Benzimidazolin-2-ylidene N-heterocyclic carbene complexes of ruthenium as a simple catalyst for the N-alkylation of amines using alcohols and diols

Article abstract of DOI:10.1039/c4ra15398g

Simple air and moisture stable ruthenium complexes 1-3 and 3a were synthesized from readily available benzannulated N-heterocyclic carbene ligands (bimy = benzimidazolin-2-ylidene). These complexes were found to be efficient catalysts for the alkylation of amines using alcohols as alkylating agents. Catalysts 1, 2 and 3a gave excellent yields of up to 99% for the alkylation of various amines using benzylic and aliphatic alcohols at 130 °C for 18 h under solventless conditions. Catalyst 3a bearing both phosphine and carbene ligands gave excellent yields of up to 98% for the synthesis of heterocyclic amines by double alkylation of primary amines using linear diols. The practical utility of these catalysts was demonstrated for the synthesis of pharmaceutically important amines in a more environmentally benign way under solventless conditions.

Full text of DOI:10.1039/c4ra15398g

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Journal Name
RSCPublishing
ARTICLE
Benzimidazolin-2-ylidene N-Heterocyclic Carbene
Complexes of Ruthenium as a Simple Catalyst for the
N-Alkylation of Amines using Alcohols and Diols
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Siah Pei Shan,a Xie Xiaoke,b Boopathy Gnanaprakasam,a,† Tuan Thanh Dang,a
Balamurugan Ramalingam,a Han Vinh Huynh*,b and Abdul Majeed Seayad*,a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Simple airꢀ and moisture stable ruthenium complexes 1-3 and 3a were synthesized from
readily available benzannulated
ylidene). These complexes were found to be efficient catalysts for the alkylation of amines
using alcohols as alkylating agents. Catalysts and 3a gave excellent yields of up to 99%
Nꢀheterocyclic carbene ligands (bimy = benzimidazolinꢀ2ꢀ
1, 2
o
for the alkylation of various amines using benzylic and aliphatic alcohols at 130 C for 18 h
under solventless conditions. Catalyst 3a bearing both phosphine and carbene ligands gave
excellent yields of up to 98% for the synthesis of heterocyclic amines by double alkylation
of primary amines using linear diols. The practical utility of these catalysts were
demonstrated for the synthesis of pharmaceutically important amines in
environmentally benign way under solventless conditions.
a more
ruthenium and iridium have been reported to be active catalysts
for the activation of alcohols by hydrogen borrowing strategy.
As an early example, Cp*ꢀfunctionalized iridiumꢀcarbene
complexes have been reported28 by Peris et al. for the
Introduction
Molecules that contain C‒N bonds are key intermediates in the
synthesis of bioactive molecules and play an important role in
pharmaceutical industry.1 Traditional methods for CꢀN bond
formation including SN2 type amination using toxic alkyl
halides2 and reductive amination using stoichiometric amounts
of reducing agents3 are not environmentally benign or atom
alkylation of aniline and
βꢀalkylation of secondary alcohols. Up
to 87% of yield was observed in the presence of strong bases
t
o
such as BuOK (110 mol%) at 110 C. Subsequently, they also
reported29 the application of imidazolinꢀ2ꢀylidene, imidazolinꢀ
4ꢀylidene and pyrazolinꢀ3ꢀylidene derived ruthenium
economical.4 Recently, transition metal catalyzed C
‒N bond
formation from alcohols and amines following the soꢀcalled
“hydrogen borrowing” methodology,5 has attracted much
attention. Alcohols are often lowꢀcost, less hazardous and
commercially available starting materials, and water is the only
byꢀproduct of this reaction, which makes this method
environmentally attractive.6 Pioneering works in this field have
been done by the groups of Grigg7 and Watanabe.8 Great
contributions have also been made by the groups of Crabtree,9
Williams,10 Milstein,11 Beller12 and Fujita.13 In most of the
cases, Ruthenium14 or Iridium15 complexes have been used as
complexes as catalyst for the
primary alcohols. In the presence of one equivalent of KOH,
βꢀalkylation of secondary and
quantitative yield of the βꢀalkylated alcohols were formed in
toluene at 110 oC. Crabtree et al.9a reported chelating
pyrimidineꢀNHC complexes of iridium and ruthenium as
effective catalysts for the alkylation of amines and secondary
alcohols. Using these catalysts,
Nꢀalkylation of both electron
deficient and electron rich amines was carried out in the
presence of NaHCO3 (50 mol%) to give the corresponding
secondary amines in 25–98% yield. Recently, Valerga et al.30a
catalysts to achieve efficient Nꢀalkylation of a variety of amines
reported the
Nꢀalkylation of both aromatic and nonꢀaromatic
amines using Ru(II)ꢀPicolylꢀNHC complex30b as a catalyst.
