A Simple Practical Method for the Synthesis of 4,6-Dimethoxy-1,3,5-triazin- 2(1H)-one Using Dimethylamine-Functionalized Solid-Phase Reagents

Article abstract of DOI:10.1055/s-0028-1083330

A simple practical method for the synthesis of 4,6-dimethoxy-1,3,5-triazin- 2(1H)-one was developed. The desired product was easily obtained from 2-chloro-4,6-dimethoxy-1,3,5-tri-azine and acetic acid by shaking with dimethylamine-functionalized silica ge

Full text of DOI:10.1055/s-0028-1083330

542
SHORT PAPER
A Simple Practical Method for the Synthesis of 4,6-Dimethoxy-1,3,5-triazin-
2(1H)-one Using Dimethylamine-Functionalized Solid-Phase Reagents
A
S
imple Practical
a
M
ethod fo
z
r
Synthesis
u
of
H
O
-DMThito Hioki,a,b Keiichi Ohshima,a Yuko Sota,a Miki Tanaka,a Munetaka Kunishima*b,c
a
b
c
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan
Cooperative Research Center of Life Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan
Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
E-mail: kunisima@ p.kanazawa-u.ac.jp
Received 22 August 2008; revised 14 October 2008
Fmoc-DMT7 and also alkyl triazinyl ethers that exhibit re-
markable herbicidal activity3 (Scheme 1).
Abstract: A simple practical method for the synthesis of 4,6-
dimethoxy-1,3,5-triazin-2(1H)-one was developed. The desired
product was easily obtained from 2-chloro-4,6-dimethoxy-1,3,5-tri-
azine and acetic acid by shaking with dimethylamine-functionalized
silica gel in ethanol. It was also demonstrated that the silica gel
could be recycled by washing it with diluted aqueous ammonia so-
lution.
Despite the usefulness of HO-DMT, there are few meth-
ods for preparing it effectively. We expected that HO-
DMT would be easily obtained by the hydrolysis of
CDMT; however, our initial attempts produced poor re-
sults (Scheme 2). It was found that reactions under both
acidic and basic conditions underwent considerable over-
reaction. Mikhailichenko and co-workers reported a
method involving the formation of (trimethylammo-
nio)triazine derivatives.8 However, it requires a tedious
isolation procedure, and the yield of HO-DMT is moder-
ate (70%). Therefore, a practical method for the prepara-
tion of HO-DMT is desirable. Here, we report a practical
method for synthesizing HO-DMT, by utilizing immobi-
lized reagents containing a dimethylamino group.
Key words: heterocycles, amines, supported reagents, nucleophilic
aromatic substitutions, alcoholysis
Heterocyclic 1,3,5-triazines, which perform various func-
tions depending on their substitution, are found as part of
the structure of several chemical compounds that are used
as, for example, dyes,1 flame retardants,2 and herbicides.3
We have previously synthesized a dehydrocondensing
reagent, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-
morpholinium chloride (DMT-MM),4 and two types of
immobilized derivatives.5 These reagents can be easily
prepared from 2-chloro-4,6-dimethoxytriazine (CDMT)
or cyanuric chloride. During dehydrocondensation, the
methylmorpholinio group of DMT-MM is replaced with a
hydroxide group originating from the carboxylate to
produce 4,6-dimethoxy-1,3,5-triazin-2(1H)-one (HO-
DMT).6 HO-DMT is a useful starting material for the syn-
thesis of amino-protected reagents such as Z-, Boc-, and
NaOH or HCl
H2O–acetone
70 °C, 1–2 h
MeO
N
Cl
MeO
N
OH
N
N
N
N
yield: 34% (NaOH);
not detected (HCl)
OMe
CDMT
OMe
HO-DMT
Scheme 2 Preliminary tests for hydrolysis of 2-chloro-4,6-di-
methoxytriazine (CDMT)
R1COOH
OMe
R1CONHR2
+
OMe
OMe
R2NH2
OMe
NH
N
N
Me
X
N
N
N
N
N
N
+
+
NMM•HX
N
MeO
N
O
MeO
N
Cl
MeO
N
OH
O
MeO
N
O
NMM
DMT-MM
OMe
CDMT
HO-DMT
X = Cl, TfO
OMe
N
N
O
R3
(artificial enzyme)
(micellar reaction catalyst)
MeO
N
O
O
N
N
O
O
S
(protecting reagents for amino group)
Z-DMT, R3 = Bzl; Boc-DMT, R3 = t-Bu;
Fmoc-DMT, R3 = 9-fluorenylmethyl
MeO
N
O
CF3
alkyl triazinyl ether
(herbicides)
DMT-OTf
Scheme 1 Utility of 4,6-dimethoxy-1,3,5-triazin-2(1H)-one (HO-DMT)
SYNTHESIS 2009, No. 4, pp 0542–0544
x
x
.
