Acid-base bifunctional catalysis of silica-alumina-supported organic amines for carbon-carbon bond-forming reactions

Article abstract of DOI:10.1002/chem.200702048

Acid-base bifunctional heterogeneous catalysts were prepared by the reaction of an acidic silica-alumina (SA) surface with silane-coupling reagents possessing amino functional groups. The obtained SA-supported amines (SA-NR ₂) were characterized by solid-state ¹³C and ²⁹Si NMR spectroscopy, FT-IR spectroscopy, and elemental analysis. The solid-state NMR spectra revealed that the amines were immobilized by acid-base interactions at the SA surface. The interactions between the surface acidic sites and the immobilized basic amines were weaker than the interactions between the SA and free amines. The catalytic performances of the SA-NR ₂ catalysts for various carbon-carbon bond-forming reactions, such as cyano-ethoxycarbonylation, the Michael reaction, and the nitro-aldol reaction, were investigated and compared with those of homogeneous and other heterogeneous catalysts. The SA-NR₂ catalysts showed much higher catalytic activities for the carbon-carbon bond-forming reactions than heterogeneous amine catalysts using other supports, such as SiO₂ and Al ₂O₃. On the other hand, homogeneous amines hardly promoted these reactions under similar reaction conditions, and the catalytic behavior of SA-NR₂ was also different from that of MgO, which was employed as a typical heterogeneous base. An acid-base dual-activation mechanism for the carbon-carbon bond-forming reactions is proposed.

Full text of DOI:10.1002/chem.200702048

FULL PAPER
DOI: 10.1002/chem.200702048
Acid–Base Bifunctional Catalysis of Silica–Alumina-Supported Organic
Amines for Carbon–Carbon Bond-Forming Reactions
Ken Motokura, Mitsuru Tomita, Mizuki Tada, and Yasuhiro Iwasawa*[a]
Abstract: Acid–base bifunctional heter-
ogeneous catalysts were prepared by
the reaction of an acidic silica–alumina
(SA) surface with silane-coupling re-
agents possessing amino functional
groups. The obtained SA-supported
amines (SA–NR2) were characterized
by solid-state 13C and 29Si NMR spec-
troscopy, FT-IR spectroscopy, and ele-
mental analysis. The solid-state NMR
spectra revealed that the amines were
immobilized by acid–base interactions
at the SA surface. The interactions be-
tween the surface acidic sites and the
immobilized basic amines were weaker
than the interactions between the SA
and free amines. The catalytic perform-
ances of the SA–NR2 catalysts for vari-
ous carbon–carbon bond-forming reac-
tions, such as cyano-ethoxycarbonyla-
tion, the Michael reaction, and the
nitro-aldol reaction, were investigated
and compared with those of homoge-
neous and other heterogeneous cata-
lysts. The SA–NR2 catalysts showed
much higher catalytic activities for the
carbon–carbon bond-forming reactions
than heterogeneous amine catalysts
using other supports, such as SiO2 and
Al2O3. On the other hand, homogene-
ous amines hardly promoted these re-
actions under similar reaction condi-
tions, and the catalytic behavior of SA–
NR2 was also different from that of
MgO, which was employed as a typical
heterogeneous base. An acid–base
dual-activation mechanism for the
carbon–carbon bond-forming reactions
is proposed.
Keywords: acid–base interactions ·
À
amines · C C coupling · hetero-
geneous catalysis · silica–alumina
Introduction
surface realizes one-pot catalytic reaction sequences and
double catalytic activation in a single reaction step for the
improvement of the reaction rate and selectivity.[2,3]
Immobilization of catalytically active species, or even almost
inactive species, on solid materials enables not only the gen-
eration of recoverable and reusable catalysts but also re-
markable catalytic performances compared with their homo-
geneous precursors before the immobilization owing to
unique environments of the surfaces. Many reasons have
been reported for the positive effects of immobilization: for
example, the increasing stability of active structures by site
isolation at surfaces, the creation of new geometric and elec-
tronic structures by surfaces, and the enhancement of sub-
strate density around active sites by high surface polarities.[1]
In addition to the increasing activity of the immobilized spe-
cies, cooperative catalysis of the support surfaces with the
immobilized species is another advantage of the use of sup-
ports.[2] The generation of multicatalytic functions on a solid
Acid–base dual-activation catalysis has received much at-
tention for highly efficient nucleophilic reactions, including
carbon–carbon bond-forming reactions.[4] In base-catalyzed
carbon–carbon couplings, nucleophilic precursors are acti-
vated by basic catalysts to generate nucleophiles by abstrac-
tion of their acidic parts, such as acyl groups and a-hydrogen
atoms, and then, the nucleophiles attack electrophiles. On
the other hand, decreasing the levels of the lowest-unoccu-
pied molecular orbital (LUMO) of the electrophiles can be
readily achieved by coordination activation of Brønsted or
Lewis acidic catalysts. On the basis of these facts, it is ex-
pected that an ideal pathway for the carbon–carbon bond-
forming reactions is dual activation of both the electrophiles
and nucleophiles by acidic and basic functions of catalysts,
respectively. Many types of homogeneous reaction systems
with acid–base dual-activation have been developed, but
with these homogeneous reagents, recovery and reuse of
both acidic and basic catalysts are industrially problematic.
In addition, strongly acidic and basic species in a single reac-
tor induces neutralization immediately, thus affording inac-
tive salts.
