Reusable supported ruthenium catalysts for the alkylation of amines by using primary alcohols

Article abstract of DOI:10.1002/cctc.201300971

Efficient and recyclable ruthenium catalysts were synthesized from readily available polystyrene-or silica-supported phosphine ligands. Catalysts bound to the polymer support through an ether linkage showed good to excellent activity towards the N-alkylation of primary and secondary amines to afford the alkylated products in 62-99 % yield at 120-140°C. The supported phosphine ligand/ruthenium ratio was found to be crucial for higher catalytic activity and lower ruthenium leaching. The continuous flow N-alkylation of amines was demonstrated by using the supported catalyst in a column reactor. By adopting the hydrogen-borrowing strategy, the synthesis of the anti-Parkinson agent Piribedil was established in 98 % yield at 140°C. Support group steals the show: An efficient Ru-based heterogeneous catalyst from readily available supported phosphine ligands is developed. The nature of the linkage and the extent of ruthenium incorporation are crucial in determining the catalytic activity. The catalyst can be recycled and used under continuous flow in a packed-bed reactor. The alkylation of cyclic amines is achieved in excellent yield at moderate temperatures in the absence of any external base.

Full text of DOI:10.1002/cctc.201300971

CHEMCATCHEM
FULL PAPERS
DOI: 10.1002/cctc.201300971
Reusable Supported Ruthenium Catalysts for the
Alkylation of Amines by using Primary Alcohols
Siah Pei Shan, Tuan Thanh Dang, Abdul Majeed Seayad, and Balamurugan Ramalingam*[a]
Efficient and recyclable ruthenium catalysts were synthesized
from readily available polystyrene- or silica-supported phos-
phine ligands. Catalysts bound to the polymer support
through an ether linkage showed good to excellent activity to-
wards the N-alkylation of primary and secondary amines to
afford the alkylated products in 62–99% yield at 120–1408C.
The supported phosphine ligand/ruthenium ratio was found to
be crucial for higher catalytic activity and lower ruthenium
leaching. The continuous flow N-alkylation of amines was dem-
onstrated by using the supported catalyst in a column reactor.
By adopting the hydrogen-borrowing strategy, the synthesis of
the anti-Parkinson agent Piribedil was established in 98% yield
at 1408C.
Introduction
Substituted amines are widely used as building blocks in the
agrochemical, dye, and detergent industries.[1] They also serve
as pharmacophores in biologically important pharmaceutical
products,[2] and N-alkylation has been frequently exploited by
pharmaceutical industries for nitrogen-substitution reactions.
Carey and co-workers[3] estimated that 64% of all nitrogen-sub-
stitution reactions performed at the process research and de-
velopment stage at Astra Zeneca, GlaxoSmithKline, and Pfizer
fall into the N-alkylation category, and 36% of them use geno-
toxic/mutagenic organic halides. Organic halides were tradi-
tionally obtained from nonhazardous alcohols and were used
as electrophiles for further alkylation of primary and secondary
amines. Alternatively, the alcohols could be utilized directly as
electrophiles for N-alkylation reactions by using transition-
metal catalysts adopting the “hydrogen-borrowing” strategy.[4]
Under this methodology, the alcohols are activated to an
active carbonyl compound by dehydrogenation. The in situ
formed carbonyl compound reacts with an amine to form an
imine intermediate, which undergoes hydrogenation to form
the corresponding amine product by using the borrowed hy-
drogen. The overall process is redox neutral and water is the
only byproduct. Adopting this strategy, Grigg[5] and Wata-
nabe[6] independently reported the N-alkylation of amines by
using RhH(PPh3)4 and RuCl2(PPh3)3, respectively, for the first
time. Subsequently, a number of Ru[7] and Ir[8] catalysts have
been reported, and they were proven to be effective for the al-
kylation of both amines and carbonyl compounds under ho-
mogenous reaction conditions. Catalysts derived from other
metals, such as Cu,[9] Fe,[10] Os,[11] and Rh,[12] have also been ex-
plored. Though progress made in the alkylation of alcohols by
homogeneous catalysts is significantly remarkable, the recov-
ery of the products from the reaction mixture often requires
more effort and becomes increasingly tedious in large-scale
processes.
