Tempo-mediated oxidation of primary alcohols to carboxylic acids by exploitation of ethers inan aqueous-organicbiphase system

Article abstract of DOI:10.1246/bcsj.82.1000

Expeditious and benign methods for primary alcohol- carboxylicacid conversions with TEMPO were developed in abiphasic system composed of aslightlymiscible ether (THP) and aqueous layer. Easily available co-oxidants such as Py-HBr₃, Bu₄NBr₃, and electrooxidation were successfully applied to generate N-oxoammonium species as a recyclable catalyst.

Full text of DOI:10.1246/bcsj.82.1000

1000 Bull. Chem. Soc. Jpn. Vol. 82, No. 8, 1000–1002 (2009)
Short Articles
5
Py·HBr3
OH
TEMPO-Mediated Oxidation of
Primary Alcohols to Carboxylic
Acids by Exploitation of Ethers in an
Aqueous-Organic Biphase System
CHO
CO2H
+
THP-
NaHCO3
1a
3a
2a
+
OBz
CO2
4a
N
O
5
Zhen-Wu Mei,1 Li-Jian Ma,1 Hiroyuki Kawafuchi,3
Takumi Okihara,2 and Tsutomu Inokuchi*1
Scheme 1. Catalytic oxidation of primary alcohols with a
combination of 4-BzOTEMPO (5) and Py¢HBr3.
1Department of Medical and Bioengineering Science,
Graduate School of Natural Science and Technology,
Okayama University, Tsushima-naka, Okayama 700-8530
the electron-withdrawing benzoyloxy group at the C4 position.7
As the first step, we examined the oxidation of 1a with a
combination of 5 (5 mol %) and a co-oxidant in THP-aqueous
saturated NaHCO3 (1:1 v/v) containing a quaternary ammo-
nium salt such as BenzylEt3NCl and acetylcholine chloride as a
phase-transfer catalyst (PTC) (Scheme 1). Thus, the addition of
Py¢HBr3 (3 equiv) as a co-oxidant to the reaction media
afforded the corresponding carboxylic acid 3a in 91% yield and
formation of dimeric ester 4a was negligible (ca. 1%). The
presence of quaternary ammonium salts in the two-phase
system was not crucial in comparison with a run without these
reagents, since pyridinium salts in this reaction media could
participate as a PTC.4d
2Department of Material Chemistry, Graduate School
of Natural Science and Technology, Okayama University,
Tsushima-naka, Okayama 700-8530
3Department of Chemical and Biochemical Engineering,
Toyama National College of Technology,
Hongo-machi, Toyama 939-8630
Received March 2, 2009; E-mail: inokuchi@cc.okayama-u.
ac.jp
Subsequently, we surveyed suitable ethereal solvents in
addition to THP for the two-phase system, and the following
results were obtained in the oxidation of 1a to 3a: cyclopentyl
methyl ether (CPME) (80%), tetrahydrofuran (THF) (80%),
diisopropyl ether (67%), methyl tert-butyl ether (89%), and
CH2Cl2 (77%). It appears that solvents slightly miscible in
water are useful as an organic layer.8 However, among these
solvents, THP should be the best in terms of high yield, easy
handling, and recoverability. Furthermore, Yasuda, Ryu, et al.
have recently demonstrated the excellent stability of THP
toward hydrogen abstraction from the oxygen-substituted
carbon, as compared with THF, as a result of their study on
tributyltin hydride-mediated radical cyclization.9 This finding
favors the use of THP since it is less likely to form peroxide
with oxygen during TEMPO oxidation.
Expeditious and benign methods for primary alcohol-
carboxylic acid conversions with TEMPO were developed in
a biphasic system composed of a slightly miscible ether
(THP) and aqueous layer. Easily available co-oxidants such
as Py¢HBr3, Bu4NBr3, and electrooxidation were success-
fully applied to generate N-oxoammonium species as a
recyclable catalyst.
Oxidation of alcohols to the corresponding carboxylic acids
is a fundamental operation in organic chemistry.1,2 TEMPO
oxidations, achieved in a catalytic manner in coordination with
stoichiometric amount of co-oxidants, have been recognized to
be inherently benign and useful for selective transformations of
alcohols.3 Conventionally, TEMPO oxidations are executed in
an aqueous-organic two-phase system and moderately or
highly water-miscible solvents such as CH2Cl2 and acetonitrile
are often employed.4 Inspired by recent development in
devising environmentally friendly procedures,5 we further
examined the improvement of TEMPO oxidation by tuning
the reaction media to replace harmful solvents and by changing
the co-oxidant. Thus, ethereal solvents like tetrahydropyran
(THP)6 were employed as the organic layer of a two-phase
system for the exhaustive conversion of primary alcohols to
carboxylic acids. In this respect, easy recoverability after
reaction and stability toward air-oxidation of the ethereal
solvent should be a criteria for practical application.