[a] Dr. K. Motokura, M. Tomita, Dr. M. Tada, Prof. Dr. Y. Iwasawa
Department of Chemistry, Graduate School of Science
The University of Tokyo, 7–3–1 Hongo
Bunkyo-ku, Tokyo 113–0033 (Japan)
Fax : (+81)3-5800-6892
E-mail: iwasawa@chem.s.u-tokyo.ac.jp
Chem. Eur. J. 2008, 14, 4017 – 4027
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4017

A possible solution to these problems is the utilization of
heterogeneous catalysts that possess both acidic and basic
functions on their surfaces. The immobilization of incompat-
ible catalytic species on different solid supports has over-
come the problem of neutralization and enabled acid–base
one-pot reaction sequences.[5] A few examples of the genera-
tion of both acidic and basic functions on the same solid sur-
face have been reported for the dual activation of electro-
philes and nucleophiles.[6–9] Although primary alkylamines
as basic immobilized groups and many types of acidic
groups, such as, hydrogen-bonding urea,[6] sulfonic and car-
boxylic acids,[7] and surface silanols,[8] were found to have
cocatalytic functions, these catalytic systems faced several
problems, such as low catalytic activity due to weak acidity,
significantly limited application in organic reactions, and
complicated catalyst preparations.
duced pressure, thus affording the SA-supported amine cat-
alyst (SA–NEt2) as a white–yellow powder. Elemental anal-
ysis (%) of SA–NEt2 revealed C 8.40, H 2.16, N 1.27, and
the C/N ratio of 7.7:1 of SA–NEt2 indicated a release of one
or two methoxy groups in DAPS.
The IR spectra of SA–NEt2 showed absorption bands
À
characteristic of the parent DAPS (n(C H)=2990–2850, ds-
G
(CH2)=1370–1480, and
1
(CH2)=765 cmÀ1).[11] Figure 1C
A
Alternatively, we recently reported a new strategy for the
design of acid–base bifunctional catalyst surfaces:[2] 1) the
utilization of strong solid acids as supports for increased cat-
alytic activity, 2) the immobilization of tertiary amines on
these supports for the expansion of applicable catalytic reac-
tions, and 3) the use of silane-coupling reactions between
the amine reagents and acidic solid supports to simplify the
catalyst preparation. Herein, we report detailed studies on
the synthesis and characterization of amorphous silica–alu-
mina-supported amine catalysts and their application to var-
ious catalytic organic reactions, such as cyano-ethoxycarbo-
nylation, the Michael reaction, and the nitro-aldol reaction
[Eqs. (1)–(3)].[10] We also present plausible mechanisms for
the amine immobilization and acid–base bifunctional cata-
lytic reactions.
Figure 1. A) 13C NMR spectra of DAPS in CDCl3 (the signals around d=
77 ppm are assignable to TMS as the internal standard). Solid-state 13C
CP/MAS NMR spectra of B) SiO2–NEt2 and C) SA–NEt2.
shows a solid-state 13C CP/MAS NMR spectrum of SA–
NEt2, with signals at d=4.0–13.0, 19.6, 43.0–53.0, and
55.6 ppm, assignable, respectively, to the carbon atom next
to the silicon and terminal carbon atoms of the amino
group, the central carbon atom in the propyl chain, the
carbon atom in the methoxy groups and next to the nitrogen
atom in the ethyl groups, and the carbon atom next to the
nitrogen atom in the propyl chain. These signal positions are
similar to those of the parent DAPS (Figure 1A) and a
SiO2-supported amine catalyst SiO–NEt2 (Figure 1B). These
IR and 13C NMR spectroscopic data demonstrate that the
main structure of the DAPS skeleton is retained in SA–
NEt2. In the 29Si MAS NMR spectrum of SA–NEt2 (Fig-
ure 2D), the Q sites were observed at around d=À100 ppm
and new signals appeared at d=À48 and À56 ppm, which
are assignable to T1 and T2 organosilica species, respectively
Results and Discussion
Preparation and characterization of the catalysts: The amine
catalysts supported on silica–alumina (SA) were prepared
by a silane-coupling reaction mode. SA was heated at 1208C
under vacuum for 3 h, followed by reaction with silane-cou-
pling reagents containing amine functional groups. A terti-
ary amine group was immobilized by reaction of SA (Nikki
Chemical Co.; SiO2 66.5, Al2O3 25.1%; 380 m2 gÀ1) with a so-
lution of 3-(diethylamino)propyltrimethoxysilane (DAPS) in
toluene under reflux for 24 h. The reaction mixture was fil-
tered, washed with dichloromethane, and dried under re-
(Tm =RSi
A
N
the amino group was immobilized on the SA surface by a
condensation reaction between the surface silanol groups of
SA and the methoxy groups of DAPS to form a covalent Si-
O-Si linkage while maintaining the tertiary amine skeleton
of DAPS. Other solid-supported tertiary amines (support–
NEt2) were synthesized and characterized by using the same
procedures. n-Octyl groups were also immobilized on SA by
4018
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Chem. Eur. J. 2008, 14, 4017 – 4027

À
Dual Activation Catalysis for C C Bond-Forming Reactions
FULL PAPER
Figure 3. A) 13C NMR spectra of aminopropyltriethoxysilane in CDCl3
(the signals around d=77 ppm are assignable to TMS as the internal
standard). Solid-state 13C CP/MAS NMR spectra for B) SiO2–NH2 and
C) SA–NH2.
Table 1. Amount of DMAP adsorbed on functionalized SA.
Figure 2. Solid-state 29Si MAS NMR spectra for A) SiO2–NH2, B) SiO2–
NEt2, C) SA–NH2, and D) SA–NEt2.
Entry
Solid
Amount of adsorbed DMAP
[mmolgÀ1
]
1
2
3
SA–NEt2
SA-octyl
SA
2.25
1.78
2.30
reaction of n-octyltrimethoxysilane with SA in a similar pro-
cedure (SA–octyl).
