Design and synthesis of some novel oxiconazole-like carboacyclic nucleoside analogues, as potential chemotherapeutic agents

Article abstract of DOI:10.1002/hlca.200900051

The syntheses of some novel carboacyclic nucleosides, 17a-17o, containing oxiconazole-like scaffolds, are described (Schemes 1-3). In this series of carboacyclic nucleosides, pyrimidine as well as purine and other imidazole derivatives were employed as an imidazole successor in oxiconazole. These compounds could be prepared in good yields by using two different strategies (Schemes 1 and 2). Due to Scheme 1, the N-coupling of nucleobases with 2-bromoacetophenones was attained for 18a-18e, and their subsequent oximation affording 19a-19e and finally O-alkylation with diverse alkylating sources resulted in the products 17a-17g, 17n, and 17o. In Scheme 2, use of 2-bromoacetophenone oximes 20, followed by N-coupling of nucleobases, provided 19f-19j whose final O-alkylation produced 17h-17m (Scheme 2). For the rational interpretation of the dominant formation of (E)-oxime ethers rather than (Z)-oxime isomers, PM3 semiempirical quantum-mechanic calculations were discussed and the calculations indicated a lower heat of formation for (E)-isomers.

Full text of DOI:10.1002/hlca.200900051

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Design and Synthesis of Some Novel Oxiconazole-Like Carboacyclic
Nucleoside Analogues, as Potential Chemotherapeutic Agents
by Mohammad Navid Soltani Rad*a), Ali Khalafi-Nezhad*b), and Somayeh Behrouzb)
a) Department of Chemistry, Faculty of Basic Sciences, 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
The syntheses of some novel carboacyclic nucleosides, 17a – 17o, containing oxiconazole-like
scaffolds, are described (Schemes 1 – 3). In this series of carboacyclic nucleosides, pyrimidine as well as
purine and other imidazole derivatives were employed as an imidazole successor in oxiconazole. These
compounds could be prepared in good yields by using two different strategies (Schemes 1 and 2). Due to
Scheme 1, the N-coupling of nucleobases with 2-bromoacetophenones was attained for 18a – 18e, and
their subsequent oximation affording 19a – 19e and finally O-alkylation with diverse alkylating sources
resulted in the products 17a – 17g, 17n, and 17o. In Scheme 2, use of 2-bromoacetophenone oximes 20,
followed by N-coupling of nucleobases, provided 19f – 19j whose final O-alkylation produced 17h – 17m
(Scheme 2). For the rational interpretation of the dominant formation of (E)-oxime ethers rather than
(Z)-oxime isomers, PM3 semiempirical quantum-mechanic calculations were discussed and the
calculations indicated a lower heat of formation for (E)-isomers.
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. 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. Hence, there
is still a need to develop and extend the safe and efficient chemotherapeutic agents with
a potent broad spectrum of antifungal activities.
Ergosterol is the major sterol of the fungal cell membrane. The azoles, which are a
well-known class of antifungal agents, disrupt ergosterol biosynthesis through the
inhibition of cytochrome P450-dependent 14a-lanosterol demethylase (P-45014DM
)
[2][3]. The structures of several famous imidazole antifungal drugs 1 – 16 are shown in
Fig. 1. One of the most established antifungal azole drugs having rational versatility in
structures is the miconazole family 5 – 16 (Fig. 1). The principal structural outline to
miconazole-analogue frameworks was attained by the structure – activity-relationship
(SAR) studies of these antifungals. These studies reveal the presence of a
pharmacophoric portion in all of these molecules, which is characterized by a phenyl
ring linked by an ethane chain to an N-atom of an azole ring (Fig. 2) [4].
Oximes and oxime ether derivatives are a prominent structural motif found in
numerous pharmaceutically active compounds. Many well-known drugs with various
chemotherapeutic activities, such as antiviral (e.g., enviroxime) [5] and anti-inflam-
ꢀ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Fig. 1. The structures of well-known imidazole antifungals
matory agents (e.g., pifoxime) [6], antidepressants (e.g., fluvoxamine) [6], nerve agent
antidotes (e.g., pralidoxime) [6][7], cephalosporin antibiotics (e.g., cefixime) [8],
macrolide antibiotics (e.g., roxithromycin) [9], and thromboxane synthase inhibitors
(e.g., ridogrel) [10], contain an oxime or oxime ether moiety in their structures.
Furthermore, oxiconazole 5 [11] is a well-known established antifungal drug that also
includes the oxime ether moiety. Recently, various structurally related oxiconazole

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Fig. 2. The SAR outline for azole antifungals analogue to miconazole 5 – 16
bioactive compounds including chromanone [12], nafimidone [13], and tetrahydro-
naphthyl [14] derivatives have been reported.
The significance of nucleoside chemistry in drug discovery is well demonstrated and
fully established in medicinal chemistry [15]. Carboacyclic nucleosides are one of the
most famous acyclic nucleoside subclasses which were proved to have remarkable
chemotherapeutic activities against cancer and infections caused by viruses, microbes,
and other pathogenic microorganisms.
Inspired by the oxiconazole scaffold and also in continuation of our interest in the
design and synthesis of novel carboacyclic nucleosides [16], we report the synthesis of
some novel carboacyclic nucleosides containing oxiconazole-like scaffolds. In these
compounds the pyrimidine as well as purine and other imidazole derivatives were
considered as imidazole moiety successors in oxiconazole. The general structure of the
title compounds is shown in Fig. 3.
Fig. 3. The general structure of oxiconazole-like carboacyclic nucleoside 17
Results and Discussion. – The synthetic pathways for compounds 17a – 7g and 17h –
17m are outlined in Schemes 1 and 2, respectively. Two different strategies were
considered for the synthesis of the title compounds with regard to discrepancies in
chemical behaviors of purine and pyrimidine nucleobases in comparison with the azole
family. The azole derivatives were synthesized according to Scheme 1 due to their

