Heterogeneously catalyzed synthesis of primary amides directly from primary alcohols and aqueous ammonia

Article abstract of DOI:10.1002/anie.201107110

In the presence of a manganese oxide based octahedral molecular sieve (OMS-2), a range of primary amides could be synthesized directly from primary alcohols and ammonia (see scheme). The observed catalysis was heterogeneous, and the recovered catalyst could be reused many times without an appreciable loss of its catalytic performance. Copyright

Full text of DOI:10.1002/anie.201107110

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DOI: 10.1002/anie.201107110
Catalytic Amide Synthesis
Heterogeneously Catalyzed Synthesis of Primary Amides Directly from
Primary Alcohols and Aqueous Ammonia**
Kazuya Yamaguchi, Hiroaki Kobayashi, Takamichi Oishi, and Noritaka Mizuno*
Amides are a very important class of compounds in chemistry
as well as biology that have widely been utilized as
intermediates in peptide and protein synthesis, intensifiers
of perfume, anti-block reagents, color pigments for inks,
detergents, and lubricants.[1] The most common procedure for
amide synthesis is the reaction of activated carboxylic acid
derivatives such as acid chlorides, anhydrides, and esters with
amines including ammonia.[2] The Beckmann rearrangement,
the Aube–Schmidt rearrangement, and the Staudinger liga-
tion are also commonly utilized procedures.[2] However, these
procedures require stoichiometric amounts of (hazardous)
reagents, and at least equimolar amounts of by-products are
formed. Therefore, the development of new environmentally
friendly procedures[3] for amide synthesis is a very important
subject in modern organic synthesis.
In 2007, Milstein and co-workers reported the direct
synthesis of secondary amides from primary alcohols and
amines with a PNN pincer-type ruthenium complex.[4] Alco-
hols are desirable starting materials because they are readily
available and inexpensive and theoretically produce only
hydrogen or water as a by-product. The reaction reported by
Milstein and co-workers is initiated by the dehydrogenation
of an alcohol to an aldehyde. Then, condensation of the
aldehyde with an amine proceeds to form a hemiaminal
intermediate, followed by dehydrogenation to the corre-
sponding secondary amide.[4] Since then, several precious-
metal-based complexes have been developed for the synthesis
of secondary amides.[5–7] However, widely applicable proce-
dures for the direct synthesis of primary amides from primary
alcohols and ammonia are very challenging because dehy-
dration, rather than dehydrogenation, of the hemiaminal
from ammonia readily occurs and/or catalysts are deactivated
in the presence of ammonia and/or water in some cases.[8]
Herein, we demonstrate that it is possible to realize the
direct synthesis of primary amides from primary alcohols and
aqueous ammonia [Eq. (1)] in the presence of manganese
oxide based octahedral molecular sieves (KMn8O16; OMS-2),
which have a 2 ꢀ 2 hollandite structure with a one-dimen-
sional pore.[9] This transformation can be realized by the triple
catalytic functions of OMS-2: 1) dehydrogenation of alcohols
to aldehydes, 2) dehydrogenation of NH aldimines to nitriles,
and 3) hydration of nitriles.[10] The procedures herein have the
following significant advantages in comparison with previ-
ously reported procedures for the synthesis of primary
amides: 1) only water is formed as a by-product [Eq. (1)],
2) easily handled aqueous ammonia can be used, 3) a variety
of primary alcohols can be used as starting materials (the use
of a variety of aldehydes and nitriles is also possible),
4) separation of the catalyst and product is very easy, 5) a
manganese-based oxide is rather inexpensive in comparison
with precious-metal-based catalysts, and 6) OMS-2 can be
reused many times without an appreciable loss of its high
catalytic performance.
Initially, a range of catalysts were applied to the trans-
formation of benzyl alcohol (1a) to benzamide (2a) in 1,4-
dioxane using aqueous ammonia and O2 (see Table S1 in the
Supporting Information). Among the various catalysts exam-
ined, only OMS-2 gave the corresponding amide 2a, for
example, when the transformation was carried out using
aqueous ammonia (28 wt%, ca. 2.6 equiv to 1a) and O2
(3 atm) at 1308C (bath temperature), after 3 hours 96%
yield of 2a was obtained as well as a small amount of
benzonitrile (3a, 2% yield; Table 1, entry 1). In the case of
other manganese-based oxides, such as b-MnO2, birnessite-
type MnO2, and spinel-type Mn3O4, no 2a was produced, and
3a and benzaldehyde (4a) were formed in moderate yields. In
the presence of activated MnO2 (for organic oxidations,
Aldrich), 1a was selectively converted into the corresponding
nitrile 3a (95% yield).[11] Other metal oxides, such as Co3O4
and CeO2, did not give 2a. KMnO4 and MnSO4·H2O, which
are precursors for OMS-2, were not effective for the trans-
formation. The supported ruthenium hydroxide catalyst,
Ru(OH)x/Al2O3,[12] gave 3a and 4a in 18% and 22% yields,
respectively, without formation of 2a under the reaction
conditions described above (see Table S1 in the Supporting
Information). 1,4-Dioxane and N,N-dimethylformamide were
good solvents for the transformation, thus giving 2a in high
yields (see Table S1, in the Supporting Information). Toluene,
dichloromethane, 1,2-dichloroethane, and water gave 3a as a
major product with moderate yields of 2a (see Table S1 in the
Supporting Information).
