Three-component synthesis of some novel N-heterocycle methyl-O-oxime ethers

Article abstract of DOI:10.1055/s-0031-1289599

A convenient and highly efficient protocol for one-pot synthesis of some novel N-heterocycle methyl-O-oxime ethers is described. In this method, three-component coupling of different types of ketoximes, with methylene iodide and nitrogen heterocycles, including imidazoles, benzimidazole, benzotriazole, and theophylline in the presence of an equimolar mixture of K₂CO ₃/Et₃N in refluxing MeCN furnished the corresponding N-heterocycle methyl-O-oxime ethers in good yields. This methodology is highly efficient for the synthesis of various structurally diverse N-heterocycle methyl-O-oxime ethers. The results of quantum mechanical studies on reaction intermediates are discussed. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289599

4068
PAPER
Three-Component Synthesis of Some Novel N-Heterocycle Methyl-O-oxime
Ethers
Synthesisof Some
N
ov
o
e
l
N
-Hetero
h
cycle
M
ethy
a
l-
O
-oxim
e
Em
thers mad Navid Soltani Rad,*a Somayeh Behrouz,*a Abdo Reza Nekoei,a Zeinab Faghih,b Ali Khalafi-Nezhadb
a
Department of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran
Fax +98(711)7354520; E-mail: soltani@sutech.ac.ir; E-mail: behrouz@sutech.ac.ir
b
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
Received 12 August 2011; revised 13 October 2011
cell and useful in the treatment of leukemia.17 In this con-
text and also in continuation of our ongoing research on
oxime chemistry,15b,18 we report now a simple and highly
efficient method for the synthesis of some novel N-hetero-
Abstract: A convenient and highly efficient protocol for one-pot
synthesis of some novel N-heterocycle methyl-O-oxime ethers is
described. In this method, three-component coupling of different
types of ketoximes, with methylene iodide and nitrogen heterocy-
cles, including imidazoles, benzimidazole, benzotriazole, and theo- cycle methyl-O-oxime ethers 3a–r using three-compo-
phylline in the presence of an equimolar mixture of K2CO3/Et3N in
nent reaction (3CR) of oximes, methylene iodide, and
refluxing MeCN furnished the corresponding N-heterocycle meth-
yl-O-oxime ethers in good yields. This methodology is highly effi-
mixture in anhydrous MeCN at reflux condition
cient for the synthesis of various structurally diverse N-heterocycle
nitrogen heterocycles in the presence of a K2CO3/Et3N
(Scheme 1).
methyl-O-oxime ethers. The results of quantum mechanical studies
on reaction intermediates are discussed.
O
Key words: three-component reaction (3CR), oxime, O-oxime
ether, methylene iodide, N-heterocycle
B
HN
O
O
N
O
N
G
Oximes and oxime ethers are important substrates in or-
ganic and medicinal chemistry.1 They are a key structural
motif in scaffolds of many drugs and bioactive com-
pounds. Many famous drugs having different chemother-
apeutic activities, such as antiviral (e.g., enviroxime),2
anti-inflammatory (e.g., pifoxime),1b antibiotics (e.g., ce-
fixime),3 nerve antidotes (e.g., pralidoxime),1b antifungals
(e.g., oxiconazole),4 macrolide antibiotics (e.g., roxithro-
mycin),5 antidepressants (e.g., fluvoxamine),1b and throm-
boxane synthase inhibitors (e.g., ridogrel),6 contain oxime
and/or oxime ether bonds in their structure.
G = Cl, Br, Me, OMe, etc.
B = purine or pyrimidine nucleobase,
imidazole, benzimidazole, etc.
2
1
Figure 1 Acycloaromatic nucleosides 1 and 1-(phenoxymethyl)-6-
azauracil (2)
R1
R2
N
R1
R2
Et3N, K2CO3
O
+ CH2I2
OH
N
+
N
H
N
MeCN, reflux, 7–12 h
3a–r
R1, R2 = alkyl, aryl, benzyl, etc.
The multi-component reactions (MCRs) are one of the
most important reactions in organic synthesis and medic-
inal chemistry.7 The MCRs offer several attractive fea-
tures to the chemical and pharmaceutical industries,
including access to a large number of novel and diverse
structures and lower production and environmental costs
due to high convergence and a greater degree of atom
economy. Many important reactions such as the Strecker,8
Hantzsch,9 Biginelli,10 Mannich,11 Passerini,12 Ugi,13 and
Gewald14 are well-known multi-component reactions.
These reactions often involve condensation processes and
ring closure. Indeed, there are only rare reports in which
an SN2 type reaction is a part of MCRs.15
N
N
N
,
,
,
:
N
H
NO2
O
N
N
N
H
H
H
H
N
N
Me
O
N
N
,
N
H
N
N
Me
Scheme 1
The first step of this synthetic approach involved optimi-
zation of the reaction conditions. Initially, the effect of
various solvents on the reaction of benzophenone oxime,
methylene iodide, and benzimidazole in the presence of
an equimolar mixture of K2CO3/Et3N was studied as a
model reaction. The results are depicted in Table 1.
