Design, synthesis and biological evaluation of novel 6,7,8,9-tetrahydro-2- (2-aryloxypyrimidin-4-yl)-2H-[1,2,4]triazolo[4,3-a]azepin-3(5H)-ones

Article abstract of DOI:10.1002/jhet.5570430520

A series of novel 6,7,8,9-tetrahydro-2-(2-aryloxypyrimidin-4-yl)-2H-[1,2,4] triazolo[4,3-a]azepin-3(5H)-ones were designed and efficiently synthesized. Their structures were determined by IR, ¹³C and ¹H NMR, mass spectroscopy, and elemental analysis. These compounds were screened for herbicidal activities against rape and barnyard grass. Compounds 5a-5f and 5m exhibited moderate herbicidal activity against rape. In addition, the synthesis of the intermediate 1-(azepan-2-ylidene)-2-(2-chloropyrimidin-4-yl)-hydrazine (3) was studied and the reason for the low yield in the initial procedure is discussed as well.

Full text of DOI:10.1002/jhet.5570430520

Sep-Oct 2006
1275
Design, Synthesis and Biological Evaluation of
Novel 6,7,8,9-tetrahydro-2-(2-aryloxypyrimidin-4-yl)-
2H-[1,2,4]triazolo[4,3-a]azepin-3(5H)-ones
Yi-Feng Wang, Wei-Min Liu, You-Quan Zhu, Xiao-Mao Zou,
Fang-Zhong Hu and Hua-Zheng Yang*
State Key Laboratory of Element-Organic Chemistry, Institute of Element-Organic Chemistry, Nankai
University, Tianjin 300071, P. R. China
e-mail: nk_yanghz@126.com
Received December 9, 2005
Cl
Cl
N
N
N
NH
N
HOAc
Cl
+
H2NHN
N
N
N
OCH3
N
H
O
O
O
Ar
N
NaH, ArOH
DMF
triphosgene, NEt3
DMAP, CH2Cl2
N
N
N
N
N
N
N
N
A series of novel 6,7,8,9-tetrahydro-2-(2-aryloxypyrimidin-4-yl)-2H-[1,2,4]triazolo[4,3-a]azepin-3(5H)-
1
ones were designed and efficiently synthesized. Their structures were determined by IR, 13C and H NMR,
mass spectroscopy, and elemental analysis. These compounds were screened for herbicidal activities
against rape and barnyard grass. Compounds 5a-5f and 5m exhibited moderate herbicidal activity against
rape. In addition, the synthesis of the intermediate 1-(azepan-2-ylidene)-2-(2-chloropyrimidin-4-yl)-
hydrazine (3) was studied and the reason for the low yield in the initial procedure is discussed as well.
J. Heterocyclic Chem., 43, 1275 (2006).
Introduction.
highly active compounds. To the best of our knowledge,
there are no reports involving the synthesis of aryloxy-
pyrimidinyl triazolinones. Herein, we report our strategy
for the synthesis of these 6,7,8,9-tetrahydro-2-(2-aryloxy-
pyrimidin-4-yl)-2H-[1,2,4]triazolo[4,3-a]azepin-3(5H)-one
compounds (5), which are illustrated in Scheme 1, and the
results of their biological activities.
Pyrimidine derivatives are very important molecules in
biology and have many applications in the areas of
pesticide [1,2] and pharmaceutical agents [3,4] such as
imazosulfuron, ethirmol and mepanipyrim [5]. Recently,
(4-trifluormethylpyrazolyl)pyrimidines [6,7] and 1,2,4-
triazolo[1,5-a]pyrimidine ether compounds [8] have been
found to exhibit excellent herbicidal activity against a
broad range of weeds. Furthermore, a new series of highly
active herbicides of substituted 2-azolyl-4-phenoxy-
pyrimidines in which azole substituents were nitrogen-
linked and include pyrazole, imidazole and triazole were
also reported [9].
