Regio- and stereoselective 1,3-dipolar cycloaddition reactions of C-aryl (or hetaryl)-N-phenylnitrones to monosubstituted ylidene malononitriles and 4-benzylidene-2-phenyloxazol-5(4H)-one

Article abstract of DOI:10.1515/znb-2016-0263

The first example of 1,3-dipolar cycloaddition reactions of C-aryl (or hetaryl)-N-phenylnitrones to monosubstituted ylidene malononitriles and 4-benzylidene-2-phenyl-oxazol-5(4H)-one is described. The reaction of C-(4-(dimethylamino)phenyl)-N-phenyl-nitro

Full text of DOI:10.1515/znb-2016-0263

Z. Naturforsch. 2017; 72(5)b: 317–326
Ramadan A. Mekheimer*, Khadijah Al-Zaydi, Mahmoud A. A. Ibrahim, Asma Al-Shamary
and Kamal Sadek
Regio- and stereoselective 1,3-dipolar cycloaddition
reactions of C-aryl (or hetaryl)-N-phenylnitrones
to monosubstituted ylidene malononitriles and
4
-benzylidene-2-phenyloxazol-5(4H)-one
DOI 10.1515/znb-2016-0263
1
Introduction
Received December 10, 2016; accepted February 15, 2017
Abstract: The first example of 1,3-dipolar cycloaddition 1,3-Dipolar cycloaddition reaction represents one of the
reactions of C-aryl (or hetaryl)-N-phenylnitrones to mono- most atom-efficient and useful procedures for the syn-
substituted ylidene malononitriles and 4-benzylidene- thesis of five-membered heterocycles from simpler start-
2
-phenyl-oxazol-5(4H)-one is described. The reaction of ing materials and these reactions are particularly often
C-(4-(dimethylamino)phenyl)-N-phenyl-nitrone (1a) with employed when the stereochemical control of the reaction
-(4-substituted-benzylidene)malononitriles 2a, b in dry is required [1–4]. Nitrones are a highly attractive class of
2
toluene, in the absence of catalyst, at reflux temperature 1,3-dipoles due to the extensive application of the corre-
furnished the novel cycloadducts 2-(3-aryl-2-phenyl-2,3-di- sponding cycloadduct and are remarkably versatile build-
hydro-1,2,4-oxadiazol-5-yl)-3-(4-methoxyphenyl)acryloni- ing blocks in organic synthesis. Moreover, they are known
triles 3a, b. Refluxing C-aryl (or hetaryl)-N-phenylnitrones to take part in 1,3-dipolar cycloaddition reactions with a
1
b–i with 2-(4-methoxy-benzylidene)malononitrile (2a) wide range of dipolarophiles such as alkenes, alkynes and
in dry toluene, in the absence of catalyst, gave the unex- allenes to give the useful heterocycles (Fig. 1) [5].
pected 2-cyano-3-(4-methoxyphenyl)-acrylamide (5), as In contrast to the wide usefulness of nitriles as impor-
the sole product. On the other hand, refluxing 4-ben- tant synthons in organic synthesis [6–14], their use as
zylidene-2-phenyloxazol-5(4H)-one (7) with an equimolar hetero-1,3-dipolarophiles in cycloaddition reactions is
amount of C-aryl (or hetaryl)-N-phenyl-nitrones 1a–c, f–i quite limited [15, 16]. Only a few reactions are known,
in absolute EtOH afforded the previously unknown 5-ani- for example, with azides, nitrile oxides and nitrile ylides
lino-4-benzoyl-2-phenyloxazole (10), as the only isolable (Fig. 2) [17–19]. To the best of our knowledge, 1,3-dipolar
product. The resulting products were formed with a high cycloaddition reactions of mono-substituted ylidene
degree of regio- and stereoselectivity. Quantum chemical malononitriles to open-chain C-aryl (or hetaryl)-N-phe-
calculations were performed to verify stereoselectivity of nylnitrones have not been reported in the literature yet.
the studied reaction. A mechanistic proposal is presented
to rationalize the formation of these products.
