The study on synthesis of some new 1,2,3-triazolylurea and carbonyl amide derivatives

Article abstract of DOI:10.1002/jccs.200300174

The study on syntheses of some N-substituted-N′-[5-methyl-1-(4- chlorophenyl)-1,2,3-triazol-4-yl]-urea 6a-e and N-substituted-[5-methyl-1-(4- chlorophenyl)-1,2,3-triazol-4-yl]carbonyl amide 6f-1 derivatives were reported in this paper. The yielded products 6a-1 were confirmed by elemental analyses, NMR, MS and IR spectra.

Full text of DOI:10.1002/jccs.200300174

Journal of the Chinese Chemical Society, 2003, 50, 1215-1219
1215
The Study on Synthesis of Some New 1,2,3-Triazolylurea and Carbonyl
Amide Derivatives
Heng-Shan Dong* (
National Laboratory of Applied Organic Chemistry, Institute of Organic Chemistry, College of Chemistry and
) and Shi-Qiang Liu (
)
Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, P. R. China
The study on syntheses of some N-substituted-N¢-[5-methyl-1-(4-chlorophenyl)-1,2,3-triazol-4-yl]-urea
6a-e and N-substituted-[5-methyl-1-(4-chlorophenyl)-1,2,3-triazol-4-yl]carbonyl amide 6f-l derivatives
were reported in this paper. The yielded products 6a-l were confirmed by elemental analyses, NMR, MS and
IR spectra.
Keywords: Synthesis; Urea; Carbamide; 5-Methyl-1-(4-chlorophenyl)-1,2,3-triazole; N-substituted-
N¢-[5-methyl-1-(4-chlorophenyl)-1,2,3-triazol-4-yl]-urea derivatives; N-Substituted-
[5-methyl-1-(4-chlorophenyl)-1,2,3-triazol-4-yl]carbonyl amide derivatives; Curtius rear-
rangement.
INTRODUCTION
Some urea (carbamide) derivatives are very good effec-
Thionyl chloride was redistilled (bp 79 °C). 5-Methyl-
1-(4-chlorophenyl)-1,2,3-triazol-4-carboxylic acid 3 was
prepared following methods in the literature.3
tive herbicides1,2 in agriculture. Certain compounds having a
1,2,3-triazole nucleus have been reported as antibacterial,
antifungal, antiviral, anti-inflammatory and analgesic.3 Re-
cently some new 1,2,3-triazole derivatives have been synthe-
sized that inhibits tumor proliferation, invasion, metastasis4
and are useful in treating CRF (corticotropin releasing fac-
tor)-related disorders, particularly anxiety, depression or
other psychiatric, neurological disorders as well as treatment
of immunology, cardiovascular or heart-related diseases, co-
lonic hypersensitivity, associability with psychopathology
disturbances and stress.5 For this reason, synthesis of several
new carbamide derivatives containing a 1,2,3-triazole nu-
cleus in a molecule is very interesting. The title compounds
were prepared according to the following method.
The preparation of 5-methyl-1-(4-chlorophenyl)-1,2,3-
triazol-4-carbonyl chloride 4
Place a mixture of 49.14 g (30 mL, 0.413 mole) of
redistilled thionyl chloride and 10 g (0.042 mole) of com-
pound 3 in a 100 mL round bottomed flask; heat and shake the
mixture on a water bath for 2 hours. Reflux for 2 hours, distil
excess thionyl chloride under reduced pressure and cool to
room temperature. A white solid is obtained and recrystal-
lized with anhydrous diethyl ether. The yield of 4 is a white
crystalline solid, m.p. 149-150 °C, 9.1 g (85%). IR umax
:
3067, 3097 (Ar-H), 1760 (C=O), 1548, 1498 (s, Ar), 1274
(C=N-N), 977.5 (w, -N-N=N-), 464.4 (m, OC Cl ) cm-1. 1H NMR
dH: 7.568-7.611 (d, 2H, J = 8.6 Hz, Ph-H), 7.399-7.442 (d,
2H, J = 8.6 Hz, Ph-H); 2.593 (s, 3H, CH3-) ppm. MS m/z (%):
255 (M , 9%), 227 (10), 220 (12), 199 (11), 192 (27), 164
(37), 154 (26), 152 (86), 128 (12), 113 (31), 111 (100), 75
(96), 63 (19).