Previously, we reported the synthesis of acycloaromatic
nucleosides 1,15a,16 which led to introduction of 1-(phe-
noxymethyl)-6-azauracil (2) (Figure 1) as an active che-
motherapeutic agents for inhibiting the growth of myeloid
From Table 1, among the examined solvents, anhydrous
MeCN (entry 4) afforded the best result and hence it was
the used solvent for all reactions. In view of the fact that
SYNTHESIS 2011, No. 24, pp 4068–4076
Advanced online publication: 09.11.2011
DOI: 10.1055/s-0031-1289599; Art ID: Z79811SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1

PAPER
Synthesis of Some Novel N-Heterocycle Methyl-O-oxime Ethers
4069
Table 1 Effect of Various Solvents on the Conversion of Benzophe-
none Oxime into 3b
Table 2 Effect of Various Bases on the Conversion of Benzophe-
none Oxime into 3b
NOH
NOH
N
N
Et3N, K2CO3
solvent, reflux
+
+
CH2I2
+
base
N
CH2I2
O
N
+
N
O
MeCN, reflux
N
N
N
3b
N
H
3b
N
H
Entry
Solventa
Time (h)
Yield (%)b
Entry
Base
K2CO3
Time (h)
Yield (%)a
65
1
2
3
4
5
6
7
8
DMSO
DMF
12
9
56
58
NRc
68
10
52
48
60
1
2
7
7
Cs2CO3
NaH
65
MeCN
MeCN
HMPA
toluene
THF
24
7
3
8
53
4
MgO
24
24
7
NRb
27
24
12
12
9
5
Et3N
6
K2CO3/Et3Nc
DBN
68
7
8
60
acetone
8
DBU
8
61
a All solvents used were anhydrous.
b Isolated yield.
9
DABCO
DMAP
24
24
NRb
NRb
c No reaction. Wet MeCN was used.
10
a Isolated yield.
b No reaction.
c 1:1 ratio.
the generated reactive intermediates in the reaction mix-
ture are very susceptible to the moisture, the use of an an-
hydrous solvent is critically essential. The explicit
interference of moisture was easily observed by the com-
parison of results obtained by use of wet MeCN versus an-
hydrous sample (Table 1, entries 3 and 4).
To compare the capability of other dihalomethanes in
progress of the reaction, the effect of various dihalo-
methane derivatives on model reaction was examined
(Table 3). As the data in Table 3 indicate, the dichlo-
romethane (Table 3, entry1) was not suitable for process-
ing the reaction. This is due to the fact that
dichloromethane exhibits the low boiling point (39.6 °C)
that normally is evolved from the reaction mixture (i.e.,
refluxing MeCN). Though dibromomethane, chloro-
iodomethane, and bromoiodomethane (Table 3, entries 2,
4, and 6) were demonstrated to give moderate yields of
3b, the bromochloromethane (Table 3, entry 5) provided
a low yield of the product.
Use of DMSO, DMF, and acetone (Table 1, entries 1, 2,
and 8) afforded 3b in moderate yields, whereas the other
solvents were inefficient even if the reaction time was
prolonged.
The choice of the reaction base for activation of the
oximes and also the nitrogen heterocycle component to re-
act with methylene iodide was found to have a great sig-
nificance. In this case, the potency of several organic and
inorganic bases on the reaction model was investigated
(Table 2). Due to demonstrated results in Table 2, among
the employed bases an equimolar mixture of K2CO3/Et3N
(entry 6) was the most efficient base for the progress of re-
action. In addition, the attained yields by use of K2CO3 (1
equiv) (Table 2, entry 1) and/or Et3N (2 equiv) (Table 2,
entry 5) distinctly were not as efficient as an equimolar
mixture of K2CO3/Et3N. Use of Cs2CO3, DBN, and DBU
(Table 2, entries 2, 7, and 8) also afforded 3b in good
yields, while the other bases were inefficient.
The scope of this method was evaluated by its extension
to various structurally diverse oximes and nitrogen het-
erocycles (Table 4). Based on the data in Table 4, this
method is applicable for various nitrogen heterocycles
such as imidazole, benzimidazole, 2-methyl-4(5)-nitro-
1H-imidazole, and theophylline. In addition, this method
is suitable for all kinds of ketoximes, including aromatic,
benzylic, aliphatic, alicyclic, and other ketoximes. Most
of the oximes used in this research are commercially
available or can be easily prepared according to the proce-
dure reported in the literature.19
The optimized stoichiometric ratios of nitrogen heterocy-
cle/CH2I2/oxime/K2CO3/Et3N for the conversion of ben-
zophenone oxime into 3b were found to be one equivalent
for each of the components.
Synthesis 2011, No. 24, 4068–4076 © Thieme Stuttgart · New York

4070
M. N. Soltani Rad et al.
PAPER
Table 4 Three-Component Synthesis of N-Heterocycle Methyl-O-
oxime Ethers Using Oximes, CH2I2, Nitrogen Heterocycles, K2CO3,
Et3N in Refluxing MeCN
Table 3 Effect of Various Dihalomethanes on the Conversion of
Benzophenone Oxime into 3b
NOH
Product Structurea
Time Yield
(h)
(%)b
N
+
Et3N, K2CO3
MeCN, reflux
N
CH2X2 or CH2XY
O
N
N
N
N
3a
7
70
N
+
N
O
O
O
O
N
N
N
N
N
N
N
N
3b
N
H
X, Y = Cl, Br, I
Entry
CH2X2 or CH2XYa
CH2Cl2
Time (h)
Yield (%)b
3b
3c
7
68
82
1
2
3
4
5
6
24
13
7
NRc
43
CH2Br2
CH2I2
68
11
CH2ClI
11
16
10
46
NO2
CH2BrCl
CH2BrI
21
52
a X, Y = Cl, Br, I.
b Isolated yield.
c No reaction.