In addition, many heterocycles containing the triazo-
linone ring were associated with a particularly wide rang
of biological properties, including 5-HT2 antagonist
activity [10], anti-inflammatory activity [11], as well as
herbicidal activity [12-14]. For example, G. Theodoridis
has investigated aryltriazolinone herbicides as protopor-
phyrinogen oxidase (Protox) inhibitors and found several
highly active herbicides [15-18]. Moreover azafenidin,
which was also a Protox inhibitor, has been developed
and commercialized in worldwide specialty markets
[19,20].
Results and Discussion.
Since the chloride at 4-position of the pyrimidine ring is
more active than at 2-position, 1-(2-chloropyrimidin-4-yl)
hydrazine (2) was obtained selectively by reaction of 2,4-
dichloropyrimidine (1) with hydrazine hydrate in the
presence of NEt3 in alcohol.
Compound 3 was obtained in good yield (70.2%) by
adding 2 into the solution of 6 in glacial acetic acid at 35
°C. Cyclization of 3 with triphosgene in the presence of
NEt3 and catalytic amount of DMAP in the solution of
CH2Cl2 provided 4 in the yield of 44.3%. This cyclization
did not proceed easily in the absence of DMAP. Since
chloride eliminated easily to introduce a new bond, the
target compounds (5) can be synthesized efficiently by the
condensation of compound (4) with sodium aryloxides in
N,N-dimethylformamide at room temperature.
Therefore, it is attractive to develop novel pyrimidinyl-
triazolinones compounds which include both the active
pyrimidine and triazolinone moiety and study their
potential pharmaceutical activities in order to discover
The structures of all the title compounds (5a-5m) are
established on the basis of elemental analysis and
spectral data. Physical properties, elemental analysis, IR
and MS spectra data are presented in Table 1. The

1276
Y.-F. Wang, W.-M. Liu, Y.-Q. Zhu, X.-M. Zou, F.-Z. Hu and H.-Z. Yang
Vol 43
Scheme 1
NHNH2
Cl
Cl
N
N
N
N
N
N
NH
a
b
Cl
Cl
N
N
H
1
2
3
O
O
O
N
Ar
Cl
N
N
N
c
N
d
N
N
N
N
N
4
5
.
Reaction conditions: a C2H5OH, NEt3, NH2NH2 H2O, 0 °C to room temperature;
b glacial acetic acid, 3,4,5,6-tetrahydro-7-methoxy-2H-azepine (6), 35 °C;
c CH2Cl2, triphosgene, NEt3, DMAP, 0 °C, d DMF, NaH, ArOH
Ar: 5a = H-C6H4; 5b = 2-CH3C6H4; 5c = 3-CH3C6H4; 5d = 4-CH3C6H4; 5e= 3-ClC6H4;
5f = 4-ClC6H4; 5g = 3-NO2C6H4; 5h = 4-NO2C6H4; 5i = 3-CF3C6H4; 5j = 4-MeO2CC6H4;
5k = 4-EtO2CCH2O2CC6H4; 5l = 4-EtO2CCH*(CH3)O2CC6H4; 5m = 4-MeO2CC2H4C6H4.
Table 1
Physical properties, Elemental Analysis Data, Infrared, and Mass Spectra of Compounds 5a-5m
Infrared spectrum ꢀ (cm - 1) (KBr) /
No.
Physical
state
MF
(MW)
mp.
(°C)
Yield
(%)
Analysis
Found (Calcd.)
Mass spectrum (m/z (relative intensity %)).
C
H
N
5a White solid C17H17N5O2 184-185 58
63.33 5.39 21.39 3135, 2930, 2850, 1714 (NC=O), 1580, 1442 /
63.15 5.30 21.66 323 (M+, 37), 220 (36), 212 (21), 171 (100).
63.81 5.70 20.39 3146, 2933, 2860, 1722 (NC=O), 1575, 1464 /
64.08 5.68 20.76 337 (M+, 81), 320 (98), 226 (100), 185 (78).
64.30 5.94 20.81 3136, 2936, 2857, 1721 (NC=O), 1581, 1450 /
64.08 5.68 20.76 337 (M+, 28), 226 (15), 220 (25), 185 (100).
63.80 5.92 21.02 3131, 2925, 2857, 1723 (NC=O), 1576, 1458 /
64.08 5.68 20.76 337 (M+, 30), 226 (20), 220 (30), 185 (100).