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better solubility, reactivity, and ease of separating of reaction products. According to
Scheme 1, the condensation of benzimidazole, benzotriazole, imidazole, and 2-phenyl-
imidazole was initially achieved with 2-bromoacetophenone for the synthesis of
ketones 18a – 18e as key intermediates. On the basis of a literature survey, we
recognized that among published methods for N-alkylation of imidazole derivatives
[17], a method established by Liu et al. [18] is the most appropriate one for N-
alkylation of azoles and their derivatives, because in this method the formation of
quaternary imidazolium salts is largely prevented. However, in our experience, using
Et3N (TEA) as a homogeneous base instead of K2CO3, which was previously employed
by Liu et al., afforded more satisfactory results. Hence, the reaction of imidazole or
benzimidazole derivatives with 2-bromoacetophenones and TEA in the presence of a
catalytic amount of Bu4NBr (TBAB) in refluxing anhydrous acetonitrile (MeCN)
provided the ketones 18a – 18e in good yields (61 – 71%). Subsequently, the ketones
18a – 18e were converted to the oxime derivatives 19a – 19e by stirring with hydroxyl-
amine hydrochloride in the presence of aqueous NaOH in EtOH at room temperature
for one day (Scheme 1).
Oximes 19a – 19e are significant and attractive precursors for the synthesis of the
title compounds. They can react with diverse alkyl halides or other sources of carbon
electrophiles. For example, the reaction of oximes 19a, 19c, and 19e with benzyl
bromide in a solution of KOH in H2O/DMSO (1:9) by stirring at room temperature
afforded the products 17a, 17c, and 17f in good yields, respectively (88, 87, and 87%).
Furthermore, other alkyl halides such as (2-chloroethoxy)benzene and allyl bromide
were condensed with oximes 19a and 19b, and 1-chloro-4-(3-chloropropoxy)benzene
with oxime 19d gave the corresponding products 17b, 17d, and 17e in good to
reasonable yields, accordingly. We have recently published the aqueous-mediated ring
opening of epoxides with oximes for obtaining b-hydroxy oxime O-ethers as potential
b-adrenergic blocking agents [19]. In that context, we synthesized compound 17g from
the regioselective ring opening of 2-(phenoxymethyl)oxirane by oxime 19a in 78% yield.
For the synthesis of the nucleoside analogs of the target compounds 17h – 17m, we
envisaged a substantial problem for processing the synthesis using a similar pathway as
shown in Scheme 1. Unfortunately, the corresponding oximes 19f – 19j were not
obtained by the method described for the synthesis of compounds 19a – 19e in
Scheme 1. There are two main factors that limited the usage of the aforementioned
pathway described in Scheme 1 for nucleobases: i) the low yield of the synthesis of
corresponding oximes 19 from ketones 18 (20 – 30%), ii) cumbersome purification
processes and failure of separation using conventional column chromatography for the
ketones 18. Thus, we have modified the procedure of Scheme 1 by first performing an
oximation of 2-bromoacetophenone [20], and subsequently coupling the attained
oxime 20 with the desired nucleobases (Scheme 2).
As shown in Scheme 2, the oximation of 2-bromoacetophenone provided an
considerable amount of 2-bromo-1-phenylethanone oxime 20 for the next reaction
step. The coupling of base-activated purine and pyrimidine nucleobases as well as
theophylline and 2-methyl-4(5)-nitro-1H-imidazole by K2CO3 in anhydrous DMF
under reflux provided the N-alkylation adducts 19f – 19j in moderate yields (31, 40, 45,
54, and 61%, resp.). In these syntheses, the N-alkylation reactions of nucleobases were
achieved regioselectively. In the case of uracil, the N(1)-alkylated compound 19f was

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Scheme 1

Helvetica Chimica Acta – Vol. 92 (2009)
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Scheme 2
obtained dominantly (31%); however, the N(1),N(3)-dialkylated adduct was also
observed in trace amounts (<10%). Moreover, adenine and N-benzyl adenine
derivatives 19g and 19h were obtained as the N(9)-isomer in yields of 40 and 45%;
while theophylline was mostly alkylated to yield the N(7)-isomer 19i (54%).
From 2-methyl-4(5)-nitro-1H-imidazole which possesses considerable medical
applications as a chemotherapeutic agent and is of potential agricultural interest

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[21], the oxime 19j was synthesized. In agreement with [18][22], the N-alkylation of 2-
methyl-4(5)-nitro-1H-imidazole with 20 afforded mainly the respective 4-NO2-isomer
19j rather than the 5-NO2-isomer. The oxiconazole nucleoside analogs 17a – 17m were
prepared by treatment of oximes 19a – 19j with various alkyl halides in the presence of
aqueous KOH in DMSO at room temperature (Schemes 1 and 2).
Inspired by the acyclovir (ACV, Zovirax) framework as potent antiviral agent
against herpes simplex virus 1&2 (HSV-1, 2), we designed and synthesized the novel
oxiconazole-like compounds 17n and 17o consisting of two ACV- and oxiconazole-like
substructures. The synthetic route for compounds 17n and 17o is summarized in
Scheme 3. As shown in Scheme 3, for the synthesis the ACV-like part of compounds 17n
and 17o, we first prepared the prerequisite a-chloro ether (1-bromo-2-(chlorome-
thoxy)ethane) using 2-bromoethanol and 1,3,5-trioxane solutions in anhydrous CH2Cl2,
which was exposed to continuous dry HCl gas stream line at 08 for 6 – 8 h [16a][23]. 1-
Bromo-2-(chloromethoxy)ethane was then coupled with 2-methyl-4(5)-nitro-1H-
imidazole (for the preparation of compound 17n) or theophylline (for the preparation
of compound 17o) using an equimolar solution of TEA in anhydrous DMF at room
temperature for 5 h. The obtained ACV-like part molecule was then coupled with the
oxime 19a, the synthesis of which was described above in Scheme 1.
Scheme 3
Our approach to the synthesis of compounds 17n and 17o was to design a novel
therapeutic agent based on the remarkable biological activity of 2-methyl-4(5)-nitro-

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1H-imidazole as a potent chemotherapeutic agent as well as theophylline as an
attractive agent with coronary vasodilation, cardiotonic, bronchodilatoion, antihista-
minic, and antiasthmatic properties [6]. For instance, we think that compound 17n
(Fig. 4) can have more than a single biological activity, as it is known in the case of
oxiconazole to be only an antifungal agent. We assume that the 2-methyl-4(5)-nitro-
1H-imidazole part can be a useful residue in potential biological activities upon
enzymatic reduction of the 4-NO2 group into a free amine [21a]. Furthermore, the
benzimidazole residue in the oxiconazole-like as well as in the imidazole core in ACV-
like residues potentially can inhibit CYP-450 to prevent membrane cell construction in
fungi [2][3].
Fig. 4. The structural designing view of compound 17n
All compounds were fully characterized, and their structures were confirmed by 1H-
and 13C-NMR, elemental analysis, mass and IR spectroscopy. Compounds 17a – 17o
were expected to be produced as two geometrical isomers ((E)- or (Z)-isomer);
however, (E)-isomers were obtained dominantly as its structure was identified by 1H-
and 13C-NMR analysis; the minor (Z)-isomer was also detected in trace amounts
(< 7%). For a rational interpretation of the excessive formation of (E)-isomers rather
than (Z)-isomers, a PM3 semiempirical quantum mechanic calculation was applied
using MOPAC in CS Chem 3D Ultra 8 (Cambridge Soft, 2004) or Hyperchem
(Hypercube Inc., Version 7). The results are summarized in the Table, in which DE
refers to the discrepancy of energy between the (Z)- and (E)-isomer (DE ¼ EZ ꢀ EE
(kcal/mol)). As can be seen (Table), calculated DE for all oxime ethers 17a – 17o have a
positive value. There is conformity to the experimental observations and calculated
data (Table) which endorses the higher stability of (E)-isomers in comparison with
(Z)-isomers, and hence predominant formation of (E)-products.

