Development of an efficient method for preparation of 1,3,5- trihydroxyisocyanuric acid (THICA) and its use as aerobic oxidation catalyst

Article abstract of DOI:10.1016/j.tetlet.2004.09.086

1,3,5-Trihydroxyisocyanuric acid (THICA), which serves as an efficient radical-producing catalyst from hydrocarbons, was successfully prepared by two methods. The reaction of O-benzylhydroxyamine with phenyl chloroformate gave formbenzyloxycarbamic acid phenyl ester of which subsequent treatment with dimethylaminopyridine (DMAP) produced 1,3,5-tribenzyloxyisocyanurate leading to THICA by hydrogenation with H₂ on Pd/C. The other method involved the direct synthesis of 1,3,5-tribenzyloxyisocyanurate from O-benzylhydroxyamine and diphenyl carbonate. The aerobic oxidation of p-methylanisole catalyzed using THICA as a key catalyst afforded p-anisic acid in almost quantitative yield (>99%).

Full text of DOI:10.1016/j.tetlet.2004.09.086

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8277–8280
Development of an efficient method for preparation of
1,3,5-trihydroxyisocyanuric acid (THICA) and its use as
aerobic oxidation catalyst
Naruhisa Hirai,a Takashi Kagayama,b Yoshinobu Tatsukawa,b
Satoshi Sakaguchib and Yasutaka Ishiib,*
aDaicel Chemical Industries, Ltd, Shinzaike, Aboshi-ku, Himeji, Hyogo 671-1283, Japan
bDepartment of Applied Chemistry, Faculty of Engineering, Kansai University, Suita, Osaka 564-8680, Japan
Received 2 August 2004; revised 11 September 2004; accepted 13 September 2004
Abstract—1,3,5-Trihydroxyisocyanuric acid (THICA), which serves as an efficient radical-producing catalyst from hydrocarbons,
was successfully prepared by two methods. The reaction of O-benzylhydroxyamine with phenyl chloroformate gave
formbenzyloxycarbamic acid phenyl ester of which subsequent treatment with dimethylaminopyridine (DMAP) produced 1,3,5-
tribenzyloxyisocyanurate leading to THICA by hydrogenation with H2 on Pd/C. The other method involved the direct synthesis
of 1,3,5-tribenzyloxyisocyanurate from O-benzylhydroxyamine and diphenyl carbonate. The aerobic oxidation of p-methylanisole
catalyzed using THICA as a key catalyst afforded p-anisic acid in almost quantitative yield (>99%).
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
O
RO
O
OR
O
N
N
N
N
RONH2
N
N
In the course of the attempts to prepare esters or salts of
hypothetical acid (HO–N@C@O), its trimer 1,3,5-tri-
hydroxyisocyanuric acid (THICA) is prepared. Thus,
THICA and its alkoxy derivatives, which are precur-
sors of THICA, are prepared by several methods.1–4
For example, 1,3,5-tribenzyloxyisocyanurate (4) was
synthesized by the reaction of O-benzylhydroxyamine
hydrochloride (1) with phosgene1 or 1.10-carbonyl-
diimidazole.2 Alkoxy 1,3,5-trimethoxyisocyanurates are
prepared by the reaction of diethyl N-ethoxyphosphor-
N
N
-BtH
N
COCl
CONHOR
OR
O
N
HO
O
OH
R: PhCH2
H2/Pd
N
N
N
BtH:
N
O
THICA
N
OH
H
3
Scheme 1. A conventional preparation of THICA.
amidate with CO2 and by the photolysis of methyl
azidoformate.4 However, these methods are insufficient
as practical methods in large-scale syntheses, since the
starting materials used are difficult to obtain from com-
mercial sources. Recently, Butula and Takac have
reported an alternative synthesis of THICA through
three steps using 1-benzotriazolecarboxylic acid as a
key compound as shown in Scheme 1.5
Quite recently, we have found that THICA serves as an
efficient catalyst for the aerobic oxidation of methylbenz-
enes substituted by electron-withdrawing substituents,
which are very difficult to be oxidized with O2 under
mild conditions.6 For instance, p-nitrotoluene was suc-
cessfully oxidized to p-nitrobenzoic acid (87%) under
atmosphere dioxygen in the presence of THICA
(5mol%), Co(OAc)2 (0.5mol%), and Mn(OAc)2
(0.05mol%) at 130°C. Thus, we are driven by necessity
to prepare THICA by
a simple method using
Keywords: Oxidation; Dioxygen; 1,3,5-Trihydroxyisocyanuric acid.
*
commercially available compounds as starting materi-
als. In this letter, we wish to report the development
Corresponding author. Tel.: +81 663680793; fax: +81 663394026;
e-mail: ishii@ipcku.kansai-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.086

