Manganese oxide-catalyzed additive-and solvent-free aerobic oxidative synthesis of primary amides from primary amines

Article abstract of DOI:10.1246/cl.2012.633

Various kinds of primary amides could be synthesized through indirect aerobic oxygenation of primary amines using simple amorphous MnO2 under additive-and solvent-free conditions. The catalyst/product separation was very easy, and the retrieved MnO₂ catalyst could be reused without an appreciable loss of its high catalytic performance.

Full text of DOI:10.1246/cl.2012.633

doi:10.1246/cl.2012.633
Published on the web June 2, 2012
633
Manganese Oxide-catalyzed Additive- and Solvent-free Aerobic Oxidative Synthesis
of Primary Amides from Primary Amines
Kazuya Yamaguchi, Ye Wang, and Noritaka Mizuno*
Department of Applied Chemistry, School of Engineering, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656
(Received April 3, 2012; CL-120289; E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp)
Various kinds of primary amides could be synthesized
through indirect aerobic oxygenation of primary amines using
simple amorphous MnO2 under additive- and solvent-free
conditions. The catalyst/product separation was very easy, and
the retrieved MnO2 catalyst could be reused without an
appreciable loss of its high catalytic performance.
Very recently, we have reported that amorphous MnO2 (with
a large specific surface area)10 shows extremely high catalytic
performance for nitrile hydration with only reduced amounts of
water (2 equiv or less with respect to nitriles, Table S1)11,19 and
that the catalytic activity of amorphous MnO2 is much higher
than that of OMS-2 (Table S2).11,19 In addition, it is well known
that manganese-based oxides possess high dehydrogenation
abilities for various substrates including alcohols and amines.9,12
Therefore, it is expected that amorphous MnO2 can efficiently
promote oxygenation of primary amines through the dehydro-
genation-hydration sequence in the absence of any additives
(Scheme 1).
Primary amides are one of the most important chemicals that
have widely been utilized as raw materials for engineering
plastics, intensifiers of perfume, antiblock reagents, color pig-
ments for inks, detergents, lubricants, and intermediates in
peptide and protein synthesis.1 Even at present, ammonolysis
of activated carboxylic acid derivatives with ammonia is
still utilized for synthesis of primary amides.2 However, this
procedure requires stoichiometric reagents such as thionyl
chloride and carbodiimide for preactivation of carboxylic acids,
and at least equimolar amounts of by-products are formed not
only during the aminolysis but also the preactivation step.2
Therefore, instead of this antiquated procedure, the development
of efficient green procedures for synthesis of primary amides
using various kinds of starting materials is a subject of urgency.3-5
Primary amines are candidates as desirable starting materi-
als for primary amides because they are readily available and
inexpensive. However, in general, it is very difficult to oxygen-
ate primary amines directly to primary amides, and reactive
stoichiometric reagents such as 2,6-di-tert-butyl-p-benzoqui-
none6 and in situ-generated RuO4 (from RuO2¢nH2O and
NaIO4)7 have typically been used for indirect oxygenation of
primary amines. Though oxygenation of primary amines through
the dehydrogenation-hydration sequence using molecular oxy-
gen (air) and water (Scheme 1) is one of the greenest procedures,
only two systems catalyzed by a supported ruthenium hydroxide
(Ru(OH)x/Al2O3)8 and a cryptomelane-type manganese oxide-
based octahedral molecular sieve (OMS-2)9 have previously
been reported to date, as far as we know. In the system of
Ru(OH)x/Al2O3, a large amount of water (reactant) is indis-
pensable because of the very low catalytic activity of Ru(OH)x/
Al2O3 for nitrile hydration (the last step of the sequence).8 The
OMS-2-catalyzed oxygenation requires “aqueous ammonia” as
an indispensable additive to prevent the formation of N-
alkylimines (by-products) and to promote nitrile hydration.9
As we expected, we herein found that amorphous MnO2 can
promote aerobic oxygenation of various kinds of primary amines
to primary amides using molecular oxygen (air) as a sole oxidant
“without any additives (even without addition of water).” During
the transformation, 2 equiv of water is generated (Scheme 1),
and the last step of nitrile hydration proceeds with the in situ-
generated water.11 It is emphasized that the MnO2-catalyzed
oxygenation efficiently proceeds even under “solvent-free”
conditions.
