'Click synthesis' of 1H-1,2,3-triazolyl-based oxiconazole (=(1Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone O-[(2,4- dichlorophenyl)methyl]oxime) analogs

Article abstract of DOI:10.1002/hlca.201100189

The 'click synthesis' of some oxiconazole analogs 5a-5v having 1H-1,2,3-triazolyl residues by Huisgen cycloaddition was achieved in four steps (Scheme 1). Oximation of phenacyl chloride (1) followed by azidation of 2-chloro-1-phenylethanone oxime (2) provided azido ketoxime 3. The CuI-catalyzed Huisgen cycloaddition of 3 with terminal alkynes gave the 4-substituted (at the triazole) 2-(1H-1,2,3-triazol-1-yl)-1-phenylethanone oximes 4a-4i. The O-alkylation of 4a-4i with various alkyl halides resulted in the formation of the target molecules 5a-5v in good yields. Copyright

Full text of DOI:10.1002/hlca.201100189

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Helvetica Chimica Acta – Vol. 94 (2011)
ꢀClick Synthesisꢁ of 1H-1,2,3-Triazolyl-Based Oxiconazole (¼(1Z)-1-(2,4-
Dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone O-[(2,4-
Dichlorophenyl)methyl]oxime) Analogs
by Mohammad Navid Soltani Rad*a), Zeinab Asrarib), Somayeh Behrouza),
Gholam Hossein Hakimelahic), and Ali Khalafi-Nezhadb)
a) Department of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran
(phone: þ 98-711-7261392; fax: þ 98-711-7354523; e-mails: soltani@sutech.ac.ir;
nsoltanirad@gmail.com)
b) Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
c) Tai Gen Biotechnology, 7F, 138 Hsin Ming Rd., Neihu Dist., Taipei, Taiwan
The ꢀclick synthesisꢁ of some oxiconazole analogs 5a – 5v having 1H-1,2,3-triazolyl residues by
Huisgen cycloaddition was achieved in four steps (Scheme 1). Oximation of phenacyl chloride (1)
followed by azidation of 2-chloro-1-phenylethanone oxime (2) provided azido ketoxime 3. The CuI-
catalyzed Huisgen cycloaddition of 3 with terminal alkynes gave the 4-substituted (at the triazole) 2-(1H-
1,2,3-triazol-1-yl)-1-phenylethanone oximes 4a – 4i. The O-alkylation of 4a – 4i with various alkyl halides
resulted in the formation of the target molecules 5a – 5v in good yields.
Introduction. – The incidence of infections caused by pathogenic fungi has
increased significantly over the years [1]. Nowadays, numerous antifungal drugs with
various structures and scaffolds are known and available [2]. However, their clinical
uses have been limited by the emergence of drug resistance, high risk of toxicity,
insufficiencies in their antifungal activity and undesirable side effects [3]. Hence, there
is still a need to develop and extend the class of safe and efficient chemotherapeutic
agents with potent antifungal activities [3].
One of the most common classes of antifungal compounds are the 1-(arylethyl)-1H-
imidazoles. Miconazole (¼1-{2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]-
ethyl}-1H-imidazole) and oxiconazole (¼(1Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-
1-yl)ethanone O-[(2,4-dichlorophenyl)methyl]oxime) analogs (Fig. 1) are well-known
drugs belonging to this family. The principal structure outlined to miconazole analogs
was first attained by SAR (structureꢀactivity relationships) studies [4]. These studies
revealed the presence of a pharmacophoric part in all of these molecules characterized
by an aryl substituent linked by an ethyl chain to the N-atom of an azole ring.
Therefore, any change in the pharmacophore of the drug leads to new compounds with
different antifungal or other pharmaceutical properties. One way to have rational
alterations in the oxiconazole scaffold is a variation in the azole moiety and in the
oxime O-substituent [5].
In general, replacing the 1H-imidazole core in 1-(arylethyl)-1H-imidazole (mico-
nazole-like analog) with those of 1H-1,2,4-triazole cores can remarkably enhance the
antifungal activity. This fact was previously demonstrated by a change in the structure
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢃrich

Helvetica Chimica Acta – Vol. 94 (2011)
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Fig. 1. Antifungal 1-(arylethyl)-1H-imidazoles: miconazole and oxiconazole
of ketoconazole into itraconazole [6]. Additionally, further investigations on (aryl-
ethyl)azoles bearing 1H-1,2,4-triazole cores have led to the incorporation of
fluconazole and voriconazole into the series of potent antifungal agents [3]. The azole
pharmacophoric site in (arylethyl)azoles plays a critical role by the inhibition of
lanosterol-14-a-demethylase (CYP51), a key enzyme in the biosynthesis of ergosterol.
The ergosterol is the main component of fungal cell membranes. This enzyme catalyzes
the oxidative removal of a specific Me group from lanosterol through a cytochrome-
P450-dependent mechanism. The azoles act through coordination to the heme group.
This coordination prevents binding of the required O-atom to initiate oxidation.
Fortunately, other azole derivatives are capable to coordinate with the heme group, and
thus they can be considered as a proper alternative for 1H-imidazole in established 1-
(arylethyl)-1H-imidazoles.
Huisgenꢁs CuI-catalyzed azideꢀalkyne cycloaddition has emerged as a powerful tool
for introducing the 1H-1,2,3-triazolyl residue into a molecular structure [7]. The high
tolerance of other functionalities and the almost quantitative transformation under
mild conditions make this reaction an ideal prototype to demonstrate the concept of
ꢀclick chemistryꢁ [8]. The incorporation of the 1H-1,2,3-triazolyl group into a molecular
structure is important since the 1H-1,2,3-triazolyl group encompasses the remarkable
biological activities as well as the recognition by enzymes and receptors in the cell [8].
Having been inspired by the oxiconazole scaffold and also in continuation of our
ongoing research to find effective chemotherapeutic agents against pathogenic fungals
[5][9], we used the ꢀclick synthesisꢁ of 1H-1,2,3-triazolyl-based oxiconazole analogs.
The general structure of these analogues is shown in Fig. 2.
Fig. 2. General structures of the synthesized 1H-1,2,3-triazolyl-based oxiconazole analogues
Results and Discussion. – The synthesis of 5a – 5v is shown in Scheme 1. The 2-
chloro-1-phenylethanone oxime (2) was obtained in excellent yield (90%) by
oximation of phenacyl chloride (1) via an established procedure [10]. The 2-azido-1-