Subsequently, we searched for a favorable co-oxidant for the
conversion of 1a to 3a in a two-phase system comprised of
THP-aqueous NaHCO3. As shown in Table 1, Entries 3-5, it
turns out that bromine salts such as Py¢HBr3,7 Bu4NBr3,10 and
electrolysis with bromide ion11 are the appropriate choice of co-
oxidizing reagent because of high yield and high catalytic
10
performance. The runs employing NaOCl4e and Ca(OCl)2 in
combination with KBr were less effective than those with the
above bromine compounds (Entries 1 and 2).
This reaction can be performed on a scale of 15 mmol of 1a
in THP (120 mL)-aqueous NaHCO3 (120 mL) in the presence
of PTC at room temperature for 5 h, giving 3a in 91% yield, in
which 83% of THP used for the reaction media and workup
solvent was recovered on a rotary evaporator after separation of
the aqueous layer.
Results and Discussion
We employed 4-benzoyloxy-2,2,6,6-tetramethylpiperidine
1-oxyl (4-BzOTEMPO, 5) for the recyclable catalyst from
various TEMPO derivatives because 5 is slightly activated by
As shown in Table 2, the present method can readily be
applied not only to aliphatic primary alcohols 1 including
Published on the web August 7, 2009; doi:10.1246/bcsj.82.1000

Z.-W. Mei et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 8 (2009) 1001
biomass,12 leads selectively to 5-formyl-2-furancarboxylic acid
(3h),13,14 useful as a precursor of 2,5-furandicarboxylic acids.
Carbohydrate derivatives 1i and 1j with primary hydroxy
groups are easily oxidized to the corresponding uronic acids 3i
and 3j in good yields (Entries 8 and 9).
Table 1. Search for Co-Oxidant in TEMPO-Mediated
Oxidation of 1a to 3aa)
4-BzOTEMPO 5-
Co-oxidant
+
1a
2a
3a
Product/%b)
In summary, we developed an efficient primary alcohol-
carboxylic acid conversion by employing TEMPO oxidation in
ethereal solvent such as THP-aqueous layer, in which bromine
complexes such as Py¢HBr3 and electrooxidation with bromide
ion were useful as co-oxidants. The method could easily be
applied to various primary alcohols including aromatic,
aliphatic, and carbohydrate derivatives, some of which are of
significant synthetic value.
Entry
Co-oxidant (equiv)
3a
2a
1
2
3
4
5
NaOCl (6)
Ca(OCl)2 (4.5)
Py¢HBr3 (3)
Bu4NBr3 (3)
Electrolysis (10 F)c)
33
59
87
72
84
48
23
®
trace
trace
a) Carried out with 5 and co-oxidant in THP (8 mL)-sat.
NaHCO3 (8 mL) in the presence of PTC. b) Based on the
isolated products. c) Electricity passed.
Experimental
A Typical Procedure for Oxidation of Primary Alcohols to
the Carboxylic Acid. To a two phase mixture of THP (8 mL) and
aqueous saturated NaHCO3 (8 mL) containing PhCH(Me)CH2OH
(1a, 137 mg, 1 mmol), 4-BzOTEMPO (5, 28 mg, 0.1 mmol), and
PTC (acetylcholine chloride, 0.1 mmol) was added Py¢HBr3 (3.0
mmol) in portions under vigorous stirring at room temperature. The
mixture was stirred for an additional 120 min with TLC monitoring,
and quenched with aqueous 5% Na2S2O3. The mixture was
acidified with aqueous tartaric acid and extracted with EtOAc.
The usual workup followed by purification of the residue by
column chromatography (SiO2, hexane-EtOAc) gave 131 mg
(87% yield) of the carboxylic acid 3a and dimeric ester 4a (trace
amount).
Table 2. Oxidation of Primary Alcohols with a Combination
of 4-BzOTEMPO (5) and Py¢HBr3
a)
5-Py·HBr3
THP-NaHCO3
O
R
OH
R
OH
1
3
Yield
/%b)
Entry
Alcohol 1
Product 3
C10H21
C10H21 CO2H
CO2H
1
2
b
c
70
74
OH
OH
AcO
AcO
Large scale operation and the recoverability of THP: To a two
phase mixture of THP (120 mL) and aqueous saturated NaHCO3
(120 mL) containing 1a (2.04 g, 15 mmol), 5 (415 mg, 1.5 mmol),
and PTC (acetylcholine chloride, 1.5 mmol) was added Py¢HBr3
(45 mmol) in portions under vigorous stirring at room temperature.