Initially, various catalysts including previously reported
8
ones such as Ru(OH)x/Al2O3 and OMS-29 were applied to the
oxygenation of benzylamine (1a) to benzamide (2a) (Table 1).13
Among them, manganese-based oxides such as amorphous MnO2
and OMS-2 gave significant yields of 2a (58-74% yields), and
the catalytic activity of amorphous MnO2 was higher than those
of other manganese-based oxides such as OMS-2,9 ¢-MnO2, and
birnessite-type MnO2. When the oxygenation of 1a was carried
out with amorphous MnO2 at 130 °C (bath temp.) in 1,4-dioxane
for 1 h, 2a and benzonitrile (3a) were obtained in 74% and 23%
yields, respectively. When the reaction time was prolonged to
3 h, 3a was completely hydrated to give a quantitative yield of 2a.
Although OMS-2 gave 2a and 3a in 58% and 20% yields,
respectively, undesirable by-products such as N-benzylidene-
benzylamine (4a) and benzaldehyde (5a) were also formed under
the conditions described in Table 1 (without aqueous ammo-
nia9).14 In the case of birnessite-type MnO2, 2a and 3a were
hardly produced, and 4a was produced as a major product (54%
yield). KMnO4 and MnSO4¢H2O (1 equiv with respect to 1a,
precursors for amorphous MnO210) were not effective for the
oxygenation, suggesting that soluble manganese species are not
active for the present oxygenation.15 Indeed, when amorphous
MnO2 (or OMS-2) was removed from the reaction mixture by
filtration at ca. 50% conversion of 1a and the filtrate was again
heated at 130 °C in 6 atm of air, no further production of 2a and
3a was observed. Thus, the above-mentioned results can rule out
any contribution to the observed catalysis from manganese
species that leached into the reaction solution, and the observed
catalysis for the present oxygenation is truly heterogeneous.16
H O
2
1/2O
H O
2
1/2O
NH
H O
2
2
2
O
R
CN
R
NH
R
2
R
NH
2
Scheme 1. Reaction path for oxygenation of primary amines
to primary amides through the dehydrogenation-hydration
sequence.
Chem. Lett. 2012, 41, 633-635
© 2012 The Chemical Society of Japan
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634
Table 1. Oxygenation of benzylamine (1a) to benzamide (2a)a
Table 2. Solvent-free oxygenation of various primary amines
with amorphous MnO2
a
O
cat.
Ph
NH2
+ Ph CN
+
+ Ph
Ph
Ph
N
4a
O
Ph
NH2
Entry
Substrate
Product
Yield/%
1a
2a
3a
5a
O
Yield/%
Entry
Catalyst
1
1a
1a
1a
2a 92 (90)
2a 94
NH2
NH2
2b
3c
2a
3a
4a
5a
2a 81
1
Amorphous MnO2
Amorphous MnO2
OMS-2
74
92
58
4
23
<1
20
<1
<1
6
<1
<1
5
O
2b
3
NH2
NH2
4
5
6
1b
1c
1d
2b >99 (94)
4c
¢-MnO2
45
36
4
O
Birnessite-type
MnO2
KMnO4
MnSO4¢H2O
Co3O4
CeO2
Ru(OH)x/Al2O3
RuHAP
None
NH2
OCH3
NH2
2c
91
5
<1
2
54
<1
OCH3
6d
7d
8
9c
10
11c
12
<1
<1
<1
<1
<1
<1
<1
2
<1
3
<1
15
28
<1
9
<1
48
9
<1
<1
<1
<1
<1
<1
<1
O
H3CO
H3CO
NH2
NH2
2d 93
NH2
NH2
O
7
1e
1e
2e
2e
98 (89)
97
5
5
8b
H3CO
Cl
H3CO
Cl
O
<1
NH2
NH2
9
1f
2f
87
aReaction conditions: 1a (0.5 mmol), catalyst (50 mg), 1,4-
dioxane (2 mL), 130 °C (bath temp.), air (6 atm), 1 h. Yields
were determined by GC using naphthalene as an internal
standard. bUnder solvent-free conditions. Amorphous MnO2
(100 mg), 3 h. cCommercially available (see the Supporting
O
NH2
NH2
NH2
10
1g
2g 60
O
NH2
NH2
NH2
d
Information19). Mn salts (0.5 mmol).