The interest in developing recyclable heterogeneous cata-
lysts is consistently increasing owing to their ease of handling
and operational simplicity. Adopting the hydrogen-borrowing
strategy, Shimizu and co-workers[13] reported alumina-support-
ed Ni nanoparticles as a heterogeneous catalyst for the N-alkyl-
ation of amines at 1448C. Under these conditions, the N-alkyl-
ation of primary and secondary amines was performed effec-
tively to provide the alkylated products in 74–99% yield. Up to
96% yield was reported by Cao et al. for the formation of sec-
ondary amines from selected substituted anilines by using Au/
TiO2[14] at 1208C in toluene. However, a higher reaction temper-
ature (1408C) and a long reaction time (50 h) were needed for
the alkylation of cyclic amines such as pyrrolidine. A supported
bimetallic Pt–Sn[15] catalyst was employed for the N-alkylation
of diols at 1458C to afford the substituted diamines in 20–94%
yield. Other heterogeneous catalysts such as Pd/MgO, Cu–Ag/
Al2O3, g-Al2O3/Ag, NiCu–FeOx, CuAl–hydrotalcite, and Ru(OH)x/
Al2O3 are also known[16] for the alkylation of aniline derivatives
at temperatures >1358C. In the presence of an excess amount
of KOH (130 mol%), impregnated ruthenium on magnetite
[a] S. Pei Shan, Dr. T. T. Dang, Dr. A. M. Seayad, Dr. B. Ramalingam
Organic Chemistry
[Ru(OH)3–Fe3O4][17] catalyzed the N-alkylation of substituted ani-
Institute of Chemical and Engineering Sciences
Agency for Science, Technology and Research (A*STAR)
8 Biomedical Grove, Neuros #07-01, Singapore 138665 (Singapore)
Fax: (+65)6464-2102
[18]
lines in 71–99% yield at 1308C. Ag/Al2O3
catalysts were
found to be active in the presence of Cs2CO3 (30 mol%) for the
N-alkylation of anilines at 1208C and gave up to 99% yield. An
iridium catalyst derived from a mesoporous silica (SBA-15)-sup-
ported N-heterocyclic carbene[19] ligand gave good to excellent
yields (58–99%) at 1108C for both the N-alkylation of amines
and the b-alkylation of secondary alcohols in the presence of
E-mail: balamurugan_ramalingam@ices.a-star.edu.sg
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300971. It contains the experimental
procedures for the a-alkylation of methyl ketones and continuous flow
alkylation and the product characterization data.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 808 – 814 808

CHEMCATCHEM
FULL PAPERS
www.chemcatchem.org
KOH (100 mol%). The catalyst was recycled 12 times without
any significant loss in catalytic activity, and no detectable level
of metal leaching was reported. In the presence of tBuOK
(200 mol%), Fe2O3 catalyzed[20] the alkylation of aromatic
amines with benzylic alcohols to form the alkylated products
in 33–99% yield at 908C with a reaction times of 7–10 days.
In general, the reported heterogeneous catalysts require
either higher reaction temperatures (>1408C) or the presence
of a base to achieve higher yields of N-alkylated products.
Major hurdles that still need to be overcome in hydrogen-bor-
rowing methodology with the use of heterogeneous catalysts
are:
1) The high reaction temperature,
2) The use of strong base,
3) The narrow substrate scope,[21]
4) The limited accessibility to reusable catalysts that are ob-
tained from readily available supported ligands.
Here, we report a promising reusable catalyst for the N-alkyl-
ation of amines by using alcohols at moderate temperatures in
the absence of an external base. Interestingly, the catalysts ob-
tained from triphenylphosphine bound to the polymer support
through an ether linkage showed superior activity towards the
alkylation of both primary and secondary amines. The catalyst
was easy to recover and was recycled over five runs; it also
showed very low ruthenium leaching. The catalyst was used in
a packed-bed reactor, and the N-alkylation of piperidine was
demonstrated under continuous flow.
Scheme 1. Catalyst synthesis from commercially available supported phos-
phine ligands. PS=polystyrene, Si=silica.
Table 1. Initial catalyst screening and optimization of the reaction condi-
tions.
