Direct amidation from alcohols and amines through a tandem oxidation process catalyzed by heterogeneous-polymer-incarcerated gold nanoparticles under aerobic conditions

Article abstract of DOI:10.1002/asia.201300733

We describe herein a highly elegant and suitable synthesis of amide products from alcohols and amines through a tandem oxidation process that uses molecular oxygen as a terminal oxidant. Carbon-black-stabilized polymer-incarcerated gold (PICB-Au) or gold/cobalt (PICB-Au/Co) nanoparticles were employed as an efficient heterogeneous catalyst depending on alcohol reactivity and generated only water as the major co-product of the reaction. A wide scope of substrate applicability was shown with 42 examples. The catalysts could be recovered and reused without loss of activity by using a simple operation. Gold standard: A highly efficient green method for amide synthesis from alcohols and amines catalyzed by gold nanoparticles stabilized by styrene-based copolymers has been developed (see scheme). Two catalysts have been used with high selectivity depending on the combination of substrates. These Au nanoparticle catalysts can be recovered and reused several times by simple operations. Copyright

Full text of DOI:10.1002/asia.201300733

FULL PAPER
DOI: 10.1002/asia.201300733
Direct Amidation from Alcohols and Amines through a Tandem Oxidation
Process Catalyzed by Heterogeneous-Polymer-Incarcerated Gold
Nanoparticles under Aerobic Conditions
Jean-FranÅois Soulꢀ, Hiroyuki Miyamura, and Shu Kobayashi*[a]
¯
1
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Shu¯ Kobayashi et al.
Abstract: We describe herein a highly
elegant and suitable synthesis of amide
products from alcohols and amines
through a tandem oxidation process
that uses molecular oxygen as a termi-
nal oxidant. Carbon-black-stabilized
polymer-incarcerated gold (PICB-Au)
or gold/cobalt (PICB-Au/Co) nanopar-
ticles were employed as an efficient
heterogeneous catalyst depending on
alcohol reactivity and generated only
water as the major co-product of the
reaction. A wide scope of substrate ap-
plicability was shown with 42 examples.
The catalysts could be recovered and
reused without loss of activity by using
a simple operation.
Keywords: alcohols
·
amides
·
heterogeneous catalysis · nanoparti-
cles · oxidation
Introduction
of the most suitable alternatives. Indeed, alcohols are the
direct reductive equivalent synthon of carboxylic acids be-
cause they can be converted to amides in situ through car-
boxylic acids or aldehydes under oxidative conditions,
namely, by means of the tandem oxidation process
(TOP).[12] In this field, the first success was made by the Mil-
stein group by using a dehydrogenative pathway with
a ruthenium pincer complex.[11b] This method is very power-
ful, because only hydrogen is generated as a coproduct.
However, this hydrogen formation also represents the prin-
cipal limitation because unsaturated compounds are often
reduced. Furthermore, high temperature is generally re-
quired. An alternative protocol to the dehydrogenative
pathway could consist of using oxidative conditions. Howev-
er, only a few catalytic systems are able to promote alcohol
oxidation in the presence of amines under mild and environ-
mentally benign (“green”) conditions.
One of the greener catalysts for alcohol oxidation has
been found using gold nanoparticles (AuNPs), with molecu-
lar oxygen as a terminal oxidant.[13] Many research groups
have worked on this popular topic to develop very active
and selective oxidative systems.[14] Our research group has
been strongly interested in heterogeneous catalysis,[15] and
we have developed our own heterogeneous AuNP catalyst
with styrene-based copolymers through a process known as
the polymer-incarcerated (PI) method, or PI with carbon
black (PICB) as a second support.[16] These heterogeneous
catalysts show a high level of activity in the aerobic oxida-
tion of alcohols under ambient pressure and temperature.[17]
The reactivity and/or the selectivity of AuNP catalysts can
be modulated with the addition of a second metal to gener-
ate bimetallic Au/M nanoparticles.[18] We have also applied
this strategy to the formation and stabilization of bimetallic
NPs of various combinations, such as Au/Pt, Au/Pd, Au/Ag,
Au/Ir, and Au/Ni.[19] The Au/Pt-NP bimetallic alloy catalyst
has shown higher selectivity and higher reactivity than
single Au- or PtNPs for the oxidation of alcohols under mild
conditions. Different combinations of Au and other metals
have shown different selectivities from AuNPs.[20]
Amides are an essential class of compounds in organic
chemistry. The amide linkage plays a major role in the elab-
oration of organic molecules, organic frameworks, and poly-
mers, and in biology. Their traditional preparation employs
free carboxylic acids with amines by using condensation re-
agents or by using prior conversion of carboxylic acids to
more reactive compounds such as chloride acids or anhy-
dride acids.[1] Although this method is very efficient and
useful, the harsh conditions required and the uses of toxic
reagents, often in stoichiometric equivalents, remain its prin-
cipal limitations. Green methods, which employ a catalytic
activation of the carboxylic acid under milder conditions,
are highly desired and currently under development.[2] Be-
cause of the popularity of amide bonds in the world of
chemistry, and to obtain greater diversity in their prepara-
tion,[3] different carboxylic acid surrogates have been investi-
gated such as thioacids or thioesters,[4] a-hydroxyenone,[5] a-
bromonitro compounds,[6] alkynes,[7] aryl halides,[8] nitriles,[9]
aldehydes,[10] and alcohols[11] (Scheme 1). Among them, alco-
hols—and aldehydes in another way—have emerged as one
Scheme 1. Different pathways for amide synthesis.
In 2008, Christensen and co-workers reported the first ex-
ample of amide synthesis from alcohols and amines by using
AuNPs supported on titanium oxide by a TOP.[21] However,
only one example has been demonstrated with low selectivi-
ty and conversion (11% yield for an amide). In 2009, Ishida
and Haruta reported the synthesis of formamides from
simple amines with MeOH and O2 over Au/NiO and Au/
Al2O3.[22] Then, in 2010, similar work was conducted by Sa-
[a] Dr. J.-F. Soulꢁ, Dr. H. Miyamura, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo (113-0033) (Japan)
Fax : (+81)3-5684-0634
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300733.
&
&
2
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Shu¯ Kobayashi et al.
kurai and co-workers with the N-formylation of amines
from methanol by using AuNPs supported on polyvinylpyr-
rolidone (Au:PVP), also under oxidative conditions.[23] How-
ever, no general or practical amide formation from alcohols
and amines under oxidative conditions has thus far been
achieved. In a preliminary communication, we reported an
example of effective bimetallic Au/M-NPs with a new com-
bination of Au and metals of the iron group (Co, Ni, Fe),
which are active in oxidative amidation, by using alcohol
and amine as starting materials in a TOP.[11l] At the same
time, Wang and co-workers have reported similar work by
using AuNPs supported on DNA.[11m] Herein we report
a complete study that includes more details with regard to
the catalyst preparations and characterization, the screening
conditions, their wider scope and applicability, and the selec-
tive amidation of benzyl alcohol in the presence of aliphatic
alcohols.
with water, tetrahydrofuran (THF), and dichloromethane
(CH2Cl2), the solid powder was slightly crushed and then
heated again at 1708C under neat conditions to afford the
PICB-Au catalyst, which can be used directly for organic
transformations. By adding a second metal salt and adjusting
the number of NaBH4 equivalents during the reduction step,
this method can be applied to the generation of bimetallic
Au/M-NPs (Scheme 2). Several bimetallic catalysts have
been synthesized using this method, and we have character-
ized them by different methods (Table 1). According to the
inductively coupled plasma (ICP) analysis, the loading of
metal is close to the target loading (0.28 mmolgÀ1); we can
see that the amount of immobilization of metals varied by
10%, but usually this variation did not change the catalytic
activity significantly. The loading between both metals is
almost in a 1:1 ratio for each catalyst, as desired. On the
basis of the adsorption/desorption isotherm, the Brunauer–
Emmett–Teller (BET) surface area for each combination of
metals was calculated, and the values were found to be simi-
lar (around 50–70 m2 gÀ1). These comparable values indicate
that the physical properties of these heterogeneous catalysts
are similar.