Erlenmeyer azlactones, or 2,4-substituted oxazolin-
5-ones, have been used as synthons in a wide variety of
reactions for the preparation of antitumor or antimicrobial
compounds [20, 21], peptides [22, 23], herbicides and fun-
gicides [24], amino acids [25], and as drugs, pesticides and
agrochemical intermediates [26] as well as biosensors or
coupling and/or photo-sensitive composition devices for
proteins [27, 28]. They have been used in active site titra-
tions of enzymes [29], as antihypertensives [30]. The car-
bon–carbon double bond of 4-arylidene-5(4H)-oxazolones
is a rather sterically hindered and electron-deficient dipo-
larophile. Given the peculiarity of the regioselectivity
behavior of electron-deficient dipolarophiles in 1,3-dipolar
cycloadditions [31, 32], the reaction of 4-arylidene-5(4H)-
oxazolones with 1,3-dipoles should be of some mecha-
nistic interest. Previously, Argyropoulos et al. studied the
Keywords: 5-anilino-4-benzoyl-2-phenyloxazole; 1,3-
dipolar cycloaddition reactions; monosubstituted ylidene
malononitriles; nitrones.
*
Corresponding author: Ramadan A. Mekheimer, Chemistry
Department, Faculty of Sciences-Al Faisaliah, King Abdulaziz
University, Jeddah 21533, Saudi Arabia; and Chemistry Department,
Faculty of Science, Minia University, Minia 61519, A.R. Egypt,
e-mail: rmekh@yahoo.com
Khadijah Al-Zaydi and Asma Al-Shamary: Chemistry Department,
Faculty of Sciences-Al Faisaliah, King Abdulaziz University, Jeddah
2
1533, Saudi Arabia
Mahmoud A. A. Ibrahim and Kamal Sadek: Chemistry Department,
Faculty of Science, Minia University, Minia 61519, A.R. Egypt
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18ꢀꢁꢁꢁꢂꢀR.A. Mekheimer et al.: 1,3-Dipolar cycloaddition reactions of C-aryl (or hetaryl)-N-phenylnitrones
O
highly expedient methods for the synthesis of bioactive
N
heterocyclic compounds, via the 1,3-dipolar cycloaddition
reactions of acyclic C-aryl (or hetaryl)-N-phenylnitrones to
different dipolarophiles [36–40], the present work inves-
tigates the 1,3-dipolar cycloaddition reactions of a series
of C-aryl (or hetaryl)-N-phenylnitrones with both mono-
substituted ylidene malononitriles and 4-benzylidene-
Isoxazolidines
O
N
O
N
2
-pheloxazol-5(4H)-one, as dipolarophiles for the first
Nitrones
Isoxazolines
time.
O
N
2
Results and discussion
Methylene isoxazolidines
Fig. 1:ꢁClassic [3ꢂ+ꢂ2]cycloaddition of nitrones with alkenes, alkynes
With the initial aim of optimizing the experimental condi-
tions, we explored the reaction of C-(4-(dimethylamino)
phenyl)-N-phenyl-nitrone (1a) with 2-(4-methoxy-ben-
zylidene)malononitrile (2a) (both possess a strong elec-
tron donating group at the para position of aryl moiety)
in different solvents such as CH Cl , CHCl , THF and
MeOH, in the absence of catalyst, at room temperature
which did not afford any product and the reactants were
recovered almost unchanged after long reaction times.
When the reaction was conducted in EtOH or benzene
either at ambient temperature or by heating under reflux
at 80°C for 100 h, the nitrone was not consumed and no
product was obtained. In order to complete the reaction
within a reasonable reaction time, a temperature above
and allenes.
1
,3-dipolar cycloaddition reactions of nitrile oxides and
nitrile imines with 4-arylidene-2-phenyl-5(4H)-oxazolo-
nes affording spiro isoxazoline and pyrazoline deriva-
tives (Fig. 3), which are easily transformed to heterocyclic
amino acid derivatives by nucleophilic ring opening of the
oxazolone ring [33, 34].
2
2
3
To the best of our knowledge, a survey on the cycload-
dition reaction of acyclic C-aryl (hetaryl)-N-phenylnitrones
to 4-arylidene-2-phenyl-5(4H)-oxazolones revealed that
this reaction has not so far been reported in the literature.
While 4-benzylidene-2-phenyl-oxazol-5(4H)-one has been
used, it is considered to be the Z-isomer as it is accepted
for the stable geometric isomer [35]. As part of an ongoing
program geared toward the development of novel and
8
0°C was required. Thus, heating the reaction mixture
in dry toluene at reflux temperature for 30 h [thin-layer
chromatography (TLC) control] gave the previously unre-
ported cycloadduct 2-(3-(4-dimethylaminophenyl)-2-phe-
nyl-2,3-dihydro-1,2,4-oxadiazol-5-yl)-3-(4-methoxyphenyl)
acrylonitrile (3a), as the only isolable product (Scheme 1).