Entry
Catalyst
Solvent
t
[h]
Yield of 1
[%][a]
Ruthenium
leaching [ppm][b]
Results and Discussion
1
2
3
4
5
6
7
8
A
B
C
D
E
F
G
H
I
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
diglyme
dioxane
water
12
12
12
12
12
12
12
12
12
5
5
5
12
12
12
5
55
60
26
40
57
65
87
91
–
–
–
–
–
Catalyst synthesis and reaction optimization
For the present study, supported catalysts A–L were obtained
from commercially available supported phosphine ligands
SL1–SL4 and [Ru(p-cymene)2Cl2]2. As shown in Scheme 1, cata-
lysts A, C, E, and G were prepared from an equimolar ratio of
the supported ligand and ruthenium, whereas the phosphine
ratio was doubled to obtain catalysts B, D, F, and H. Ruthenium
incorporation was determined by inductively coupled plasma
(ICP) analysis (see Table S1, Supporting Information). The fol-
lowing important points were observed from the initial screen-
ing of catalysts A–H (5 mol%) for the alkylation of piperidine
by using benzyl alcohol at 1208C in toluene (Table 1,
entries 1–8):
–
125
99
12
5
2
2
–
–
–
–
9
>99 (82)[c]
>99 (21)[d]
>99 (27)[d]
>99 (36)[d]
31
10
11
12
13
14
15
16
17
J
K
L
L
L
L
L
–
40
n.r.[e]
toluene
toluene
24[f]
12
n.r.[e]
–
[a] Determined by gas chromatography by using hexadecane as an inter-
nal standard. [b] Calculated from ICP analysis. [c] Yield obtained after 5 h.
[d] Yield obtained after 1 h. [e] No reaction; benzyl alcohol remained un-
reacted. [f] Reaction at 1008C.
1) Catalysts G and H obtained from SL4 gave a better yield of
87 and 91% (Table 1, entries 7 and 8), respectively, than the
other catalysts.
2) Catalysts obtained with Ru/P=1:2, as in B, D, F, and H,
gave better yields than the corresponding 1:1 analogues,
that is, A, C, E, and G (Table 1, entries 2, 4, 6, 8 vs. 1, 3, 5, 7).
3) Ruthenium leaching for catalyst G (125 ppm; Table 1,
entry 7) was higher than that for catalyst H (99 ppm;
Table 1, entry 8); this suggests the benefit of having
a higher number of equivalents of the phosphine in mini-
mizing ruthenium leaching.
Accordingly, catalysts I–L (Scheme 1) were synthesized by
using SL4, and their use in N-alkylation reactions was explored
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 808 – 814 809

CHEMCATCHEM
FULL PAPERS
www.chemcatchem.org
further. To our delight, upon increasing the Ru/P ratio to 1:3 as
in catalyst I, a quantitative yield of 1 was obtained (Table 1,
entry 9) in 12 h. Additionally, ruthenium leaching was signifi-
cantly reduced (Table 1, entry 8 vs. 9) from 99 to 12 ppm with
the higher amount of phosphine. A further increase in the Ru/
P ratio to 1:4 (for J), 1:5 (for K), and 1:6 (for L) had a clear influ-
ence on the catalytic activity and in minimizing ruthenium
leaching (Table 1, entries 10 and 11). The catalytic reaction was
complete in 5 h upon employing catalysts J–L (5 mol%;
Table 1, entries 10–12). Although catalysts J–L showed similar
catalytic activity, L gave a higher yield of the product (36%;
Table 1, entry 12) than both J (21%; Table 1, entry 10) and K
(27%; Table 1, entry 11) in 1 h. Hence, catalyst L was selected
for further studies. Upon performing the catalytic reaction in
ether solvents such as diglyme and dioxane at 1208C, product
1 was obtained in only 31 (Table 1, entry 13) and 40% yield
(Table 1, entry 14), respectively. No reaction was observed in
water (Table 1, entry 15) as the solvent.
after 2 h, and the yield of product 1 was 37%. No further clear
change in the product yield (39%) was observed upon con-
tinuing the reaction for an additional 12 h without catalyst L at
1208C. Further, ICP analysis of the reaction mixture obtained
by hot filtration showed only <2 ppm ruthenium leaching. All
these observations indicate that the catalytic reaction mainly
proceeds in the presence of a heterogeneous catalyst and may
not be due to a trace amount of ruthenium leached into the
reaction mixture.
