Novel 2,2,6,6-tetramethylpiperidine 1-oxyl-iodobenzene hybrid catalyst for oxidation of primary alcohols to carboxylic acids

Article abstract of DOI:10.1002/adsc.201100024

Novel bifunctional hybrid-type catalysts bearing 2,2,6,6- tetramethylpiperidine-1-oxyl (TEMPO) and iodobenzene moieties (1a and 1b) were developed and used for the environmentally benign oxidation of primary alcohols to carboxylic acids. Reaction of primary alcohols 2 with a catalytic amount of 1 in the presence of peracetic acid as a co-oxidant under mild conditions gave the corresponding carboxylic acids 3 in excellent yields.

Full text of DOI:10.1002/adsc.201100024

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DOI: 10.1002/adsc.201100024
Novel 2,2,6,6-Tetramethylpiperidine 1-Oxyl–Iodobenzene Hybrid
Catalyst for Oxidation of Primary Alcohols to Carboxylic Acids
Takayuki Yakuraa,* and Ayaka Ozonoa
a
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
Fax : (+81)-76-434-7558; phone: (+81)-76-434-7558; e-mail: yakura@pha.u-toyama.ac.jp
Received: January 12, 2011; Published online: April 12, 2011
Abstract: Novel bifunctional hybrid-type catalysts
bearing 2,2,6,6-tetramethylpiperidine-1-oxyl
ACHTUNGTRENtNGNU ages, catalytic hypervalent iodine oxidations using
catalytic amounts of an iodobenzene derivative and a
co-oxidant have recently been developed and report-
ed by several researchers,[11] including our group.[12] In
2006 Li and co-workers reported an oxidation of the
primary alcohols to the aldehydes using catalytic
amounts of both TEMPO and PIDA without a sol-
vent.[13] However, reaction mixture had to be heated
to 808C or a higher temperature. These results en-
couraged us to develop an efficient double-redox
cycle system using both TEMPO and iodobenzene as
catalysts under mild conditions, and to apply this
system to a hybrid catalysis (Scheme 1). Hybridization
of these two moieties should render the oxidation
step of the TEMPO moiety by hypervalent iodine
more efficient because the reaction would change to
an intramolecular mode. Furthermore, it should make
(TEMPO) and iodobenzene moieties (1a and 1b)
were developed and used for the environmentally
benign oxidation of primary alcohols to carboxylic
acids. Reaction of primary alcohols 2 with a catalyt-
ic amount of 1 in the presence of peracetic acid as a
co-oxidant under mild conditions gave the corre-
sponding carboxylic acids 3 in excellent yields.
Keywords: carboxylic acids; hybrid catalysts; hyper-
valent iodine; oxidation; primary alcohols; 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO)
The oxidation of primary alcohols to the correspond- the recovery and reuse of the catalyst easier, because
ing carboxylic acids is one of the most important only one molecule of catalyst would be used. As a
transformations in synthetic organic chemistry.[1,2] En- part of our studies for the development of practical
vironmentally benign procedures are strongly re- and environmentally benign oxidation reactions,[12,14]
quired especially for the production of pharmaceuti- we report herein a direct oxidation of primary alco-
cals, flavours and fragrances, and agrochemicals.
2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO),
a
stable nitroxyl radical, and its derivatives in combina-
tion with a co-oxidant have received much attention;
furthermore, they have been used as environmentally
sensitive chemical reagents[3] to achieve this essential
transformation. Some successful methods have been
developed for the direct conversion to carboxylic
acids using TEMPO with some co-oxidants such as
NaOCl,[4]
NaOCl/NaClO2,[5]
(III) diacetate (PIDA),[7] and
trichloroisocyanuric
acid,[6] phenyliodine
AHCTUNGTRENNUNG
Py·HBr3.[8] A combination of TEMPO and a hyperva-
lent iodine compound[9,10] has been widely used for
the total syntheses of complex natural products be-
cause of the mild reaction conditions required and the
reactionꢀs chemoselectivity. However, hypervalent
iodine reagents are expensive; moreover, stoichiomet-
ric amounts of iodine reagents are necessary during
oxidation to produce equimolar amounts of organic
iodine waste. In addition, some of the reagents are
Scheme 1. Double catalyst system and hybridization of
potentially explosive. To overcome these disadvan- TEMPO and iodobenzene.
Adv. Synth. Catal. 2011, 353, 855 – 859
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855

