Retro-ene reactions in heterocyclic synthesis. V. A novel synthetic method for 1,3,5-triazine-2,4(1H,3H)-diones

Article abstract of DOI:10.1002/jhet.5570440648

(Chemical Equation Presented) N-t-Butylamidines 1 on heating with diphenyl carbonate (2) at 150-180° gave the 1,3,5-triazine-2,4(1H,3H)-dione derivatives 5. Acylation of amidines 1 and cyclocondensation of the resulting carbamates 3 gave [1,3,5,7]tetrazocine-2,6-dione derivatives 4, and subsequent retro-ene reaction and ring contraction afforded triazine derivatives 5.

Full text of DOI:10.1002/jhet.5570440648

Nov-Dec 2007
1533
Retro-Ene Reactions in Heterocyclic Synthesis.
V. A Novel Synthetic Method for
1,3,5-Triazine-2,4(1H,3H)-diones
The late Kunio Ito, Chiharu Sekiguchi, Asuka Wakai Hiroyuki Miida and Shogo Ihara*
Department of Applied Chemistry, Faculty of Engineering, Toyo University,
Kujirai, Kawagoe, Saitama 350-8585, Japan
E-mail: ihara@eng.toyo.ac.jp
Received August 17, 2006
H2
C
H
N
Me
Me
O
O
O
O
2
N
NH
NH
R
PhO
OPh
N
OPh
N
- 2
Me2C CH2
- RCN
N
NH
2
2
N
2
R
R
R
NH
- 2 PhOH
- 2 PhOH
R
N
H
O
Me
O
Me
C
H
H2
1
3
5
4
N-t-Butylamidines 1 on heating with diphenyl carbonate (2) at 150-180˚ gave the 1,3,5-triazine-
2,4(1H,3H)-dione derivatives 5. Acylation of amidines 1 and cyclocondensation of the resulting carba-
mates 3 gave [1,3,5,7]tetrazocine-2,6-dione derivatives 4, and subsequent retro-ene reaction and ring
contraction afforded triazine derivatives 5.
J. Heterocyclic Chem., 44, 1533 (2007).
We previously reported synthetic methods for a variety
from the literature [5,6]. The elimination of nitrile was
confirmed by isolation of benzonitrile via redistillation
of the low boiling materials (78 %). Although the
intermediate tetrazocine derivative 4a could not be
isolated, the characterization of these by-products
supports the contention that the reaction mechanism is
as shown in Scheme 1. It seems that steric strain
between the t-butyl and phenyl groups in the
intermediate tetrazocine derivative 4a is an important
factor in the easy elimination of 2-methylpropene, as
described in our previous papers [1,2,4].
of heterocyclic compounds via sterically assisted retro-
ene reactions [1-4]. In the fourth paper in this series, we
reported a convenient synthesis of 6-aryl-substituted
1,3,5-triazine-2,4(1H,3H)-diones from amidines and
diphenyl imidodicarboxylate [4]. This report deals with a
new and interesting synthetic method for 1,3,5-triazine-
2,4(1H,3H)-dione derivatives.
The addition of a solution of N-t-butylbenzamidine
(1a) in benzene to a stirred solution of diphenyl
carbonate (2) in benzene, with stirring for 1 hour at
room temperature, gave the N-acylated product phenyl
(t-butylamino)-phenylmethylenecarbamate (3a) in 96%
yield. A solution of carbamate 3a in tetraglyme was
heated in an oil bath at 180˚ for 5 hours; after the
removal of low boiling materials and solvent under
reduced pressure, 6-phenyl-1,3,5-triazine-2,4(1H,3H)-
dione (5a) was obtained in 83% yield. Scheme 1
shows the mechanism for the reaction. On heating at
180˚, 3a underwent cyclocondensation to form
[1,3,5,7]tetrazocine-2,6-dione derivative 4a, which
subsequently underwent a retro-ene reaction with
elimination of 2-methylpropene and a ring contraction
reaction with elimination of benzonitrile to afford
triazine derivative 5a. The structures of 3a and 5a
were confirmed on the basis of elemental analysis and
spectral data. 2-Methylpropene eliminated during the
reaction was collected by trapping generated gases (83
%), and was identified by agreement with spectral data
Synthesis of 6-phenyl-1,3,5-triazine-2,4(1H,3H)-dione
(5a) was also successfully carried out in a one-pot
procedure in which a solution of amidine 1a in diglyme
was gradually added to a stirred solution of 2 in diglyme
at room temperature during 10 monutes, followed by
heating under reflux in a 180˚ oil bath for 5 hours. After
work up as described in experimental section, triazine
derivative 5a was obtained in 83% yield. Similarly,
various N-t-butylamidines 1 were allowed to react with
diphenyl carbonate (2) by means of one-pot procedure
under the reaction conditions indicated in Table 1; the
results obtained are summarized in Table 1.