Alkylation of secondary amines
The alkylation of cyclic amines was performed by using differ-
ent primary alcohols under the optimized reaction conditions
in the presence of catalyst L (Table 2). We focused our atten-
tion on the alkylation of various secondary amines, as they are
Reducing the reaction temperature to 1008C (Table 1,
entry 16) led to a poor yield of 1. Among catalysts G–L that
were derived from SL4, L showed the highest activity and G
was the least active. The higher activity of L may be due to the
greater stabilization of the ruthenium center in the presence
of a higher percentage of phosphine. Scanning electron mi-
croscopy (SEM) analysis of catalyst beads G and L before and
after the reaction[22] (Figures S1–S3, Supporting Information) in-
dicated that the surface of L was largely unchanged after the
reaction, whereas G suffered under the reaction conditions.[22]
Table 2. Substrate scope for the alkylation of secondary amines by using
catalyst L.[a]
Entry Alcohol
1
Amine
Product
Yield [%][b]
94 (5 h)
1
2
Catalyst recycling studies
X=p-Me (2)
p-OMe (3)
p-F (4)
86 (20 h)
96 (20 h)
98 (20 h)
99 (20 h)
65 (20 h)
90 (20 h)
The recyclability of catalyst L was examined by its use
(5 mol%) in the benzylation of piperidine under the optimized
reaction conditions (Figure 1). After a reaction time of 4 h, the
catalyst was recovered and reused over five runs without a sig-
nificant loss in activity. Ruthenium leaching was determined by
ICP analysis after each cycle and was found to be significantly
low (<2.5 ppm). To understand the heterogeneous nature of
the catalyst, catalyst L was removed from the reaction mixture
3
4
5
6
7
p-Cl (5)
p-Br (6)
o-OMe (7)
8
70 (24 h)
8
9
9
87 (18 h)
79 (24 h)
89 (24 h)
10
11
10
11
12
13
95 (24 h)
94 (24 h)
12
13
Figure 1. Recycling studies by using catalyst L (5 mol%). Reactions were per-
formed with benzyl alcohol (1.2 mmol) and piperidine (1 mmol) in toluene
(3 mL) at 1208C for 4 h.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 808 – 814 810

CHEMCATCHEM
FULL PAPERS
www.chemcatchem.org
Table 2. (Continued)
Table 3. Substrate scope for the alkylation of primary amines by using
catalyst L.[a]
Entry Alcohol
Amine
Product
Yield [%][b]
78 (24 h)
Entry Alcohol
Amine
Product
Yield [%][b]
14
1
14
X=H (19)
69
86
82
2
3
CH3 (20)
Cl (21)
15
16
68 (30 h)
15
16
95 (24 h)[c]
4
Y=H (22)
CH3 (23)
88
86
67
17
18
68 (24 h)[c]
64 (24 h)[c]
5
6
OCH3 (24)
17
7
8
63[c,d]
25
26
90[c]
18
[a] Reactions were performed with the alcohol (1.2 mmol) and amine
(1 mmol). [b] Yield of isolated product; the reaction time is given in pa-
rentheses. [c] Reactions were performed at 1408C.
9
87[c]
27
28
generally poorer substrates[21] under the hydrogen-borrowing
strategy as a result of the involvement of an disfavored imini-
um intermediate. Substituted benzyl alcohols with electron-do-
nating and electron-withdrawing groups reacted with piperi-
dine to give products 2–6 in high yields (Table 2, entries 2–6).
The presence of a OMe group at the ortho position did not
affect the reactivity of the alcohols towards piperidine, and al-
kylated product 7 was obtained in 90% yield (Table 2, entry 7).
Other cyclic amines such as pyrrolidine, morpholine, azepane,
tetralin, and 1-methylpiperazine were benzylated to respective
tertiary amines 8–12 in good to excellent yields (Table 2, en-
tries 8–12). Importantly, alkylated products 13 and 14 were ob-
tained in 94 (Table 2, entry 13) and 78% yield (Table 2,
entry 14), respectively, from more challenging aliphatic alco-
hols such as cyclohexylmethanol and 1-octanol. Tertiary amines
15–18 were isolated in 64–95% yield from acyclic secondary
amines (Table 2, entries 15–18).
10
11
77
84
29
12
73
30
[a] Reactions were performed with the alcohol (1.2 mmol) and amine
(1 mmol) in toluene (3 mL) by using catalyst L (5 mol%). [b] Yield of iso-
lated product after 24 h at 1208C. [c] Reaction was performed at 1408C.