The SA-supported primary amine catalyst (SA–NH2) was
also synthesized by modification of the SA surface with 3-
aminopropyltriethoxysilane in solution with toluene under
reflux conditions. The result of the elemental analysis (%)
of SA–NH2 was C 6.41, H 1.99, N 1.57. The IR spectra of
SA–NH2 showed peaks assignable to 3-aminopropyltriethox-
À
Interaction between the amines and acidic sites: The IR
spectra for SA–NEt2, NEt3 adsorbed on SA, and DAPS are
shown in Figure 4, and the peak positions are listed in
Table 2. In the case of NEt3 adsorbed on a SA surface, the
À
ysilane
(n
A
and
ds
A
N H stretching vibrations of the protonated amines were
1480 cmÀ1).[13] The solid-state 13C CP/MAS NMR spectro-
scopic analysis showed the retention of the primary amine
structure (Figure 3): d=10.0, 16.5, 21.0–27.0, 44.3, and
57.7 ppm, assignable, respectively, to the carbon atom next
to the silicon atom, the terminal carbon atom in the ethoxy
groups, the central carbon atom of the propyl chain, the
carbon atom next to the nitrogen atom, and the carbon
atoms next to the oxygen atoms. The T sites were also ob-
served in the solid-state 29Si MAS NMR spectra of SA–NH2
(Figure 3C). These results suggest that the primary amine
groups were immobilized on the SA surface by the forma-
tion of the Si-O-Si covalent bonds, similar to the above terti-
ary amine groups.
observed at n˜ =2804, 2746, 2689, and 2497 cmÀ1 (Table 2),[14]
whereas these peaks were definitely not observed for the
immobilized catalyst SA–NEt2. These results suggest that
the interaction between the immobilized NEt2 groups and
the acidic sites on the SA surface is much weaker than the
direct interaction between the free amines and the acidic
sites on the SA surface.
We also recorded solid-state 13C NMR spectra to examine
the surface acid–base interactions between the acidic sites of
SA and the immobilized tertiary amine groups. It is well
known that the 13C NMR signal of the terminal carbon atom
of the ethyl amino group shifts upfield through the interac-
tion between the acidic species and the nitrogen atom.
Figure 5 shows the 13C NMR signals assignable to the termi-
nal carbon atom of the free or immobilized diethyl amino
groups. The signals of immobilized amines on Al2O3, SiO2,
and SA shifted upfield (d=11.0, 10.0, and 9.4 ppm, respec-
tively; Figures 5B–D) relative to the signal of DAPS in solu-
tion (d=11.9 ppm; Figure 5A). The larger shift for SA–
NEt2 than those for Al2O3–NEt2 and SiO2–NEt2 may be de-
The acid density of the SA and SA–NEt2 surfaces was de-
termined from the amount of adsorbed 4-dimethylaminopyr-
idine (DMAP) in the liquid phase. After the amine immobi-
lization onto the SA surface, the amount of acidic sites did
not change significantly (see Table 1, entry 1 vs. 3). On the
other hand, the acid density of SA decreased with the im-
mobilization of n-octyltrimethylsilane.
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Y. Iwasawa et al.
Figure 4. IR spectra of A) SA–NEt2, B) NEt3 adsorbed on SA, and
C) DAPS. These spectra were recorded at room temperature in a trans-
mission mode. The solid samples were pressed into a disk with KBr.
Table 2. IR vibration absorptions of SA–NEt2, triethylamine adsorbed
on SA, DAPS, triethylamine, and triethylamine hydrochloride.
À1
À1
À
À
Sample
n
(C H) [cm
]
n
N
]
SA–NEt2
SA+NEt3
DAPS
2986, 2954, 2855
2996, 2963
2974, 2946, 2843
2971, 2936, 2798
3000, 2976, 2938
Figure 5. A) 13C NMR spectra of DAPS in CDCl3. Solid-state 13C CP/
MAS NMR spectra for B) Al2O3–NEt2, C) SiO2–NEt2, D) SA–NEt2,
E) SA treated with a solution of DAPS in toluene for 5 min at room tem-
perature (SA+DAPS), and F) triethylamine adsorbed at the terminal
carbon atoms of the amino groups on the SA surface.
2804, 2746, 2693, 2497
–
–
[a]
NEt3
NEt3·HCl[a]
2803, 2739, 2678, 2492
[a] Data from ref. [14]
main signal (Figure 6B), whereas the majority of sites in
SA–NEt2 were T2 sites (Figure 6 A). From these results, the
mechanism for amine immobilization on the SA surface is
proposed to be as follows (Scheme 1): i) the nitrogen atom
of free DAPS interacts with the strong Brønsted acid on the
rived from the stronger Brønsted acidity of the SA surface.
The signals from mixtures of SA and free DAPS or triethyl-
amine appeared more upfield than that for SA–NEt2. For
example, the signal for triethylamine (NEt3) adsorbed on
the SA surface showed the largest upfield shift (from d=
11.8 (free NEt3) to 7.5 ppm; Figure 5F). This outcome is in
agreement with the above IR results: a weak acid–base in-
teraction with the immobilized SA–NEt2.