The mixture was stirred for an additional 5 h with TLC monitoring.
The mixture was worked up in the manner described above by
using THP (170 mL) as an extractive solvent. The extract was
separated on a rotary evaporator for the recovery of THP (240 mL)
and the crude material was purified by column chromatography
(SiO2, hexane-EtOAc) to give 2.07 g (91% yield) of the carboxylic
acid 3a.
CO2H
OH
OH
3
d
e
92
92
4c)
CO2H
Ac
Ac
CO2H
OH
5
f
82
O
O
87c)
85
O
O
OH
6
7
g
MeO
O
MeO
O
CO2H
OHC
h
OHC
O
O
O
CO2H
OH
A Typical Procedure for Electrochemical Oxidation of
Primary Alcohols to the Carboxylic Acid. Two platinum foils
were immersed to the lower layer of a two phase mixture
comprised of THP (8 mL) and aqueous saturated NaHCO3 (8 mL)-
25% NaBr solution which contained 1a (128 mg, 1 mmol), 5
(28 mg, 0.1 mmol), and PTC (acetylcholine chloride, 0.1 mmol).
The mixture was electrolyzed under a constant current of
HO2C
HO
O
O
8
9
i
97
97
O
OMe
OMe
O
O
HO
HO2C
O
O
¹2
O
O
20 mA cm (applied voltage: 1.5-2.5 V) with a moderate stirring.
j
O
O
O
The electrolysis was continued until the starting material was
consumed. It required about 10 F mol¹1 of electricity. The mixture
was worked up in the manner described to give 84% of 3a after
column chromatography.
Spectral data and physical properties of selected products in
Table 2 are included here.
O
O
O
a) Carried out by the reaction of 1 (1 mmol) with 5 (5-
10 mol %) and Py¢HBr3 (2.5-3.5 equiv) at room temperature.
b) Based on isolated products after column chromatography.
c) Yield based on the crude product.
2-Phenylpropanoic Acid (3a):
Yield 92%; Rf = 0.59
(hexane-EtOAc 1:1); IR (neat): 3088, 2982, 1705, 1601, 1497,
¹1
acyclic (Entries 1, 2, and 6) and cyclic structures (Entry 5), but
also to aromatic (Entries 3 and 4) and hetero aromatic alcohols
(Entry 7), producing the corresponding carboxylic acids 3
respectively. The oxidation of 5-(hydroxymethyl)-2-furalde-
hyde (HMF, 1h), a value-added chemical available from
1454, 1414, 1263, 1233, 1064, 939, 860, 760, 727, 698 cm
;
1H NMR (300 MHz): ¤ 1.52 (d, J = 7.1 Hz, 3H), 3.74 (q, J =
7.1 Hz, 1H), 7.25-7.34 (m, 5H); 13C NMR (75.5 MHz): ¤ 18.0,
45.4, 127.3, 127.6 (2C), 128.6 (2C), 139.8, 180.8.
7-Acetoxy-3-methyloctanoic Acid (3c): Yield 74%; Rf = 0.35

1002 Bull. Chem. Soc. Jpn. Vol. 82, No. 8 (2009)
© 2009 The Chemical Society of Japan
(hexane-EtOAc 1:1); IR (neat): 2938, 2874, 1736, 1707, 1458,
1375, 1246, 1130, 1032, 949 cm¹1; 1H NMR (600 MHz): ¤ 0.96 (d,
J = 6.6 Hz, 3H), 1.20 (d, J = 6.6 Hz, 3H), 1.20-1.40 (m, 4H), 1.46
(m, 1H), 1.56 (m, 1H), 1.95 (m, 1H), 2.03 (s, 3H), 2.16 (ddd,
J = 15.1, 8.1, 2.4 Hz, 1H), 2.33 (ddd, J = 15.1, 6.1, 3.2 Hz, 1H),
4.88 (m, 1H); 13C NMR (75.5 MHz): ¤ 19.48 + 19.51, 19.8, 19.9,
21.3, 22.6, 35.8, 36.20 + 36.22, 41.39 + 41.45, 70.84 + 70.87,
170.9, 179.2. HRMS (ESI) calcd for C11H21O4 (MH+) 217.1440,
found 217.1436 (MH+).
Supporting Information
Spectral data including IR, H NMR, and 13C NMR spectra of
3a-3j are provided. This material is available free of charge on the
web at http://www.csj.jp/journals/bcsj/.
1
References
1
G. Tojo, M. Fernández, Oxidation of Primary Alcohols to
Carboxylic Acids: A Guide to Current Common Practice, Springer,
New York, 2006.