The structure of 3a was confirmed as the reaction product
from its IR, NMR and correct elemental analysis as well as
mass spectrum. Thus, the IR spectrum of 3a revealed the
N
NH
Na N
N
N
N
R
Azides
N
1
H-Tetrazoles
−1
presence of an absorption band at 1633 cm due to C=N
1
vibration. The H NMR spectrum of 3a showed, besides
R
N
the signals due to aromatic and three singlet signals of
methyl protons in N(CH ) and OCH groups, two singlet
R1
C
N
O
3
2
3
R
C
N
O
R1
signals at δ 6.10 and 7.28 ppm attributable to one proton
Nitrile oxides
N
Nitriles
3
linked with an sp carbon at position 3 in the 1,2,4-oxadia-
1
,2,4-Oxadiazoles
zoline ring and the olefinic HC=, respectively. Moreover,
R1
N
its structure was supported by C NMR, which was com-
13
N
patible with the assigned structure (see the Experimen-
tal section). The elemental analysis and mass spectrum
of this molecule clearly revealed that the product was
formed by the addition of one molecule of 1a to one mole-
cule of 2a without any elimination. Similarly, nitrone
R1
C
N
CH R2
R2
R
4H-Imidazoles
Fig. 2:ꢁReaction of nitriles with azides, nitrile oxides and nitrile ylides. 1a reacted with ylidene 2b to afford the cycloadduct 3b
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R.A. Mekheimer et al.: 1,3-Dipolar cycloaddition reactions of C-aryl (or hetaryl)-N-phenylnitronesꢀꢂꢁꢁꢁꢀ319
H
Ar
Ph
N
O
R
C
N
O
Nitrile oxides
N
O
Ph
R
O
N
Ar
Spiro isoxazolines
O
H
R1
O
O
N
O
R
C
N
N
R1
N
Oxazolin-5-ones
Nitrile imines
N
Ph
R
Ar
H
Spiro pyrazolines
Fig. 3:ꢁ1,3-Dipolar cycloaddition reactions of 4-arylidene-2-phenyl-5(4H)-oxazolones with nitrile oxides and nitrile imines.
Ar1
CN
O
H
Ph
O
N
N
H
Ph
N
Ar
a, Ar = 4-Me N-C H ; Ar = 4-MeO-C H ( 75%)
Ar
1
3
2
6
4
6 4
1
a−i
1
Toluene (dry)
reflux
b, Ar = 4-Me N-C H ; Ar = 4-Me N-C H (73%)
2 6 4 2 6 4
+
In case of
C
N
N
1a + 2a, b
H
Ar1
CN
Ar1
C
CN
Ar
2
a−h
O
N
Ph
Ar1
1
Ar
4-Me N-C H
6 4
2
a
b
c
d
e
f
6
4-MeO-C H4
a
b
c
d
e
f
2
4-Me N-C H
6 4
C H
6
2
5
C H
6 5
4-Cl-C H
6
4
4-Cl-C H4
4-Br-C H
6
6
4
4-Br-C H4
4-NO -C H
6 4
6
2
4-NO -C H
4-MeO-C H
2
6
4
6
4
g
h
2-furyl
g
h
i
3,4-methylenedioxyphenyl
2-furyl
2-thienyl
2-thienyl
Scheme 1:ꢁ1,3-Dipolar cycloaddition reactions between nitrones 1a–i and ylidene malononitriles 2a–h.
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20ꢀꢁꢁꢁꢂꢀR.A. Mekheimer et al.: 1,3-Dipolar cycloaddition reactions of C-aryl (or hetaryl)-N-phenylnitrones
(
Scheme 1). Also, the structure of 3b could be established vibrational frequencies were then calculated. According
on the basis of analytical and spectral data (see the to the results, no imaginary vibrational frequencies were
Experimental section).
computed, which indicates that these conformers repre-
Such high regio- and stereoselectivity with the for- sent a minimum on the corresponding conformational
mation of only one isomer suggests the approach of a energy surfaces. The single-point energies were finally cal-
nitrone dipole from the least sterically hindered of the two culated on the optimized structures at the MP2/6-311++G**
diastereotopic nitrile functions. Theoretical calculations level of theory. According to the calculated energies, the
were performed on stereoisomers of compounds 3a and E-isomer is more stable than the corresponding Z-isomer
−
1
3
3
b. The molecular structures of E- and Z-stereoisomers of by 3.08 and 3.02 kcal mol in case of compounds 3a and
a and 3b were first optimized by the B3LYP model with 3b, respectively.
the 6-311++G** basis set in the vacuum. Figure 4 shows
Unfortunately, our trials to react nitrone 1a
the optimized structure of the studied compounds. The with the ylidene malononitriles 2c–h, having both
Fig. 4:ꢁPlots of the optimized molecular structures of E- and Z-isomers of compounds 3a (i) and 3b (ii).