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Scheme 1. Synthesis of the 1H-1,2,3-Triazolyl-Based Oxiconazole Analogues 5a – 5v
phenylethanone oxime (3) is the critical precursor for the envisaged Huisgen
cycloaddition. It was prepared from 2 in 95% yield by treatment with NaN3 in
acetone/H2O 1:1 at room temperature for 12 h.
A few terminal alkynes were commercially available (propargyl alcohol (¼ prop-2-
yn-1-ol), 2-methylbut-3-yn-2-ol, and phenylethyne); however, most alkynes used for
the azideꢀalkyne cycloaddition were synthesized from propargyl bromide and various
Scheme 2. Terminal Alkynes from Propargyl Bromide and Nucleophiles

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nucleophiles (Scheme 2). The different nucleophiles including theophylline (¼ 3,7-
dihydro-1,3-dimethyl-1H-purine-2,6-dione), uracil ¼ pyrimidine-2,4(1H,3H)-dione, 1-
phenylpiperazine, phthalimide, 1H-benzimidazole, and 4-chlorophenol were treated
with propargyl bromide and K2CO3 in refluxing DMF in the presence of a catalytic
amount of tetrabutylammonium bromide (Bu4NBr) to give the corresponding terminal
alkynes in yields of 74 – 96%.
Huisgenꢁs CuI-catalyzed azideꢀalkyne cycloaddition was then employed for the
regioselective synthesis of 1-phenyl-2-(4-R-1H-1,2,3-triazol-1-yl)ethanone oximes 4a –
4i from 3 and the terminal alkynes. The CuI mediated 1,3-dipolar cycloaddition of 3
and terminal alkynes in refluxing THF/H2O 1:1 afforded 4a – 4i exclusively as 1,4-
substituted isomers. Oximes 4a – 4i can react with diverse alkyl halides or other C-
electrophiles. Oximes are known to be ambident nucleophiles [11][12], i.e., the
alkylation of oximes can take place at the O-atom to afford the O-alkyl derivatives or at
the N-atom to generate nitrones [13]. Likewise, the site of alkylation of an oxime anion
is affected by factors such as base and solvent type, the nature of the alkylating agent,
the cation type, the geometry of the substrate, the functionality, the degree of
dissociation of the oxime salt, etc. [13][14]. Recently, we have reported the selective O-
alkylation of oximes with various electrophiles in KOH solution in DMSO/H2O 1 :1 at
room temperature [5][11]. Employing this method with 4a – 4i, various 1H-1,2,3-
triazolyl-based oxiconazole analogs 5a – 5v were obtained in good to excellent yields
(64 – 86%), and no nitrone was found, even in trace amounts (Table 1). The residues in
5a – 5v were chosen to enhance the potential biological activities, i.e., 4-chlorophenol,
theophylline, phthalimide, 1-phenylpipirazine, 1H-benzimidazole, and uracil were used
in the synthesis of 5a – 5v because these molecules are important pharmacophores in
the structure of many drugs having antiseptic, vascular, antihistaminic, antibacterial,
antifungal, anticancer, and antiviral properties [2]. For instance, uracil is incorporated
in 5p since the presence of this residue may provide the potential interference and
interaction with DNA or RNA of a pathogenic agent and may behave similarly to a
well-known class of therapeutic compounds, the so-called carboacyclic nucleosides
[9][16].
Dissymmetric ketoximes are usually present as a mixture of (E)- and (Z)-isomers.
In the same way, azido ketoxime 3 is expected to exist as (E)- and (Z)-isomers. It is well
demonstrated that tautomeric interconversions of (E)- and (Z)-oximes readily occur
via a 1,3-H shift [17]. The semiempirical quantum-mechanical calculation with the
parameterized model 3 (PM3) run on MOPAC in CS Chem 3D Ultra 9 (2005,
Cambridge Soft) and Hyperchem (Hypercube Inc., version 7) indicated the simulta-
neous existence of both stereoisomers because of the marginal differences in energy of
the two isomers (i.e., heat of formation) (Table 2) [18]. The calculated values DE ¼
E(Z) – E(E) (kcal/mol) for all products 3, 4a – 4i, and 5a – 5v were either negative or
positive, the negative values referring to a preference of the (Z)-isomer and the
positive values to a preference of the (E)-isomer. Thus, oximes 4a – 4i were calculated
to be (Z)-isomers. An explanation is the possibility of intramolecular H-atom bonding
between OH and N(2) of the 1H-1,2,3-triazole core in 4a – 4i, a situation that cannot be
considered in 5a – 5v. While compounds 5c – 5e, 5g – 5i, 5o, and 5p preferred the (Z)-
oxime, the other compounds 3 and 5 showed a preference for the (E)-isomer. Analysis
of the 1H- and 13C-NMR and HPLC data confirmed the close conformity of calculated

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Table 1. Synthesized 1H-1,2,3-Triazolyl-Based Oxiconazole Analogs
Structurea)
M.p. [8]
Yield [%]b)
81
62
–
78
77
57
–
79
75
108
186
84
201
73
81
–

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2199
Table 1 (cont.)
Structurea)
M.p. [8]
Yield [%]b)
67
217
90
84
93
–
85
77
124
109
–
72
67
65
163
64
–
–
76
75

