Catalysis in flow: Au-catalysed alkylation of amines by alcohols

Article abstract of DOI:10.1039/c1gc16118k

By using a greater reaction space afforded by a flow reactor, commercially available Au/TiO₂ can be used for highly selective direct alkylation of amines by alcohols, without the need for an inert atmosphere or base. A brief survey of substrates includes the alkylation of aromatic, aliphatic and chiral amines by a number of primary and secondary alcohols, in high yield and selectivity. The synthesis of Piribedil, a drug used in the treatment of Parkinson's disease, can be achieved in a single synthetic operation without the need for column chromatography. Mechanistic aspects of the reaction were revealed through modelling of reaction profiles, and the origin of selectivity is attributed to the accessibility of high temperature. The presence of water was found to be crucial for catalyst activity.

Full text of DOI:10.1039/c1gc16118k

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PAPER
Catalysis in flow: Au-catalysed alkylation of amines by alcohols†
Natalia Zotova,a Felicity J. Roberts,b Geoffrey H. Kelsall,b Alan S. Jessiman,c Klaus Hellgardt*b and
King Kuok (Mimi) Hii*a
Received 6th September 2011, Accepted 18th October 2011
DOI: 10.1039/c1gc16118k
By using a greater reaction space afforded by a flow reactor, commercially available Au/TiO2 can
be used for highly selective direct alkylation of amines by alcohols, without the need for an inert
atmosphere or base. A brief survey of substrates includes the alkylation of aromatic, aliphatic and
chiral amines by a number of primary and secondary alcohols, in high yield and selectivity. The
synthesis of Piribedil, a drug used in the treatment of Parkinson’s disease, can be achieved in a
single synthetic operation without the need for column chromatography. Mechanistic aspects of
the reaction were revealed through modelling of reaction profiles, and the origin of selectivity is
attributed to the accessibility of high temperature. The presence of water was found to be crucial
for catalyst activity.
An alternate strategy is to employ a catalyst to oxidise an
1
Introduction
alcohol to a reactive carbonyl compound, which condenses with
the amine to form an imine, before it is reduced to the amine
(Scheme 1). The redox steps can be achieved using a catalyst
to transfer H2 from the alcohol to the imine via metal-hydride
intermediates (‘borrowing hydrogen’).5 Perhaps unsurprisingly,
metal complexes that are also known to effect reversible dehydro-
genation of alcohols (transfer hydrogenation catalysts) have been
studied extensively in this context. Accordingly, homogeneous
Ru and Ir catalysts are the most prevalent and effective.5,6
Some Cu and Fe catalysts have been reported, however, up
to 1 equivalent of base is required.7–9 In terms of practicality,
heterogeneous catalysts are much more attractive, as they can
be easily separated from the product stream. In this regard,
Ru(OH)x/TiO2 was found to have the widest applicability,
including the preparation of highly substituted amines from
urea,10,11 and the alkylation of (hetero)aromatic amines.12 The
scope of first-row transition metal catalysts (Cu, Fe) appears
to be limited to certain substrates, such as activated benzyl
alcohols or aromatic amines.13–15 More recently, a heterogeneous
Ag/Mo oxide catalyst has been shown to be effective for the
The ability to construct increasingly complex molecular struc-
tures is a key challenge for organic synthesis, fuelling the demand
for synthetic methodologies that can deliver considerable step-
economy and high efficiency.1,2 Concurrently, the overall sustain-
ability of a chemical process is important for it to be adopted on
an industrial scale. This involves issues such as atom-economy,
E-factors and selectivity, which ultimately governs economical
and environmental costs of chemical production.3
Alcohol activation for nucleophilic substitution is frequently
used for the preparation of fine chemicals and active pharma-
ceutical ingredients (APIs), where there is an urgent need for
better methodologies. The direct nucleophilic substitution of an
alcohol does not occur easily, and generally requires replacement
of the OH by a better leaving group, e.g. halides or OSO2R. In the
pharmaceutical industry, it has been estimated that 64% of all
nitrogen substitution reactions are alkylations.4 These reactions
are very often difficult to control, due to significant side reactions
(over-alkylation or competitive elimination), as well as practical
limitations, particularly safety and disposal issues associated
with the use of mutagenic alkylating reagents.
aDepartment of Chemistry, Imperial College London, Exhibition Road,
South Kensington, London, SW7 2AZ, United Kingdom.