Me
3d
3e
10
12
75
60
N
O
N
O
Synchronous reaction of oxime with methylene iodide
and nitrogen heterocycle is normally expected to give
three products. In this synthetic methodology, N-hetero-
cycle methyl-O-oxime ethers were obtained predominant-
ly. However, other products were formed either by N-
alkylation of the nitrogen heterocycles or O-alkylation of
oximes with methylene iodide in trace amounts (<5%).
MCRs can be used for domino reactions with inseparable
intermediates or sequential reactions with separable inter-
mediates.20 It is worthy to note that the anticipated iodo-
methyl-O-oxime ether intermediate, which has the close
resemblance with classic a-halo ethers, is quite unstable
and cannot be separated by normal separation techniques.
Consequently, the preparation of compounds 3a–r cannot
be achieved using stepwise synthesis and they must be
merely synthesized via the three-component reaction
(3CR).
Me
N
NO2
O
N
N
N
3f
9
65
O
N
N
Oximes are known to be ambident nucleophiles.21 The
alkylation of an oxime can be achieved either at the oxy-
gen to afford O-alkyl ether or at the nitrogen to generate
nitrones.22 Similarly, other ambident nucleophiles, the site
of alkylation in the oxime anion is affected by numerous
factors, such as base and types of solvent, the nature of
alkylating agents and cation, the geometry of the sub-
strate, functional groups present on the oxime, and the de-
gree of dissociation of the oxime salts.22,23 Using the
present method, the O-alkyl ethers were mainly obtained
and no nitrones were detected, even in trace amounts.
N
Me
N
3g
3h
8
7
72
69
O
N
N
O
N
O
Me
N
O
N
N
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PAPER
Synthesis of Some Novel N-Heterocycle Methyl-O-oxime Ethers
4071
Table 4 Three-Component Synthesis of N-Heterocycle Methyl-O-
oxime Ethers Using Oximes, CH2I2, Nitrogen Heterocycles, K2CO3,
Et3N in Refluxing MeCN (continued)
forded the respective 4-NO2 isomers rather than 5-NO2
isomers. Moreover, the N-alkylation reactions of theo-
phylline and 1H-benzotriazole were also achieved regio-
selectively. Theophylline derivatives were obtained as the
N7-isomers, while the 1H-benzotriazole was mostly
alkylated at N1 atom affording 3q in 73% yield.
Product Structurea
Time Yield
(h)
(%)b
N
Me
Theoretical Aspect
N
O
N
3i
8
74
N
It is well known that a-halo ethers (HE) are very sensitive
to water, and they decompose to the corresponding alco-
hols and aldehydes, immediately:
O
N
O
Me
N
RCH2OCH2X + H2O → RCH2OH + CH2O + HX
3j
10
60
O
O
N
N
a-Halo-O-oxime ethers (HOEs), the intermediates in the
present work, are the examples of more stable (in the other
word, less unstable) a-halo ether compounds in compari-
son with classic (linear) a-halo ethers. In HOE, because of
another resonance form of molecule (in which the lone-
pair electrons of oxygen move toward nitrogen atom), the
weakening of C–X bond (X as the halogen atom) is de-
creased. In a-halo ethers (HE), the anomeric effect, that is,
the interaction between oxygen lone-pair orbital and anti-
bonding sigma orbital associated with antiperiplanar C–X
bond [n(O) → s*(C–X)] causes the weakening of C–X bond.
As the result, the HOEs are less unstable than linear HE
intermediates, and could lead to the target products.
Quantum mechanical calculations by Gaussian 03W27 and
NBO 5.0 programs,28 using DFT method at B3LYP/6-
311G** level of theory, have been carried out on some
HE and HOE molecules to investigate and compare their
anomeric effects. For computational simplification, chlo-
rine atom was selected as halogen in calculated mole-
cules. Additionally, various R groups were investigated,
since the R groups with different electronic properties
have different influences on the anomeric effect
(Figure 2). In order to evaluate the effect of phenyl substi-
tution on HOE, the influence of the electron-withdrawing
CF3 and methyl groups has been selected for comparing.
N
N
N
Me
N
3k
8
11
9
70
62
70
O
N
O
Me
N
3l
O
O
N
N
N
N
N
Me
N
3m
3n
N
N
O
N
O
O
Me
Me
N
O
N
10
62
O
N
Me
N
3o
3p
8
8
68
70
NO2
O
O
N
N
N
N
N
N
N
The calculated results for some bond lengths, Wiberg
bond orders (WBO), atomic natural charges, and second
order perturbation energies of some donor-acceptor orbit-
al interactions for selected compounds are given in
Tables 5 and 6.
N
N
3q
3r
7
7
73
75
O
O
N
N
By comparing the selected bond lengths and WBOs for
HE and HOE compounds in Table 5, it is concluded that
the lone pair of oxygen atom in HOE molecules leans to-
ward the N atom, therefore their O–C bond length is long-
er than the corresponding value in HE molecules. As the
result of this electron charge dispersion, the C–X bond
lengths are shorter and stronger in HOE compounds in
such a way that in the presence of water they are more sta-
ble than classic HE and can be formed as reaction interme-
diates (e.g., this work).