EXPERIMENTAL
All melting points are uncorrected and determined on
an XT4-100x microscopic melting point apparatus. IR spectra
were obtained in KBr discs on a Shimadzu IR-435 spectrome-
ter. MS were performed on a HP-5988A spectrometer (EI at
70 eV). 1H NMR spectroscopy (CDCl3 or DMSO-d6) was re-
corded on an Avance DRX 200 NMR instrument with TMS as
an internal standard. Elemental analyses were carried out on a
Yanaco CHN Corder MT-3 analyzer.
The preparation of 5-methyl-1-(4-chlorophenyl)-1,2,3-
triazol-4-carbonyl azide 5
Stir a suspended mixture of compound 4 9 g (0.035
mole), 50 mL n-pentane and sodium azide 3.4 g (0.052
mole) in a 100 mL round bottomed flask until compound 4
has disappeared (track by TLC) at room temperature. The
suspended mixture was filtered and crude solid products

1216 J. Chin. Chem. Soc., Vol. 50, No. 6, 2003
Scheme I The synthesis route of title compounds
Dong and Liu
COOH
CH3
N
N
N2Cl
NH2
Cl
N3
N
NaNO2,HCl
o
NaN3
CH3COCH2COOEt
EtONa,EtOH
SOCl2
C
0~5
Cl
2
Cl
1
Cl
3
O
C
NH
R
N
N
N
CH3
COCl
R=ArNH
CON3
CH3
N
N
Cl
6
N
N
N
CH3
a-e
N
NaN3
RNH2
n-Pentane
O
C
R
N
Cl
4
Cl
5
N
CH3
R=ArNH, RNH or R2N
N
Cl
6f-l
were dissolved with acetone in order to remove less soluble
impurities and then recrystallized. A white solid is obtained.
The yield of 5 is a white crystalline solid, m.p. 129-130 °C
(dec.), 7.9 g (86%). IR u max: 3067, 3098 (Ar-H), 2132, 2167
RESULTS AND DISCUSSION
Some new N-substituted-N¢-[5-methyl-1-(4-chloro-
phenyl)-1,2,3-triazol-4-yl]-urea derivatives 6a-e have been
synthesized by the Curtius rearrangement of 5-methyl-1-
(4-chlorophenyl)-1,2,3-triazol-4-carbonyl azide 5 and the
addition of its products isocyanates with various amino group
derivatives.6 Some new N-substituted-[5-methyl-1-(4-chlo-
rophenyl)-1,2,3-triazol-4-yl]carbonyl amides 6f-l have been
synthesized by the reaction of 5-methyl-1-(4-chlorophenyl)-
1,2,3-triazol-4-carbonyl azide 5 with various amino group
derivatives. We isolated products 6a-e and 6f-l when most of
these reactions yielded the products under reaction condi-
tions. We claim that the reaction mechanism is the following
formation under the neutral reaction conditions. The high
electronegativity of the substitute group on the aromatic cy-
cle decreases the electron density on the amino group nitro-
gen atom; thus aromatic ammine is unsuitable to attack the
carbonyl of compound 5. The nucleophilicity of amino group
derivatives is weak or the obstruction of space is very large,
the reaction products are 6a-e by the Curtius rearrangement
of 5. The nucleophilicity of amino group derivatives is
strong; reaction products are 6f-l by the substitution of 5.
