2-ylidene](p-cymene)ruthenium(II) (2f)
(CH3C6H4(CH(CH3)2)-4); 29,6 (CH3C6H4(CH(CH3)2)-4); 51.8
(CH2C6H4(CH3)-4) and (CH2C6H4(OCH3)-3); 54.3
(CH2C6H4(OCH3)-3); 83.9, 84.0, 84.2, 84.4 (arom Cs of p-
cymene); 95.9, 107.0, 110.6, 110.7, 110.8, 111.7, 117.1, 121.1,
122.2, 124.8, 128.6, 129.0, 133.4, 134.5, 134.6, 136.1, 138.2,
(0.582 g, yield 74%) 1H NMR (300 MHz, CDCl3, 25 oC, TMS): δ
(ppm) = 1.26 (s, 18H, CH2C6H3(C(CH3)3)-3,5); 1.28 (d, J = 6.9
Hz, 6H, CH(CH3)2 of p-cymene); 2.07 (s, 3H, CH3 of p-cymene);
2.20, 2.30 and 2.34 (s, 15H, CH2C6(CH3)5-2,3,4,5,6); 2.82 (hept,
J = 6.9 Hz, 1H, CH(CH3)2 of p-cymene); 5.32 (d, J = 5.2 Hz, 2H,
CH2C6H3(C(CH3)3)-3,5); 5.38 (d, J = 5.3 Hz, 2H, CH2C6(CH3)5-
2,3,4,5,6); 5.30-5.72 (m, 3H, arom. CH of p-cymene); 6.19 (d, J
= 8.4 Hz, 1H, arom. CH of p-cymene); 6.86 and 7.31 (s, 3H,
arom. CH, CH2C6H3(C(CH3)3)-3,5); 6.76-6.81 (m, 2H, arom. CH
of benzimidazole, NC6H4N); 6.94-7.04 (m, 2H, arom. CH of
benzimidazole, NC6H4N) ppm. 13C NMR (75 MHz, CDCl3, 25
oC, TMS): δ = 16.7, 17.1 and 17.3 (CH2C6(CH3)5-2,3,4,5,6); 18.5
(CH3C6H4(CH(CH3)2)-4); 22.3 (CH3C6H4(CH(CH3)2)-4); 30.9
(CH3C6H4(CH(CH3)2)-4); 31.4 (CH2C6H3(C(CH3)3)-3,5); 34.9
(CH2C6H3(C(CH3)3)-3,5); 52.6 (CH2C6(CH3)5-2,3,4,5,6); 53.5
(CH2C6H3(C(CH3)3)-3,5); 84.5, 85.4, 85.5 and 86.0 (arom Cs of
p-cymene); 96.0, 107.0, 111.2, 111.8, 119.7, 120.8, 122.3, 122.6,
129.4, 135.5, 135.6, 136.9, 151.4 (arom. Cs, NC6H4N,
CH2C6(CH3)5-2,3,4,5,6 and CH2C6H3(C(CH3)3)-3,5); 189.9 (s,
Ru-Ccarbene). Elemental analysis calcd (%) for C44H58Cl2N2Ru (Mr
= 786.93 g.mol-1): C 67.16, H 7.43, N 3.56; found (%): C 67.24,
H 7.47, N 3.57.
158.1
(arom.
Cs,
NC6H4N,
CH2C6H4(CH3)-4
and
CH2C6H4(OCH3)-3); 190.6 (Ru-Ccarbene). Elemental analysis
calcd. (%) for C33H36Cl2N2ORu (Mr = 648.63 g.mol-1): C 61.11,
H 5.59, N 4.32; found (%): C 61.19, H 5.66, N 4.37.
