Design, synthesis, and anticancer activity evaluation of novel aziridine-1,2,3-triazole hybrid derivatives

Article abstract of DOI:10.1080/00397911.2017.1353632

Some new 1-aryl-4-[(aziridine-1-yl)diaryl-methyl]-5-methyl-1H-1,2,3-triazole derivatives 7j–s were synthesized by the one-pot reaction of diaryl-(1-aryl-5-methyl-1H-1,2,3-triazol-4-yl)methanol compounds 6j–s formed from 1-aryl-5-methyl-1H-1,2,3-triazole-4

Full text of DOI:10.1080/00397911.2017.1353632

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Design, synthesis and anticancer activity
evaluation of novel aziridine-1,2,3-triazole hybrid
derivatives
Hong-Ru Dong, Jian-Guo Wu & Zhong-Lian Gao
To cite this article: Hong-Ru Dong, Jian-Guo Wu & Zhong-Lian Gao (2017): Design, synthesis
and anticancer activity evaluation of novel aziridine-1,2,3-triazole hybrid derivatives, Synthetic
Communications, DOI: 10.1080/00397911.2017.1353632
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1353632
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Date: 01 August 2017, At: 21:36

Design, synthesis and anticancer activity evaluation of novel
aziridine-1,2,3-triazole hybrid derivatives
Hong-Ru Dong*
School of Chemical Engineering, Lanzhou University of Arts and Science, Lanzhou, P.R. China
Jian-Guo Wu
School of Chemical Engineering, Lanzhou University of Arts and Science, Lanzhou, P.R. China
Zhong-Lian Gao
School of Chemical Engineering, Lanzhou University of Arts and Science, Lanzhou, P.R. China
Address correspondence to Hong-Ru Dong. E-mail: donghr@luas.edu.cn
ABSTRACT
Some new 1-aryl-4-[(aziridine-1-yl)diaryl-methyl]-5-methyl-1H-1,2,3-triazole derivatives
7j-s were synthesized by a one-pot reaction of diaryl-(1-aryl-5-methyl-1H-1,2,3-triazol-4-
yl)methanol compounds 6j-s formed from 1-aryl-5-methyl-1H-1,2,3-triazole-4-carboxylic acid
derivatives. The new compounds 7j-s and 6j-s are investigated by 1H and 13C NMR, MS, and IR.
The anticancer activity of the synthesis target compounds was evaluated against human leukemia
(HL-60) cells and human hepatoma G2 cells. Some of the compounds were highly efficient. The
1H-NMR signals of the aziridine-ring cis-H/trans-H protons were found to be two group peaks at
1.800-1.884 and 1.183-1.327 ppm.
1

GRAPHICAL ABSTRACT
KEYWORDS: 1H-1,2,3-triazole, anticancer, aziridine, human hepatoma G2, human leukaemia
(HL-60), synthesis
Introduction
Some reactions and synthetic methodologies have been accompanied by dramatic increases
in molecular complexity and impressive selectivity.[1] The vast majority of reported biologically
important molecules, such as drugs and natural products, contain nitrogen in their framework.
Experience has shown that compounds with biological activity are often derived from heterocyclic
structures. Aziridines are well known as important heterocycles in organic and medicinal
chemistry. In addition to their utility as synthetic endpoints, aziridines are also important
intermediates in organic chemistry.[2] Substituted aziridines are ubiquitous building blocks in
natural products and have important biological activities (Scheme 1). The functionality of aziridine
is present in a small number of naturally occurring molecules. The biological properties of
[5]
aziridine-containing compounds such as azicemicins,[3] miraziridine,[4],
azinomycins,[6]
ficellomycin,[7] FR-900482[8] and mitomycins[9] are of significant interest. The antibiotic and
2

antitumour properties of several such compounds are well-known. Mitomycin C has a broad
activity against a range of tumours and has been applied clinically since the 1960s.
In addition to aziridine, molecules containing the 1,2,3-triazole nucleus are also important
heterocycles and pharmacologically active molecules. Hence, they have been applied extensively
to modify and potentiate anticancer,[10–12] antibacterial,[13], [14] antifungal,[15] antiviral,[16] anti-
inflammatory and analgesic activities.[17] However, there is little information describing
compounds containing these two heterocyclic moieties, aziridine and 1,2,3-triazole, in one
molecule. Because compounds containing aziridines among several active functional groups are
difficult to synthesize, we devoted our attention to the synthesis of this type of compound. Some
new 1-aryl-4-[(aziridin-1-yl)diaryl-methyl]-5-methyl-1H-1,2,3-triazole derivatives have been
synthesized by a one-pot reaction. Substituted 1,2,3-triazoles are often applied as building blocks
in designing drugs to inhibit the growth, invasion and migration of cancer cells (Scheme 2).
Results and Discussion
Some new 1-aryl-4-[(aziridin-1-yl)diaryl-methyl]-5-methyl-1H-1,2,3-triazole derivatives
(7j-s) have been synthesized by the one-pot reaction of diaryl-(1-aryl-5-methyl-1H-1,2,3-triazol-
4-yl) methanol (6j-s) beginning from 1-aryl-5-methyl-1H-1,2,3-triazole-4-carboxylic acid
derivatives. The synthetic route is shown in Scheme 3.
Our interest in the development of some new 1-aryl-4-[(aziridin-1-yl)diaryl-methyl]-5-
methyl-1H-1,2,3-triazole derivatives (7j-s) with anticancer activities and in extending this type of
one-pot reaction prompted us to examine potential applications and generalizations for the
synthesis of compounds with substituted aziridine and 1,2,3-triazole.
3