Me
N
N
O
N
O
Me
a All products were characterized by 1H and 13C NMR, IR, CHN, and
MS analysis.
b Isolated yield.
In the case of 2-methyl-4(5)-nitro-1H-imidazole, which
has proved to have the considerable medical and agricul-
tural applications,24 compounds 3c, 3e, and 3o were syn-
thesized accordingly. In agreement with the literature,25,26
the N-alkylation of 2-methyl-4(5)-nitro-1H-imidazole
with iodomethyl-O-oxime ether intermediates mainly af-
These results are in best agreement with the calculated do-
nor-acceptor orbital interaction energies and atomic natu-
ral charges in Table 6. The first entry in Table 6 shows the
energy for n(O) to s*
orbital interaction in HEs and
(C–X)
HOEs, which is directly related to the anomeric effect. It
Synthesis 2011, No. 24, 4068–4076 © Thieme Stuttgart · New York

4072
M. N. Soltani Rad et al.
PAPER
Figure 2 Selected a-halo and a-halo-O-oxime ethers with different substitutions
Table 5 Selected Bond Lengths in Å and Wiberg Bond Orders (WBO) Calculated at B3LYP/6-311G** Level of Theory
a-Chloro-O-oxime ether
a-Chloro ether
Bond length
N/C–Oa
O–C
HOE(1)
1.376
HOE(2)
HOE(3)
1.416
HOE(4)
1.427
HE(1)
1.416
1.372
1.851
HE(2)
1.438
1.361
1.871
1.401
1.387
1.830
1.403
1.377
1.374
C–Cl
1.811
1.845
1.850
WBO
N–O
1.041
0.925
1.004
0.994
0.955
0.979
0.971
0.980
0.954
0.956
0.989
0.947
0.911
0.988
0.950
0.875
1.020
0.923
O–C
C–Cl
a N–O bond length for HOEs and C–O bond length for HEs.
is obvious that the anomeric effect is significantly reduced markable resonance conjugation with this segment. That
in HOE compounds. Instead, another notable interaction is why the phenyl group has less reducing role on the ano-
of type n(O) to p*
is detected in HOE molecules, meric effect in comparison with CF3 group. In addition,
(C–N)
whereas this type of interaction is absent in HE com- calculations for HOE(3) molecule show a donor-acceptor
pounds.
interaction of type p(C–C)Ph → p*
(16.32 kcal/mol),
(C–N)
which is an evidence for another direction of p-electron
resonance conjugation from phenyl toward C=N–O part
of molecule. This direction is in contrast with the way that
weakens the anomeric effect.
All these data suggest that there is an electron delocaliza-
tion from O atom toward R functional groups in HOEs
(which is confirmed by atomic natural charges, Table 6).
Also it is obvious that the phenyl and electron-withdraw-
ing CF3 groups in R positions can assist this delocalization In conclusion, a convenient and simple protocol is de-
and reduce the anomeric effect to more stabilize the HOE scribed for synthesis of novel N-heterocycle methyl-O-
intermediates. Comparison between calculated data of oxime ethers 3a–r via three-component reaction (3CR) of
HOE molecules with different R substituents shows that oximes with methylene iodide and nitrogen heterocycles.
the phenyl influence on reducing anomeric effect is more The regioselectivity of the reaction, simple experimental
than that of methyl group but less than that of CF3 group. procedure, mild reaction condition, and relatively high
Because of steric hindrance, the phenyl group cannot be yields of products are advantages of this method. Finally,
fully coplanar with C=N–O segment of molecule (CCCN to rationalize the experimental outcomes, quantum me-
dihedral angles are 45.5° for R1 = Ph and R2 = Me, and chanical studies on the basis of DFT method have been
18.6° for R1 = Me and R2 = Ph), and therefore has not re-
Table 6 Selected Second Order Perturbation Energies E(2)a and Some Atomic Natural Charges
a-Chloro-O-oxime ether
a-Chloro ether
Parameter
HOE(1)
14.38
HOE(2)
HOE(3)
19.32
HOE(4)
20.22
HE(1)
HE(2)
23.77
LP(2) O1 to BD*(1) C–Cl
LP(2) O1 to BD*(2) C–N
C charge
16.91
16.58
0.166
–0.129
–0.399
20.56
22.66
13.46
12.29
0.030
0.266
0.290
N charge
–0.072
–0.371
–0.176
–0.407
–0.187
–0.417
O charge
–0.536
–0.548
a Donor-acceptor orbital interactions in kcal/mol.
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PAPER
Synthesis of Some Novel N-Heterocycle Methyl-O-oxime Ethers
4073
IR (KBr): 3021, 2928, 2848, 1648, 1530, 1494, 1334 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.43 (s, 3 H, CH3), 5.72 (s, 2 H,
OCH2N), 7.09–7.38 (m, 10 H, aryl), 7.82 (s, 1 H, H-5, imidazole).
used to support the considerable preference for formation
of HOE intermediates.
13C NMR (62.5 MHz, CDCl3): d = 13.25, 77.78, 120.12, 128.08,
128.30, 128.46, 128.68, 128.74, 129.44, 130.46, 132.25, 134.81,
145.59, 161.33.