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Table. Calculated Heat of Formation of Synthesized Oxime Ethers 17a – 17o Using PM3
a
b
EE
)
EZ
)
DEc)
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
17l
17m
17n
17o
118.28791
89.16137
41.98483
138.67261
155.37681
57.15787
124.89792
1.20885
80.60935
142.43687
23.16306
ꢀ 13.67089
251.47961
228.66448
18.53776
118.78426
93.41994
48.64398
144.26355
161.41013
59.56520
134.90852
11.06290
85.65297
147.01618
25.06594
ꢀ 12.78417
351.12156
249.38301
20.02120
0.49635
4.25857
6.65915
5.59094
6.03332
2.40733
10.01060
9.85405
5.04362
4.57931
1.90288
0.88672
99.64195
20.71853
1.48344
a) Heat of formation of the (E)-isomer (kcal/mol). b) Heat of formation of the (Z)-isomer (kcal/mol).
c) DE ¼ EZ ꢀ EE (kcal/mol).
The biological studies of 17a – 17o are currently under investigation and will be
reported in due course.
We appreciate Shiraz University of Technology and Shiraz University Research Councils for partial
support of this work. We are also grateful to Mr. H. Sajedian Fard for recording NMR spectra.
Experimental Part
1. General. All chemicals were obtained from Fluka or Merck. Solvents were purified and dried by
standard procedures, and stored over 3-ꢂ molecular sieves. Reactions were followed by TLC using
SILG/UV 254 silica-gel plates. Column chromatography (CC): silica gel 60 (SiO2; 0.063 – 0.200 mm, 70 –
230 mesh; ASTM). Melting points (M.p.): Bꢀchi 510 apparatus; in open capillaries (uncorrected). IR
Spectra: Shimadzu FT-IR-8300 spectrophotometer; in cmꢀ1. 1H- and 13C-NMR Spectra: Bruker Avance-
DPX-250 spectrometer; at 250/62.5 MHz, resp., d in ppm, J in Hz. GC/MS: Shimadzu GC/MS-QP 1000-
EX apparatus; in m/z (rel. %). Elemental analyses (CHNS) were performed on a Perkin-Elmer 240-B
micro-analyzer.
2. General Procedure for the Synthesis of Ketones 18a – 18e. In a double-necked round bottomed flask
(100 ml) equiped with a condenser, a mixture of the appropriate N-heterocyle (0.01 mol), 2-
bromoacetophenone (2.38 g, 0.012 mol), anh. TEA (1.01 g, 0.01 mol), and cat. amounts of TBAB
(0.1 g) were dissolved in dry MeCN (40 ml). Then, the mixture was heated to reflux for 10 h (TLC
control). The solvent was evaporated at reduced pressure, the residue was dissolved in CHCl3 (200 ml),
and washed with H2O (2 ꢁ 100 ml). The org. layer was dried (10 g of Na2SO4) and concentrated to afford
the crude product, which was purified by CC on SiO2 eluting with appropriate solvents.
3. General Procedure for the Synthesis of Oximes 19a – 19e. In a round bottomed flask (100 ml) a
mixture of the appropriate ketone 18a – 18e (0.01 mol), hydroxylamine hydrochloride (1.03 g,
0.015 mol), NaOH (0.6 g, 0.015 mol), and H2O (minimum amount for solvation of hydroxylamine
hydrochloride and NaOH) was dissolved in EtOH (20 ml), and then the soln. was stirred for 24 h at r.t.
Afterwards, the mixture was poured into 20 g ice/10 g H2O. Oxime precipitate immediately formed which
was filtered and washed with cold H2O and dried. Recrystallization from hot MeOH/H2O afforded pure
oximes 19a – 19e which were used for the next step.

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4. General Procedure for the Synthesis of Compounds 19f – 19j. In a double-necked round bottomed
flask (100 ml) equiped with a condenser, a mixture of the appropriate nucleobase (0.01 mol) and K2CO3
(1.38 g, 0.01 mol) was dissolved in DMF (30 ml) and stirred for 20 min under reflux. Subsequently, oxime
20 (2.20 g, 0.013 mol) was added to the mixture and heated under reflux for 1.5 h (TLC control). The
solvent was evaporated at reduced pressure, the residue was dissolved in AcOEt (200 ml), and washed
with H2O (2 ꢁ 100 ml). The org. layer was dried (10 g of Na2SO4) and concentrated to afford the crude
product, which was purified by CC on SiO2 eluting with appropriate solvents.
5. General Procedure for the Synthesis of Compounds 17a – 17o. In a double-necked round bottomed
flask (100 ml) equipped with a condenser, an appropriate alkyl halide (0.013 mol) was added portionwise