When 1-aryl-4-[(aziridin-1-yl)diaryl-methyl]-5-methyl-1H-1,2,3-triazole derivatives were
synthesized by a one-pot reaction, PCl3/dry benzene followed by dry benzene, aziridine, Et3N, and
acetonitrile were applied to the reaction, and the yield was 32%. When PCl3 was replaced by POCl3
in dry benzene, and benzene, aziridine, Et3N, and acetonitrile were applied to the reaction, the
yield was 25%. When SOCl2 was applied to the one-pot reaction in dry benzene, and then benzene,
aziridine, Et3N, and acetonitrile were applied to the reaction, the yield was 41%. When dry HCl/dry
benzene were refluxed, and benzene, aziridine, Et3N, and acetonitrile were applied to the reaction,
the yield was a good 86%. If Et3N was not applied to the reaction in the second step, the yield was
relatively low.
As we know, aziridine and 1,2,3-triazole were the functional groups. Their main function
was to provide high biological activity. In designing the new synthetic route, in this paper, we
synthesized the new compounds 6j-s and 7j-s. Aziridine and 1,2,3-triazole were connected to one
structure among compounds 7j-s that had anticancer activity. This synthesis is the biggest bright
spot in this paper.
A hydroxy compound was identified as showing IR absorption at 3320-3524 cm-1 in 6j-s,
but this signal disappeared in compounds 7j-s. 1H NMR showed the proton signals of the aziridine
ring at 1.800-1.884 and 1.183-1.327 ppm in compounds 7j-s.
13
13
Compound 7n was characterized by 1D and 2D NMR (1H, C and C -1H COSY or
gHSQC). The 1H and 13C NMR chemical shifts and coupling constant data for 7n were determined
1
(Figures 1 and 2). In the H NMR spectrum, the signals of most protons were shown as general
1H NMR spectrum absorption peaks and JH-H coupling patterns, except for the proton signal of the
CH2 group connected to the N atom in the aziridine-ring. In the normal case, it appeared as a sharp
peak at ~2.50 ppm, according to earlier literature.[18], [19] We found two group peaks at 1.800-1.884
4

and 1.183-1.327 ppm in compounds 7j-s. To determine the two group peaks, a 13C-1H one-bond
13
correlation experiment (13C -1H COSY) was applied. From the C -1H COSY (Figure 3; Table
1) spectra and spectral data, we observed strong cross peaks for carbon and hydrogen. Then, we
determined that the two group peaks at 1.800-1.884 and 1.183-1.327 ppm were the signal of the
aziridine-ring cis-H/trans-H proton. Since we had achieved unambiguous assignments for all the 1H
13
signals, 13C signals were assigned in a straightforward manner by analysis of the C -1H COSY
spectra for the proton and carbon atoms. It is worth mentioning that the cis-H/trans-H protons of the
methylene groups attached directly to the central N atom appear as two group peak signals,
probably due to the presence of this central N atom in the aziridine-ring.
If the target compound was substituted at the 2-position of the Ar group attached to the
triazole, the chemical shift of the triazole-ring methyl proton was decreased from ~2 ppm to 1.696-
1.792 ppm in compounds 7j, 7k, 7m, 7n, and 7r, which was due-to the steric hindrance of the
aromatic ring substituted at the 2-position and the triazole-ring, as the methyl proton was in the
shielding environment of the aromatic ring current.
Experimental Section
5-Methyl-1-substituted-1,2,3-triazol-4-carboxylic acids were prepared by an
existing literature method; ethyl 1-aryl-5-methyl-1H-1,2,3-triazol-4-carboxylate 5
was also prepared by a literature method.[20] Therefore, we used the same method
to synthesize some new compounds, (1-aryl-5-methyl-1H-1,2,3-triazol-4-
yl)diarylmethanols 6j-s
5

A three-necked round-bottomed flask (250 mL) was fitted with an efficient stirrer unit, a
dropping funnel and an efficient reflux condenser; calcium chloride guard-tubes were placed on
the top of the funnel and on the condenser. All parts of the apparatus were thoroughly dry. First,
1.06 g (0.044mole) of fresh magnesium turnings and a few crystals of iodine were placed in the
flask, 5 mL of sodium-dried diethyl ether was added, and then 2 mL of a mixture of 0.044 mole
(4.4 mL) bromo-benzene and 30 mL sodium-dried diethyl ether was added directly to the flask.
After the reaction had proceeded for a few minutes and the iodine colour had disappeared, the
bottom of the flask was heated with a bath of hot water until the iodine began to vaporize and was
then allowed to cool. The remainder of the bromo-benzene and ether were dropped into the flask
through the dropping funnel under stirring. Stirring and refluxing were continued for an hour after
the dropwise addition was completed.
A mixture of ethyl 1-aryl-5-methyl-1H-1,2,3-triazole-4-carboxylate (0.02 mole)[20] in
benzene was added completely. Stirring was continued for 2~3 h at room temperature. The mixture
was decomposed by a mixture of ice, water and ammonium chloride. The organic layer was
separated, and the solvent was distilled off. The crude product was recrystallized from benzene to
give 6j-s. Some of the new compounds (1-aryl-5-methyl-1H-1,2,3-triazol-4-yl)diarylmethanols 6j-
s are shown below:
(5-Methyl-1-o-tolyl-1H-1, 2,3-triazol-4-yl)diphenylmethanol 6j,
Yield 84%, white flaky crystals, m.p. 127-128oC. 1H NMR (CDCl3-d1), δ7.229-7.463(m,
4H, Ar1-3,4,5,6), 7.327-7.360(m, 10H, Ar2), 4.306(s, 1H, OH), 2.037 (s, 3H, Ar1-CH3), 1.528(s,
13
3H, TRZ-CH3). C NMR (CDCl3-d1), δ 148.7, 145.2, 135.6, 135.1, 131.1, 131.2, 130.4, 128.0,
127.8, 127.6, 127.4, 126.9, 17.1, 8.6; MS m/z: 355(6.8) (M+), 326(100), 310(31), 250(12), 222(7.5),
6