Results and Discussion
Catalyst Preparation
We prepared various combinations of bimetallic AuNPs
(PICB-Au/M) by using a slight modification of a previously
reported method for the preparation of PICB-Au, PICB-Au/
Pd, and PICB-Au/Pt (Scheme 2).
Direct Oxidative Amide Bond Formation: Reaction
Optimization
4-Methylbenzyl alcohol (2a)
and benzylamine (3a) were se-
lected as standard-coupling
partners in a 1:1 ratio for the
model reaction. We initially se-
lected the optimized reaction
conditions described for the
esterification from alcohols in
TOP with PICB-Au as catalyst
in the presence of 1 equivalent
of
potassium
carbonate
(K2CO3) with a solvent modifi-
cation. THF was employed in-
stead of methanol—to avoid
the ester formation—under
1 atm of oxygen atmosphere
(balloon).[24] However, there
was no reaction at room tem-
perature; even alcohol 2a was
Scheme 2. Catalyst preparation.
not oxidized to the correspond-
We have previously reported that AuNPs can be stabilized
by the p electrons of benzene rings in the copolymer. The
carbon black (CB) support can prevent aggregation of parti-
cles and enlarge the surface area of the catalyst. Chloro(tri-
phenylphosphine)gold ([AuClPPh3]) is the best gold sour-
ce.[11e,17] This complex is reduced by sodium borohydride
(NaBH4) in diglyme to generate AuNPs stabilized by the co-
polymer. Diethyl ether (Et2O) was slowly added to this solu-
tion to afford microencapsulated AuNPs (MCCB-Au). Heat-
ing under neat conditions at 1508C led to the cross-linking
of side chains in the copolymer. After washing successively
ing aldehyde 6a (Table 2, entry 1). We attributed this lack of
reactivity of the PICB-Au catalyst under these conditions to
the presence of amine 3a, which can strongly interact with
the gold surface. Finally, by raising the temperature to 608C,
the oxidation could proceed, but only a mixture of aldehyde
6a and imine 5aa were obtained, and no desired amide
product 4a was detected (Table 1, entry 2).[25] On the basis
of our previous work, in which we demonstrated that bimet-
allic AuNPs can be more selective than single AuNPs,[20] we
turned our attention to the effect of the second metals on
the amide synthesis from alcohols and amines (Table 1, en-
3
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Shu¯ Kobayashi et al.
Table 1. Characterization of PICB-Au/M catalysts.
bases such as potassium carbonate (K2CO3), sodium bicar-
bonate (NaHCO3), and barium hydroxide (Ba(OH)2), or or-
ganic bases (1,8-diazabicycloACTHNUTRGNEUGN[5.4.0]undec-7-ene (DBU)), no
PICB
Au/M
Second metal
source
Au loading
M loading
Surface area
[a]
[a]
[b]
[mmolgÀ1
]
[mmolgÀ1
]
[m2 gÀ1
]
Au
Au/Pd Pd
Au/Pt Na2PtCl6·6H2O
Au/Ni NiF2
Au/Fe FeCl2
Au/Co CoCl2
Au/Cu CuACHTUNGTRENNUNG
Au/Ru
–
0.254
0.226
0.241
0.260
0.211
0.212
0.198
0.165
–
48.55
54.55
49.67
52.53
68.44
49.95
–
reaction occurred (Table 3, entries 1–3, 7, and 8). The use of
hydroxide anions as stronger bases (e.g., NaOH, KOH, and
LiOH) afforded a good conversion but a poor selectivity be-
tween amide 4aa and imine 5aa, and/or aldehyde 6a
(Table 3, entries 4–6). Ultimately, NaOH was identified as
the best base for this reaction; it afforded amide product
4aa in 40% yield (Table 3, entry 5). Next, we examined the
effect of solvent on the reaction (Table 3, entries 9–22). A
significant solvent effect was observed. Reactions in protic
and polar solvents such as methanol gave poor conversion,
and only methyl ester and imine 5aa and/or aldehyde 6a
were detected; in tert-butanol (tBuOH) no reaction
occurred (Table 3, entries 9 and 10). In water the
conversion was full, but amide 4aa was obtained
with only 26% yield, and the corresponding carbox-
ylic acid and imine 5aa and/or aldehyde 6a were
detected with 30 and 44% yield, respectively
(Table 3, entry 11). In CH2Cl2 and in toluene the
conversion was very low (Table 3, entries 12 and
G
0.235
0.221
0.251
0.198
0.203
0.234
0.153
A
–
Au/Rh
A
0.161
0.175
–
[a] Determined by ICP analysis. [b] Evaluated from BET analysis.
[c] cod=1,5-cyclooctadiene.
Table 2. Initial optimization (1): Catalyst screening.
14). Conversion was moderate in acetonitrile
(CH3CN) and dimethoxyethane (DME; Table 3, en-
tries 13 and 15). Thus, by using wet THF as the sol-
vent, the conversion was improved (Table 3, en-
tries 16–18). The best result was obtained with
THF/water in a 19:1 ratio with 44% of amide 4aa
and 56% of a mixture of imine 5aa and/or alde-
hyde 6a (Table 3, entry 18). As the concentration of
the reaction mixture increased, selectivity in favor
of amide 4aa increased. The highest selectivity was
obtained at 0.75 m with 87% yield of the amide
product 4aa (Table 3, entries 19–22).
Entry
Catalyst [x mol%]
Conversion [%][a]
4aa [%][a]
5aa and 6a [%][a]
1[b]
2[c]
3[c]
4[c]
5[c]
6[c]
7[c]
8[c]
9[c]
PICB-Au (1)
PICB-Au (1)
0
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
2
n.d.
48
49
53
18
22
42
45
21
50
55
55
25
25
45
50
25
PICB-Au/Pd (1)
PICB-Au/Pt (1)
PICB-Au/Ru (1)
PICB-Au/Rh (1)
PICB-Au/Fe (1)
PICB-Au/Ni (1)
PICB-Au/Co (1)
5
n.d.
[a] Determined by GC using dodecane as an internal standard. [b] The reaction was
performed at RT. [c] 4-Methylbenzoic acid was detected; n.d. =not detected; Conver-
sion=conversion based on 2a.
At this point in our optimization studies, the opti-
mal conditions for the direct oxidative amide for-
tries 2–9). Catalysts with normally higher reactivity (for the
alcohol oxidation) such as PICB-Au/Pd and PICB-Au/Pt
showed an activity similar to single AuNPs, and the amide
product 4aa was not detected (Table 2, entries 2–4). The
combinations of Au and Ru or Rh showed poor conversion
without the formation of the amide product 4aa (Table 2,
entries 5 and 6). Surprisingly, we found that a combination
of Au/Fe or Au/Ni could be active under these conditions,
thereby leading to amide 4aa with a very low amide yield of
2 and 5%, respectively (Table 2, entries 7 and 8). However,
PICB-Au/Co under these reaction conditions was not able
to furnish amide 4aa (Table 2, entry 9). Nevertheless, in all
cases, over-oxidation of aldehyde 6a to 4-methylbenzoic
acid was observed.
Having temporarily determined the best catalyst for the
formation of amide products under a TOP with PICB-Au/
Ni, we screened the other reaction parameters: bases and
solvents (Table 3). First, the base effect was investigated by
using THF as a solvent at room temperature to minimize
the formation of the corresponding carboxylic acid. In the
absence of a base or in the presence of weak inorganic
mation afforded the desired product 4aa in 87% yield, with
11% of a mixture that included imine 5aa and aldehyde 6a
as byproducts (Table 3, entry 21). We had previously shown
that the second metals have a strong effect on this reaction
(Table 2), so we reexamined the effects of bimetallic cata-
lysts by using the optimized base and solvent reaction condi-
tions (Table 4). Only AuNPs gave poor selectivity in favor
of amide 4aa (45%; Table 4, entry 1). Thereafter, we exam-
ined various combinations of Au and other Period 5 and 6
metals, such as Au/Pd-NPs, Au/Pt-NPs, Au/Ru-NPs, and Au/
Rh-NPs. These catalysts are mostly selective in favor of
imine 5aa and/or aldehyde 6a: 73, 75, 81, and 54%, respec-
tively (Table 4, entries 2–5). Interestingly, the combination
between Au and the iron-group metals gave high selectivi-
ties in favor of amide 4aa (Table 4, entries 6–9). Ultimately,
Co was identified as the best second metal for this reaction;
the desired product 4aa was obtained in 94% isolated yield
(Table 4, entry 9). Finally, we examined the TOP using air
(under balloon pressure) as the terminal oxidant and found
that the reaction proceeded smoothly under our optimized
reaction conditions (Table 4, entry 10).