2-(4-Acetylphenyl)propanoic Acid (3e): Yield 92%; Rf =
0.37 (hexane-EtOAc 1:1); IR (neat): 2970, 1709, 1680, 1605, 1456,
2
a) M. Cleij, A. Archelas, R. Furstoss, J. Org. Chem. 1999,
1420, 1358, 1329, 1271, 1246, 1188, 1119, 1082, 997, 961, 932,
64, 5029. b) J.-H. Xie, Z.-T. Zhou, W.-L. Kong, Q.-L. Zhou, J. Am.
Chem. Soc. 2007, 129, 1868. c) X. Li, B. List, Chem. Commun.
2007, 1739.
¹1
866, 851, 833, 764, 692 cm
;
1H NMR (300 MHz): ¤ 1.53 (d,
J = 7.1 Hz, 3H), 2.58 (s, 3H), 3.80 (q, J = 7.1 Hz, 1H), 7.41
(d, J = 8.2 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H); 13C NMR (75.5
MHz): ¤ 17.8, 26.4, 45.2, 127.8 (2C), 128.6 (2C), 135.9, 145.2,
179.0, 198.1.
3
TEMPO oxidation, reviews: a) T. Vogler, A. Studer,
Synthesis 2008, 1979. b) P. L. Bragd, H. van Bekkum, A. C.
Besemer, Top. Catal. 2004, 27, 49. c) W. Adam, C. R. Saha-Möller,
P. A. Ganeshpure, Chem. Rev. 2001, 101, 3499. d) T. Inokuchi, S.
Matsumoto, S. Torii, J. Synth. Org. Chem., Jpn. 1993, 51, 910.
3-Oxolanecarboxylic Acid (3f):
Yield 82%; Rf = 0.32
(hexane-EtOAc 1:1); IR (neat): 2982, 2884, 1736, 1710, 1417,
1211, 1188, 1065, 905 cm¹1; 1H NMR (300 MHz): ¤ 2.10-2.29 (m,
2H), 3.09-3.18 (m, 1H), 3.79-3.95 (m, 2H), 3.99 (d, J = 6.6 Hz,
2H); 13C NMR (75.5 MHz): ¤ 29.3, 43.4, 68.1, 69.4, 179.0.
4
In MeCN-aqueous system: a) M. Zhao, J. Li, E. Mano, Z.
Song, D. M. Tschaen, E. J. J. Grabowski, P. J. Reider, J. Org.
Chem. 1999, 64, 2564. b) P. Gancitano, R. Ciriminna, M. L. Testa,
A. Fidalgo, L. M. Ilharco, M. Pagliaro, Org. Biomol. Chem. 2005,
3, 2389. c) J. B. Epp, T. S. Widlanski, J. Org. Chem. 1999, 64,
293. In CH2Cl2-aqueous system: d) K. Kloth, M. Brünjes, E.
Kunst, T. Jöge, F. Gallier, A. Adibekian, A. Kirschning, Adv.
Synth. Catal. 2005, 347, 1423. e) P. L. Anelli, C. Biffi, F.
Montanari, S. Quici, J. Org. Chem. 1987, 52, 2559. In aqueous
system: f) T. Yoshida, M. Kuroboshi, J. Oshitani, K. Gotoh, H.
Tanaka, Synlett 2007, 2691.
3,6,9-Trioxadecanoic Acid (3g):
Yield 87%; Rf = 0.59
(hexane-EtOAc 5:1); IR (neat): 2928, 2891, 1717, 1452, 1356,
1316, 1277, 1248, 1200, 1177, 1113, 1072, 1026, 852, 718,
684 cm¹1; 1H NMR (300 MHz): ¤ 3.39 (s, 3H), 3.56-3.59 (m, 2H),
3.68-3.72 (m, 4H), 3.76-3.79 (m, 2H), 4.12 (s, 2H).
5-Formyl-2-furancarboxylic Acid (3h):
Yield 85%; IR
(KBr): 3144, 3107, 2930, 1674, 1568, 1518, 1435, 1397, 1346,
¹1
1294, 1260, 1221, 1165, 1043, 963, 849, 783 cm
;
1H NMR
(300 MHz in methanol-D4): ¤ 7.38 (d, J = 3.8 Hz, 1H), 7.50 (d,
J = 3.8 Hz, 1H), 9.79 (s, 1H); 13C NMR (75.5 MHz in methanol-
D4): ¤ 119.0, 121.1, 148.4, 154.4, 158.6, 179.3, 179.3.