E-mail: mimi.hii@imperial.ac.uk
bDepartment of Chemical Engineering and Chemical Technology,
Imperial College London, Exhibition Road, South Kensington, London,
SW7 2AZ, United Kingdom. E-mail: k.hellgardt@imperial.ac.uk
cPfizer Global Research & Development, Ramsgate Road, Sandwich,
CT13 9NJ, United Kingdom
† Electronic supplementary information (ESI) available: details of
kinetic analysis and fitted curves, pressure effects, Arrhenius plots, and
1H NMR spectra of products. See DOI: 10.1039/c1gc16118k
Scheme 1 Direct alkylation of an amine by an alcohol by sequential
redox processes.
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Table 1 Reported Au-catalysed reactions between benzyl alcohol (1a) and aniline (2a)
Entry
[Au]
1a : 2a, conditions
Conv.a (%)
3 : 4a
Ref.
1
2
3
4
5
6
Au/TiO2
1 : 1, Cs2CO3, toluene, N2, 110 ◦
C
>99
93
99
7
>99
71
22:15b
49 : 38c
>99 : 1
99 : 1
19
20
21
22
23
23
Au/MgO
Au/HDPd
Au/TiO2
1 : 3, PhCF3, N2, 180 ◦
C
1 : 1, O2, toluene, 60 ◦
C
1 : 1, O2, CH3OK (10 mol%), CH3OH, r.t.
Au/TiO2-VSe
1 : 1, 5 atm. N2, 120 ◦C, toluene
7.5 : 92f
6 : 64h
1 : 1, 5 atm. N2, 120 ◦C, toluene
g
Au/TiO2
a GC conversions based on alcohol. b Product mixture contained PhCHO and PhCO2Bn side products. c Product mixture contained benzene and
toluene side products. d HDP: Hydroxyapatite. e Mean particle size ~1.8 nm. f <0.5% ‘others’. g Obtained from WGC, mean particle size, ~3.2 nm.
h 1% ‘others’.
alkylation of a number of aromatic amines, carboxamides and
sulfonamides. However, the system required 20–40 mol% of base
(t-BuOK for the alkylation of amines), hence requiring column
chromatography for product purification.16
Heterogeneous gold catalysts are known to be highly effective
for the selective oxidation of alcohols17 as well as the hydro-
genation of aldehydes, ketones and imines.18 Thus, there have
been several attempts to utilise heterogeneous gold catalysts
for the direct alkylation of amines by alcohols. Using benzyl
alcohol (1a) and aniline (1b) as typical model substrates (Scheme
2), initial studies largely produced the intermediate imine 3
as a major product (Table 1, entries 1 and 2), which was
produced exclusively if the reaction was performed under an
O2 atmosphere (entries 3 and 4). More recently, the catalytic
activity of Au/TiO2 was re-examined under 5 atm of N2 in an
Fig. 1 Configuration of the flow reactor (continuous recycle mode).
Table 2 Reactions between 1a and 2a using Au/TiO2 under flow
autoclave. In this case, very high selectivity was achieved only by
using Au catalyst of very small particle size (entry 5 vs. entry 6).
conditionsa
Entry T/◦C 1a : 2a/M [Au] (mol%) t/h Conv.b (%) 3 : 4a : PhCHO
1
2
3
4
130
150
180
180
0.29 : 0.16 2.7
0.29 : 0.16 2.7
0.16 : 0.16 2.7
0.51 : 0.5 0.9
7
4
1
3
65
27 : 65 : 8
0 : 94 : 6
0 : 93 : 7
>99
>99
99
<2 : 97 : <1
Scheme 2 Model reaction: alkylation of aniline by benzyl alcohol.
a Reaction conditions: a mixture of 1a, 2a and dodecane (0.35 mL,
internal standard) in toluene (10 mL) was circulated through a heated
cartridge of 1.5 wt% Au/TiO2, at a flow rate of 1.5 mL min-1 (residence
time = 27 s), 50 bar pressure. b GC conversions based on aniline.