56.92 4.79 19.66 3145, 2930, 2852, 1719 (NC=O), 1586, 1472 /
57.07 4.51 19.57 357 (M+, 30), 220 (40), 205 (100), 153 (11).
56.88 4.75 19.30 3131, 2930, 2849, 1724 (NC=O), 1590, 1467 /
57.07 4.51 19.57 357 (M+, 28), 220 (38), 205 (100), 153 (11).
55.51 4.31 22.97 3104, 2937, 2857, 1724 (NC=O), 1593, 1525
323.4
5b White solid C18H19N5O2 170-172 44
337.4
5c White solid C18H19N5O2 164-166 67
337.4
5d White solid C18H19N5O2 162-163 63
337.4
5e White solid C17H16ClN5O2 144-145 53
357.79
5f White solid C17H16ClN5O2 164-165 56
357.79
5g Yellow solid C17H16N6O4 198-200 58
368.4
(NO2), 1468, 1351 (NO2) /
55.43 4.38 22.82
369 (M++1, 25), 323 (100), 221 (24), 216 (84).
5h White solid C17H16N6O4 211-213 41
55.19 4.32 23.06 3118, 2922, 2857, 1724 (NC=O), 1591, 1517
(NO2), 1467, 1350 (NO2) /
55.43 4.38 22.82
368.4
369 (M++1, 17), 323 (100), 221 (30), 216 (80).
5i White solid C18H16F3N5O2 125-126 53
55.07 4.34 17.66 3143, 2936, 2860, 1723 (NC=O), 1584, 1466 /
55.24 4.12 17.90 391 (M+, 25), 280 (16), 239 (100), 220 (25).
59.85 5.08 18.15 3149, 2947, 2851, 1724 (NC=O, ArC=O), 1588,
391.4
5j White solid C19H19N5O4 174-175 57
381.4
1458 /
59.84 5.02 18.36
382 (M++1, 100), 368 (28), 351 (15), 350 (97).
5k White solid C22H23N5O6 160-161 55
58.38 5.33 15.58 3139, 2930, 2858, 1751 (CH2C=O), 1722 (NC=O,
ArC=O), 1577, 1458 /
58.27 5.11 15.44
453.5
454 (M++1, 23), 382 (100), 368 (30), 350 (92).
5l White solid C23H25N5O6 163-164 61
59.38 5.51 15.12 3134, 2932, 2860, 1751 (CH2C=O), 1721 (NC=O,
ArC=O), 1583, 1471 /
59.09 5.39 14.98
467.5
468 (M++1, 32), 382 (100), 368 (29), 350 (91).
5m White solid C21H23N5O4 140-141 64
61.50 5.61 17.11 3127, 2933, 2857, 1727 (NC=O, CH2C=O), 1581,
1460 /
61.60 5.66 17.10
409.4
410 (M++1, 5), 379 (30), 378 (100), 336 (19).
difference between found value and calculated value of
0.4%. The 1H and 13C NMR data for the compound 5 are
elemental analysis of all the compounds 5 is under
given in Table 2.