O
C
O
(m,
), 1696 (s, C=O), 1559, 1499
N
N
N
C
N
N
N
O
(s, Ar), 1262 (C=N-N), 1217 (s,
N ), 975.0 (s, -N-N=N-)
C
cm-1. H NMR dH: 7.568-7.611 (d, 2H, J = 8.6 Hz, Ph-H),
7.405-7.462 (d, 2H, J = 8.6 Hz, Ph-H); 2.640 (s, 3H, -CH3)
ppm. MS m/z (%): 262 (M , 4%), 234 (1), 220 (2), 192 (2),
180 (14), 178 (43), 165 (14), 163 (39), 154 (12), 152 (36), 139
(10), 137 (31), 128 (4), 113 (29), 111 (100), 75 (76), 63 (13).
1
General procedure of preparation of N-substituted-N¢-
[5-methyl-1-(4-chlorophenyl)-1,2,3-triazol-4-yl]urea deriv-
atives 6a-l
A solution of the mixture of 1.9 mmole 5-methyl-1-
(4-chlorophenyl)-1,2,3-triazol-4-carbonyl azide 5 and 1.9
mmole amino group derivatives in 5-10 mL DMF was heated
under reflux (range of 80~100 °C) until compound 5 had dis-
appeared. After the reaction mixture was cooled and 5-10 mL
water were added, the solid residue was separated by column
chromatography (CH3CO2CH2CH3:petroleum ether = 1:3) to
afford 6a-l.

Synthesis of 1,2,3-Triazolylurea & Carbonyl Amide Derivatives
J. Chin. Chem. Soc., Vol. 50, No. 6, 2003 1217
Scheme II The reaction mechanism of title compounds 6a-e
O
O
O
C
NH
C
R
N
N N
N
C
O
C
N
N
N
N
N
N
N
N
N
CH
CH
CH
N
N
3
3
CH
N
3
N
3
N2
R'NH2
Cl
5
Cl
Cl
Cl
6a-e
Scheme III The reaction mechanism of title com-
pounds 6f-l
Table 1. Structures, Yields and Melting Points of Alkyl\aryl N-
[5-methyl-1-(4-chlorophenyl)-1,2,3-triazol-4-Yl]-
carbamic Acid Derivatives 6a-l
O
Compounda
R
Yield (%)
M.p. (°C)
O
O
C
R
C
N
N N
6a
6b
6c
6d
6e
6f
6g
6h
6i
a-C10H7-NH-
b
-C10H7-NH-
90
60
49
24
78
95
96
95
97
21
56
87
254-255
244-245
200-201
252-253
186-187
102-103
104-105
137-138
202-203
191-192
200-202
202-203
N
C
N
N3
N
N
NH2R'
3-BrC6H4-NH-
4-BrC6H4-NH-
2,5-Cl2C6H3-NH-
(CH3CH2)2N-
(CH3CH2CH2)2N-
(CH3)3C-NH-
N
N
CH
N
3
CH
N
3
CH
N
3
R'NH2
HN3
Cl
Cl
5
C6H5-NH-
Cl
6f-l
6j
6k
6l
3-BrC6H4-NH-
4-BrC6H4-NH-
4-CH3O-C6H4-NH-
The reaction of 3-BrC6H4-NH2 and 4-BrC6H4-NH2 with
a Satisfactory microanalyses were obtained for all the compounds
azide 5 produces 6c, 6j and 6d, 6k.