2
Results and discussion
Description of the flow system
inherently safe by containing the reaction zone, operating under
high temperatures and pressures, within a small reactor volume
(< 1 mL). The system also allows for easy access to the reaction
mixture for reaction progress analysis using a range of online
and offline tools.
Previously, we have demonstrated the advantages of using a
continuous flow reactor for the catalytic oxidation of alcohols
by O2.24 Using a small packed bed of heterogeneous catalyst
(70 ¥ 4 mm), reactions can be performed safely at elevated
temperature and pressures, while precise control of reaction
parameters ensures reproducibility and a high space–time yield.
Herein, we will demonstrate a successful application of the flow
system to gold-catalysed alkylation of amines by alcohols, which
can be achieved under highly practical and atom-economical
conditions.
Using commercially available Au/TiO2 as catalyst, the reac-
tion between model substrates 1a and 2a was examined under
continuous recycle mode conditions (Fig. 1), where a mixture of
the substrates in toluene was pressurised and passed through a
heated cartridge containing 1 wt% Au/TiO2 in a packed bed. The
mixture of substrates and product(s) was collected in a reservoir
and then re-circulated through the system. By separating the
bulk of reactants from the catalyst, the system can be rendered
Effect of temperature
Applying a pressure of 50 bar to maintain a single-phase flow,
a marked improvement in conversion and selectivity for 4a was
observed when increasing the reaction temperature from 130
through 150 to 180 ◦C (Table 2, entries 1–3). Furthermore,
by adopting nearly equimolar equivalents of the reactants
at a higher concentration and lower catalytic loading, the
reaction proceeded smoothly to completion with extremely high
selectivity for the formation of the secondary amine 4a – with
less than 3% of by-product being formed (entry 4).
As a comparison, the same reaction mixture and the Au/TiO2
catalyst was subjected to reflux under an N2 atmosphere at
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ambient pressure. Under these conditions, only 35% conversion
of the aniline, and 68% selectivity for 4a can be achieved, broadly
in line with the earlier report (Table 1, entry 6).
After 24 h, the reaction mixture was simply evaporated and the
residue recrystallised from ethanol–water to furnish the desired
product in 77% yield with high purity, without the need for
column chromatography.
Hence, by expanding the reaction space, the effectiveness of a
gold catalyst can be significantly enhanced, in terms of turnover
and selectivity. Based on the result of the last entry of Table
2 a turnover frequency (TOF) of ca. 37 h-1 can be derived,
which is broadly compatible, if not better, than other reported
homo- and heterogeneous catalytic systems. The efficiency of the
system is also accompanied by its practicality – high selectivity
for the amine can be obtained with the reaction mixture left
exposed to air over the course of the reaction, i.e. the need for
rigorously anaerobic conditions, required by all the previous
catalytic systems, is not necessary in this system.
Reaction mechanism
The reaction between benzyl alcohol and aniline was analysed
in our preliminary kinetic/mechanistic study. Remarkably, the
selectivity and rate of the reaction are unaffected by applying
pressures of between 5–100 bar (Fig. S4, ESI†). This implies
that nascent H2 is not present in the system, i.e. reduction of
the C N bond occurs exclusively through adsorbed hydrides.
In contrast, reaction temperature has a dramatic effect on the
selectivity of the reaction: a significant accumulation of imine
and benzaldehyde was observed at lower temperature (130 ◦C),
which was suppressed when the reaction temperature was raised
to 150 or 180 ◦C (Fig. 2a, b and c).
A closer examination of the reaction profile revealed that the
presence of imine 3 was observed in the initial stages of all
three reactions. At the lower reaction temperature (130 ◦C),
the concentration of oxidised products (imine and aldehyde)
continues to rise over the course of the reaction. In contrast,
at higher temperatures, the formation of the imine ceased to be
competitive, and started to behave as a reaction intermediate
(Fig. 2d).
Substrate scope
The potential application of the catalytic flow system is demon-
strated by conducting a small substrate screen with a selection of
primary and secondary alcohols and amines (Table 3). Electron-
rich and electron-poor substituents on benzyl alcohol (entries 1–
3) and aniline (entries 4 and 5) can be introduced, with very high
conversions achieved in just a few hours. The reaction of benzyl
alcohol and optically pure a-methylbenzylamine (2c) proceeded
very smoothly to give the substituted product 4f with complete
retention of stereochemistry (entry 6).