The present method offers a facile synthetic route to a
variety of 6-aryl and 6-alkyl-substituted 1,3,5-triazine-
2,4(1H,3H)-dione derivatives.
Ready availability of
starting materials, experimental simplicity and
satisfactory yields contribute to the usefulness of this
method.

1534
The late K. Ito, C. Sekiguchi, A. Wakai, H. Miida and S. Ihara
Vol 44
Scheme 1
H2
C
H
N
Me
Me
O
O
O
2
N
NH
NH
R
PhO
OPh
N
OPh
N
2
2
N
R
2
R
R
NH
- 2 PhOH
- 2 PhOH
Me
O
Me
C
H2
H
1
3
4
Me2C CH2
- 2
R
R
O
O
HO
N
H
N
a
Ph
Pr
i-Pr
C6H11
Ph-CH2
h
i
j
k
l
m
n
N
N
R
R
b
c
d
e
f
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-Br-C6H4
Me
N
N
NH
- RCN
N
R
R
N
H
R
N
H
O
N
O
4-Me-C6H4-CH2
4-MeO-C6H4-CH2
4-Cl-C6H4-CH2
OH
g
Et
5
Table 1
during 30 minutes. The mixture was stirred for an additional 1
hour at room temperature. Then the reaction mixture was shaken
with 0.5 M aqueous sodium hydroxide solution (200 ml). The
benzene layer was separated and washed with water (100 ml), dried
over anhydrous sodium sulfate, and concentrated. The resulting
residue was cooled, and the precipitated crystals were collected and
washed with small amount of hexane to give 28.51 g (96 %) of
carbamate 3a as a colorless powder, mp 115.4-117.2˚. A sample
was recrystallized from methanol for analysis; mp 117.0-117.5˚; ir
3319, 3294, 1674, 1589, 1575, 1549, 1493 cm-1; 1H nmr: ꢀ 1.41
(9H, s, C(CH3)3), 6.79 (2H, d, J=7.5 Hz, aromatic), 7.11 (1H, t,
J=7.5 Hz, aromatic), 7.28 (2H, t, J=7.5Hz, aromatic), 7.44–7.51
(5H, m, aromatic), 7.88 (1H, brs, NH); ms: (CI) m/z 297 (MH+).
Anal. Calcd. for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45. Found: C,
73.13; H, 6.82; N, 9.41.
Preparation of Compounds 5
Reaction
Compd.