207(12), 143(11), 132(26), 107(32), 105(66), 91(43), 77(52), 64(42). IR: 3385(b, OH), 3085, 3057,
3026(m, Ar-H), 2959, 2925, 2856(w, CH3), 1598, 1551 (w), 1493, 1446(s, Ar), 1465, 1373(m,
CH3), 1317(m, OH), 1267, 1214(m), 1131, 1028, 894(s, triazole ring), 1166(s, C-O), 770, 760,
699(s, Ar-H) cm-1. Calcd for C23H21N3O: C, 77.72; H, 5.96; N, 11.82; Found: C, 77.75; H, 5.98;
N, 11.86.
[1-(2-Chlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]diphenylmethanol 6k,
1
Yield 83%, white flaky crystals, m.p. 157-158oC. H NMR (CDCl3-d1), δ7.565-7.590(d,
1H, J = 7.5Hz, Ar1-3), 7.432-7.524(m, 3H, Ar1-4,5,6), 7.284-7.358(m, 10H, Ar2), 4.288(s, 1H,
13
OH), 1.574(s, 3H, TRZ-CH3). C NMR (CDCl3-d1), δ 148.7, 145.1, 133.8, 132.8, 131.9, 131.6,
130.4, 129.3, 128.0, 127.9, 127.8, 127.7, 8.6; MS m/z: 375(5.7) (M+), 377(2.7), 348(30), 346(100),
332(11), 330(27), 294(10), 272(2.7), 270(9), 244(4.6), 242(13), 207(14), 167(8), 165(20), 154(13),
152(41), 129(14), 127(45), 113(18), 111(48), 105(66), 77(35). IR: 3400(b, OH), 3088, 3060,
3027(m, Ar-H), 2924(w, CH3), 1596, 1552(w), 1491, 1447 (s, Ar), 1372(m, CH3), 1321(m, OH),
1274, 1211, 1134(m), 1026, 895(s, triazole ring), 1167(s, C-O), 767, 699(s, Ar-H), 1083, 639(m)
cm-1. Calcd for C22H16ClN3O: C, 70.32; H, 4.83; Cl, 9.43;N, 11.18; Found: C, 70.35; H, 4.84; N,
11.16.
[1-(3-Chlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]diphenylmethanol 6l,
Yield 80%, white needle crystals, m.p. 156-157oC. 1H NMR (CDCl3-d1), δ7.466-7.492(m,
3H, Ar1-2,4,6), 7.250-7.434(m, 11H, Ar1-5, Ar2), 4.124(s, 1H, OH), 1.782(s, 3H, TRZ-CH3). 13C
NMR (CDCl3-d1), δ 149.6, 145.0, 137.2, 135.2, 131.2, 130.4, 129.7, 128.1, 127.7, 125.8, 123.6,
9.5; MS m/z: 375(4.6) (M+), 377(2.1), 348(31), 346(100), 332(8.6), 330(22), 294(5), 272(3),
270(10), 244(3), 242(11), 207(11), 167(4.8), 165(15), 154(10), 152(33), 129(11), 127(34), 113(10),
7

111(28), 105(53), 77(30). IR: 3443(b, OH), 3081, 3025(m, Ar-H), 2928(w, CH3), 1591, 1550(w),
1489, 1445(s, Ar), 1393(m, CH3), 1344(m, OH), 1273, 1221(m), 1140, 1047, 900(s, triazole ring),
1164(s, C-O), 875, 792, 769, 697(s, Ar-H), 1253, 1094, 630(s) cm-1. Calcd for C22H18ClN3O: C,
70.30; H, 4.83; Cl, 9.43;N, 11.18; Found: C, 70.32; H, 4.85; N, 11.20.
[1-(2,5-Dichlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]diphenylmethanol 6m,
Yield 92%, white flaky crystals, m.p. 166-167oC. 1H NMR (CDCl3-d1), δ7.496(s, 3H, Ar1-
3,4,6), 7.260-7.420(m, 10H, Ar2), 4.169(s, 1H, OH), 1.593(s, 3H, TRZ-CH3). 13C NMR (CDCl3-
d1), δ 148.9, 144.9, 134.6, 133.6, 132.9, 131.8, 131.3, 130.4, 129.6, 128.6, 127.7, 8.6; MS m/z:
409(3.1) (M+), 413(0.6), 411(2), 384(10), 382(53), 380(82), 368(2), 366(12), 364(17), 330(2),
328(7), 308(0.7), 306(3), 304(5), 280(2), 278(9), 276(12), 243(5), 241(13), 201(3), 199(5), 190(5),
188(19), 186(28), 161(17), 149(4), 147 (13), 145(18), 105(100), 77(46). IR: 3524(b, OH), 3055,
3027(m, Ar-H), 2926, 2852(w, CH3), 1584(m), 1486, 1445(s, Ar), 1366(s, CH3), 1304(m, OH),
1263, 1210(m), 1122, 1016, 908(s, triazole ring), 1164(s, C-O), 824, 763, 700(s, Ar-H), 1097,
578(s) cm-1. Calcd for C22H17Cl2N3O: C, 64.40; H, 4.18; Cl, 17.28; N, 10.24; Found: C, 64.42; H,
4.16; N, 10.22.
[1-(2-Bromophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]diphenylmethanol 6n,
1
Yield 82%, white flaky crystals, m.p. 158-159oC. H NMR (CDCl3-d1), δ7.737-7.762(d,
1H, J = 7.5Hz, Ar1-3), 7.395-7.501(m, 3H, Ar1-4,5,6), 7.315-7.344(m, 10H, Ar2), 4.279(s, 1H,
13
OH), 1.555(s, 3H, TRZ-CH3). C NMR (CDCl3-d1), δ 148.8, 145.1, 135.5, 133.6, 132.6, 131.9,
129.4, 128.5, 128.1, 127.8, 127.7, 121.9, 8.7; MS m/z: 419(2.8) (M+), 421(2.7), 392(46), 390(53),
376(9), 374(12), 316(1.6), 314(2.3), 288(7.2), 286(7.8), 234(14), 207(15), 198(15), 196(17),
173(18), 171(20), 157(13), 155(15), 129(26), 105(100), 77(52). IR: 3395(b, OH), 3086, 3059,
8