À
SA surface, ii) one Si OMe bond of DAPS reacts with the
À
surface Si OH species near the strongly acidic site to form
À
a covalent Si-O-Si
(surface) bond, and iii) another Si OMe
À
species further reacts with a neighboring Si OH bond on
heating, thus resulting in decreased acid–base interactions
between the strongly acidic site and the nitrogen atom. The
formation of a T2 silicon species with two covalent Si-O-Si-
Proposed mechanism for amine immobilization: The SA
surface was treated with a solution of DAPS in toluene for
5 min at room temperature, followed by filtration. The ob-
tained solid (SA+DAPS) was subjected to solid-state 13C
and 29Si NMR spectroscopic analysis. A 13C NMR peak as-
signable to the terminal carbon atom of adsorbed DAPS
was observed at around d=8.0 ppm (Figure 5E), which indi-
cates that the acid–base interactions are stronger than those
in SA–NEt2 after complete immobilization under reflux for
24 h (d=9.4 ppm; Figure 5D). Figure 6 shows the 29Si NMR
spectra for the Tm sites in SA–NEt2 and SA+DAPS, in
which the 29Si NMR spectra are noisy as a result of the
small amount of the Tm sites at the surface. In the case of
SA+DAPS, the T1 site was observed at d=À49 ppm as a
A
amine group and the acidic site, which induces a decrease in
the acid–base interactions. The silane-coupling reaction of
the Brønsted acid with the alkoxysilane, which maintains
the quantity of strongly acidic sites (Table 1), is prevented
from proceeding by these acid–base interactions. In the
solid-state 29Si NMR spectra of SA–octyl, the formation of
not only T2 but also T3 sites was observed in the absence of
basic amino groups (Figure 6C), which suggests that the al-
koxysilane groups randomly reacted with two or three sur-
face hydroxy groups, including the strongly acidic sites. The
ability of the acid–base to coexist on the SA–NR2 surface
4020
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À
Dual Activation Catalysis for C C Bond-Forming Reactions
FULL PAPER
Catalysis of the amine-immobilized solid acid: Cyanohydrins
are important building blocks in synthetic organic chemis-
try,[15] and they have been synthesized by the cyanation of
carbonyl compounds with HCN or trimethysilyl cyanide.[16]
However, HCN and trimethylsilyl cyanide are toxic, unsta-
ble, and expensive; hence, the use of alternative cyanation
reagents is desirable. Recently, one-pot catalytic cyanation/
O-protection with cyanoformic esters has been investigated
as a novel synthetic pathway.[17] Although several examples
of the cyanation/O-protection reactions by homogenous
acid–base bifunctional catalysts have been demonstrated,[17c–-
f, i]
heterogeneous catalysts for the cyanation reaction have
not yet been reported. We found that our heterogeneous
acid–base bifunctional catalysts were active towards cyana-
tion/O-protection with a cyanoformic ester as a cyanation
regent.
First, the cyano-ethoxycarbonylation of benzaldehyde
(1a) with ethyl cyanoformate (2a) was studied in the pres-
ence of heterogeneous and homogeneous catalysts (Table 3).
Table 3. Cyano-ethoxycarbonylation using various catalysts.[a]
Entry
Catalyst
Yield [%][b]
1
SA–NEt2
SA–NEt2
SiO2–NEt2
Al2O3–NEt2
H-USY–NEt2
SA–NH2
Et3N+SA
Et3N+p-TsOH·H2O
Et3N
DAPS
SA
SiO2
Al2O3
95
57
17
16
3
trace
70
trace
1
2[c]
3
4
5
6
7[d,e]
8[d,f]
9[d]
10[g]
11[e]
12[e]
13[e]
14[e]
15
Figure 6. Solid-state 29Si MAS NMR spectra of Tm sites. A) SA–NEt2,
B) SA treated with a solution of DAPS in toluene for 5 min at room tem-
perature (SA+DAPS), and C) SA–octyl.
1
trace
trace
trace
trace
trace
MgO
none
without neutralization tempted us to envisage that SA–NR2
could act as a heterogeneous acid–base bifunctional catalyst
for efficient organic syntheses.
[a] Reagents and conditions: catalyst (0.034 mmol of amine), 1a
(0.5 mmol), 2a (1.0 mmol), toluene (5 mL), room temperature, 1 h.
[b] Determined by GC, based on 1a. [c] SA (SiO2: 82.5; Al2O3: 12.6%)
was used as
a support. [d] Triethylamine (0.034 mmol). [e] Catalyst
(0.038 g). [f] p-TsOH (0.034 mmol). [g] DAPS (0.034 mmol).
Among the amine-immobilized
catalysts, the SA-supported ter-
tiary amine catalyst showed the
highest performance to afford
cyanophenylmethyl ethyl car-
bonate (3aa) in an excellent
yield (Table 3, entry 1). A de-
crease in the Al content in SA
induced a decrease in the activi-
ty of the cyanation reaction
(Table 3, entry 2). Other solid-
Scheme 1. Proposed mechanism for amine immobilization on the SA surface. i) Interaction between the nitro-
gen atom of free DAPS with a Brønsted acid, ii) formation of a covalent Si-O-Si
A
creased acid–base interactions between the strongly acidic site and the nitrogen atom as a result of another
À
À
Si OMe species reacting with a neighboring Si OH bond.
Chem. Eur. J. 2008, 14, 4017 – 4027
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4021

Y. Iwasawa et al.
supported tertiary amine catalysts, such as SiO2–NEt2 and
Al2O3–NEt2, were much less active (Table 3, entries 3–5).
These results suggest that the stronger surface acidic sites of
SA play a pivotal role in the promotion of cyano-ethoxycar-
bonylation. Interestingly, the reaction scarcely proceeded
with either homogeneous amines (Table 3, entries 9 and 10)
or acidic solid supports (Table 3, entries 11–13). The mixture
of triethylamine and SA showed catalytic activity, but the
product yield was lower than for SA–NEt2 under the same
reaction conditions (Table 3, entry 7). When the acidic sup-
port SA was replaced by para-toluenesulfonic acid (p-
TsOH) in a homogeneous system, the reaction did not occur
(Table 3, entry 8). A poor result was obtained with MgO as
a typical heterogeneous base (Table 3, entry 9). These re-
sults suggest that both the acidic and basic functions on the
surface are highly efficient for the promotion of cyano-
ethoxycarbonylation.