R
Temp
[˚C]
Time
[h]
Yield
[%]
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
Ph
180
180
180
150
150
180
180
180
180
180
180
150
150
180
5
5
5
8
8
5
5
5
5
5
5
9
9
5
83
83
85
84
85
82
82
84
80
65
57
53
43
71
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-Br-C6H4
Me
Et
Pr
i-Pr
C6H11
Ph-CH2
Conversion to 1,3,5-Triazine-2,4(1H,3H)-dione Derivative
5a of Carbamate 3a. A solution of carbamate 3a (17.78 g, 60.0
mmoles) in tetraglyme (120 ml) was heated with stirring in 180˚
oil bath for 5 hours. The eliminated 2-methylpropene during the
reaction was captured by means of the cooled (-60˚) trap
connected to the top of the condenser by the rubber tube. After
concluding the heating, 2.80 g of volatile liquid was collected,
4-Me-C6H4-CH2
4-MeO-C6H4-CH2
4-Cl-C6H4-CH2
EXPERIMENTAL
1
and its H nmr and ms spectral data were identical with those
All melting points are uncorrected. The ir spectra were
recorded on a Horiba FT-720 spectrometer in potassium
bromide pellets. The H nmr data were obtained with a JEOL
from literature on the 2-methylpropene [5,6]. The yield of 2-
methylpropene was 83 %. The reaction mixture was distilled
under reduced pressure after low-boiling fraction of bp 80-120˚
(2.5 mmHg) was collected solvent was removed. The residual
solid was triturated with ether (10 ml) and was collected by
filtration, giving 4.69 g of 1,3,5-triazine-2,4(1H,3H)-dione
derivative 5a (83 %), mp 288˚ dec. To a cooled low-boiling
fraction were added ether (60 ml) and 1 M aqueous sodium
hydroxide solution (60 ml) and the mixture was vigorously
shaken. The ether layer was separated and the aqueous layer
was extracted with ether (2x30 ml). The combined extracts were
dried over anhydrous sodium sulfate, concentrated, and redis-
tilled through a 50-cm spinning band column, giving 2.40 g of
benzonitrile, bp 95-98˚ (35 mmHg). The collected benzonitrile
was confirmed by direct comparison with ir and 1H nmr spectral
data of an authentic sample. The yield of benzonitrile was 78 %.
1
JNM-ECX500M (500 MHz) spectrometer in deuteriodimethyl
sulfoxide by using tetramethylsilane (0.03 %) as an internal
standard. Mass spectra were measured with a Shimadzu GCMS-
QP5050A spectrometer at 70 eV of ionization energy by use of a
direct-inlet system. Elemental analyses were performed by
using a Perkin-Elmer 2400 II CHN Analyzer.
N-t-Butylamidines 1 were prepared by the method of Cooper
and Partridge [7]. Diphenyl carbonate (2) was commercially
available and used without further purification.
Phenyl (t-Butylamine)phenylmethylenecarbamate (3a). To a
stirred solution of diphenyl carbonate (2) (21.45 g, 100 mmoles) in
benzene (200 ml) at room temperature was added a solution of N-t-
butylbenzamidine (1a) (17.63 g, 100 mmoles) in benzene (200 ml)

Nov-Dec 2007
Retro-Ene Reactions in Heterocyclic Synthesis. V
1535
1,3,5-Triazine-2,4(1H, 3H)-diones 5. To a stirred solution of
diphenyl carbonate (2) (20.0 mmoles) in diglyme (20 ml) at
room temperature was added dropwise a solution of N-t-butyl-
amidines 1 (20.0 mmoles) in diglyme (20 ml) during 10 minutes.
The mixture was heated with stirring at the temperature
indicated in Table 1. The reaction mixture was cooled, and the
precipitated product was collected by filtration and washed with
ether (10 ml). Evaporation of the combined filtrate under
reduced pressure and washing the residual solid with ether (5
ml) gave an additional amount of product. All the products 5
obtained were of satisfactory purity as judged by 1H nmr
spectroscopy. Samples for analysis were recrystallized from
dimethylformamide.
6-Phenyl-1,3,5-triazine-2,4(1H, 3H)-dione (5a). This compound
was obtained as a colorless powder, mp 288˚ dec (reference [4], mp
290˚ dec); ir: 3178, 3132, 1728, 1676, 1603, 1566, 1483, 1400 cm-1;
1H nmr: ꢀ 7.56 (2H, dd, J=8.3,7.5 Hz, aromatic), 7.67 (1H, t, J=7.5
Hz, aromatic), 8.09 (2H, d, J=8.3 Hz, aromatic), 11.40 and 12.42
(each 1H, brs, NH); ms: (CI) m/z 190 (MH+).
6-(4-Methylphenyl)-1,3,5-triazine-2,4(1H, 3H)-dione (5b).
This compound was obtained as a colorless powder, mp 305˚
dec (reference [4], mp 310.5˚ dec); ir: 3227, 3151, 1741, 1670,
1595, 1560, 1485, 1408 cm-1; 1H nmr: ꢀ 2.40 (3H, s, CH3), 7.36
and 8.01 (each 2H, d, J=8.6 Hz, aromatic), 11.34 and 12.30
(each 1H, brs, NH); ms: (CI) m/z 204 (MH+).