to a soln. of the appropriate oxime (0.01 mol), KOH (0.56 g, 0.01 mol), and 2 ml of H2O in DMSO
(20 ml). The mixture was stirred for 2 – 4 h at r.t. (TLC control). Then, the crude product was dissolved in
CHCl3 (150 ml) and washed with H2O (3 ꢁ 200 ml). The org. layer was dried (10 g of Na2SO4) and
concentrated to afford the crude product, which was purified by CC on SiO2 eluting with proper solvents.
6. Synthesis of 1-Bromo-2-(chloromethoxy)ethane. In a three-necked bottom flask (250 ml), a soln.
of 2-bromoethanol (12.4 g, 0.1 mol) and 1,3,5-trioxane (3.5 g, 0.04 mol) in anh. CH2Cl2 (150 ml) was
stirred for moments to provide a homogeneous mixture. Then, the flask was immersed in an ice bath, and
dry HCl gas was bubbled through the mixture for 8 h. Afterwards, the mixture was diluted with 100 ml of
dry CH2Cl2 and transferred into a canonical flask (150 ml) equipped with moisture absorbent tube,
containing 20 g anh. CaCl2. The mixture was shaken vigorously for 15 min. The mixture was then flash-
filtered, and the solvent was evaporated in a rotavapor. The remaining liquid was corked and stored in
refrigerator.
2-(1H-Benzimidazol-1-yl)-1-phenylethanone (18a). Purified by CC (SiO2; AcOEt/hexane 8 :2).
Yield: 1.49 g (63%). Pale-yellow crystals. Rf (AcOEt) 0.39. M.p. 150 – 1528. IR (KBr): 3047.3m, 2939.3m,
1710.8s, 1596.9m, 1581.5m, 1373.2m. 1H-NMR (CDCl3): 8.01 – 7.16 (m, 9 arom. H, HꢀC(2) of
benzimidazole); 5.43 (s, NCH2). 13C-NMR (CDCl3): 50.31; 109.40; 120.37; 122.30; 123.23; 128.02;
129.12; 134.10; 134.23; 134.44; 143.46; 143.87; 191.43. MS: 236.09 (30.8, Mþ). Anal. calc. for C15H12N2O
(236.27): C 76.25, H 5.12, N 11.86; found: C 76.17, H 5.07, N 11.94.
2-(1H-Benzimidazol-1-yl)-1-(1,1’-biphenyl-4-yl)ethanone (18b). Purified by CC (SiO2; AcOEt/
hexane 8 :2). Yield: 1.90 g (61%). Yellow crystals. Rf (AcOEt) 0.36. M.p. 222 – 2248. IR (KBr): 3078.2m,
2823.6m, 1715.8s, 1596.9s, 1488.9m. 1H-NMR ((D6)DMSO): 8.22 – 7.20 (m, 13 arom. H, HꢀC(2) of
benzimidazole); 6.07 (s, NCH2). 13C-NMR ((D6)DMSO): 50.72; 110.54; 119.29; 121.42; 122.29; 127.02;
128.55; 128.89; 129.11; 133.22; 134.67; 138.66; 143.12; 144.95; 145.26; 145.31; 192.93. MS: 312.12 (24.1,
Mþ). Anal. calc. for C21H16N2O (312.36): C 80.75, H 5.16, N 8.97; found: C 80.67, H 5.24, N 8.91.
2-(1H-Benzotriazol-1-yl)-1-phenylethanone (18c). Purified by CC (SiO2; AcOEt/hexane 2 :8).
Yield: 1.54 g (65%). Pale-yellow crystals. Rf (AcOEt) 0.75. M.p. 112 – 1148. IR (KBr): 3024.2m, 2908.4m,
1951.8m, 1710.5s, 1604.7s, 1488.9m. 1H-NMR (CDCl3): 8.04 – 7.27 (m, 9 arom. H); 6.06 (s, NCH2).
13C-NMR (CDCl3): 53.82; 109.61; 119.97; 123.99; 127.77; 128.23; 128.47; 129.10; 133.94; 134.51; 146.00;
190.52. MS: 237.09 (19.6, Mþ). Anal. calc. for C14H11N3O (237.26): C 70.87, H 4.67, N 17.71; found: C 70.96,
H 4.75, N 17.63.
2-(1H-Imidazol-1-yl)-1-phenylethanone (18d). Purified by CC (SiO2; AcOEt). Yield: 1.13 g (61%).
Yellow-orange crystals. Rf (AcOEt) 0.27. M.p. 116 – 1188. IR (KBr): 3047.3m, 2954.7m, 2908.4m, 1714.5s,
1589.2s, 1434.9s. 1H-NMR ((D6)DMSO): 8.03 – 8.00 (m, 2 arom. H); 7.55 – 7.50 (m, 3 arom. H, HꢀC(2) of
imidazole); 7.14 (s, HꢀC(4) of imidazole); 6.96 (s, HꢀC(5) of imidazole); 5.76 (s, NCH2). 13C-NMR
((D6)DMSO): 52.57; 120.90; 127.42; 127.93; 128.57; 133.88; 134.42; 138.33; 193.56. MS: 186.07 (33.2,
Mþ). Anal. calc. for C11H10N2O (186.21): C 70.95, H 5.41, N 15.04; found: C 70.86, H 5.35, N 15.11.
1-Phenyl-2-(2-phenyl-1H-imidazol-1-yl)ethanone (18e). Purified by CC (SiO2; AcOEt/hexane 8 :2).
Yield: 1.86 g (71%). Bright brown oil. Rf (AcOEt) 0.49. IR (film): 3053.1m, 2954.7m, 2829.4m, 1715.7s,
1606.6s, 1506.3s, 1172.6s. 1H-NMR (CDCl3): 8.00 – 7.95 (m, 2 arom. H); 7.71 – 7.68 (m, 3 arom. H); 7.58 –
7.51 (m, 5 arom. H); 7.03 (s, HꢀC(4) of imidazole); 6.82 (s, HꢀC(5) of imidazole); 5.28 (s, NCH2).
13C-NMR (CDCl3): 44.75; 119.11; 119.81; 127.41; 124.74; 132.01; 133.48; 134.52; 134.85; 142.16; 142.72;
150.35; 193.04. MS: 262.11 (29.9, Mþ). Anal. calc. for C17H14N2O (262.31): C 77.84, H 5.38, N 10.68;
found: C 77.79, H 5.42, N 10.71.