&
&
4
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Shu¯ Kobayashi et al.
Table 3. Initial optimization (1): Effect of base and solvent.
To identify the reaction pathway, we conduct-
ed additional control experiments (Table 4, en-
tries 17–20, and Scheme 3). Four scenarios exist
for the direct oxidative amidation catalyzed by
Au/M-NPs. All of these scenarios started from
an oxidation of alcohol 2a to aldehyde 6a; alde-
hyde as an intermediate was confirmed when
the reaction was started from aldehyde: the re-
action proceeded, but with lower selectivity
(Table 4, entry 17). However, when the reaction
started from aldehyde 6a in the presence of
amine 3a when using only PICB-Co as catalyst,
no amide formation occurred (Table 4,
entry 18). In addition, imine could not be
formed in the absence of any catalyst (Table 4,
entry 19). However, thanks to the AuNP activity
and the nucleophilic attack of amine 3a, the al-
dehyde intermediate 6a can be converted to
either carbinolamine (hemiaminal) 7aa or imine
5aa. From the control experiment, the scenario
in which imine 5aa was an intermediate could
be denied (Table 4, entry 20). Alternative path-
ways could proceed through direct amidation
from free carboxylic acid 9a, which was generat-
ed by oxidation of alcohol 2a in the presence of
water and a strong base. However, this scenario
was also unlikely due to the control experiment
(Table 4, entry 21). Recently, Riisager and co-
workers published the amide synthesis from al-
cohols and amines using Au/TiO2-NPs, which in-
volved a methyl ester intermediate.[11n] Consid-
ering this possibility, and the possibility that
Entry
Base [x equiv] Solvent [molLÀ1
]
Conversion 4aa
5aa and 6a
[%][a]
[%][a] [%][a]
1
2
3
4
5
6
7
8
–
THF (0.16)
THF (0.16)
THF (0.16)
THF (0.16)
THF (0.16)
THF (0.16)
THF (0.16)
THF (0.16)
MeOH (0.16)
tBuOH (0.16)
water (0.16)
CH2Cl2 (0.16)
CH3CN (0.16)
PhCH3 (0.16)
DME (0.16)
THF/water (4:1, 0.16)
THF/water (9:1, 0.16)
THF/water (19:1, 0.16)
THF/water (19:1, 0.32)
THF/water (19:1, 0.5)
THF/water (19:1, 0.75)
THF/water (19:1, 1)
0
0
0
90
90
90
0
0
25
0
100
6
55
10
30
100
100
100
100
100
100
60
n.d.
n.d.
n.d.
n.d.
40
n.d.
n.d.
n.d.
75
50
78
n.d.
n.d.
12
n.d.
44
2
41
n.d.
26
65
59
56
38
27
K2CO3 (1)
NaHCO3 (1)
LiOH (1)
NaOH (1)
KOH (1)
Ba(OH)2 (1)
DBU (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
13
n.d.
n.d.
n.d.
n.d.
26
n.d.
4
9
11
34
41
44
9
10
11[b]
12
13
14
15
16
17
18
19
20
21
22
62
70
87
57
11
3
[a] Determined by GC using dodecane as an internal standard. [b] 4-Methylbenzoic acid
was detected; n.d.=not detected; Conversion=conversion based on 2a.
The positive effect of the bimetallic structure of PICB-
Au/Co on this reaction was confirmed by control experi-
ments (Table 4, entries 11–14). When we attempted to use
PICB-Co alone as the catalyst, no reaction occurred
(Table 4, entry 12). On the other hand, with a mixture of
two separate catalysts, PICB-Au and PICB-Co, a moderate
selectivity was observed (Table 4, entry 13). The activity of
Co2+ ions in the presence of PICB-Au was examined, and
a lower selectivity in favor of amide 4aa was observed
(Table 4, entry 14). These results indicated that the active
species was not Co2+. During the catalyst preparation
method, the standard procedure employed a simultaneous
reduction of Au and Co by using a premixing solution of
AuClPPh3 and CoCl2. We also investigated different proce-
dures in which the Au and Co salts were added alternately.
First, Au solution was added to a NaBH4 solution that con-
Scheme 3. Reaction pathway.
tained copolymer 1 and CB followed by the addition of Co
solution after 5 h. The reaction mixture was stirred for an
additional 12 h, then the normal procedure was applied to
lead to new PICB-Au-Co catalysts. A similar procedure was
employed for the synthesis of PICB-Co-Au by changing the
order of Au and Co addition. These catalysts showed differ-
ent activities from the standard catalyst and indicate that
the order of Au and Co addition during the catalyst prepara-
tion was also important (Table 4, entries 15 and 16).
ester 11a could form under aerobic oxidative conditions cat-
alyzed by Au/M-NPs as well as by a Tishchenko reaction for
the ester formation from aldehyde 6a, a control experiment
was conducted. However, this scenario was also excluded by
a control experiment: when the reaction commenced from
ester 11a, no reaction occurred (Table 4, entry 22). Accord-
ingly, the direct oxidation of carbinolamine 7aa to amide
5
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Shu¯ Kobayashi et al.
Table 4. Initial optimization (2): Effect of the second metals.
Table 5. Optimization of reaction for aliphatic alcohols.
Entry Catalyst [x mol%]
T
Conversion
4ba
5ba and 6b
[8C] [%][a]
[%][a]
[%][a]
Entry Catalyst [x mol%]
Conversion 4aa
5aa and
6a [%][a]
[%][a]
[%][a]
1
2
3
4
PICB-Au/Co (1)
PICB-Au/Pd (1)
PICB-Au/Pt (1)
PICB-Au (1)
PICB-Au (1.5)
PICB-Au (1.5)
PICB-Au (2)
25
25
25
25
40
40
40
50
40
14
0
0
53
86
84
100
87
44
10
n.d.
n.d.
50
85 (83)
84
76
80
44
3
n.d.
n.d.
n.d.
1
n.d.
n.d.
1
1
2
3
4
5
6
7
8
PICB-Au (1)
95
75
80
100
76
81
100
100
100
94
100
0
45
2
5
19
12
46
87
94
50
73
75
81
54
29
13
6
PICB-Au/Pd (1)
PICB-Au/Pt (1)
PICB-Au/Ru (1)
PICB-Au/Rh (1)
PICB-Au/Cu (1)
PICB-Au/Ni (1)
PICB-Au/Fe (1)
PICB-Au/Co (1)
PICB-Au/Co (1)
PICB-Au (1.5)
PICB-Co (1)
5
6[b]
7
8
9
PICB-Au (1.5)
PICB-Au/Co (1.5)
n.d.
9
96 (94)
4
[a] Determined by GC using dodecane as internal standard. The number
in parentheses showed the isolated yield. [b] Reaction was performed
under an atmosphere of air for 24 h; n.d.=not detected; Conversion=
conversion based on 2a.
10[b]
11
12
13
14
15
16
17[e]
18[e]
19[e]
20[g]
21[f]
22[h]
94 n.d.
25
n.d. n.d.
76
43
91
82
45
n.d. 100
n.d. 100
n.d. 100
n.d. n.d.
n.d. n.d.
63
PICB-Au (1) and PICB-Co (1) 100
9
27
9
5
55
PICB-Au (1) and CoCl2 (1)
PICB-Au-Co[c]
PICB-Co-Au[d]
PICB-Au/Co (1)
PICB-Co (1)
100
100
87
100
0
0
0
0
0
zylamine (3a), poor conversion and only 10% of amide 4ba
were detected (Table 5, entry 1).
