N-Alkylation and N,C-Dialkylation of Amines with Alcohols in the Presence of Ruthenium Catalysts with Chelating N-Heterocyclic Carbene Ligands

Article abstract of DOI:10.1021/om501066n

A series of new benzimidazolium salts and ruthenium(II) complexes containing chelating N-heterocyclic carbenes (NHCs) functionalized with a benzylic group and an acetal group were prepared. All of the synthesized compounds were characterized by elemental analysis and NMR spectroscopy, and the molecular structures of 2c and 2d were determined by X-ray crystallography. All of the complexes were tested in the alkylation of cyclic amine derivatives with alcohols and showed excellent activity in this reaction. Cyclic amines were alkylated with primary and heteroaromatic alcohols. The Ru-NHC complexes also catalyzed N,C3-dialkylation of cyclic amines. (Chemical Equation Presented).

Full text of DOI:10.1021/om501066n

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pubs.acs.org/Organometallics
N‑Alkylation and N,C-Dialkylation of Amines with Alcohols in the
Presence of Ruthenium Catalysts with Chelating N‑Heterocyclic
Carbene Ligands
†
†
,†
ahin,‡ Orhan Buyukgungor,§ Mathieu Achard,∥
̈
̇
Zeynel Şahin, Nevin Gurbuz, Ismail Ozdemir,* Onur Ş
̈ ̈
̈
̈
̈
̈
and Christian Bruneau∥
†Catalysis Research and Application Center, Inonu University, 44280 Malatya, Turkey
̈
̈
‡Scientific and Technological Research Application and Research Center, Sinop University, 57010 Sinop, Turkey
§Department of Physics, Ondokuz Mayıs University, 55139 Samsun, Turkey
∥Universite
France
́
de Rennes 1, UMR6226: Institut des Sciences Chimiques de Rennes, Centre de Catalyse et Chimie Verte, 35042 Rennes,
S
* Supporting Information
ABSTRACT: A series of new benzimidazolium salts and
ruthenium(II) complexes containing chelating N-heterocyclic
carbenes (NHCs) functionalized with a benzylic group and an
acetal group were prepared. All of the synthesized compounds
were characterized by elemental analysis and NMR spectros-
copy, and the molecular structures of 2c and 2d were
determined by X-ray crystallography. All of the complexes
were tested in the alkylation of cyclic amine derivatives with
alcohols and showed excellent activity in this reaction. Cyclic
amines were alkylated with primary and heteroaromatic
alcohols. The Ru−NHC complexes also catalyzed N,C3-
dialkylation of cyclic amines.
Scheme 1. Hydrogen Borrowing Strategy for the Alkylation
of Amines with Alcohols
INTRODUCTION
■
The first N-heterocyclic carbene (NHC) complexes were
synthesized independently by Ofele, Wanzlick, and Lappert in
̈
the early 1970s.1 In 1991 Arduengo et al.2 isolated free 1,3-
bis(adamantyl)imidazolin-2-ylidene, which triggered the devel-
opment of important studies related to these nucleophilic
ligands. Because of their strong σ-donor ligand properties,
NHCs were extensively introduced as phosphine substitutes in
metal complexes for applications in catalytic reactions.3 Since
then, various aspects of the chemistry of NHC-based metal
catalysts and catalysis have been extensively reviewed.4−8
Amines are important building blocks that have found
widespread applications for the synthesis of pharmaceuticals,
agrochemicals, dyes, and polymers.9,10 N-Alkylamines are
obtained by the reaction of primary or secondary amines with
alkyl halides in the presence of stoichiometric amounts of
mineral bases or by reductive amination of aldehydes or
ketones.9b The generation of inorganic salts and the use of
unstable and expensive carbonyl compounds constitute the
main drawbacks of these procedures.
Since the pioneering work of Guerbet,12 in situ dehydrogen-
ative activation of alcohols in the presence of alkoxide as a base
has been extended to amines, alcohols, and alkanes with
heterogeneous catalysts and more recently under homogeneous
conditions. Alkylation of amines with alcohols proceeding via
the hydrogen borrowing route using heterogeneous nickel
catalysts has been known since 1932.13 In 1981, Grigg and
Watanabe independently reported homogeneous catalysts for
the amination of alcohols using late-transition-metal cata-
Alternatively, in a greener approach, readily available alcohols
have been used as alkylating agents using a catalytic “hydrogen
borrowing” strategy (Scheme 1).11 This process produces water
as the only byproduct and hence offers a sustainable method for
N-alkylation reactions.11
Special Issue: Mike Lappert Memorial Issue
Received: October 27, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/om501066n
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lysts.14,15 Since then, a number of very successful results from
RESULTS AND DISCUSSION
Preparation of Benzimidazolium Salts. 1,3-Dialkylben-
zimidazolium salts 1a−e were prepared according to known
methods33 by the reaction of the corresponding benzyl halides
with 1-(2,2-dimethoxyethyl)benzimidazole in dimethylforma-
mide and were isolated in yields of 85−90% (Scheme 2). The
■
the groups of Beller,16 Williams,17 Kempe,18 Fujita,19 Martin-
́
Matute,20 Crabtree,21 Madsen,22 Peris,23 and Yus24 have been
obtained for alkylation of amines with alcohols.