Turn over numbers (TON) of up to 480 were reported in the
presence of 50 mol% of KOH at 100 oC.
or ammonia with primary or secondary alcohols including
diols. In recent years, catalysts based on other noble metals
such as Au,16 Ag,17 Os,18 Rh,19 and Pd20 as well as nonꢀnoble
metals such as Fe,21 Cu,22 Ni,23 Bi,24 In25 and Re26 were also
Bifunctional Ir catalysts bearing alcohol/alkoxide tethered
NHC have been reported for Nꢀalkylation of various amines at
reported to be effective as catalysts for the use of alcohols as
alkylating agents adopting hydrogen borrowing strategy.
Nꢀ
o
temperature as low as 50 C.15c The catalysts were reported to
have the ability to accept both proton and the hydride in order
to form the products in 77ꢀ99% yield in the absence of any
external base. Anderson et al. reported Ir complexes of
N
ꢀheterocyclic carbenes (NHCs) have become ubiquitous
ligands for homogeneous catalysis,27 and NHC complexes of
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DOI: 10.1039/C4RA15398G
chelating ligand containing phosphine and NHC moiety as downfield compared to their imidazolinꢀ2ꢀylidene analogues
13
catalysts for Nꢀmonoalkylation of amines.15m Notably, the (ca. 170 ppm).33 The gradual downfield shifts of the
C
carbene
catalyst promoted the alkylation at 50 oC and at room signals in these three complexes is reflective of the decreasing
temperature for selected substrates, in the presence of 50 mol%
of tBuOK to give the alkylated products in 63ꢀ97% yields.
To the best of our knowledge, only imidazolinꢀ2ꢀylidene29
+I effect of the wing tip Nꢀsubstituents on the carbene ligands.
based complexes having chelating
N
ꢀpyrimidyl9a or
N
ꢀpicolyl30
substituents have been reported for the
Nꢀalkylation of amines,
while simpler nonꢀchelating or benzimidazolinꢀ2ꢀylidene based
ruthenium complexes have not been explored yet. Herein, we
report simple and nonꢀchelating Ru(II)ꢀNHC complexes of the
general
formula
[RuCl2(pꢀcymene)(bimy)]
(bimy
=
benzimidazolinꢀ2ꢀylidene) as efficient catalysts for the
alkylation of amines using alcohols.
Nꢀ
Results and discussion
The preparation of complexes [RuCl2(p
ꢀcymene)(iPr2ꢀbimy)]
(1) and [RuCl2(pꢀcymene)(Bn2ꢀbimy)] (3) bearing symmetrical
benzimidazolinꢀ2ꢀylidene ligands were reported previously.31
Their preparation is improved in this work, and in analogy, the
Fig. 1. Molecular structure of complex 2 showing 50% probability ellipsoids.
Hydrogen atoms have been omitted for clarity. Selected bond lengths (Å) and
bond angles (deg): Ru1−C1 2.0692(24), Ru1−Cl1 2.4096(10), Ru1−Cl2 2.4381(9);
new complex [RuCl2(pꢀcymene)(iPr,Bnꢀbimy)] (
2) containing
Ru1−Cl18 2.2073(24), Ct‒Ru1 1.693; Ru1−Cl21 2.2638(26); Cl1−Ru1−Cl2
83.795(2), Cl1−Ru1−C1 89.200(6), Cl2−Ru1−C1 91.721(7).
an unsymmetrically substituted NHC was readily synthesized
by treating the [RuCl2(pꢀcymene)]2 dimer directly with the
corresponding Agꢀcarbene species, that in turn was generated in
situ by mixing the known benzimidazolium salt B32 with Ag2O
in CH2Cl2 (Scheme 1).
