Coupling of two multistep catalytic cycles for the one-pot synthesis of propargylamines from alcohols and primary amines on a nanoparticulated gold catalyst

Article abstract of DOI:10.1002/chem.201201837

A one-pot reaction was performed with a nanoparticulated gold catalyst. A secondary amine is formed through N-monoalkylation of a primary amine with an alcohol by a borrowing hydrogen methodology in a three-step reaction. The secondary amine formed enters into a second A³-coupling cycle to give propargylamines. The multistep reaction requires a gold species formed and stabilized on a ceria surface. Copyright

Full text of DOI:10.1002/chem.201201837

FULL PAPER
DOI: 10.1002/chem.201201837
Coupling of Two Multistep Catalytic Cycles for the One-Pot Synthesis of
Propargylamines from Alcohols and Primary Amines on a Nanoparticulated
Gold Catalyst
Avelino Corma,* Javier Navas, and Marꢀa J. Sabater*[a]
Abstract: A one-pot reaction was performed with a nanoparticulated gold catalyst.
A secondary amine is formed through N-monoalkylation of a primary amine with
Keywords: alkylation · domino re-
an alcohol by a borrowing hydrogen methodology in a three-step reaction. The
actions · gold · hydrogen transfer ·
secondary amine formed enters into a second A3-coupling cycle to give propargyl-
propargylamines
amines. The multistep reaction requires a gold species formed and stabilized on a
ceria surface.
Introduction
active site is regenerated. It may be possible to integrate the
above reaction for the formation of amines with an addi-
tional catalytic cycle to access more-complex structures, for
example, propargylamines,[12,13] preferably in the presence of
the same catalyst.
Gold has recently attracted considerable attention in the
area of homo- and heterogeneous catalysis.[1–3] Analogously
À
to other transition metals, Au H hydride-type complexes
have been synthesized[3h] or postulated as intermediates in a
number of gold-catalyzed reactions, such as hydrogena-
Propargylamine or 2-propinylamine derivatives are mole-
cules of pharmaceutical relevance and important building
blocks in the preparation of nitrogen-containing com-
pounds.[12] Because these compounds can be obtained from
secondary amines and terminal alkynes in the presence of
gold nanoparticles supported on nanometric oxides such as
CeO2,[13] we envisaged connecting the two catalytic cycles in
a gold-catalyzed cascade (Scheme 1). In the first cycle (A,
Scheme 1), N-monoalkylation of amines with alcohols will
take place to afford secondary amines under hydrogen-
transfer conditions. In a consecutive cycle (B, Scheme 1), 2-
propinylamines will be formed through a multicomponent
A3 transformation (Scheme 1).
tions,[3b,c,4] hydrosilylations,[5] dehydrogenative silylation of
alcohols,[6] hydroboration,[7] C H activation, and aerobic
[8]
À
oxidation of alcohols, among others.[9,10] For oxidation of al-
cohols it has been proposed that these gold hydride species
can react with oxygen and regenerate the Au catalytic sites
with concomitant production of water.[9b] Nonetheless, the
replacement of O2 by other hydrogen acceptor molecules
may yield additional products of high added value. The
strategy relates to the so-called borrowing hydrogen meth-
odology, which combines hydrogen transfer reactions with
additional transformations to obtain more complex struc-
tures.[11]
This strategy might lead to the direct formation of diverse
À
À
It has recently been described that a diverse range of
metals catalyze the N-monoalkylation of primary amines
with alcohols under hydrogen-transfer conditions to afford
secondary amines after three coupled reactions, dehydrogen-
ation–condensation–hydrogenation.[11] In this case, after de-
hydrogenation by a metal catalyst, the hydrogen-donor com-
pound (the alcohol) gives a carbonyl compound that can
condense with an amine to form an imine and a metal hy-
dride. Finally, the imine is hydrogenated by the metal-hy-
dride complex to afford a secondary amine and the metal
C C and C N bonds with a single catalyst in a straightfor-
ward fashion, through four successive transformations with-
out interference. The result would be a more-intensive proc-
ess with higher product yield and fewer waste products.
Scheme 1. Schematic representation of the one-pot synthesis of propar-
gylamines. Cycle A: monoalkylation of a primary amine; cycle B: A3 cou-
pling reaction.
[a] Prof. A. Corma, J. Navas, Dr. M. J. Sabater
Instituto de Tecnologꢀa Quꢀmica UPV-CSIC
Avda. Los Naranjos s/n
46022, Valencia (Spain)
Fax : (+34)963877809
E-mail: acorma@itq.upv.es
Results and Discussion
mjsabate@itq.upv.es
Gold nanoparticles deposited on an oxide surface (e.g.,
CeO2, ZrO2, TiO2) were used as the catalyst for the multi-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201837.
