Aerobic oxidation of primary amines to oximes catalyzed by DPPH and WO 3/Al2O3

Article abstract of DOI:10.1002/anie.200705002

(Chemical Equation Presented) Catalytic teamwork: Aerobic oxidation of primary amines to the corresponding oximes proceeds highly efficiently in the presence of the catalysts 1,1-diphenyl-2-picrylhydrazyl (DPPH) and WO ₃/Al₂O₃ under mild conditions (see scheme). This new method is both selective and environmentally benign.

Full text of DOI:10.1002/anie.200705002

Angewandte
Chemie
DOI: 10.1002/anie.200705002
Aerobic Catalytic Oxidation
Aerobic Oxidation of Primary Amines to Oximes Catalyzed by DPPH
and WO3/Al2O3
Ken Suzuki,* Tomonari Watanabe, and Shun-Ichi Murahashi*
Since the catalytic oxidation of amines is important for
enzymatic[1] and synthetic processes,[2] various methods have
been examined; however, useful methods for the oxidation of
amines are limited because of the sensitivy of amines.
Selective catalytic oxidative transformations of secondary
amines to nitrones[3,4] and imines[5,6] have been explored.
However, selective catalytic oxidation of primary amines 1 to
oximes 2 [see Eq. (1)] has been not achieved, although oximes
are useful intermediates for the synthesis of fine chemicals,
medicines, and biologically active compounds.[7] Catalytic
oxidation of primary amines with hydrogen peroxide gives
oximes along with by-products such as nitroalkanes, carbonyl
compounds, and imines.[8–12]
complexes as catalysts was found to give nitriles resulting
from extensive oxidative dehydration.[16] Furthermore, dehy-
dration of aldoximes occurs at higher temperatures to give
nitriles.[19] Next, we examined organocatalysts. Attempts
using typical catalysts such as flavin,[4] 2,2,6,6-tetramethylpi-
peridine-N-oxyl (TEMPO),[20] and phthalimide-N-oxyl
(PINO) derived from N-hydroxyphthalimide (NHPI)[21]
failed. We then focused on DPPH, which had never been
used for catalytic oxidation. Ultimately, the combination of
DPPH and WO3/Al2O3 proved to be an excellent catalyst.
The catalytic activity of various catalysts for the aerobic
oxidation of cyclohexylamine is summarized in Table 1.
Among the catalysts examined, the system of DPPH and
WO3/Al2O3 proved to be the best catalyst (Table 1, entry 1).
The reaction of cyclohexylamine in the presence of DPPH
(2.5 mol%) and WO3/Al2O3 (1 mol%) under molecular
oxygen diluted with molecular nitrogen for safety (O2/N2 =
7:93 v/v, 5 MPa, under the explosion limit) in acetonitrile at
808C for 4h gave cyclohexanone oxime with 95% selectivity
Aerobic oxidation under mild conditions is one of the
current challenges in view of environmental and economical
aspects;[13,14] however, aerobic oxidative transformations of
amines are limited to a few reactions, which include the
ruthenium-catalyzed oxidative cyanation of tertiary
amines,[15] transition-metal-catalyzed oxidation of secondary
amines to imines[6] and of primary amines to nitriles,[16] and
flavin-catalyzed oxidation of secondary amines to nitrones.[4]
There is no efficient method so far for the aerobic oxidation of
primary amines to oximes. The reported method employing a
heterogeneous catalyst such as SiO2 gel at higher temperature
(> 1508C) gives oximes only in low yields.[17] Herein, we
report a highly selective and efficient catalytic method for the
oxidation of primary amines to oximes by employing 1,1-
diphenyl-2-picrylhydrazyl (DPPH; 3)[18] and tungstated alu-
mina (WO3/Al2O3) as the catalyst and molecular oxygen as
the terminal oxidant [Eq. (1)].