The molecular structure of
2 (Fig. 1) was determined by Xꢀ
ray diffraction on single crystals obtained by diffusion of
diethyl ether into a dichloromethane solution. This complex
adopts threeꢀlegged piano stool geometry with the facial planar
Scheme 1. Synthesis of Ruthenium NHC complexes 1‒3
p
ꢀcymene representing the “seat”, and the two chlorido and one
NHC ligands form the three “legs”. Although the carbon atom
C21 is situated “transoid” to the carbene donor C1 (C21 Ru1
C1 = 162.13°), no trans influence from the NHC ligand can be
discerned as all RuꢀCcymene bonds are of essentially the same
length within 3σ with an average value of 2.209 Å. The Ruꢀ
R1
R1
N
‒
‒
N
1. Ag2O, CH2Cl2
Ru
Cl
Cl
Br
2. [RuCl2(p-cymene)]2
N
R2
N
R2
A: R1 = R2 = Isopropyl
B: R1 = Isopropyl, R2 = Benzyl
C: R1 = R2 = Benzyl
1: R1 = R2 = Isopropyl (58%)
2: R1 = Isopropyl, R2 = Benzyl (70%)
3: R1 = R2 = Benzyl (81%)
centroid distance amounts to 1.693 Å. Both the
and the ꢀisopropyl group are pointing away from the
Ruthenium center to avoid steric repulsion, and the bulkier
isopropyl group in the ꢀcymene ring is also oriented away
Nꢀbenzyl group
N
p
In terms of stereoelectronic properties, complex
and 3 32
a midway between complexes Pure samples can be
obtained by washing the crude products with water and diethyl
ether. The yields of complexes and were 58%, 70% and
81%, respectively. Notably, the reaction for the preparation of
complex is more sluggish than that for complex and 3.
2 represents
from the benzimidazolinꢀ2ꢀylidene ligand for the same reason.
The catalytic activity of the ruthenium benzimidazolinꢀ2ꢀ
1
.
ylidene complexes
1 – 3 for alcohol activation towards Nꢀ
1
,
2
3
alkylation was investigated by taking the coupling between
benzyl alcohol and aniline as a standard reaction (Table 1).
1
2
Catalyst
1 having the NHC ligand symmetrically substituted
1
About 20% of unreacted Ru dimer can still be observed by H
NMR analysis after 12 h. The lower acidity of the C2ꢀH proton
with isopropyl group was selected for initial optimization of the
reaction conditions. Only a moderate 40% yield (entry 1) of the
in precursor
effects from two
of the required silver carbene species comparatively more
challenging. Furthermore, the bulkier isopropyl groups in
A
as a consequence of the positive inductive
ꢀisopropyl substituents makes the generation
N
ꢀbenzylamine product was obtained after 18 h at a lower
N
catalyst loading of 1.0 mol% and at a reaction temperature of
130 C under solventless conditions. The yield increased to
70% upon increasing the amount of the catalyst to 2.5 mol%
(entry 2). Increase in temperature showed no significant
improvement (entry 3), but the yield decreased when the
temperature was lowered (entry 4).
o
precursor
from the Ag complex to the Ru dimer.
Complexes are soluble in most organic solvents, such as
A could also slow down the carbene transfer rate
1−3
CH2Cl2, CHCl3, MeOH and CH3CN, with the exception of
nonpolar ones, such as hexane and diethyl ether. Their
formation is supported by ESI mass spectra, where base peaks
corresponding to the [M – 2Cl + OH + MeCN]+ fragment were
In general, the initial catalytic activity observed was higher
and up to 60% yield was obtained for a 6 h reaction at 130 C
o
(entry 5). Under these conditions, doubling the catalyst loading
improved the yield to 80% (entry 6). At this point, the catalytic
performance in presence of a solvent was investigated. The
catalytic performance decreased drastically, and only 13% and
8% yields were observed with common solvents generally used
for this reaction such as toluene and diglyme (entries 7 & 8),
respectively.