11
1h
1h
2h 96 (86)
2h 98
12b
N
O
N
O
O
2i
2j
40d
O
S
Co3O4 and CeO2 did not give 2a as well as 3a, and the
corresponding alkylimine 4a was formed as a major product
(9-48% yields). Supported ruthenium catalysts such as
13
1i
1j
NH2
S
8
14e
89
Ru(OH)x/Al2O3 and RuHAP (HAP: hydroxyapatite)17 did not
NH2
work well for the synthesis of 2a under the conditions described
in Table 1. 1,4-Dioxane and toluene were good solvents for the
oxygenation of 1a, giving 54-74% yields of 2a (Table S3).19 On
the other hand, highly polar solvents such as N,N-dimethylform-
amide (DMF) and ethanol gave lower yields of 2a (1-24%
yields) (Table S3).19 Notably, the oxygenation also efficiently
proceeded even under “solvent-free” conditions, affording 2a in
92% yield without formation of any by-products (Entry 2 in
Table 1). We hereafter carried out oxygenation under solvent-
free conditions.13
aReaction conditions: substrate (0.5 mmol), amorphous MnO2
(100 mg), 130 °C (bath temp.), air (6 atm), 3 h. Yields were
determined by GC using naphthalene or biphenyl as an internal
standard (see Table S4 in more detail19). Values in the
c
parentheses are isolated yields. bReuse experiments. Amor-
phous MnO2 (20 mg). dUnidentified by-products were formed.
e2 h.
Next, the scope of the present MnO2-catalyzed solvent-free
oxygenation of various kinds of structurally diverse primary
amines was examined (Table 2). Typically, oxygenation was
carried out with 100 mg of amorphous MnO2. The amount of
amorphous MnO2 could be much reduced. For example, the
oxygenation of 1a with 20 mg of amorphous MnO2 gave 81%
yield of 2a under the conditions described in Table 2 (Entry 3).
Oxygenation of benzylamine derivatives 1a-1g, which contain
electron-donating as well as electron-withdrawing substituents at
different positions, efficiently proceeded to afford the corre-
sponding benzamide derivatives (²60% yields). Oxygenation
of ortho-, meta-, and para-substituted benzylamine derivatives
1c-1e proceeded well, and the yields of the corresponding
substituted benzamide derivatives were almost equal (91-98%
yields), suggesting that the steric effect of substituents on the
phenyl rings is negligible. Heteroaromatic methylamines such as
pyridine (1h), furan (1i), and thiophene (1j) methylamines gave
the corresponding heteroaromatic amides in moderate to high
yields (40-96% yields). Unfortunately, the oxygenation of an
aliphatic amine of n-octylamine was unsuccessful (2% yield of
n-octanamide at >99% conversion of n-octylamine) because of
formation of many unidentified by-products.
After oxygenation was completed, amorphous MnO2 was
easily retrieved from the reaction mixture by simple filtration
with >95% recovery.13 The retrieved MnO2 catalyst could be
reused without an appreciable loss of its high catalytic perform-
ance for oxygenation of various primary amines (Entries 2, 8,
and 12 in Table 2).
Furthermore, we also found that primary amides could be
synthesized from “secondary amines” and aqueous ammonia
(Scheme 2). For example, dibenzylamine (6a) could be con-
verted into 2a in 99% yield in the presence of amorphous MnO2
under solvent-free conditions. This transformation is composed
of six relay steps. The reaction profile showed that an alkylimine
4a was initially produced. We confirmed that 4a was quantita-
tively converted into 2a under the same conditions in the
Chem. Lett. 2012, 41, 633-635
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

635
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N. A. Owston, A. J. Parker, J. M. J. Williams, Org. Lett. 2007, 9, 73.
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Ph
N
H
Ph
Ph
N
Ph
6a
4a
Ph
O
O
5a
Ph CN
3a
Ph
NH
+
5
Ph
NH
2
Ph
NH
2
2a (99% yield)
1a
Scheme 2. Transformation of dibenzylamine (6a) to benz-
amide (2a). Reaction conditions: 6a (0.25 mmol), amorphous
MnO2 (100 mg), 28% aq. ammonia (50 ¯L, ca. 2.6 equiv with
respect to 6a), 130 °C (bath temp.), air (6 atm), 3 h.
6
7
8
9
presence of aqueous ammonia. In addition, an aldehyde 5a was
also quantitatively converted into 2a under the same conditions
in the presence of aqueous ammonia.18 Therefore, all relay steps
in Scheme 2 can be promoted by amorphous MnO2.9,11
In summary, simple amorphous MnO2 could act as an
efficient, reusable catalyst for indirect oxygenation of primary
amines through the dehydrogenation-hydration sequence. The
present procedure has the following significant advantages in
comparison with previously reported systems; (i) oxygenation
efficiently proceeds even under additive- and solvent-free
conditions, (ii) catalyst separation and product isolation are
very easy, (iii) amorphous MnO2 is easily prepared and rather
inexpensive in comparison with precious metal-based catalysts,
e.g., Ru(OH)x/Al2O3,8 and/or (iv) MnO2 can be reused without
an appreciable loss of its high catalytic performance for various
substrates. This convenient procedure demonstrated herein will
provide a green route to primary amides, which can completely
avoid utilization of (hazardous) stoichiometric reagents and
formation of vast amounts of inorganic by-products, and will be
one of the choices for green amide synthesis.