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R.A. Mekheimer et al.: 1,3-Dipolar cycloaddition reactions of C-aryl (or hetaryl)-N-phenylnitronesꢀꢂꢁꢁꢁꢀ321
electron-withdrawing and hetaryl substituents at 13C NMR gave conclusive evidence for the formation of
β-position, under the previous conditions, were unsuc- compound 5, which confirmed the presence of a CO
cessful. Starting materials were recovered even upon carbon at δ 163.1 ppm. Moreover, the mass spectrum of
+
heating for extended periods.
this product showed the molecular ion m/z 202 (M , 100)
An attempt to extend the scope of this process to and other peaks (see the Experimental section) that con-
differently aryl substituted nitrones and ylidene malon- firmed the structure. Analytical data are in accordance
onitriles has led to a different result and the unexpected with the structure shown for compound 5.
2
-cyano-3-(4-methoxyphenyl)acrylamide (5) was the only
To obtain unequivocal evidence for the structure
isolable product. Interestingly, when a mixture of equimo- of compound 5, it was prepared separately by reacting
lar amounts of C,N-diphenylnitrone (1b) and ylidene 2a cyanoacetamide with p-methoxybenzaldehyde according
was heated at reflux in dry toluene, in the absence of cat- to [41] (Scheme 1). This product was identical in all aspects
1
alyst for 11 h (TLC control), the unexpected 5 (Scheme 2) (mp, mixd mp, IR, H NMR) to the compound obtained
was isolated in good yield, without the formation of the by the reaction of ylidene 2a with the acyclic nitrone 1b.
desired cycloadduct 2-(2,3-diphenyl-2,3-dihydro-1,2,4- Similarly, ylidene 2a reacted with nitrones 1c–i, under the
oxadiazol-5-yl)-3-(4-methoxyphenyl)-acrylonitrile (3) or same optimal reaction conditions, to give the same acryla-
even the other cycloadduct 5-(4-methoxyphenyl)-2,3-di- mide 5 as the only isolated product. Thus, this reaction
phenyl-isoxazolidine-4,4-dicarbonitrile (4) (Scheme 1). constitutes a new practical and regioselective method for
The pure product was obtained simply by recrystalliza- the synthesis of 5. It is clearly obvious that the nature of
tion from EtOH without involving any chromatographic the nitrone aryl substituent plays an important role in
purification. The chemical structure of 5 was confirmed determining the reaction product.
as the reaction product from its IR, NMR and correct
A plausible mechanism for the formation of 5 can be
elemental analysis as well as mass spectrum. The IR explained by an initial 1,3-dipolar cycloaddition of the
spectrum showed the presence of absorption at 3444, nitrone 1b to the nitrile function of 2a giving the 1,2,4-oxa-
−
1
3
165 and 1662 cm assignable to NH and CO functions, diazoline intermediate 3. This cycloadduct undergoes
2
1
respectively, while the H NMR spectrum contained three the 1,2- and the 3,4-bond fission to give the nitrene inter-
singlet signals at δ 7.68, 7.81 and 8.10 ppm attributable mediate 6 besides the Schiff bases, corresponding to the
to the amide and olefinic protons, respectively. In addi- nitrone. The nitrene intermediate 6 abstracts hydrogen
tion, signals due to methoxy and four aromatic protons from toluene, as reductant [42], to give the final product
were observed in their expected positions. Furthermore, 5 (Scheme 3). Presumably, the thermal decomposition of
H3CO
CN
H3CO
CHO
H
CN
2
a
CN
CN
Toluene (dry)
EtOH/ Pip.
reflux, 1h
+
+
reflux, 11−35 h
H
CONH2
CONH2
H
Ph
O
5
OCH3
N
Ar
Reaction
Yield of 5 (%)
1
b−i
2a + 1b
2a + 1c
2a + 1d
2a + 1e
2a + 1f
2a + 1g
2a + 1h
2a + 1i
76
72
74
70
85
72
77
78
Scheme 2:ꢁReaction of ylidene 2a with nitrones 1b–i.