x
x
.2
0
0
9
Advanced online publication: 27.01.2009
DOI: 10.1055/s-0028-1083330; Art ID: F18408SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
A Simple Practical Method for Synthesis of HO-DMT
543
In the dehydrocondensation with DMT-MM, HO-DMT
should be generated, along with its coupling product, in an
equimolar amount. We have previously reported a method
for recovering HO-DMT from the reaction mixture and
successfully converting it into either 4,6-dimethoxy-
1,3,5-triazin-2-yl trifluoromethanesulfonate (DMT-OTf)
or CDMT.9 DMT-OTf is a useful precursor of the dehy-
drocondensing reagent DMT-MM(OTf), which does not
produce chloromethane, and functionalized dehydrocon-
densing reagents utilized in artificial enzyme models and
micellar reaction systems.10
Table 1 Preparation of HO-DMT with Supported Reagents under
Different Conditionsa
OMe
OMe
N
N
N
N
MeO
N
Cl
MeO
N
OH
Entry Supported Solvent AcOX
reagent
Time (h) Yieldb (%)
1
2
3
4
5
6e
AG®4-X4 MeOH
AG®4-X4 EtOH
AG®4-X4 EtOH
AG®4-X4 EtOH
AcOH
AcOH
10
3
64c
87
As mentioned above, the hydrolysis of CDMT result in an
undesirable side reaction. Although CDMT rapidly reacts
with tertiary amines, the hydrolysis of the resulting qua-
ternary ammonium salts is a very slow process. In fact, we
have found that DMT-MM is stable in water, and there-
fore, it can be utilized with an aqueous solvent for the
amide-forming reaction.11 This may be the reason for the
moderate yield of HO-DMT obtained by Mikhailichen-
ko’s method. Taking into account the fact that DMT-MM
is converted into HO-DMT in good yield during dehydro-
condensation, we attempted to generate HO-DMT from
CDMT along with ethyl acetate by using solid-supported
tertiary amines.
NaOAc
NH4OAc
AcOH
3
87d
85d
98
3
Si-DMA
Si-DMA
EtOH
EtOH
3
AcOH
3
94
a The reactions were performed with CDMT (100 mg, 0.57 mmol),
AG®4-X4 or Si-DMA (3.1 equiv), AcOX (2.0 equiv), ROH.
b Isolated yields.
c The product contained 2,4,6-trimethoxy-1,3,5-triazine (11%).
d NMR yield.
e The reaction was performed with CDMT (1.0 g, 5.7 mmol).
was washed with aqueous ammonia solution (1.5%), wa-
ter, and ethanol multiple times to regenerate the free dim-
ethylamino form. After drying under reduced pressure,
the recycled silica gel was used for the next reaction.
Thus, the procedure for the preparation of HO-DMT with
recycled silica gel followed by the recycling of the gel was
carried out repeatedly. After using the recycled silica gel
five times, HO-DMT could be obtained without a consid-
erable decrease in its yield (Table 2).
First, several reaction conditions were examined using an
ion exchange resin (Bio-Rad, AG®4-X4). A mixture of
CDMT, acetic acid, and resin in methanol was shaken for
10 hours at room temperature (Table 1, entry 1), and then
filtered. After the filtrates evaporated, HO-DMT was ob-
tained in 64% yield along with 2,4,6-trimethoxy-1,3,5-tri-
azine in 11% yield. 2,4,6-Trimethoxy-1,3,5-triazine was
formed due to the nucleophilic substitution of CDMT by
methanol. Therefore, we employed ethanol, whose nu-
cleophilicity toward CDMT is low, and obtained HO-
DMT in 87% yield at room temperature after three hours.
Although HO-DMT was obtained in good yield, it could
be recovered from the reaction mixture (EtOH, 5 mL) in
only 50% yield after washing the resin four times with
methanol (5 mL). The resin was washed multiple times in
order to recover HO-DMT (see the experimental section).