3026(w, Ar-H), 2924(w, CH3), 1596, 1551(w), 1489, 1447 (m, Ar), 1373(m, CH3), 1322(m, OH),
1273, 1212, 1130(m), 1026, 894(s, triazole ring), 1166(m, C-O), 768, 749, 698(s, Ar-H), 1068,
639, 567(m) cm-1. Calcd for C22H18BrN3O: C, 62.87; H, 4.32; Br, 19.01; N, 10.00; Found: C,
62.88; H, 4.34; N, 10.01.
[1-(4-Bromophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]diphenylmethanol 6o,
Yield 91%, white needle crystals, m.p. 159-160oC. 1H NMR (CDCl3-d1), δ7.628-7.682(d,
2H, J = 8.1Hz, Ar1-3,5), 7.272-7.350(m, 12H, Ar1-2,6, Ar2), 4.165(s, 1H, OH), 1.773(s, 3H, TRZ-
CH3). 13C NMR (CDCl3-d1), δ 149.6, 145.0, 135.1, 132.6, 131.1, 128.3, 128.1, 127.7, 126.9, 123.6,
9.5; MS m/z: 419(1.4) (M+), 421(1.3), 392(98), 390(100), 376(20), 374(22), 316(6), 314(6.5),
288(6), 286(6.9), 234(17), 207(33), 198(32), 196(34), 173(39), 171(44), 157(27), 155(19), 129(16),
105(90), 77(45). IR: 3320(b, OH), 3089, 3055, 3025(w, Ar-H), 2930(w, CH3), 1596, 1551(w),
1493, 1446 (s, Ar), 1398(m, CH3), 1349(m, OH), 1273, 1222, 1137(m), 1048, 901(s, triazole ring),
1184(m, C-O), 827, 759, 699(s, Ar-H), 1073, 731, 630(m) cm-1. Calcd for C22H16BrN3O: C, 62.87;
H, 4.32; Br, 19.01; N, 10.00; Found: C, 62.89; H, 4.34; N, 10.02.
[1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl]diphenylmethanol 6p,
Yield 89%, white needle crystals, m.p. 167-168oC. 1H NMR (CDCl3-d1), δ7.268-7.370(m,
12H, Ar1-2,6, Ar2), 7.000-7.030(d, 2H, J = 9.0Hz, Ar1-3,5), 4.198(s, 1H, OH), 3.868(s, 3H, Ar1-
OCH3), 1.699(s, 3H, TRZ-CH3). 13C NMR (CDCl3-d1), δ 160.3, 149.0, 145.2, 131.2, 129.1, 128.0,
127.8, 127.6, 126.9, 114.5, 55.6, 9.4; MS m/z: 371(0.8) (M+), 342(100), 326(14), 266(6), 238(14),
223(7.9), 161(4.6), 148(23), 123(28), 108(9), 105(40), 92(6), 77(26). IR: 3373(b, OH), 3078,
3018(w, Ar-H), 2971, 2941, 2845(w, CH3), 1610, 1551(w),1515, 1448(s, Ar), 1383(w, CH3),
1348(m, OH), 1254, 1044(s, C-O-C), 1165(s, C-O),1304, 1223, 1135, 1021, 902(s, triazole ring),
9

837, 758, 702(s, Ar), 731, 629(m) cm-1. Calcd for C23H21N3O2: C, 74.37; H, 5.70; N, 11.31; Found:
C, 74.35; H, 5.72; N, 11.29.
[1-(4-Ethoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl]diphenylmethanol 6q,
Yield 78%, white needle crystals, m.p. 117-118oC. 1H NMR (CDCl3-d1), δ7.270-7.379(m,
12H, Ar1-2,6, Ar2), 6.975-7.004(d, 2H, J = 8.7Hz, Ar1-3,5), 4.284(s, 1H, OH), 4.038-4.109(q, 2H,
J = 6.9Hz, Ar1-OCH2-), 1.705(s, 3H, TRZ-CH3), 1.418- 1.463(t, 3H, J = 6.9Hz, Ar1-OCH2CH3).
13C NMR (CDCl3-d1), δ 159.7, 149.0, 145.2, 131.2, 128.9, 128.0, 127.8, 127.6, 126.9, 114.9, 63.9,
14.7, 9.4; MS m/z: 385(0.4) (M+),356(100), 340(18), 280(5), 252(18), 224(4.3), 175(4.7), 162(22),
137(26), 121(2), 105(52), 93(4), 91(5), 77(22). IR: 3335(b, OH), 3084, 3060, 3024(w, Ar-H), 2975,
2930(w, CH3), 2759(w, OCH2), 1605, 1553(w), 1515, 1446(s, Ar), 1389(m, CH3), 1251, 1044(s,
C-O-C), 1172(s, C-O), 1298, 1210, 1139, 1025, 899(m, triazole ring), 838, 763, 703(s, Ar), 636(m)
cm-1. Calcd for C24H23N3O2: C, 74.78; H, 6.01; N, 10.90; Found: C, 74.77; H, 6.00; N, 10.92.
[5-Methyl-1-(naphthalen-1-yl)-1H-1,2,3-triazol-4-yl]diphenylmethanol 6r,
1
Yield 84%, white flaky crystals, m.p. 153-154oC. H NMR (CDCl3-d1), δ8.001-8.027(d,
1H, J = 7.8Hz, Ar1-5), 7.923-7.948(d, 1H, J = 7.5Hz, Ar1-8), 7.480- 7.560(m, 4H, Ar1-2,3,6,7),
7.302-7.429(m, 10H, Ar2), 7.153-7.181(d, 1H, J = 8.4Hz, Ar1-4), 4.365(s, 1H, OH), 1.528(s, 3H,
TRZ-CH3). 13C NMR (CDCl3-d1), δ 148.8, 145.2, 134.1, 133.1, 132.3, 130.7, 129.8, 128.3, 128.1,
128.0, 127.8, 127.7, 127.1, 125.4, 125.0, 122.0, 8.8; MS m/z: 391(0.5) (M+), 362(100), 346(30),
286(10), 258(41), 243(23), 180(45), 168(29), 143(41), 127(63), 105(40), 101(6), 77(27). IR:
3406(b, OH), 3090, 3058, 3006(w, Ar-H), 2928(w, CH3), 1596, 1558(w), 1489, 1444 (m, Ar),
1379(w, CH3), 1305(m, OH), 1256, 1202, 1046, 884(m, triazole ring), 1128 (m, C-O), 820, 774,
10