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22ꢀꢁꢁꢁꢂꢀR.A. Mekheimer et al.: 1,3-Dipolar cycloaddition reactions of C-aryl (or hetaryl)-N-phenylnitrones
H3CO
H3CO
CN
H
Ph
O
C
N
N
Toluene (dry)
reflux
N
+
H
O
C
H
N
Ar
N
Ph
1b-i
2a
Ar
−
ArCH=NPh
H3CO
H3CO
CN
CONH2
CN
Abstract hydrogen
from toluene
H
H
O
5
N
6
Scheme 3:ꢁProposed mechanism for the formation of 2-cyano-3-(4-methoxyphenyl)-acrylamide (5).
1
these Schiff bases under these reaction conditions pre- [43]. The H NMR spectrum of 10 disclosed, besides the
vents their isolation.
signal characteristic for the aromatic protons, only one
To chemically verify that the product 5 was formed singlet signal at δ 8.40 ppm attributable to NH at C-5 in
from the sequential cycloaddition/rearrangement reaction the oxazole ring and the absence of any singlet signals
of 1b and 2a and not via the hydrolysis of the CN group of due to the methine and olefinic protons in cycloadducts 8
1
3
the ylidene malononitrile 2a, under these reaction condi- and 9. The C NMR spectrum gave strong evidence for the
tions, ylidene malononitrile 2a was heated separately in formation of 10 showing a chemical shift at δ 186.6 ppm
dry toluene to reflux temperature for 80 h. To our delight, corresponding to the benzoyl C=O at C-4 in the oxazole
the ylidene malononitrile 2a was recovered in quantitative ring. Furthermore, the mass spectrum of this product has
+
yield and no product was detected.
the molecular ion m/zꢀ=ꢀ340 (M ) and peaks at 105 (PhCO)
As an extension of our studies and in order to inves- and 92 (PhNH) confirming its presumed structure (see the
tigate the scope of this reaction, we also investigated the Experimental section). Analytical data are in accordance
reaction of 4-benzylidene-2-phenyloxazol-5(4H)-one (7), as with the proposed structure for compound 10. Unfortu-
another model system of activated heterocyclic ylidenes, nately, we did not succeed in growing single crystals of 10
with various acyclic nitrones. Surprisingly, when 7 was suitable for X-ray diffraction.
refluxed with an equimolar amount of nitrones 1a–c,
A reasonable mechanism to rationalize the rearrange-
f–i in absolute EtOH for 20–40 h (TLC control), it failed ment is outlined in Scheme 5. The first step involves an
to yield the targeted spirocycloadducts 8 and 9, but fur- initial [3ꢀ+ꢀ4] cycloaddition [44] to give the 1,4,2-diox-
nished instead the previously unknown 5-anilino-4-ben- azepane 11 as a transient intermediate. In the next step,
zoyl-2-phenyloxazole (10), as the sole isolable product, in the cycloadduct 11 undergoes an intramolecular rearrange-
good to excellent yields (70–90%) (Scheme 4). To the best ment followed by spontaneous aldehyde elimination to
of our knowledge, compound 10 has not been previously yield the isoxazoline intermediate 12. The latter undergoes
reported. Its structure was established and confirmed a 1,3-hydrogen shift to give the isomeric isoxazoline inter-
for the reaction product on the basis of its analytical and mediate 13, which undergoes thermal cleavage of the weak
spectral data. Thus, the IR spectrum revealed the presence O–N linkage followed by ring closure to give the aziridine
−1
of absorption bands at ν 3272 and 1676 cm due to the NH intermediate 14. A subsequent rearrangement by way of a
and benzoyl C=O groups, respectively, and the disappear- 1,3-hydrogen shift and ring opening ultimately gives the
ance of the lactone C=O at 1794 cm−1 in cycloadduct 8 final product 10 (Scheme 5). To the best of our knowledge,
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R.A. Mekheimer et al.: 1,3-Dipolar cycloaddition reactions of C-aryl (or hetaryl)-N-phenylnitronesꢀꢂꢁꢁꢁꢀ323
Ph
N
O
Ar
O
Ph
N
O
Ph
8
H
Ph
O
N
Ar
Ph
1
a−c, f−i
O
N
abs. EtOH
reflux
O
+
Ph
Ar
O
N
O
Ph
N
Ph
9
O
H
Reaction
Yield of 10 (%)
7
O
7
7
7
7
7
7
7
+ 1a
+ 1b
+ 1c
+ 1f
+ 1g
+ 1h
+ 1i
90
78
70
84
71
81
83
Ph
NHPh
N
O
Ph
1
0
Scheme 4:ꢁ1,3-Dipolar cycloaddition reactions between nitrones 1a–c, f–i and 4-benzylidene-2-phenyloxazol-5(4H)-one (7). Synthesis of
5
-anilino-4-benzoyl-2-phenyloxazole (10).
