N-formylation of amines catalyzed by nanogold under aerobic oxidation conditions with MeOH or formalin

Article abstract of DOI:10.1246/cl.2010.1174

Gold nanoclusters stabilized by poly(N-vinyl-2-pyrrolidone) (Au:PVP) are active and selective catalysts for N-formylation of amines under aerobic oxidation using methanol or formalin as a formyl source.

Full text of DOI:10.1246/cl.2010.1174

doi:10.1246/cl.2010.1174
1174
Published on the web October 9, 2010
N-Formylation of Amines Catalyzed by Nanogold
under Aerobic Oxidation Conditions with MeOH or Formalin
Patcharee Preedasuriyachai,1 Hiroaki Kitahara,2 Warinthorn Chavasiri,3 and Hidehiro Sakurai*2,4
1Program in Petrochemistry and Polymer Science, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
2Research Center for Molecular Scale Nanoscience, Institute for Molecular Science, Myodaiji, Okazaki, Aichi 444-8787
3Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
4PRESTO, Japan Science and Technology Agency, Tokyo 102-0075
(Received August 17, 2010; CL-100708; E-mail: hsakurai@ims.ac.jp)
Gold nanoclusters stabilized by poly(N-vinyl-2-pyrrolidone)
(Au:PVP) are active and selective catalysts for N-formylation of
amines under aerobic oxidation using methanol or formalin as a
formyl source.
Table 1. The reactions of 1a under aerobic MeOH oxidation
conditions
Conditions
+
+
MeOH:H2O
air, 4 h
N
NH
NH2
N
H
CHO
CHO
1a
2a
3a
4a
Direct formation of amides from alcohols or aldehydes with
amines has recently received attention from the viewpoint of the
development of environmentally benign processes.1 In partic-
ular, N-formylation of amines using MeOH or formaldehyde
(especially formalin) is very important. The use of simple
reactants makes it possible to understand the reaction mecha-
nism. Furthermore, the starting materials are both economical
and the formamide derivatives produced in the reaction are
important intermediates in organic synthesis. Until now though,
only a few examples of this transformation have been reported.
Cu hydroxy salts have been used in the presence of hydrogen
peroxide.2 Aerobic oxidation has been achieved with nanosized-
gold supported on metal oxide3 with MeOH, and formylation of
dimethylamine with formaldehyde has been carried out using
metallic gold4 or silver5 surfaces as a catalyst. Practical
procedures for N-formylation by aerobic oxidation that tolerate
a wide scope of amines are still needed.
Conditions
Yielda/%
Solvent ratio Temperature
Entry
Au:PVP LiOH
/atom % /mol %
(MeOH:H2O)
/°C
1a 2a 3a 4a
1
2
3
4
5
6
7
8
9b
10
®
10
10
10
10
10
5
®
1:2
1:2
1:2
1:2
1:2
1:1
1:0
1:2
1:2
refluxc
refluxc
refluxc
50
27
50
50
refluxc
refluxc
no reaction
no reaction
® 94 5 ®
200
200
200
200
200
200
200
200
16 80 2
2
no reaction
63 35 ® 1
no reaction
9 81 6
2 89 8
4
2
5
aGC yields using hexadecane (C16) as an internal standard.
bReaction time: 8 h. Bath temperature: 80 °C.
c
Nanosized-gold metal has recently attracted a great deal of
interest because of its high activity6 and potential application in
the emerging area of green oxidation chemistry. We have recently
demonstrated that gold nanoclusters stabilized by poly(N-vinyl-
2-pyrrolidone) (Au:PVP) act as an excellent quasi-homogenous
catalyst for the aerobic oxidation of benzylic alcohols,7 gener-
ation of H2O2 in the presence of ammonium formate,8 homo-
coupling reaction of arylboronic acids,9 and other cyclization
reactions.10 Herein, we wish to report highly selective direct N-
formylation using MeOH or formalin as a formyl source in the
presence of Au:PVP under aerobic conditions.
Given our recent achievements in the aerobic oxidation of
alcohol by Au:PVP,7 we decided to conduct an N-formylation
reaction similar to those used for methanol oxidation. N-
Formylation of N-methylaniline was screened in MeOH/H2O
and the results are listed in Table 1.
(3a) in 5% yield, which is produced via oxidative demethylation
followed by N-formylation. The reaction also proceeded at 50 °C
and the yields of the products, 2a, 3a, and aniline (4a) after 4 h
were 80%, 2%, and 2% yields, respectively with 1a also
recovered in 16% yield (Entry 4). No reaction was observed at
27 °C (Entry 5). The importance of water and the amount of
catalyst were then investigated. It was found that the amount of
H2O is crucial in this reaction. When a 50/50 MeOH/H2O
mixture was used as the solvent at 50 °C for 4 h (Entry 6), the
reaction rate drastically decreased and the yield of 2a declined to
35%, while 1a was recovered in 63% yield. In addition, no
reaction occurred in 100% MeOH solution (Entry 7). When the
amount of catalyst was reduced to 5 atom %, the conversion
yields after 4 and 8 h were 91% and 98%, respectively, and the
yields of by-products 3a and 4a slightly increased, as shown in
Entries 8 and 9.