Sep-Oct 2006
Design, Synthesis and Biological Evaluation
1277
Table 2
1H and 13C NMR (ꢀ, CDCl3) of Compounds 5a-5m
5a 1.79 - 1.90 (m, 6H, NCH2(CH2)3), 2.84 - 2.88 (m, 2H, =CCH2, 3.83 - 3.86 (m, 2H, NCH2), 7.20 - 7.45 (m, 5H, ArH), 7.95
(d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.45 (d, 1H, J = 5.7 Hz, pyrimidine 6-H) /
165.33, 160.67, 157.78, 153.03, 152.61, 152.50, 129.78, 125.62, 121.83, 103.92, 42.66, 30.78, 28.78, 28.22, 25.73
5b 1.79 - 1.90 (m, 6H, NCH2(CH2)3), 2.20 (s, 3H, ArCH3), 2.86 - 2.90 (m, 2H, =CCH2), 3.83 - 3.86 (m, 2H, NCH2), 7.01 -
7.30 (m, 4H, ArH), 7.95 (d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.42 (d, 1H, J = 5.7 Hz, pyrimidine 6-H) /
165.16, 160.77, 157.85, 152.61, 152.53, 151.53, 131.49, 130.90, 127.26, 125.95, 122.00, 103.71, 42.66, 30.77, 28.78,
28.22, 25.73, 16.60
5c 1.79 - 1.90 (m, 6H, NCH2(CH2)3), 2.38 (s, 3H, ArCH3), 2.84 - 2.89 (m, 2H, =CCH2), 3.83 - 3.86 (m, 2H, NCH2), 6.99 -
7.33 (m, 4H, ArH), 7.94 (d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.45 (d, 1H, J = 5.7 Hz, pyrimidine 6-H) /
165.45, 160.70, 157.76, 153.00, 152.59, 152.52, 139.98, 129.49, 126.51, 122.39, 118.82, 103.82, 42.66, 30.80, 28.78,
28.22, 25.75, 21.65
5d 1.72 - 1.82 (m, 6H, NCH2(CH2)3), 2.29 (s, 3H, ArCH3), 2.77 - 2.81 (m, 2H, =CCH2), 3.78 - 3.79 (m, 2H, NCH2), 7.10 (d,
2H, J = 9.0 Hz ArH), 7.22 (d, 2H, J= 9.0 Hz ArH), 7.86 (d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.37 (d, 1H, J = 5.7 Hz,
pyrimidine 6-H) /
165.55, 160.66, 157.76, 152.53, 150.80, 150.60, 135.21, 130.34, 121.56, 103.78, 42.66, 30.80, 28.79, 28.22, 25.75, 21.15
5e 1.79 - 1.90 (m, 6H, NCH2(CH2)3), 2.84 - 2.88 (m, 2H, =CCH2), 3.84-3.87 (m, 2H, NCH2), 7.11 - 7.38 (m, 4H, ArH), 7.99
(d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.46 (d, 1H, J = 5.7 Hz, pyrimidine 6-H) /
164.82, 160.63, 157.83, 153.53, 152.76, 152.45, 134.93, 130.49, 125.85, 122.44, 120.20, 104.29, 42.66, 30.75, 28.74,
28.20, 25.72
5f 1.79 - 1.90 (m, 6H, NCH2(CH2)3), 2.84 - 2.88 (m, 2H, =CCH2), 3.83 - 3.86 (m, 2H, NCH2), 7.17 (d, 2H, J = 8.7 Hz, ArH),
7.38 (d, 2H, J = 8.7 Hz, ArH), 7.97 (d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.45 (d, 1H, J = 5.7 Hz, pyrimidine 6-H) /
164.94, 160.60, 157.81, 152.71, 152.44, 151.50, 130.83, 129.81, 123.21, 104.19, 42.65, 30.75, 28.74, 28.20, 25.72
5g 1.80 - 1.90 (m, 6H, NCH2(CH2)3), 2.84 - 2.89 (m, 2H, =CCH2), 3.84 - 3.87 (m, 2H, NCH2), 7.58 - 7.60 (m, 2H, ArH), 8.03
(d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.11 - 8.17 (m, 2H, ArH), 8.47 (d, 1H, J = 5.7 Hz, pyrimidine 6-H) /
5h 1.79 - 1.90 (m, 6H, NCH2(CH2)3), 2.84 - 2.88 (m, 2H, =CCH2), 3.84 - 3.88 (m, 2H, NCH2), 7.42 (d, 2H, J = 9.0 Hz, ArH),
8.04 (d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.31 (d, 2H, J = 9.0 Hz, ArH), 8.49 (d, 1H, J = 5.7 Hz, pyrimidine 6-H) /
168.78, 160.68, 157.95, 154.00, 152.97, 152.42, 144.97, 125.63, 122.19, 104.97, 42.73, 30.75, 28.76, 28.23, 25.73
5i 1.77 - 1.89 (m, 6H, NCH2(CH2)3), 2.84 - 2.88 (m, 2H, =CCH2), 3.83 - 3.86 (m, 2H, NCH2), 7.21 - 7.43 (m, 4H, ArH), 7.95