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Helvetica Chimica Acta – Vol. 94 (2011)
Table 1 (cont.)
Structurea)
M.p. [8]
Yield [%]b)
75
87
136
146
127
74
73
71
a) All products were characterized by 1H- and 13C-NMR, IR, CHN, and MS analysis. b) Yield of isolated
product.
and experimental data, establishing the formation of the major (Z)- and/or (E)-
isomers in 85 – 97% in comparison with the related minor isomer.
Conclusions. – We described a four-steps synthesis of 1H-1,2,3-triazolyl-based
oxiconazole analogs 5a – 5v starting with the oximation of phenacyl chloride (1) to 2-
chloro-1-phenylethanone oxime (2). The subsequent azidation of 2 led to 2-azido-1-
phenylethanone oxime (3) in almost quantitative yield. The azido oxime 3 was
employed in Huisgenꢁs CuI-catalyzed azideꢀalkyne cycloaddition with synthesized
terminal alkynes which led to the regioselective formation of 2-(4-R-1H-1,2,3-triazol-1-
yl)-1-phenylethanone oximes 4a – 4i. The O-alkylation of 4a – 4i with various alkyl
halides resulted in the formation of the target molecules 5a – 5v in good yields.
We thank the Shiraz University of Technology and Shiraz University Research Councils for partial
support of this work.
Experimental Part
General. All chemicals, except for some terminal alkynes, were purchased from Fluka, Merck, and/or
SigmaꢀAldrich. Solvents were purified and dried by standard procedures and stored over 3-ꢄ molecular
sieves. TLC: SILG/UV 254 silica gel (SiO2) plates. Column chromatography (CC): SiO2 60 (0.063 –
0.200 mm, 70 – 230 mesh ASTM). M.p.: Bꢀchi-510 apparatus in open capillaries; uncorrected. IR
.
Spectra: Shimadzu-FT-IR-8300 spectrophotometer; ˜n in cmꢀ1 1H- and 13C-NMR Spectra: Bruker
Avance-DPX-250 spectrometer; at 250 and 62.5 MHz, resp.; d in ppm, J in Hz. GC/MS: Shimadzu-GC/
MS-QP-1000-EX apparatus; m/z (rel. %). Elemental analyses: PerkinꢀElmer-240-B micro-analyzer.

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Table 2. Calculated Heat of Formation of Synthesized Compounds by Means of PM3
a
b
E(E)
)
E(Z)
)
DEc)
3
110.15
148.99
272.71
63.05
84.76
45.43
128.45
155.43
38.58
57.22
81.51
5.89
144.98
54.65
173.75
95.88
70.51
109.35
85.69
133.87
62.79
75.15
44.86
128.00
152.38
37.22
57.08
87.00
9.32
128.58
53.68
172.45
99.54
57.51
ꢀ 0.80
ꢀ 63.30
ꢀ 138.84
ꢀ 0.25
ꢀ 9.61
ꢀ 0.57
ꢀ 0.45
ꢀ 3.04
ꢀ 1.35
ꢀ 0.14
5.48
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
5g
5h
5i
3.43
ꢀ 16.39
ꢀ 0.96
ꢀ 1.29
3.66
ꢀ 12.99
ꢀ 1.29
ꢀ 0.88
9.30
ꢀ 15.31
ꢀ 16.61
94.21
93.33
5j
51.76
61.06
5k
5l
85.91
86.78
0.86
1.57
0.30
1.77
ꢀ 0.96
ꢀ 2.35
1.35
1.91
1.30
ꢀ 30.83
129.26
159.69
152.08
82.16
52.32
101.04
88.94
ꢀ 29.26
129.57
161.47
151.11
79.81
53.68
102.95
90.25
5m
5n
5o
5p
5q
5r
5s
5t
ꢀ 8.85
ꢀ 6.70
2.14
0.71
1.71
5u
5v
98.43
99.15
64.01
65.737
a) Heat of formation of the (E)-isomer in kcal/mol. b) Heat of formation of the (Z)-isomer in kcal/mol.
c) DE ¼ E(Z) – E(E) [kcal/mol].
Terminal Alkynes: General Procedure. Propargyl bromide (2.61 g, 0.022 mol) was added portionwise
to a soln. of uracil (or another nucleophile; 0.02 mol), K2CO3 (2.76 g, 0.02 mol), and a cat. amount of
Bu4NBr (0.1 g ) in anh. DMF (45 ml). The soln. was refluxed until TLC monitoring indicated no further
progress of the reaction (6 – 8 h). After cooling and solvent evaporation, the resulting foam was
suspended in CHCl3 (150 ml) and washed with H2O (2 ꢁ 200 ml). The org. layer was dried (Na2SO4) and
concentrated and the crude product purified by CC.
2-Chloro-1-phenylethanone Oxime (2). To a soln. of 2-chloro-1-phenylethanone (15.5 g, 0.1 mol) in
EtOH (200 ml), a soln. of NH2OH · HCl (10.4 g, 0.15 mol) and KOH (8.4 g, 0.15 mol) in H2O (30 ml) was
added. The resulting soln. was stirred at r.t. for 6 h. Then, the mixture was poured in cooled H2O
(500 ml), whereby 2 immediately separated from the soln. as a pale yellow solid which was filtered and
stored in a refrigerator for the subsequent step (15.3 g, 90%).
2-Azido-1-phenylethanone Oxime (3). A soln. of 2 (8.5 g, 0.05 mol) and NaN3 (3.3 g, 0.05 mol) in
acetone/H2O 1:1 (100 ml) was stirred at r.t. for 12 h. After completion of the reaction (TLC monitoring),