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step transformation described above and the characteristics
of the catalyst are given in Table 1S (see the Supporting In-
formation). First, we studied the one-pot N-monoalkylation
of amines with alcohols to give secondary amines by a bor-
rowing hydrogen methodology. Second, the amine generated
in situ was reacted in a multicomponent catalytic A3 cou-
pling to afford propargylamines (Scheme 1). Comprehensive
studies for the catalytic A3 coupling on heterogeneous gold
catalysts have shed light on the mechanism of the reac-
trifluorotoluene (TFT) as the solvent, as well as under sol-
vent-free conditions.
In general, the results collected in Table 1 show that gold
supported on cerium oxide gives the highest conversions
and yields of the secondary amine P2, when compared with
gold supported on other carriers, regardless of the metal
loading. The evolution of reactants and products over time
with an Au/CeO2 catalyst are shown in Figure 1.
ACHTUNGTRENNUNG
tion,[13a] therefore we initially focused on the gold-catalyzed
synthesis of N-monoalkylated amines to discern how the re-
action proceeds kinetically and mechanistically on the metal
surface.[11d] Finally, the optimum catalyst and experimental
conditions were tuned to carry out the two cycles coupled as
a single process.
Gold-catalyzed N-monoalkylation of alcohols to give secon-
dary amines by a borrowing hydrogen strategy: N-Monoal-
kylation of benzylamine with benzyl alcohol to afford diben-
zylamine (P2) was chosen as a model reaction. No conver-
sion was found in the absence of catalyst. The experimental
results obtained for the one-pot synthesis of the secondary
amine P2 at different temperatures and metal loadings are
summarized in Table 1. The reactions were performed with
!
&
*
( ),
Figure 1. Plots showing the yields of benzyl alcohol ( ), P1 ( ), P2
~
and P3 ( ) versus time in the N-alkylation of benzylamine with benzyl al-
Table 1. Direct gold-catalyzed synthesis of P2 from benzyl alcohol and
benzylamine.[a]
cohol catalyzed by Au/CeO2 (1.7% wt; Table 1, entry 1).
Interestingly, secondary products (such as benzene and
toluene), typically formed when working from similar one-
pot reactions with other metals,[11a,b] were not detected.
Nonetheless, in some cases, minor amounts of the dialkylat-
ed product, tribenzylamine (P3), were formed (Table 1),
which indicated that the N-alkylation proceeds in a stepwise
manner.
The yield of monoalkylated amine did not improve either
with an excess of alcohol or in the presence of H2 (5 bar),
which indicates that H2 does not dissociate under these ex-
perimental conditions or hydrogenation by hydrogen trans-
fer is not the rate-determining step.
Finally, it should be noted that the conversion and yield
of the secondary amine P2 are also very high in the presence
of Au/CeO2 under solvent-free conditions (Table 1, entries 1,
4–7). This fact is especially relevant when seeking compati-
bility for catalysts involved in sequential transformations be-
cause, in an ideal situation, the residual products (solvent,
additives, and even the catalyst) from preceding steps
should not interfere with the catalyst involved in the next
catalytic cycle (Scheme 1). In a practical sense, the fact that
solvent is not required will eliminate potential limitations
when multiple catalytic cycles are combined.
Entry Catalyst
([% wt])
Conv.
t
Yield [%]
TON[c] TOF[d]
ACHTUNGTRENNUNG
[%][b] [h] P1 P2 P3
1[e,f]
2
Au/CeO2 (1.7)
Au/CeO2 (1.7)
À
96
100
7
2
2
2
7
90
94
4
2
2
294
95
86
127
207
86
65
238
257
40
20
14
–
3[g]
Au/CeO2 NH (1.7) 100
13 85
4[e,h,i] Au/CeO2 (2.05)
64
96
100
94
62
90
13
42
50
63
24 10 54 <1 286
5[e,j]
6[e,k]
7[e]
8[e]
9
10
11
12
13
Au/CeO2 (1.3)
Au/CeO2 (2.05)
Au/CeO2 (4)
Au/ZrO2 (2.5)
Au/TiO2 (1.5)
Au/Fe2O3 (4.4)
Au/ZnO (1)
Au/MgO (1)
Au/C (1)
9
9
2
8
7
86
10 86
85
10 52
3
4
7
–
–
1
–
1
1
662
424
79
156
84
2
19 50 10
5
6
8
5
10
42
42
2
–
7
–
86
50
14
6
27 35
75
16
[a] Reaction conditions: PhCH2OH (1 mmol), PhCH2NH2 (1 mmol), TFT
(1 mL), catalyst (0.9 mol%), dodecane (0.2 mmol), 1808C, N2. [b] Con-
version (amount of benzyl alcohol transformed) determined by GC.