Ph
H
N
Ph
N
Ar
Ar
O
O
N
Ph
H
O
Ph
1
a-c, f-i
N
O
O
EtOH
reflux
Ph
- ArCHO
+
O
N
Ph
N
Ph
Ph
12
11
O
H
O
7
1
,3-H shift
O
Ph
NHPh
O
Ph
N
Ph
N
Ph
O
H
N
O
H
O
Ph
N
O
N
Ph
10
Ph
Ph
1
4
13
Scheme 5:ꢁProposed mechanism for the formation of 5-anilino-4-benzoyl-2-phenyloxazole (10).
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24ꢀꢁꢁꢁꢂꢀR.A. Mekheimer et al.: 1,3-Dipolar cycloaddition reactions of C-aryl (or hetaryl)-N-phenylnitrones
this is the first reported transformation of 7–10 via a reflux for 30 h, until the TLC showed the disappearance of
tandem cycloaddition/rearrangement process. the starting compounds. After concentration and cooling
In summary, we have developed, for the first time, a to room temperature, the precipitated solid product was
new, convenient and simple methodology to achieve the collected by filtration, dried and recrystallized from
1
,3-dipolar cycloaddition between some acyclic C-aryl (or EtOH to give compounds 3a, b. In case of the reaction of
hetaryl)-N-phenylnitrones and different dipolarophiles 1b–i (2.5 mmol) with 2a (0.460 g, 2.5 mmol), the reaction
such as monosubstituted ylidene malononitriles and 7, in mixture was refluxed in dry toluene (10 mL) for 11–35 h.
which the heterocyclic ring system containing a ylidene Then, the reaction mixture was worked up as described
moiety at position four, under a thermal catalyst-free reac- above for 3a, b to give compound 5.
tion conditions, which allowed the reaction to complete
in short time, avoided the degradation and gave excellent
yields of products. This thermal catalyst-free cycloaddition 3.2 2-(3-(4-Dimethylaminophenyl)-
is strongly influenced by the nature of substituent not only
2
-phenyl-2,3-dihydro-1,2,4-oxadiazol-
at the nitrone carbon center but also at the β-position in
ylidene malononitriles. In all cases, the resulting products
were formed with a high degree of regio- and stereoselec-
tivity. With these results in hand, we are now expanding
this reaction to other dipolarophiles and applying it to the
synthesis of several new nitrogenated compounds, which
might be used in many different areas.
5
-yl)-3-(4-methoxyphenyl)-acryloni-
trile (3a)
Yield: 0.660 g (75%); yellow crystals; m.p. 162–164°C. –
IR (KBr): νmaxꢀ=ꢀ3067 (CH, aromatic), 2838 (CH, aliphatic),
−
1
1
2
216 (CN), 1633 (C=N) cm . – H NMR (600 MHz, [D ]
6
DMSO): δꢀ=ꢀ3.01 (s, 3H, N-CH ), 3.03 (s, 3H, N-CH ), 3.90 (s,
H, OCH ), 6.10 (s, 1 H, CH at C-3 in 1,2,4-oxadiazole ring),
.65 (d, 2H, Jꢀ=ꢀ9 Hz, Ar-H), 6.76 (d, 2H, Jꢀ=ꢀ9 Hz, Ar-H), 6.95
(d, 2H, Jꢀ=ꢀ8.4 Hz, Ar-H), 7.12 (d, 2H, Jꢀ=ꢀ9 Hz, Ar-H), 7.28 (s,
H, olefinic HC=), 7.41 (m, 3 Ar-H), 7.81 (d, 2H, Jꢀ=ꢀ8.4 Hz,
3
3
3
6
3
3
Experimental section
1
1
3
All melting points were determined using open capillaries Ar-H). – C NMR (150 MHz, [D ]DMSO): δꢀ=ꢀ40.49 (2 N-CH ),
6
3
on Büchi melting point B-540 apparatus and were uncor- 55.54 (OCH ), 107.18 (C=C–CN), 112.04 (1,2,4-oxadiazole
3
rected. Infrared spectra were recorded on a Nicollet Magna C-3), 117.62 (CN), 114.54, 123.92, 125.14, 125.90, 126.12, 127.14,
5
20 FT-IR spectrophotometer using potassium bromide 127.28, 129.57, 132.46, 133.37, 149.78, 152.60, 158.98 (Ar-C),
−1
1
13
disks. Peaks were reported in cm . H and C NMR spectra 149.55 (olefinic HC=C), 158.77 (1,2,4-oxadiazole C-5). – MS:
1
+
+
were recorded on a Bruker DPX (600 MHz for H NMR and m/z (%)ꢀ=ꢀ425 (27) [Mꢀ+ꢀ1] , 424 (92) [M] , 423 (83), 322 (28),
1
50 MHz for 13C NMR) spectrometer with [D ]DMSO as 321 (100), 320 (98), 266 (16), 250 (12), 239 (15), 213 (12), 212
6
solvent and tetramethylsilane (TMS) as an internal stand- (57), 211 (64), 210 (43), 197 (31), 196 (30), 195 (23), 194 (24),
ard; the chemical shifts were given in δ units (ppm). Mass 186 (34), 185 (32), 168 (19), 167 (48), 166 (41), 165 (13), 158
spectra were performed on a Shimadzu GCMS-QP 1000 EX (26), 157 (21), 143 (11), 136 (36), 135 (80), 134 (11), 121 (12),
mass spectrometer at 70 eV. Analytical TLC was performed 115 (15), 105 (15), 104 (16), 103 (15), 92 (19), 91 (16), 78 (12),
on aluminum sheets pre-coated with silica gel (Merck, 77 (51), 65 (17). – Analysis calcd. for C H N O : C 73.56, H
2
6
24
4
2
Kieselgel 60 PF ). Visualization was accomplished by UV 5.70, N 13.20; found C 73.49, H 5.89, N 13.28.