(d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.45 (d, 1H, J = 5.7 Hz, pyrimidine 6-H) /
164.70, 160.64, 157.86, 153.14, 152.79, 152.47, 132.32, 131.99, 130.26, 125.33, 122.27 (3JC-F = 4 Hz), 119.06 (3JC-F = 4
Hz), 104.44, 42.68, 30.76, 28.75, 28.21, 25.72
5j 1.79 - 1.90 (m, 6H, NCH2(CH2)3), 2.84 - 2.88 (m, 2H, =CCH2), 3.85 - 3.87 (m, 2H, NCH2), 3.92 (s, 3H, COOCH3), 7.30
(d, 2H, J = 9.0 Hz, ArH), 8.00 (d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.11 (d, 2H, J = 9.0 Hz, ArH), 8.47 (d, 1H, J = 5.70 Hz,
pyrimidine 6-H) /
166.60, 164.63,160.65, 157.85, 156.79, 152.75, 152.44, 131.55, 127.26, 121.54, 104.45, 52.34, 42.66, 30.75, 28.75, 28.20,
25.73
5k 1.30 (t, 3H, J = 7.2 Hz, CH2CH3), 1.79 - 1.90 (m, 6H, NCH2(CH2)3), 2.84 - 2.88 (m, 2H, =CCH2), 3.84 - 3.87 (m, 2H,
NCH2), 4.26 (q, 2H, J = 7.2 Hz, CH2CH3), 4.85 (s, 2H, OCH2), 7.32 (d, 2H, J = 9.0 Hz, ArH), 8.01 (d, 1H, J = 5.7 Hz,
pyrimidine 5-H), 8.17 (d, 2H, J = 9.0 Hz, ArH), 8.47 (d, 1H, J = 5.7 Hz, pyrimidine 6-H) /
167.95, 165.45, 164.58, 160.65, 157.86, 157.20, 152.78, 152.44, 131.94, 126.32, 121.66, 104.50, 61.65, 61.44, 42.66,
30.75, 28.74, 28.20, 25.72, 14.35
5l 1.29 (t, 3H, J = 7.2 Hz, CH2CH3), 1.63 (d, 3H, J = 7.2 Hz, CHCH3), 1.79 - 1.90 (m, 6H, NCH2(CH2)3), 2.84 - 3.88 (m, 2H,
=CCH2), 3.85 - 3.87 (m, 2H, NCH2), 4.24 (q, 2H, J = 7.2 Hz, CH2CH3), 5.31 (q, 1H, J = 7.2 Hz, CHCH3), 7.31 (d, 2H, J =
9.0 Hz, ArH), 8.01 (d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.16 (d, 2H, J = 9.0 Hz, ArH), 8.47 (d, 1H, J = 5.7 Hz, pyrimidine
6-H) /
170.94, 165.42, 164.63, 160.65, 157.88, 157.09, 152.76, 152.45, 131.85, 126.63, 121.60, 104.48, 69.40, 61.58, 42.66,
30.75, 28.75, 28.20, 25.72, 17.30, 14.33
5m 1.79 - 1.90 (m, 6H, NCH2(CH2)3), 2.65 (t, 2H, J = 7.5 Hz, ArCH2), 2.84 - 2.88 (m, 2H, =CCH2), 2.97 (t, 2H, J = 7.5 Hz,
CH2CO), 3.69 (s, 3H, OCH3), 3.83 - 3.86 (m, 2H, NCH2), 7.14 (d, 2H, J = 9.0 Hz, ArH), 7.25 (d, 2H, J = 9.0 Hz, ArH),
7.95 (d, 1H, J = 5.7 Hz, pyrimidine 5-H), 8.44 (d, 1H, J = 5.7 Hz, pyrimidine 6-H) /
173.48, 165.36, 160.62, 157.76, 152.61, 152.49, 151.41, 137.72, 129.63, 121.80, 103.87, 51.88, 42.65, 35.80, 30.78, 30.56,
28.77, 28.21, 25.76
Scheme 2
N
NHNHR
NHNH2
NHNHCOCH3
NH
HN
HN
NH
N
N
N
N
N
N
N
N
CH3COOH
+
+
Cl
Cl
N
n
Cl
2
9
7 R=H, n=2, 3
8 R=COCH3, n=1,2,3,...,10

1278
Y.-F. Wang, W.-M. Liu, Y.-Q. Zhu, X.-M. Zou, F.-Z. Hu and H.-Z. Yang
Vol 43
Table 3
Bioassay Test of Compounds 5a-5m Against rape and Barnyard grass (100ppm, inhibitory rate %)
5a
54.23 54.34 51.74 60.59 48.33 54.80 28.70 35.76 41.79 16.67 0.00 13.48 72.73
barnyard grass 12.00 28.37 29.70 19.32 21.40 19.72 7.34 0.00 21.07 27.16 28.06 0.00 22.71
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
rape
In our initial synthesis of 3, compound 6 was added to a
solution of 2 in methanol saturated with HCl according to
the literature procedure [21]. The yield was very low
(<10%). When the solvent was replaced by glacial acetic
acid, it was found that increasing the amount of reactants
lowered the yield dramatically (40% to 10%). Variation of