Takayuki Yakura and Ayaka Ozono
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spectively, along with 29% of starting alcohol 2a after
24 h (entry 1). Next, the substituent effects on the
benzene ring of iodobenzene were examined (en-
tries 2–5). Electron-withdrawing groups such as car-
boxy and acyloxy groups decreased the catalytic activ-
ity (entries 2 and 3), whereas electron-donating
groups slightly increased the catalytic activity (en-
tries 4 and 5). p-Iodotoluene gave the best result
among all of them (entry 5). Using a fluoro alcohol
such as 2,2,2-trifluoroethanol as a co-solvent resulted
in a lower reactivity of the catalyst in contrast to
Kitaꢀs report[15] (entry 6). When a similar reaction
with 10 equiv. of PAA was performed, the reaction
was completed within 24 h to afford 3a in quantitative
Scheme 2.
hols to carboxylic acids using a novel bifunctionalized yield (entry 7). Using 0.5 equiv. of p-iodotoluene
TEMPO–iodobenzene hybrid catalyst 1 and peracetic shortened the reaction time to 5 h (entry 8). Reac-
acid (PAA) as a co-oxidant.
tions without TEMPO (entry 9) and without iodoar-
We chose PAA as a co-oxidant of the double redox ene (entry 10) gave only trace amounts of the oxi-
cycle system: PAA oxidizes iodoarenes to a hyperva- dized products. These results indicate that the two
lent species,[15] although the combination of PAA and catalysts work together in this catalytic oxidation.
TEMPO was not found to give satisfactory results for When the aldehyde 4a was reacted with only PAA,
the oxidation of alcohols.[5a] Also, PAA is known to the carboxylic acid 3a was obtained. This observation
be a safe and environmentally friendly oxidant that showed that PAA works as the main oxidant for the
releases non-toxic acetic acid as the co-product and is conversion of aldehyde into carboxylic acid.
commercially available in acetic acid solutions. We
After the double redox cycle system using catalytic
first investigated the double catalytic reaction of 4-ni- amounts of TEMPO and iodoarene had been ach-
trobenzyl alcohol (2a) as a substrate with a catalytic ieved, we next attempted to design and synthesize a
amount of TEMPO and several iodoarenes in a 9% novel bifunctionalized hybrid-type catalyst 1 that in-
acetic acid solution of PAA at 308C (Scheme 2). The corporates both TEMPO and p-substituted iodoben-
results are summarized in Table 1. When 2a was react- zene moieties (Scheme 3). Phthalic acid was chosen as
ed with 0.1 equiv. of TEMPO and 0.1 equiv. of iodo- a linking unit to reduce the distance between the two
benzene in the presence of 5 equiv. of PAA, the oxi- catalyst sites, which are required to react with each
dation proceeded slowly to give 4-nitrobenzoic acid other. Reaction of 4-hydroxy-TEMPO with phthalic
(3a) and the aldehyde 4a in 57% and 9% yields, re- anhydride in the presence of 4-N,N-dimethylamino-
pyridine (DMAP) gave mono ester 5 which was cou-
pled with 4-iodobenzyl alcohol by using N,N-dicyclo-
hexylcarbodiimide (DCC) to afford the diester 1a in
76% yield in two steps. Esterification of 5 with 4-io-
dophenol gave 1b in 70% yield in two steps. When 2a
was reacted with 0.1 equiv. of 1a in the presence of
Table 1. Oxidation of 2a using double catalyst system.[a]
[a]
Reactions were carried out with 0.1 equiv of TEMPO at
308C.
Isolated yields.
Recovery of unreacted starting alcohol 2a.
The reaction was carried out without TEMPO.
[b]
[c]
[d]
[e]
No attempt to recover 2a was made.
Scheme 3. Synthesis of hybrid catalysts 1a and 1b.
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Adv. Synth. Catal. 2011, 353, 855 – 859