For less activated substrates (entries 7–10), good conversions
can be obtained by increasing the temperature to 200 ◦C;
excellent selectivities can be achieved with an aliphatic alcohol
(entry 7), a secondary amine (entry 8), as well as cyclic and
acyclic secondary alcohols (entries 9 and 10). ICP analyses of
crude reaction mixtures did not reveal any detectable metal
content (<0.02 ppm), thus catalyst leaching does not occur
under these conditions.
The synthetic utility of the system is also demonstrated
for more complex substrates by the synthesis of Piribedil 4k,
a piperazine-pyrimidine derivative used in the treatment of
Parkinson’s disease.25 A solution of piperonyl alcohol 1g and 1-
(pyrimidin-2-yl)piperazine 2g in toluene was circulated through
the heated catalyst maintained at 200 ◦C and 50 bar (Scheme 3).
A catalytic cycle was thus proposed based on these obser-
vations, from which four rate equations can be derived. The
competitive processes leading to the formation of the imine by-
product is represented by two equilibria KA and KB, associated
with the desorption of the aldehyde from the catalyst surface, and
the subsequent condensation reaction, respectively (Scheme 4).
The reaction progress curves obtained under different reaction
conditions (Fig. 2a, b and c) were subjected to kinetic analysis,
using the model developed (in Berkeley Madonna26), and the
results are summarised in Table 4.
The conversion of benzyl alcohol to benzaldehyde catalysed
by Au/CeO2 had been extensively studied previously in a body
of work by Corma and co-workers,27 whereby benzyl alcohol
undergoes fast and reversible binding to the catalyst surface to
give an alkoxide species (I). In the present system, Langmuir–
Hinshelwood type saturation kinetics was also observed, where
the rate-limiting step is found to be the formation of the
benzaldehyde (k1), with an activation energy of 93.7 kJ mol-1. In
all three cases, the initial oxidation of the alcohol to the carbonyl
compound is the rate-limiting step of the catalytic cycle.
Slow b-hydride elimination occurs to generate II, consisting
of gold-hydride and surface-bound benzaldehyde, which may
be liberated into solution. Condensation with aniline gives
adsorbed or free imines III or 3, respectively. In our proposed
model, only adsorbed imine III can be reduced by AuH to the
desired product 4a. The rate of the hydrogenation step (k2) is
found to be at least two orders of magnitude faster than the
dehydrogenation of the alcohol, and is likely to be irreversible.
This is supported by the observation that the stereochemistry
of a chiral amine substrate can be retained during the process
(Table 2, entry 6).
The selectivity of the reaction is defined by the relative ratio
of amine (4a) to imine (3), formed through the partitioning
Scheme 3 Synthesis of Piribedil 4k by direct alkylation of piperazine-
pyrimidine derivative 2g by 1g.
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Table 3 Scope of gold-catalysed alkylation of amine by alcoholsa
Entry
R1, R2
R3
Product (4)
x(mol%)
T/◦C
t/h
Conv.b (%)
Selectivityc (%)
1
2
Ph, H (1a)
4-anisyl, H (1b)
Ph (2a)
2a
4a
0.9
0.9
180
180
3
1
99
93
97
93
3
4
4-ClC6H4, H (1c)
2a
1.8
1.8
180
180
2
2
83
99
93
97
1a
2-MeC6H4 (2b)
5
1a
1a
4-ClC6H4 (2c)
1.8
1.8
180
180
2
7
97
91
94
98
6d
(S)-Ph(Me)CH (2d)
7
8
PhCH2, H (1d)
2a
1.8
1.8
200
200
7
6
59
98
>99
1a
-(CH2)5- (2e)
100
9
-(CH2)5- (1e)
Ph, Me (1f)
2a
1.8
1.8
200
200
7
7
85
85
100
10
n-C6H13 (2f)
>99
a Reaction conditions: amine (0.5 M), alcohol (0.5 M), 0.9–1.8 mol% Au, toluene (10 mL), 50 bar, 1.5 mL min-1 (t = 27 s). b Determined by GC, using
dodecane as internal standard. c Determined by 1H NMR. d Product is enantiomerically pure, as determined by chiral HPLC.