The first application of NHC complexes for the alkylation of
amines through the hydrogen borrowing reaction was described
by Peris in 2008.23a With regard to redox-neutral processes
involving hydrogen transfers, different Cp*-chelating NHC,
alcohol/alkoxide-tethered NHC, picolyl-NHC, phosphine-
NHC, and supported NHC systems containing Ir20b,21,23a,b,25
and Ru26 complexes have been reported.
Scheme 2. Synthesis of 1,3-Dialkylbenzimidazolium Salts
1a−e
The presence of an NHC ligand and a second different
donating group on the metal can radically alter the catalytic
properties. Also, the chelating nature of these ligands results in
the production of highly stable complexes. NHCs are known to
be compatible with a wide set of nitrogen-, oxygen-, and arene-
containing electron-donor functionalities.27
Among these ligands, only a few examples of NHC-based
ligands containing η6-arene-η1-carbene,28 η5-indenyl-η1-car-
bene,29 or η5-cyclopentadienyl-η1-carbene23a have been re-
ported. The hemilable arm in such ligands is capable of
reversible dissociation to produce vacant coordination sites,
allowing complexation of substrates during the catalytic cycle.
At the same time, the strong donor carbene moiety remains
connected to the metal center. We have shown a route to
prepare metal complexes containing mixed arene and carbene
ligands that provide eight electrons to the metal and found that
the natural orientation of the carbene in the complex is
significantly modified.28
salts are air- and moisture-stable both in the solid state and in
solution and are soluble in chlorinated solvents, alcohols, and
water. Benzimidazolium salts 1a−e were isolated as solids in
Recently, our research group has focused on NHC ligands,
their metal complexes, and their catalytic activity.30 We have
reported the application of imidazolidin-2-ylidene and
benzimidazolidin-2-ylidene ruthenium complexes in transfer
hydrogenation of aromatic ketones.31 We have also investigated
half-sandwich ruthenium(II) complexes bearing N-coordinated
benzimidazole ligands in the alkylation of amines with
alcohols.32 In view of the growing interest in the catalytic
activity of ruthenium complexes to act as efficient catalysts in
hydrogen borrowing reactions, we synthesized N,N′-dimethox-
yethyl-substituted benzimidazolium salts. The complexes
bearing methoxyethyl substituents on the N atom have been
found to be more efficient. It is believed that this effect is due to
the hemilabile functionality of the methoxy group.27,28b We
now report five η6-arene-η1-carbene ruthenium complexes (2a−
e) obtained from deprotonated 1,3-dialkylbenzimidazolium
salts containing one benzylic group linked to a nitrogen atom.
Also, the reaction of [RuCl2(p-cymene)]2 with Ag−NHC
complexes afforded [(p-cymene)Ru(NHC)] complexes (3a
and 3b). All of the synthesized compounds were characterized
1
very good yields and fully characterized by H and 13C NMR
spectroscopy, IR spectroscopy and elemental analysis, and their
melting points were determined. The 13C NMR chemical shifts
are consistent with the proposed structures: the imino carbon
appears as a typical singlet in the 1H-decoupled mode at 143.5,
150.0, 152.4, 144.3, and 143.4 ppm for benzimidazolium salts
1
1a−e, respectively. The H NMR spectra of the benzimidazo-
lium salts further support the assigned structures: the resonance
for C2−H appears as a sharp singlet at 11.31, 11.40, 11.26,
11.40, and 10.34 ppm for 1a−e, respectively, characteristic of
the NCHN proton. The IR data for benzimidazolium salts 1a−
e clearly indicate the presence of the −CN− group with a
ν(CN) vibration at 1566, 1560, 1561, 1557, and 1554 cm−1,
respectively. These values are in good agreement with the
previously reported results.34
Preparation of Ruthenium−Carbene Complexes 2a−
e. In situ deprotonation of an azolium salt to produce the
desired NHC simplifies the reaction workup.35 This method
was used for the preparation of complexes 2a−e. The carbene
ligands formed by deprotonation of benzimidazolium salts 1a−
e using Cs2CO3 were reacted with [RuCl2(p-cymene)]2 in
toluene at 110 °C (Scheme 3).36 After 5 h the reactions were
complete, and the mononuclear neutral ruthenium(II)
complexes 2a−e were obtained as red-brown crystalline solids
in yields of 70−82%. Complexes 2c and 2d were obtained in
crystalline form. The ruthenium carbene complexes (except 2c)
are soluble in solvents such as dichloromethane, chloroform,
toluene, and tetrahydrofuran.