Table 1: The aerobic oxidation of cyclohexylamine to cyclohexanone
oximes using various catalysts.[a]
Entry
Catalyst
Conversion of
amine [%][b]
Selectivity for
oxime [%][b]
We sought to find a catalyst for the aerobic catalytic
oxidation of cyclohexylamine. Attempts at transition-metal-
catalyzed oxidation of amines to oximes failed. Aerobic
catalytic oxidation of primary amines with transition-metal
1
2
3
DPPH–WO3/Al2O3
DPPH
WO3/Al2O3
59
21
7
95
3
0
4
5
6
7
8
9
10
11
12
13[c]
14[d]
DPPH–WO3/ZrO2
DPPH–TS-1
DPPH–[Ti(OiPr)4]
DPPH–[TiO(acac)2]
DPPH–Nb2O5
DPPH-H–WO3/Al2O3
DOPH–WO3/Al2O3
TEMPO–WO3/Al2O3
NHPI–WO3/Al2O3
TEMPO–[RuCl2(PPh3)3]
NHPI–[Co(acac)2]
63
14
67
61
50
41
62
4
86
93
88
89
80
96
96
2
[*] Prof. Dr. S.-I. Murahashi
Department of Applied Chemistry
Okayama University of Science
1-1, Ridai-cho, Okayama 700-0005 (Japan)
Fax : (+81)86-256-4292
E-mail: murahashi@high.ous.ac.jp
K. Suzuki, T. Watanabe
7
21
36
3
0
0
Chemical Technology Laboratory
Asahi Kasei Chemicals Corporation
2767-11, Niihama Shionasu Kojima
Kurashiki, Okayama 711-8510 (Japan)
Fax : (+81)86-458-3335
[a] Reaction conditions: Cyclohexylamine (5 mmol), organocatalyst
(2.5 mol%), transition-metal catalyst (metal: 1 mol%) in acetonitrile
(3 mL), O2 (O2/N2 =7:93; 5 MPa) at 808C for 4 h. [b] Determined by GC
analysis using an internal standard. [c] 3 mol% TEMPO, 1 mol%
[RuCl2(PPh3)3]. [d] 10 mol% NHPI, 0.5 mol% [Co(acac)2]. acac=acetyl-
acetonate.
E-mail: suzuki.kd@om.asahi-kasei.co.jp
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author. DPPH=1,1-
diphenyl-2-picrylhydrazyl.
Angew. Chem. Int. Ed. 2008, 47, 2079 –2081
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2079

Communications
Table 2: Aerobic oxidation of primary amines to oximes catalyzed by
and 59% conversion. Control experiments showed that
DPPH–WO3/Al2O3.[a]
DPPH and WO3/Al2O3 alone exhibited no catalytic activity,
and the coexistence of DPPH and WO3/Al2O3 is necessary for
the high catalytic activity (Table 1, entries 2 and 3). WO3/
ZrO2, TS-1, [Ti(OiPr)4], [TiO(acac)2], and Nb2O5 can be used
as the cocatalyst of DPPH (Table 1, entries 4–8), while MoO3/
Al2O3, [MoO2(acac)2], [VO(acac)2], [Fe(acac)3], and [Co-
(acac)2] are ineffective. The use of 1,1-diphenyl-2-picrylhy-
drazine (DPPH-H) or 1,1-di(4-tert-octylphenyl)-2-picrylhy-
drazyl (DOPH) instead of DPPH gave good results (Table 1,
entries 9 and 10), while N-oxyl radicals[20a] such as TEMPO
and PINO showed very low catalytic activity (Table 1,
entries 11 and 12). Catalysts which show excellent activity
for aerobic oxidation of alcohols or hydrocarbons, such as
TEMPO with [RuCl2(PPh3)3][20] or NHPI with [Co(acac)2],[21]
are inactive (Table 1, entries 13 and 14).
Entry
Substrate
t
[h]
Conversion
[%][b]
Yield of
oxime [%][b]
1
8
98
90 (85)[c]
2
3
4
16
8
98
97
96
89[d]
82
48
73
5
48
95
80
6
7
8
48
8
90
97
97
72
85
82
The choice of a solvent is also important. The reaction in a
polar aprotic solvent such as acetonitrile or N,N-dimethylfor-
mamide gave a high conversion, while the reaction in a
nonpolar solvent such as toluene or chlorobenzene gave a low
conversion. Use of a protic solvent such as water, methanol,
or tert-butanol resulted in low conversions.