[c] Turnover number=(mmol benzyl alcohol converted)/[mmol catalyst
(total Au content)]. [d] Turnover frequency=[mmol benzyl alcohol con-
verted)/mmol catalyst (total Au content]ꢂh. [e] No solvent used. [f] Au
Rate-determining step for the gold-catalyzed N-monoalkyla-
tion of amines with alcohols: Similar monoalkylations of
amines with alcohols have been carried out with solid palla-
dium-based bifunctional catalysts. Kinetic studies have
À
(0.3 mol%). [g] Unreduced Au/CeO2 NH sample was used as the cata-
lyst (see the Experimental Section for catalyst preparation). [h] Reaction
carried out at 1408C. [i] Au (0.24 mol%). [j] Au (0.14 mol%). [k] Au
(0.24 mol%).
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One-Pot Synthesis of Propargylamines
FULL PAPER
shown that the rate-determining step for the reaction is the
hydrogen transfer from the surface hydride moieties to the
olefin.[11a,b] In the case of gold catalysts, we first performed a
kinetic study to determine the rate-determining step for the
N-monoalkylation of amines by alcohols, not only for gain-
ing further insight into the reaction mechanism, but also to
determine what catalyst parameters should be changed to
improve the reaction rate.
The three elementary steps for the N-monoalkylation of
benzylamine with benzyl alcohol—that is, alcohol dehydro-
genation, condensation between the aldehyde and the pri-
mary amine to form the imine, and finally hydrogenation of
the imine—have been formulated in Equations 1–3
(Scheme 2):
Scheme 2. The three reaction steps and their kinetic constants, ka, kb,
and kc.
From these equations, three kinetic rate expressions were
derived by assuming that each step [dehydrogenation of
benzyl alcohol to give benzaldehyde and metal hydride
[Eq. (1)], the condensation reaction [Eq. (2)], or the hydro-
genation [Eq. (3)] in turn was the overall rate-determining
step, with the other two steps in equilibrium (Table 2).
Figure 2. a) Initial reaction rate (r0) versus PhCH2NH2/PhCH2OH
(1 mmol); b) r0 versus PhCH2OH/PhCH2NH2 (1 mmol).
Table 2. Kinetic rate expressions obtained for each potential rate-deter-
mining step.
Entry Rate-
determining
Rate equation[a,b]
lyzed N-monoalkylation. If so, a positive effect on the rate
of alcohol dehydrogenation when the crystallite size of the
gold nanoparticles is decreased could be expected.[9d] We
prepared a series of Au/CeO2 catalysts with different metal
crystal size[9d] and, taking into account the particle-size dis-
tribution, TOF values were calculated by dividing the initial
reaction rate for dehydrogenation of benzyl alcohol by the
number of surface metal atoms. The results were plotted
versus the average particle size for the different catalysts
(Figure 3).[XXX]
As can be observed, the TOF for dehydrogenation of
benzyl alcohol increases as the gold crystal size decreases,
which indicates that dehydrogenation of the alcohol occurs
preferentially on gold atoms with lower coordination, that
is, those located at crystal edges and corners.
step
1
2
3
Eq. (1)
Eq. (2)
Eq. (3)
r0 =k
aA
r0 =k
N
ACHTUNGTRENNUNG
À
r0 =kc[P1]CATHNUGNERT[NNUG Au H]=kcKbKaACHUTNRTEGN[GNUN PhCH2NH2]CAHTNUGTRNEN[UGN PhCH2OH]
[a] ka, kb, and kc are the kinetic constants for steps 1–3, respectively.
[b] Ka and Kb are the steady-state constants for the dehydrogenation and
condensation steps, respectively.
To discriminate among the three kinetic expressions, the
initial concentration of the alcohol was kept constant
(1 mmol) and the initial concentration of the amine was
varied. The initial reaction rates were measured with Au/
CeO2 as the catalyst. The same procedure was applied with
the initial concentration of amine constant (1 mmol) and
variation of the initial concentration of the alcohol. Interest-
ingly, and contrarily to what was observed with palladi-
Mechanism of hydrogen-transfer reduction; alcohol–alde-
hyde equilibrium on Au/CeO2: To shed light on the mecha-
nism of gold-mediated hydrogen transfer to imines, we con-
sidered the alcohol–aldehyde equilibrium established at an
initial stage of the reaction and the possible intermediates
involved in this process. Our aim was to determine how the
hydrogen transfer occurs and, if possible, the nature of the
gold catalytic species involved.
ACHTUNGTRENNUNG
um,[11a,b] the initial reaction rate (r0) was first order with re-
spect to the alcohol ([PhCH2OH]) but did not depend on
the concentration of the amine ([PhCH2NH2]) (Figure 2).