of reaction pathway via the common intermediate II. This is
dependent upon the overall rate of conversion of II to 4a
(k2), and the rate of formation of imine 3 from the desorbed
benzaldehyde, expressed by a combination of two equilibrium
constants (KA·KB). At 130 ◦C, k2 is sufficiently slow, such
that the favourable formation of the imine (KA·KB = 6.96 ¥
10-2) is competitive. At higher temperatures, imine formation
becomes disfavoured, particularly at higher conversions (where
the amount of water in the system increases). This effectively
counteracts the desorption process by increasing the amount
of benzaldehyde in the system, thus allowing it to re-enter the
productive catalytic cycle. At 180 C, very high selectivity can
◦
be achieved, even though the process is dominated by the larger
KA·KB equilibria. It is interesting that k2 appears to decrease
when the temperature was raised from 150 to 180 ◦C. It is
important to keep in mind that k2 embraces several key bond-
forming steps (formation of imine, reduction and liberation from
the surface), and this break from the Arrhenius linearity suggests
there may be a change in the mechanism of at least one of these
steps.
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Fig. 2 a), b) and c) Temporal reaction profiles between 1a and 2a corresponding to entries in Table 2 ( = [2a], = [3], ᭡ = [4a], = [PhCHO]); and
d) effect of temperature on the temporal evolution of imine 3.
Table 4 Kinetic and thermodynamic parameters derived from data
fittinga
T/◦C
k1/s-1
KA·KB
k2/M-1 s-1
130
150
2.05 ¥ 10-5
8.61 ¥ 10-5
4.53 ¥ 10-4
93.7
6.96 ¥ 10-2
3.78 ¥ 10-1
1.46
3.58 ¥ 10-2
0.1
180
5.65 ¥ 10-2
—
Ea/kJ mol-1
91.2
a See ESI.†
(Unexpected) Effect of water
Given that water is generated as a by-product of this process,
it is not unreasonable to assume that the removal of water can
have a beneficial effect on the process. With this in mind, further
experiments were conducted under anhydrous conditions, with
a sample of a catalyst dried in an oven overnight at 150 ◦C, and
by passing the reaction stream through a cartridge of molecular
sieves. Rather surprisingly, catalyst activity and selectivity were
practically annihilated under these conditions (Fig. 3) – only
10% conversion was achieved after 3 h with 29% selectivity
for the amine product. It is notable that even the formation
of benzaldehyde was sequestered under these conditions, i.e.
water plays a crucial role in activating the catalyst at the onset of
Fig. 3 Reaction between 1a and 2a under anhydrous conditions (
=
[2a], = [3], ᭡ = [4a], = [PhCHO]). Reaction conditions: 180 ◦C, 50
bar, 1.5 mL min-1, 1 mol% Au/TiO2.
the reaction. The interaction between water and TiO2 is key to
several important energy and environmental applications (e.g.
solar-hydrogen production and photodecomposition of organic
pollutants). As the subject of numerous studies over the last few
230 | Green Chem., 2012, 14, 226–232
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Scheme 4 Proposed catalytic cycle and associated rate equations.
decades,28 it is generally accepted that water can dissociate over
certain TiO2 surfaces to generate –OH and –H species which
affects its acid–base properties. Very recently, the interaction of
alcohols with TiO2 surfaces has also been investigated at the
solid–liquid boundary.29 Hence, we postulated that the presence
of water is critical in activating the surface of TiO2 towards
adsorption of substrates that are critical for catalytic activity.
activityofthe gold catalystcan be overcome by adoptinga higher
reaction temperature (>150 ◦C) afforded by a flow system, where
the formation of imine become reversible and can re-enter the
productive catalytic cycle.
The current study also uncovered a possible change in reaction
◦
mechanism at 180 C, and an unexpected role of water in the
activation of the catalyst. These will be investigated further.
Modifications of the catalyst will also be attempted to further
improve its efficiency, including widening of the reaction scope
to a broader range of substrates.