[*] Dr. K. Yamaguchi, H. Kobayashi, T. Oishi, Prof. Dr. N. Mizuno
Department of Applied Chemistry, School of Engineering
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp
[**] This work was supported in part by the Global COE Program
(Chemistry Innovation through Cooperation of Science and Engi-
neering) and Grants-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology. T.O. is
grateful for a JSPS Research Fellowship for Young Scientists.
To verify whether the observed catalysis is derived from
solid OMS-2 or a leached manganese species, the trans-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107110.
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Table 1: Synthesis of amides from primary alcohols and ammonia.[a]
well as electron-withdrawing substituents at different posi-
tions, efficiently proceeded to afford the corresponding
substituted benzamide derivatives in almost quantitative
yields (ꢀ 95% yields). In the transformation of an allylic
alcohol (1g), the corresponding unsaturated amides could be
obtained without isomerization and hydrogenation of the
double bond. Heteroatom-containing alcohols such as thio-
phene (1h) and pyridine (1i) methanols afforded the corre-
sponding heteroaromatic amides in excellent yields. Also, an
aliphatic alcohol (1j) could be converted into the correspond-
ing aliphatic amide. To show the practical value of the present
procedure, a gram-scale transformation of 1 f (1.03 g; 13-fold
scale) was carried out [Eq. (2)]. The transformation effi-
Entry
Substrate
t
[h]
Product
Yield
[%]
1
2
1a
1b
3
3
2a
2b
96
97
3
1c
3
2c
96
4
5
1d
1e
3
3
2d
2e
98
97
6
7
1 f
3
3
2 f
95
99
ciently proceeded without any decrease in the performance in
comparison with the small-scale transformation in Table 1,
and 2 f and 3 f (nitrile) were produced in 97% and 3% yields
(by GC analysis), respectively. OMS-2 was separated by
filtration and washed with ethanol (ca. 50 mL). Evaporation
of the combined filtrate gave a crude product, which was
washed with n-hexane (ca. 10 mL) to afford 1.06 g of 2 f (95%
yield, > 98% purity by GC and NMR spectroscopy).[14]
After the reaction was completed, OMS-2 was recovered
from the reaction mixture by filtration (> 95% recovery). The
retrieved OMS-2 catalyst could be reused for the trans-
formation of 1i at least eleven times without an appreciable
loss of its high catalytic performance (see Figure S1 in the
Supporting Information). The structure of OMS-2 was
1g
2g
8
1h
1i
3
1
2h
87
9
2i
2j
95
65
10[b]
1j 24
[a] Reaction conditions: OMS-2 (100 mg), substrate (0.5 mmol), 28% aq.
ammonia (100 mL, ca. 2.6 equiv), 1,4-dioxane (2 mL), O2 (3 atm), 1308C preserved even after the eleventh reuse (see Figure S2 in
(bath temp.). See Table S2 in the Supporting Information for more details.
Yields were determined by GC using biphenyl or naphthalene as an
internal standard. [b] OMS-2 (200 mg).
the Supporting Information), showing the high durability of
OMS-2.
When amines, e.g., methylamine (40% aqueous solution),
instead of ammonia were used in the transformation of 1a
under the reaction conditions described in Table 1, the
formation of 1a to 2a was carried out under the reaction
conditions described in Table 1, and OMS-2 was removed
from the reaction mixture by filtration at 50–60% conversion
of 1a. Then, the filtrate was heated at 1308C in 3 atm of O2. In
this case, no further production of 2a and 3a was observed.
This result was confirmed by inductively coupled plasma
atomic-emission spectroscopy (ICP-AES) analysis, as no
manganese species was detected in the filtrate (below
0.001%). All these facts can rule out any contribution to
the observed catalysis from a manganese species that has
leached into the reaction solution; thus the observed catalysis
is intrinsically heterogeneous.[13]
Next, the scope of the present OMS-2 catalytic system
with regard to a range of structurally diverse primary alcohols
was examined. OMS-2 showed high catalytic activities for the
transformation of benzylic, allylic, heteroatom-containing,
and aliphatic alcohols (Table 1). The transformation of
benzylic alcohols 1a–1 f, which contain electron-donating as
corresponding secondary amides were not produced at all.