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N. Hirai et al. / Tetrahedron Letters 45 (2004) 8277–8280
position of 3 during the reaction course. Imidazole was
H
N
pyridine
OPh
also effective to form 4 in moderate yield (Run 8). By the
treatment of a weak base like pyridine at 90°C, 3 was
not converted into 4. A strong base like t-BuOK did
not promote the conversion of 3 to 4. It seems that the
basicity of bases is important to obtain 4 from 3 in
satisfactory yield.
O
Cl
Ph
O
Ph
ONH HCl
+
Ph
2
CH3CN
0-2 ºC, 20 min
O
O
1
3
2
O
BnO
O
OBn
- PhOH
N
N
3
4
Ph
O N C O
DMAP, 120 ºC
N
O
O
On the basis of these results, the reaction was carried
out by the use of DMAP under several conditions
(Table 2).
OBn
4
HO
OH
N
N
Pd/C
H2
+
O
N
OH
O
THICA
The reaction by the use of 3 isolated gave almost the
same result as that by successive reaction (Run 1). Here-
after, the reaction was examined without isolation of 3.
The reaction of 3 in the presence of 0.1 and 0.5equiv of
DMAP afforded 4 in 15% and 44% yields, respectively
(Runs 2 and 3). These results suggest that a stoichiomet-
ric amount of a base is needed to convert 3 to 4, prob-
ably because of the formation of a salt with phenol
liberated from 3 during the reaction. The reaction at
160°C resulted in a decrease of 4. Although this method
was found to provide THICA in good yield, the use of
phenyl chloroformate 2, which is easily decomposed in
the presence of water, is limited to the reaction under
anhydrous condition. Therefore, if THICA can be syn-
thesized by the reaction of 1 with diphenyl carbonate
(DPC) instead of 2, this method would provide a very
convenient new route to THICA, since DPC is stable
to water and is an easily available compound which is
produced in industrial scale as a key component of poly-
carbonate resins. Thus, we next tried the development of
a new route to THICA from 1 and DPC.
Scheme 2.
of a versatile method for the synthesis of THICA and its
use as the catalyst for the aerobic oxidation of p-methyl-
anisole to p-anisic acid.
2. Results and discussion
A new synthetic route to THICA using 1 and phenyl
chloroformate (2) is depicted in Scheme 2. A typical
reaction is carried out as follows: To a mixture of 1,
pyridine and dried CH3CN were added dropwise 2
under N2 at 0°C followed by stirring at room temperature
to afford formbenzyloxycarbamic acid phenyl ester (3).
After the evaporation of solvent, the residue was treated
with 4-dimethylaminopyridine (DMAP) at 120°C to
give 1,3,5-tribenzyloxyisocyanurate (4) in 82% yield.
The hydrogenolysis of 4 on Pd/C afforded THICA in
almost quantitative yield.
It was found that 4 can be produced by one step reaction
of 1 with DPC in the presence of a base (Scheme 3). The
results are shown in Table 3.
Thus, the reaction of 1 with 2 was examined in the pres-
ence of various bases without the isolation of 3. It was
found that the yield of 4 was considerably affected by
the bases used and the reaction temperatures. These
results are summarized in Table 1.
A mixture of 1 (10mmol), DPC (10mmol), and DMAP
(10mmol) was heated under N2 at 120°C for 20min to
Among the bases examined, DMAP was found to be the
best base followed by triethylamine (TEA) and
DABCO. The reaction of 3 in the presence of 1equiv
of DMAP at 90 and 120°C afforded 4 in 66% and
82% yields, respectively (Runs 6 and 7). Upon treatment
of 3 with a strong base like DBU at 90°C, 4 was
obtained in 28% yield. However, no product was
obtained by the reaction at 120°C because of the decom-
Table 2. Reaction of 1 with 2 using DMAP under several conditionsa
Run
DMAP (equiv)
Yield of 4 (%)
1
1
81
15
44
23
2
0.1
0.5
1
3
4b
a The isolated 3 was reacted with DMAP.
b 160°C.
Table 1. Effect of bases and temperature for the formation of 4a
Run
Base (pKa)
Temp/°C
Yield of 4/%
1
DBU (11.5)
90
120
90
28
Decomp.
O
2
+
Ph
Ph
Ph
ONH2
HCl
Base
O
O
3
TEA (10.72)
DABCO (8.7)
69
35
45
66
82
42
0
120 ºC, 20 min
1
DPC
4
90
5
120
90
O
6
DMAP (9.65)
BnO
O
OBn
N
N
7
120
120
120
90
+
2PhOH
8
Imidazole (7.01)
Lutidine (6.90)
Pyridine (5.2)
t-BuOK
N
O
9
OBn
10
11
0
4
120
0
a The reaction method is shown in Experimental.
Scheme 3.