We next decided to screen different catalysts. When using
PICB-Au/Pd and PICB-Au/Pt at 258C, no reaction occurred
(Table 5, entries 2 and 3); only when PICB-Au was used was
the desired product obtained in 50% yield (Table 5,
entry 4). By raising the temperature to 408C and using
1.5 mol% PICB-Au, 83% of amide 4ba was isolated
(Table 5, entry 5). To improve the conversion in this reac-
tion, we tried to raise the temperature to 508C, but under
the harsher conditions the selectivity of the amide dropped
because of the formation of the corresponding carboxylic
acid (Table 5, entry 8). A similar phenomenon was observed
when 2 mol% of catalyst was used (Table 5, entry 7). Under
the same temperature and catalyst loading conditions,
PICB-Au/Co gave a lower yield (Table 5, entry 9). Finally,
we examined the reaction when using air (under balloon
pressure) as the terminal oxidant and found that the reac-
tion proceeded smoothly under our optimized reaction con-
ditions (Table 5, entry 6).
–
PICB-Au/Co (1)
PICB-Au/Co (1)
PICB-Au/Co (1)
[a] Determined by GC using dodecane as an internal standard. The
number in parentheses indicates the isolated yield. [b] Reaction was per-
formed under an atmosphere of air for 24 h. [c] Catalyst prepared with
separated addition of Au and Co (Au follow by Co after 5 h). [d] Catalyst
prepared with separated addition of Au and Co (Co follow by Au after
5 h). [e] 4-Methylbenzylaldehyde 6a was used instead of 2a. [f] 4-Methyl-
benzoic acid 9a was used instead of 2a. [g] N-(4-Methylbenzylidene)ben-
zylamine (5aa) was used instead of 2a. [h] 4-Methylbenzyl-4-methylben-
zoate (11a) was used instead of 2a; n.d.=not detected; Conversion=
conversion based on 2a or its alternatives (entries 17–20).
4aa by Au/M-NPs was confirmed as the direct pathway and
was consistent with the observations made by the Friend
and Madix groups on the interaction between carbinola-
mines (hemiaminals)—which resulted from the reaction of
aldehydes and amines—and the surface of the metallic
Au.[26]
At this point in our optimization studies, the optimal con-
ditions for direct amidation starting from benzylic alcohol
(activated alcohol) allowed for the formation of the desired
amide in 94% yield. We next examined the reactivity of ali-
phatic alcohols (i.e., nonactivated alcohols), which are gen-
erally more difficult to oxidize (Table 5). When previous
conditions were applied to the oxidative amidation of 3-phe-
nylpropan-1-ol (2b) in the presence of 1 equivalent of ben-
Direct Oxidative Amide Bond Formation: Reaction Scope
With these two optimized reaction conditions available, the
scope of the reaction was examined by varying the substitu-
tion patterns on both coupling partners for each catalyst.
Generally, PICB-Au/Co catalyst is effective for the activated
alcohols (Table 6), and PICB-Au is effective for the nonacti-
vated alcohols (Table 7).
The catalytic experiments were conducted under an
oxygen atmosphere in the presence of 1 mol% PICB-Au/Co
catalyst at 258C. It was found that both electron-poor and
&
&
6
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Shu¯ Kobayashi et al.
Table 6. Scope of the reaction using PICB-Au/Co catalyst.
Entry 1
Entry 5
Entry 2
Entry 6
Entry 3
Entry 7
Entry 4
Entry 8
Entry 9
Entry 10
Entry 11
Entry 12
Entry 13
Entry 17
Entry 14
Entry 18
Entry 15
Entry 19
Entry 16
Entry 20
Entry 21
Entry 25
Entry 22
Entry 26
Entry 23
Entry 27
Entry 24
Entry 28
[a] Two equivalents of alcohol were used. [b] Six equivalents of NH3·H2O were used. [c] Two equivalents of NaOH in THF/water (9:1) were used.
electron-rich benzylic alcohols were successfully converted
to the corresponding amides 4aa–4ja in good to excellent
yields (Table 6, entries 1–9). We also confirmed that the re-
actions of alcohols that bore heterocycles and naphthalene
proceeded very well to afford the corresponding amides
4ka–4na in good yields (Table 6, entries 10–13). Next, allylic
alcohols were examined. Cinnamyl alcohol and allylic alco-
hol produced moderate yields (Table 3, entries 14 and 15).
Propargyl alcohol was also tried, and 68% of amide 4qa
and 3n; no oxidized products from amines were detected
(Table 6, entries 2, 17–20, 24, and 25). A bulky amine such
as cyclopentanamine (3d) afforded amide 4cd in good yield
(Table 6, entry 19). The reaction with a primary aromatic
amine proceeded smoothly to afford amide 4cf in good
yield (Table 6, entry 21). When an aqueous solution of am-
monia was used, this TOP directly afforded primary amide
4cg in good yield (Table 6, entry 22).[11g] On the other hand,
the secondary amine N-methylbenzylamine 3l completely
inhibited the activity of the PICB-Au/Co catalyst, and only
a trace of amide 4al was obtained (Table 6, entry 23). Allyl
amine (3o) can be used under these conditions without loss
of the unsaturated moiety, and the desired product 4co was
isolated in 97% yield (Table 6, entry 26). Interestingly, when
the oxidative amidation reaction was applied to an optically
active amino acid and its derivatives, the reaction proceeded
smoothly with yields of 72 and 69%, respectively (Table 6,
À
was isolated (Table 6, entry 16). It is noted that the carbon
À
carbon double-bond or the carbon carbon triple-bond moi-
eties were tolerant in the present amide formation, whereas
a reduction of double-bond moieties occurred in alternative
processes when using ruthenium pincer catalysts.[11b,c] We
also investigated the scope of amines. Good to excellent
yields toward amide products were obtained with benzylic
primary amine 3a or aliphatic primary amines 3b–3e, 3m,
7
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Shu¯ Kobayashi et al.
Table 7. Scope of the reaction using the PICB-Au catalyst.
Entry 1
Entry 5
Entry 2
Entry 6
Entry 3
Entry 7
Entry 4
Entry 8
Entry 9
Entry 10
Entry 14
Entry 11
Entry 15
Entry 12
Entry 16
Entry 13
[a] The reaction was performed at 608C. [b] Two equivalents of NaOH in THF/water (9:1) were used.
entries 27 and 28). No racemization occurred in these reac-
tions, and free amino acids could be used directly.
PICB-Au/Co. These results, together with the finding of the
very poor reactivity of aliphatic alcohols with this catalyst,
suggested that it might be possible to achieve chemoselec-
tive oxidative amidation with two alcohols that possess dif-
ferent reactivities (i.e., benzylic and aliphatic). This study fo-
cused on a mixture of the alcohols 2a and 2b, and we tested
their reactivity with both catalysts (PICB-Au/Co and PICB-
Au; Table 8). By using PICB-Au/Co as a catalyst and one or
two equivalents of benzylamine (3a) and NaOH as a base,
the competition between benzylic alcohol (2a) and aliphatic
alcohol 2b led to a high selectivity in favor of amide 4aa
(Table 8, entries 1 and 2). However, the same competition
using PICB-Au as a catalyst gave lower selectivity, and
a mixture of amides 4aa and 4ba was obtained (Table 8, en-
tries 3 and 4). These results demonstrate that the activity of
the PICB-Au/Co catalyst system can be tuned to achieve
highly selective oxidative amidation of benzylic alcohols.
One limitation of PICB-Au/Co described above was the
low reactivity of aliphatic alcohols and secondary amines.
However, we did demonstrate that PICB-Au was more effi-
cient for these substrates (Table 5). This simple variation al-
lowed us to obtain aliphatic and tertiary amides. To demon-
strate this reactivity, we commenced investigations into this
reaction using PICB-Au as the catalyst (Table 7).
The catalytic experiments were generally conducted
under an oxygen atmosphere in the presence of 1.5 mol%
PICB-Au catalyst at 408C. Aliphatic alcohols such as 1-phe-
nylpropanol (2b) or heptanol (2t) were successfully convert-
ed to their corresponding amides 4ba and 4ta in good yields
(Table 7, entries 1 and 3). The steric bulk of the aliphatic al-
cohol has no effect on the reaction; cyclohexylmethanol
(2u) reacts with good yield (71%), and ethanol (2s) can be
used directly to obtain the acetyl-protected amide 4sa in ex-
cellent yield (Table 7, entries 2 and 4). Under the reaction
conditions used, the desired tertiary amides were obtained
with good yields from secondary amines and either benzylic
or aliphatic alcohols (Table 7, entries 5–12), and with indo-
line (3w) the corresponding N-acyl indoline 4cw was ob-
tained in 59% yield. Amino acids could also be used with
PICB-Au without epimerization (Table 7, entries 13 and 14).