6-(4-Methoxyphenyl)-1,3,5-triazine-2,4(1H, 3H)-dione (5c).
This compound was obtained as a colorless powder, mp
304.5˚ dec; ir: 3246, 3163, 1718, 1697, 1595, 1558, 1473, 1398
cm-1; 1H nmr: ꢀ 3.86 (3H, s, OCH3), 7.10 and 8.12 (each 2H, d,
J=8.7 Hz, aromatic), 11.28 and 12.23 (each 1H, brs, NH); ms:
(CI) m/z 220 (MH+). Anal. Calcd. for C10H9N3O3: C, 54.79; H,
4.14; N, 19.17. Found: C, 54.81; H, 4.07; N, 19.39.
6-(4-Chlorophenyl)-1,3,5-triazine-2,4(1H, 3H)-dione (5d).
This compound was obtained as a colorless powder, mp 312.5˚
dec (reference [4], mp 318˚ dec); ir: 3167, 3130, 1741, 1675,
1593, 1556, 1477, 1412 cm-1; 1H nmr: ꢀ 7.64 and 8.10 (each 2H,
d, J=8.9 Hz, aromatic), 11.42 and 12.47 (each 1H, brs, NH); ms:
(CI) m/z 224 (MH+).
6-(4-Bromophenyl)-1,3,5-triazine-2,4(1H, 3H)-dione (5e).
This compound was obtained as colorless needles, mp 320˚ dec
(reference [4], mp 325.5˚ dec); ir: 3219, 3167, 1743, 1670,
1595, 1558, 1477, 1406 cm-1; 1H nmr: ꢀ 7.83 and 8.01 (each 2H,
d, J=8.5 Hz, aromatic), 11.42 and 11.97 (each 1H, brs, NH); ms:
(CI) m/z 268 and 270 (MH+).
6-Methyl-1,3,5-triazine-2,4(1H, 3H)-dione (5f). This
compound was obtained as a pale yellow powder, mp 275.5˚ dec
(reference [8], mp 273-275˚ dec); ir: 3215, 3130, 1774, 1691,
1587, 1498, 1402 cm-1; 1H nmr: ꢀ 2.15 (3H, s, CH3), 11.18 and
12.05 (each 1H, brs, NH); ms: (CI) m/z 128 (MH+).
6-Isopropyl-1,3,5-triazine-2,4(1H, 3H)-dione (5i). This
compound was obtained as a colorless powder, mp 246.5˚ dec;
ir: 3209, 3134, 1759, 1674, 1599, 1508, 1425 cm-1; 1H nmr: ꢀ
1.14 (6H, d, J=7.0 Hz, 2CH3), 2.66 (1H, sep, J=7.0 Hz, CH),
11.19 and 12.00 (each 1H, brs, NH); ms: (CI) m/z 156 (MH+).
Anal. Calcd. for C6H9N3O2: C, 46.45; H, 5.85; N, 27.08. Found:
C, 46.08; H, 5.70; N, 27.21.
6-Cyclohexyl-1,3,5-triazine-2,4(1H, 3H)-dione (5j). This
compound was obtained as colorless needles, mp 310˚ dec; ir:
3132, 1755, 1676, 1595, 1500, 1423 cm-1; 1H nmr: ꢀ 1.18, 1.21,
1.25 (each 1H, t, J=12.6 Hz, C6H11), 1.41 (1H, td, J=12.0, 2.3 Hz,
C6H11), 1.44 (1H, td, J=12.6, 2.9 Hz, C6H11), 1.65 (1H, d, J=11.5
Hz, C6H11), 1.75 and 1.81 (each 2H, d, J=12.6 Hz, C6H11), 2.37
(1H, tt, J=12.0, 3.4 Hz, C6H11), 11.17 and 11.93 (each 1H, brs,
NH); ms: (CI) m/z 196 (MH+). Anal. Calcd. for C9H13N3O2: C,
55.37; H, 6.71; N, 21.52. Found: C, 55.50; H, 6.81; N, 21.50.