697(s, Ar) cm-1. Calcd for C26H21N3O: C, 79.77; H, 5.41; N, 10.73; Found: C, 79.76; H, 5.43; N,
10.76.
[5-Methyl-1-(naphthalen-1-yl)-1H-1,2,3-triazol-4-yl]diphenylmethanol 6s,
Yield 84%, white flaky crystals, m.p. 133-134oC. 1H NMR (CDCl3-d1), δ7.882-7.999(m,
4H, Ar1-5,6,7,8), 7.515-7.618(m, 3H, Ar1-1,3,4), 7.288-7.401(m, 10H, Ar2), 4.261(s, 1H, OH),
1.803(s, 3H, TRZ-CH3). 13C NMR (CDCl3-d1), δ 149.4, 145.2, 133.5, 133.2, 132.9, 131.3, 129.6,
128.3, 128.1, 127.9, 127.8, 127.6, 127.4, 127.3, 124.4, 123.0, 9.6; MS m/z: 391(1) (M+), 362(100),
346(31), 286(14), 258(60), 243(32), 180(18), 168(31), 143(47), 127(64), 105(57), 101(6), 77(36).
IR: 3492(b, OH), 3059, 3028(w, Ar-H), 2924(w, CH3), 1600, 1553(w), 1510, 1446(m, Ar), 1387(w,
CH3), 1356(m, OH), 1250, 1126, 1045, 894(m, triazole ring), 1167(m, C-O), 859, 814, 755, 699(s,
Ar) cm-1. Calcd for C26H21N3O: C, 79.77; H, 5.41; N, 10.73; Found: C, 79.76; H, 5.43; N, 10.75.
Some new 1-aryl-4-[(aziridin-1-yl)diaryl-methyl]-5-methyl-1H-1,2,3-triazole
derivatives 7j-s were prepared by one-pot synthesis
A mixture of 0.04 mole (1-aryl-5-methyl-1H-1,2,3-triazol-4-yl)diphenylmethanol 6j-s, 20
mL benzene was placed in a 50 mL three-necked round-bottomed flask equipped with an automatic
water separator carrying a reflux condenser with calcium chloride guard-tubes. All parts of the
apparatus were thoroughly dry. The bottom of the flask was refluxed with a bath of hot oil under
rapid stirring. Dry hydrogen chloride was passed into the three-neck bottle until the lighter benzene
passed back into the flask. The reaction device was changed to a distillation apparatus, and the
solvent benzene was evaporated. The heating device was removed, 10 mL anhydrous benzene was
added, and 0.06 mole aziridine was added under rapid stirring. When the solution turned yellow,
0.08 mole triethylamine was added. After the mixture solution was stirred at 45 °C for
11

approximately an hour, the solvent was evaporated, and the raw product was given. Either it was
recrystallized with ethyl acetate, or the crude product was purified by column chromatography
with silica gel as the adsorbent and ethyl acetate/petroleum ether as the eluent. Compounds 7j-s
were given. The physical constants and yields of compounds7j-s are shown below:
4-[(Aziridin-1-yl)diphenylmethyl]-5-methyl-1-(2-tolyl)-1H-1,2,3-triazole 7j,
Yield 87%, white flaky crystals, m.p. 170-171 oC. 1H NMR (CDCl3-d1), δ7.587-7.616(m,
4H, Ar1-3,4,5,6), 7.204-7.419(m, 10H, Ar2), 1.979(s, 3H, TRZ-CH3), 1.837-1.843(d, 2H, J =
13
1.8Hz, AZI-CH2-), 1.696(s, 3H, Ar-CH3), 1.241-1.252(d, 2H, J = 3.3Hz, AZI-CH2-); C NMR
(CDCl3-d1), δ144.5, 144.1, 135.6, 135.3, 134.1, 131.0, 130.1, 128.8, 127.5, 127.4, 126.73, 126.71,
69.6, 21.8, 17.0, 9.6. MS m/z: 380(M+), 0.74), 351(0.61), 338(7.5), 323(0.39), 310(0.76),
247(0.36), 232(0.41), 217 (0.69), 204(0.57), 190(0.85), 178(4.5), 165(2.8), 152(1.5), 132(100),
117(4), 91(45), 77(8), 65(22). IR: 3054, 3019(m, Ar-H), 2988, 2922, 2852(m, CH3, CH2), 1596(w),
1491, 1444(s, Ar), 1382(m, CH3), 1261, 993, 903(s, triazole ring), 1116(m, C-N), 768,745, 699(s,
Ar-H) cm-1. Anal. Calcd for C25H24N4: C, 78.92; H, 6.36; N, 14.73; Found: C, 78.67; H, 6.08; N,
14.56.
4-[(Aziridin-1-yl)diphenylmethyl]-5-methyl-1-(2-chlorophenyl)-1H-1,2,3-triazole
7k,
Yield 88%, white flaky crystals, m.p. 171-172 oC. 1H NMR (CDCl3-d1), δ7.558-7.618(m,
4H, Ar1-3,4,5,6), 7.200-7.450(m, 10H, Ar2), 1.850(s, 2H, AZI-CH2-), 1.725(s, 3H, TRZ-CH3),
1.270(s, 2H, AZI-CH2-); 13C NMR (CDCl3-d1), δ144.4, 135.1, 134.1, 132.1, 131.5, 130.4, 129.4,
128.8(×2), 127.8, 127.6, 126.8, 69.6, 21.9, 9.6. MS m/z: 400(M+, 0.26), 371(0.14), 360(1.1),
358(4.5), 346(0.89), 330(0.72), 267(0.14), 252 (0.23), 217(0.66), 203(0.9), 190(1.6), 178(7.8),
12