Allyl amine (3o) could be also used with PICB-Au catalysts
without the loss of the double-bond moiety (Table 7,
entry 15). Finally, both aliphatic alcohol and amine were
coupled to give amide 4bn in high yield (Table 7, entry 16).
The studies outlined above revealed that most benzylic al-
cohols underwent very efficient oxidative amidation with
Recovery and Reuse of Catalyst
As reported in the preceding sections, two catalysts have
shown good activity and selectivity: PICB-Au and PICB-Au/
Co in the direct amide formation from alcohols and amines.
Next, we examined the feasibility of recycling the PICB-Au/
M (M=–, Co) catalysts for each reaction (Figure 1).
We found that PI/CB-Au/M (M=–, Co) could be recov-
ered by using a simple operation and reused up to five times
without noticeable loss of activity. However, pretreatment
of PICB-Au/M (M=–, Co) was necessary to reactivate the
catalyst. This pretreatment involved washing the catalyst
with pure water, followed by a heating step at 1708C for 4 h
&
&
8
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Shu¯ Kobayashi et al.
Table 8. Selective oxidative amidation.
phology, because the intermetallic interactions that
arise from their constitutional and morphological
combinations contribute to the modification of the
properties of the nanocatalysts. On the basis of the
results of EDS mapping and EDS line analysis
(Figure 2), the morphologies of the NPs (eight pos-
sibilities are described in the literature)[28] were de-
scribed. Two types of morphology were found in
our screening of bimetallic NPs. When Pd and Pt
were used as second metals with Au, alloy struc-
tures were obtained; in the case of Au/Pt-NPs, an
alloy with a 1:1 ratio between both metals was ob-
served, whereas in the case of Au/Pd-NPs, an alloy
with a 2:1 ratio between Au and Pd was observed.
Yet another morphology, called separate NPs, was
Entry Catalyst [x mol%] T [8C] x equiv 4aa [%][a] 4ba [%][a] Selectivity
1
2
PICB-Au/Co (1)
PICB-Au/Co (1)
PICB-Au (1.5)
PICB-Au (1.5)
25
25
40
40
1
2
1
2
96
92
43
51
3
2
11
42
96.9
97.9
79.6
54.8
3[b]
4[b]
[a] Determined by GC using dodecane as an internal standard. [b] Imine 5aa and/or
aldehyde 6a were detected.
observed in the case of the combination of Au and the iron-
group metals: Au/Ni-NPs, Au/Fe-NPs, and Au/Co-NPs.
Effect of Bimetallic Structures on Reactivity and Selectivity
In this work, we developed three types of mono- or bimetal-
lic Au/M-NPs that were efficient in the oxidative condensa-
tion of alcohols and amines using a TOP. First, bimetallic
alloy Au/M-NPs (M=Pt or Pd) have shown a high selectivi-
ty for imine products.[29] The formation of this alloy struc-
ture from the two metals gives NPs with different properties
from those of the individual metal NPs: Au-NPs and Pt-NPs
or Pd-NPs. We can expect that Pt or Pd in the alloy NPs ex-
press more electropositive properties, and Au expresses
more electronegative properties because of their relative
electronegativities. The Pd and Pt moieties of PICB-Au/Pd
and PICB-Au/Pt obtained in this way have a strong Lewis
acid character,[20] thereby resulting in an acceleration rate of
the dehydration step. This explains why a high selectivity in
favor of imine products is obtained with the PICB-Au/Pd or
PICB-Au/Pt catalysts, and this might operate in favor of
imine formation. On the other hand, PICB-Au and PICB-
Au/M (M=Fe group) have shown high selectivity in favor
of the amide products. To understand the positive effect of
bimetallic structures on this selectivity, the electrophilicity
of aldehydes and their concentrations during the reaction
should be discussed. Indeed, when the reaction is performed
from aldehyde 6a, the selectivity decreases in an equivalent
ratio between imine 5aa and amide 4aa (Table 3, entry 15).
With benzylic alcohols, PICB-Au/Co is considered the best
catalyst for this reaction. Structural analysis confirmed that
the alloy NPs are not formed; by contrast, separate AuNPs
and a cobalt species are observed (Figure 2). We propose
two main factors for the superiority of PICB-Au/Co in the
benzylic secondary amide formation reactions. First, tuning
the catalytic activity of the AuNP; and second, facilitating
the hemiaminal formation or suppression of imine forma-
tion. It is clear that interactions exist between AuNPs and
Co, because the rate of consumption of alcohols 2a and 2b
decreases when PICB-Au/Co is used instead of PICB-Au,
and PICB-Au/Co shows a lower activity with aliphatic alco-
hols (Table 4, entries 5 and 9, and Table 7). This decrease in
Figure 1. Recovery and reuse of the catalysts.
under neat conditions (without solvents). Examination of
the resulting filtrate of the reaction mixture by ICP analysis
revealed no leaching of Au and Co under the conditions
used.
Characterization of Catalysts
To obtain more complete information about the catalysts,
such as the diameters of NPs and the morphologies of bi-
metallic structures, we conducted scanning transmission
electron microscopy (STEM) and energy-dispersive spec-
troscopy (EDS) analyses of each PICB-Au/M catalyst
(Figure 2).
The electronic properties of the bimetallic particles could
be altered extensively, depending on the size, atomic order,
and continuity of the metal phase.[28] In our nanoparticle cat-
alysts, the size of the particles was almost comparable in all
combinations, and the Feret diameter of the PICB-Au/M
catalyst was between 2.0 and 2.7 nm. Another important var-
iable of the bimetallic and multimetallic NPs is the NP mor-
9
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Shu¯ Kobayashi et al.
Figure 2. STEM-EDS analysis of catalysts.
the rate of consumption of alcohol 2a can control the con-
centration of aldehyde 6a at an appropriate level in the re-
action media and can improve the selectivity of the amide
product. Furthermore, cobalt species can play the role of
a Lewis acid and activate less electrophilic aldehydes and/or
stabilize the hemiaminal intermediate. Aldehyde 6b has
never been observed as an intermediate in the course of the
reaction for aliphatic amide formation, probably because of
the difficulty of oxidation of aliphatic alcohols and its higher
reactivity with amine nucleophiles relative to benzylic alde-
hydes. Therefore, the more reactive PICB-Au can be utilized
directly as a catalyst instead of PICB-Au/Co without the
loss of selectivity to amides. With secondary amines, the use
of PICB-Au/Co cannot lead to the corresponding amide
products in high yield. This catalyst is less effective for rea-
sons including the strong interaction of the electron-rich sec-
ondary amines with the surface of the AuNPs. The higher
coordination ability of secondary amines completely inhibits
the oxidative ability of the less reactive PICB-Au/Co. Be-
cause of the higher activity of PICB-Au and the lack of for-
mation of imines with secondary amines, tertiary amides can
be obtained in good yields. Similar phenomena could be ap-
plied in case of PICB-Au/Fe and PICB-Au/Ni catalysts,
which present a similar morphology.
&
&
10
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Shu¯ Kobayashi et al.
1008C; initial t: 0 min; rate: 108CminÀ1; final T: 3008C; final t: 10 min;
tR =10.0 (internal standard), 22.1 min (product); 1H NMR (500 MHz,
CDCl3, 208C): d=7.60 (d, J=8 Hz, 2H), 7.26–7.22 (m, 4H), 7.21–7.16
(m, 1H), 7.13–7.09 (m, 2H), 6.45 (brs, 1H), 4.52 (d, J=6 Hz, 2H),
2.29 ppm (s, 3H); 13C NMR (150 MHz, CDCl3, 208C): d=167.5, 142.1,
138.5, 131.7, 129.4, 128.9, 128.0, 127.7, 127.2, 44.2, 21.6 ppm.