N. Hirai et al. / Tetrahedron Letters 45 (2004) 8277–8280
8279
Table 3. Reaction of 1 with diphenyl carbonate (DPC) under several
conditionsa
In conclusion, we have developed a new versatile method
for the synthesis of THICA, which is an efficient catalyst
of the aerobic oxidation of methylbenzenes.
Run Base (equiv) Temp (°C) Time (min) Yield of 4 (%)
1
DMAP (1)
DMAP (2)
DMAP (2)
TEA (2)
Bu3N (3)
—
120
120
120
90
20
20
50
70
72
52
67
2
3b
3. Experimental
30
20
4
All starting materials were commercially available and
used without any purification.
5
90
120
180
6
No reaction
a The reaction method is shown in Experimental.
b The reaction was carried out by 100-mmol scale of 1.
3.1. Procedure for the preparation of THICA by the
reaction of 1 with 2
Phenyl chloroformate (2) (1.57g, 10mmol) was added
dropwise to a mixture of O-benzylhydroxyamine hydro-
chloride (1) (1.60g, 10mmol), pyridine (1.58g, 20mmol),
and anhydrous CH3CN (20mL) over a period of 20min
under N2 at 0–2°C followed by at 25°C for 2h. The reac-
tion mixture was concentrated at 30°C followed by dilu-
tion with ethyl acetate (50mL). The precipitate was
filtered off and the filtrate was concentrated. The precipi-
tate involving 3 was added to DMAP (1.22g, 10mmol)
and heated to 120°C for 20min. After cooling to room
temperature, methanol (10mL) was added to the reactant
and stirred for 20min. The precipitate was filtered off,
washed with methanol (10mL), and dried in vacuo at
80°C for 12h to give 4 (1.22g) in 82% yield. The hydro-
genolysis of 4 (0.95g, ca. 2mmol) on Pd/C (10% Pd,
0.25g) was carried out in dioxane (50mL) under normal
pressure of H2 at room temperature for 3h. The catalyst
was filtered off from the reaction mixture and washed with
dried dioxane (10mL). The filtrate was evaporated under
reduced pressure to give THICA (0.37g) in almost quan-
titative yield. Spectral data of the resulting THICA were
in agreement with those of literature values.5 3 could be
isolated in 94% yield by the reaction of 1 with 2.
give 4 in 50% yield (Run 1). When the amount of
DMAP was doubled under these conditions, the yield
of 4 increased to 70% based on 1 used (Run 2). We tried
the preparation of 4 in a 100-mmol scale and obtained
almost the same result as that in the 10-mmol scale
(Run 3). It is interesting to note that 4 can be easily pre-
pared from 1 and DPC by a short-time reaction. The
reaction using a cheap base like TEA in place of DMAP
gave 4, although the yield somewhat decreased (Run 4).
It is because the reaction must be carried out at up to
90°C due to the low boiling point (88.8°C) of TEA.
No reaction took place in the absence of a base (Run 6).