According to the rate equations shown in Table 2, only
Equation (1) depends only on the concentration of the alco-
hol. The results from Figure 2 indicate that the dehydrogen-
ation reaction should be the slowest step in the gold-cata-
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A. Corma, J. Navas, and M. J. Sabater
Figure 5. 13C NMR, spectra recorded in CDCl3, of PhCD2OH treated
~
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with Au/CeO2 at the equilibrium. CDH ( ), CD ( ), CH2 ( ).
Figure 3. Initial reaction rate (r0) per surface atom as a function of metal
particle size for dehydrogenation of benzyl alcohol to afford benzalde-
energy Au 4f7/2 =83.7 eV; 100%). The persistence of the
CD2 signal may simply be ascribed to the existence of un-
reacted PCD2OH provided that no other gold species are
detected by XPS. These experimental facts evidence that, at
least with the reduced Au/CeO2 catalyst, hydrogen transfer
by the pathway shown in Figure 4 takes place through H/D
scrambling mediated by metallic gold species, as suggested
by previous theoretical studies.
&
*
hyde ( ), condensation to give P1
( ), and hydrogenation to afford P2
~
).
(
Thus, theoretical DFT calculations have shown that the
selective oxidation of ethanol to ethanal can proceed
through two elementary steps: 1) homolytic activation of the
0
À
OH group on Au ; 2) homolytic breaking of the C H posi-
tioned a to the OH group with formation of ethanal and
Au H species on the metal surface.
calculations, the gold-catalyzed dehydrogenation of
Scope of the reaction: The scope of the reaction has been
studied with different amines and alcohols in the presence
of Au/CeO2 (Table 3). In general, the selectivity of the reac-
tion and conversion into P2 were higher with benzyl alcohol
(Table 3, entries 1–6) than with simple aliphatic alcohols
(Table 3, entries 7 and 12). The catalytic results were much
worse when both substrates where aliphatic (Table 3,
entry 12).
The presence of halogen substituents at the para position
of the aromatic alcohol slowed the reaction, but the conver-
sion and selectivity values towards P2 were still excellent
(Table 3, entry 8). Electron-donating substituents at the para
position did not improve the selectivity of the reaction to-
wards P2 (Table 3, entries 9 and 10).
[9d]
À
According to these
À
À
PhCD2OH should afford PhCDO and Au H and Au D in-
termediate species on the catalyst surface. Then, in the equi-
À
À
librium, Au H and Au D would hydrogenate the aldehyde
(or in general a multiple bond, for example, the imine P1)
and a mixture of deuterated alcohols should be obtained at
the end of the reaction, if the pathway presented in Figure 4
is followed.[11a]
The hydrogen transfer in this pathway would take place
through H/D scrambling, which should be easily recognized
by NMR spectroscopy. Isotopically enriched alcohol
PhCD2OH was reacted with freshly reduced Au/CeO2 at
1808C and the 13C NMR spectrum was recorded after the re-
action reached equilibrium. In this case, three different sig-
nals were detected in the 13C NMR spectrum, which were
assigned to CD2, CDH, and CH2.
When sterically hindered secondary alcohol 1-phenyl-
ethanol was used the conversion values were only slightly
lower, but the yield of P2 fell to 5% and imine P1 was the
major product (Table 3, entry 11).
The appearance of CDH and CH2 signals (Figure 5) con-
firmed the existence of H/D scrambling and indicated that
homolytic activation of OH on metallic gold (Figure 4) is
operative under our reaction conditions.
X-Ray photoelectron spectroscopy (XPS) data of the
freshly reduced Au/CeO2 catalyst confirmed that the gold is
almost exclusively in the form of Au0 species (binding
Domino gold-catalyzed N-monoalkylation of amines and A3
coupling reaction: The successful N-monoalkylation of pri-
mary amines to secondary amines by a borrowing hydrogen
methodology offers the possibility to increase the complexi-
ty of the reaction by coupling the secondary amine formed
in situ to an aldehyde and an alkyne to afford 2-propinyl-
AHCTUNGTERGaNNUN mine derivatives in one-pot
(Scheme 3; Table 4).
It has been shown that gold
can catalyze the second cata-
lytic cycle, therefore, we first
carried out the N-monoalkyla-
tion[13a,15] at 1608C until reac-
Figure 4. Dehydrogenation–hydrogenation reaction of PhCD2OH on supported Au0 nanoparticles.
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One-Pot Synthesis of Propargylamines
FULL PAPER
Table 3. Monoalkylation of amines with alcohols catalyzed by Au/CeO2 (2.5% wt).[a]
In this case, the best results for the global one-
pot experiments were achieved with an Au/CeO2
sample (2.5 wt%) treated at 2508C with a H2 flow
(see the Experimental Section); the kinetic profile
of the global reaction (cycles A+B, Scheme 1) in
the presence of Au/CeO2 is given in Figure 6.