Conclusion
In conclusion, we have developed a useful atom-economical
and green method for amide synthesis. Alcohols can be used
instead of free carboxylic acid under a TOP catalyzed by
Au/M-NPs (M=Co or –) and molecular oxygen with only
the generation of water as a co-product. Two catalysts have
been found to be very active for the direct amidation reac-
tion depending on the coupling partners. PICB-Au/Co was
successfully employed with activated alcohols (e.g., benzylic,
allylic, propargyl), and PICB-Au was used with nonactivated
(e.g., aliphatic) alcohols. PICB-Au/Co was not active with
secondary amines, even for the oxidation of benzylic alco-
hols; however, PICB-Au can lead to amide products in high
yield. Moreover, PICB-Au/Co can be used for selective ami-
dation of benzylic alcohol in the presence of aliphatic alco-
hols. Thanks to these two catalysts, a very broad scope of
amides have been achieved including unsaturated substrates
(which are difficult to obtain when using a dehydrogenative
pathway catalyzed by the pincer complex), aqueous ammo-
nia, and aliphatic alcohols under very mild conditions (i.e.,
at room temperature, under atmospheric conditions). For
both catalysts, no leaching of metals was detected, and the
catalysts can be recovered and reused at least five times
without loss of activity or selectivity.
Recovery and Reuse of PICB-Au/Co
4-Methylbenzyl alcohol (2a; 200 mg, 1.64 mmol, 1 equiv), benzylamine
(180 mL, 1.64 mmol, 1 equiv), NaOH (65.5 mg, 1.64 mmol, 1 equiv),
PICB-Au/Co (0.28 mmolgÀ1, 58.5 mg, 1 mol%), and THF/water (19:1,
2.2 mL) were combined in a round-bottomed flask. After the mixture
was stirred using a stirring bar and a magnetic stirrer for 12 h under an
O2 atmosphere at room temperature, the catalyst was collected by filtra-
tion and washed with THF and water using a Kiriyama Rohto funnel.
The aqueous layer was washed with diethyl ether (20 mL). The yield was
determined by GC analysis with reference to an internal standard (IS=
dodecane). After determining the yield, the solvents of both aqueous and
organic layers were removed under vacuum. Sulfuric acid and aqua regia
were added to each residue, then the volume of the residue was adjusted
to 50 mL by using water to give a sample for ICP analyses for the mea-
surement of the leaching of gold and cobalt. The filtered catalysts was
dried under vacuum and heated at 1708C for 5 h without solvent under
argon and 55.1 mg of catalyst was collected. About 6–7 mg of catalyst
was trapped by filtration paper in every use.
Preparation of PICB-Au
Ketjenblack (0.5 g) was added to a solution of copolymer 1 (0.5 g) in di-
glyme (25 mL). The resulting suspension was cooled to 08C, and then
a solution of NaBH4 (32.1 mg, 0.85 mmol, 3 equiv) in diglyme (5 mL) was
added dropwise. The reaction mixture was stirred for approximately
15 min, and then a solution of PPh3AuCl (140 mg, 0.28 mmol, 1 equiv) in
diglyme (10 mL) was added dropwise. The reaction mixture was allowed
to warm to room temperature and then stirred for 12 h. Diethyl ether
(150 mL) was added dropwise. The suspension was filtered and washed
with an excess amount of diethyl ether. The isolated microencapsulated
catalyst (MCCB-Au) was allowed to dry, gently ground with a mortar
and pestle, and then heated at 1508C for 5 h under an argon atmosphere.
The polymer-incarcerated catalyst, PICB-Au, was then re-suspended in
a THF/water mixture (1:1); filtered; washed successively with an excess
amount of water, THF, and CH2Cl2; and allowed to dry for 5 h at 1708C
under an argon atmosphere to afford PICB-Au/Co (0.955 g, Au loading:
0.251 mmolgÀ1, B loading: 0.018 mmolgÀ1).
Experimental Section
Preparation of PICB-Au/Co
Ketjenblack (0.5 g) was added to a solution of copolymer 1 (0.5 g) in di-
glyme (25 mL). The resulting suspension was cooled to 08C, and then
a solution of NaBH4 (128 mg, 3.40 mmol, 12 equiv) in diglyme (5 mL)
was added dropwise. The reaction mixture was stirred for approximately
15 min, and then a solution of PPh3AuCl (140 mg, 0.28 mmol, 1 equiv)
and CoCl2 (36 mg, 0.28 mmol, 1 equiv) in diglyme (10 mL) was added
dropwise. The reaction mixture was allowed to warm to room tempera-
ture and then stirred for 12 h. Diethyl ether (150 mL) was added drop-
wise. The suspension was filtered and washed with an excess amount of
diethyl ether. The isolated microencapsulated catalyst (MCCB-Au/Co)
was allowed to dry, gently ground with a mortar and pestle, and then
heated at 1508C for 5 h under an argon atmosphere. The polymer-incar-
cerated catalyst, PICB-Au/Co, was then re-suspended in a THF/water
mixture (1:1); filtered; washed successively with an excess amount of
water, THF, and CH2Cl2; and allowed to dry for 5 h at 1708C under an
argon atmosphere to afford PICB-Au/Co (0.945 g, Au loading:
0.212 mmolgÀ1, Co loading: 0.203 mmolgÀ1, B loading: 0.025 mmolgÀ1).
Typical Procedure for the PICB-Au-Catalyzed TOP from Alcohols and
Amines to Amides.
PICB-Au (21.9 mg, 5.5 mmol, 1.5 mol% with respect to Au), 3-phenylpro-
pan-1-ol (2b; 48 mL, 0.368 mmol, 1 equiv), benzylamine (3a; 41 mL,
0.368 mmol, 1 equiv), NaOH (14.7 mg, 0.368 mmol, 1 equiv), and THF/
water (19:1, 0.5 mL) were added to a screw-cap glass vial. The reaction
mixture was stirred for 12 h at 408C under a balloon of oxygen gas. Then
the reaction mixture was filtered and washed with CH2Cl2 and a saturated
aqueous solution of NH4Cl. The aqueous phase was extracted three times
with CH2Cl2, and the combined organic phases were dried over Na2SO4.
After filtration and then concentration under reduced pressure, the crude
product was obtained. It was purified by column chromatography
(EtOAc/hexane 7:3) to afford 4ba (72.5 mg, 83%) as a white solid. GC
flow rate: 157.4 kPa, He; inject: 1008C; detection: 3008C; initial T:
1008C; initial t: 0 min; rate: 108CminÀ1; final T: 3008C; final t: 10 min;
tR =10.0 (internal standard), 22.5 min (product); 1H NMR (500 MHz,
CDCl3, 208C): d=7.24–7.16 (m, 5H), 7.15–7.11 (m, 3H), 7.09–7.04 (m,
2H), 5.59 (brs, 1 H), 4.32 (d, J=6 Hz, 2H), 2.92 (t, J=8 Hz, 2H),
2.42 ppm (t, J=8 Hz, 2H); 13C NMR (150 MHz, CDCl3, 208C): d=172.1,
140.9, 138.4, 128.9, 128.8, 128.6, 127.9, 127.8, 126.5, 43.7, 38.7, 31.9 ppm.
Typical Procedure for the PICB-Au/Co-Catalyzed TOP from Alcohols
and Amines to Amides
PICB-Au/Co (17.4 mg, 3.7 mmol, 1 mol% with respect to Au), 4-methyl-
benzyl alcohol (2a; 45 mg, 0.368 mmol, 1 equiv), benzylamine (3a; 41 mL,
0.368 mmol, 1 equiv), NaOH (14.7 mg, 0.368 mmol, 1 equiv), and THF/
water (19:1, 0.5 mL) were added to a screw-cap glass vial. The reaction
mixture was stirred for 12 h at 258C under a balloon of oxygen gas. Then
the reaction mixture was filtered and washed with CH2Cl2 and a saturated
aqueous solution of NH4Cl. The aqueous phase was extracted three times
with CH2Cl2, and the combined organic phases were dried over Na2SO4.
After filtration and then concentration under reduced pressure, the crude
product was obtained. It was purified by column chromatography
(EtOAc/hexane 7:3) to afford 4aa (78 mg, 94%) as a white solid. GC
flow rate: 157.4 kPa, He; inject: 1008C; detection: 3008C; initial T:
Recovery and Reuse of PICB-Au
3-Phenylpropan-1-ol (2b; 180 mg, 1.32 mmol, 1 equiv), benzylamine
(151 mL, 1.32 mmol, 1 equiv), NaOH (53 mg, 1.32 mmol, 1 equiv), PICB-
11
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Shu¯ Kobayashi et al.