75%
70%
6 + 4-BrC6H4NH2
6d + 6k
6 + 3-BrC6H4NH2
6c + 6j
56%
24%
49%
21%
characteristic peaks at 3185-3202, 3265-3270 and 1670-1692
cm-1 could be found. These peaks could be assigned to NH
and nC=O. The vibration bands of N-N=N were in the region of
972-979 cm-1. The IR spectra data of compound 6f-l show
The structure of these compounds was characterized
with 1H NMR, IR and MS spectroscopy and results are given
in Tables 2, 3 and 4. The IR spectra data of compound 6a-e
Table 2. IR Spectral Data for Compounds 6a-l
Compound
IR (cm 1) (KBr disc)
6a
6b
6c
6d
6e
6f
6g
6h
6I
6j
3265, 3185, 3095, 3065, 2918, 1670, 1647, 1613, 1564, 1499, 1264, 1236, 1092, 1007, 972, 833, 788, 762, 700
3267, 3187, 3100, 3049, 2918, 1690, 1611, 1585, 1561, 1503, 1253, 1215, 1095, 1009, 979, 833, 746, 706
3294, 3234, 3100, 3047, 2917, 1718, 1594, 1548, 1498, 1481, 1257, 1230, 1096, 1009, 978, 829, 766, 676, 614
3275, 3201, 3101, 3064, 2925, 1701, 1612, 1556, 1501, 1291, 1251, 1215, 1094, 1007, 976, 828, 752, 705
3270, 3202, 3101, 3061, 2924, 1692, 1615, 1585, 1535, 1504, 1257, 1215, 1094, 1007, 978, 834, 772, 710
3066, 2985, 2966, 2934, 1609, 1544, 1502, 1484, 1458, 1267, 1207, 1093, 1006, 979, 839, 775, 700
3076, 2966, 2932, 2869, 1616, 1556, 1500, 1468, 1431, 1243, 1094, 1005, 977, 835, 751, 706
3100, 3078, 2970, 2928, 1667, 1572, 1505, 1455, 1268, 1217, 1091, 1007, 982, 834, 745, 708
3100, 3054, 2972, 2925, 1673, 1597, 1527, 1495, 1440, 1037, 1272, 1242, 1095, 997, 829, 757, 694
3103, 3075, 2924, 2854, 1675, 1588, 1521, 1495, 1419, 1270, 1240, 1161, 1092, 1068, 984, 830, 779
3383, 3100, 2925, 1684, 1590, 1568, 1522, 1497, 1421, 1300, 1237, 1091, 1068, 1004, 978, 833, 811
3100, 3003, 2953, 2931, 1669, 1612, 1572, 1515, 1497, 1255, 1231, 1177, 1090, 971, 831
6k
6l

1218 J. Chin. Chem. Soc., Vol. 50, No. 6, 2003
Dong and Liu
Table 3. 1H NMR Spectral Data for Compounds
Compound
1H NMR d (ppm)
6a
6b
6c
6d
6e
6f
(CDCl3) 8.613 (b, 1H, NH), 7.442-7.550 (q, 4H, p-C6H4Cl), 7.442-8.274 (m, 7H, a-C10H7), 7.450 (b, 1H, NH), 2.398 (s,
3H, CH3)
(DMSO-d6) 9.074 (b, 1H, NH), 8.581 (b, 1H, NH), 7.677-7.836 (q, 4H, p-C6H4Cl), 7.322-8.048 (m,7H, b-C10H7), 2.256
(s, 3H, CH3)
(DMSO-d6) 9.054 (b, 1H, NH), 8.064 (b, 1H, NH), 7.573-7.617 (d, 2H, J = 8.8 Hz, p-C6H4Cl), 7.426-7.470 (d, 2H, J =
8.8 Hz, p-C6H4Cl), 7.202-7.617 (m, 4H, m-C6H4Br), 2.691 (s, 3H, CH3)
(DMSO-d6) 9.021 (b, 1H, NH), 8.566 (b, 1H, NH), 7.229-7.694 (q, 4H, p-C6H4Cl), 7.229-7.694 (q, 4H, p-C6H4Br), 2.246
(s, 3H, CH3)
(DMSO-d6) 9.438 (b, 1H, NH), 8.930 (b, 1H, NH), 7.505-7.549 (d, 2H, J = 8.8 Hz, p-C6H4Cl), 7.106-7.144 (d, 2H, J =