The aerobic oxidation of p-methylanisole (5) to p-anisic
acid (6) by THICA was compared with that by N-
hydroxyphthalimide (NHPI). The oxidation of 5 under
dioxygen atmosphere (1atm) in acetic acid by THICA
combined with small amounts of Co(OAc)2 and
Mn(OAc)2 at 80°C afforded 6, which is an important
component of polyesters, in almost quantitative yield
(>99%), while in the reaction using NHPI (10mol%),
6 and p-methoxybenzaldehyde (7) were formed even at
100°C for 10h (Scheme 4). This shows that THICA pos-
sesses higher catalytic activity than NHPI for the aero-
bic oxidation of 5. Similarly, THICA promoted the
oxidation of 2-methylnaphthalene (8) to form the corre-
sponding carboxylic acid 9 in excellent yield (Scheme 5).
3.2. Procedure for the preparation of 4 by the reaction of
1 with DPC
A mixture of 1 (1.60g, 10mmol), DPC (2.14g, 10mmol),
and DMAP (2.44g, 20mmol) was heated at 120°C for
20min. After cooling to room temperature, methanol
(10mL) was added to the reaction mixture and stirred
for 20min. The resulting precipitate was filtered off
and washed with additional methanol (10mL). The pre-
cipitate was dried under reduced pressure at 80°C to
give 4 (1.05g, 70% yield).
THICA or NHPI
Co(OAc)2 (0.5 mol%)
Mn(OAc)2 (0.05 mol%)
+
O2
AcOH (5 mL)
MeO
80 or 100 ºC, 6 h
3 mmol
1 atm
5
CHO
COOH
+
3.3. Procedure of the oxidation of 5 and 8
6
MeO
MeO
7
THICA (3 mol%) >99%
NHPI (10 mol%) 83%
n.d.
6%
An acetic acid solution (5mL) of 5 (3mmol), THICA,
Co(OAc)2, and Mn(OAc)2 was paced in a 50mL pear-
shaped flask with a balloon filled with O2. The mixture
was stirred at 100°C for 6h. The conversions and yields
of products were estimated from the peak areas based on
the internal standard technique using GLC. The oxidation
of 8 was carried out by a similar manner as that of 5.
Scheme 4.
THICA or NHPI
Co(OAc)2 (2 mol%)
Mn(OAc)2 (2 mol%)
COOH
+
Air
AcOH/ Ac2O (5/0.1 mL)
120 ºC, 3 h
9
8
Acknowledgements
20 atm
2 mmol
THICA (5 mol%) 92%
NHPI (10 mol%) 26%
This work was partially supported by a Grant-in-Aid
for Scientific Research (S) from the Ministry of
Scheme 5.

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N. Hirai et al. / Tetrahedron Letters 45 (2004) 8277–8280
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3. Major, R. T.; Hedrick, R. J. J. Org. Chem. 1965, 30, 1268.
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Education, Culture, Sports and Technology (MEXT),
Japan.
References and notes
5. Butula, I.; Takac, M.-J. M. Croat. Chem. Acta 2000, 73,
569.
6. Hirai, N.; Sawatari, N.; Nakamura, N.; Sakaguchi, S.; Ishii,
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