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Helvetica Chimica Acta – Vol. 94 (2011)
acetone was evaporated and the residual mixture dissolved in CHCl3 (150 ml) and washed with H2O (2 ꢁ
200 ml). The org. layer was dried (Na2SO4, 10 g) and evaporated to result in almost pure 3 as a red oil
(7.0 g, 80%).
(1Z)-2-(4-R-1H-1,2,3-Triazol-1-yl)-1-phenylethanone Oximes 4a – 4i. A mixture of 3 (5.3 g,
0.03 mol), the terminal alkyne (0.03 mol), and a cat. amount of CuI (0.05 g) in THF/H2O 1:1 (40 ml)
was refluxed until TLC monitoring indicated no further progress of the reaction (4 – 6 h). The solvent was
evaporated, the remaining oil dissolved in CHCl3 (100 ml), and the soln. washed with H2O (3 ꢁ 100 ml),
dried (Na2SO4, 10 g), and concentrated. The crude product was purified by CC (AcOEt): 4a – 4i in 65 –
70% yield.
2-(4-R-1H-1,2,3-Triazol-1-yl)-1-phenylethanone O-Alkyloximes 5a – 5v. To a soln. of 4 (0.01 mol)
and KOH (0.56 g, 0.01 mol) in DMSO/H2O 1:1 (40 ml) was added the appropriate alkyl halide
(0.01 mol) and stirred until TLC monitoring indicated no further progress of the reaction (3 – 6 h). The
mixture was diluted with H2O (200 ml) and extracted with CHCl3 (5 ꢁ 50 ml), the org. layer dried
(Na2SO4, 5 g) and concentrated and the residue purified by CC.
(1E)-2-{4-[(4-Chlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}-1-phenylethanone O-Butyloxime (5a):
CC (AcOEt) gave a pale-yellow solid (3.23 g, 81%). M.p. 628. Rf (AcOEt/hexane 1:1) 0.93. IR (KBr):
3155, 3043, 2879, 1500, 1240, 1056. 1H-NMR (CDCl3): 0.83 (t, J ¼ 7.5, Me); 1.29 – 1.35 (m, MeCH2); 1.57 –
1.68 (m, CH2CH2O); 4.17 (t, J ¼ 5.0, CH2CH2O); 5.00 (s, NCH2C¼N); 5.51 (s, ArOCH2); 6.74 (d, J ¼ 8.3,
2 arom. H); 7.08 (d, J ¼ 8.3, 2 arom. H); 7.23 – 7.26 (m, 3 arom. H); 7.56 (s, HꢀC(5), triazole); 7.61 – 7.65
(m, 2 arom. H). 13C-NMR (CDCl3): 13.88; 19.14; 31.17; 44.90; 62.20; 75.17; 116.90; 123.50; 126.10;
126.23; 128.76; 129.36; 129.90; 133.24; 143.92; 150.13; 156.74. EI-MS: 398 (3.3, Mþ). Anal. calc. for
C21H23ClN4O2: C 63.23, H 5.81, Cl 8.89, N 14.05; found: C 63.19, H 5.93, Cl 8.78, N 14.17.
Ethyl 2-{{{(1E)-2-{4-[(4-Chlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}-1-phenylethylidene}ami-
no}oxy}propanoate (5b): CC (AcOEt) afforded a brown oil (3.5 g, 78%). Rf (AcOEt/hexane 1:1)
0.83. IR (film): 3145, 3023, 2839, 1741, 1512, 1238, 1053. 1H-NMR ((D6)DMSO): 1.13 (t, J ¼ 7.5, MeCH2),
1.43 (d, J ¼ 5.0, MeCH), 4.09 (q, J ¼ 7.5, MeCH2), 4.92 (q, J ¼ 5.0, MeCH), 5.10 (s, NCH2C¼N), 5.77 (s,
ArOCH2), 7.00 (d, J ¼ 7.5, 2 arom. H), 7.28 (d, J ¼ 7.5, 2 arom. H), 7.36 – 7.39 (m, 3 arom. H), 7.67 – 7.69
(m, 2 arom. H), 8.23 (s, HꢀC(5), triazole). 13C-NMR ((D6)DMSO): 13.93; 16.44; 43.54; 60.60; 61.18;
77.73; 116.42; 124.53; 125.38; 126.54; 128.56; 129.14; 130.01; 132.56; 142.56; 152.63; 156.70; 171.48. EI-
MS: 442 (1.2, Mþ). Anal. calc. for C22H23ClN4O4: C 59.66, H 5.23, Cl 8.00, N 12.65; found: C 59.73, H 5.17,
Cl 8.12, N 12.73.
(1Z)-1-Phenyl-2-{4-[(4-phenylpiperazin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}ethanone O-Butyloxime
(5c): CC (AcOEt) afforded bright crystals (3.4 g, 78%). M.p. 578. Rf (AcOEt) 0.67. IR (KBr): 3129,
2988, 2857, 1495, 1233, 1023. 1H-NMR (CDCl3): 0.85 (t, J ¼ 7.5, Me); 1.29 – 1.38 (m, MeCH2); 1.60 – 1.68
(m, CH2CH2O); 2.48 – 2.52 (m, 2 CH2N); 3.04 – 3.07 (m, 2 CH2N); 3.58 (s, CH2N); 4.19 (t, J ¼ 7.5,
CH2CH2O); 5.53 (s, NCH2C¼N); 6.77 – 6.81 (m, 3 arom. H); 7.11 – 7.25 (complex, 5 arom. H); 7.45 (s,
HꢀC(5), triazole); 7.59 – 7.62 (m, 2 arom. H). 13C-NMR (CDCl3): 13.95; 19.17; 31.28; 44.15; 48.97; 52.82;
53.27; 75.11; 116.01; 119.66; 123.36; 126.33; 128.71; 129.08; 129.79; 133.30; 144.49; 150.46; 151.23. EI-MS:
432.2 (8.6, Mþ). Anal. calc. for C25H32N6O: C 69.42, H 7.46, N 19.43; found: C 69.57, H 7.34, N 19.37.
Ethyl 2-{{{(1Z)-1-Phenyl-2-{4-[(4-phenylpiperazin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}ethylidene}-
amino}oxy}propanoate (5d): CC (AcOEt/MeOH 10 :1) afforded a brown oil (3.8 g, 79%). Rf (AcOEt)
0.73. IR (film): 3055, 2942, 1742, 1599, 1446, 1210, 1046. 1H-NMR (CDCl3): 1.18 (t, J ¼ 7.5, MeCH2); 1.49
(d, J ¼ 7.5, MeCH); 2.52 – 3.06 (m, 4 CH2N); 3.61 (s, CH2N); 4.12 (s, NCH2C¼N); 4.83 (q, J ¼ 7.5,
MeCH2); 5.52 (q, J ¼ 7.5, MeCH); 6.70 – 7.60 (m, 10 arom. H); 7.83 (s, HꢀC(5), triazole). 13C-NMR
(CDCl3): 14.24; 17.02; 44.08; 48.94; 52.77; 53.24; 61.18; 78.45; 115.99; 119.62; 123.87; 126.53; 128.43;
129.06; 130.17; 132.69; 144.54; 151.26; 152.14; 172.10. EI-MS: 476 (6.2, Mþ). Anal. calc. for C26H32N6O3:
C 65.53, H 6.77, N 17.63; found: C 65.69, H 6.81, N 17.79.
(1Z)-1-Phenyl-2-{4-[(4-phenylpiperazin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}ethanone O-(Phenylme-
thyl)oxime (5e): CC (AcOEt/MeOH 10 :1) afforded a brown solid (3.50 g, 75%). M.p. 1088. Rf (AcOEt)
0.49. IR (KBr): 3029, 2918, 2823, 1497, 1223, 1013.1H-NMR ((D6)DMSO): 2.41 – 2.47 (m, 2 CH2N);
3.03 – 3.10 (m, 2 CH2N); 3.52 (s, CH2N); 5.27 (s, CH2O), 5.72 (s, NCH2C¼N); 6.71 – 6.89 (m, 3 arom. H);
7.15 – 7.36 (m, 10 arom. H); 7.62 – 7.64 (m, 2 arom. H); 7.87 (s, HꢀC(5), triazole). 13C-NMR ((D6)DMSO):
43.85; 48.03; 52.07; 52.10; 76.08; 115.28; 118.71; 126.16; 126.56; 127.86; 127.96; 128.42; 128.43; 128.83;