All chemicals were purchased from either Fluka or Merck. Solvents
were purified and dried by standard procedures, and stored over 3 Å
molecular sieves. Reactions were followed by TLC using SILG/UV
254 silica gel plates. Column chromatography was performed on
silica gel 60 (0.063–0.200 mm, 70–230 mesh; ASTM). Melting
points were measured using a Büchi-510 apparatus in open capillar-
ies and are uncorrected. IR spectra were obtained using a Shimadzu
FT-IR-8300 spectrophotometer. 1H and 13C NMR Spectra were ob-
tained using a Bruker Avance-DPX-250 spectrometer operating at
250/62.5 MHz, respectively (d in ppm, J in Hz). GC/MS were per-
formed on a Shimadzu GC/MS-QP 1000-EX apparatus (m/z; rel%).
Elemental analyses were performed on a Perkin–Elmer 240-B mi-
croanalyzer.
MS: m/z (%) = 336.12 (43.8).
Anal. Calcd for C18H16N4O3: C, 64.28; H, 4.79; N, 16.66. Found: C,
64.33; H, 4.81; N, 16.61.
7-Benzhydrylideneaminooxymethyl-1,3-dimethyl-3,7-dihydro-
purine-2,6-dione (3d)
Pale-yellow crystals; mp 154.4 °C; Rf = 0.71 (EtOAc–n-hexane,
2:1).
IR (KBr): 3085, 2939, 1720, 1704, 1643, 1434 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.33 (s, 3 H, N1-CH3), 3.53 (s, 3
H, N3-CH3), 6.16 (s, 2 H, OCH2N), 7.15–7.35 (m, 10 H, aryl), 7.95
(s, 1 H, H-8, theophylline).
13C NMR (62.5 MHz, CDCl3): d = 27.84, 29.72, 60.24, 106.26,
128.00, 128.11, 128.21, 129.08, 129.26, 129.99, 132.09, 135.38,
142.28, 148.75, 151.57, 154.85, 170.97.
Three-Component Synthesis of N-Heterocycle Methyl-O-oxime
Ethers 3a–r; General Procedure
In a double-necked round-bottomed flask (100 mL) equipped with
a condenser was added a mixture consisting of oxime (0.01 mol), ni-
trogen heterocycle (0.01 mol), methylene iodide (2.67 g, 0.01 mol),
Et3N (1.01 g, 0.01 mol), and K2CO3 (1.38 g, 0.01 mol) in anhyd
MeCN (40 mL). The mixture was heated at reflux until TLC (eluent:
see Rf for products listed below) indicated no further improvement
in the conversion (Table 4). The solvent was evaporated under vac-
uum and the remaining foam was dissolved in CHCl3 (100 mL) and
subsequently washed with H2O (2 × 100 mL). The organic layer
was dried (Na2SO4) and evaporated. The crude product was purified
by column chromatography on silica gel eluting with the solvents
described below for Rf.
MS: m/z (%) = 389.15 (34.6).
Anal. Calcd for C21H19N5O3: C, 64.77; H, 4.92; N, 17.98. Found: C,
64.84; H, 4.98; N, 17.91.
1,3-Diphenylpropan-2-one O-(2-Methyl-4-nitro-1H-imidazol-1-
yl) Methyl Oxime (3e)
Pale-yellow crystals; mp 59.0 °C Rf = 0.53 (EtOAc–n-hexane, 1:1).
IR (KBr): 3050, 2968, 2848, 1693, 1525, 1453, 1339 cm–1.
Benzophenone O-(1H-Imidazol-1-yl) Methyl Oxime (3a)
Yellow crystals; mp 104.9 °C; Rf = 0.68 (EtOAc–n-hexane, 5:1).
IR (KBr): 3047, 2939, 1691, 1481 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.41 (s, 3 H, CH3), 3.40 (s, 2 H,
PhCH2), 3.54 (s, 2 H, PhCH2), 5.74 (s, 2 H, OCH2N), 6.93–7.06 (m,
4 H, aryl), 7.13–7.36 (m, 6 H, aryl), 7.77 (s, 1 H, H-5, imidazole).
13C NMR (62.5 MHz, CDCl3): d = 13.07, 33.83, 39.86, 77.31,
120.23, 126.87, 127.08, 128.59, 128.68, 128.76, 128.90, 129.09,
135.34, 135.43, 145.49, 162.72.
1H NMR (250 MHz, CDCl3): d = 5.36 (s, 2 H, OCH2N), 6.76–7.16
(m, 12 H, aryl, H-4 and H-5, imidazole), 7.36 (s, 1 H, H-2, imida-
zole).
13C NMR (62.5 MHz, CDCl3): d = 77.69, 119.22, 127.99, 128.13,
128.58, 128.83, 129.08, 129.67, 129.98, 132.63, 135.37, 137.84,
159.68.
MS: m/z (%) = 364.15 (37.1).
Anal. Calcd for C20H20N4O3: C, 65.92; H, 5.53; N, 15.38. Found: C,
65.87; H, 5.59; N, 15.34.
MS: m/z (%) = 277.12 (21.3).
1,3-Diphenylpropan-2-one O-(1H-Benzo[d]imidazol-1-yl) Me-
thyl Oxime (3f)
Brown crystals; mp 57.8 °C; Rf = 0.72 (EtOAc–n-hexane, 4:1).
Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15. Found: C,
73.71; H, 5.49; N, 15.13.
IR (KBr): 3100, 2952, 2847, 1686, 1470 cm–1.
Benzophenone O-(1H-Benzo[d]imidazol-1-yl) Methyl Oxime
(3b)
1H NMR (250 MHz, CDCl3): d = 3.26 (s, 2 H, PhCH2), 3.41 (s, 2 H,
PhCH2), 5.90 (s, 2 H, OCH2N), 6.79–7.81 (m, 14 H, aryl), 7.97 (s,
1 H, H-2, benzimidazole).
13C NMR (62.5 MHz, CDCl3): d = 33.45, 39.52, 75.87, 110.62,
120.21, 122.68, 123.40, 126.60, 126.87, 128.58, 128.84, 129.11,
129.35, 129.88, 133.51, 135.41, 135.97, 143.82, 161.27.
Bright brown crystals; mp 116.4 °C; Rf = 0.60 (EtOAc–n-hexane,
3:1).
IR (KBr): 3025, 2954, 1695, 1434 cm–1.
1H NMR (250 MHz, CDCl3): d = 5.84 (s, 2 H, OCH2N), 7.03–7.82
(m, 14 H, aryl), 8.01 (s, 1 H, H-2, benzimidazole).
13C NMR (62.5 MHz, CDCl3): d = 76.20, 110.59, 120.27, 122.69,
123.34, 128.06, 128.14, 128.31, 128.93, 129.11, 129.66, 130.01,
132.62, 133.58, 135.39, 144.01, 159.71.
MS: m/z (%) = 355.17 (29.5).
Anal. Calcd for C23H21N3O: C, 77.72; H, 5.96; N, 11.82. Found: C,
77.63; H, 6.01; N, 11.70.
MS: m/z (%) = 327.14 (25.9).
7-(1-Benzyl-2-phenylethylideneaminooxymethyl)-1,3-dimethyl-
3,7-dihydropurine-2,6-dione (3g)
Pale-yellow crystals; mp 125.6 °C; Rf = 0.70 (EtOAc–n-hexane,
2:1).
Anal. Calcd for C21H17N3O: C, 77.04; H, 5.23; N, 12.84. Found: C,
77.01; H, 5.29; N, 12.81.
Benzophenone O-(2-Methyl-4-nitro-1H-imidazol-1-yl) Methyl
Oxime (3c)
IR (KBr): 3065, 2931, 2871, 1718, 1705, 1691, 1446 cm–1.
Pale-yellow crystals; mp 135.5 °C; Rf = 0.90 (EtOAc–n-hexane,
2:1).
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M. N. Soltani Rad et al.
PAPER
IR (KBr): 3100, 2948, 2860, 1723, 1705, 1692, 1458 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.82 (s, 3 H, CH3), 2.45 (t, J = 7.3
Hz, 2 H, CH2CN), 2.79 (t, J = 7.3 Hz, 2 H, PhCH2), 3.42 (s, 3 H, N1-
CH3), 3.61 (s, 3 H, N3-CH3), 6.07 (s, 2 H, OCH2N), 7.11–7.29 (m,
5 H, aryl), 7.69 (s, 1 H, H-8, theophylline).
13C NMR (62.5 MHz, CDCl3): d = 15.01, 27.96, 29.82, 32.08,
37.42, 76.67, 106.16, 126.15, 128.17, 128.41, 140.68, 142.27,
148.84, 151.66, 155.07, 160.61.
1H NMR (250 MHz, CDCl3): d = 3.39 (s, 4 H, PhCH2), 3.51 (s, 3 H,
N1-CH3), 3.62 (s, 3 H, N3-CH3), 6.18 (s, 2 H, OCH2N), 6.95–7.31
(m, 10 H, aryl), 7.77 (s, 1 H, H-8, theophylline).
13C NMR (62.5 MHz, CDCl3): d = 27.96, 29.85, 33.72, 39.83,
76.85, 106.19, 126.49, 126.96, 128.40, 128.62, 128.83, 129.11,
135.64, 135.77, 142.20, 148.91, 151.66, 154.98, 162.29.
MS: m/z (%) = 417.18 (37.3).
Anal. Calcd for C23H23N5O3: C, 66.17; H, 5.55; N, 16.78. Found: C,
66.19; H, 5.59; N, 16.71.
MS: m/z (%) = 355.16 (27.4).
Anal. Calcd for C18H21N5O3: C, 60.83; H, 5.96; N, 19.71. Found: C,
60.79; H, 5.90; N, 19.63.
(E)-Acetophenone O-(1H-Benzo[d]imidazol-1-yl) Methyl
Oxime (3h)
Pale-yellow crystals; mp 134.2 °C; Rf = 0.58 (EtOAc–n-hexane,
3:1).
IR (KBr): 3100, 2975, 2845, 1693, 1459 cm–1.
Cyclohexanone O-(1H-Benzo[d]imidazol-1-yl) Methyl Oxime
(3l)
Pale-yellow crystals; mp 114.7 °C; Rf = 0.64 (EtOAc–n-hexane,
4:1).