4.3.4. Dichloro-[1-(3-methoxybenzyl)-3-(4-methoxybenzyl)benz-
imidazole-2-ylidene](p-cymene)ruthenium(II) (2d)
o
(0.445 g, yield 67%); 1H NMR (300 MHz, CDCl3, 25 C, TMS):
δ (ppm) = 1.13 (d, J = 6.6 Hz, 6H, CH(CH3)2 of p-cymene); 1.87
(s, 3H, CH3 of p-cymene); 2.73 (h, J = 6.9 Hz, 1H, CH(CH3)2 of
p-cymene);
3.71
(s,
6H,
CH2C6H4(OCH3)-3
and
CH2C6H4(OCH3)-4); 4.98 (d, J = 5.9 Hz, 2H, CH2C6H4(OCH3)-
3); 5.31 (d, J = 5.9 Hz, 2H, CH2C6H4(OCH3)-4); 5.61-6.57 (m,
4H, arom. CH of p-cymene); 6.60-7.25 (m, 12H, arom. CH,
NC6H4N, CH2C6H4(OCH3)-3 and CH2C6H4(OCH3)-4). 13C NMR
(75 MHz, CDCl3, 25 oC, TMS):
δ
(ppm)
=
18.5
(CH3C6H4(CH(CH3)2)-4); 22.5 (CH3C6H4(CH(CH3)2)-4); 30,7
(CH3C6H4(CH(CH3)2)-4);
CH2C6H4(OCH3)-4);
52.9
55.3
(CH2C6H4(OCH3)-3
(CH2C6H4(OCH3)-3
and
and
CH2C6H4(OCH3)-4); 83.6, 84.0, 85.8, 86.1 (arom Cs of p-
cymene); 97.5, 108.6, 111.6, 112.0, 112.6, 118.0, 123.2, 123.4,
127.8, 129.0, 130.1, 133.3, 133.4, 135.2, 135.4, 135.8, 139.2,
160.1 (arom. Cs, NC6H4N, CH2C6H4(OCH3)-3 and
CH2C6H4(OCH3)-4); 191.9 (Ru-Ccarbene). Elemental analysis
calcd. (%) for C33H36Cl2N2O2Ru (Mr = 664.63 g.mol-1): C 59.64,
H 5.46, N 4.21; found (%): C 59.67, H 5.48, N 4.26.
4.4. General Procedure for the Preparation of Cyclic Amines
(3a-f)
To a stirred solution of N-methylpiperidine (1.5 mmol) was
added aldehyde derivatives (1.0 mmol). Subsequently ruthenium
complexes 2a-f (2.5 mol%) were added and then sealed Schlenk
tube was stirred in at 150 oC (oil bath temperature) for 16 h. After
the reaction mixture was cooled down and then HCO2H (2.0 eq.)
4.3.5. Dichloro-[1-(4-methoxybenzyl)-3-(4-tert-butylbenzyl)benz-
imidazole-2-ylidene](p-cymene)ruthenium(II) (2e)
o
was added and stirring continued at 140 C for 1 h. The crude
mixture was directly taken for GC analysis and purified by
column chromatography (CHCl3/MeOH) to afford the C(3)-
alkylated N-methylpiperidine derivatives 3a-f.
o
(0.283 g, yield 41%); 1H NMR (600 MHz, CDCl3, 25 C, TMS):
δ (ppm) = 1.18 (d, J = 6.9 Hz, 6H, CH(CH3)2 of p-cymene); 1.31
(s, 9H, CH2C6H4(C(CH3)3)-4); 1.90 (s, 3H, CH3 of p-cymene);
2.72 (h, J = 6.9 Hz, 1H, CH(CH3)2 of p-cymene); 3.80 (s, 3H,
4.4.1. 3-Benzyl-N-methylpiperidine (3a)
o
1H NMR (600 MHz, CDCl3, 25 C, TMS): δ (ppm) = 7.38-7.12
CH2C6H4(OCH3)-4); 5.07 (d,
CH2C6H4(C(CH3)3)-4); 5.36 (d,
J
=
19.3 Hz, 2H,
= 19.2 Hz, 2H,
J
(m, 5H); 2.87 (t, 2H, J = 7.0 Hz); 2.54 (d, 2H, J = 7.1 Hz); 2.31
CH2C6H4(OCH3)-4); 5.72, 5.85, 6.36 and 6.59 (d, J = 16.2 Hz,
4H, arom. CH of p-cymene); 7.06-7.37 (m, 12H, arom. CH,
NC6H4N, CH2C6H2(C(CH3)3)-4 and CH2C6H4(OCH3)-4). 13C
NMR (150 MHz, CDCl3, 25 oC, TMS): δ (ppm) = 18.4