To prove the generality of the method, we sys-
tematically varied the reactants (amine, aldehyde,
alkyne) for the two catalytic cycles but maintained
the aromatic nature of the hydrogen donor
(Table 4).
As expected, the conversion and selectivity for
P4 were higher when aryl alcohols and aryl amines
were used as substrates (Table 4), which were also
the best substrates for synthesis of the N-monoal-
kylated product P2 (Table 3). The nature of the al-
Entry Alcohol
Amine
Conv.
t
Yield [%]
P1 P2 P3
TON[c] TOF[d]
[%][b] [h]
1
100
88
5
6
3
90
85
4
–
1
152
231
112
64
52
81
48
93
76
13
2[e]
6.5
6
3
100
100
94
15 84
4
7.5 17 71
10 133
3
4
ꢀ
dehyde (R CHO) and alkyne (R C CH) also had
a critical influence on the global reaction. The best
combination was to use a benzyl alcohol and ben-
zylamine for steps a–c, then a cyclic aliphatic alde-
hyde and an aromatic terminal alkyne for step d.
The strong association experienced by different
gold species on the ceria lattice is thought to be
the key factor that stabilizes the gold nanoparticles
during the one-pot reaction.
5
18
11 70
22 72
13
2
90
6
96
7
6
138
7
71
8
50
13 108
8
100
100
95
9
3
14 85
34 65
1
1
176
100
39
79
19
Conclusion
Gold on CeO2 (Au/CeO2) is able to sequentially
activate reactants in two catalytic cycles for pro-
duction of propargylamines or 2-propinylamines in
one-pot. In this catalytic system, gold atoms at the
crystal corners promote the N-monoalkylation of
amines with alcohols to give secondary amines in
moderate to good yields.
9
10
30
19 76 <1 184
Because cationic gold works better for the A3
consecutive reaction, the experimental conditions
(temperature, metal loading, preparation of cata-
lyst) were optimized to avoid a sharp decrease of
these oxidized gold active species, as well as their
sinterization.
The strong interaction between different gold
species on ceria accounts for the observed high ac-
tivity and stability of the catalytic species during
the overall cascade reaction.
11
12
90
51
21
8
65
31
5
8
20 120
12 53
268
35
[a] Reaction conditions: alcohol (1 mmol), amine (1 mmol), Au/CeO2 (2.5% wt, 0.4–
0.7 mol%), TFT (1 mL), dodecane (1 mmol), 1808C, N2. [b] The amount of alcohol
transformed was determined by GC. [c] Calculated as (mmol alcohol converted)/
(mmol catalyst). [d] Calculated as [(mmol alcohol converted)/(mmol catalyst)]ꢂh.
[e] No solvent used.
Experimental Section
Reagents and solvents were supplied by Aldrich and they were used as
received. CeO2 (specific surface area, Brunauer–Emmett–Teller (BET) ꢁ
252 m2 gÀ1) was supplied by Rhodia. MgO (surface area=670 m2 gÀ1) was
Scheme 3. One-pot synthesis of propargylamines.
purchased from NanoScale Materials. Carbon (surface area=1400 m2 gÀ1
)
tion completion and then temperature was reduced to 858C
for the second cycle.
was purchased from Norit. ZrO2 (surface areaꢁ100 m2 gÀ1) was pur-
chased from Sigma–Aldrich. TiO2 (Aeroxide-P25, surface area=35–
65 m2 gÀ1) was purchased from Evonik. Au/Fe2O3 (4.4% wt) was supplied
Chem. Eur. J. 2012, 00, 0 – 0
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A. Corma, J. Navas, and M. J. Sabater
Table 4. Synthesis of 2-propinylamine derivatives P4 by N-monoalkyla-
tion coupled to a multicomponent catalytic A3 coupling with an Au/CeO2
catalyst.[a]
Entry Product
Conv. [%][b] Conv. [%][c] Yield P4
step a
step d
[%][d]
1
100
100
80
2
3
100
100
65
60
50
~
*
Figure 6. Plot showing the evolution of products P2 ( ) and P4 ( ) in the
&
one-pot reaction (cycle A+B) between benzyl alcohol ( ), benzyl amine,
cyclohexylcarboxaldehyde, and phenylacetylene in the presence of Au/
CeO2 (2.5% wt; Table 4, entry 1). Cyclohexylcarboxaldehyde and phenyl-
acetylene were incorporated when almost all of the imine P1, formed in
the condensation step, was hydrogenated to the amine P2.