48
9
36
48
94
95
73[e]
75[e]
10
The results of the oxidation of various primary amines
catalyzed by DPPH (5 mol%) and WO3/Al2O3 (1 mol%) in
acetonitrile under O2/N2 (7:93 v/v, 5 MPa) at 808C for 8 h are
summarized in Table 2. The oxidation of cyclohexylamine
gave cyclohexanone oxime (90%) along with nitrocyclohex-
ane (4%) and cyclohexanone (2%; Table 2, entry 1). From a
gram-scale reaction cyclohexanone oxime was obtained in
85% yield of isolated product. No decomposition of DPPH
was observed under the reaction conditions. The WO3/Al2O3
catalyst was separated by filtration, after which tungsten was
not observed in the filtrate by ICP analyses. The oxidation
proceeded efficiently under atmospheric pressure of molec-
ular oxygen (1 atm, balloon; Table 2, entry 2), whereas the
reaction did not occur in the absence of molecular oxygen. A
manometric measurement of oxygen uptake revealed that an
equimolar amount of molecular oxygen was consumed for the
oxidation of the amine. The cyclohexanone oxime thus
obtained is an important precursor of e-caprolactam, a raw
material of nylon 6. Alicyclic amines can be converted into
the corresponding oximes in excellent yields (Table 2,
entries 3–7). The aerobic oxidation of aliphatic amines also
gave the corresponding oximes in good yields. Typically, the
oxidation of octylamine gave the corresponding oxime (73%)
and nitrile (7%; Table 2, entry 9). The reaction can tolerate
other oxidizable groups and seems to be quite selective for
amines. Thus, the oxidation of 4-hydroxylcyclohexylamine
proceeded chemoselectively to afford the corresponding
oxime in 82% yield (Table 2, entry 8). Chemoselective
oxidation of 5-hydroxylpentylamine was also observed
(Table 2, entry 10). The reaction of tertiary amines such as
tert-butylamine did not occur.
[a] Reaction conditions: primary amine (5 mmol), DPPH (5 mol%),
WO3/Al2O3 (W: 1 mol%) in acetonitrile (3 mL), O2 (O2/N2 =7:93;
5 MPa) at 808C. [b] Determined by GC analysis using an internal
standard. [c] The yield of isolated product obtained from a gram-scale
reaction is in parentheses. [d] O2 atmosphere (1 atm, balloon) at 808C.
[e] 10 mol% DPPH.
Table 3: Recycling of the catalyst DPPH–WO3/Al2O3 for the aerobic
oxidation of cyclohexylamine.[a]
Cycle
Conversion [%][b]
Yield of oxime [%][b]
1
2
3
98
97
99
90
91
90
[a] Reaction conditions: cyclohexylamine (5 mmol), DPPH (5 mol%),
WO3/Al2O3 (W: 1 mol%) in acetonitrile (3 mL) under O2/N2 (7:93;
5MPa) at 808C for 8 h. Recycling of the catalyst: after the reaction, WO3/
Al2O3 could be easily separated from the reaction mixture by filtration,
and the isolated WO3/Al2O3 was reused. Kugelrohr distillation (1008C,
30 mmHg) gave cyclohhexanone, acetonitrile, and the residue of DPPH,
which was reused. [b] Determined by GC analysis using an internal
standard.
primary amine 1 to DPPH occurs to give a complex of
aminium cation radical 4 and DPPH anion 5.[22] Fast electron
transfer from amine to DPPH was observed by UV spectra
obtained in nitrogen atmosphere. The aminium cation radical
4 thus formed undergoes deprotonation to give DPPH-H (7)
and a-aminoalkyl radical 6. The latter undergoes reaction
with molecular oxygen to afford the a-aminoalkylperoxyl
radical 8, which undergoes abstraction of hydrogen from 7 to
give a-aminoalkylhydroperoxide 9 and DPPH (3) to com-
plete the catalytic cycle. The high efficiency of DPPH in
comparison with other typical radical catalysts such as
TEMPO and PINO is probably due to the fast electron
transfer from DPPH to amines. It is unlikely that radical 6 is
formed by direct hydrogen abstraction of DPPH from amine
1.
Importantly, the DPPH–WO3/Al2O3 catalyst could be
reused without loss of catalytic activity or selectivity. The
yield of cyclohexanone oxime could be kept at a similar value
through three cycles of catalyst recycling (Table 3).
The reaction can be rationalized by assuming the mech-
anism shown in Scheme 1. Initially, fast electron transfer from
2080 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 2079 –2081

Angewandte
Chemie
[6] a) S.-I. Murahashi, Y. Okano, H. Sato, T. Nakae, N. Komiya,
Synlett 2007, 1675 – 1778; b) J. S. M. Samec, A. H. Ell, J. E.