Au (0.20 mmolgÀ1, 99.1 mg, 1.5 mol%), and THF/water (19:1, 1.8 mL)
were combined in a round-bottomed flask. After the mixture was stirred
using a stirring bar and a magnetic stirrer for 12 h under an O2 atmos-
phere at 408C, the catalyst was collected by filtration and washed with
THF and water by using a Kiriyama Rohto funnel. The aqueous layer
was washed with diethyl ether (20 mL). The yield was determined by GC
analysis with reference to an internal standard (IS=dodecane). After de-
termining the yield, the solvents of both aqueous and organic layers were
removed under vacuum. Sulfuric acid and aqua regia were added to each
residue, then the volume of the residue was adjusted to 50 mL by using
water to give a sample for ICP analyses to measure the leaching of gold
and cobalt. The filtered catalysts were dried under vacuum and heated
1708C for 5 h without solvent under argon and 93.3 mg of catalyst was
collected. About 6–7 mg of catalyst was trapped by filtration paper in
every use.
[9] a) K. Yamaguchi, M. Matsushita, N. Mizuno, Angew. Chem. 2004,
116, 1602–1606; Angew. Chem. Int. Ed. 2004, 43, 1576–1580;
b) P. K. Mascharak, Coord. Chem. Rev. 2002, 225, 201–214; c) J. H.
Kim, J. Britten, J. Chin, J. Am. Chem. Soc. 1993, 115, 3618–3622.
[10] a) Y. Tamaru, Y. Yamada, Z. Yoshida, Synthesis 1983, 474–476;
b) A. Tillack, I. Rudloff, M. Beller, Eur. J. Org. Chem. 2001, 523–
528; c) J.-J. Shie, J.-M. Fang, J. Org. Chem. 2003, 68, 1158–1160;
d) W.-J. Yoo, C. J. Li, J. Am. Chem. Soc. 2006, 128, 13064–13065;
e) J. W. Bode, S. S. Sohn, J. Am. Chem. Soc. 2007, 129, 13798–
13799; f) J. Chan, K. D. Baucorn, J. A. Murry, J. Am. Chem. Soc.
2007, 129, 14106–14107; g) K. Ekoue-Kovi, C. Wolf, Org. Lett. 2007,
9, 3429–3432; h) L. Wang, H. Fu, Y. Y. Jiang, Y. F. Zhao, Chem.
Eur. J. 2008, 14, 10722–10726; i) J. Gao, G. W. Wang, J. Org. Chem.
2008, 73, 2955–2958; j) K. R. Reddy, C. U. Maheswari, M. Venka-
teshwar, M. L. Kantam, Eur. J. Org. Chem. 2008, 3619–3622; k) L.
Colombeau, T. Traore, P. Compain, O. R. Martin, J. Org. Chem.
2008, 73, 8647–8650; l) S. Seo, T. J. Marks, Org. Lett. 2008, 10, 317–
319; m) C. Fang, W. X. Qian, W. L. Bao, Synlett 2008, 2529–2531;
n) Y. Suto, N. Yamagiwa, Y. Torisawa, Tetrahedron Lett. 2008, 49,
5732–5735; o) J. M. Li, F. Xu, Y. Zhang, Q. Shen, J. Org. Chem.
2009, 74, 2575–2577; p) M. A. Ali, T. Punniyamurthy, Adv. Synth.
Catal. 2010, 352, 288–292; q) C. L. Allen, S. Davulcu, J. M. J. Wil-
liams, Org. Lett. 2010, 12, 5096–5099; r) S. De Sarkar, A. Studer,
Org. Lett. 2010, 12, 1992–1995; s) J. Liang, J. Lv, Z.-c. Shang, Tetra-
hedron 2011, 67, 8532–8535; t) S. C. Ghosh, J. S. Y. Ngiam, C. L. L.
Chai, A. M. Seayad, T. T. Dang, A. Chen, Adv. Synth. Catal. 2012,
354, 1407–1412; u) K. S. Goh, C.-H. Tan, RSC Adv. 2012, 2, 5536–
5538.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Science Re-
search from the Japan Society for the Promotion of Science (JSPS), the
Global COE Program, the University of Tokyo, MEXT, Japan, Japan Sci-
ence and Technology Agency (JST), and NEDO. We also thank Mr. Nor-
iaki Kuramitsu (The University of Tokyo) for STEM and EDS analyses.
[11] a) T. Naota, S. I. Murahashi, Synlett 1991, 693–694; b) C. Gunana-
than, Y. Ben-David, D. Milstein, Science 2007, 317, 790–792;
c) L. U. Nordstrøm, H. Vogt, R. Madsen, J. Am. Chem. Soc. 2008,
130, 17672–17673; d) K. Shimizu, K. Ohshima, A. Satsuma, Chem.
Eur. J. 2009, 15, 9977–9980; e) A. J. A. Watson, A. C. Maxwell,
J. M. J. Williams, Org. Lett. 2009, 11, 2667–2670; f) T. Zweifel, J.-V.
Naubron, H. Grꢂtzmacher, Angew. Chem. 2009, 121, 567–571;
Angew. Chem. Int. Ed. 2009, 48, 559–563; g) S. C. Ghosh, S. Mu-
thaiah, Y. Zhang, X. Y. Xu, S. H. Hong, Adv. Synth. Catal. 2009, 351,
2643–2649; h) S. Muthaiah, S. C. Ghosh, J. E. Jee, C. Chen, J.
Zhang, S. H. Hong, J. Org. Chem. 2010, 75, 3002–3006; i) R.
Ohmura, M. Takahata, H. Togo, Tetrahedron Lett. 2010, 51, 4378–
4381; j) Y. Zhang, C. Chen, S. C. Ghosh, Y. Li, S. H. Hong, Organo-
metallics 2010, 29, 1374–1378; k) C. Chen, S. H. Hong, Org. Biomol.
Chem. 2011, 9, 20–26; l) J.-F. Soulꢁ, H. Miyamura, S. Kobayashi, J.
Am. Chem. Soc. 2011, 133, 18550–18553; m) Y. Wang, D. Zhu, L.
Tang, S. Wang, Z. Wang, Angew. Chem. 2011, 123, 9079–9083;
Angew. Chem. Int. Ed. 2011, 50, 8917–8921; n) S. Kegnæs, J. Mielby,
U. V. Mentzel, T. Jensen, P. Fristrup, A. Riisager, Chem. Commun.
2012, 48, 2427–2429; o) J. Mielby, S. Kegnaes, P. Fristrup, Chem-
CatChem 2012, 4, 1037–1047; p) J.-F. Soulꢁ, H. Miyamura, S. Ko-
bayashi, Asian J. Org. Chem. 2012, 1, 319–321; q) K. Yamaguchi, H.
Kobayashi, T. Oishi, N. Mizuno, Angew. Chem. 2012, 124, 559–562;
Angew. Chem. Int. Ed. 2012, 51, 544–547; r) J. Zhu, Y. Zhang, F.
Shi, Y. Deng, Tetrahedron Lett. 2012, 53, 3178–3180.
[1] a) R. C. Larock, Comprehensive Organic Transformations: A Guide
to Functional Group Preparations, 2nd ed., Wiley-VCH, New York,
1999; b) M. B. Smith, Compendium of Organic Synthetic Methods,
Vol. 9, 2001.
[2] a) E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606–631; b) K.
Ishihara, S. Ohara, H. Yamamoto, J. Org. Chem. 1996, 61, 4196–
4197; c) R. M. Al-Zoubi, O. Marion, D. G. Hall, Angew. Chem. 2008,
120, 2918–2921; Angew. Chem. Int. Ed. 2008, 47, 2876–2879; d) H.
Charville, D. Jackson, G. Hodges, A. Whiting, Chem. Commun.
2010, 46, 1813–1823; e) C. L. Allen, B. N. Atkinson, J. M. J. Wil-
liams, Angew. Chem. 2012, 124, 1412–1415; Angew. Chem. Int. Ed.
2012, 51, 1383–1386.
[3] V. R. Pattabiraman, J. W. Bode, Nature 2011, 480, 471–479.