3
Conclusions
The use of gold as a viable heterogeneous catalyst for the
alkylation of amines by alcohols has been achieved for the first
time under aerobic conditions using a continuous flow reactor
and commercially-available catalysts that are otherwise not
selective in batch reactors.30 Very high reactivity and selectivity
can be accomplished in several systems.
Compared to previously reported systems, the gold-catalysed
flow process has a number of notable advantages:
(i) Catalysis occurs entirely at the surface of Au–TiO2, and
there is no detectable leaching;
(ii) Unlike all other catalysts, rigorous exclusion of air and/or
moisture is not necessary;
(iii) Reactions can be performed using commercially-available
catalysts from several sources;
(iv) Equimolar amounts of the reactants can be used, and
addition of exogenous base is not necessary, thus greatly
simplifying product purification; and
(v) The system allows for easier and safer scale-up of processes.
Key steps of the catalytic cycle have been elucidated by kinetic
modelling. The study show that the inherent lower catalytic
4
Experimental
General
Starting materials were procured commercially and used without
purification. Reactions were performed in reagent grade toluene.
The conversion of alcohols to products was monitored using
a HP6890 gas chromatography system fitted with an SPB-
5 column (30 m ¥ 0.2 mm ¥ 0.8 mm). The percentage of
conversion/selectivity was determined by comparison with
known standards, using a calibration plot for product and
reactant, against dodecane as an internal standard. The identity
of all products was further verified by comparison of their
1H NMR spectra to that reported, recorded in CDCl3 using
a Bruker Avance NMR spectrometer at 400 MHz. ICP analyses
(%Au) were performed using a Perkin–Elmer 2000 DV ICP-OE
spectrometer. The BET surface area and mean pore size of the
catalyst were obtained by low temperature N2 adsorption studies
at 77 K using a Micromeritics Tristar 3000 instrument.
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Catalyst characterisation
4 D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. L.
Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A.
Wells, A. Zaks and T. Y. Zhang, Green Chem., 2007, 9, 411–420.
5 T. D. Nixon, M. K. Whittlesey and J. M. J. Williams, Dalton Trans.,
2009, 753–762.
6 G. Guillena, D. J. Ramon and M. Yus, Chem. Rev., 2010, 110, 1611–
1641.
7 F. Shi, M. K. Tse, X. J. Cui, D. Gordes, D. Michalik, K. Thurow, Y.
Q. Deng and M. Beller, Angew. Chem., Int. Ed., 2009, 48, 5912–5915.
8 A. Martinez-Asencio, D. J. Ramon and M. Yus, Tetrahedron Lett.,
2010, 51, 325–327.
9 Y. Zhao, S. W. Foo and S. Saito, Angew. Chem., Int. Ed., 2011, 50,
3006–3009.
1 wt% Au/TiO2 obtained from Strem (AUROliteTM Au/TiO2),
was ground using a mortar and pestle and sieved. Particle sizes
of 125–250 microns were employed. Average gold crystallite size
is ca. 2–3 nm. BET surface area = 40 m2 g-1, mean pore size =
0.26 cm3 g-1, mean pore diameter = 26 nm.
Catalytic reactions
Reactions were performed using a ThalesNano X-CubeTM
flow reactor.31 A solution of the alcohol (0.29/0.5 M) and
amine (0.16/0.5 M) in toluene (10 mL) containing dodecane
(0.18 M) as an internal standard, was (re)circulated through a
heated cartridge containing 1 wt% Au/TiO2 (0.6–1.8 g) at 180–
200 ◦C, under an applied pressure of between 5–100 bar. The
progress of the reaction was monitored by GC analysis. Upon
completion, the solution was evaporated to afford the corre-
sponding substituted amine with >90% recovery. The purity and
identity of the product were verified by 1H NMR spectroscopy
(ESI†).
10 J. L. He, J. W. Kim, K. Yamaguchi and N. Mizuno, Angew. Chem.,
Int. Ed., 2009, 48, 9888–9891.
11 K. Yamaguchi, J. L. He, T. Oishi and N. Mizuno, Chem.–Eur. J.,
2010, 16, 7199–7207.
12 J. W. Kim, K. Yamaguchi and N. Mizuno, J. Catal., 2009, 263, 205–
208.