Bäckvall, Chem. Eur. J. 2005, 11, 2327 – 2334; c) Y. Maeda, T.
Nishimura, S. Uemura, Bull. Chem. Soc. Jpn. 2003, 76, 2399 –
2403.
[7] G. M. Robertoson, Comprehensive Functional Group Trans-
formation, Vol. 3 (Ed.: A. R. Katritzky, O. Meth-Cohn, C. W.
Rees), Elsevier, Oxford, 1995, pp. 425 – 441.
[8] Sodium salt of tungstic acids: K. Kahr, Angew. Chem. 1960, 72,
135 – 137.
[9] Peroxo tungstophosphate: S. Sakaue, Y. Sakata, Y. Nishiyama, Y.
Ishii, Chem. Lett. 1992, 289 – 291.
[10] [Mo(O)(O2)(H2O)(hmpa)]
(hmpa = hexamethylphosphor-
amide): a) S. Tollari, S. Bruni, C. Bianchi, L. M. Rainoni, F.
Porta, J. Mol. Catal. 1993, 83, 311 – 322; b) J. S. Reddy, A. Sayari,
Appl. Catal. A 1995, 128, 231 – 242.
Scheme 1. Proposed mechanism for the DPPH–WO3/Al2O3-catalyzed
aerobic oxidation of primary amines to oximes. Pic=picryl.
[11] Titanium silicate: P. A. Jacob , J. S. Reddy, J. Chem. Soc. Perkin
Trans. 1 1993, 2665 – 2666.
[12] Methyltrioxorhenium (MTO): S. Yamazaki, Bull. Chem. Soc.
Jpn. 1997, 70, 877 – 883.
[13] a) R. A. Sheldon, Pure Appl. Chem. 2000, 72, 1233 – 1246;
b) B. A. Trost, Acc. Chem. Res. 2002, 35, 695 – 700; c) P. T.
Anastas, M. M. Kilchhoff, Acc. Chem. Res. 2002, 35, 686 – 694.
[14] Recent reviews: a) R. A. Sheldon, I. W. C. E. Arends, G. J.
ten Brink, A. Dijksman, Acc. Chem. Res. 2002, 35, 774– 779;
b) T. Punniyamurthy, S. Velusamy, J. Iqubal, Chem. Rev. 2005,
105, 2329; c) C. H. Hill, Angew. Chem. 2004, 116, 406 – 408;
Angew. Chem. Int. Ed. 2004, 43, 402 – 404; d) Y. Ishii, S. Sakaguti,
Catal. Today 2006, 117, 105 – 113; e) S. S. Stahl, Angew. Chem.
2004, 116, 3480 – 3501; Angew. Chem. Int. Ed. 2004, 43, 3400 –
3420; f) I. E. Marko, P. R. Giles, M. Tsukazaki, A. Gautier, R.
Duneunier, K. Doda, F. Philippart, I. Chelle-Regnault, J.-L.
Mutonkole, S. M. Brown, C. J. Urch in Transition Metals for
Organic Synthesis, Vol. 2, 2nd ed. (Eds.: M. Beller, C. Bolm),
Wiley-VCH, Weinheim, 2004, pp. 437 – 478; g) M. J. Schultz,
M. S. Sigman, Tetrahedron 2006, 62, 8227 – 8241.
[15] S.-I. Murahashi, N. Komiya, H. Terai, T. Nakae, J. Am. Chem.
Soc. 2003, 125, 15321 – 15323, and references therein.
[16] a) K. Yamaguchi, N. Mizuno, Angew. Chem. 2003, 115, 1518 –
1521; Angew. Chem. Int. Ed. 2003, 42, 1480 – 1483; b) K. Mori, K.
Yamaguchi, T. Mizugaki, K. Ebitani, K. Kaneda, Chem.
Commun. 2001, 461 – 462; c) R. Tang, S. E. Diamond, N.
Neary, F. Mares, J. Chem. Soc. Chem. Commun. 1978, 562 – 563.
[17] a) J. N. Armor, E. J. Carlson, R. Riggitano, J. Yamanis, P. M.
Zambri, J. Catal. 1983, 83, 487 – 490; b) A. Kaszonyi, Z.