1
by H and 13C NMR, IR, and elemental analysis techniques,
which support the proposed structures. The molecular and
crystal structures of the complexes dibromo[1-(2,2-dimethox-
yethyl)-3-(4-tert-butylbenzyl)benzimidazol-2-ylidene]-
ruthenium(II) (2c) and dichloro[1-(2,2-dimethoxyethyl)-3-
(2,4,6-trimethylbenzyl)benzimidazol-2-ylidene]ruthenium(II)
(2d) were determined by single-crystal X-ray diffraction.
Furthermore, the synthesized complexes effectively used as
catalysts in the alkylation of cyclic amine derivatives. To the
best of our knowledge, there has been no previous report
describing Ru−NHC complexes that catalyze alkylation at the
N- and C3-positions of cyclic amines using primary alcohols.
Complexes 2a−e with the aryl group η6-coordinated to the
ruthenium atom were obtained in good yields (Scheme 3).
These results show that in refluxing toluene, the p-cymene
B
DOI: 10.1021/om501066n
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Structural Characterization of 2c and 2d. Crystals of 2c
and 2d suitable for X-ray analysis were obtained from a
chloroform solution layered with diethyl ether. The molecular
structures of these complexes were confirmed by single-crystal
X-ray analyses. Details of the data collection and crystal
structure determinations are given in the Supporting
Information. The molecular structures of 2c and 2d with the
atom labeling are shown in Figures 1 and 2.
Scheme 3. Synthesis of Ruthenium−Carbene Complexes
ligand can be intramolecularly displaced by an aryl group.
1
Complexes 2a−e were characterized by H and 13C NMR and
FTIR spectroscopy, elemental analysis, and X-ray diffraction.
The ruthenium complexes 2a−e exhibit a characteristic
ν(NCN) band at 1401, 1402, 1401, 1410, and 1402 cm−1,
respectively.30,36 13C chemical shifts provide a useful diagnostic
tool for this type of metal carbene complex. The chemical shifts
for the carbene carbon atom are located in the 182−186 ppm
range and are similar to those found in other ruthenium−
carbene complexes.30,36
Figure 1. Molecular structure of 2c showing the atom-numbering
scheme. Selected bond lengths (Å) and angles (deg): C12−Ru1 =
2.086(11), Br1−Ru1 = 2.5083(17), Br2−Ru1 = 2.4948(17), C12−N1
= 1.324 (13), C12−N2 = 1.347(13), N1−C12−Ru1 = 115.2(8), N2−
C12−Ru1 = 137.6(7), N1−C12−N2 = 107.2(9), C12−Ru1−Br1 =
91.1(3), C12−Ru1−Br2 = 93.4(3), Br2−Ru1−Br1 = 88.14(6).
Preparation of p-Cymeneruthenium−Carbene Com-
plexes 3a and 3b. Ruthenium complexes 3a and 3b were
prepared by means of the Ag−carbene transfer method
developed by Wang and Lin.37 The silver monocarbene
complexes, which should subsequently serve as carbene-transfer
agents, were synthesized by the reaction of Ag2O with 2 equiv
of salts 1c and 1e in CH2Cl2 at ambient temperature. We
conveniently reacted the Ag−NHC complexes with [RuCl2(p-
cymene)]2 in the dark, and the mixtures were allowed to stir for
24 h at room temperature (Scheme 4). The air- and moisture-
Scheme 4. Synthesis of Complexes 3a and 3b
Figure 2. Molecular structure of 2d showing the atom-numbering
scheme. Selected bond lengths (Å) and angles (deg): C11−Ru1 =
2.042(4), Cl1−Ru1 = 2.4184(11), Cl2−Ru1 = 2.4200(10), C11−N1 =
1.364(4), C11−N2 = 1.346(5), N2−C11−N1 = 105.7(3), N2−C11−
Ru1 = 138.9(2), N1−C11−Ru1 = 115.4(3), C11−Ru1−Cl1 =
87.12(11), C11−Ru1−Cl2 = 98.28(10), Cl1−Ru1−Cl2 = 87.52(4).