When ammonium acetate or sodium acetate was used in-
Table 2 Repeat Test for the Formation of HO-DMT with Recycled
Silica Gel Reagenta
recycled Si-DMA
AcOH
CDMT
HO-DMT
EtOH
Number of times recycled
0
1
2
3
4
5
stead of acetic acid, HO-DMT was produced in good yield Yield (%) of HO-DMT
(entries 3 and 4). However, HO-DMT obtained from the
98
94
92
91
87
93
a Reaction conditions: The preparation of HO-DMT: CDMT (0.57
mmol, 1 equiv), recycled Si-DMA (3.1 equiv), AcOH (2 equiv). The
weight loss (ca. 3–5%) of Si-DMA during the regeneration step was
compensated by the addition of the regenerated Si-DMA.
reaction mixture contained salts such as ammonium ace-
tate, sodium acetate, or ammonium chloride. Finally, the
reaction was carried out by utilizing dimethylamine-
derivatized silica gel [SiliCycle, SiBond Dimethylamine
(Si-DMA)] under the same conditions as those used when
the reaction was carried out by utilizing acetic acid and
ethanol (entry 5). The yield of HO-DMT increased to
98%, and it could be obtained with high purity simply by
only filtration and concentration. One gram of CDMT was
found to undergo the reaction in 94% yield under the same
conditions (entry 6).
In conclusion, we have developed a convenient method
for the preparation of HO-DMT using a dimethylamine-
functionalized immobilized reagent, which involves only
filtration and concentration. Moreover, we have demon-
strated that the derivatized silica gel can be recycled. In
this process, ethyl acetate is produced, which is readily re-
moved by a rotary evaporator. Other esters or amides can
also be prepared by employing the present method.
Furthermore, the reuse of silica gel was examined. Be-
cause the dimethylamino groups of the silica gel may
transform into ammonium salts after the reaction, the gel
Synthesis 2009, No. 4, 542–544 © Thieme Stuttgart · New York

544
K. Hioki et al.
SHORT PAPER
der reduced pressure. The residue was washed with hexane (5 mL)
to give HO-DMT as a colorless solid (88 mg, 98%).
All chemicals and solvents were obtained from commercial sources
and used without further purification. Silica gel (SiliCycle Inc.,
SiliaBond Dimethylamine, Si-DMA) and an ion exchange resin
(Bio-Rad Laboratories inc., AG®4-X4) were used as dimethyl-
amine-functionalized reagents. 1H NMR spectra were observed us-
ing a Bruker DPX-400 spectrometer. MS spectra were recorded on
a Bruker Daltonics micrOTOF-Q spectrometer Melting points were
measured with a Yanaco micro melting point apparatus. IR data
were recorded on a Nicolet FT-IR AVATAR 360 spectrophotome-
ter. The preparation of HO-DMT was carried out in a rotary shaker
N-500 manufactured by Kokusan Chemical Co., Ltd.
Anal. Calcd for C5H7N3O3·0.25 H2O: C, 37.15; H, 4.68. Found: C,
37.21; H, 4.83.
Regeneration of Dimethylamine-Derivatized Silica Gel
(Si-DMA)
Dilute, 1.4% aq NH3 (200 mL) and de-ionized H2O (200 mL) were
continuously passed through the used silica gel in the column at a
flow rate of 6–8 mL/min; 50 mL of each eluate was collected. After
the absence of chloride ions was confirmed by the addition of a few
drops of 0.01 M AgNO3 to the eluates, the silica gel was washed
with EtOH (10 mL) and dried under reduced pressure.
Hydrolysis of 2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT)
To a suspension of CDMT (100 mg, 0.57 mmol) in acetone (1.4
mL) was added aq 1 M NaOH (1.4 mL, 1.4 mmol). This mixture
was refluxed by heating at 70–80 °C for 1 h; CDMT was consumed
within 30–60 min. After cooling to r.t., the soln was neutralized
with AcOH and evaporated under reduced pressure. Maleic acid
was added to the residue as an internal standard and the yield of HO-
DMT (34%) was calculated by NMR. O-Monomethylcyanuric acid
and cyanuric acid were detected as byproducts in the crude mixture
by HPLC-MS analysis (yields were not determined).
Acknowledgment
This work was supported by KAKENHI (19590025).