Novel 2,2,6,6-Tetramethylpiperidine 1-Oxyl–Iodobenzene Hybrid Catalyst for Oxidation
Table 2. Catalytic oxidation of primary alcohols to carboxyl-
ic acids with 1.[a]
Scheme 4.
Table 3. Catalytic oxidation of secondary alcohols to ketones
with 1a.[a]
[a]
Reactions were carried out with 0.1 equiv. of 1a in the
presence of 10 equiv. of PAA (9% acetic acid solution)
at 308C.
0.3 equiv. of catalyst was used.
Figure in parenthesis is the yield of recovered 6c.
[b]
[c]
in good yields (entries 5–12). In all cases, the first oxi-
dation step was more rapid than the second step. Ali-
phatic primary alcohols were readily oxidized to give
the corresponding carboxylic acids in good yields (en-
tries 13–17). The catalyst 1b showed slightly lower re-
activity than that of 1a (entries 6, 14, and 17). Secon-
dary alcohols (6a–c) were also reacted with 1a under
the same conditions to afford the corresponding ke-
tones (Table 3). Benzylic secondary alcohols reacted
smoothly (entries 1 and 2); by contrast, an aliphatic
secondary alcohol reacted slowly even with 0.3 equiv.
[a]
Reactions were carried out with 0.1 equiv. of catalyst in
the presence of 10 equiv. of PAA (9% acetic acid solu-
tion) at 308C.
Figures in parentheses are the yields of aldehydes 4.
15 equiv. of PAA were used.
[b]
[c]
[d]
[e]
0.3 equiv. of catalyst was used.
After esterification with CH2N2.
10 equiv. of PAA at 308C for 24 h, almost the same of 1a (entry 3). The catalyst was recovered in 60–80%
result was observed as that using TEMPO and p-iodo- yield in all cases.
toluene giving carboxylic acid 3a in 99% yield. In this
A possible reaction mechanism is shown in
reaction, 1a was recovered in 70% yield (Table 2, Scheme 5. The oxoammonium cation A formed from
entry 1). By contrast, a similar reaction of 2a with 1 is most likely the active oxidant in this reaction.[17]
0.1 equiv. of 1b, that has the less reactive p-benz- Primary alcohol 2 is oxidized with A to produce B
ACHTUNGTRENNUNGoyloxy group on the iodobenzene moiety (see, and aldehyde 4, which would then be converted into
Table 1, entry 3),[16] showed an enhancement of the the carboxylic acid 3 by a Baeyer–Villiger-type reac-
catalytic activity to afford 3a in 94% yield along with tion with PAA. The iodoarene moiety of B is reacted
4% of aldehyde 4a after 24 h and 77% recovery of 1b with PAA to form the hypervalent iodine species C,
(Table 2, entry 2).
which should intramolecularly oxidize the hydroxyla-
Various primary alcohols (2b–l) were oxidized with mine moiety to A for reuse in the next oxidation. In
a catalytic amount of the unique catalyst 1 and PAA the case of a benzylic alcohol bearing an electron-do-
(Scheme 4). The results are summarized in Table 2. nating group, the Baeyer–Villiger-type reaction of the
When benzyl alcohol 2b and 4-methylbenzyl alcohol resulting aldehyde may be relatively slow leading to a
2c were reacted with 1a and PAA, both 2b and 2c longer reaction time.
were consumed within 10 h, but the second oxidation
In conclusion, we have designed and synthesized bi-
step from the aldehyde to the carboxylic acid required functional hybrid-type catalysts bearing two catalyst
a longer reaction time. The carboxylic acid 3b was ob- sites, TEMPO and iodobenzene moieties (1a and 1b).
tained in 59% yield along with 4b in 28% yield after These catalysts proved to be efficient for the environ-
24 h (entry 3), while the carboxylic acid 3c was ob- mentally benign oxidation of primary alcohols to car-
tained in 37% yield along with 4c in 55% yield after boxylic acids. Reaction of primary alcohols with a cat-
24 h (entry 4). The oxidation of other benzylic alco- alytic amount of 1 in the presence of peracetic acid as
hols gave the carboxylic acids as the major products a co-oxidant under mild conditions gave the corre-
Adv. Synth. Catal. 2011, 353, 855 – 859
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857