2
54
light. Microanalytical data were obtained from the Micro-
analytical Data Unit at Cairo University, and analytical
values obtained are within ±0.4% of the calculated values. 3.3 3-(4-Dimethylaminophenyl)-2-(3-
(
4-dimethylaminophenyl)-2-phenyl-
2
,3-dihydro-1,2,4-oxadiazol-5-yl)acrylo-
3
.1 General procedure for the preparation
of 2-(3-aryl-2-phenyl-2,3-dihydro-1,2,4-
oxadiazol-5-yl)-3-(4-methoxyphenyl)-
acrylonitriles 3a, b and 2-cyano-3-
nitrile (3b)
Yield: 0.665 g (73%); orange crystals; m.p. 250–252°C. –
IR (KBr): ν ꢀ=ꢀ2891, 2809 (CH, aliphatic), 2205 (CN), 1630
max
−1
1
(
C=N) cm . – H NMR (600 MHz, [D ]DMSO): δꢀ=ꢀ2.92 (s,
(4-methoxyphenyl)acrylamide (5)
6
3
H, N-CH ), 2.94 (s, 3H, N-CH ), 3.06 (s, 3H, N-CH ), 3.10 (s,
3
3
3
A mixture of nitrone 1a (0.50 g, 2.08 mmol) and 2a, b 3H, N-CH ), 6.09 (s, 1 H, CH at C-3 in 1,2,4-oxadiazole ring),
3
(
2.08 mmol) in dry toluene (10 mL) was heated under 6.62 (ABq, 2H, J ꢀ=ꢀ9 Hz, Ar-H), 6.74 (d, 2H, Jꢀ=ꢀ9 Hz, Ar-H),
AB
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R.A. Mekheimer et al.: 1,3-Dipolar cycloaddition reactions of C-aryl (or hetaryl)-N-phenylnitronesꢀꢂꢁꢁꢁꢀ325
6
.90 (d, 2H, Jꢀ=ꢀ7.8 Hz, Ar-H), 7.11 (d, 2H, Jꢀ=ꢀ7.8 Hz, Ar-H), 128.9 (2 Ar-C), 129.0 (4 Ar-C), 129.1 (2 Ar-C), 129.2 (1 Ar-C),
7
.25 (s, 1 H, olefinic HC=), 7.40 (m, 3 Ar-H), 7.79 (d, 2H, 130.2 (1 Ar-C), 132.5 (1 Ar-C), 132.6 (1 Ar-C), 133.4 (1 Ar-C),
13
Jꢀ=ꢀ7.8 Hz, Ar-H). – C NMR (150 MHz, [D ]DMSO): δꢀ=ꢀ111.82 137.7 (oxazole C-5), 163.6 (oxazole C-2), 186.6 (C=O). – MS:
6
+
+
(C=C–CN), 112.16 (1,2,4-oxadiazole C-3), 118.77 (CN), 112.72, m/z (%)ꢀ=ꢀ341 (2) [Mꢀ+ꢀ1] , 340 (2) [M] , 324 (2), 251 (2), 250
1
1
23.40, 125.38, 125.79, 126.20, 127.47, 128.27, 128.96, 129.69, (9), 249 (7), 248 (4), 247 (2), 180 (4), 179 (3), 118 (2), 117 (4),
33.39, 137.40, 152.70, 153.34, 154.38 (Ar-C), 149.50 (olefinic 116 (3), 106 (7), 105 (100), 93 (57), 92 (49), 91 (4), 90 (4), 89
HC=C), 158.95 (1,2,4-oxadiazole C-5). – MS: m/z (%)ꢀ=ꢀ438 (5), 88 (4), 78 (4), 77 (58), 65 (4), 51 (18). – Analysis calcd.