13 P. R. Likhar, R. Arundhathi, M. L. Kantam and P. S. Prathima, Eur.
J. Org. Chem., 2009, 5383–5389.
14 R. Martinez, D. J. Ramon and M. Yus, Org. Biomol. Chem., 2009, 7,
2176–2181.
15 J. He, K. Yamaguchi and N. Mizuno, Chem. Lett., 2010, 39, 1182–
1183.
16 X. Cui, Y. Zhang, F. Shi and Y. Deng, Chem.–Eur. J., 2011, 17,
1021–1028.
17 C. Della Pina, E. Falletta, L. Prati and M. Rossi, Chem. Soc. Rev.,
Synthesis of Piribedil (4k)
2008, 37, 2077–2095.
18 L. McEwan, M. Julius, S. Roberts and J. C. Q. Fletcher, Gold Bull.,
2010, 43, 298–306.
A mixture of the alcohol 1g (760 mg, 5 mmol) and piperazine 2g
(827.4 mg, 5 mmol) in toluene (10 mL) was circulated for 24 h
through 1.8 ◦mol% of Au/TiO2 mounted in 2 heated cartridges,
held at 200 C and 50 bar pressure. The reaction mixture was
evaporated to dryness, and the residue was recrystallised from
hot EtOH–H2O, to give the desired product as a buff-coloured
solid (1.15 g, 77%). 1H NMR data (ESI†) is in accordance with
reported values.32
19 T. Ishida, N. Kawakita, T. Akita and M. Haruta, Gold Bull., 2009,
42, 267–274.
20 A. Corma, T. Rodenas and M. J. Sabater, Chem.–Eur. J., 2010, 16,
254–260.
21 H. Sun, F. Z. Su, J. Ni, Y. Cao, H. Y. He and K. N. Fan, Angew.
Chem., Int. Ed., 2009, 48, 4390–4393.
22 S. Kegnaes, J. Mielby, U. V. Mentzel, C. H. Christensen and A.
Riisager, Green Chem., 2010, 12, 1437–1441.
23 L. He, X.-B. Lou, J. Ni, Y.-M. Liu, Y. Cao, H.-Y. He and K.-N. Fan,
Chem.–Eur. J., 2010, 16, 13965–13969.
24 N. Zotova, K. Hellgardt, G. H. Kelsall, A. S. Jessiman and K. K.
Hii, Green Chem., 2010, 12, 2157–2163.
Acknowledgements
25 M. J. Millan, Pharmacol. Ther., 2010, 128, 229–273.
26 http://www.berkeleymadonna.com/.
The work is funded by an EPSRC grant for Flow Chemistry
(EP/G027544/1), with additional support by Pfizer Inc. We
thank the Pharmacat Consortium for useful discussions.
27 A. Abad, A. Corma and H. Garc´ıa, Chem.–Eur. J., 2008, 14, 212–222.
28 C. H. Sun, L. M. Liu, A. Selloni, G. Q. Lu and S. C. Smith, J. Mater.
Chem., 2010, 20, 10319–10334.
29 V. M. Sanchez, E. de la Llave and D. A. Scherlis, Langmuir, 2011,
27, 2411–2419.
30 Au/TiO2 attained from other sources such as World Gold Council
and donated by Johnson Matthey plc, were also found to be effective
under these conditions.
31 ThalesNano Nanotechnology Inc., Graphisoft Park, H-1031
Budapest Zahony u. 7, Hungary (see: http://www.thalesnano.com/
products/x-cube).
Notes and references
1 P. A. Wender, V. A. Verma, T. J. Paxton and T. H. Pillow, Acc. Chem.
Res., 2008, 41, 40–49.
2 T. Newhouse, P. S. Baran and R. W. Hoffmann, Chem. Soc. Rev.,
2009, 38, 3010–3021.
3 P. J. Dunn, A. S. Wells and M. T. Williams, ed., Green Chemistry in
the Pharmaceutical Industry, Wiley-VCH, 2010.
32 A. J. A. Watson, A. C. Maxwell and J. M. J. Williams, J. Org. Chem.,
2011, 76, 2328–2331.
232 | Green Chem., 2012, 14, 226–232
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