[d] Approximately 8% of tribenzylamine was identified together with 25
in the crude reaction mixture.
amines were alkylated to secondary amines 28–30 in 73–84%
yield (Table 3, entries 10–12). Secondary alcohols such as
1-phenylethanol and 1-(naphthalen-2-yl)ethanol gave only
<30% yield for the alkylation of piperidine in 48 h.
Alkylation of primary amines
The catalyst also showed good activity towards the alkylation
of primary amines. Aniline and substituted anilines were ben-
zylated to secondary amines 19–21 (Table 3, entries 1–3) in
good yields. Notably, more challenging 1-octanol was also
used as an electrophilic partner for the alkylation of anilines
and afforded alkylated products 22–24 in 67–88% yield
(Table 3, entries 4–6). Benzylamine was alkylated by using
benzyl alcohol and cyclopropylmethanol to give secondary
amines 25 (Table 3, entry 7) and 26 (Table 3, entry 8), respec-
tively. a-Branched cyclohexanamine was benzylated to product
27 in 87% yield at 1408C (Table 3, entry 9). Linear aliphatic
Piribedil synthesis
Further, the use of catalyst L was demonstrated in the synthe-
sis[23] of piribedil, which is used for the treatment of Parkinson’s
disease. 1-(Pyrimidin-2-yl)piperazine was directly alkylated in
nearly quantitative yield by using piperonyl alcohol
(Scheme 2). After the initial run, the catalyst was recovered by
simple filtration and reused in two subsequent runs effectively
with comparable yields in each cycle.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 808 – 814 811

CHEMCATCHEM
FULL PAPERS
www.chemcatchem.org
yield by using a Au/TiO2 catalyst
under flow conditions at temper-
atures >1808C. The N-alkylation
of morpholine with benzyl alco-
hol by using supported rutheni-
um catalysts in a fixed-bed reac-
tor was reported.[26] A high con-
version (>98%) was achieved by
Scheme 2. Synthesis of piribedil by using catalyst L.
using p-xylene as the solvent at
1508C. The efficient recyclability
and low ruthenium leaching of
a-Alkylation of methyl ketones
catalyst L encouraged us to use it in a packed-bed reactor
for performing the N-alkylation reaction under continuous
flow (Figure 2a). For the initial studies, supported catalyst L
The activity of catalyst L was also examined in CÀC bond-form-
ing reactions by adopting the hydrogen-borrowing strategy.
The alkylation of methyl ketones was performed with benzyl
alcohol under the conditions described in the literature for the
homogeneous RuCl2(PPh3)3 catalyst.[24] In the presence of cata-
lyst L (2 mol%), alkylated products 31–34 were obtained in
60–78% yield (Table 4). The preliminary results obtained with
the current catalyst system under the unoptimized conditions
show the broad applicability of the catalyst for reactions in
which alcohols can be used as alkylating agents.
Table 4. a-Alkylation of methyl ketones by adopting the hydrogen-bor-
rowing strategy.[a]
Entry
1
Ketone
Product
Yield [%][b]
65
31
32
Figure 2. a) Fluidic setup for the continuous flow benzylation of piperidine.
b) Reaction progress towards the formation of 1 with respect to time.
2
60
(1.20 g) was packed in a column reactor (6.6 mm diameterꢁ
3
4
78
73
80 mm length); a mixture of benzyl alcohol (0.37m) and piper-
idine (0.31m) in toluene was then infused (20 mLminÀ1
)
33
34
through the reactor at 1208C with a back pressure of 2 bar
(2 bar=200 kPa). Fractions were collected at regular intervals
for GC analysis. With a residence time of approximately
30 min, 30% of benzyl alcohol was converted into product 1.