the reaction temperature (0-70 °C) and the reaction time
(4-48 h) also failed to elevate the yield. However,
compound 3 was obtained in good yield (70.2%)
regardless of the amount of reactants when compound 2
was added to a solution of 6 in glacial acetic acid at 35
°C. Further investigation showed that the yield of
compound 3 was largely dependent of the adding
sequence of the reactants and the reaction temperature.
These results indicated that there might be some
undesirable occurrence of self-polymerization of
compound 2 and/or the reaction between 2 with glacial
acetic acid due to the strong nucleophilic ability of the
hydrazine group at the 4-position. In order to confirm this
suggestion, 2 was treated in glacial acetic acid at 35-40 °C
and monitored by thin layer chromatography. After 2 h,
some yellow deposits (7 and 8) came out of the solution
with little formation of 9. After an 8 h reaction time, the
mixture of 7 and 8 were collected by filtration and 9 was
isolated by flash chromatography in 10% yield.
The preliminary biological activity of these 6,7,8,9-
tetrahydro-2-(2-aryloxypyrimidin-4-yl)-2H-[1,2,4]tria-
zolo[4,3-a]azepin-3(5H)-one compounds was evaluated
against barnyard grass and rape using a previously
reported procedure [22]. The biological data were
presented in Table 3. The results showed that some
compounds 5 possessed an inhibition effect against rape
and weak against barnyard grass. For example, the
inhibitory rate of compound 5d and 5m were 60.59%,
72.73% to rape and 19.32%, 22.71% to barnyard grass at
100 ppm respectively.
Conclusion.
In conclusion, we have reported useful methodology for
the synthesis of 6,7,8,9-tetrahydro-2-(2-aryloxypyrimidin-4-
yl)-2H-[1,2,4]triazolo[4,3-a]azepin-3(5H)-one compounds.
An improved process to prepare intermediate 1-(azepan-
2-ylidene)-2-(2-chloropyrimidin-4-yl)hydrazine (3) was
developed, and a reason for the low yield in the initial
procedure is discussed. All compounds were tested for
herbicidal activity. However, only a few compounds
exhibited moderate activity against rape and weak activity
against barnyard grass. Further biological evaluation and
structure modifications are in progress in our laboratory.
The mass spectra of mixture of 7 and 8 exhibited strong
fragment ion peaks corresponding to [M+1]+ of all
assigned structures. The fragment ion peaks at m/z 469
and 577 showed that n was 2 and/or 3 in the compound 7.
On the other hand, there were ten fragment ion peaks
every m/z 108 from m/z 403 to m/z 1375, every increased
m/z 108 could be attributed to an increment of a structural
unit of NH-NH-C4H2N2. These results showed that n was
in the range from 1 to 10 in the compound 8.
EXPERIMENTAL
General Methods.
Melting points were measured on a Thomas-Hoover apparatus
and were not corrected. Infrared spectra were recorded on a
Bruker Equinox55 spectrophotometer as potassium bromide
1
tablets. H and 13C-NMR spectra were measured on a Bruker
XL-300 spectrometer (1H, 300 MHz and 13C, 75 MHz) or
Varian 400 spectrometer (1H, 400 MHz and 13C, 100 MHz).