The high performances of the SA–NEt2 catalyst for the
cyano-ethoxycarbonylation of various carbonyl compounds
are shown in Table 4. Both electron-rich and electron-defi-
cient benzaldehydes acted as good substrates, thus giving
the corresponding O-protected cyanohydrin derivatives in
excellent yields (Table 4, entries 1–5). An allylic aldehyde,
such as cinnamaldehyde, also underwent a reaction with 2a
in the presence of SA–NEt2 (Table 4, entry 6). A sulfur het-
eroatom did not affect the reaction rate: the cyanation reac-
tion of 2-thiophenecarboxyaldehyde took place readily
(Table 4, entry 8). Notably, many types of aliphatic alde-
hydes, such as acyclic, branched, and cyclic aldehydes, un-
derwent a reaction with 2a, affording excellent yields of the
corresponding products (Table 4, entries 9–11). To extend
the scope of the carbonyl substrates, the use of ketones was
also examined. Cyanoformic ester 2a underwent a reaction
with cyclohexenone to afford the corresponding product in
88% yield after
a prolonged reaction time (Table 4,
entry 12). To the best of our knowledge, this report is the
first of a one-pot cyano/O-protection of carbonyl com-
pounds with cyanoformic ester using a heterogeneous cata-
lyst.
After the first run of the cyano-ethoxycarbonylation reac-
tion was completed, the SA–NEt2 catalyst was separated
from the reaction mixture and was reusable with retention
of the high catalytic activity and selectivity (Table 4,
1
entry 2). The H NMR spectroscopic analysis of the filtrate
showed no leaching of the immobilized amine compounds,
and the elemental analysis of the recovered catalyst also in-
dicated no decrease in the amount of the amino group.
These facts rule out any contribution of the amines to the
carbon–carbon bond-forming reaction by leaching into the
reaction solution.
This amine-immobilized solid acid catalyst was applicable
to the Michael reaction of nitrile compounds 4 with elec-
tron-deficient alkenes 5 (Table 5). The SA–NEt2 catalyst
showed the highest catalytic activity for the Michael reac-
tion of ethyl 2-cyanopropionate (4a) with ethyl acrylate
(5a) to afford 2-cyano-2-methyl glutaric acid diethyl ester in
94% yield (Table 5, entry 1). The reaction did not proceed
in the case of the SA-supported primary amine (SA–NH2;
Table 5, entry 3). Other solid supports, such as SiO2, were
less active (Table 5, entry 2), and neither triethylamine nor
SA promoted the desired addition reaction (Table 5, en-
Table 4. Cyano-ethoxycarbonylation using SA–NEt2.[a]
Entry
Carbonyl
Time [h] Conversion [%][b] Yield [%][b]
Table 5. Michael reaction of a-substituted ethyl cyanoacetates with elec-
tron-deficient alkenes.[a]
1
2
3
4
5
R=H
R=H
R=Cl
R=Me
1a
1a
1b
1c
1d
1
1
3
1
3
>99
>99
>99
>99
>99
98
97[c]
99
99
98
Entry
Catalyst
R3
EWG
Yield [%][b]
R=OMe
1
2
3
SA–NEt2
SiO2--NEt2
SA–NH2
Et3N+SA
Et3N
Me (4a)
Me
Me
Me
Me
Me
Ph (4b)
Ph
Ph
Me
CO2Et (5a)
CO2Et
CO2Et
CO2Et
CO2Et
94
9
trace
5
3
1
99
6
7
1e
1 f
2
1
>99
>99
91
99
4[c,d]
5[c]
6[c]
SA
CO2Et
8
9
1g
1h
1I
1
1
1
>99
>99
>99
98
99
92
7[e,f]
8[e,f]
9[e,f]
10[e]
11[e,f]
12[e,f]
SA–NEt2
SA–NEt2
SA–NEt2
SA–NEt2
SA–NEt2
Et3N
CO2Me (5b)
CO2Me
CO2Me
CN (5c)
CN
99[g]
94[h]
95
66
17
10
11
12
1j
1
>99
99
88
Me
Me
CN
1k 48
90
[a] Reagents and conditions: catalyst (0.09 mmol of amine), 4 (1.0 mmol),
5 (3 mmol), toluene (1 mL), 908C, 24 h. [b]Determined by GC and
1H NMR spectroscopic analysis, based on 4. [c]Triethylamine
(0.09 mmol). [d] Catalyst (0.05 g). [e]Catalyst (0.045 mmol of amine);
608C. [f] Reaction time: 3 h. [g] Second reuse experiment. [h] Fourth
reuse experiment. EWG=electron-withdrawing group.
[a] Reagents and conditions:
1 (0.5 mmol), 2a (0.6 mmol), toluene
(1 mL), SA–NEt2 (0.038 g; N: 0.034 mmol), room temperature. [b] Deter-
mined by GC and 1H NMR spectroscopic analysis, based on 1. [c] Reuse
experiment.
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À
Dual Activation Catalysis for C C Bond-Forming Reactions
FULL PAPER
tries 5 and 6). In addition, the reaction scarcely proceeded
in the presence of the mixture of triethylamine and SA
(Table 5, entry 4). Notably, the SA–NEt2-catalyzed reaction
of ethyl phenylcyanoacetate (4b) with methyl acrylate (5b)
successfully proceeded to give 2-cyano-2-phenyl glutaric
acid 1-ethyl-5-methyl ester, which is a highly useful inter-
mediate for glutarimide synthesis (Table 5, entry 7).[18] The
SA–NEt2 catalyst was reusable at least four times with re-
tention of its high catalytic activity and selectivity in the Mi-
chael reaction (Table 5, entries 8 and 9). In addition, SA–
NEt2 showed higher catalytic activity for the reaction of 4a
with acrylonitrile (5c; Table 5, entries 10 and 11) than the
homogeneous amine (Table 5, entry 12).