5
Reviews: a) M. J. Schultz, M. S. Sigman, Tetrahedron
2006, 62, 8227. b) I. E. Marko, P. R. Giles, M. Tsukazaki, A.
Gautier, R. Dumeunier, K. Dodo, F. Philippart, I. Chelle-Regnault,
J.-L. Mutonkole, S. M. Brown, C. J. Urch, Transition Metals for
Organic Synthesis, 2nd ed., Wiley-VCH, Weinheim, 2004, Vol. 2,
p. 437.
1-O-Methyl-3,4-O-cyclohexylidene-¡-D-ribouronic Acid (3i):
31
Yield 97%; Rf = 0.4 (hexane-EtOAc 1:2); ½¡ꢀD ¹50.2° (c 0.9,
CHCl3); IR (neat): 2937, 2862, 2673, 1715, 1450, 1417, 1368,
1273, 1223, 1165, 1115, 1047, 949, 924, 853, 833, 800, 752,
673 cm¹1; 1H NMR (300 MHz): ¤ 1.39 (m, 2H), 1.55 (m, 4H), 1.61
(m, 2H), 1.70 (m, 2H), 3.43 (s, 3H), 4.57 (d, J = 5.2 Hz, 1H),
4.67 (brs, 1H), 5.08 (s, 1H), 5.17 (d, J = 5.7 Hz, 1H); 13C NMR
(75.5 MHz): ¤ 23.7, 23.9, 24.9, 34.4, 36.0, 55.6, 81.7, 83.62,
83.70, 109.6, 113.7, 175.1. HRMS (ESI) calcd for C12H19O6
(MH+) 259.1182, found 259.1151 (MH+).
6
Manufacturing preparation process of THP was recently
established: I. Yamagami, H. Yasuda, PCT Int. Appl. WO
2006062211, 2006; I. Yamagami, H. Yasuda, CAN 145:62784.
7
Z.-W. Mei, T. Omote, M. Mansour, H. Kawafuchi, Y.
Takaguchi, A. Jutand, S. Tsuboi, T. Inokuchi, Tetrahedron 2008,
64, 10761.
8
Solubility (wt %) of water to the solvent (of the solvent to
1,2:3,4-Di-O-isopropylidene-¡-D-galactopyranuronic Acid
(3j): Yield 97%; Rf = 0.2 (hexane-EtOAc 1:5); mp 149-150 °C
water): THP = 2.5 (8.1), CPME = 0.3 (1.1), MTBE = 1.5 (4.8),
THF = ¨ (¨) (Cited from technical reports of Showadenko Co.
and ZEON Corporation, Japan).
22
(from hexane-EtOAc) (lit.4d 152 °C); ½¡ꢀD ¹91.2° (c 1.4, CHCl3)
(Ref.4d ¹102.9°); 1H NMR (300 MHz): ¤ 1.35 (s, 6H), 1.45 (s,
3H), 1.53 (s, 3H), 4.40 (dd, J = 4.95, 2.5 Hz, 1H), 4.46 (d,
J = 2.2 Hz, 1H), 4.63 (dd, J = 7.7, 2.2 Hz, 1H), 4.69 (dd, J = 7.7,
2.5 Hz, 1H), 5.65 (d, J = 4.95 Hz, 1H).
9
H. Yasuda, Y. Uenoyama, O. Nobuta, S. Kobayashi, I. Ryu,
Tetrahedron Lett. 2008, 49, 367.
10 T. Inokuchi, S. Matsumoto, M. Fukushima, S. Torii, Bull.
Chem. Soc. Jpn. 1991, 64, 796.
11 a) T. Inokuchi, S. Matsumoto, S. Torii, J. Org. Chem. 1991,
56, 2416. b) T. Inokuchi, S. Matsumoto, T. Nishiyama, S. Torii,
J. Org. Chem. 1990, 55, 462.
12 a) J. N. Chheda, G. W. Huber, J. A. Dumesic, Angew.
Chem., Int. Ed. 2007, 46, 7164. b) J.-P. Lange, Biofuels, Bioprod.
Biorefin. 2007, 1, 39.
13 H. Takada, Jpn. Kokai Tokkyo Koho JP 03101672, 1991.
14 W. Partenheimer, V. V. Grushin, Adv. Synth. Catal. 2001,
343, 102.
This work was supported by the Electric Technology
Research Foundation of Chugoku, which is gratefully acknowl-
edged. We thank Wesco Scientific Promotion Foundation for
scholarship support. We are grateful to “SC-NMR laboratory of
Okayama University” for high-field NMR experiments, to
Professor Junzo Nokami, Okayama University of Science, for
HRMS analyses, and to Showadenko Co. for a generous gift of
THP.