Mass spectra were recorded on a Thermo Finnigan LCQ
Advantage LC/mass detector instrument. Elemental analyses
were performed on Yanaco-CHN CORDER MT-3 elementary
analyzer. The starting material, 2,4-dichloropyrimidine has been
obtained from commercial suppliers.
Hence, the reason for the low yield in the initial
procedure may be that the high concentration of unaltered
2 in glacial acetic acid induced the high probability of
undesirable self-polymerization of
2
and/or the
condensation of 2 with glacial acetic acid with increasing
temperature. In contrast, in the improved process where 2
was slowly added into the solution of 6 in glacial acetic
acid at 35 °C, the concentration of 2 was always kept at
lower level and greatly decreased the occurrence of the
side reaction. Furthermore, the reaction rate of 2 with 6
was slightly faster than the side reactions, so that the yield
was greatly increased.
Preparation of 1-(2-Chloropyrimidin-4-yl)hydrazine (2).
Hydrazine hydrate (85%, 3.50 g, 0.06 mol) was added
dropwise over the course of 30 minutes at 0-5 °C, to a solution
of 2,4-dichloropyrimidine (7.45 g, 0.05 mol) and NEt3 (5.5 g,
0.055 mol) in 100 ml of ethanol. After stirring in the cold for 2
h, a heavy precipitate came out of solution. The mixture was
allowed to warm and stir at room temperature for 5 h until the

Sep-Oct 2006
Design, Synthesis and Biological Evaluation
1279
reaction was completed as monitored by TLC. The suspended
solid was collected and washed with water and recrystallized
from ethanol to give pure white crystal in 80.1% yield; mp 175-
176 °C; 1H NMR (300 MHz, DMSO-d6): ꢀ 4.47 (br, 2H,
NHNH2), 6.73 (br, 1H, pyrimidine 5-H), 7.97 (br, 1H,
pyrimidine 6-H), 8.86 (br, 1H, NHNH2); 13C NMR (75MHz,
DMSO-d6) ꢀ 167.62, 160.46, 157.85, 101.39; ms: m/z 145
(M++1).
phenols and the mixture stirred for 30 min. A sample of 0.2 g
(0.75 mmol) of triazolone 4 was added, the mixture was stirred
at room temperature. After the reaction was completed as
monitored by TLC (petroleum ether (bp 60-90 °C): ethyl acetate
(1:1, v/v, Rf (4) =0.4), the mixture was partitioned between
CH2Cl2 and water. The aqueous layer was extracted with
CH2Cl2, the combined extracts were dried over anhydrous
sodium sulfate and the solvent removed. The crude product was
purified by flash chromatography on silica gel (200-300 mesh),
eluent with petroleum ether (bp 60-90 °C):ethyl acetate (1:1,
v/v).
Preparation of 1-(Azepan-2-ylidene)-2-(2-chloropyrimidin-4-
yl)hydrazine (3).
A solution of 2.82 g (0.022 mol) caprolactim methyl ether in
40 ml of glacial acetic acid at 35 °C was treated dropwise with a
Treatment of 1-(2-Chloropyrimidin-4-yl)hydrazine (2) in Glacial
Acetic acid.
solution of 3.22
g (0.022 mol) 1-(2-chloropyrimidin-4-
yl)hydrazine in 80 ml of glacial acetic acid over a 2 h period.
The yellow solution was kept at 35-40 °C for 4 h and excess
glacial acetic acid was distilled off under water-pump vacuum.