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2-(1H-Benzimidazol-1-yl)-N-hydroxy-1-phenylethanimine (19a). Recrystallized from MeOH/H2O.
Yield: 2.38 g (95%). Pale-yellow crystals. Rf (AcOEt) 0.53. M.p. 205 – 2078. IR (KBr): 3264.1 (br.),
1
3039.6m, 2864.1m, 1690.4s, 1593.1m, 1456.2s. H-NMR ((D6)DMSO): 12.27 (s, OH, exchangeable with
D2O); 8.31 (s, HꢀC(2) of benzimidazole); 7.63 – 7.48 (m, 4 arom. H); 7.21 – 7.11 (m, 5 arom. H); 5.66 (s,
NCH2). 13C-NMR ((D6)DMSO): 37.67; 110.14; 119.20; 121.80; 122.62; 126.24; 128.00; 128.38; 129.08;
133.76; 142.52; 144.34; 151.64. MS: 251.10 (17.5, Mþ). Anal. calc. for C15H13N3O (251.28): C 71.70, H 5.21,
N 16.72; found: C 71.65, H 5.22, N 16.68.
2-(1H-Benzimidazol-1-yl)-1-(biphenyl-4-yl)-N-hydroxyethanimine (19b). Recrystallized from
MeOH/H2O. Yield: 2.88 g (88%). White crystals. Rf (AcOEt) 0.50. M.p. 213 – 2158. IR (KBr): 3525.6
(br.), 3035.2s, 2839.0s, 1680.4m, 1488.9s. 1H-NMR ((D6)DMSO): 11.95 (s, OH, exchangeable with D2O);
8.35 (s, HꢀC(2) of benzimidazole); 7.79 – 7.18 (m, 13 arom. H); 5.67 (s, NCH2). 13C-NMR ((D6)DMSO):
36.71; 110.92; 119.13; 121.40; 122.23; 125.24; 126.31; 126.56; 127.25; 128.83; 133.74; 135.59; 138.57; 139.59;
143.06; 144.47; 147.35. MS: 327.13 (23.6, Mþ). Anal. calc. for C21H17N3O (327.38): C 77.04, H 5.23, N 12.84;
found: C 77.12, H 5.29, N 12.89.
2-(1H-Benzotriazol-1-yl)-N-hydroxy-1-phenylethanimine (19c). Recrystallized from MeOH/H2O.
Yield: 2.37 g (94%). White crystals. Rf (AcOEt) 0.76. M.p. 186 – 1888. IR (KBr): 3364.1 (br.), 3039.6m,
2864.1m, 1687.4s, 1593.1m, 1456.2s. 1H-NMR ((D6)DMSO): 12.22 (s, OH, exchangeable with D2O);
8.15 – 7.28 (m, 9 arom. H); 6.07 (s, NCH2). 13C-NMR ((D6)DMSO): 54.08; 119.04; 126.22; 127.30; 128.20;
128.32; 128.90; 129.10; 133.97; 134.22; 145.10; 150.65. MS: 252.10 (23.6, Mþ). Anal. calc. for C14H12N4O
(252.27): C 66.65, H 4.79, N 22.21; found: C 66.67, H 4.82, N 22.24.
N-Hydroxy-2-(1H-imidazol-1-yl)-1-phenylethanimine (19d). Recrystallized from MeOH/H2O.
Yield: 1.91 g (95%). White crystals. Rf (AcOEt): 0.24. M.p. 163 – 1658. IR (KBr): 3234.1 (br.), 3118.7s,
2988.2m, 1684.2m, 1575.7m, 14407s. 1H-NMR ((D6)DMSO): 12.29 (s, OH, exchangeable with D2O);
7.68 – 7.34 (m, 5 arom. H, HꢀC(2) of imidazole); 7.05 (s, HꢀC(4) of imidazole); 6.84 (s, HꢀC(5) of
imidazole); 5.33 (s, NCH2). 13C-NMR ((D6)DMSO): 39.04; 119.53; 125.96; 128.30; 128.48; 129.10;
133.96; 137.59; 151.81. MS: 201.09 (35.7, Mþ). Anal. calc. for C11H11N3O (201.22): C 65.66, H 5.51, N
20.88; found: C 65.69, H 5.53, N 20.87.
N-Hydroxy-1-phenyl-2-(2-phenyl-1H-imidazol-1-yl)ethanimine (19e). Recrystallized from MeOH/
H2O. Yield: 2.58 g (93%). Pale-yellow crystals. Rf (AcOEt) 0.51. M.p. 167 – 1698. IR (KBr): 3139.9 (br.),
1
3070.5m, 2977.9m, 1690.2s, 1527.5s, 1404.1m. H-NMR ((D6)DMSO): 12.03 (s, OH, exchangeable with
D2O); 7.55 – 7.21 (m, 10 arom. H); 7.09 (d, J ¼ 1.0, HꢀC(4) of imidazole); 6.91 (d, J ¼ 1.0, HꢀC(5) of
imidazole); 5.42 (s, NCH2). 13C-NMR ((D6)DMSO): 40.87; 121.57; 126.04; 127.70; 127.90; 127.98; 128.15;
128.32; 128.85; 130.52; 133.98; 146.84; 152.24. MS: 277.12 (56.8, Mþ). Anal. calc. for C17H15N3O (277.32):
C 73.63, H 5.45, N 15.15; found: C 73.69, H 5.48, N 15.12.
1-[2-(Hydroxyimino)-2-phenylethyl]pyrimidine-2,4(1H,3H)-dione (19f). Purified by CC (SiO2;
AcOEt/hexane 6 :4). Yield: 0.76 g (31%). Pale-yellow crystals. Rf (AcOEt) 0.51. M.p. 164 – 1668. IR
(KBr): 3321.2 (br.), 3254.9s, 3108.5m, 3047.3m, 2839.1m, 1690.8m, 1662s, 1659.2s, 1450.4m. 1H-NMR
((D6)DMSO): 12.01 (s, OH, exchangeable with D2O); 10.75 (s, NH, exchangeable with D2O); 7.65 (d, J ¼
7.2, HꢀC(6) of uracil); 7.85 – 7.19 (m, 5 arom. H); 5.24 (d, J ¼ 7.2, HꢀC(5) of uracil); 5.01 (s, NCH2).
13C-NMR ((D6)DMSO): 51.25; 100.64; 127.83; 128.57; 128.89; 134.15; 146.12; 151.02; 155.15; 163.80. MS:
245.08 (11.6, Mþ). Anal. calc. for C12H11N3O3 (245.23): C 58.77, H 4.52, N 17.13; found: C 58.69, H 4.61, N
17.05.
9-[2-(Hydroxyimino)-2-phenylethyl]-9H-purin-6-amine (19g). Purified by CC (SiO2; AcOEt/MeOH
10 :1). Yield: 1.07 g (40%). White crystals. TLC (AcOEt/MeOH 10 :1): Rf 0.45. M.p. 233 – 2358. IR
(KBr): 3374.2 (br.), 3300 – 3100s, 3042.5m, 3019.2m, 2898.6m, 2338.1m, 1685.5s, 1579.7m, 1459.1m.
1H-NMR ((D6)DMSO): 12.00 (s, OH, exchangeable with D2O); 8.13 (s, HꢀC(8) of adenine); 7.99 (s,
HꢀC(2) of adenine); 7.63 (s, NH2, exchangeable with D2O), 7.28 – 7.18 (m, 5 arom. H); 5.42 (s, NCH2).
13C-NMR ((D6)DMSO): 36.88; 118.01; 126.26; 128.26; 128.96; 133.99; 140.74; 149.38; 152.11; 152.51;
155.81. MS: 258.10 (15.1, Mþ). Anal. calc. for C13H12N6O (268.27): C 58.20, H 4.51, N 31.33; found: C
58.25, H 4.49, N 31.37.
N-Benzyl-9-[2-(hydroxyimino)-2-phenylethyl]-9H-purin-6-amine (19h). Purified by CC (SiO2;
AcOEt/hexane 8 :2). Yield: 1.61 g (45%). Pale-yellow crystals. Rf (AcOEt) 0.66. M.p. 176 – 1788. IR
(KBr): 3342.5 (br.), 3276.8s, 3051.2m, 3024.2m, 2854.4m, 1690.2s, 1581.5m, 1456.2m. 1H-NMR