8.8 Hz, p-C6H4Cl), 7.704, 8.306 (s, 3H, 2, 5-Cl2C6H3), 2.278 (s, 3H, CH3)
(CDCl3) 7.534-7.578 (d, 2H, J = 8.8 Hz, p-C6H4Cl), 7.396-7.440 (d, 2H, J = 8.8 Hz, p-C6H4Cl), 3.805-3.909, 3.522-3.628
(q, 4H, J = 7Hz, 2-CH2-), 1.234-1.306, 1.306-1.385 (t, 6H, J = 7Hz, 2-CH3), 2.534 (s, 3H, CH3)
(CDCl3) 7.532-7.576 (d, 2H, J = 8.8 Hz, p-C6H4Cl), 7.397-7.441 (d, 2H, J = 8.8 Hz, p-C6H4Cl), 3.435-3.512, 3.741-3.818
(t, 4H, J = 7Hz, 2-CH2-), 1.656-1.816 (m, 4H, J = 7Hz, 2-CH2-), 0.867-1.017 (m, 6H, J = 7 Hz,2-CH3), 2.524 (s, 3H,
CH3)
6g
6h
6i
(CDCl3) 7.535-7.579 (d, 2H, J = 8.8 Hz, p-C6H4Cl), 7.374-7.418 (d, 2H, J = 8.8 Hz, p-C6H4Cl), 7.163 (b, 1H, NH), 2.620
(s, 3H, CH3)
(CDCl3) 9.059 (b, 1H, NH), 7.571-7.614 (d, 2H, J = 8.6 Hz, p-C6H4Cl), 7.357-7.398 (d, 2H, J = 8.6 Hz, p-C6H4Cl),
7.128-7.739 (m, 5H, -C6H5), 2.696 (s, 3H, CH3)
6j
6k
6l
(CDCl3) 7.277-7.272 (d, 1H, J = 2 Hz, m-C6H4Br), 7.063 (s, 1H, NH), 6.985-7.204 (d, 2H, J = 8.8 Hz, p-C6H4Cl), 6.838-
6.914 (d, 2H, J = 8.8 Hz, p-C6H4Cl), 6.573-6.900 (m, 3H, m-C6H4Br), 2.691 (s, 3H, CH3)
(CDCl3) 10.070 (b, 1H, NH), 7.835-7.879 (d, 2H, J = 8.6 Hz, p-C6H4Cl), 7.730 (s, 4H, p-C6H4Br), 7.504-7.548 (d, 2H, J
= 8.6 Hz, p-C6H4Cl), 2.572 (s, 3H, CH3)
(CDCl3) 8.961 (b, 1H, NH), 7.563-7.608 (d, 2H, J = 8.8 Hz, p-C6H4Cl), 7.432-7.477 (d, 2H, J = 8.8 Hz, p-C6H4Cl),
7.608-7.654 (d, 2H, J = 9 Hz, p-C6H4OCH3), 6.916-6.961 (d, 2H, J = 9 Hz, p-C6H4OCH3), 3.838 (s, 3H, -CH3), 2.697 (s,
3H, CH3)
Table 4. MS Spectral Data for Compounds 6a-l
No
m/z (%)
M
6a
6b
6c
6d
6e
6f
377(3)
362(1) 349(1) 314(1) 312(4) 237(1) 235(4) 221(2) 208(9) 192(7) 181(9) 179(22) 171(11) 163(13) 154(30) 152(84)
143(80) 138(35) 127(21) 111(100) 102(9) 75(83)
362(2) 349(1) 313(1) 312(1) 237(1) 235(2) 221(3) 208(6) 197(4) 181(10) 179(23) 169(62) 163(9) 154(24) 152(72)
143(100) 138(27) 127(26) 111(77) 102(9) 75(56)
377(3)
405(1.7) 407(1.5) 368(2) 326(1) 264(2) 255(2) 236(3) 234(2) 227(9) 208(5) 199(34) 197(37) 181(17) 179(45) 173(39)
171(52) 165(13) 163(13) 154(25) 152(75) 145(96) 138(31) 131(9) 111(90) 102(8) 75(60) 55(57) 44(100)
405(1)
395(1)
292(1)
320(1)
292(1)
407(1.3) 379(1) 331(1) 252(1) 235(1) 234(1) 225(1) 208(5) 197(22) 181(17) 179(42) 173(37) 171(53) 163(11)
154(28) 152(86) 145(100) 138(35) 127(4) 111(91) 102(7) 75(77)
360(1) 345(1) 332(1) 297(1) 234(1) 219(1) 208(4) 206(4) 189(18) 181(22) 179(60) 171(9) 163(48) 161(57) 154(29)
152(87) 145(96) 138(45) 124(26) 111(100) 102(7) 91(25) 75(86)
221(1) 219(2) 212(5) 207(3) 195(2) 194(5) 181(2) 179(3) 169(2) 167(4) 163(3) 154(6) 152(11) 145(4) 139(5) 135(7)
121(14) 113(15) 111(42) 97(20) 91(63) 69(48) 44(100)