The residue was treated by the dropwise addition of saturated
aqueous potassium carbonate until pH = 8. The crude product
was washed with water to give pure yellow solid in 70.2% yield;
1-(2-Chloropyrimidin-4-yl)hydrazine (2) (0.22 g, 1.53 mmol)
was treated in 20 ml glacial acetic acid at 35-40 °C. After a 2 h
reaction time, some unsolvable deposits came out of the
solution, and the mixture was still kept stirred until the reaction
was completed as monitored by TLC. The suspended solid was
collected and washed with ethanol, the mixture of compounds 7
and 8 were obtained as yellow solid, mp > 250 °C; ms: m/z 403,
469, 511, 577, 619, 727, 835, 943, 1051, 1159, 1267, 1375. The
filtrate was removed in vacuo, the white product 9 was isolated
by flash chromatography on silica gel (200-300 mesh), eluent
with petroleum ether (bp 60-90 °C): acetone (1:1, v/v) in 10%
yield; mp 191-193 °C; 1H NMR (300MHz, DMSO-d6): ꢀ 1.95(s,
3H, COCH3), 6.41(br, 1H, pyrimidine 5-H), 7.97(br, 1H,
pyrimidine 6-H), 8.70(br, 1H, NHNH), 9.41 (s, 1H, NHNH); ms:
m/z 186 (M+).
1
mp 167-169 °C; H NMR (300 MHz, CDCl3): ꢀ 1.79-1.89 (m,
6H, NCH2(CH2)3), 2.87 (m, 2H, =CCH2), 3.48(s, 1H, NH), 3.85
(m, 2H, NCH2), 5.81(s, 1H, NH), 8.24 (d, 1H, J = 5.7 Hz,
pyrimidine 5-H), 8.59 (d, 1H, J = 5.7 Hz, pyrimidine 6-H). 13C
NMR (75MHz, CDCl3): ꢀ 164.14, 160.03, 157.93, 157.63,
102.66, 44.21, 32.87, 30.63, 30.38, 25.81. ms (relative intensity
%): m/z 241 (M++2, 15), 240 (M++1, 7), 239 (M+, 47), 204
(100), 111 (17), 96 (15).
Anal. Calcd. for C10H14ClN5 (239.09), C, 50.11; H, 5.89; N,
29.22. Found C, 49.98; H, 6.02; N, 29.18.
Anal. Calcd. for C6H7ClN4O (186.03) (Compound 9): C,
38.62; H, 3.78; N, 30.03. Found C, 38.42; H, 3.75; N, 30.33.
Preparation of 2-(2-Chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-2H-
[1,2,4]triazolo[4,3-a]azepin-3(5H)-one (4).
Acknowledgement.
The hydrazine 3 (0.72 g, 3 mmol), NEt3 (0.94 g, 9.3 mmol)
and DMAP (0.04 g, 0.3 mmol) were placed in 30 ml of dry
CH2Cl2 at –10 °C under N2. A solution of 0.45 g (1.5 mmol)
triphosgene in 6 ml of dry CH2Cl2 was added dropwise and the
red-brown clear solution was kept at –10 °C for a further 2 hours
followed by gradual warming to ambient temperature for 8 h.
The mixture was quenched with 30 ml of water and partitioned
between H2O and CH2Cl2. The organic layer was washed with
brine and dried over anhydrous sodium sulfate, filtered, and the
solvent was removed in vacuo. The white product was isolated
by flash chromatography on silica gel (200-300 mesh), eluent
with petroleum ether (bp 60-90 °C): ethyl acetate (1:1, v/v,
Rf=0.4) in the yield of 44.3%; mp 185-186 °C; 1H NMR
(300MHz, CDCl3): ꢀ 1.79-1.89 (m, 6H, NCH2(CH2)3), 2.87 (m,
2H, =CCH2), 3.84 (m, 2H, NCH2), 8.24(d, 1H, J=5.7 Hz,
pyrimidine 5-H), 8.59 (d, 1H, J=5.7 Hz, pyrimidine 6-H); 13C
NMR (75MHz, CDCl3): ꢀ 161.16 (CO), 160.55, 156.75, 153.16,
152.25, 107.27, 42.64, 30.58, 28.58, 28.08, 25.56; ms (relative
intensity %): m/z 267 (M++2, 33), 266 (M++1, 19), 265 (M+,
100), 181 (19), 168 (34), 158 (17), 156 (51).
This work was supported by the National Key Project for
Basic Research (2003CB114400), the National Natural Science
Foundation of China (20372040), and the Research Foundation
for the Doctoral Program of Higher Education (20050055042).
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