Helvetica Chimica Acta – Vol. 92 (2009)
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((D6)DMSO): 11.84 (s, OH, exchangeable with D2O); 8.06 – 7.80 (m, HꢀC(2) and HꢀC(8) of N-benzyl
adenine and NH); 7.44 – 7.42 (m, 2 arom. H); 7.03 – 6.99 (m, 8 arom. H); 5.21(s, NCH2); 4.44 (s, PhCH2N).
13C-NMR ((D6)DMSO): 36.89; 42.83; 118.36; 126.25; 126.51; 127.06; 128.10; 128.29; 128.99; 134.02;
136.25; 140.01; 140.76; 152.02; 152.50; 154.29. MS: 358.15 (15.8, Mþ). Anal. calc. for C20H18N6O (358.39):
C 67.02, H 5.06, N 23.45; found: C 67.09, H 5.14, N 23.41.
7-[2-(Hydroxyimino)-2-phenylethyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (19i). Purified
by CC (SiO2; AcOEt/hexane 8 :2). Yield: 1.69 g (54%). Pale-yellow crystals. Rf (AcOEt) 0.58. M.p.
234 – 2368. IR (KBr): 3309.6 (br.), 3085.9m, 2939.3m, 2877.6m, 1889.5s, 1704.9s, 1680s, 1643.2s, 1434.9s.
1H-NMR ((D6)DMSO): 12.03 (s, OH, exchangeable with D2O); 7.84 (s, HꢀC(8) of theophylline); 7.48 –
7.22 (m, 5 arom. H); 5.58 (s, NCH2); 3.26 (s, MeꢀN(3)); 3.13 (s, MeꢀN(1)). 13C-NMR ((D6)DMSO):
27.38; 29.17; 40.10; 106.07; 126.18; 128.21; 128.89; 133.61; 142.22; 147.63; 150.66; 151.66; 154.32. MS:
313.11 (46.2, Mþ). Anal. calc. for C15H15N5O3 (313.31): C 57.50, H 4.83, N 22.35; found: C 57.53, H 4.85, N
22.37.
N-Hydroxy-2-(2-methyl-4-nitro-1H-imidazol-1-yl)-1-phenylethanimine (19j). Purified by CC (SiO2;
AcOEt/hexane 8 :2). Yield: 1.59 g (61%). White crystals. Rf (AcOEt) 0.63. M.p. 195 – 1978. IR (KBr):
3312.5 (br.), 3032.5m, 2962.3m, 2854.5m, 1685s, 1542.9m, 1535.2s, 1496.7m, 1388.7s. 1H-NMR
((D6)DMSO): 11.94 (s, OH, exchangeable with D2O); 7.91 (s, HꢀC(5) of imidazole); 7.34 – 7.30 (m, 2
arom. H); 7.10 – 7.08 (m, 3 arom. H); 5.17 (s, NCH2); 2.00 (s, Me). 13C-NMR ((D6)DMSO): 12.52; 40.73;
122.47; 126.49; 128.54; 129.30; 133.36; 144.99; 145.18; 151.04. MS: 260.09 (10.3, Mþ). Anal. calc. for
C12H12N4O3 (260.25): C 55.38, H 4.65, N 21.53; found: C 55.32, H 4.60, N 21.49.
(1E)-2-(1H-Benzimidazol-1-yl)-N-(benzyloxy)-1-phenylethanimine (17a). Purified by CC (SiO2;
AcOEt/hexane 5 :5). Yield: 3.00 g (88%). White crystals. Rf (AcOEt) 0.57. M.p. 121 – 1238. IR (KBr):
3033.8s, 2922.0s, 2852.5m, 1764.7m, 1699.2m, 1666.4m, 1492.8s, 1020.8s. 1H-NMR ((D6)DMSO): 8.26 (s,
HꢀC(2) of benzimidazole); 7.65 – 7.10 (m, 14 arom. H); 5.69 (s, NCH2); 5.38 (s, NOCH2). 13C-NMR
((D6)DMSO): 38.52; 76.36; 109.98; 119.47; 121.66; 122.50; 126.62; 128.11; 128.42; 128.60; 129.63; 132.80;
133.47; 135.27; 137.23; 143.09; 144.37; 153.29. MS: 341.15 (26.3, Mþ). Anal. calc. for C22H19N3O (341.41):
C 77.40, H 5.61, N 12.31; found: C 77.48, H 5.66, N 12.28.
(1E)-2-(1H-Benzimidazol-1-yl)-N-(2-phenoxyethoxy)-1-phenylethanimine (17b). Purified by CC
(SiO2; AcOEt/hexane 4 :6). Yield: 3.04 g (82%). Pale-yellow crystals. Rf (AcOEt) 0.50. M.p. 108 – 1108.
1
IR (KBr): 3033.8m, 2974.0m, 2864.1m, 1758.9m, 1658.7m, 1598.9s, 1444.6m, 1245.9s, 1080.1s. H-NMR
((D6)DMSO): 8.31 (s, HꢀC(2) of benzimidazole); 7.66 – 6.95 (m, 14 arom. H); 5.69 (s, NCH2); 4.66 (t,
J ¼ 5.3, PhOCH2); 4.37 (t, J ¼ 5.3, NOCH2). 13C-NMR ((D6)DMSO): 38.30; 65.86; 73.00; 109.97; 114.48;
119.44; 120.77; 121.66; 122.57; 126.70; 128.41; 129.55; 129.66; 132.69; 133.47; 143.06; 144.45; 153.43;
158.39. MS: 371.16 (43.1, Mþ). Anal. calc. for C23H21N3O2 (371.43): C 74.37, H 5.70, N 11.31; found: C
74.31, H 5.77, N 11.35.
(1E)-2-(1H-Benzotriazol-1-yl)-N-(benzyloxy)-1-phenylethanimine (17c). Purified by CC (SiO2;
AcOEt/hexane 2 :8). Yield: 2.97 g (87%). Pale-yellow crystals. Rf (AcOEt) 0.83. M.p. 75 – 778. IR (KBr):
3055.0m, 2916.2m, 2898.5m, 1691.2m, 1612.4m, 1589.2m, 1450.4s, 1018.3s. 1H-NMR ((D6)DMSO): 7.74 –
7.28 (m, 14 arom. H); 6.09 (s, NCH2); 5.33 (s, NOCH2). 13C-NMR ((D6)DMSO): 62.99; 76.32; 119.10;
123.90; 127.32; 127.67; 127.97; 127.99; 128.38; 128.72; 128.78; 129.68; 132.94; 137.07; 142.50; 144.83; 152.12.
MS: 342.14 (19.8, Mþ). Anal. calc. for C21H18N4O (342.39): C 73.67, H 5.30, N 16.36; found: C 73.72, H
5.33, N 16.32.
(1E)-2-(1H-Benzimidazol-1-yl)-1-(biphenyl-4-yl)-N-(prop-2-en-1-yloxy)ethanimine (17d). Purified
by CC (SiO2; AcOEt/hexane 8 :2). Yield: 3.20 g (87%). White crystals. Rf (AcOEt) 0.26. M.p. 175 – 1778.
IR (KBr): 3027.2s, 2917.1s, 2884.3m, 1759.6m, 1685.7m, 1664.1m, 1487.1s, 1019.1s. 1H-NMR (CDCl3): 8.02
(s, HꢀC(2) of benzimidazole); 7.60 – 7.24 (m, 13 arom. H); 6.16 – 5.94 (m, ¼ CH), 5.43 (s, NCH2); 5.35
(d, J ¼ 5.3, NOCH2); 4.84 (dd, J ¼ 1.2, 4.7, ¼ CH2). 13C-NMR (CDCl3): 39.15; 49.05; 109.68; 110.39;
117.94; 118.82; 120.39; 122.30; 123.16; 126.74; 127.10; 127.18; 127.48; 127.79; 128.21; 128.85; 132.26;
133.41; 143.26; 151.68. MS: 367.16 (24.9, Mþ). Anal. calc. for C24H21N3O (367.44): C 78.45, H 5.76, N
11.44; found: C 78.51, H 5.74, N 11. 50.
(1E)-N-[3-(4-Chlorophenoxy)propoxy]-2-(1H-imidazol-1-yl)-1-phenylethanimine (17e). Purified
by CC (SiO2; AcOEt). Yield: 3.14 g (85%). Bright-brown oil. Rf (AcOEt) 0.22. IR (film): 3031.8m,
2948.1m, 2839.4m, 1636.1m, 1612.3m, 1467.2m, 1024.6s. 1H-NMR (CDCl3): 7.45 (s, HꢀC(2) of imidazole);