Helvetica Chimica Acta – Vol. 94 (2011)
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129.05; 129.62; 132.99; 137.26; 150.93; 152.31. EI-MS: 466.0 (4.2, Mþ). Anal. calc. for C28H30N6O: C 72.08,
H 6.48, N 18.01; found: C 72.15, H 6.35, N 18.20.
2-{{1-{(2E)-2-[(2-(Phenylethoxy)imino]-2-phenylethyl}-1H-1,2,3-triazol-4-yl}methyl}-1H-isoindole-
1,3(2H)-dione (5f): CC (AcOEt) afforded a pale-yellow solid (3.91 g, 84%). M.p. 1868. Rf (AcOEt) 0.45.
IR (KBr): 3126, 2854, 1705, 1660, 1549, 1225, 1029. 1H-NMR ((D6)DMSO): 3.15 (t, J ¼ 5.0, CH2CH2O);
3.33 (t, J ¼ 5.0, CH2CH2O); 5.47 (s, CH2N); 5.65 (s, NCH2C¼N); 7.13 – 7.42 (m, 10 arom. H); 7.59 (s,
HꢀC(5), triazole); 7.94 – 8.10 (m, 4 arom. H). 13C-NMR ((D6)DMSO): 27.48; 29.34; 42.97; 65.15; 124.65;
126.02; 126.44; 127.52; 127.83; 128.11; 128.31; 128.87; 129.01; 132.21; 133.88; 142.31; 150.55; 161.25; 165.3.
EI-MS: 465.1 (15.6, Mþ). Anal. calc. for C27H23N5O3: C 69.66, H 4.98, N 15.04; found: C 69.61, H 4.85, N
15.16.
(7-{{1-[(2Z)-2-(Butoxyimino)-2-phenylethyl]-1H-1,2,3-triazol-4-yl}methyl}-3,7-dihydro-1,3-dimeth-
yl-1H-purine-2,6-dione (5g): CC (AcOEt) afforded a yellow solid (3.33 g, 74%). M.p. 2018. Rf (AcOEt)
1
0.50. IR (KBr): 3155, 2967, 1716, 1705, 1495, 1234, 1057. H-NMR (CDCl3): 0.86 (t, J ¼ 7.5, MeCH2);
1.32 – 1.35 (m, MeCH2); 1.65 – 1.68 (m, CH2CH2O); 3.32 (s, MeꢀN(3)); 3.50 (s, MeꢀN(1)); 4.20 (t, J ¼ 5.0,
CH2CH2O); 5.46 (s, CH2N); 5.53 (s, NCH2C¼N); 7.19 – 7.61 (m, 5 arom. H); 7.69 (s, HꢀC(5), triazole);
7.80 (s, HꢀC(8), theophylline). 13C-NMR (CDCl3): 13.86; 19.11; 27.89; 29.76; 31.10; 41.40; 44.33; 75.19;
76.52; 77.02; 77.53; 124.50; 126.23; 128.65; 129.78; 141.20; 148.28; 151.53; 154.23; 176.83. EI-MS: 450 (8.5,
Mþ). Anal. calc. for C22H26N8O3: C 58.65, H 5.82, N 24.87; found: C 58.51, H 5.94, N 24.73.
Ethyl 2-{{{(1Z)-1-Phenyl-2-{4-[(2,3,6,7-tetrahydro-1,3-dimethyl-2,6-dioxo-1H-purin-7-yl)methyl]-
1H-1,2,3-triazol-1-yl}ethylidene}amino}oxy}propanoate (5h): CC (AcOEt) afforded a yellow oil
(4.00 g, 81%). Rf (AcOEt) 0.44. IR (film): 3155, 2980, 1719, 1707, 1490, 1214, 1047. 1H-NMR
((D6)DMSO): 1.06 (t, J ¼ 7.5, MeCH2); 1.40 (d, J ¼ 5.0, MeCH); 2.57 (s, MeꢀN(3)); 3.59 (s, MeꢀN(1));
3.96 (q, J ¼ 7.5, MeCH2); 4.78 (s, CH2N); 4.79 (q, J ¼ 5.0, MeCH); 5.69 (s, NCH2C¼N); 7.60 (s, HꢀC(5),
triazole); 7.61 – 7.86 (m, 5 arom. H); 8.10 (s, HꢀC(8), theophylline). 13C-NMR ((D6)DMSO): 13.89;
16.38; 32.76; 38.76; 42.80; 43.65; 60.45; 77.64; 123.06; 124.25; 126.49; 128.50; 129.93; 131.48; 132.61;
134.41; 142.25; 152.61; 167.18; 171.41. EI-MS: 494.2 (15.9, Mþ). Anal. calc. for C23H26N8O5: C 55.86, H