1
observed. In the H NMR spectra, the absence of downfield
signals characteristic for the benzimidazolium salts indicates
the formation of the expected RuꢀNHC complexes. The carbene
signals in the 13C NMR spectra of complexes
1−3 are observed
at 187.4, 189.5 and 191.6 ppm, respectively, which are more
2 | J. Name., 2012, 00, 1-3
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Table 1: Optimization of catalyst and reaction Table 2:
Catalytic activity of various Ru-NHC
conditionsa
complexesa
entry catalyst
amount
temp.
time (h)
yield,
(%)
of catalyst (oC)
(mol%)
1
1.0
2.5
2.5
2.5
2.5
5.0
5.0
5.0
5.0
5.0
5.0
5.0
130
130
140
120
130
130
130
130
130
130
130
130
18
18
18
18
6
40
70
68
53
60
80
13b
8c
1
1
1
1
1
1
1
1
2
3
1
2
2
entry
catalyst
additive
yield (%)
3
4
1
2
3
4
5
6
7
8
9
Nil
Nil
Nil
Nil
24
19
88
74
4
5
6
7
7
4
5
1
2
3
5
6
6
7
6
8
6
9
6
62
5
PPh3 (5 mol%) 75
PPh3 (5 mol%) 51
PPh3 (5 mol%) 48
PPh3 (5 mol%) 87
PPh3 (5 mol%) 64
PPh3 (5 mol%) 85
10
11
12
6
18
18
>99
>99
a
Reaction conditions: 1 mmol of aniline, 1.2 mmol of benzyl
alcohol. % yields were determined by GC analysis using
docecane as the internal standard. bToluene as solvent,
cDiglyme as a solvent.
10
a
Reaction conditions: 1 mmol of aniline, 1.2 mmol of benzyl
Under the present optimized conditions, catalyst
2 having
o
alcohol. 5 mol% of RuꢀNHC catalyst at 130 C for 6 hrs. %
one of the isopropyl substituents replaced with a benzyl group
gave a yield of 62% (entry 9). However, the catalytic activity
was nearly suppressed when both the isopropyl groups were
yields were determined by GC analysis using docecane as the
internal standard.
replaced with benzyl groups as in catalyst
effect of the benzyl groups on the catalytic performance may be
due to a possible
ꢀcoordination34 of benzyl moiety to the Ruꢀ
center upon removal of ꢀcymene or other ligands under the
reaction conditions, thus hindering the coordination and further
activation of substrates and intermediates. Although catalyst
shows slightly lower initial activity compared to , both the
catalysts ( and ) gave near quantitative yields upon increasing
3. The unfavorable
The performance of catalysts
in the presence of PPh3 giving up to 87% and 64% yields,
respectively (entries 8 and 9). However, the 1,3ꢀdibenzylꢀ
1 and 2 marginally improved
π
p
benzimidazolinꢀ2ꢀylidene complex
3 became much more active
in the presence of PPh3 yielding up to 85% of the product (entry
10). This favorable effect of the phosphine could be due to its
coordination to the ruthenium center, which may sterically
prevent the π−coordination of benzyl moiety to the Ruꢀcenter.
2
1
1
2
the reaction time to 18 h (entries 11 & 12).
The catalytic performances of the benzimidazolinꢀ2ꢀylidene
Scheme 2: Synthesis of Ru-NHC-Phosphine complex 3a
ruthenium complexes
common ruthenium imidazolinꢀ and imidazolidinꢀ2ꢀylidene
complexes ( ) under the same optimized conditions, and the
results are given in Table 2. Complexes and with IMes and
IiPr ligands gave lower yields of 24% and 19% (entries 1 & 2),
respectively. Grubb’s second generation catalyst ( ) bearing the
SIMes gave an improved yield of 88% while, the Hoveydaꢀ
Grubb’s catalyst ( ) gave up to 74% yield (entries 3 & 4). We
reckoned that the improved catalytic performance observed
with Grubbs II catalyst compared to other catalysts may be
1 – 3, were compared with those of some
4
– 7
4
5
6
7
6
due to the presence of a phosphine (PCy3) as an additional
ligand. Hence, the addition of phosphine was investigated to
examine if any beneficial synergistic effect exists. No specific
In order to understand this beneficial effect on relatively
inactive complexes such as
3, the new mixed NHC/Phosphine
effect was observed with the HoveydaꢀGrubb’s catalyst (
7) in
ruthenium complex [RuCl2(pꢀcymene)(bimy)Cl(PPh3)]PF6 (3a
)
the presence of PPh3.35 However, enhanced catalytic activity
was prepared as shown in Scheme 2 for the purpose of further
comparison. A small improvement in catalytic activity was
was noted with catalysts
4 and 5, and up to 51% and 45% yields
were observed at 130 oC after 6 h (entries 5 & 6).