100
À
Preparation of Au/CeO2 NH (1.6% wt): HAuCl4·3H2O (120 mg) was
dissolved in deionized H2O (150 mL) and adjusted to pH 10 with NaOH
(0.2m). A suspension of CeO2 (3.0 g) in deionized H2O (150 mL) was
added. The mixture was readjusted to pH 10 with NaOH (0.2m) and stir-
red for 18 h at RT. The agitation was stopped and the slurry was aged for
2 h. The mixture was filtered with deionized H2O to completely eliminate
chlorides, then washed with acetone (100 mL). The residue was dried
overnight (18 h) in an oven (1008C).
4
5
100
94
50
35
48
31
Preparation of Au/ZrO2: ZrO2 (1.5 g) was calcined (25–4008C;
58CminÀ1; 7 h) then diluted in deionized water. HAuCl4·3H2O (50 mg) in
H2O (50 mL) was incorporated by pump infusion (0.83 mLminÀ1). The
mixture was adjusted to pHꢂ7.6 by addition of NaOH (0.2m) and stirred
overnight.
6
7
100
90
75
79
40
60
The mixture was readjusted to pH=7.6 with NaOH (0.2m), aged for
about 10 h, filtered, and washed with deionized H2O (2 L) and acetone
(100 mL). The solid was dried in an oven (1008C) for 24 h, then calcined
under air (20–2508C; 58CminÀ1; 2 h).
Preparation of Au/TiO2: HAuCl4·3H2O (77.8 mg) in deionized water
(150 mL) was mixed with TiO2 (2 g). The mixture was heated to 708C
and adjusted to pH 9 with NaOH (2m). The mixture was stirred over-
night. The solid was filtered and washed with deionized water (2 L) and
acetone (100 mL), dried in an oven (1008C) for 24 h, then calcined under
air (20–4008C; 58CminÀ1; 4 h).
[a] Reaction conditions: steps a)–c) R1CH2OH (1 mmol), R2NH2
(1 mmol), Au/CeO2 (2.5% wt, 1 mol%), 1608C, N2, TFT (1 mL);
4
step d) R3CHO (1.5 mmol),
R
C CH (1.5 mmol), 858C, under air.
À ꢀ
[b] The amount of R1CH2OH transformed was calculated by GC. [c] The
amount of R3CHO transformed was calculated by GC. [d] Isolated yield.
Catalyzed N-alkylation of amines with alcohols: Alcohol (1 mmol),
amine (1 mmol), catalyst (0.0075 mmol), trifluorotoluene (1 mL), and n-
dodecane (20 mL) as an internal standard were placed into an autoclave.
The mixture was vigorously stirred at 1808C under nitrogen. The reaction
was monitored by GC.
Catalyzed A3 coupling of aldehydes, alkynes, and secondary amines gen-
erated in situ: A mixture of alcohol (1 mmol), amine (1 mmol), catalyst
(0.0075 mmol), trifluorotoluene (1 mL), and n-dodecane (20 mL) as an in-
ternal standard were placed into an autoclave. The mixture was vigorous-
ly stirred at 1808C under nitrogen, and monitored by GC. After the alco-
hol was transformed into secondary amine, the temperature was lowered
to 808C and alkyne (1 mmol) and aldehyde (1 mmol) were incorporated
into the reactor. The reaction was monitored by GC at 858C under air.
by World Gold Council. Au/ZnO (1% wt) was supplied by Mintek. Au/
MgO and Au/C were prepared by literature procedures.[11a]
Preparation of Au/CeO2
ACHTUNGTRNE(NUNG x% wt): The appropriate amount of
HAuCl4·3H2O was dissolved in deionized water (100 mL). The solution
was adjusted to pH 10 with NaOH (0.2m) and a suspension of CeO2
(1.5 g) in deionized H2O (50 mL) was added. The resulting mixture was
readjusted to pH 10 with NaOH (0.2m) and stirred for 18 h at RT. The
agitation was stopped and the slurry was aged for 2 h. The mixture was
filtered and the solid washed with deionized H2O, to completely elimi-
nate chlorides, then washed with acetone (100 mL). The residue was
dried overnight (18 h) in an oven (1008C) then treated with a H2 flow
(80 mLminÀ1) at 2508C for 2 h.
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One-Pot Synthesis of Propargylamines
FULL PAPER
lesias, F. Sanchez, G. Ujaque, J. Catal. 2008, 254, 226; f) F. Z. Su, L.
He, J. Ni, Y. Cao, H. Y. He, K. N. Fan, Chem. Commun. 2008, 3531;
g) V. Amir-Ebrahimi, J. J. Rooney, Catal. Lett. 2009, 127, 20.