rated nitro compounds, which are important building blocks
in the synthesis of pharmaceutical products.[20] The a-hydro-
gen atom of a nitroalkane can be abstracted by strong bases
owing to its acidity, but the selective production of a nitroal-
kene using conventional strong bases is generally difficult
because the side reaction of a conjugate addition of the ni-
troalkane to the carbon–carbon double bond of the nitroal-
kene occurs to give a bis
(nitro) compound.[21] Because of
A
the highly useful nature of nitroalkenes, the nitro-aldol reac-
tion of nitroalkanes with aldehydes was also investigated
(Table 7).[22] The SA–NH2 catalyst gave a quantitative yield
Table 7. Nitro-aldol reaction of aldehydes with nitroalkanes using various
catalysts.[a]
It is noteworthy that the SA–NEt2 catalyst also showed
excellent performance for the bis-substitution reaction of
ethyl cyanoacetate (4c) with methyl vinyl ketone (5d), thus
producing 5-carboethoxy-5-cyano-2,8-nonanedione (6 cd) in
90% yield within 30 minutes (Table 6, entry 1). A SiO2-sup-
Entry Catalyst
R1
R4
Time Yield
[h]
[%][b]
1
2
SA–NH2
SA–NEt2
Ph (1a)
Ph
H (7a)
6
6
6
6
99 (97)[c]
<1
12
Table 6. Michael reaction of 4c with 5d using various catalysts.[a]
H
H
H
3[d,e] n-hexylamine+SA Ph
4[d,f]
n-hexylamine+
p-TsOH·H2O
n-hexylamine
SA
Ph
<1
5[d]
6[e]
Ph
Ph
Ph
H
H
H
H
6
6
6
2
2
4
13
<1
<1
88
88
90
Entry
Catalyst
Conversion [%][b]
Yield [%][b]
7[e,f]
8[g]
none
1
2
3
SA–NEt2
SiO2–NEt2
SA–NH2
Et3N+SA
Et3N
SA
SiO2
MgO
None
>99
83
<1
90
<1
<1
<1
82
90
43
<1
66
<1
<1
<1
52
SA–NH2
SA–NH2
SA–NH2
c-hexyl (1j)
n-octyl (1h)
Ph
9[g]
H
10[g]
Me (7b)
4[c,d]
5[c]
6[d]
7[d]
8[d]
9
[a] Reagents and conditions: catalyst (0.015 mmol of amine),
(5.0 mmol), (2 mL), 1008C. [b] Determined by GC, based on 1.
[c] Fourth reuse experiment. [d] n-Hexylamine (0.015 mmol). [e]Catalyst
(0.0145 g). [f] p-TsOH acid (0.015 mmol). [g] Aldehyde (1 mmol); SA–
NH2 (0.056 mmol).
1
7
<1
<1
[a] Catalyst (0.091 mmol of amine), 5d (1.5 mmol), 4c (0.5 mmol), tolu-
ene (1 mL), 608C, 30 min. [b]Determined by GC, based on 4c. [c]Trie-
thylamine (0.091 mmol). [d]Catalyst (0.1 g).
of b-nitrostyrene from 1a and nitromethane (7a; Table 7,
entry 1). The homogeneous primary amine was much less
active (Table 7, entry 5) and the low catalytic activity was
not improved by the addition of SA (Table 7, entry 3). Nota-
bly, the reaction hardly proceeded using SA–NEt2 instead of
SA–NH2 (Table 7, entry 2). In the case of the SA–NH2-cata-
lyzed reaction of 7a with 1a, the turnover number (TON)
based on the amine reached up to 330. This value is signifi-
cantly higher than that of the previously reported amine cat-
alysts: MCM-41-supported amine (TON=37),[22c] aminopro-
pylsilica (TON=17),[22d] and a silica-supported urea–amine
bifunctional catalyst (TON=125).[6] The SA–NH2 catalyst
was found to be applicable to the nitro-aldol reaction of
other aldehydes with nitroalkanes. The reaction of aliphatic
aldehydes, such as cyclohexanecarboxyaldehyde (1j) and n-
octylaldehyde (1h), produced the corresponding nitroal-
kenes in excellent yields (Table 7, entries 8 and 9). Nitro-
ethane (7b) also acted as a good donor substrate (Table 7,
entry 10). After the nitro-aldol reaction of 7a with 1a, the
recovered SA–NH2 catalyst was washed with toluene and re-
usable under the same reaction conditions: the first and
ported tertiary amine catalyst also gave 6 cd in a moderate
yield of 43% (Table 6, entry 2). Neither triethylamine nor
SA produced 6 cd (Table 6, entries 5 and 6), whereas the
mixture of triethylamine and SA gave a 66% yield of 6 cd
(Table 6, entry 4). A typical heterogeneous base of MgO
also gave the corresponding product (Table 6, entry 8), but
the catalytic activity was lower than for the same weight of
SA–NEt2. Generally, strong bases or transition-metal cata-
lysts are needed for the 1,4-addition of nitrile compounds to
electron-deficient alkenes.[19] However, these reaction sys-
tems present difficulty in their handling as a result of mois-
ture sensitivity and deactivation by air containing carbon di-
oxide. The present SA–NEt2 catalyst can solve these prob-
lems because of the use of the simple and stable alkylamines
immobilized on the stable SA as a heterogeneous catalyst,
which contributes to environmentally friendly organic syn-
theses.
The condensation reaction of nitroalkanes with carbonyl
compounds, namely, the nitro-aldol reaction, is one of the
most powerful procedures for the production of a,b-unsatu-
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4023

Y. Iwasawa et al.
second runs afforded product yields of 99 and 97%, respec-
tively.