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4RA15398G
observed (87%, under the reaction conditions given in Table 2)
Next, the substrate scope of amines was investigated using
with wellꢀdefined 3a compared to that of the inꢀsitu generated benzyl alcohol as the alkylating agent (Table 4). Electron
species by external addition of PPh3 to catalyst (85%, Table donating ꢀMe substituted aniline gave 21 in moderate yield of
2, entry 10). Notably, near quantitative yield was observed for 62%, while an increased yield up to 86% was observed for 22
3a upon increasing the reaction time to 18 h. Since the when ꢀchloro aniline was used as the substrate. Benzylamine
benzimidazolinꢀ2ꢀylidene (bimy) complexes and 3a gave gave dibenzylamine (23) in 81% yield, whereas 47% yield of
3
p
p
1, 2
similar results for the
Nꢀalkylation using primary alcohols the secondary amine 24 was observed when an aliphatic amine
under the optimized conditions (at 130 oC for 18 h under such as hexylamine was used. Near quantitative yield of the
solventless conditions), they were further evaluated for tertiary amine 25 was achieved for the alkylation of six
substrate scope and limitations.
Alkylation of aniline using various benzylic and aliphatic such
alcohols gave good to excellent results using catalyst as tetrahydroisoquinoline were also readily alkylated giving the
presented in Table 3. Excellent isolated yield of 95% was corresponding cyclic tertiary amines 26 28 in 70 – 73%
achieved for the secondary amine when ꢀMe substituted isolated yields.
benzylalcohol was used as the alkylating agent. ꢀF and ꢀCl The possible application of the benzimidazolinꢀ2ꢀylidene
substituted benzyl alcohols gave the corresponding secondary complexes and 3a were further examined for the synthesis
amine products 10 and 11 in 91% and 61% isolated yields of pharmaceutically important secondary and tertiary amines.
respectively. The ꢀBr substituted benzyl alcohol showed poor For this purpose, Fendiline (29), an antiꢀanginal agent was
activity yielding 12 in 25% with lower conversion. Both ꢀOMe chosen as an initial example (Scheme 3). The direct synthesis
and
ꢀOMe substituted benzyl alcohols were coupled with of Fendiline36 was reported previously by Williams and
membered cyclic amine such as piperidine. Other cyclic amines
as pyrrolidine, morpholine and 1,2,3,4ꢀ
1
–
9
p
p
p
1, 2
p
p
o
aniline giving the corresponding secondary amine products 13 coworkers adopting hydrogen borrowing strategy in presence of
(80%) and 14 (70%) in very good yields. The relatively less [Cp*IrCl2]2 as the catalyst. 37
reactive aliphatic alcohols were also found to be promising
alkylating agents and up to 73% isolated yield of
Nꢀoctyl
Table 4. Alkylation of various amines using benzyl
alcohola
aniline (15) was obtained when 1ꢀoctanol was used. Secondary
amines such as 16 and 17 were obtained in good yield of 66%
and 77% respectively, when cyclohexylmethanol and
cyclopropylmethanol were used as the alkylating agents.
Aliphatic alcohol such as 3ꢀphenylpropanol gave only moderate
yield of 45% of the secondary amine 18 under the present set of
conditions. Secondary alcohols such as 1ꢀphenylethanol and 2ꢀ
octanol were found to be poor alkylating agents in the presence
of catalyst
1, 2 and 3a providing maximum yields of 52% (19)
and 49% (20).