Takayuki Yakura and Ayaka Ozono
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trated. The residue was purified using silica gel column
chromatography to give pure 1b as orange crystals; yield:
182 mg (70%); mp 142–1448C (20% EtOAc in hexane); IR
(KBr): n=1746, 1738, 1597, 1581, 1480, 1393, 1378, 1281,
1273, 1261, 1197 cmÀ1; anal. calcd. for C23H25INO5: C 52.88,
N 2.68, H 4.82; found: C 52.75, N 3.16, H 4.68; HR-MS
(EI): m/z=522.0742, calcd. for C23H25INO5: 522.0778.
Typical Experimental Procedure for the Oxidation of
Primary Alcohols
In a typical experimental procedure for the oxidation of pri-
mary alcohols, to a solution of primary alcohol (0.5 mmol)
in a 9% acetic acid solution of PAA (4.232 g, 5 mmol), the
hybrid catalyst (0.05 mmol) was added at 308C and the re-
sulting mixture was stirred at the same temperature. The
mixture was diluted with ethyl acetate and extracted with
50% K2CO3 solution. The organic layer was then washed
with an aqueous saturated Na2S2O3 solution, dried, and con-
centrated to give the recovered catalyst which was purified
by recrystallization from ethyl acetate-hexane. The alkaline
solution was acidified by a 10% HCl solution and extracted
with ethyl acetate. The organic layer was dried and concen-
trated to give the pure carboxylic acid. In all cases, except
for the oxidation of 1-tetradecanol, the products were isolat-
ed directly in >98% purity as determined by 1H and
13C NMR without the need for further purification. The car-
boxylic acid products were compared spectroscopically with
their commercially available counterparts.
Scheme 5. Possible catalytic cycle.
sponding carboxylic acids in excellent yields with re-
covery of catalyst 1.
Experimental Section
Acknowledgements
Preparation of Compound 1a
The authors wish to thank Professor Yasuyuki Kita (Emeri-
tus, Osaka University, Ritsumeikan University, Japan) for
helpful discussions. The present work was partially supported
by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan.
To a solution of 4-hydroxy-TEMPO (517 mg, 3 mmol) in
pyridine (10 mL), phthalic anhydride (2.132 g, 15 mmol) and
DMAP (183 mg, 1.5 mmol) were added at room tempera-
ture. The mixture was stirred for 1 h and the reaction mix-
ture was then concentrated. The residue was passed through
a short pad of silica gel to give the crude mono ester 5,
which was used without further purification. The crude
mono ester 5 was added to a solution of 4-iodobenzyl alco-
hol (772 mg, 3.3 mmol), DMAP (73 mg, 0.6 mmol), cam-
phorsulfonic acid (CSA, 70 mg, 0.3 mmol), and DCC
(1.237 g, 6 mmol) in benzene (70 mL). The mixture was
stirred for 30 min and the reaction mixture was then concen-
trated. The residue was purified using silica gel column
chromatography to give pure 1a as orange crystals; yield:
1.216 g (76%); mp 127–1298C (20% EtOAc in hexane); IR
(KBr): n=1718, 1591, 1487, 1448, 1383, 1365, 1314, 1291,
1279 cmÀ1; anal. calcd. for C24H27INO5: C 53.74, N 2.61, H,
5.07; found: C 53.40, N 2.98, H 5.06; HR-MS (EI): m/z=
536.09520, calcd. for C24H27INO5: 536.09342.
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