5.30, N 22.66; found: C 55.75, H 5.25, N 22.73.
2,3,6,7-Tetrahydro-1,3-dimethyl-7-{{1-{(2Z)-2-phenyl-2-[(prop-2-en-1-yloxy)imino]ethyl}-1H-1,2,3-
triazol-4-yl}methyl}-1H-purine-2,6-dione (5i): CC (AcOEt) afforded a bright brown solid (2.91 g, 67%).
M.p. 2178. Rf (AcOEt) 0.47. IR (KBr): 3126, 3057, 1720, 1709, 1426, 1398, 1102. 1H-NMR ((D6)DMSO):
3.18 (s, MeꢀN(3)); 3.37 (s, MeꢀN(1)); 4.67 (d, J ¼ 5.6, CH2O); 4.96 – 4.99 (m, CH2); 5.48 (s, CH2N); 5.69
(s, NCH2C¼N); 5.88 – 5.95 (m, CH); 7.32 (s, HꢀC(5), triazole); 7.58 – 8.11 (m, 5 arom. H); 8.27 (s,
HꢀC(8), theophylline). 13C-NMR ((D6)DMSO): 27.41; 29.30; 43.78; 59.68; 74.97; 105.70; 117.52; 124.91;
126.41; 129.53; 132.43; 130.55; 133.97; 142.28; 148.26; 151.80; 154.23;164.28; 193.70. EI-MS: 434.0 (8.5,
Mþ). Anal. calc. for C21H22N8O3: C 58.06, H 5.10, N 25.79; found: C 58.16, H 5.24, N 25.63.
(1E)-2-[4-(1-Hydroxy-1-methylethyl)-1H-1,2,3-triazol-1-yl]-1-phenylethanone O-Cyclopentyloxime
(5j): CC (AcOEt/hexane 1:1) afforded a pale yellow solid (2.8 g, 85%). M.p. 908. Rf (AcOEt/hexane
1:1) 0.30. IR (KBr): 3330, 3050, 2936, 1445, 1335, 995.6. 1H-NMR (CDCl3): 1.56 (s, Me2C); 1.58 – 1.89 (m,
4 CH2); 2.98 (s, OH, exchangeable with D2O); 4.87 – 4.93 (m, CHO); 5.52 (s, NCH2C¼N); 7.30 – 7.35 (m,
3 arom. H); 7.48 (s, HꢀC(5), triazole); 7.71 – 8.03 (m, 2 arom. H). 13C-NMR (CDCl3): 23.74; 30.32; 32.45;
44.09; 68.31; 86.79; 119.83; 126.24; 128.68; 129.72; 133.64; 155.72; 173.65. EI-MS: 328 (17.4, Mþ). Anal.
calc. for C18H24N4O2: C 65.83, H 7.37, N 17.06; found: C 65.71, H 7.42, N 17.18.
(1E)-2-[4-(1-Hydroxy-1-methylethyl)-1H-1,2,3-triazol-1-yl]-1-phenylethanone O-(Phenylmethyl)ox-
ime (5k): CC (AcOEt/hexane 1:1) afforded a pale-yellow solid (3.0 g, 85%). M.p. 938. Rf (AcOEt/
hexane 1:1) 0.15. IR (KBr): 3336, 3034, 2913, 1494, 1228, 1015. 1H-NMR (CDCl3): 1.47 (s, Me2C); 3.14 (s,
OH, exchangeable with D2O); 5.19 (s, CH2O); 5.41 (s, NCH2C¼N); 7.19 – 7.63 (m, 10 arom. H); 7.20 (s,
HꢀC(5), triazole). 13C-NMR (CDCl3): 30.49; 44.02; 68.42; 77.25; 120.14; 126.76; 127.39; 128.46; 128.73;
128.82; 129.99; 134.33; 136.77; 151.14; 155.81. EI-MS: 350 (12.8, Mþ). Anal. calc. for C20H22N4O2: C 68.55,
H 6.33, N 15.99; found: C 68.71, H 6.25, N 15.85.
Ethyl 2-{{{(1E)-2-[4-(1-hydroxy-1-methylethyl)-1H-1,2,3-triazol-1-yl]-1-phenylethylidene}amino}-
oxy}propanoate (5l): CC (AcOEt/hexane 1:1) afforded a yellow oil (2.8 g, 77%). Rf (AcOEt/hexane
1:1) 0.30. IR (film): 3335, 3151, 2980, 1716, 1497, 1224, 1049. 1H-NMR (CDCl3): 1.19 (t, J ¼ 5.0, MeCH2);
1.51 – 1.52 (m, Me2C, MeCH); 3.52 (s, OH, exchangeable with D2O); 4.14 (q, J ¼ 5.0, MeCH2); 4.88 (q,