Catalytic N-Alkylation and N,C3-Dialkylation of Cyclic
Amines with Alcohols. Although several examples adopting
the hydrogen borrowing strategy have been documented for the
construction of N-alkylated amines,13−26 and C-alkylated
products arising from alcohols,38 a one-step process for the
simultaneous alkylation of both the N atom and the unactivated
C3 carbon of secondary amines corresponding to a formal
C(sp3)−H activation was unknown until Bruneau and co-
workers reported the N,C3-dialkylation of saturated cyclic
amines in the presence of ruthenium precatalysts equipped with
stable ruthenium carbene complexes 3a and 3b are soluble in
1
polar and halogenated solvents and were characterized by H
and 13C NMR spectroscopy, FTIR spectroscopy, and elemental
analysis. These complexes show typical spectroscopic signatures
that are in line with those recently reported for other
[RuCl2(NHC)(arene)] complexes.30,36
C
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a phosphinesulfonate ligand acting as a P,O chelate.39 The Ru−
NHC complexes 2a−e, 3a, and 3b featuring an acetal moiety,
which upon hydrolysis generates an aldehyde as a potential
internal hydrogen acceptor or prochelate, were evaluated to
explore their activities in the alkylation of cyclic amines. The
alkylation of pyrrolidine with benzyl alcohol was investigated as
a model reaction (Table 1). All of the reactions were carried
out with a catalyst loading of 1.0 mol % in toluene under an
argon atmosphere using a 1:2.5 amine/alcohol ratio in the
presence of D-(+)-camphorsulfonic acid (CSA) (40 mol %),
corresponding to the conditions from the present literature.39
The reaction was not successful in the absence of any catalyst.
When [RuCl2(p-cymene)]2 was used as the catalyst, the
alkylation product obtained from pyrrolidine and benzyl
alcohol was obtained with <5% conversion. Full conversions
of the corresponding amines were observed by GC analysis for
the reactions of pyrrolidine and benzyl alcohol derivatives. The
results are summarized in Table 1. Also, the time dependence
of the conversion was followed with complex 2b (Figure 3).
Table 1. N-Alkylation and N,C3-Dialkylation of Pyrrolidine
with Benzyl Alcohol Derivatives
a
a
Reagents and conditions: pyrrolidine (1.0 mmol); alcohol (2.5
mmol); CSA (40 mol %); Ru−NHC (1 mol %); toluene (1 mL); 120
Figure 3. Time dependence of the alkylation of pyrrolidine.
Conditions: pyrrolidine (1.0 mmol); alcohol (2.5 mmol); CSA (40
mol %); 2b (1 mol %); toluene (1 mL); 120 °C.
°C, 16 h. The yields of a and b were determined by GC using
b
c
dodecane as an internal standard. 72% conversion. 68% conversion.
Tracing the reactions by GC−MS showed that the N-
alkylation and N,C3-dialkylation products were formed in all of
the reactions involving benzyl alcohol and pyrrolidine but in
various unpredictable ratios (Table 1, entries 1−7). For
example, when 2b was used as the catalyst, the N-alkylation
and N,C3-dialkylation products were observed in 24:76 ratio
(Table 1, entry 2), whereas in the case of 2e the N-alkylation
product was favored (Table 1, entry 5). When complex 3a with
p-cymene was used as the catalyst, the N-alkylation and N,C3-
dialkylation products were observed in an 89:11 ratio (Table 1,
entry 6), while the chelating complex 2c gave these products in
a 34:66 ratio (Table 1, entry 3). These reaction conditions were
applied to the coupling of pyrrolidine with various alcohols
(Table 1). Benzylic alcohols with either electron-donating or
electron-withdrawing substituents on the aromatic ring reacted
smoothly with pyrrolidine. Complex 2e was shown to be
selective toward N-alkylation of pyrrolidine with p-methoxy and
p-chlorobenzyl alcohol (Table 1, entries 19 and 26). Complex
3b with p-cymene was shown to be selective toward N,C3-
dialkylation of pyrrolidine with p-methylbenzyl alcohol (Table
1, entry 14). However, in the case of p-methoxybenzyl alcohol,
only the N-alkylation product was obtained in 68% conversion
(Table 1, entry 21), whereas the chelating complex 2e afforded
full conversion and the N-alkylation product was favored
(83:17 ratio; Table 1, entry 19). It is worth noting that cleavage
of the halogen atoms was not observed when p-chloro-
substituted benzyl alcohol was used (Table 1, entries 22−26).
Morpholine is an important moiety in many pharmaceutical
molecules and organic chemical intermediates. Therefore,
alkylation of morpholine was explored next, and typical results
are shown in Table 2. Morpholine was alkylated to give the
corresponding tertiary amines along with the N,C3-dialkylated
products within 16 h with 100% conversion, except for complex
3b with p-cymene, for which the products were obtained with
75% conversion (Table 2, entry 7). The N,C3-dialkylation
product was observed as minor product in all of the reactions
conducted using benzyl alcohol and morpholine (Table 2,
entries 1−7). In contrast with pyrrolidine, we observed that N-
alkylation of morpholine occurred with high selectivity. For
example, when 2a was used as the catalyst, the N-alkylation
D
DOI: 10.1021/om501066n
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