[5] H. Ito, T. Yajima, J. Tateiwa, A. Hosomi, Chem. Commun. 2000,
981.
Acknowledgements
Financial support by the Direcciꢃn General de Investigaciꢃn Cientꢀfica y
Tꢄcnica of Spain (Projects Consolider-Ingenio 2009 MIYCIN (CSD2009–
00050) and MAT2011–28009).
[6] a) H. Ito, K. Takagi, T. Miyahara, M. Sawamura, Org. Lett. 2005, 7,
3001; b) P. Raffa, C. Evangelisti, G. Vitulli, P. Salvadori, Tetrahedron
Lett. 2008, 49, 3221.
[7] R. T. Baker, J. C. Calabrese, S. A. Westcott, J. Organomet. Chem.
1995, 498, 109.
[8] a) C. Wei, C.-J. Li, J. Am. Chem. Soc. 2003, 125, 9584; b) R. Skouta,
C.-J. Li, Angew. Chem. 2007, 119, 1135; Angew. Chem. Int. Ed. 2007,
46, 1117.
[9] a) A. Abad, C. Almela, A. Corma, H. Garcia, Chem. Commun.
2006, 3178; b) A. Abad, A. Corma, H. Garcꢀa, Chem. Eur. J. 2008,
14, 212; c) M. Conte, H. Miyamura, S. Kobayashi, V. Chechik, J.
Am. Chem. Soc. 2009, 131, 7189–7196; d) A. Corma, M. Boronat, F.
Illas, J. Radilla, T. Rꢃdenas, M. J. Sabater, J. Catal. 2011, 278, 50.
[10] H. Ito, T. Yajima, J. Tateiwa, A. Hosomi, Tetrahedron Lett. 1999, 40,
7807.
[11] a) A. Corma, T. Rꢃdenas, M. J. Sabater, Chem. Eur. J. 2010, 16, 254;
b) A. Corma, T. Rꢃdenas, M. J. Sabater, J. Catal. 2011, 279, 319;
c) T. Ishida, N. Kawakita, T. Akita, M. Haruta, Gold Bull. 2009, 42,
267; d) L. He, X.-B. Lou, J. Ni, Y.-M. Liu, Y. Cao, H.-Y. He, K.-N.
Fan, Chem. Eur. J. 2010, 16, 13965.
[12] a) A. A. Boulton, B. A. Davis, D. A. Durden, L. E. Dyck, A. V.
Juorio, X. M. Li, I. A. Paterson, P. H. Yu, Drug Dev. Res. 1997, 42,
150; b) M. Miura, M. Enna, K. Okuro, M. Nomura, J. Org. Chem.
1995, 60, 4999; c) I. Naota, H. Takaya, S. I. Murahashi, Chem. Rev.
1998, 98, 2599.
[13] a) A. Corma, X. Zhang, Angew. Chem. 2008, 120, 4430; Angew.-
Chem. Int.Ed. 2008, 47, 4358; b) D. Aguilar, M. Contel, E. P. Urrio-
labeiti, Chem. Eur. J. 2010, 16, 9287; c) S. Carrettin, M. C. Blanco,
A. Corma, A. S. K. Hashmi, Adv. Synth. Catal. 2006, 348, 1283;
d) M. Baron, O. Bondarchuk, D. Stacchiola, S. Shaikhutdinov, H.-J.
Freund, J. Phys. Chem. C. 2009, 113, 6042; e) C. Zhang, A. Michae-
lides, D. A. King, S. J. Jenkins, J. Chem. Phys. 2008, 129, 194708.
[14] a) N. Mahata, V. Vishwanathan, J. Catal. 2000, 196, 262; b) S. Domꢀ-
nguez-Domꢀnguez, A. Berenguer-Murcia, A. Linares-Solano, D. Ca-
zorla-Amorꢃs, J. Catal. 2008, 257, 87; c) R. Van Hardeveld, F.
Hartog, Surf. Sci. 1969, 15, 189; d) R. E. Benfield, J. Chem. Soc.
Faraday Trans. 1992, 88, 1107; e) M. Boudart, Chem. Rev. 1995, 95,
661.
[1] a) A. S. K. Hashmi, Angew. Chem. 2005, 117, 7150; Angew. Chem.
Int. Ed. 2005, 44, 6990; b) A. S. K. Hashmi, G. J. Hutchings, Angew.
Chem. 2006, 118, 8064; Angew. Chem. Int. Ed. 2006, 45, 7896;
c) D. J. Gorin, F. D. Toste, Nature 2007, 446, 395; d) A. S. K.