To increase the residence time, catalyst L (5.8 g) was packed
[a] Reactions were performed with the alcohol (1 mmol), amine
(1.1 mmol), and KOH (1 mmol). [b] Yield of isolated product.
into
a
bigger reactor (16 mm diameterꢁ80 mm length),
and the premixed reagents were infused at a flow rate of
30 mLminÀ1 (residence timeꢀ90 min). Notably, the reaction
proceeded smoothly for approximately 6 h after reaching
a steady state to form 1 in 71% yield (Figure 2b). We found
that the yield slowly decreased to 59% over a period of 5 h
and remained constant for an additional 10 h. The total turn-
over number was calculated to be 74 for 21 h of reaction. In-
terestingly, ruthenium leaching in the combined fractions was
Continuous flow N-alkylation
Developing continuous flow methodology would be more
practical if dealing with heterogeneous catalysts, and only
a few reports are available for the alkylation of amines under
continuous flow. Recently, Hii and co-workers[25] reported the
alkylation of aromatic, aliphatic, and chiral amines in 59–99%
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 808 – 814 812

CHEMCATCHEM
FULL PAPERS
www.chemcatchem.org
found to be lower (<1 ppm) than that in the batch
reaction. Currently, we are exploring the application of the
catalyst bed for other pharmaceutically important drug
intermediates.
Keywords: alcohol activation · alkylation · continuous flow ·
hydrogen borrowing · supported catalysts
[1] a) S. A. Lawrence in Amines: Synthesis Properties, and Applications (Ed)
Cambridge University, Cambridge, 2006; b) A. R. Cartolano, G. A.
Vedage in Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 2,
Wiley, New York 2004, pp. 476–498; c) S. Gomez, J. A. Peters, T. Masch-
meyer, Adv. Synth. Catal. 2002, 344, 1037–1057; d) R. N. Salvatore, C. H.
Yoon, K. W. Jung, Tetrahedron 2001, 57, 7785–7811.
[2] Top 200 World’s Best Selling Medicines, Med Ad News 2004, 23, 60–64.
[3] J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Biomol. Chem.
2006, 4, 2337–2347.
[4] a) J. M. J. Williams in Sustainable Catalysis: Challenges and Practices for
Pharmaceutical and Fine Chemical Industries (Eds.: P. J. Dunn, K. K. Hii,
M. J. Krische, M. T. Williams), Wiley, NJ, 2013, pp. 121–137; b) S. Bꢂhn, S.
Imm, L. Neubert, M. Zhang, H. Neumann, M. Beller, ChemCatChem 2011,
3, 1853–1864; c) G. E. Dobereiner, R. H. Crabtree, Chem. Rev. 2010, 110,
681–703; d) G. Guillena, D. J. Ramꢃn, M. Yus, Chem. Rev. 2010, 110,
1611–1641; e) A. J. A. Watson, J. M. J. Williams, Science 2010, 329, 635–
636.
Conclusions
In summary, a robust ruthenium-based catalyst was developed
from readily available supported phosphine ligands. The N-al-
kylation of primary and secondary amines was performed at
a moderate reaction temperature relative to that required for
existing heterogeneous catalysts in the absence of any external
base. The catalyst was shown to be effective for the a-alkyla-
tion of cyclic and acyclic methyl ketones. The supported cata-
lyst was not only recyclable under batch, but it also offered
a short residence time and low ruthenium leaching under flow
conditions for the N-alkylation of piperidine. The current heter-
ogeneous catalyst offers a highly atom efficient method for
producing secondary and tertiary amines in a more sustainable
manner.
[5] R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit, N. Tongpenyai, J. Chem. Soc.
Chem. Commun. 1981, 611–612.
[6] Y. Watanabe, Y. Tsuji, Y. Ohsugi, Tetrahedron Lett. 1981, 22, 2667–2670.
[7] Ruthenium based homogeneous catalysts: a) D. Weickmann, W. Frey, B.
Plietker, Chem. Eur. J. 2013, 19, 2741–2748; b) S. Agrawal, M. Lenor-
mand, B. Martin-Matute, Org. Lett. 2012, 14, 1456–1459; c) A. J. A.
Watson, A. C. Maxwell, J. M. J. Williams, Org. Biomol. Chem. 2012, 10,
240–243; d) M. H. S. A. Hamid, C. Liana Allen, G. W. Lamb, A. C. Maxwell,
H. C. Maytum, A. J. A. Watson, J. M. J. Williams, J. Am. Chem. Soc. 2009,
131, 1766–1774; e) C. Gunanathan, D. Milstein, Angew. Chem. 2008,
120, 8789–8792; Angew. Chem. Int. Ed. 2008, 47, 8661–8664;
f) M. H. S. A. Hamid, J. M. J. Williams, Tetrahedron Lett. 2007, 48, 8263;
g) I. Yamaguchi, T. Sakano, H. Ishii, K. Osakada, T. Yamamoto, J. Organo-
met. Chem. 1999, 584, 213–216; h) S. Ganguly, F. L. Joslin, D. M. Round-
hill, Inorg. Chem. 1989, 28, 4562–4564.