165(4.9), 154(32), 152(100), 113(9.4), 111(29), 75(17). IR: 3051, 3022(m, Ar-H), 2990, 2921,
2851(m, CH3, CH2), 1595(w), 1491, 1444(s, Ar), 1385(m, CH3), 1256, 989, 903(s, triazole ring),
1117(s, C-N), 767, 744, 697(s, Ar- H), 1081(m) cm-1. Anal. Calcd for C24H21ClN4: C, 71.90; H,
5.28; Cl, 8.84; N, 13.98; Found: C, 71.76; H, 5.08; Cl, 8.63; N, 14.06.
4-[(Aziridin-1-yl)diphenylmethyl]-5-methyl-1-(3-chlorophenyl)-1H-1,2,3-triazole
7l,
Yield 90%, white flaky crystals, m.p. 149-150 oC. 1H NMR (CDCl3-d1), δ7.441-7.562(m,
7H, Ar1-2,4,5,6, Ar2), 7.255-7.336(m, 7H, Ar2), 2.098(s, 3H, TRZ- CH3), 1.803-1.822(t, 2H, J =
1.9Hz, AZI-CH2-), 1.185-1.205(t, 2H, J = 1.9Hz, AZI-CH2-); 13C NMR (CDCl3-d1), δ146.6, 143.2,
137.4, 135.0, 132.8, 130.3, 129.4, 129.2, 127.5, 126.9, 125.9, 123.7, 70.0, 21.7, 10.5. MS m/z:
400(M+, 0.72), 402(0.24), 371(0.5), 360(2.1), 358(4.7), 343(0.72), 330(0.52), 267(0.15),
252(0.74), 219(2.9), 202(0.87), 190(1.2), 178(5.8), 165(3.8), 154(25), 152(100), 113(11), 111(33),
75(12). IR: 3059, 3022(m, Ar-H), 2989, 2925, 2850(m, CH3, CH2), 1592, 1489, 1441(s, Ar),
1388(m, CH3), 1263, 1013, 902(s, triazole ring), 1118(m, C-N), 873, 783, 748, 703(s, Ar-H),
1089(s) cm-1. Anal. Calcd for C24H21ClN4: C, 71.90; H, 5.28; Cl,8.84; N, 13.98; Found: C, 71.82;
H, 5.02; Cl,8.70; N, 14.03.
4-[(Aziridin-1-yl)diphenylmethyl]-5-methyl-1-(2,5-dichlorophenyl)-1H-1,2,3-
triazole 7m,
Yield 89%, white needle crystals, m.p. 159-160oC. 1H NMR (CDCl3-d1), δ 7.450-7.598(m,
7H, Ar1-3,4,6, Ar2), 7.195-7.356(m, 6H, Ar2), 1.834-1.853(t, 2H, J = 1.9Hz, AZI-CH2-), 1.792(s,
3H, TRZ-CH3), 1.253(s, 2H, AZI-CH2-); 13C NMR (CDCl3-d1), δ145.0, 143.9, 135.0, 134.9, 133.5,
131.6, 131.1, 130.5, 129.6, 128.8, 127.6, 126.9, 69.6, 21.8, 9.7. MS m/z: 434(M+, 0.24), 405(0.13),
13

396(0.37), 394(2.7), 392(4.3), 374(0.37), 366(0.45), 364(0.7), 328(0.17), 252(0.59), 217(0.75),
202(1.6), 198(2.9), 196(2.7), 190(13), 188(65), 186(100), 178(14), 165(6.4), 151(5.1), 147(13),
145(20), 109 (13), 77(16). IR: 3061, 3024(m, Ar-H), 2984, 2924(m, CH3, CH2), 1586(m), 1487,
1446(s, Ar), 1384 (m, CH3), 1262, 1019, 902(s, triazole ring), 1117(m, C-N), 876, 829, 748, 703(s,
Ar- H), 1095(s)cm-1. Anal. Calcd for C24H20Cl2N4: C, 66.21; H, 4.63; Cl, 16.29; N, 12.87; Found:
C, 66.34; H, 4.82; Cl, 16.35; N, 12.63.
4-[(Aziridin-1-yl)diphenylmethyl]-5-methyl-1-(2-bromophenyl)-1H-1,2,3-triazole
7n,
Yield 91%, white flaky crystals, m.p. 164-165oC. 1H NMR (CDCl3-d1), δ 7.604-7.740(m,
5H, Ar1-3,4,5,6, Ar2), 7.216-7.462(m, 9H, Ar2), 1.843(s, 2H, AZI-CH2-), 1.707(s, 3H, TRZ-CH3),
1.283(s, 2H, AZI-CH2-); 13C NMR (CDCl3-d1), δ144.3, 135.7, 134.9, 133.5, 131.7, 129.4, 128.7,
128.4, 127.6(×2), 126.8, 122.1, 69.6, 21.9, 9.8. MS m/z: 444(M+, 0.25), 446(0.24), 417(0.25),
415(0.29), 404(5.6), 402(4), 387(0.11), 374(1.1), 311(0.13), 294(2.1), 252(1), 217(1.8), 208(0.85),
202(2.4), 198(95), 196 (100), 190(3.1), 178(17), 165(8.6), 157(26), 155(28), 152(6.5), 77(27). IR:
3087, 3054, 3018(m, Ar-H), 2990, 2926(m, CH3, CH2), 1583(w), 1489, 1443(s, Ar), 1384(m,
CH3), 1253, 993, 903(s, triazole ring), 1120(s, C-N), 766, 745, 698(s, Ar- H), 1071(m)cm-1. Anal.
Calcd for C24H21BrN4: C, 64.73; H, 4.75; Br, 17.94; N, 12.58; Found: C, 64.56; H, 4.55; Br, 17.76;
N, 12.32.
4-[(Aziridin-1-yl)diphenylmethyl]-5-methyl-1-(4-bromophenyl)-1H-1,2,3-triazole
7o,
1
Yield 91%, white flaky crystals, m.p. 178-179oC. H NMR (CDCl3-d1), δ 7.632-7.660(d,
2H, J = 8.4Hz, Ar1-3,5), 7.517-7.544(d, 4H, J = 8.1Hz, Ar2-2,6), 7.210-7.360(m, 8H, Ar2), 2.083(s,
14