References
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(5) (a) Hioki, K.; Kameyama, S.; Tani, S.; Kunishima, M.
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Yamamoto, K.; Hioki, K.; Kondo, T.; Hasegawa, M.; Tani,
S. Tetrahedron 2007, 63, 2604.
(6) Although it is known that the keto form of such compounds
is more stable than the enol form, we represent it as the enol
form and abbreviate to HO-DMT in order to emphasize that
it is a triazine derivative: (a) Srinivas, K.; Sitha, S.; Sridhar,
B.; Rao, V. J.; Bhanuprakash, K.; Ravikumar, K. Struct.
Chem. 2006, 17, 561. (b) Glowka, M. L.; Bertolasi, V. Acta
Crystallogr., Sect. C 1987, 43, 149.
(7) (a) Hioki, K.; Kinugasa, M.; Kishimoto, M.; Fujiwara, M.;
Tani, S.; Kunishima, M. Synthesis 2006, 1931. (b) Hioki,
K.; Fujiwara, M.; Tani, S.; Kunishima, M. Chem. Lett. 2002,
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(8) Mikhailichenko, S. N.; Chesniyuk, A. A.; Zavodnik, V. E.;
Firgand, S. I.; Konyushkin, L. D.; Zaplishny, V. N. Chem.
Heterocycl. Compd. (Engl. Transl.) 2002, 38, 292.
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S. Tetrahedron Lett. 2002, 43, 3323.
(10) (a) Kunishima, M.; Yoshimura, K.; Morigaki, H.;
Kawamata, R.; Terao, K.; Tani, S. J. Am. Chem. Soc. 2001,
123, 10760. (b) Kunishima, M.; Imada, H.; Kikuchi, K.;
Hioki, K.; Nishida, J.; Tani, S. Angew. Chem. Int. Ed. 2005,
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In the case of hydrolysis under acidic conditions, aq 1 M HCl (1.4
mL, 1.4 mmol) was used instead of the NaOH soln and the mixture
was refluxed for 2 h. After the evaporation of the product mixture,
HO-DMT was not detected in the residue by NMR. Recrystalliza-
tion of the residue (H2O) gave cyanuric acid (35 mg, 47%).
4,6-Dimethoxy-1,3,5-triazin-2(1H)-one (HO-DMT)
Using Ion Exchange Resin (AG®4-X4)
CDMT (100 mg, 0.57 mmol) and EtOH (10 mL) were added to the
ion exchange resin (1.63 g, 1.77 mmol). After shaking the reaction
tube for 10 min in order to dissolve CDMT, AcOH (68 mg, 1.14
mmol) was added to the mixture. This mixture was shaken at r.t. for
3 h and filtered by suction. The resin was rinsed with MeOH (4 × 5
mL). The combined alcoholic phases were evaporated to afford
HO-DMT in 50% yield. The resin was shaken with MeOH (5 mL)
for 12 h, filtered, and rinsed with MeOH (4 × 5 mL). After the evap-
oration of the combined washings, HO-DMT was recovered in 21%
yield. Furthermore, the resin was washed by the above-mentioned
methods. Finally, HO-DMT was recovered in 16% yield, and the
total yield of the desired product was 87%; colorless crystals; mp
183–184 °C.
IR (KBr): 1684, 1615, 1559, 1472, 1372, 1338, 1122, 918, 800
cm–1.
1H NMR (400 MHz, D2O): d = 4.03 (s, 6 H).
HRMS (ESI): m/z [M]+ calcd for C5H8N3O3: 158.0560; found:
158.0560.
Using Dimethylamine-Derivatized Silica Gel (Si-DMA)
CDMT (100 mg, 0.57 mmol) and EtOH (10 mL) were added to the
dimethylamine-derivatized silica gel Si-DMA (1.19 g, 1.77 mmol).
After shaking the reaction tube for 10 min in order to dissolve the
CDMT, AcOH (68 mg, 1.14 mmol) was added to the mixture. The
mixture was shaken at r.t. for 3 h and filtered by suction. The silica
gel was rinsed with MeOH (2 × 5 mL). To wash HO-DMT thor-
oughly, the silica gel was shaken with MeOH (2 × 20 mL) for 15
min. All the alcoholic washings were combined and evaporated un-
Synthesis 2009, No. 4, 542–544 © Thieme Stuttgart · New York