Cvengrosoova, M. Hronec, J. Mol. Catal. A 2000, 160, 393 – 402.
[18] DPPH (3) is commercially available.
[19] K. Yamaguchi, H. Fujiwara, Y. Ogasawara, M. Kotani, N.
Mizuno, Angew. Chem. 2007, 119, 3996 – 3999; Angew. Chem.
Int. Ed. 2007, 46, 3922 – 3925.
[20] a) R. A. Sheldon, I. W. C. E. Arends, Adv. Synth. Catal. 2004,
346, 1051 – 1069; b) R. A. Sheldon, I. W. C. E. Arends, J. Mol.
Catal. A 2006, 251, 200 – 214; c) A. Dijksman, A. Marino-
Gonzales, A. M. Pageras, I. W. C. E. Arends, R. A. Sheldon, J.
Am. Chem. Soc. 2001, 123, 6826 – 6833.
[21] a) Y. Ishii, S. Sakaguchi, T. Iwahama, Adv. Synth. Catal. 2001,
343, 220, and references therein; b) Y. Ishii, T. Iwahama, S.
Sakaguchi, K. Nagayama, Y. Nishiyama, J. Org. Chem. 1996, 61,
4520 – 4526.
[22] a) J. C. McGowan, T. Powell, R. Raw, J. Chem. Soc. 1959, 3103 –
3110; b) G. S. Hammond, C. E. Boozer, C. E. Hamilton, J. N.
Sen, J. Am. Chem. Soc. 1955, 77, 3238 – 3244.
The alkylhydroperoxide 9 thus formed is converted into
the oxime 2 by reaction with the WO3/Al2O3 catalyst. Indeed,
when 1-hydroperoxycyclohexylamine, which was prepared
from cyclohexanone, NH3, and H2O2,[23] was allowed to react
with the WO3/Al2O3 catalyst at room temperature, cyclo-
hexanone oxime was obtained in 75% yield. It is noteworthy
that the same reaction in the absence of WO3/Al2O3 catalyst
gave cyclohexanone in 90% yield.
In conclusion, we have found that a novel, efficient,
aerobic oxidative transformation of primary amines with
DPPH–WO3/Al2O3 catalyst affords oximes under mild con-
ditions. We are currently working on the reaction mechanism
and on the extension of this catalytic system to the other
oxidation reactions.
Received: October 29, 2007
Published online: February 5, 2008
Keywords: amines · heterogeneous catalysis · oxidation ·
.
oximes · radical reactions
[1] a) P. R. Ortiz de Montellano, Cytochrome P450: Structure,
Mechanism, and Biochemistry, Plenum, New York, 1995;
b) R. B. Silverman, Acc. Chem. Res. 1995, 28, 335 – 342.
[2] a) S.-I. Murahashi, Angew. Chem. 1995, 107, 2670 – 2693; Angew.
Chem. Int. Ed. Engl. 1995, 34, 2443 – 2246; b) S.-I. Murahashi, N.
Komiya in Biomimetic Oxidations Catalyzed by Transition Metal
Complexes (Ed.: B. Meunier), Imperial College Press, London,
2000, pp. 563 – 613; c) S.-I. Murahashi, Y. Imada in Transition
Metals for Organic Synthesis, Vol. 2, 2nd ed. (Eds.: M. Beller, C.
Bolm), Wiley-VCH, Weinheim, 2004, pp. 497 – 507.
[3] S.-I. Murahashi, H. Mitsui, T. Siota, T. Tsuda, S. Watanabe, J.
Org. Chem. 1990, 55, 1736 – 1744, and references therein.
[4] Y. Imada, H. Iida, S. Ono, S.-I. Murahashi, J. Am. Chem. Soc.
2003, 125, 2868 – 2869.
[5] a) S.-I. Murahashi, T. Naota, H. Taki, J. Chem. Soc. Chem.
Commun. 1985, 613 – 614; b) H. Choi, M. P. Doyle, Chem.
Commun. 2007, 745 – 747; c) A. Goti, M. Romani, Tetrahedron
Lett. 1994, 35, 6567 – 6570.
[23] E. G. E. Hawkins, J. Chem. Soc. C 1969, 2663 – 2670.
Angew. Chem. Int. Ed. 2008, 47, 2079 –2081
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2081