[4] a) D. Crich, K. Sasaki, Org. Lett. 2009, 11, 3514–3517; b) P. Dawson,
T. Muir, I. Clark-Lewis, S. Kent, Science 1994, 266, 776–779; c) D.
Crich, I. Sharma, Angew. Chem. 2009, 121, 2391–2394; Angew.
Chem. Int. Ed. 2009, 48, 2355–2358; d) R. V. Kolakowski, N. Shang-
guan, R. R. Sauers, L. J. Williams, J. Am. Chem. Soc. 2006, 128,
5695–5702; e) N. Shangguan, S. Katukojvala, R. Greenberg, L. J.
Williams, J. Am. Chem. Soc. 2003, 125, 7754–7755; f) R. Merkx,
A. J. Brouwer, D. T. S. Rijkers, R. M. J. Liskamp, Org. Lett. 2005, 7,
1125–1128.
[5] P.-C. Chiang, Y. Kim, J. W. Bode, Chem. Commun. 2009, 0, 4566–
4568.
[6] B. Shen, D. M. Makley, J. N. Johnston, Nature 2010, 465, 1027–1032.
[7] a) S. H. Cho, E. J. Yoo, I. Bae, S. Chang, J. Am. Chem. Soc. 2005,
127, 16046–16047; b) M. P. Cassidy, J. Raushel, V. V. Fokin, Angew.
Chem. 2006, 118, 3226–3229; Angew. Chem. Int. Ed. 2006, 45, 3154–
3157.
[8] a) A. Brennfꢂhrer, H. Neumann, M. Beller, Angew. Chem. 2009,
121, 4176–4196; Angew. Chem. Int. Ed. 2009, 48, 4114–4133; b) A.
Schoenberg, R. F. Heck, J. Org. Chem. 1974, 39, 3327–3331; c) S.
Ho, G. Bondarenko, D. Rosa, B. Dragisic, A. Orellana, J. Org.
Chem. 2012, 77, 2008–2012; d) J. McNulty, J. J. Nair, A. Robertson,
Org. Lett. 2007, 9, 4575–4578; e) J. R. Martinelli, D. A. Watson,
D. M. M. Freckmann, T. E. Barder, S. L. Buchwald, J. Org. Chem.
2008, 73, 7102–7107; f) J. R. Martinelli, T. P. Clark, D. A. Watson,
R. H. Munday, S. L. Buchwald, Angew. Chem. 2007, 119, 8612–
8615; Angew. Chem. Int. Ed. 2007, 46, 8460–8463; g) W. Mꢃgerlein,
A. F. Indolese, M. Beller, Angew. Chem. 2001, 113, 2940–2943;
Angew. Chem. Int. Ed. 2001, 40, 2856–2859.
[12] R. J. K. Taylor, M. Reid, J. Foot, S. A. Raw, Acc. Chem. Res. 2005,
38, 851–869.
[13] a) M. Haruta, T. Kobayashi, H. Sano, N. Yamada, Chem. Lett. 1987,
16, 405–408; b) M. Haruta, N. Yamada, T. Kobayashi, S. Iijima, J.
Catal. 1989, 115, 301–309; c) M. Haruta, Nature 2005, 437, 1098–
1099; d) A. Corma, H. Garcia, Chem. Soc. Rev. 2008, 37, 2096–
2126; e) T. Mallat, A. Baiker, Chem. Rev. 2004, 104, 3037–3058;
f) T. Tsukuda, H. Tsunoyama, H. Sakurai, Chem. Asian J. 2011, 6,
736–748; g) A. S. K. Hashmi, G. J. Hutchings, Angew. Chem. 2006,
118, 8064–8105; Angew. Chem. Int. Ed. 2006, 45, 7896–7936.
[14] a) C. Della Pina, E. Falletta, L. Prati, M. Rossi, Chem. Soc. Rev.
2008, 37, 2077–2095; b) C. D. Pina, E. Falletta, M. Rossi, Chem.
Soc. Rev. 2012, 41, 350–369; c) B. Guan, D. Xing, G. Cai, X. Wan,
N. Yu, Z. Fang, L. Yang, Z. Shi, J. Am. Chem. Soc. 2005, 127,
18004–18005.
[15] R. Akiyama, S. Kobayashi, Chem. Rev. 2009, 109, 594–642.
&
&
12
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Shu¯ Kobayashi et al.
[16] a) S. Kobayashi, H. Miyamura, Chem. Rec. 2010, 10, 271–290; b) S.
Kobayashi, H. Miyamura, Aldrichimica Acta 2013, 46, 3–19.
[17] a) H. Miyamura, R. Matsubara, Y. Miyazaki, S. Kobayashi, Angew.
Chem. 2007, 119, 4229–4232; Angew. Chem. Int. Ed. 2007, 46, 4151–
4154; b) C. Lucchesi, T. Inasaki, H. Miyamura, R. Matsubara, S. Ko-
bayashi, Adv. Synth. Catal. 2008, 350, 1996–2000.
[18] a) D. I. Enache, J. K. Edwards, P. Landon, B. Solsona-Espriu, A. F.
Carley, A. A. Herzing, M. Watanabe, C. J. Kiely, D. W. Knight, G. J.
Hutchings, Science 2006, 311, 362–365; b) S. Meenakshisundaram,
E. Nowicka, P. J. Miedziak, G. L. Brett, R. L. Jenkins, N. Dimitratos,
S. H. Taylor, D. W. Knight, D. Bethell, G. J. Hutchings, Faraday Dis-
cuss. 2010, 145, 341–356.
[23] P. Preedasuriyachai, H. Kitahara, W. Chavasiri, H. Sakurai, Chem.
Lett. 2010, 39, 1174–1176.
[24] a) H. Miyamura, T. Yasukawa, S. Kobayashi, Green Chem. 2010, 12,
776–778; b) T. Yasukawa, H. Miyamura, S. Kobayashi, Chem. Asian
J. 2011, 6, 621–627.
[25] To determine the conversion and yield, we used GC analysis. Un-
fortunately, by this method, we cannot know if imine 5aa was gener-
ated during the reaction or during the GC analysis itself by the reac-
tion between aldehyde 6a and amine 3a.
[26] a) C. G. F. Siler, B. Xu, R. J. Madix, C. M. Friend, J. Am. Chem. Soc.
2012, 134, 12604–12610; b) L. Zhou, C. G. Freyschlag, B. J. Xu,
C. M. Friend, R. J. Madix, Chem. Commun. 2010, 46, 704–706.
[27] W.-J. Yoo, H. Miyamura, S. Kobayashi, J. Am. Chem. Soc. 2011, 133,
3095–3103.
[19] H. Miyamura, R. Matsubara, S. Kobayashi, Chem. Commun. 2008,
2031–2033.
[20] K. Kaizuka, H. Miyamura, S. Kobayashi, J. Am. Chem. Soc. 2010,
132, 15096–15098.
[28] J. He, I. Ichinose, T. Kunitake, A. Nakao, Y. Shiraishi, N. Toshima, J.
Am. Chem. Soc. 2003, 125, 11034–11040.
[21] S. K. Klitgaard, K. Egeblad, U. V. Mentzel, A. G. Popov, T. Jensen,
E. Taarning, I. S. Nielsen, C. H. Christensen, Green Chem. 2008, 10,
419–423.
[29] J.-F. Soulꢁ, H. Miyamura, S. Kobayashi, Chem. Commun. 2013, 49,
355–357.
Received: May 30, 2013
[22] T. Ishida, M. Haruta, ChemSusChem 2009, 2, 538–541.
Published online: && &&, 0000
13
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

FULL PAPER
Heterogeneous Catalysis
Jean-FranÅois Soulꢀ,
Hiroyuki Miyamura,
Shu¯ Kobayashi*
&&&& — &&&&
Direct Amidation from Alcohols and
Amines through a Tandem Oxidation
Process Catalyzed by Heterogeneous-
Polymer-Incarcerated Gold Nanoparti-
cles under Aerobic Conditions
Gold standard: A highly efficient
used with high selectivity depending
on the combination of substrates.
These Au nanoparticle catalysts can be
recovered and reused several times by
simple operations.
green method for amide synthesis from
alcohols and amines catalyzed by gold
nanoparticles stabilized by styrene-
based copolymers has been developed
(see scheme). Two catalysts have been
&
&
14
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!