1H NMR (250 MHz, CDCl3): d = 2.01 (s, 3 H, CH3), 5.89 (s, 2 H,
OCH2N), 7.21–7.79 (m, 9 H, aryl), 8.05 (s, 1 H, H-2, benzimida-
zole).
13C NMR (62.5 MHz, CDCl3): d = 12.84, 75.99, 110.42, 120.24,
122.61, 123.32, 126.48, 128.38, 129.30, 129.62, 133.55, 135.47,
143.81, 157.29.
IR (KBr): 3065, 2954, 2849, 1694, 1473 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.33–1.40 (m, 6 H, 3 CH2), 1.94–
2.03 (m, 4 H, 2 CH2), 5.84 (s, 2 H, OCH2N), 6.17–7.73 (m, 4 H, ar-
yl), 8.09 (s, 1 H, H-2, benzimidazole).
13C NMR (62.5 MHz, CDCl3): d = 14.13, 21.32, 25.52, 26.73,
31.94, 75.76, 110.52, 119.75, 122.73, 123.39, 133.32, 143.61,
163.62, 174.61.
MS: m/z (%) = 265.12 (40.7).
Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C,
72.33; H, 5.81; N, 15.71.
MS: m/z (%) = 243.14 (45.2).
Anal. Calcd for C14H17N3O: C, 69.11; H, 7.04; N, 17.27. Found: C,
69.17; H, 7.12; N, 17.20.
(E)-1,3-Dimethyl-7-(1-phenylethylideneaminooxymethyl)-3,7-
dihydropurine-2,6-dione (3i)
Pale-yellow crystals; mp 164.8 °C; Rf = 0.68 (EtOAc–n-hexane,
2:1).
IR (KBr): 3070, 2952, 2865, 1720, 1708, 1686, 1465 cm–1.
7-Cyclohexylideneaminooxymethyl-1,3-dimethyl-3,7-dihydro-
purine-2,6-dione (3m)
Pale-yellow crystals; mp 130.9 °C; Rf = 0.64 (EtOAc–n-hexane,
2:1).
1H NMR (250 MHz, CDCl3): d = 2.22 (s, 3 H, CH3), 3.42 (s, 3 H,
N1-CH3), 3.55 (s, 3 H, N3-CH3), 6.23 (s, 2 H, OCH2N), 7.33–7.37
(m, 3 H, aryl), 7.53–7.57 (m, 2 H, aryl), 7.90 (s, 1 H, H-8, theophyl-
line).
13C NMR (62.5 MHz, CDCl3): d = 13.25, 27.97, 29.2, 76.97,
106.21, 126.55, 128.45, 129.82, 135.39, 142.44, 148.94, 151.61,
155.09, 158.18.
IR (KBr): 3085, 2939, 2877, 1720, 1706, 1698, 1434 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.45–1.55 (m, 6 H, 3 CH2), 2.04–
2.09 (m, 4 H, 2 CH2), 3.31 (s, 3 H, N1-CH3), 3.52 (s, 3 H, N3-CH3),
6.00 (s, 2 H, OCH2N), 7.78 (s, 1 H, H-8, theophylline).
13C NMR (62.5 MHz, CDCl3): d = 24.59, 25.14, 25.53, 26.76,
27.83, 29.69, 31.88, 76.54, 106.06, 142.24, 148.73, 151.54, 154.94,
163.78.
MS: m/z (%) = 327.13 (28.4).
Anal. Calcd for C16H17N5O3: C, 58.71; H, 5.23; N, 21.39. Found: C,
58.75; H, 5.31; N, 21.48.
MS: m/z (%) = 305.15 (36.8).
Anal. Calcd for C14H17N3O: C, 55.07; H, 6.27; N, 22.94. Found: C,
55.10; H, 6.21; N, 22.86.
(E)-4-Phenylbutan-2-one-O-(1H-benzo[d]imidazol-1-yl)Methyl
Oxime (3j)
Bright-brown foam; Rf = 0.67 (EtOAc–n-hexane, 4:1).
IR (film): 3057, 2930, 2848, 1695, 1464 cm–1.
(E)-7-sec-Butylideneaminooxymethyl-1,3-dimethyl-3,7-dihy-
dropurine-2,6-dione (3n)
Pale-yellow crystals; mp 106.7 °C; Rf = 0.56 (EtOAc–n-hexane,
3:1).
1H NMR (250 MHz, CDCl3): d = 1.53 (s, 3 H, CH3), 2.19 (t, J = 7.2
Hz, 2 H, CH2CN), 2.58 (t, J = 7.2 Hz, 2 H, PhCH2), 5.70 (s, 2 H,
OCH2N), 6.88–7.64 (m, 9 H, aryl), 7.80 (s, 1 H, H-2, benzimida-
zole).
13C NMR (62.5 MHz, CDCl3): d = 14.84, 32.13, 37.53, 75.76,
110.46, 120.20, 122.55, 123.25, 126.14, 128.09, 128.24, 128.44,
133.57, 140.87, 143.70, 159.94.
IR (KBr): 3070, 2983, 2865, 1724, 1707, 1693, 1472 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.94 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.76 (q, J = 7.4 Hz, 2 H, CH2Me), 2.06 (s, 1 H, CH3), 3.31 (s, 3 H,
N1-CH3), 3.49 (s, 3 H, N3-CH3), 6.02 (s, 2 H, OCH2N), 7.82 (s, 1
H, H-8, theophylline).