The reaction did not proceed without either base (Entry 1)
or Au:PVP (Entry 2). The basic conditions are important for
oxidation of MeOH to generate the key intermediate for N-
formylation. The best results were obtained when 200 mol % of
LiOH was used and LiOH was included in all further reactions.11
Reaction temperature was then evaluated. The reaction proceed-
ed smoothly in the presence of 10 atom % of Au:PVP under
reflux conditions (Entry 3),12 giving N-formyl-N-methylaniline
(2a) in 94% yield along with the formation of N-formylaniline
Aerobic oxidation of MeOH with Au catalysts3 affords
formaldehyde (HCHO), formic acid (HCOOH), methyl formate
(HCOOMe), or carbon dioxide (CO2). To clearify the possible
intermediate in the formylation reaction, different formyl
sources were substituted for MeOH. The results are represented
in Table 2.
The reactions were carried out in EtOH:H2O (1:2) under
conditions analogous to those used with MeOH:H2O (1:2) as the
solvent, except that the temperature was lower (50 °C) to avoid
Chem. Lett. 2010, 39, 1174-1176
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1175
Table 2. Variation of formyl source
Table 3. Scope and limitation of N-formylation catalyzed by
Au:PVP
Conditionsa
Yield/%b
1a 2a 3a 4a
no reaction
R1
R2
Temperature
1 atom% Au:PVP, 100 mol% NaOH
150 mol% HCHO, EtOH:H2O (1:2), 27 °C
R1
R2
Entry
Au:PVP Formyl reagent
/atom % /100 mol %
N
H
N
/°C
CHO
2
1
1
10
10
10
10
1
®
HCHO
HCOOMe
HCOOH
HCHO
50
50
50
50
27
2
3
4
5c
21 81 ®
no reaction
no reaction
1
Amines
Entry
1
Isolated yield/%
97
1a
® 97 ® ®
N
H
aConditions: 0.05 mmol N-methylaniline, 200 mol % LiOH,
EtOH:H2O (1:2), under air, 1 h. GC yields using hexadecane
(C16) as an internal standard. Conditions: 150 mol % HCHO,
100 mol % NaOH, 9 h.
CH3OH
2
3
1b (4a)
1c
53 (96a)
>99
b
NH2
c
N
H
MeO
O2N
1d
1e
4
5
86
oxidation
R1
R2
N
H
R1
H
R2
O
R1
H
R2
N
H
N
N
oxidation
HCHO
oxidation
HCO2Me or HCOOH
no reaction
no reaction
OH
N
H
hemiaminal
1f
6
7
N
H
Scheme 1. Possible formyl source diagram for N-formylation
of amine and methanol.
1g
1h
2
N
H
N-acetylation via oxidation of ethanol to acetaldehyde. No
reactions took place in the absence of a formyl source (Entry 1).
In all of the other reactions listed in Table 2 except Entry 5,
100 mol % of various kinds of formyl reagents were added. The
N-formylation product 2a was obtained in 81% yield in the
presence of formalin (Entry 2). In contrast, no reaction occurred
in the presence of HCOOMe or HCOOH (Entries 3 and 4).
These results strongly suggest that a possible reaction pathway
might involve the formation of a hemiaminal by the reaction of
formaldehyde with amine, which is then further oxidized by
Au:PVP, rather than proceeding via oxidation of MeOH to a
formic acid equivalent followed by amidation (Scheme 1).
These results are not consistent with a report on the reaction
on heterogeneous Au/NiO published by Ishida and Haruta.3
They found that Au/NiO catalyzed the oxidation of MeOH to
HCO2Me under conditions (0.5 MPa O2, 100 °C, 5 h) where it
might react with benzylamine to give the N-formyl product.
On the other hand, Friend et al. proposed the existence of a
hemiaminal intermediate in the reaction of dimethylamine and
formaldehyde on the surface of O/Au.4 Also, a hemiaminal
intermediate has been considered in a reaction on a Ag
catalyst.1e,5
95
8
9
N
H
1i
1j
81
NH
98a
10
11
12
N
H
1k
1l
88 (>99b)
87
N
H
NH2
NH2
13
1m
78a
a10 atom % Au:PVP was used. 5 atom % Au:PVP was used.
b
conditions catalyzed by Au:PVP. Typical reaction conditions
are as follows: 1 atom % of Au:PVP, 100 mol % of NaOH,
150 mol % of HCHO (added as a 37% formalin solution),
EtOH:H2O (1:2), 27 °C, 9 h.12 The results of this reaction with
various amines are summarized in Table 3.