[8] Iridium based homogeneous catalysts: a) A. Wetzel, S. Wçckel, M.
Schelwies, M. K. Brinks, F. Rominger, P. Hofmann, M. Limbach, Org. Lett.
2013, 15, 266–269; b) Y. H. Chang, Y. Nakajima, F. Ozawa, Organometal-
lics 2013, 32, 2210–2215; c) A. Bartoszewicz, R. Marcos, S. Sahoo, A. K.
Inge, X. Zou, B. Martin-Matute, Chem. Eur. J. 2012, 18, 14510–14519;
d) J. Norinder, A. Boerner, ChemCatChem 2011, 3, 1407–1409; e) M. A.
Berliner, S. P. A. Dubant, T. Makowski, K. Ng, B. Sitter, C. Wager, Y. Zhang,
Org. Process Res. Dev. 2011, 15, 1052–1060; f) R. Kawahara, K. i. Fujita, R.
Yamaguchi, Adv. Synth. Catal. 2011, 353, 1161–1168; g) S. Michlik, R.
Kempe, Chem. Eur. J. 2010, 16, 13193–13198; h) O. Saidi, A. J. Blacker,
M. M. Farah, S. P. Marsden, J. M. J. Williams, Chem. Commun. 2010, 46,
1541–1543; i) A. Prades, R. Corberan, M. Poyatos, E. Peris, Chem. Eur. J.
2008, 14, 11474–11479; j) K. i. Fujita, Z. Li, N. Ozeki, R. Yamaguchi, Tetra-
hedron Lett. 2003, 44, 2687–2690.
Experimental Section
Synthesis of catalysts
Catalyst A was prepared by using an equimolar ratio of ruthenium
and supported phosphine ligand SL1. A mixture of [Ru(p-cyme-
ne)Cl2]2 (306.2 mg, 0.5 mmol) and SL1 0.33 g, 1.0 mmol) was stirred
in toluene (15 mL) at 1108C for 3 h. After cooling, the supported
catalyst was filtered and washed with toluene (3ꢁ10 mL) and pen-
tane (3ꢁ10 mL). The catalyst obtained was dried overnight under
vacuum at 1008C and stored in a desiccator. The filtrate and wash-
ings were combined, and the volatiles were removed under re-
duced pressure. The residue was dissolved in concentrated nitric
acid, and the ruthenium content was calculated by ICP analysis
(Table S1). Accordingly, the amount of ruthenium incorporated into
the polymer was calculated on the basis of the unreacted rutheni-
um present in the filtrate. Catalysts B–L were synthesized by vary-
ing the supported phosphine ligands (SL1–SL4) and their ratios by
adopting the above procedure.
General procedure for the alkylation of amines
[9] A. Martꢄnez-Asencio, D. J. Ramꢃn, M. Yus, Tetrahedron 2011, 67, 3140–
3149.
[10] Y. S. Zhao, S. W. Foo, S. Saito, Angew. Chem. 2011, 123, 3062–3065;
Angew. Chem. Int. Ed. 2011, 50, 3006–3009.
[11] M. Bertoli, A. Choualeb, A. J. Lough, B. Moore, D. Spasyuk, D. G. Gusev,
Organometallics 2011, 30, 3479–3482.
[12] P. Satyanarayana, G. M. Reddy, H. Maheswaran, M. L. Kantam, Adv. Synth.
Catal. 2013, 355, 1859–1867.
[13] K.-I. Shimizu, N. Imaiida, K. Kon, S. M. A. Hakim Siddiki, A. Satsuma, ACS
Catal. 2013, 3, 998–1005.
[14] a) L. He, B. Lou, J. Ni, Y. Cao, H. Y. He, K. N. Fan, Chem. Eur. J. 2010, 16,
13965–13969; b) Alkylation of urea using alcohols: L. He, Y. Qian, R. S.
Ding, Y. M. Liu, H. Y. He, K. N. Fan, Y. Cao, ChemSusChem 2012, 5, 621–
624.