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Helvetica Chimica Acta – Vol. 94 (2011)
J ¼ 5.0, MeCH); 5.58 (s, CH2N); 7.25 – 7.27 (m, 3 arom. H); 7.63 – 7.90 (m, 2 arom. H), 7.90 (s, HꢀC(5),
triazole). 13C-NMR (CDCl3): 14.14; 16.92; 30.24; 43.89; 61.14; 68.16; 78.41; 120.68; 126.44; 128.37;
130.10; 132.75; 151.95; 156.01; 172.13. EI-MS: 360 (1.4, Mþ). Anal. calc. for C18H24N4O4: C 59.99, H 6.71,
N 15.55; found: C 59.83, H 6.79, N 15.59.
(1E)-1-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanone O-Cyclopentyloxime (5m): CC (AcOEt/
hexane 1:5) afforded a white solid (2.50 g, 72%). M.p. 1248. Rf (AcOEt/hexane 1:1) 0.72. IR (KBr):
1
3116, 2941, 2854, 1440, 1339, 994. H-NMR (250 MHz, CDCl3): 1.68 – 1.74 (m, 2 CH2); 1.81 – 1.93 (m,
2 CH2); 4.95 – 4.98 (m, CHO); 5.63 (s, NCH2C¼N); 7.26 – 7.82 (m, 6 arom. H, HꢀC(5), triazole); 7.78 –
7.82 (m, 5 arom. H).13C-NMR (CDCl3): 23.84; 32.27; 44.17; 86.88; 119.54; 125.56; 126.05; 128.35; 128.45;
128.76; 129.82; 130.57; 133.61; 147.86; 150.25. EI-MS: 346 (14.6, Mþ). Anal. calc. for C21H22N4O: C 72.81,
H 6.40, N 16.17; found: C 72.74, H 6.51, N 16.31.
(1E)-1-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanone O-(Prop-2-en-1-yl)oxime (5n): CC
(AcOEt/hexane 1:5) afforded a white solid (2.2 g, 68%). M.p. 1098. Rf (AcOEt/hexane 1:1) 0.54. IR
(KBr): 3077, 2912, 1686, 1435, 1219, 1012. 1H-NMR (CDCl3): 4.67 (d, J ¼ 5.0, CH2O); 5.27 (m, CH2); 5.45
(s, NCH2C¼N); 5.93 – 6.09 (m, CH); 7.34 – 7.53 (m, 8 arom. H); 7.77 – 7.79 (m, 2 arom. H); 8.05 (s,
HꢀC(5), triazole). 13C-NMR (CDCl3): 53.61; 62.99; 118.01; 119.57; 120.01; 125.69; 126.39; 128.19; 128.31;
128.79; 129.17; 130.06; 133.73; 134.54; 150.58. EI-MS: 318.0 (17.8, Mþ). Anal. calc. for C19H18N4O: C
71.68, H 5.70, N 17.60; found: C 71.75, H 5.67, N 17.67.
(1Z)-2-[4-((1H-Benzoimidazol-1-ylmethyl)-1H-1,2,3-triazol-1-yl]-1-phenylethanone O-Butyloxime
(5o): CC (AcOEt/hexane 8 :1) afforded a yellow foam (3.0 g, 77%). Rf (AcOEt) 0.64. IR (film): 3136,
1
2961, 2854, 1488, 1041. H-NMR (CDCl3): 0.77 (t, J ¼ 7.5, Me); 1.18 – 1.21 (m, MeCH2); 1.46 – 1.52 (m,
CH2CH2O); 4.06 (t, J ¼ 6.7, CH2CH2O); 5.28 (s, CH2N); 5.43 (s, NCH2C¼N); 7.13 – 7.57 (m, 9 arom. H);
7.35 (s, HꢀC(5), triazole); 7.58 (s, HꢀC(2), benzimidazole). 13C-NMR (CDCl3): 13.76; 18.95; 30.93;
40.37; 44.17; 75.00; 109.88; 120.20; 122.26; 123.00; 126.17; 128.04; 128.30; 128.64; 129.09; 132.54; 133.03;
142.83; 143.66; 150.02. EI-MS: 388 (8.6, Mþ). Anal. calc. for C22H24N6O: C 68.02, H 6.23, N 21.63; found:
C 68.13, H 6.11, N 21.59.
1-{{1-{(2Z)-2-Phenyl-2-[(Phenylmethoxy)imino]ethyl}-1H-1,2,3-triazol-4-yl}methyl}pyrimidine-
2,4(1H,3H)-dione (5p): CC (AcOEt/hexane 8 :1) afforded a pale-yellow solid (2.7 g, 64%). M.p. 1638. Rf
(AcOEt) 0.64. IR (KBr): 3236, 3038, 1725, 1710, 1450, 1233, 1041. 1H-NMR ((D6)DMSO): 4.87 (s,
CH2N); 5.25 (s, CH2O); 5.54 (d, J ¼ 7.5, HꢀC(5), uracil); 5.71 (s, NCH2C¼N); 7.27 – 7.37 (m, 10 arom. H);
7.63 (d, J ¼ 7.5, HꢀC(6), uracil), 8.00 (s, HꢀC(5), triazole); 11.32 (s, HꢀN(3), exchangeable with D2O).
13C-NMR ((D6)DMSO): 42.14; 43.73; 76.10; 101.19; 124.38; 126.47; 127.96; 128.12; 128.48; 129.00;
130.25; 132.96; 137.20; 142.14; 145.27; 150.66; 151.94; 163.63. EI-MS: 416.0 (14.9, Mþ). Anal. calc. for
C22H20N6O3: C 63.45, H 4.84, N 20.18; found: C 63.49, H 4.79, N 20.25.
(1E)-2-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]-1-phenylethanone O-Butyloxime (5q): CC
(AcOEt) afforded a brown oil (2.19 g, 76%). Rf (AcOEt) 0.70. IR (film): 3358.8, 3035, 2932, 1445,
1
1228. H-NMR ((D6)DMSO): 0.86 (t, J ¼ 7.5, Me); 1.34 – 1.39 (m, MeCH2); 1.62 – 1.65 (m, CH2CH2O);
4.16 (t, J ¼ 7.5, CH2CH2O); 5.41 (s, CH2OH); 5.51 (s, NCH2C¼N); 7.23 – 7.66 (m, 5 arom. H); 7.64 (s,
HꢀC(5), triazole); 11.75 (s, OH, exchangeable with D2O).13C-NMR ((D6)DMSO): 13.73; 18.59; 30.80;
54.74; 66.14; 73.78; 122.91; 126.39; 128.31; 129.14; 129.50; 133.75; 154.31. EI-MS: 288.0 (11.1, Mþ). Anal.
calc. for C15H20N4O2: C 62.48, H 6.99, N 19.43; found: C 62.53, H 6.83, N 19.57.
3-{{{(1E)-2-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]-1-phenylethylidene}amino}oxy}propaneni-
trile (5r): CC (AcOEt) afforded a brown oil (2.14 g, 75%). Rf (AcOEt) 0.79. IR (film): 3358, 3050, 2932,
1445, 1228. 1H-NMR (CDCl3): 2.45 (t, J ¼ 5.0, CH2CH2O); 3.52 (t, J ¼ 5.0, CH2CH2O); 4.47 (s, CH2OH);
5.29 (s, OH, exchangeable with D2O); 5.42 (s, NCH2C¼N); 7.15 (s, HꢀC(5), triazole); 7.18 – 7.64 (m, 5
arom. H). 13C-NMR (CDCl3): 18.85; 43.77; 64.35; 66.61; 123.79; 126.42; 126.97; 128.46; 128.76; 129.43;
130.20; 164.97. EI-MS: 285.1 (12.4, Mþ). Anal. calc. for C14H15N5O2: C 58.94, H 5.30, N 24.55; found: C
58.85, H 5.42, N 24.67.
(1E)-2-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]-1-phenylethanone O-(Prop-2-en-1-yl)oxime (5s):
CC (AcOEt) afforded a pale-yellow solid (2.0 g, 75%). M.p. 878. Rf (AcOEt) 0.44. IR (KBr): 3339, 3043,
2931, 1445, 1228. 1H-NMR (CDCl3): 3.87 (s, OH, exchangeable with D2O); 4.66 (s, CH2OH); 4.77 (d, J ¼
5.0, CH2O); 5.25 (dd, J ¼ 1.3, 10.5, 1 H, CH2); 5.37 (dd, J ¼ 1.3, 18.2, 1 H, CH2); 5.58 (s, NCH2C¼N);
5.96 – 6.12 (m, CH); 7.31 – 7.33 (m, 3 arom. H); 7.60 (s, HꢀC(5), triazole); 7.68 – 7.72 (m, 2 arom. H).