Reaction of 1b was slightly different from that seen with 1a
(Entry 1). Aggregation of the Au clusters was observed to occur
gradually as the reaction proceeded, leading to only 53% yield in
the presence of 1 atom % of Au:PVP. The yield was improved
up to 96% when the amount of catalyst was increased
to 10 atom % (Entry 2). A remarkable electronic effect was
observed in the reaction with para-substituted N-methylaniline
derivatives. Anilines with an electron-donating group (1c and
Since the rate determining step would be the aerobic
oxidation of MeOH to formaldehyde, and the oxidation of the
hemiaminal to amide would occur smoothly, the reaction
conditions were expected to be much milder in the presence of
formalin compared to MeOH. In fact, when 150 mol % HCHO
was used, the N-formamide 2a was obtained almost quantita-
tively (97% yield) at 27 °C for 9 h, even with only by 1 atom %
of Au:PVP (Entry 5, Table 2).
The above result motivated us to develop a practical method
for N-formylation of amines with formalin under aerobic
Chem. Lett. 2010, 39, 1174-1176
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1176
1d) afforded the N-formyl products 2c and 2d in excellent yields
(>99% and 86% of 2c and 2d, respectively). On the other hand,
no reaction was observed in the case of para-nitro derivative 1e
due to the strong electron-withdrawing effect. It was also found
that the reaction is susceptible to steric effects, a characteristic
that has often been observed in previous studies.9 N-Formylation
did not proceed for N-methyl-ortho-toluidine (1f) and only 2%
of desired product 2g was obtained from diphenylamine (1g) as
shown in Entries 6 and 7.
References and Notes
1
a) C. Gunanathan, Y. Ben-David, D. Milstein, Science 2007,
317, 790. b) L. U. Nordstrøm, H. Vogt, R. Madsen, J. Am.
Chem. Soc. 2008, 130, 17672. c) W.-J. Yoo, C.-J. Li, J. Am.
Chem. Soc. 2006, 128, 13064. d) S. Seo, T. J. Marks, Org.
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2
H. Tumma, N. Nagaraju, K. V. Reddy, J. Mol. Catal. A:
Chem. 2009, 310, 121.
Except for these cases, the formylation reaction conditions
were applicable to many types of amines. Cyclic arylamines 1h-
1j in Entries 8-10 proceeded to give the desired products 2h-2j
in high yields (81-98%). In addition, piperidine (1k) also
underwent N-formylation in excellent yield (88%, Entry 11) in
the presence of 1 atom % of Au:PVP and quantitative yield
when 5 atom % Au:PVP was used. As for primary amines,
alkylamine 1l in Entry 12 underwent N-formylation to furnish 2l
in 87% yield, and ¡-naphthylamine 1m in Entry 13 also gave
the product 2m in 78% yield.
As described above, Au:PVP was found to be an excellent
catalyst for the direct N-formylation of amine with MeOH or
formalin as a formyl source. In particular, only 1 atom % of
catalyst was needed and the reaction proceeded under ambient
conditions in the reaction with formalin solution. The results
strongly indicate that Au:PVP might possess superior catalytic
activity toward the oxidation of hemiaminal intermediate when
compared to other catalysts. Such characteristic features of
Au:PVP will be applicable to many types of practical organic
syntheses.
3
4
T. Ishida, M. Haruta, ChemSusChem 2009, 2, 538.
B. Xu, L. Zhou, R. J. Madix, C. M. Friend, Angew. Chem.,
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Catal. Today 2006, 111, 22, and references therein.
a) H. Tsunoyama, H. Sakurai, Y. Negishi, T. Tsukuda, J. Am.
Chem. Soc. 2005, 127, 9374. b) H. Tsunoyama, T. Tsukuda,
H. Sakurai, Chem. Lett. 2007, 36, 212. c) H. Tsunoyama, H.
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5
6
7
8
9
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Soc. Jpn. 2006, 31, 521.
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This work was supported by PRESTO-JST (Search for
Nanomanufacturing Technology and Its Development), MEXT,
IMS International Joint Research, and NEDO from Japan, as
well as by The Development and Promotion of Science and
Technology Talent Project (DPST), The institute for the
Promotion of Teaching Science and Technology (IPST) and
The 90th Anniversary of Chulalongkorn University Fund
(Ratchadaphiseksomphot Endowment Fund) Center for Petro-
leum, Petrochemicals, and Advanced Materials from Thailand.
We appreciate Ms. Berit Topolinski (visiting student from FU
Berlin) and Mr. Sabyasachi Chakraborty (visiting student from
National University of Singapore sponsored by JENESYS
Programme) for their assistance with preliminary experiments.
We also thank Ms. Noriko Kai for preparation of the Au:PVP
catalyst.
10 a) I. Kamiya, H. Tsunoyama, T. Tsukuda, H. Sakurai, Chem.
Lett. 2007, 36, 646. b) H. Kitahara, I. Kamiya, H. Sakurai,
Chem. Lett. 2009, 38, 908. c) H. Kitahara, H. Sakurai, Chem.
Lett. 2010, 39, 46.
11 The variation of bases was studied and 2a was obtained in
moderate to excellent yield (61-94%). The % yield from
different bases is showed here; 94% (KOH), 94% (NaOH),
93% (LiCO3), 89% (CsCO3), 83% (K2CO3), 79%
(Ca(OH)2), 61% (KHCO3). Lower amounts of base dimin-
ished the reaction rate, while more than 200 mol % of base
had no affect.
12 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2010, 39, 1174-1176
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/