Table 3. Alkylation of aniline using various alcoholsa
a
Reaction conditions: 1 mmol of amine, 1.2 mmol of benzyl
alcohol, 5 mol% of catalyst
are given.
1
at 130 oC for 18 h. Isolated yields
Scheme 3: Catalyst optimization for the synthesis of
Fendiline
a
Catalyst
1 having symmetrically substituted isopropyl
Reaction conditions: 1 mmol of aniline, 1.2 mmol of alcohol, 5
mol% of catalyst
at 130oC for 18h. Isolated yields are given. b
was used as the catalyst; catalysts and 3a gave 18% and
22% yields respectively. c 2 was used as the catalyst; catalysts
and
a gave 40% and 43% yields respectively. dCatalyst 3a was
used, catalysts and gave lower yields.
groups gave up to 69% yield, while the unsymmetrically
substituted catalyst
24 h reaction. Interestingly, catalyst 3a gave an improved yield
of 74% and was selected for further applications in the
synthesis of pharmaceutically important amines. Under the
standardized conditions as shown in Scheme 3, good isolated
2
o
2 gave a lower yield of 43% at 130 C after
2
1
1
3
1
2
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C4RA15398G
yield of 62 – 70% were achieved for the synthesis of some of and
the pharmaceutically important compounds such as Alverine38 pentandiol giving the cyclized product 35 and 36 in 76% and
30), Fenpiprane39 31) and Prozapine39
32) (Fig. 2). To the 88% yields, respectively. Excellent yields were also achieved
best of our knowledge, Hꢀborrowing strategy has not been for the synthesis of 37 (98%) and 38 (93%) using 4ꢀmethoxy
demonstrated for the synthesis of pharmaceutically important and 3,4ꢀdimethoxy substituted anilines. 1ꢀ(4ꢀ
molecules 30 32
pꢀMe substituted anilines were double alkylated with 1,5ꢀ
(
(
(
ꢀ
.
chlorophenyl)piperidine (39) was obtained in 63% yield from
4ꢀchlorophenyl aniline and 1,5ꢀpentandiol. 1,4ꢀdi(piperidinꢀ1ꢀ
yl)benzene (40) was obtained in 73% yield from 4ꢀ(piperidinꢀ1ꢀ
yl)aniline and 1,5ꢀpentanediol. Both 1,4ꢀbutanediol and 1,6ꢀ
hexandiol react smoothly with aniline to form 1ꢀ
phenylpyrrolidine (41) and 1ꢀphenylazepane (42), respectively,
in very good yields.
Table 6. Synthesis of various cyclic amines by
alkylation using diolsa
N-
Fig. 2: Synthetic application of catalyst 3a for the preparation of
pharmaceutically important amines.
The cyclization using diols following hydrogen borrowing
strategy is a convenient protocol to prepare several valueꢀadded
cyclic amines from the corresponding primary amines.
Yamaguchi et al. employed iridium catalyst for the synthesis of
cyclic tertiary amines by reaction of various primary amines
with suitable diols to achieve good yields.40 Ruthenium
catalysts were reported to be effective for using diols as
alkylating agents for the preparation of cyclic amines.10a,41
Considering the importance of cyclic amines, we have
investigated the catalytic performance of the benzannulated
NHC complexes 1, 2 and 3a for their synthesis using diols as
alkylating agents.
Table 5. Optimization of
N
-alkylation using diolsa
a
Reaction conditions: 2 mmol of aniline, 2 mmol of diol, 150
oC, 24h. 2.5 mol% of RuꢀNHC catalyst for 24 h. Isolated yields
are reported.
Ruthenium catalyzed alcohol activation is reported to
proceed through the formation of a RuꢀH species as an active
intermediate that initiate the catalytic cycle.42 In the present Ruꢀ
entry catalyst temp.
(oC)
conv.