Therefore, it can be concluded that the present transforma-
tion does not proceed through direct dehydrogenation of
hemiaminal intermediates as has been reported for the
precious-metal catalytic systems.[4,5] The reaction profile for
the transformation of 1a into 2a showed that the correspond-
ing nitrile 3a was initially produced as a major product,
followed by the formation of 2a (see Figure S3 in the
Supporting Information). During the transformation, the
corresponding aldehyde and aldimine[15] were also detected,
albeit in only small amounts (below 1%). Under the reaction
conditions described in Table 1, the absence of ammonia
resulted in the quantitative conversion of 1a into the
corresponding aldehyde 4a within 20 minutes [Eq. (3)].[10]
OMS-2 showed high catalytic performance for the trans-
formation of a variety of structurally diverse aldehydes,
including benzylic, allylic, heteroatom-containing, and ali-
phatic ones, into the corresponding amides in the presence of
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Table 3: Hydration of nitriles.[a]
Entry
Substrate
t
[h]
Product
Yield
[%]
1
3
3
91
81
2[b]
3a
2a
ammonia (Table 2). In addition, the OMS-2-catalyzed hydra-
tion of various nitriles proceeded efficiently to give the
corresponding amides in excellent yields (Table 3). Among
the catalysts examined, only OMS-2 promoted the nitrile
hydration (see Table S1 in the Supporting Information).[10]
3
4
3b
3d
3
3
2b
2d
98
94
Table 2: Synthesis of amides from aldehydes and ammonia.[a]
Entry
Substrate
t
[h]
Product
Yield
[%]
5
3e
3
2e
97
1
2
4a
4b
3
3
2a
2b
89
91
6
7
3 f
3
3
2 f
97
93
3g
2g
3
4
5
4d
3
2d
2e
2g
97
98
87
8
3h
3i
3
1
2h
88
4e
4g
4i
3
3
1
9
2i
2j
96
98
10[c]
3j 24
[a] Reaction conditions: OMS-2 (100 mg), substrate (0.5 mmol), 28%
aq. ammonia (100 mL, ca. 2.6 equiv), 1,4-dioxane (2 mL), Ar (3 atm),
1308C (bath temp.). See Table S4 in the Supporting Information for more
details. Yields were determined by GC using biphenyl or naphthalene as
an internal standard. [b] Water (50 mL, ca. 5.5 equiv) was used instead of
aq. ammonia. [c] OMS-2 (200 mg).
6
2i
2j
94
77
7[b]
4j 24
[a] Reaction conditions: OMS-2 (100 mg), substrate (0.5 mmol), 28%
aq. ammonia (100 mL, ca. 2.6 equiv), 1,4-dioxane (2 mL), O2 (3 atm),
1308C (bath temp.). See Table S3 in the Supporting Information for more
details. Yields were determined by GC using biphenyl or naphthalene as
an internal standard. [b] OMS-2 (200 mg).
All the above-mentioned experimental evidences indicate
that the present OMS-2-catalyzed transformation possibly
proceeds through the following sequence of reactions
(Scheme 1): 1) aerobic oxidative dehydrogenation of an
alcohol to an aldehyde, 2) dehydrative condensation of the
aldehyde and ammonia to an aldimine via a hemiaminal
intermediate, 3) aerobic oxidative dehydrogenation of the
aldimine to a nitrile, and 4) successive hydration to the
desired primary amide.
Scheme 1. Possible reaction pathway for the OMS-2-catalyzed trans-
formation of primary alcohols to primary amides.
In summary, OMS-2 acted as an efficient heterogeneous
catalyst for a widely applicable synthesis of primary amides
directly from primary alcohols and ammonia. The synthesis
from aldehydes or nitriles was also possible in the presence of
OMS-2. The separation of the catalyst and product was very
easy. The observed catalysis was truly heterogeneous, and
OMS-2 could be reused many times without an appreciable
loss of its high catalytic performance. The heterogeneously
catalyzed reaction using OMS-2 described herein will provide
a new route for sustainable amide synthesis, which can
completely avoid utilization of conventional (hazardous)
stoichiometric reagents and the formation of vast amounts
of inorganic by-products.
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synthesis of secondary amides from alcohols and amines: K.
Experimental Section
Shimizu, K. Ohshima, A. Satsuma, Chem. Eur. J. 2009, 15, 9977.