305(1) 291(9) 263(2) 235(17) 222(8) 220(23) 207(1) 194(9) 193(10) 192(13) 180(2) 178(5) 166(8) 164(19) 154(14)
152(45) 138(4) 128(7) 111(45) 100(100) 75(33) 43(66)
6g
6h
6i
277(18) 249(6) 235(2) 222(4) 220(10) 208(10) 207(7) 192(19) 191(11) 181(4) 179(7) 173(4) 167(12) 164(39)
154(13) 152(41) 145(11) 138(13) 127(9) 111(42) 75(50) 57(100)
312(28) 283(1) 269(1) 255(3) 241(3) 234(1) 214(3) 205(1) 194(17) 192(53) 181(4) 179(4) 164(45) 152(35) 146(5) 138(18)
129(20) 127(32) 113(31) 111(100) 93(44) 77(44) 75(72) 65(30)
6j
390(16) 392(23) 363(1) 349(1) 347(1) 321(2) 294(2) 268(2) 247(9) 236(5) 219(5) 194(25) 192(72) 171(9) 164(56) 152(39)
146(6) 143(3) 138(19) 127(45) 111(100) 91(29) 75(84) 63(33)
6k
6l
390(45) 392(60) 335(2) 321(3) 294(3) 268(2) 247(9) 236(7) 219(8) 194(22) 192(59) 171(15) 164(50) 152(46) 146(12) 143(9)
138(23) 127(25) 111(100) 91(25) 75(45) 63(19)
342(46) 311(1) 285(3) 271(8) 251(4) 244(5) 236(2) 219(2) 207(1) 194(9) 192(28) 181(9) 179(9) 164(46) 155(31) 153(100)
140(16) 138(45) 134(16) 128(9) 122(38) 111(96) 108(27) 95(21) 75(59)

Synthesis of 1,2,3-Triazolylurea & Carbonyl Amide Derivatives
J. Chin. Chem. Soc., Vol. 50, No. 6, 2003 1219
characteristic peaks at 3100-3103 and 1609-1675 cm-1 could
be found. These peaks could be assigned to NH and nC=O. The
vibration bands of N-N=N were in the region of 971-997
cm-1.
ACKNOWLEDGEMENTS
The authors wish to acknowledge that this project was
supported by NNSFC (chuangxin qunti, 2002-001), Univer-
sity Key Teacher by the Ministry of Education and Lanzhou
University NLAOC.
Comparing the 1H NMR spectra of 5 with 6, we could
see that after the Curtius rearrangement to 6a-e the most no-
ticeable change is that the signals of amino protons at d
8.613-9.430, 7.450-8.930 ppm appeared. The chemical shift
of the triazole ring methyl group shows in the range d 2.256-
2.620 ppm, whereas the aromatic protons resonate at d
7.229-8.930 ppm. We could see that after the Curtius rear-
rangement to 6f-l the most noticeable change is that the sig-
nals of amino protons at d 7.163-9.059 ppm appeared. The
chemical shift of the triazole ring methyl group shows in the
range d 2.256-2.620 ppm, whereas the aromatic protons reso-
nate at d 6.961-8.064 ppm.
Received September 10, 2002.
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(naphthyloxy). Analyzing the fragments from the subsequent
cleavage of the molecular ions, we found that the MS spectra
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181 (9-22), 179 (22-60), 154 (24-30).
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