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Helvetica Chimica Acta – Vol. 92 (2009)
7.43 – 7.41 (m, 2 arom. H); 7.25 – 7.22 (m, 3 arom. H); 7.12 – 7.09 (m, 2 arom. H); 6.85 (s, HꢀC(4) of
imidazole); 6.76 (s, HꢀC(5) of imidazole); 6.72 – 6.68 (m, 2 arom. H); 5.03 (s, NCH2); 4.37 (t, J ¼ 6.2,
ArOCH2); 3.89 (t, J ¼ 6.2, NOCH2); 2.14 – 1.98 (m, NOCH2CH2OAr). 13C-NMR (CDCl3): 29.07; 40.72;
64.68; 71.57; 115.78; 119.29; 126.15; 127.67; 128.46; 128.82; 129.30; 129.94; 133.44; 137.36; 151.91; 157.43.
MS: 369.12 (48.5, Mþ). Anal. calc. for C20H20ClN3O2 (369.84): C 64.95, H 5.45, Cl 9.59, N 11.36; found: C
64.90, H 5.47, Cl 9.52, N 11.39.
(1E)-N-(Benzyloxy)-1-phenyl-2-(2-phenyl-1H-imidazol-1-yl)ethanimine (17f). Purified by CC
(SiO2; AcOEt/hexane 4 :6). Yield: 3.19 g (87%). Pale-yellow crystals. Rf (AcOEt) 0.59. M.p. 91 – 938.
IR (KBr): 3024.2m, 2921.9m, 2848.7m, 1629.7m, 1604.7m, 1471.6m, 1018.3s. 1H-NMR ((D6)DMSO):
7.50 – 7.21 (m, 15 arom. H); 7.09 (d, J ¼ 1.0, HꢀC(4) of imidazole); 6.92 (d, J ¼ 1.0, HꢀC(5) of
imidazole); 5.46 (s, NCH2); 5.16 (s, NOCH2). 13C-NMR ((D6)DMSO): 41.70; 75.93; 121.66; 126.56;
127.64; 127.85; 127.98; 128.01; 128.18; 128.25; 128.32; 128.44; 129.41; 130.48; 132.90; 142.50; 146.95;
153.88. MS: 367.16 (48.5, Mþ). Anal. calc. for C24H21N3O (367.44): C 78.45, H 5.76, N 11.44; found: C
78.49, H 5.81, N 11.48.
1-({[(1E)-2-(1H-Benzimidazol-1-yl)-1-phenylethylidene]amino}oxy)-3-phenoxypropan-2-ol (17g).
Purified by CC (SiO2; AcOEt/hexane 4 :6). Yield: 3.13 g (78%). Pale-yellow oil. Rf (AcOEt) 0.61. IR
(film): 3417.3 (br.), 2979.8m, 2921.9m, 2844.8m, 1662.5m, 1633.6m, 1600.8m, 1456.2m, 1234.3s. 1H-NMR
(CDCl3): 8.00 (s, HꢀC(2) of benzimidazole); 7.39 – 6.85 (m, 14 arom. H); 5.15 – 5.11 (m, CHOH); 4.45 (s,
OH, exchangeable with D2O); 4.02 – 3.78 (m, NCH2, NOCH2, PhOCH2). 13C-NMR (CDCl3): 54.77;
67.58; 69.52; 77.78; 114.44; 119.59; 120.45; 121.82; 122.72; 126.64; 128.10; 129.47; 129.71; 130.39; 132.84;
133.58; 143.10; 144.37; 153.25; 158.72. MS: 401.17 (48.5, Mþ). Anal. calc. for C24H23N3O3 (401.46): C
71.80, H 5.77, N 10.47; found: C 71.89, H 5.78, N 10.52.
1-{(2E)-2-[(Benzyloxy)imino]-2-phenylethyl}pyrimidine-2,4(1H,3H)-dione (17h). Purified by CC
(SiO2; AcOEt/hexane 4 :6). Yield: 1.88 g (56%). White crystals. Rf (AcOEt) 0.76. M.p. 162 – 1648. IR
(KBr): 3242.1s, 3082.0m, 2956.7m, 1731.9m, 1697.2m, 1652.9m, 1558.4s, 1456.2m, 1234.3s. 1H-NMR
((D6)DMSO): 11.21 (s, NH, exchangeable with D2O); 7.68 (d, J ¼ 7.5, HꢀC(6) of uracil); 7.48 – 7.19 (m,
10 arom. H); 5.72 (d, J ¼ 7.5, HꢀC(5) of uracil); 4.95 (s, NCH2); 4.82 (s, NOCH2). 13C-NMR
((D6)DMSO): 43.30; 50.81; 100.04; 127.06; 127.40; 127.96; 128.09; 128.26; 128.98; 131.51; 136.95; 144.83;
150.03; 150.99; 162.33. MS: 335.12 (14.8, Mþ). Anal. calc. for C19H17N3O3 (335.36): C 68.05, H 5.11, N
12.53; found: C 68.11, H 5.14, N 12.60.
9-[(2E)-2-{[3-(4-Chlorophenoxy)propoxy]imino}-2-phenylethyl]-9H-purin-6-amine (17i). Purified
by CC (SiO2; AcOEt/MeOH 10 :1). Yield: 2.71 g (62%). White crystals. Rf (AcOEt/MeOH 10 :1) 0.33.
M.p. 148 – 1508. IR (KBr): 3300 – 3100s, 3057.1m, 3024.9m, 2956.7m, 2831.4m, 1634.8s, 1569.1m, 1471.3m.
1H-NMR ((D6)DMSO): 8.09 (s, HꢀC(8) of adenine); 8.03 (s, HꢀC(2) of adenine); 7.61 (s, NH2,
exchangeable with D2O); 7.30 – 7.23 (m, 7 arom. H); 6.92 (d, J ¼ 8.8, 2 arom. H); 5.44 (s, NCH2); 4.31 (t,
J ¼ 6.0, PhOCH2); 3.98 (t, J ¼ 6.0, NOCH2); 2.11 – 2.06 (m, NOCH2CH2OAr). 13C-NMR ((D6)DMSO):
28.50; 38.00; 64.54; 70.91; 116.06; 118.03; 124.10; 126.69; 128.26; 129.14; 129.42; 133.18; 140.87; 149.41;
152.53; 153.26; 155.80; 157.28. MS: 436.14 (10.3, Mþ). Anal. calc. for C22H21ClN6O2 (436.89): C 60.48, H
4.84, Cl 8.11, N 19.24; found: C 60.45, H 4.90, Cl 8.16, N 19.28.
N-Benzyl-9-[(2E)-2-{[(2-methylbenzyl)oxy]imino}-2-phenylethyl]-9H-purin-6-amine (17j). Puri-
fied by CC (SiO2; AcOEt/hexane 6 :4). Yield: 3.10 g (67%). White crystals. Rf (AcOEt) 0.43. M.p.
119 – 1218. IR (KBr): 3285.4s, 3057.1m, 2997.4m, 1745.9m, 1685.6m, 1651.9m, 1554.9s, 1451.6m, 1262.4s.
1H-NMR ((D6)DMSO): 8.17 (s, HꢀC(8) of N-benzyl adenine); 7.93 (s, HꢀC(2) of N-benzyl adenine);
7.64 – 7.62 (m, 2 arom. H); 7.30 – 7.13 (m, 12 arom. H); 5.46 (s, NCH2); 5.28 (s, NOCH2); 4.65 (s, NH,
exchangeable with D2O); 3.35 (s, PhCH2NH); 2.29 (s, Me). 13C-NMR ((D6)DMSO): 18.50; 37.88; 42.82;
74.53; 125.66; 126.51; 126.67; 127.07; 128.09; 128.26; 128.31; 129.05; 129.49; 129.84; 129.97; 133.09; 135.10;
136.18; 136.56; 140.01; 140.59; 152.47; 153.32; 154.22. MS: 462.21 (12.5, Mþ). Anal. calc. for C28H26N6O
(462.55): C 72.71, H 5.67, N 18.17; found: C 72.68, H 5.69, N 18.14.
7-{(2E)-2-[(Benzyloxy)imino]-2-phenylethyl}-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (17k).
Purified by CC (SiO2; AcOEt/hexane 4 :6). Yield: 3.59 g (89%). White crystals. Rf (AcOEt) 0.74. M.p.
108 – 1108. IR (KBr): 3028.0m, 2931.6m, 2892.3m, 1701.1s, 1691.4s, 1654.8s, 1604.7s, 1446.5m, 1232.4s.
1H-NMR ((D6)DMSO): 7.88 (s, HꢀC(8) of theophylline); 7.60 – 7.28 (m, 10 arom. H); 5.61 (s, NCH2);
5.21 (s, NOCH2); 3.27 (s, MeꢀN(3)); 3.11 (s, MeꢀN(1)). 13C-NMR ((D6)DMSO): 27.36; 29.20; 41.62;