(CH3C6H4(CH(CH3)2)-4); 22.8 (CH3C6H4(CH(CH3)2)-4); 31,0
(CH3C6H4(CH(CH3)2)-4); 31.4 (CH2C6H4(C(CH3)3)-4); 34.6
(CH2C6H4(C(CH3)3)-4); 52.5 (CH2C6H4(C(CH3)3)-4); 52.6
(CH2C6H4(OCH3)-4); 55.4 (CH2C6H4(OCH3)-4); 84.4, 84.6, 85.9,
86.0 (arom Cs of p-cymene); 97.4, 107.8, 111.7, 111.8, 114.3,
123.0, 123.1, 125.5, 125.8, 127.3, 129.4, 134.4, 135.5, 135.7,
150.5, 158.9 (arom. Cs, NC6H4N, CH2C6H4(C(CH3)3)-4 and
CH2C6H4(OCH3)-4); 191.3 (Ru-Ccarbene). Elemental analysis
(s, 3H); 1.99-1.95 (m, 2H); 1.97-1.90 (m, 1H); 1.76-1.62 (m,
o
2H); 1.02-0.85 (m, 2H). 13C NMR (150 MHz, CDCl3, 25 C,
TMS): δ (ppm) = 24.6, 29.5, 36.9, 40.7, 45.6, 55.7, 61.1, 126.1,
128.4, 129.1, 139.4. Elemental analysis calcd. (%) for C13H19N
(Mr = 189.20 g.mol-1): C 82.48, H 10.12, N 7.40; found (%): C
82.50, H 10.13, N 7.41.
4.4.2. 3-(4-Methyl)benzyl-N-methylpiperidine (3b)
o
1H NMR (600 MHz, CDCl3, 25 C, TMS): δ (ppm) = 7.15-7.03
(s, 4H); 2.87 (t, 2H, J = 7.2 Hz); 2.50 (d, 2H, J = 7.2 Hz); 2.34 (s,
3H); 2.33 (s, 3H); 2.08-1.93 (m, 2H); 1.83-1.71 (m, 2H); 1.70-
1.63 (m, 2H); 1.01-0.86 (m, 2H). 13C NMR (150 MHz, CDCl3, 25

9
oC, TMS): δ (ppm) = 21.0, 24.1, 29.3, 36.7, 40.2, 45.5, 55.7,
61.0, 128.9, 129.0, 135.7, 135.9. Elemental analysis calcd. (%)
for C14H21N (Mr = 203.20 g.mol-1): C 82.70, H 10.41, N 6.89;
found (%): C 82.71, H 10.43, N 6.88.
3.
Vitaku E, Smith DT, Njardarson JT, J Med Chem. 2014;57:10257-
10274.
ACCEPTED MANUSCRIPT
4.
5.
6.
Lawrence SA, Amines: Synthesis, Properties and Applications. New
York; Cambridge University Press, 2004.
Nugent, TC, Chiral Amine Synthesis: Methods, Development and
Applications. Weinheim; Wiley-VCH Verlag, 2010.
(a) Seayad J, Tillack A, Hartung CG, Beller M, Adv Synth Catal.
2002;344:795-813;
(b) Müller TE, Hultzsch KC, Yus M, Foubelo F, Tada M, Chem Rev.
2008;108:3795-3892;
(c) Andrews I, Cui J, DaSilva J, Dudin L, Dunn P, Hayler J, Hinkley
B, Hughes D, Kaptein B, Kolis S, Lorenz K, Mathew S, Rammeloo
T, Wang L, Wells A, White T, Xie C, Zhang F, Org. Process Res Dev.
2009;13:397-408;
4.4.3. 3-(4-Chloro)benzyl-N-methylpiperidine (3c)
o
1H NMR (600 MHz, CDCl3, 25 C, TMS): δ (ppm) = 7.28 (dd,
2H, J = 11.6 Hz); 7.08 (d, 2H, J = 8.1 Hz); 2.85 (t, 2H, J = 7.8
Hz); 2.50 (d, 2H, J = 7.1 Hz); 2.34 (s, 3H); 2.04-1.83 (m, 2H);
1.81-1.66 (m, 1H); 1.65-1.56 (m, 2H); 1.04-0.92 (m, 2H). 13C
o
NMR (150 MHz, CDCl3, 25 C, TMS): δ (ppm) = 24.8, 29.8,
37.4, 40.2, 46.1, 56.0, 61.4, 128.3, 130.3, 131.7, 138.3 (arom. Cs
of CH2CH2CH2CHCH2N(CH3)-3-CH2(C6H4)-4-(Cl)). Elemental
analysis calcd. (%) for C13H18NCl (Mr = 223.10 g.mol-1): C
69.79, H 8.11, N 6.26; found (%): C 69.81, H 8.13, N 6.28.