3H, TRZ-CH3), 1.800(s, 2H, AZI-CH2-), 1.183(s, 2H, AZI-CH2-); 13C NMR (CDCl3-d1), δ146.6,
143.2, 135.4, 132.7, 132.5, 129.2, 127.4, 127.0, 126.8, 123.3, 70.0, 21.7, 10.5. MS m/z: 444(M+,
0.13), 446(0.12), 417(0.27), 415(0.13), 404(3.8), 402(4.4), 387(0.28), 374(0.5), 294(0.97), 252(1),
217(1.4), 208(0.92), 202(2.1), 198(89), 196(100), 190 (2.5), 178(20), 165(8.8), 157(30), 155(32),
152(5.5), 76(31). IR: 3055, 3023(m, Ar-H), 2987, 2922, 2851(m, CH3, CH2), 1595(w), 1491,
1446(s, Ar), 1397(m, CH3), 1261, 1004, 906(s, triazole ring), 1120(m, C-N), 831, 749, 706(s, Ar-
H), 1070(s) cm-1. Anal. Calcd for C24H21BrN4: C, 64.73; H, 4.75; Br, 17.94; N, 12.58; Found: C,
64.60; H, 4.65; Br, 17.80; N, 12.30.
4-[(Aziridin-1-yl)diphenylmethyl]-5-methyl-1-(4-methoxyphenyl)-1H-1,2,3-
triazole 7p,
1
Yield 89%, white flaky crystals, m.p. 152-153oC. H NMR (CDCl3-d1), δ7.547-7.583(d,
4H, J = 7.2Hz, Ar2-2,6), 7.219-7.348(m, 8H, Ar1-2,6, Ar2), 6.970- 7.014(d, 2H, J = 8.8Hz, Ar1-
3,5), 3.851(s, 3H, Ar1-OCH3), 1.967(s, 3H, TRZ-CH3), 1.804-1.819(t, 2H, J = 1.5Hz, AZI-CH2-),
1.218(s, 2H, AZI-CH2-); 13C NMR (CDCl3-d1), δ160.1, 145.6, 143.7, 133.1, 129.3, 129.1, 127.4,
127.0, 126.7, 114.3, 69.9, 55.6, 21.7, 10.4. MS m/z: 396(M+, 1.1), 367(1.7), 354(11), 341(5.6),
326(7.3), 294(0.18), 237(0.38), 219(24), 202 (0.5), 191(1.2), 178(5.8), 165(4), 152(3.2), 148(100),
107(6.3), 92(20), 77(47), 43(46). IR: 3052, 3024(m, Ar-H), 2987, 2922, 2844(m, CH3, CH2),
1607(m), 1517, 1443(s, Ar), 1490(s, CH2), 1254(s, C-O-C), 1125(s, C-N), 1007, 905(s, triazole
ring), 835, 753, 705(s, Ar-H) cm-1. Anal. Calcd for C25H24N4O: C, 75.73; H, 6.10; N, 14.13; Found:
C, 75.57; H, 5.98; N, 14.06.
4-[(Aziridin-1-yl)diphenylmethyl]-5-methyl-1-(4-ethoxyphenyl)-1H-1,2,3-triazole
7q,
15

1
Yield 90%, white flaky crystals, m.p. 148-149oC. H NMR (CDCl3-d1), δ7.549-7.589(d,
4H, J = 8Hz, Ar2-2,6), 7.218-7.334(m, 8H, Ar1-2,6, Ar2), 6.955-7.000 (d, 2H, J = 9Hz, Ar1-3,5),
4.018-4.123(q, 2H, J = 7Hz, Ar1-OCH2-), 1.959(s, 3H, TRZ-CH3), 1.803-1.821(t, 2H, J = 1.8Hz,
AZI-CH2-), 1.403-1.473(t, 3H, J = 7Hz, Ar1-CH3), 1.202-1.220(t, 2H, J = 1.8Hz, AZI-CH2-); 13C
NMR (CDCl3-d1), δ159.5, 145.5, 143.8, 133.1, 129.13, 129.07, 127.4, 126.9, 126.7, 114.9, 69.9,
63.8, 21.7, 14.7, 10.4. MS m/z: 410(M+, 2), 381(2.9), 368(15), 353(1.5), 340(14), 312(3.4),
219(10), 208(1.5), 202 (0.6), 190(0.98), 178(7.3), 165(5.5), 162(100), 152(2.7), 134(16), 105 (13),
93(8.4), 91(8.1), 77(25), 65(24), 43(24). IR: 3056(m, Ar-H), 2982, 2930(s, CH3, CH2), 1608, 1517,
1442(s, Ar), 1487, 1395(m, CH3, CH2), 1252, 1044(s, C-O-C), 1111(s, C-N), 1008, 900(s, triazole
ring), 830, 751, 702(s, Ar-H) cm-1. Anal. Calcd for C26H26N4O: C, 76.07; H, 6.38; N, 13.65; Found:
C, 76.27; H, 6.21; N, 13.46.
4-[(Aziridin-1-yl)diphenylmethyl]-5-methyl-1-α-naphthalenyl-1H-1,2,3-triazole
7r,
Yield 89%, white flaky crystals, m.p. 134-136oC. 1H NMR (CDCl3-d1), δ7.906-8.016(m,
2H, Ar1), 7.630-7.670(m, 4H, Ar1), 7.502-7.567(m, 4H, Ar2), 7.236-7.364(m, 6H, Ar2), 7.047-
7.099(d, 1H, J = 10.4Hz, Ar1), 1.868-1.884(t, 2H, J = 1.6 Hz, AZI-CH2-), 1.734(s, 3H, TRZ-CH3),
13
1.321-1.327(d, 2H, J = 0.6Hz, AZI-CH2-); C NMR (CDCl3-d1), δ144.9, 144.0, 135.2, 134.1,
132.6, 130.5, 129.9, 129.0, 128.3, 127.9, 127.6, 126.9, 126.8, 125.4, 125.0, 122.0, 69.8, 21.9, 9.9.
MS m/z: 416(M+, 1.6), 387(3.4), 374(14), 359(0.63), 346(3), 330(0.44), 283(0.17), 268(0.69),
215(0.58), 208(1.1), 202(0.77), 190(0.71), 178(5.1), 168(100), 165(3.5), 152(2.4), 127(47), 77(14).
IR: 3053(m, Ar-H), 2992, 2923(m, CH3, CH2), 1596, 1487, 1445(s, Ar), 1392(m, CH3), 1263, 999,
901(s, triazole ring), 1113(s, C-N), 771, 743, 704(s, Ar-H) cm-1. Anal. Calcd for C28H24N4: C,
80.74; H, 5.81; N, 13.45; Found: C, 80.67; H, 5.88; N, 13.26.
16