Proposed catalytic reaction mechanism: Table 8 shows the
effect of solvents on the performances of the catalysts, and
the dielectric constant values e of the solvents as a criterion
Table 8. Solvent effect on the Michael reaction.[a]
Entry
Catalyst
Solvent
(dielectric constant (e))
Conversion
[%][b]
Yield
[%][b]
1
2
3
4
5
6
7
SA–NEt2
SA–NEt2
SA–NEt2
SA–NEt2
SA–NEt2
MgO
n-heptane
toluene
Et2O
DMSO
DMF
C
>99
88
86
20
8
32
64
56
20
<1
33
G
G
toluene
DMF
33
58
MgO
U
46
[a] Reagents and conditions: catalyst (0.1 g), 5e (0.75 mmol), 4c
(0.5 mmol), solvent (1 mL), 608C, 3 h. [b]Determined by 1H NMR spec-
troscopic analysis, based on 4c.
Figure 7. IR spectra of A) SA–NEt2 +2a after treatment with 1a, B) SA–
NEt2 +2a, C) SA+2a, and D) free 2a. These spectra were measured at
room temperature in transmission mode. The solid samples were pressed
into a disk with KBr.
of polarity are also listed. Toluene was the most effective
solvent among the solvents for the Michael reaction of 4c
with 2-cyclohexen-1-one (5e; Table 8, entry 2), whereas di-
methyl sulfoxide (DMSO) and N,N-dimethylformamide
(DMF) were substantially less active (Table 8, entries 4 and
5). n-Heptane allowed an excellent conversion of 4c to be
obtained, but the selectivity was low (Table 8, entry 1).
These results suggest that nonpolar solvents with low dielec-
tric constants are good media for the Michael reaction and
that polar and electron-donating solvents with higher dielec-
tric constants resulted in lower reaction rates. On the other
hand, a polar solvent, DMF, gave a good result relative to
toluene when MgO, as a typical heterogeneous base, was
used as a catalyst for the Michael reaction (Table 8, entry 6
vs. 7).
site on the SA surface, respectively (Scheme 2). The initial
rate of the triethylamine-catalyzed cyanation of 1a with 2a
is first-order with respect to the concentration of 1a and
zero-order with respect to the concentration of 2a, thus indi-
cating that the rate-determining step is the carbon–carbon
bond-forming step. On the other hand, the initial reaction
kinetics in the SA–NR2-catalyzed reaction shows zero-order
dependence with respect to both 1a and 2a. It is suggested
From these contrary results, it is reasonable to conclude
that the Brønsted acidic sites on the SA surface, which can
be deactivated by electron-donating solvents, play a crucial
role in the catalytic mechanism of SA–NEt2.[23] After the
treatment of SA–NEt2 with 2a, the n(CN) peak for 2a ap-
peared at 2221 cmÀ1 (Figure 7B),[24] which is lower than that
for free 2a (2247 cmÀ1; Figure 7D). The shifted n(CN) ab-
sorption band disappeared on treatment with 1a, accompa-
nied with the production of 3aa (Figure 7A). This peak shift
was not observed when the SA surface was treated with 2a
(Figure 7C). These results indicate that the nucleophilic CN
species forms through interaction with the surface tertiary
amine group. As consequence, we proposed a reaction
mechanism for the SA–NEt2-catalyzed reactions involving
the dual activation of the donor and acceptor substrates at
the basic amine site and the neighboring Brønsted acidic
Scheme 2. Reaction mechanism for SA–NEt2-catalyzed reactions involv-
ing dual activation of the donor (i) and acceptor (ii) substrates on the SA
surface.
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Chem. Eur. J. 2008, 14, 4017 – 4027

À
Dual Activation Catalysis for C C Bond-Forming Reactions
FULL PAPER
that the electron-withdrawing activation of a carbonyl com-
pound by surface acidic sites is a new and very fast reaction
step.
imine species forms, and a nitroalkane moiety reacts with
the activated imine to afford the nitroalkene product.
Table 7 and several previous reports[22b] show the substan-
tially low catalytic activity of tertiary amine catalysts for the
nitro-aldol reaction relative to primary amine catalysts in
spite of the larger electron-donating effect of tertiary amine
groups as a result of alkyl moieties. To determine the reac-
tion intermediate, IR spectra of the SA–NH2 catalyst after
treatment with a solution of 1a in toluene were recorded
(Figure 8). New peaks appeared at 1650 and 1457 cmÀ1,
Conclusion
Silica–alumina was used as a support for basic amines in the
development of acid–base bifunctional catalysts (SA–NEt2
and SA–NH2) in carbon–carbon bond-forming reactions for
the first time. The amine-immobilization process on the SA
surface was examined by solid-state NMR spectroscopic
analysis, which revealed a weak acid–base interaction be-
tween the amine and the acidic site of SA–NEt2. The coexis-
tence of both a moderately acidic site and an amine base at
the same solid surface without neutralization realized the
acid–base bifunctional catalyst with a high performance: the
SA–NR2 surface was found to be an extremely active heter-
ogeneous catalyst for carbon–carbon bond-forming reac-
tions, such as cyano-ethoxycarbonylation, the Michael reac-
tion, and the nitro-aldol reaction. Refinement of multifunc-
tional solid surfaces may achieve highly efficient organic
synthesis including brand new reactions.
Experimental Section
1
General: H and 13C NMR spectra were recorded on a JNM-AL400 spec-
trometer at 400 MHz using CDCl3 as the solvent and trimethylsilane
(TMS) as an internal standard. Solid state 13C and 29Si MAS NMR spec-
tra (MAS rate: 4 kHz) were recorded on a Chemagnetics CMX-300 spec-
trometer operating at 75.5 and 59.7 MHz, respectively. 13C MAS NMR
spectra with cross polarization (CP) were acquired at a contact time of
5.0 ms. 29Si NMR spectra were measured by a single-pulse detection
method with hydrogen decoupling (pulse duration: 1.5 ms, rotor-spin rate:
4 kHz, delay time: 15 (13C) and 20 s (29Si). Hexamethylbenzene (13C: d=
17.17 and 176.46 ppm) and TMS (29Si: d=0 ppm) were used as external
standards for the calibration of the chemical shifts. The accumulation
numbers were fixed at about 20000 (13C) and 10000 (29Si). The IR spectra
were recorded on a JASCO FTIR-410 spectrometer. Analytical GLC and
GLC–MS were carried out on a Shimadzu GC-2010 machine with a
flame ionization detector equipped using a silicon SE-30 column.