10 Amorphous MnO2 was prepared as follows: An aqueous solution
of KMnO4 (5.89 g, 100 mL) was added dropwise to an aqueous
solution of MnSO4¢H2O (8.8 g, 30 mL). The resulting mixture was
stirred at room temperature for 10 min. Then, the dark brown solid
formed was filtered off, washed with a large amount of deionized
water (ca. 4 L), and dried under air at 150 °C for 12 h, affording 5.0 g
of amorphous MnO2 as a dark brown powder (BET surface area:
304 m2 g¹1).
11 K. Yamaguchi, Y. Wang, H. Kobayashi, N. Mizuno, Chem. Lett.
2012, 41, 574.
12 a) Y.-C. Son, V. D. Makwana, A. R. Howell, S. L. Suib, Angew.
Chem., Int. Ed. 2001, 40, 4280. b) F. Schurz, J. M. Bauchert, T.
Merker, T. Schleid, H. Hasse, R. Gläser, Appl. Catal., A 2009, 355,
42.
13 A typical procedure for oxygenation: Amorphous MnO2 (100 mg)
and a primary amine 1a (0.5 mmol) were placed in a Teflon vessel
with a magnetic stir bar (conditions described in Table 2). The Teflon
vessel was attached inside an autoclave, and the reaction was carried
out at 130 °C (bath temp.) in 6 atm of air. After the oxygenation was
completed (3 h), MnO2 was separated by filtration (>95% catalyst
recovery, BET surface area of retrieved MnO2: 190 m2 g¹1) and
washed with ethanol. Then, the filtrate was analyzed by GC. The
product 2a was isolated by evaporation of volatiles, followed by
rinse with n-hexane (54.3 mg, 90% isolated yield). The retrieved
MnO2 was washed with water, and then dried at 150 °C under air
atmosphere for 1 h just before using for the reuse experiment.
14 Alkylimines and aldehydes are possibly formed through the hydro-
lytic decomposition of aldimine intermediates. The amount and
We thank Mrs. T. Oishi and H. Kobayashi (The University
of Tokyo) for their help with preliminary experiments. This
work was supported in part by the Global COE Program
(Chemistry Innovation through Cooperation of Science and
Engineering), Japan Chemical Innovation Institute (JCII), and
Grants-in-Aid for Scientific Researches from Ministry of
Education, Culture, Sports, Science and Technology.
¹1
density of acidic sites of OMS-2 were 1.23 mmol g and 12.7
¯mol m¹2, respectively, and larger than those of amorphous MnO2
¹1
¹2
References and Notes
(amount: 1.04 mmol g ; density: 3.42 ¯mol m )
(Table S519).
1
a) C. E. Mabermann, in Encyclopedia of Chemical Technology, ed.
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Therefore, it is likely that OMS-2 has higher ability for decom-
position of aldimine intermediates to undesirable by-products such as
alkylimines and aldehydes.
15 Under the conditions described in Table 1, KMnO4 and MnSO4¢H2O
were slightly soluble in the reaction solution. Even when the reaction
was carried out under the conditions described in Table 1 with water
(1 mL, manganese salts were soluble in this case), the desired amide
2a was not produced at all.
16 R. A. Sheldon, M. Wallau, I. W. C. E. Arends, U. Schuchardt, Acc.
Chem. Res. 1998, 31, 485.
17 The step-by-step synthesis of nicotinamide (2h) from 3-picolylamine
(1h) using RuHAP catalyst has been reported: K. Mori, K.
Yamaguchi, T. Mizugaki, K. Ebitani, K. Kaneda, Chem. Commun.
2001, 461.
2
3
4
The following excellent review article summarizes various green
synthetic procedures for amides: C. L. Allen, J. M. J. Williams,
Chem. Soc. Rev. 2011, 40, 3405.
Hydration of nitriles is also an attractive procedure for synthesis of
primary amides: a) K. Yamaguchi, M. Matsushita, N. Mizuno,
18 K. Yamaguchi, H. Kobayashi, T. Oishi, N. Mizuno, Angew. Chem.,
Int. Ed. 2012, 51, 544.
19 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2012, 41, 633-635
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/