4-[(Aziridin-1-yl)diphenylmethyl]-5-methyl-1-β-naphthalenyl-1H-1,2,3-triazole
7s,
Yield 90%, white needle crystals, m.p. 180-181oC. 1H NMR (CDCl3-d1), δ7.860-7.982(m,
4H, Ar1), 7.494-7.610(m, 7H, Ar1, Ar2), 7.197-7.349(m, 6H, Ar2), 2.089(s, 3H, TRZ-CH3),
13
1.836(s, 2H, AZI-CH2-), 1.255(s, 2H, AZI-CH2-); C NMR (CDCl3-d1), δ146.1, 143.6, 133.8,
133.2, 133.1, 133.0, 129.4, 129.2, 128.2, 127.8, 127.5, 127.3, 127.2, 126.8, 124.5, 123.5, 70.0,
21.8, 10.6. MS m/z: 416(M+, 0.43), 387(1), 374(6.6), 359(0.7), 346(1.1), 330(0.29), 283(0.51),
268(0.73), 215(0.88), 208(0.76), 202(1.1), 190(1.7), 178(17), 168(100), 165(5.7), 152(4.7),
127(82), 77(21). IR: 3052, 3028(m, Ar-H), 2983, 2920, 2850(m, CH3, CH2), 1598, 1486, 1444(m,
Ar), 1386(m, CH3), 1261, 1010, 898(s, triazole ring), 1112(s, C-N), 811,750,702(s, Ar-H) cm-1.
Anal. Calcd for C28H24N4: C, 80.74; H, 5.81; N, 13.45; Found: C, 80.62; H, 5.78; N, 13.36.
Biological evaluation of target compounds.
The potential effects on cell viability were investigated under our previously reported
conditions,[21], [22] using the MTT assay [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
bromide, Sigma, France] as an indicator of metabolically active cells.
Human leukaemia cells and human hepatoma G2 cells was plated into 96-well plates at a
density of 5×103 cells/well and incubated for 12 h before the addition of test compounds. Cells
were then exposed for 48 h at 37 °C to known concentrations of the compound to be tested (10 or
160 μM, expressed as final concentration). After drug exposure, the culture medium was removed,
and 200 mL of MTT reagent (diluted in culture medium, 0.25 mg/mL) was added. After incubation
for 4 h, the MTT/medium was removed, and DMSO (200 mL) was added to dissolve the formazan
deposits or crystals. The absorbance of the coloured solution was measured on a microplate
17

photometer (PerkinElmer Victor3) using a test wavelength of 570 nm and a reference wavelength
of 630 nm. The results were evaluated by comparing the absorbance of the wells containing
compound-treated cells with the absorbance of wells containing 0.1% DMSO alone (solvent
control). Conventionally, cell viability was determined for each assay by including wells that did
not contain cells as blank wells. All experiments were performed at least twice in triplicate. The
anticancer activity (IC50) of the synthesized compounds in two cancer cell lines (µM) is shown in
Table 2. The resulting effectiveness was as follows: (+) reflects an inhibition rate >50% for the
growth of tumour cells at 10-5 mol/L; (++++) reflects an inhibition rate >90% at 10-5 mol/L.
Conclusions
Some new 1-aryl-4-[(aziridin-1-yl)diaryl-methyl]-5-methyl-1H-1,2,3-triazole derivatives
(7j-s) were synthesized by a one-pot reaction of diaryl-(1-aryl-5-methyl-1H-1,2,3-triazol-4-
yl)methanol. The synthesis of 1-aryl-4-[(aziridin-1-yl)diaryl-methyl]-5-methyl-1H-1,2,3-triazole
derivatives is a highly efficient one-pot reaction. The anticancer activity of the synthesized
compounds was evaluated. Compound 7j was highly efficient in inhibiting human hepatoma G2
cells, and the compounds 7j, 7m and 7n were highly efficient in inhibiting human leukaemia cells.
Thus, the synthesis and testing in vitro show that the compounds 7j-s can be applied successfully
to design and develop better anticancer agents.
Acknowledgements
The authors wish to acknowledge the funding support by the education department in
Gansu province (2016B-124) and by the Lanzhou University of Arts and Science (High levels of
achievement projects 2015GSP05).
18

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[20] Dong, H. S.; Huo, G. Y.; Ma, Z. T. Indian J. Chem., Sect. B 2008, 47, 171–174.
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[22] Iyengar, B. S.; Dorr, R. T.; Remers, W. A. J. Med. Chem. 2004, 47, 218–223.
19

Table 1. Yield and structure of compounds 6j–s and 7j–s.
Entry
1
Ar
Yield(℅)[a] Yield(℅)[b] -CH3 Aziridine-δH
Aziridine-δH
1.241–
2-CH3C6H4 6j 84
7j 92
1.696 1.837–
1.843d1.8
1.252d3.3
1.270
2
3
2-ClC6H4
3-ClC6H4
6k 83
6l 80
7k 88
7l 90
1.725 1.850
2.098 1.803–
1.185–
1.822t1.9
1.792 1.834–
1.853t1.9
1.205t1.9
1.253
4
2,5-
6m 92
7m 89
Cl2C6H3
5
6
7
2-BrC6H4
4-BrC6H4
6n 82
6o 91
6p 89
7n 91
7o 90
7p 89
1.707 1.843
2.083 1.800
1.967 1.804–
1.283
1.183
1.218
4-
CH3OC6H4
1.819t1.5
1.959 1.803–
1.821t1.8
1.734 1.868–
1.884t1.8
2.089 1.836
8
4-
6q 78
6r 84
6s 84
7q 90
7r 89
7s 91
1.202–
C2H5OC6H4
1.220t1.8
9
α-C10H7
β-C10H7
1.321–
1.327d0.6
10
1.255
[a]Isolated yield.
[b]Isolated yield.
20

Table 2. Anticancer activity of synthesized compounds in two cancer cell lines.
No
7j
7k
7l
7m
7n
7o
7p
7q
7r
HL-60
hepG2
+++
++
+
+
+
+
+++
+
++++
+
+
+
+
+
+
+
++
+
21

Figure 1. 1H NMR spectra of compound 7n.
22

Figure 2. 13C NMR spectra of compound 7n.
23

Figure 3. Part 2D NMR(1H, 13C and gHSQC) spectra of compound 7n.
24

Scheme 1. Fuse-aziridine-containing in natural products.
25

Scheme 2. Anticancer compounds containing 1,2,3-triazole.
26

Scheme 3. The synthesis of compounds 7j-s.
27