+
+
(
(
22) [Mꢀ+ꢀ1] , 437 (59) [M] , 436 (8), 334 (28), 266 (20), 250 for C H N O : C 77.63, H 4.74, N 8.23; found C 77.49, H 4.85,
22 16 2 2
7), 212 (30), 199 (100), 196 (17), 171 (58), 169 (18), 166 (14), N 8.30.
56 (16), 155 (18), 137 (16), 135 (10), 128 (13), 115 (6), 105
8), 104 (14), 103 (6), 92 (7), 77(33). – Analysis calcd. for
C H N O: C 74.12, H 6.22, N 16.01; found C 74.25, H 6.04,
1
(
2
7
27
5
3.6 Theoretical calculations
N 16.17.
All quantum mechanical calculations were performed
with the help of Gꢁꢂꢃꢃꢄꢁꢅ09 software [46]. The studied
molecules were optimized using Becke’s three-parameter
and Lee–Yang–Parr correlation functionals [47, 48] with
the Pople split-valence triple-zeta basis set with polari-
zation and diffuse functions (6-311++G**) [49]. For the
optimized geometries, the vibrational frequencies were
calculated to confirm that the obtained structures are real
minima. The single-point energies were calculated by the
Møller–Plesset second-order perturbation [50] method
with the 6-311++G** basis set [49].
3
.4 2-Cyano-3-(4-methoxyphenyl)-
acrylamide (5)
Yield: 70%–85%; colorless crystals; m.p. 215–216°C (lit.
[
45] 216). – IR (KBr): ν ꢀ=ꢀ3444, 3165 (NH ), 2206 (CN),
max 2
−1
1
1
662 (CO) cm . – H NMR (600 MHz, [D ]DMSO): δꢀ=ꢀ3.84
6
(
2
s, 3H, OCH ), 7.12 (d, 2H, Jꢀ=ꢀ9 Hz, Ar-H), 7.68, 7.81 (br s,
H, NH ), 7.95 (d, 2H, Jꢀ=ꢀ9 Hz, Ar-H), 8.10 (s, 1 H, olefinic
3
2
13
HC=). – C NMR (150 MHz, [D ]DMSO): δꢀ=ꢀ55.6 (OCH ),
6
3
1
1
02.8 (–HC=C–CN), 114.8 (2 Ar-C), 117.1 (CN), 124.4 (1 Ar-C),
32.5 (2 Ar-C), 150.2 (HC=C–CN), 162.6 (1 Ar-C), 163.1 (amide
+
+
C=O). – MS: m/z (%)ꢀ=ꢀ203 (16) [Mꢀ+ꢀ1] , 202 (69) [M] , 201
(
(
100), 200 (63), 187 (28), 186 (24), 185 (12), 158 (16), 157 References
22), 149 (24), 143 (29), 142 (8), 136 (16), 135 (22), 127 (12),
[
[
[
[
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18 (14), 116 (16), 103 (22), 102 (10), 100 (18), 93 (18), 87
2
391.
(
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6
3
.5 5-Anilino-4-benzoyl-2-phenyloxazole (10)
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.20 mmol) in absolute EtOH (10 mL) was heated to reflux
1
[
[
[
[
for 20–40 h, until the TLC showed the disappearance of
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–
IR (KBr): νmaxꢀ=ꢀ3272 (NH), 3064 (CH, aromatic), 1676 [10] S. L. Kuklish, R. T. Backer, M. J. Fisher, A. M. Kempema,
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1
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6
[
[
Jꢀ=ꢀ7.2 Hz, Ar-H), 7.34 (m, 5 Ar-H), 7.47 (m, 4 Ar-H), 7.59 (m,
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3
C NMR (150 MHz, [D ]DMSO): δꢀ=ꢀ116.5 (1 Ar-C), 120.2
6
(
1 Ar-C), 124.6 (oxazole C-4), 127.6 (2 Ar-C), 127.9 (1 Ar-C), [13] R. Kant, V. Singh, A. Agarwal, C. R. Chim. 2016, 19, 306.
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