Hashmi, Chem. Rev. 2007, 107, 3180; e) A. Arcadi, Chem. Rev. 2008,
108, 3266; f) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem. Rev. 2008,
108, 3351; g) A. S. K. Hashmi, M. Rudolph, Chem. Soc. Rev. 2008,
37, 1766; h) Z. Li, C. Brouwer, C. He, Chem. Rev. 2008, 108, 3239;
i) N. Marion, S. P. Nolan, Chem. Soc. Rev. 2008, 37, 1776; j) N. T.
Patil, Y. Yamamoto, Chem. Rev. 2008, 108, 3395; k) A. S. K.
Hashmi, Angew. Chem. 2010, 122, 5360; Angew. Chem. Int. Ed.
2010, 49, 5232; l) M. Rudolph, A. S. K. Hashmi, Chem. Commun.
2011, 47, 6536; m) M. Rudolph, A. S. K. Hashmi, Chem. Soc. Rev.
2012, 41, 2448.
[2] a) G. J. Hutchings, J. Catal. 1985, 96, 292; b) Y. Ito, M. Sawamura, T.
Hayashi, J. Am. Chem. Soc. 1986, 108, 6405; c) M. Haruta, T. Ko-
bayashi, H. Sano, N. Yamada, Chem. Lett. 1987, 16, 405; d) Y.
Fukuda, K. Utimoto, Bull. Chem. Soc. Jpn. 1991, 64, 2013; e) J. H.
Teles, S. Brode, M. Chabanas, Angew. Chem. 1998, 110, 1475;
Angew. Chem. Int. Ed. 1998, 37, 1415; f) A. S. K. Hashmi, L.
Schwarz, J. H. Choi, T. Frost, Angew. Chem. 2000, 112, 2382; Angew.
Chem. Int. Ed. 2000, 39, 2285; g) J. J. Kennedy-Smith, S. T. Staben,
F. D. Toste, J. Am. Chem. Soc. 2004, 126, 4526; h) J. L. Zhang, C. G.
Yang, C. He, J. Am. Chem. Soc. 2006, 128, 1798.
[3] For selected examples of gold-catalyzed hydrogenations, see: a) P.
Claus, Appl. Catal. A 2005, 291, 222; b) C. Gonzalez-Arellano, A.
Corma, M. Iglesias, F. Sanchez, Chem. Commun. 2005, 3451; c) A.
Comas-Vives, C. Gonzalez-Arellano, A. Corma, M. Iglesias, F. San-
chez, G. Ujaque, J. Am. Chem. Soc. 2006, 128, 4756; d) A. Corma, P.
Serna, Science 2006, 313, 332; e) A. Corma, P. Concepcion, P. Serna,
Angew. Chem. 2007, 119, 7404; Angew. Chem. Int. Ed. 2007, 46,
7266; f) A. Corma, P. Serna, H. Garcꢀa, J. Am. Chem. Soc. 2007,
129, 6358; g) A. Grirrane, A. Corma, H. Garcꢀa, Science 2008, 322,
1661; h) E. Y. Tsui, P. Mꢅller, J. P. Sadighi, Angew. Chem. 2008, 120,
9069; Angew. Chem. Int. Ed. 2008, 47, 8937; for other publications
for gold-catalyzed hydrogenation including earlier works, see ref. 1b.
[4] a) M. Boronat, P. Concepcion, A. Corma, S. Gonzalez, F. Illas, P.
Serna, J. Am. Chem. Soc. 2007, 129, 16230; b) E. Bus, R. Prins, J. A.
van Bokhoven, Catal. Commun. 2007, 8, 1397; c) A. Corma, M. Bor-
onat, S. Gonzalez, F. Illas, Chem. Commun. 2007, 3371; d) Y.
Segura, N. Lopez, J. Perez-Ramꢀrez, J. Catal. 2007, 247, 383; e) A.
Comas-Vives, C. Gonzalez-Arellano, M. Boronat, A. Corma, M. Ig-
[15] a) V. K. Y. Lo, Y. Liu, M. K. Wong, C.-M. Che, Org. Lett. 2006, 8,
1529; b) B. Huang, X. Yao, C.-J. Li, Adv. Synth. Catal. 2006, 348,
1528.
Received: May 25, 2012
Revised: July 30, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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A. Corma, J. Navas, and M. J. Sabater
Gold Catalysis
A. Corma,* J. Navas,
M. J. Sabater* ................. &&&& — &&&&
Coupling of Two Multistep Catalytic
Cycles for the One-Pot Synthesis of
Propargylamines from Alcohols and
Primary Amines on a Nanoparticu-
lated Gold Catalyst
All in one: A one-pot reaction was
performed with a nanoparticulated
gold catalyst. A secondary amine was
formed through N-monoalkylation of
a primary amine with an alcohol by a
borrowing hydrogen methodology. The
secondary amine entered into a second
coupling cycle to give propargylamines
(see scheme).
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Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!