Figure 8. IR spectra for A) SA, B) SA–NH2, and C) SA–NH2 treated
with benzaldehyde. These spectra were measured at room temperature in
transmission mode. The solid samples were pressed into a disk with KBr.
À
which are assignable to the C=N stretching and C C vibra-
tion modes in
a
benzylimine species, respectively
(Figure 8).[25] From these results and previously reported
data, the reaction mechanism for the SA–NH2-catalyzed
nitro-aldol reaction is proposed in Scheme 3: 1) an aldehyde
is activated by a surface acidic site and the immobilized
NH2 group attacks the carbonyl carbon atom in the alde-
hyde, 2) a dehydration reaction occurs so that a surface
Unless otherwise noted, the materials were purchased from Wako Pure
Chemicals (Tokyo Kasei Co.) and Aldrich Inc. and were used after ap-
propriate purification. Amorphous silica–alumina (SA) N633HN (SiO2,
66.5; Al2O3, 25.1%; 380 m2 gÀ1) was purchased from Nikki Chemical Co.
SA containing a lower Al content (N633 L; SiO2, 82.5; Al2O3, 12.6%;
429 m2 gÀ1) was also obtained from Nikki Chemical Co. Silica (Aerosil
300; 300 m2gÀ1), alumina (g-Al2O3; Soekawa Chemicals), and H-USY
(Tosoh Co. HSZ-330HUA; Si/Al=3.17:1; 626 m2gÀ1) were used as sup-
ports. The products were confirmed by
comparison with reported mass spec-
trometric and NMR spectroscopic
data.
Preparation of the SA–NEt2 surface:
SA was pretreated at 393 K for 3 h
under vacuum. SA (1.0 g) was added
to
a solution of 3-(diethylamino)-
propyl trimethoxysilane (2 mmol) in
toluene (20 mL). The reaction mixture
was heated to reflux for 24 h. The sol-
vent was removed by filtration, and
the obtained functionalized SA was
washed with dichloromethane, fol-
Scheme 3. Reaction mechanism for the SA–NH2-catalyzed nitro-aldol reaction. i) Attack on the carbonyl
carbon atom by the immobilized NH2 group and ii) a dehydration reaction followed by the formation of the ni-
troalkene product.
Chem. Eur. J. 2008, 14, 4017 – 4027
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www.chemeurj.org
4025

Y. Iwasawa et al.
lowed by drying under vacuum. Elemental analysis (%) of SA–NEt2: C
8.40, H 2.16, N 1.27. Other supported amines (support–NR2) were also
prepared by using similar procedures. Elemental analysis (%) for SA–
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[9] An amorphous aluminophosphate (AlPO) was also tested as an
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[10] For recent reports on silica-supported amine catalysts, see: a) B. M.
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NH2: C 6.41, H 1.99, N 1.57; SA(lower Al)–NEt2: C 8.49, H 2.08, N 1.17;
A
SiO2–NEt2: C 6.58, H 1.42, N 0.99; Al2O3–NEt2: C 4.07, H 1.26, N 0.54;
H-USY–NEt2: C 7.38, H 2.19, N 0.63.
Cyano-ethoxycarbonylation using the SA–NEt2 surface: SA–NEt2
(0.038 g, 0.034 mmol), toluene (5 mL), ethyl cyanoformate (1.0 mmol),
and benzaldehyde (0.5 mmol) were placed in a pyrex glass reactor. The
resulting mixture was vigorously stirred at room temperature under N2,
and the catalyst was separated by filtration after 1 h. GC analysis of the
filtrate showed 95% yield of the addition product.
Michael reaction using the SA–NEt2 surface: SA–NEt2 (0.1 g,
0.091 mmol), toluene (1 mL), ethyl cyanoacetate (0.5 mmol), and methyl
vinyl ketone (1.5 mmol) were placed in a pyrex glass reactor. The result-
ing mixture was vigorously stirred at 608C, and the catalyst was separated
by filtration after 30 min. GC analysis of the filtrate showed a quantita-
tive conversion of ethyl cyanoacetate and 90% yield of the bisaddition
product.
[11] The strong broad absorption resulting from the SA support did not
À
Nitro-aldol reaction using the SA–NH2 surface: SA–NH2 (0.0135 g,
0.015 mmol), nitromethane (2 mL), and benzaldehyde (5.0 mmol) were
placed in a pyrex glass reactor. The resulting mixture was vigorously
stirred at 1008C, and the catalyst was separated by filtration after 6 h.
GC analysis of the filtrate showed 99% yield of the b-nitrostyrene prod-
uct.
allow us to detect the n(C N) signal in SA–NEt2, which may appear
G
around n=1100 cmÀ1
.
[12] a) E. J. R. Sudhçlter, R. Huis, G. R. Hays, N. C. M. Alma, J. Colloid
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IR spectroscopic analysis: After exposure of the SA, SA–NEt2, and SA–
NH2 surfaces to the substrates in toluene, the solid catalysts were filtered,
dried under atmospheric pressure, and pressed into a disk with KBr.
À
À
allow us to detect the n
U
G
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Dual Activation Catalysis for C C Bond-Forming Reactions
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Received: December 28, 2007
Published online: March 20, 2008
Chem. Eur. J. 2008, 14, 4017 – 4027
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