Dry toluene (3 mL) was added to a mixture of amine (1.00 mmol),
alcohol (1.20 mmol), and catalyst L (0.19 g, 0.05 mmol) in a pressure
tube (10 mL), which was then sealed. The reaction tube was
heated to the required reaction temperature (120–1408C) in an oil
bath with constant stirring (500 rpm). The filtrate was concentrat-
ed, and the crude product was purified by column chromatogra-
phy. For recycling studies, the catalyst was recovered by filtration
and washed with toluene (2 mL) and pentane (5 mL) after the reac-
tion mixture was cooled to room temperature.
Acknowledgements
[15] L. Wang, W. He, K. Wu, S. He, C. Sun, Z. Yu, Tetrahedron Lett. 2011, 52,
7103–7107.
[16] a) Pd/Mgo catalyst: A. Corma, T. Rꢃdenas, M. J. Sabater, Chem. Eur. J.
2010, 16, 254–260; b) Cu-Ag/Al2O3 catalyst: K.-I. Shimizu, K. Shimura, M.
Nishimura, A. Satsuma, RSC Adv. 2011, 1, 1310–1317; c) g-Al2O3/Ag cata-
lyst: K. Shimizu, M. Nishimura, A. Satsuma, ChemCatChem 2009, 1, 497–
This work was funded by the GSK-EDB Singapore Partnership for
Green and Sustainable Manufacturing and the Institute of Chemi-
cal and Engineering Sciences (ICES), Agency for Science, Technolo-
gy and Research (A*STAR), Singapore.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 808 – 814 813

CHEMCATCHEM
FULL PAPERS
www.chemcatchem.org
503; d) NiCu-FeOx catalyst: X. Cui, X. Dai, Y. Deng, F. Shi, Chem. Eur. J.
2013, 19, 3665–3675; e) CuAl–hydrotalcite catalyst: P. R. Likhar, R. Ar-
undhathi, M. L. Kantam, P. S. Prathima, Eur. J. Org. Chem. 2009, 5383–
5389; f) Ru(OH)x/Al2O3 catalyst: J. W. Kim, K. Yamaguchi, N. Mizuno, J.
Catal. 2009, 263, 205–208.
L at 1208C in 3 mL of toluene. After 12 h, the recovered catalysts were
analyzed by SEM and compared with that of fresh catalysts.
[23] Synthesis of Piribedil was reported using homogeneous Ru-dppf cata-
lyst in 87% isolated yield, see. A. J. A. Watson, A. C. Maxwell, J. M. J. Wil-
liams, J. Org. Chem. 2011, 76, 2328–2331. Piribedil synthesis was also
demonstrated under continuous flow at 2008C (50 bar) using Au/TiO2
catalyst with 77% yield, see ref. 25.
[24] C. Sik Cho, B. Tae Kim, T. Kim, S. Chul Shim, Tetrahedron Lett. 2002, 43,
7987–7989.
[25] N. Zotova, F. J. Roberts, G. H. Kelsall, A. S. Jessiman, K. Hellgardt, K. K.
Hii, Green Chem. 2012, 14, 226–232.
[17] R. Cano, D. J. Ramꢃn, M. Yus, J. Org. Chem. 2011, 76, 5547–5557.
[18] H. Liu, G. Chuah, S. Jaenicke, J. Catal. 2012, 292, 130–137.
[19] D. Wang, X. Q. Guo, C. X. Wang, Y. N. Wang, R. Zhong, X. H. Zhu, L. H.
Cai, Z. W. Gao, X. F. Hou, Adv. Synth. Catal. 2013, 355, 1117–1125.
[20] R. Martꢄnez, D. J. Ramꢃn, M. Yus, Org. Biomol. Chem. 2009, 7, 2176–
2181.
[21] Primary amines and anilines were mainly used as substrates for N-alky-
lation using heterogeneous catalysts. To the best of our knowledge,
only a few reports deal with cyclic amines such as pyrrolidine, piperi-
dine and morpholine at temperatures above 1408C. See, references 13–
15 and 25.
[26] G. W. Lamb, F. A. Al Badran, J. M. J. Williams, S. T. Kolaczkowski, IChemE
2010, 88, 1533–1540.
Received: November 12, 2013
Revised: December 10, 2013
[22] To examine the change in catalyst morphology under identical condi-
tions, benzylation of piperidine was performed by using catalysts G and
Published online on January 27, 2014
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 808 – 814 814