(d) Xie J-H, Zhu S-F, Zhou Q-L, Chem Rev. 2011;111:1713-1760.
Garattini S, Valzelli L, Serotonin. Amsterdam; Elsevier; 1965.
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G, Fromtling RA, Onishi J, Monaghan R, J Antibiot. 1988;41:1774-
1779;
7.
8.
(b) Csatayová K, Špánik I, Ďurišová V, Szolcsányi P, Tetrahedron
Lett. 2010;51:6611-6614;
4.4.4. 3-(Naphtholen-3-yl)methyl-N-methylpiperidine (3d)
(c) Lesma G, Sacchetti A, Silvani A, Tetrahedron Asymmetry
2010;21:2329-2333;
o
1H NMR (600 MHz, CDCl3, 25 C, TMS) δ 7.90–7.25 (m, 7H),
5.32 (s, 1H), 2.91 (t, J = 7.0 Hz, 2H), 2.72 (d, J = 6.9 Hz, 2H),
(d) Zheng G, Dwoskin LP, Deaciuc AG, Crooks PA, Bioorg Med
Chem Lett. 2008;18:6509-6512;
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2.34 (s, 3H), 2.10-2.0 (m, 2H), 1.92–1.60 (m, 3H), 1.05-1.01 (m,
o
2H). 13C NMR (150 MHz, CDCl3, 25 C, TMS) δ 136.2, 133.4,
132.2, 128.1, 127.6, 127.4, 127.3, 126.0, 125.4, 60.6, 55.5, 45.1,
40.6, 36.1, 29.1, 23.7. Elemental analysis calcd. (%) for C19H21N
(Mr = 263.20 g.mol-1): C 86.64, H 8.04, N 5.32; found (%): C
86.65, H 8.06, N 5.33.
9.
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1H NMR (600 MHz, CDCl3, 25 oC, TMS): δ (ppm) = 2.89 (d, J =
8.0 Hz, 2H), 2.33 (s, 3H), 1.99-1.65 (m, 7H), 1.29-1.18 (m, 12H),
0.87 (t, 3H, J = 8.0 Hz); 0.85–0.78 (m, 2H). 13C NMR (150 MHz,
CDCl3, 25 oC, TMS): δ (ppm) = 14.0, 22.6, 24.1, 26.4, 35.0, 55.8,
29.2, 29.4, 29.5, 29.7, 31.8, 34.2, 45.4, 61.4. Elemental analysis
calcd. (%) for C14H29N (Mr = 211.20 g.mol-1): C 79.55, H 13.83,
N 6.63; found (%): C 79.57, H 13.85, N 6.65.
4.4.6. 3-(Cyclohexyl)-N-methylpiperidine (3f)
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1H NMR (600 MHz, CDCl3, 25 oC, TMS): δ (ppm) = 2.91 (t,
J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.82-1.64 (m, 11H), 1.06 (t, 2H, J =
7.0 Hz); 1.34-1.13 (m, 5H), 0.93-0.77 (m, 2H). 13C NMR (150
o
MHz, CDCl3, 25 C, TMS): δ (ppm) = 24.3, 26.2, 26.3, 26.5,
30.0, 32.1, 33.4, 33.7, 34.2, 42.2, 45.6, 55.8, 61.8. Elemental
analysis calcd. (%) for C13H25N (Mr = 195.20 g.mol-1): C 79.93,
H 12.90, N 7.17; found (%): C 79.94, H 12.92, N 7.18.
Appendix A. Supplementary data
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ACCEPTED MANUSCRIPT
• A series of new benzimidazolium halides (1a-f) as N-heterocyclic carbene (NHC) ligand precursors
and their corresponding new ruthenium(II) complexes (2a-f) with general formula
[RuCl2(arene)(NHC)], (arene = η6-p-cymene) were synthesized.
• All new compounds were fully characterized by analytical and spectral methods.
• Ruthenium(II) complexes were tested as promising catalyst for selective β-C(sp3)-H
functionalization of N-methylpiperidine with various aldehydes through hydrogen transfers in
presence of external acidic additive.