6-Benzyl-1,3,5-triazine-2,4(1H, 3H)-dione (5k). This compound
was obtained as a light beige powder, mp 242.5˚ dec (reference [8],
mp 254-255˚); ir: 3154, 1757, 1673, 1589, 1500, 1423 cm-1; 1H
nmr: ꢀ 3.74 (2H, s, CH2), 7.25 - 7.34 (5H, m, aromatic), 11.26 and
12.29 (each 1H, brs, NH); ms: (CI) m/z 204 (MH+).
6-(4-Methylbenzyl)-1,3,5-triazine-2,4(1H, 3H)-dione (5l).
This compound was obtained as a light beige powder, mp 267.5˚
dec; ir: 3126, 1753, 1670, 1593, 1500, 1423 cm-1; 1H nmr: ꢀ
2.28 (3H, s, CH3), 3.68 (2H, s, CH2), 7.14 and 7.22 (each 2H, d,
J=8.0 Hz, aromatic), 11.25 and 12.26 (each 1H, brs, NH); ms:
(CI) m/z 218 (MH+). Anal. Calcd. for C11H11N3O2: C, 60.82; H,
5.10; N, 19.34. Found: C, 60.86; H, 5.24; N, 19.53.
6-(4-Methoxybenzyl)-1,3,5-triazine-2,4(1H, 3H)-dione (5m).
This compound was obtained as a colorless powder, mp 238.5˚
dec; ir: 3228, 1763, 1736, 1695, 1591, 1514, 1400 cm-1; 1H
nmr: ꢀ 3.66 (2H, s, CH2), 3.73 (3H, s, OCH3), 6.90 and 7.26
(each 2H, d, J=8.6 Hz, aromatic), 11.24 and 12.27 (each 1H, brs,
NH); ms: (CI) m/z 234 (MH+). Anal. Calcd. for C11H11N3O3: C,
56.65; H, 4.75; N, 18.02. Found: C, 56.85; H, 4.81; N, 17.85.
6-(4-Chlorobenzyl)-1,3,5-triazine-2,4(1H, 3H)-dione (5n).
This compound was obtained as a colorless powder, mp 273˚
dec; ir: 3124, 1755, 1672, 1602, 1587, 1493, 1425 cm-1; 1H
nmr: ꢀ 3.75 (2H, s, CH2), 7.36 and 7.40 (each 2H, d, J=8.6 Hz,
aromatic), 11.27 and 12.31 (each 1H, brs, NH); ms: (CI) m/z
238 (MH+). Anal. Calcd. for C10H8ClN3O2: C, 50.54; H, 3.39; N,
17.68. Found: C, 50.61; H, 3.40; N, 17.33.
Acknowlegement. This study was supported as “High-Tech
Research Center” Project for Private Universities: matching fund
subsidy from MEXT (Ministry of Education Culture, Sports,
Science and Technology), 2004-2008.
REFERENCES
6-Ethyl-1,3,5-triazine-2,4(1H, 3H)-dione (5g). This compound
was obtained as a colorless powder, mp 209-210˚; ir: 3138, 1751,
1672, 1599, 1500, 1415 cm-1; 1H nmr: ꢀ 1.12 (3H, t, J=7.4 Hz,
CH3), 2.42 (2H, q, J=7.4 Hz, CH2), 11.07 and 12.00 (each 1H, brs,
NH); ms: (CI) m/z 142 (MH+). Anal. Calcd. for C5H7N3O2: C,
42.55; H, 5.00; N, 29.77. Found: C, 42.19; H, 4.89; N, 29.89.
6-Propyl-1,3,5-triazine-2,4(1H, 3H)-dione (5h). This
compound was obtained as colorless needles, mp 214.5-216˚; ir:
3211, 3138, 1769, 1676, 1597, 1508, 1319 cm-1; 1H nmr: ꢀ 0.91
(3H, t, J=7.4 Hz, CH3), 1.64 (2H, sex, J=7.4 Hz, CH2), 2.39 (2H,
t, J=7.4 Hz, CH2), 11.19 and 12.00 (each 1H, brs, NH); ms: (CI)
m/z 156 (MH+). Anal. Calcd. for C6H9N3O2: C, 46.45; H, 5.85;
N, 27.08. Found: C, 46.72; H, 5.98; N, 27.20.
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