(%)
89
yield of yield of
33 (%)
34 (%)
NHC catalyst system, formation of a RuꢀH species43 at
δ
= ꢀ
9.62 ppm was detected by 1H NMR spectroscopy (Fig. 3,
spectrum ) from an intermediate reaction sample after 2 h of
the standard
catalyst . Apart from this signal, additional signals at ꢀ1.69 and
ꢀ2.93 ppm were also observed. In the presence of one additional
equivalent of PPh3,44 two doublets at ꢀ7.36 (
= 53.4 Hz) and ꢀ
9.41 ppm ( = 56.2 Hz) as well as two triplets at ꢀ9.81 ( = 35.8
Hz) and ꢀ13.28 ppm (
= 19.9 Hz) were observed45 showing the
formation multiple RuꢀH species coordinated with PPh3 (Fig. 3,
Spectrum ). The nearly inactive complex showed one
prominent RuꢀH signal at ꢀ8.3 ppm along with a slightly upfield
1
130
33
55
1
2
3
4
5
130
130
150
150
150
82
96
98
87
86
23
66
93b
47
45
58
29
4
38
39
2
A
3a
3a
1
o
N
ꢀalkylation reaction44 (Table 1) at 100 C using
1
6
2
a
J
Reaction conditions: 2 mmol of aniline, 2 mmol of 1,5ꢀ
J
J
pentanediol. 2.5 mol% of RuꢀNHC catalyst for 24 h. Yields
were determined by GC analysis using dodecane as the internal
standard. b 89% isolated yield
J
B
3
As shown in Table 5, yields of 23 ꢀ 33% were observed for
shifted, low intensity broad resonance (Fig. 3, Spectrum
C),
the cyclized product
of 89% at 130 C after 24 h using 2.5 mol% catalysts and 2.
N
ꢀphenyl piperidine (33) with a conversion
o
which may be attributed to a possible formation of stable
π
ꢀ
1
benzyl coordinated species that may restrict coordination of the
intermediate imine for completing the catalytic cycle. However,
in the presence of added one equivalent of PPh3, this RuꢀH
species was considerably reduced with the formation of three
In both the cases, the monoalkylated product 34 was found to
be the major product (entries 1 & 2). However, up to 66% yield
to 33 was observed with the catalyst 3a, which was further
improved to 93% (entry 4) upon increasing the temperature to
o
sets of doublets (δ = ꢀ9.09, ꢀ9.82 and ꢀ10.01; approx.
and two sets of triplets (δ = ꢀ9.81 and ꢀ10.88; = 35.7 Hz) (Fig.
3, Spectrum ). Some of these hydride signals were found to
disappear with time.
J = 48 Hz)
150 C. No specific temperature effect was observed for the
J
catalyst
1 or 2. This optimized condition was used to extend the
D
substrate scope using various diols as alkylating agents for the
synthesis of cyclic amines.
Excellent yields up to 98% were achieved for various
o
anilines as substrates at 150 C as given in Table 6. Both
o
ꢀMe
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DOI: 10.1039/C4RA15398G
of coordinated
complexes.
p
ꢀcymene ligand in these intermediate
In an effort to further characterize the intermediates,
31P{1H}NMR analysis (Fig 4) was carried out with the samples
obtained under reaction conditions from complexes +PPh3
1
(Spectrum ), +PPh3 (Spectrum ) and 3a (Spectrum H). In
F
3
G
the case of 3a, two new species were detected at 27.18 and
25.39 ppm together with free PPh3 (ꢀ5.29 ppm) and 3a (33.17
ppm). Complex
3 in the presence of added PPh3 gave a major
signal at 24.52 ppm and several 31P NMR signals in the range
of 20 to 55 ppm, which were difficult to assign to any particular
intermediate species. However, complex
1 with added PPh3
gave five sharp signals in the range of 25 to 55 ppm with a
major signal at 24.56 ppm. The signal at 24.5 ppm in both these
cases can be assigned to a phosphine coordinated precatalyst
such as [RuCl2(NHC)(PPh3)(pꢀcymene)], similar to species Ia
in Scheme 2. The other signals may correspond to various
phosphineꢀcoordinated Ru species including that of rutheniumꢀ
hydrido intermediates.