13C NMR (62.5 MHz, CDCl3): d = 10.68, 19.26, 21.14, 28.97,
29.70, 76.53, 106.02, 142.46, 148.60, 151.52, 158.83, 162.35.
MS: m/z (%) = 293.15 (43.0).
Anal. Calcd for C18H19N3O: C, 73.69; H, 6.53; N, 14.32. Found: C,
73.64; H, 6.49; N, 14.24.
MS: m/z (%) = 279.13 (34.5).
Anal. Calcd for C14H17N3O: C, 51.60; H, 6.14; N, 25.08. Found: C,
51.57; H, 6.23; N, 25.01.
(E)-1,3-Dimethyl-7-(1-methyl-3-phenylpropylideneamino-
oxymethyl)-3,7-dihydropurine-2,6-dione (3k)
Pale-yellow crystals; mp 112.1 °C; Rf = 0.71 (EtOAc–n-hexane,
2:1).
Synthesis 2011, No. 24, 4068–4076 © Thieme Stuttgart · New York

PAPER
Synthesis of Some Novel N-Heterocycle Methyl-O-oxime Ethers
4075
Propan-2-one O-(2-Methyl-4-nitro-1H-imidazol-1-yl) Methyl
Oxime (3o)
Pale-yellow crystals; mp 114.4 °C; Rf = 0.90 (EtOAc–n-hexane,
References
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IR (KBr): 3021, 2958, 2848, 1695, 1533, 1494, 1344 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.77 (s, 6 H, 2 CH3), 2.43 (s, 3 H,
CH3), 5.61 (s, 2 H, OCH2N), 7.77 (1 H, s, H-5, imidazole).
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13C NMR (62.5 MHz, CDCl3): d = 13.13, 15.78, 21.64, 77.13,
120.36, 145.39, 151.16, 159.02.
MS: m/z (%) = 212.09 (25.1).
Anal. Calcd for C8H12N4O3: C, 45.28; H, 5.70; N, 26.40. Found: C,
45.34; H, 5.79; N, 26.32.
Propan-2-one O-(1H-Benzo[d]imidazol-1-yl) Methyl Oxime
(3p)
Pale-yellow crystals; mp 90.7 °C; Rf = 0.48 (EtOAc–n-hexane, 1:3).
IR (KBr): 3073, 2934, 2870, 1687, 1468 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.73 (s, 6 H, 2 CH3), 5.53 (s, 2 H,
OCH2N), 6.91–7.50 (m, 4 H, aryl), 7.70 (s, 1 H, H-2, benzimida-
zole).
13C NMR (62.5 MHz, CDCl3): d = 15.52, 21.15, 75.51, 110.31,
119.98, 121.93, 122.33, 123.07, 133.41, 143.62, 157.57.
MS: m/z (%) = 203.11 (40.5).
Anal. Calcd for C11H13N3O: C, 65.01; H, 6.45; N, 20.68. Found: C,
65.09; H, 6.51; N, 20.56.
(7) Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley-
VCH: Weinheim, 2005.
Propan-2-oneO-(1H-Benzo[d][1,2,3]triazol-1-yl)MethylOxime
(3q)
White crystals; mp 157.6 °C; Rf = 0.87 (EtOAc–n-hexane, 1:1).
IR (KBr): 3080, 2962, 2875, 1697, 1454 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.68 (s, 6 H, 2 CH3), 6.32 (s, 2 H,
OCH2N), 7.26–7.97 (m, 4 H, aryl).
13C NMR (62.5 MHz, CDCl3): d = 15.73, 23.89, 78.33, 110.79,
118.63, 119.66, 124.06, 127.57, 133.19, 158.09.
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MS: m/z (%) = 204.10 (22.9).
Anal. Calcd for C10H12N4O: C, 58.81; H, 5.92; N, 27.43. Found: C,
58.75; H, 5.98; N, 27.37.
7-Isopropylideneaminooxymethyl-1,3-dimethyl-3,7-dihydropu-
rine-2,6-dione (3r)
White crystals; mp 154.4 °C; Rf = 0.55 (EtOAc–n-hexane, 1:2).
IR (KBr): 3085, 2958, 2863, 1720, 1704, 1694, 1482 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.75 (s, 6 H, 2 CH3), 3.31 (s, 3 H,
N1-CH3), 3.49 (s, 3 H, N3-CH3), 6.01 (s, 2 H, OCH2N), 7.77 (s, 1
H, H-8, theophylline).
13C NMR (62.5 MHz, CDCl3): d = 15.91, 21.65, 27.83, 29.68,
76.52, 106.03, 142.27, 148.78, 151.53, 154.92, 158.43.
Babamohammadi, S.; Behrouz, S. Helv. Chim. Acta 2010,
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(18) (a) Soltani Rad, M. N.; Behrouz, S.; Dianat, M. Synthesis
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Anal. Calcd for C11H15N5O3: C, 49.81; H, 5.70; N, 26.40. Found: C,
49.72; H, 5.76; N, 26.37.
Acknowledgment
(19) Buck, J. S.; Ide, W. S. Org. Synth. Coll. Vol. 2; Wiley: New
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We wish to thank Pars Industrial Pioneer Engineering for financial
support of this work. We are also grateful to Shiraz University of
Technology and Shiraz University Research Councils for partial
support of this work.
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