Helvetica Chimica Acta – Vol. 94 (2011)
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13C-NMR (CDCl3): 43.94; 55.97; 79.06; 118.82; 122.62; 126.32; 128.27; 130.00; 133.02; 133.32; 148.02;
150.83. EI-MS: 272.0 (16.7, Mþ). Anal. calc. for C14H16N4O2: C 61.75, H 5.92, N 20.58; found: C 61.67, H
5.98, N 20.63.
Methyl 2-{{{(1E)-2-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]-1-phenylethylidene}amino}oxy}ace-
tate (5t): CC (AcOEt) afforded a pale-yellow solid (2.3 g, 75%). M.p. 1368. Rf (AcOEt) 0.71. IR
(KBr): 3379, 3019, 2864, 1445, 1234, 1011. 1H-NMR ((D6)DMSO): 3.57 (s, MeO); 4.39 (s, CH2O); 5.46 (s,
CH2OH); 5.53 (s, NCH2C¼N); 7.17 – 7.69 (m, 5 arom. H); 7.52 (s, HꢀC(5), triazole); 11.69 (s, OH,
exchangeable with D2O). 13C-NMR ((D6)DMSO): 42.96; 54.73; 65.77; 74.43; 126.54; 128.15; 128.44;
129.87; 132.60; 134.63; 152.18; 153.47. EI-MS: 304.1 (10.1, Mþ). Anal. calc. for C14H16N4O4: C 55.26, H
5.30, N 18.41; found: C 55.29, H 5.37, N 18.43.
(1E)-2-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]-1-phenylethanone O-(Phenylmethyl)oxime (5u):
CC (AcOEt) afforded a pale-yellow solid (2.35 g, 73%). M.p. 1468. Rf (AcOEt) 0.66. IR (KBr): 3358,
1
3029, 2854, 1445, 1011. H-NMR ((D6)DMSO): 4.81 (s, CH2O); 5.87 (s, CH2OH); 5.94 (s, NCH2C¼N);
7.69 – 8.11 (m, 10 arom. H); 7.92 (s, HꢀC(5), triazole); 12.18 (s, OH, exchangeable with D2O). 13C-NMR
((D6)DMSO): 42.94; 54.72; 65.76; 123.15; 126.54; 126.69; 128.27; 128.45; 128.52; 129.14; 132.59; 134.62;
152.17; 153.48. EI-MS: 322.0 (21.3, Mþ). Anal. calc. for C18H18N4O2: C 67.07, H 5.63, N 17.38; found: C
67.03, H 5.72, N 17.22.
(1E)-2-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]-1-phenylethanone O-(2-Phenoxyethyl)oxime
(5v): CC (AcOEt) afforded a pale-yellow solid (2.50 g, 71%). M.p. 1278. Rf (AcOEt) 0.75. IR (KBr):
1
3349, 3038, 2854, 1445, 1222, 1011. H-NMR ((D6)DMSO): 4.36 (t, J ¼ 5.0, PhOCH2); 5.11 (t, J ¼ 5.0,
NOCH2); 5.45 (s, CH2OH); 5.52 (s, NCH2C¼N); 7.26 – 7.68 (m, 10 arom. H); 7.49 (s, HꢀC(5), triazole);
11.75 (s, OH, exchangeable with D2O). 13C-NMR ((D6)DMSO): 42.91; 54.70; 65.76; 75.54; 123.03;
126.41; 126.54; 127.98; 128.26; 128.51; 129.87; 132.60; 134.63; 152.19; 153.47. EI-MS: 352.1 (24.4, Mþ).
Anal. calc. for C19H20N4O3: C 64.76, H 5.72, N 15.90; found: C 64.72, H 5.84, N 15.81.
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Received February 11, 2011