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76.10; 106.18; 126.73; 127.64; 127.78; 128.01; 128.15; 129.68; 132.72; 137.05; 142.45; 147.59; 150.65; 153.41;
154.20. MS: 403.16 (34.6, Mþ). Anal. calc. for C22H21N5O3 (403.43): C 65.50, H 5.25, N 17.36; found: C
65.43, H 5.20, N 17.31.
1,3-Dimethyl-7-{(2E)-2-[(2-phenoxyethoxy)imino]-2-phenylethyl}-3,7-dihydro-1H-purine-2,6-dione
(17l). Purified by CC (SiO2; AcOEt/hexane 4 :6). Yield: 3.42 g (79%). White crystals. Rf (AcOEt) 0.70.
M.p. 96 – 988. IR (KBr): 3048.7m, 2945.1m, 2843.4m, 1699.2s, 1658.7s, 1600.8s, 1582.3m, 1442.7m, 1244.0s.
1H-NMR (CDCl3): 7.34 – 6.95 (m, 10 arom. H, HꢀC(8) of theophylline); 5.68 (s, NCH2); 4.65 (t, J ¼ 5.1,
PhOCH2); 4.30 (t, J ¼ 5.1, NOCH2); 3.51 (s, MeꢀN(3)); 3.38 (s, MeꢀN(1)). 13C-NMR (CDCl3): 27.95;
29.70; 39.45; 65.90; 73.34; 106.72; 114.55; 121.14; 126.40; 128.79; 129.53; 130.16; 132.51; 141.80; 148.30;
151.51; 152.69; 155.42; 158.43. MS: 433.17 (38.1, Mþ). Anal. calc. for C23H23N5O4 (433.46): C 63.73, H
5.35, N 16.16; found: C 63.78, H 5.30, N 16.23.
(1E)-N-(Benzyloxy)-2-(2-methyl-4-nitro-1H-imidazol-1-yl)-1-phenylethanimine (17m). Purified by
CC (SiO2; AcOEt/hexane 5 :5). Yield: 3.08 g (88%). Pale-yellow foam. Rf (AcOEt) 0.77. IR (KBr):
3021.5m, 2908.4m, 2848.7m, 2858.8s, 1533.2m, 1494.7m, 1334.6s, 1292.2s. 1H-NMR ((D6)DMSO): 8.17 (s,
HꢀC(5) of imidazole); 7.66 – 7.30 (m, 10 arom. H); 5.46 (s, NCH2); 5.31 (s, NOCH2); 2.20 (s, Me).
13C-NMR ((D6)DMSO): 12.66; 41.52; 76.50; 126.77; 127.96; 128.15; 128.20; 128.30; 128.33; 128.61;
129.86; 132.48; 136.93; 145.17; 152.37. MS: 350.13 (22.2, Mþ). Anal. calc. for C19H18N4O3 (350.37): C
65.13, H 5.18, N 15.99; found: C 65.19, H 5.24, N 16.06.
(1E)-2-(1H-Benzimidazol-1-yl)-N-{2-[(2-methyl-4-nitro-1H-imidazol-1-yl)methoxy]ethoxy}-1-phe-
nylethanimine (17n). Purified by CC (SiO2; AcOEt/hexane 8 :2). Yield: 3.60 g (83%). Pale-yellow oil. Rf
(AcOEt) 0.20. IR (film): 3055.0m, 2925.8m, 2879.5m, 1612.4m, 1541.0s, 1494.7s, 1338.5s. 1H-NMR
(CDCl3): 7.94 – 7.18 (m, 9 arom. H, HꢀC(2) of benzimidazole, HꢀC(5) of imidazole); 5.36 (s, OCH2N);
5.16 (s, NCH2); 4.35 (t, J ¼ 4.2, NOCH2); 3.71 (t, J ¼ 4.2, CH2O); 2.19 (s, Me). 13C-NMR (CDCl3): 12.81;
39.09; 67.33; 73.22; 77.11; 109.75; 119.85; 120.44; 122.10; 123.00; 126.24; 128.64; 129.91; 132.95; 133.57;
143.14; 143.46; 145.39; 146.05; 152.80. MS: 434.17 (18.9, Mþ). Anal. calc. for C22H22N6O4 (434.45): C
60.82, H 5.10, N 19.34; found: C 60.89, H 5.16, N 19.29.
7-{[2-({[(1E)-2-(1H-Benzimidazol-1-yl)-1-phenylethylidene]amino}oxy)ethoxy]methyl}-1,3-dimeth-
yl-3,7-dihydro-1H-purine-2,6-dione (17o). Purified by CC (SiO2; AcOEt/hexane 4 :6). Yield: 4.13 g
(85%). Pale-yellow crystals. Rf (AcOEt) 0.11. M.p. 93 – 958. IR (KBr): 3037.3m, 2952.8m, 2877.6m,
1
1697.2s, 1647.1s, 1604.2s, 1446.5m, 1045.3s. H-NMR ((D6)DMSO): 8.30 (s, HꢀC(8) of theophylline);
8.19 (s, HꢀC(2) of benzimidazole); 7.59 – 7.10 (m, 9 arom. H); 5.73 (s, OCH2N); 5.56 (s, NCH2); 4.37 (t,
J ¼ 4.6, NOCH2); 3.92 (t, J ¼ 4.6, CH2O); 3.30 (s, MeꢀN(3)); 3.12 (s, MeꢀN(1)). 13C-NMR
((D6)DMSO): 27.48; 29.42; 40.36; 66.84; 73.10; 74.88; 105.72; 109.82; 119.34; 121.54; 122.43; 126.50;
127.99; 128.35; 129.61; 132.63; 133.35; 143.23; 144.24; 148.37; 150.69; 153.06; 154.18. MS: 487.19 (31.7,
Mþ). Anal. calc. for C25H25N7O4 (487.51): C 61.59, H 5.17, N 20.11; found: C 61.50, H 5.09, N 20.05.
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Received February 17, 2009