Scheme 2: Proposed catalytic cycle
1
Fig. 3. H NMR spectroscopic (400 MHz) analysis for Ru-H species formed under
reaction conditions with Complex 1 (A, CDCl3), Complex 1+PPh3 (B, CDCl3),
D, CDCl3) and Complex 3a (E, DMSO-d6).44
Complex 3 (C, CDCl3), Complex 3+PPh3
(
Based on the detection of various RuꢀH species and RuꢀP
species as well as other literature reports42 we are proposing a
simple catalytic cycle as shown in scheme 3 likely involving a
Fig. 4
formed under reaction conditions with Complex
+PPh3 (G, CDCl3) and Complex 3a (F, DMSO-d6)
.
31P{1H} NMR spectroscopic analysis (162 MHz) for intermediate Ru species
+PPh3 (H, CDCl3), Complex
1
3
Ruꢀalkoxide complex I formed from the phosphine coordinated
RuꢀNHC preꢀcatalyst upon reaction with the alcohol, as the
active catalytic species initiating the catalytic cycle. The Ruꢀ
Unfortunately, the intermediate complexes obtained from
3a were not very stable and immediately precipitated as the
parent compound 3a upon dissolving in common deuterated
solvents (CDCl3, CD3OD, etc.). However, from a dilute
solution obtained by warming the reaction mixture in DMSOꢀ
d6, we could observe multiple RuꢀH signals (Fig. 3, Spectrum
complex
I is transformed to a possible RuꢀH complex II by
elimination of the carbonyl intermediate, which condenses with
the amine to form the imine intermediate. Insertion of this
imine intermediate into the RuꢀH species II generates the Ruꢀ
complex III, which produces the amine product and the active
E
) such as three doublets {ꢀ7.61 ppm, (
(d, = 52.1 Hz and ꢀ10.28 ppm (d, = 48.3 Hz)}, one triplet at
ꢀ10.28 ppm (d, = 48.3 Hz); and one doublet of doublet at ꢀ
9.18 ppm ( = 49.2, 13.4 Hz). In all these cases two to four sets
of
ꢀcymene signals44 were also detected showing the presence
J = 47.3 Hz), ꢀ8.01 ppm
complex
I upon subsequent reaction with the alcohol. PPh3 is
J
J
optionally coordinated and in its absence, a corresponding
neutral RuꢀCl complex or cationic complex with a vacant
coordination site can be envisaged. Notably, all proposed
catalytic intermediates are chiralꢀatꢀmetal. In combination with
J
J
p
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C4RA15398G
the planar chirality resulting from restricted rotation of the pꢀ
3
4
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cymene ligand, diastereomeric mixtures can be anticipated,
which also explains the multiple species noted in Figure 3 and
4. A detailed analysis, both experimental and theoretical
calculations, is required to understand the exact nature of the
various ruthenium intermediates formed under the reaction
conditions to validate this proposed mechanism and is currently
5
in progress at our laboratory
.
Conclusions
In conclusion, we have reported the synthesis of ruthenium
complexes bearing symmetrically and 3a and
unsymmetrically substituted benzimidazolinꢀ2ꢀylidene
ChemCatChem, 2011,
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(
1
,
3
)
(2)
ligands. These rutheniumꢀNHC complexes showed promising
catalytic activity for the alkylation of various amines using
alcohols under solventꢀfree conditions in the absence of any
external base. The catalysts were shown to be effective for the
synthesis of pharmaceutically important amines such as
Fendiline, Alverine, Fenpiprane and Prozapine giving generally
,
7
6
7
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amines were synthesized expediently from the corresponding
diols using the cationic Ru catalyst 3a having both phosphine
and carbene ligands. In general, the initial catalytic activity was
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Green and Sustainable manufacturing and the Institute of Chemical
and Engineering Sciences (ICES), Agency for Science, Technology
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Department of Chemistry, National University of Singapore, 3 Science
Drive 3, Singapore 117543.
† Indian Institute of Science Education and Research, Dr. Homi Bhabha
Road, Pashan, Pune 411 008. India.
*eꢀmail: abdul_seayad@ices.a-star.edu.sg; chmhhv@nus.edu.sg
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DOI: 10.1039/C4RA15398G
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DOI: 10.1039/C4RA15398G
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Simple non-chelating ruthenium benzimidazolin-2-ylidene complexes as efficient N-alkylation catalyst
using alcohols and diols following hydrogen borrowing strategy.