[8] Very recently, three catalytic systems for the synthesis of primary
amides from alcohols and ammonia have been reported. In the
OMS-2 was prepared according to the literature procedure (see the
Supporting Information).[9a] A typical procedure for the synthesis of
the amides was as follows: 1a (0.5 mmol), OMS-2 (100 mg), 1,4-
dioxane (2 mL), an aqueous solution of ammonia (28 wt%, 100 mL,
ca. 2.6 equiv with respect to 1a) were placed in a Teflon vessel with a
magnetic stir bar. The Teflon vessel was attached inside an autoclave
and the reaction was carried out at 1308C (bath temperature) in O2
(3 atm). The reaction rates were not affected by stirring rates from
500 to 1000 rpm. After the reaction was completed (3 h), the OMS-2
catalyst was separated by filtration, washed with acetone, and then
dried at 1508C prior to its use in the reuse experiment. The products
(amides) could be isolated by evaporation of volatiles, followed by a
wash with n-hexane (column chromatography on silica gel, if
necessary; initial eluent: n-hexane, after elution of by-products:
ethyl acetate). The products were confirmed by the comparison of
catalytic system with
a rhodium diolefin amido complex,
methylmethacrylate (3 equiv with respect to the alcohol) is
required to promote the reaction, and easily handled aqueous
ammonia is not used.[8a] Although various secondary amides can
be synthesized from alcohols and amines in water with the water-
soluble gold/DNA catalyst and LiOH·H2O (indispensable addi-
tive, 1.1 equiv with respect to an alcohol), the applicability of this
catalytic system to the synthesis of primary amides is limited to
2a, and the yield is low (50%).[8b] After Wangꢁs report,
Kobayashi and co-workers reported a similar gold catalytic
system.[8c] In this system also, the applicability is limited to 2a,
and NaOH (1 equiv) is required. Thus, as far as we know, widely
applicable, efficient procedures for the direct aerobic synthesis
of primary amides from alcohols and ammonia without additives
are previously unknown, and the development is a challenging
subject: a) T. Zweifel, J.-V. Naubron, H. Grꢂtzmacher, Angew.
Chem. 2009, 121, 567; Angew. Chem. Int. Ed. 2009, 48, 559; b) Y.
Wang, D. Zhu, L. Tang, S. Wang, Z. Wang, Angew. Chem. 2011,
123, 9079; Angew. Chem. Int. Ed. 2011, 50, 8917; c) J.-F. Soulꢃ, H.
Miyamura, S. Kobayashi, J. Am. Chem. Soc. 2011, 133, 18550.
[9] OMS-2 has been recognized as a good catalyst and a support
because of the following advantageous properties: 1) a large
(external) surface area (ca. 100 m2 gÀ1), 2) electron-conducting
property, and 3) dioxygen-reduction ability: a) R. N. DeGuz-
man, Y.-F. Shen, E. J. Neth, S. L. Suib, C.-L. OꢁYoung, S. Levine,
J. M. Newsam, Chem. Mater. 1994, 6, 815; b) Y.-C. Son, V. D.
Makwana, A. R. Howell, S. L. Suib, Angew. Chem. 2001, 113,
4410; Angew. Chem. Int. Ed. 2001, 40, 4280; c) S. L. Suib, J.
Mater. Chem. 2008, 18, 1623; d) S. L. Suib, Acc. Chem. Res. 2008,
41, 479; e) X. Yang, J. Han, Z. Dub, H. Yuan, F. Jin, Y. Wu, Catal.
Commun. 2010, 11, 643; f) T. Oishi, K. Yamaguchi, N. Mizuno,
ACS Catal. 2011, 1, 1351.
[10] Although OMS-2 has been reported to be active for the aerobic
oxidation of alcohols,[9b] the excellent catalytic properties for the
aerobic oxidation of amines and imines as well as the hydration
of nitriles, demonstrated herein, have never been reported so far.
[11] G. D. McAllister, C. D. Wilfred, R. J. K. Taylor, Synlett 2002,
1291.
[12] Recently, we have reported the direct synthesis of nitriles from
alcohols and ammonia by the supported ruthenium hydroxide
catalyst, Ru(OH)x/Al2O3. In the presence of Ru(OH)x/Al2O3,
the direct synthesis of amides was very difficult (see Table S1,
entry 18 in the Supporting Information) because of the low
ability of Ru(OH)x/Al2O3 for nitrile hydration (a large amount
of water is required to attain high yields) in comparison with
OMS-2: a) T. Oishi, K. Yamaguchi, N. Mizuno, Angew. Chem.
2009, 121, 6404; Angew. Chem. Int. Ed. 2009, 48, 6286; b) T.
Oishi, K. Yamaguchi, N. Mizuno, Top. Catal. 2010, 53, 479.
[13] R. A. Sheldon, M. Wallau, I. W. C. E. Arends, U. Schuchardt,
Acc. Chem. Res. 1998, 31, 485.
their GC retention times, GC mass spectra, and/or H and 13C NMR
spectra with those of authentic data.
1
Received: October 7, 2011
Published online: November 23, 2011
Keywords: alcohols · amides · ammonia ·
.
heterogeneous catalysis · manganese oxide
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