Utilization of ultrasonic irradiation as green and effective one-pot protocol to prepare a novel series of bis-2-amino-1, 3, 4-oxa(thia)diazoles and bis-tetrazoles

Article abstract of DOI:10.24820/ark.5550190.p010.197

In an effective and straightforward conversion, bis-semicarbazones and bis-thiosemicarbazones are transformed into a diversity of novel substituted bis-2-amino-1, 3, 4-oxadiazoles and bis-2-amino-1, 3, 4-thiadiazoles, respectively under ultrasonic irradiation. Bis-tetrazoles are obtained from the dialdehydes by sequential reaction with hydroxylamine hydrochloride, phosphorus pentoxide and sodium azide without isolation of the intermediates oximes and nitriles. All the reactions proceed cleanly and smoothly under mild conditions, with short reaction times and broad functional groups possibility. No side reactions were observed.

Full text of DOI:10.24820/ark.5550190.p010.197

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Arkivoc 2017, part v, 327-340
Organic Chemistry
Utilization of ultrasonic irradiation as green and effective one-pot protocol to
prepare a novel series of bis-2-amino-1,3,4-oxa(thia)diazoles and bis-tetrazoles
Wael Abdelgayed Ahmed Arafa*a,b and Ahmed Fawzy Abdel-Magied c,d
a Chemistry Department, College of Science, Aljouf University, P.O. Box 2014, Sakaka, Aljouf,
Kingdom of Saudi Arabia
b Chemistry Department, Faculty of Science, Fayoum University P.O. Box 63514, Fayoum City, Egypt
c Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden
d Nuclear Material Authority, P. O. Box 530, El Maadi, Cairo, Egypt
Email: waa00@fayoum.edu.eg
Received 05-30-2017
Accepted 10--18-2017
Published on line 11-19-2017
Abstract
In an effective and straightforward conversion, bis-semicarbazones and bis-thiosemicarbazones are
transformed into a diversity of novel substituted bis-2-amino-1,3,4-oxadiazoles and bis-2-amino-1,3,4-
thiadiazoles, respectively under ultrasonic irradiation. Bis-tetrazoles are obtained from the dialdehydes by
sequential reaction with hydroxylamine hydrochloride, phosphorus pentoxide and sodium azide without
isolation of the intermediates oximes and nitriles. All the reactions proceed cleanly and smoothly under mild
conditions, with short reaction times and broad functional groups possibility. No side reactions were observed.
Keywords: Ultrasound, one-pot reaction, bis-heterocycles, dialdehydes
DOI: https://doi.org/10.24820/ark.5550190.p010.197
Page 327
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
Introduction
Semicarbazides and thiosemicarbazides constitute advantageous precursors for the preparation of 1,3,4-
oxadiazoles and 1,3,4-thiadiazoles, respectively. These five-membered rings are an important class of
heterocyclic systems which have worthy applications in medicinal, materials, and synthetic chemistry.1,2 1,3,4-
Oxadiazole derivatives are of particular concern for medicinal chemistry due to plentiful of these derivatives
acquire strong anticonvulsant, anticancer and antibacterial activities.3 They are also applied in material science
for the production of optical brighteners and organic light-emitting diodes (OLEDs).4-6 Furthermore, the 1,3,4-
oxadiazole scaffolds are used as sensors for several anions or cations.7 Also, bis-oxadiazoles are attractive
systems having many biological activities8 and can be used as scintillators because of their luminescent
properties.9 1,3,4-Thiadiazoles are another important category of heterocyclic compounds which are known
for many important pharmacological activities like antimitotic, hypolipidemic, anti-inflammatory, hypo-
glycaemic, analgesic, anticonvulsive and antimicrobial activities.10 Tetrazoles are also an important class of
nitrogen containing heterocycles with a broad range of medicinal applications such as the synthesis of
antihistaminic family drugs (Pranlukast and Pemiroplast) and sartan drugs (Losartan and Candesartan).11,12
Moreover, tetrazoles are widely used in information recording systems,13 high density energy materials,14 and
explosives.15 Many research papers have dealt with the synthesis of 5-substituted 1H-tetrazoles,16-21 1,3,4-
oxadiazoles22-25 and 1,3,4-thiadiazoles26-28 under the influence of diverse catalysts and various solvent
conditions. Almost all of these methods suffer from habitual obstacles such as expensive reagents, low yield,
strong Lewis acids used, long reaction time, water sensitivity and harsh reaction conditions. Thus, there is still
some space to develop and improve novel, efficient, mild, and simple synthetic protocols to diminish these
drawbacks and would be of considerable relevance to both medicinal and synthetic chemists.
Recently, sonochemical synthesis of several classes of organic compounds has received great interest.29,30
This is because the ultrasound technique with acoustic cavitation creates highly localized temperatures and
pressures that cannot be obtained by other methods. Acoustic cavitation comprises the formation, expansion,
and immediately collapse of bubbles in the solution. This process liberates the intensified stored energy in
collapsing bubbles in a short time. The released energy can elevate both temperature and pressure up to
5000 K, and 1000 bar, respectively, when the applied frequencies range from 20 to 40 kHz.31 Therefore, the
~
~
ultrasound-assisted process can be appropriate for reactions which are inaccessible by conventional methods.
The cavitation phenomena can influence a reaction both physically and chemically.32 The physical influence is
generation of intensive local convection in the liquid that promotes the mass transfer merits of the system.
The chemical influence encompasses the creation of extremely reactive radicals inside the bubble. The radicals
created inside the cavitation bubble get discharged into the medium with the shatter of the bubble where
they can activate and expedite the chemical reactions; this is the so-called sonochemical effect.33 To the best
of our knowledge, there are no literature examples of the synthesis of bis-1,3,4-oxadiazoles, bis-1,3,4-
thiadiazoles and bis-tetrazoles under ultrasound irradiation. Hence, based on the above-mentioned and in
continuation with our concern in the development of environment-friendly, mild, and operationally simple
protocols for the synthesis of bis-heterocyclic compounds,34-37 we report hither a rapid ultrasound accelerated
synthesis of these compounds.
Page 328
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
Results and Discussion
The key intermediate bis-semicarbazones 2a-f were synthesized form semicarbazide hydrochloride by its
condensation reaction with substituted dialdehydes 1a-f in ethanol-water mixture at room temperature in
good yields (Scheme 1). According to our previous results for the preparation of bis-thiosemicarbazone
derivatives,36 ultrasound irradiation can be used to improve the yields and shorten the reaction times in
comparison to conventional method. Under ultrasound irradiation (40 kHz), the desired bis-semicarbazone
derivatives 2a-f were obtained within 5 min in quantitative yields (Scheme 1) and were used in the next step
1
without any extra purification. The newly synthesized compounds were characterized by IR, H NMR and 13C
1
NMR, mass spectral and elemental analyses. In the H NMR spectrum of the bis-semicarbazone 2a, the CH
signal of the azomethine group appeared at 8.11 ppm as a singlet. Two characteristic singlets appeared at δ =
6.43 and 10.30 ppm corresponding to NH2 and NH groups, respectively. In the 13C NMR spectra of the reaction
products, the signal corresponding to the carbon of the aldehydic group (HC=O) disappeared and a new signal,
which belong to the azomethine carbon atom (CH=N) of the products was observed.
Scheme 1. Synthesis of bis-semicarbazones (2a-f).
The oxidative cyclization of the obtained bis-semicarbazone derivatives 2a-f with iodine was investigated
aiming to obtain the hitherto unreported bis-1,3,4-oxadiazoles 3a-f. We started our endeavours with bis-
semicarbazone 2a, potassium carbonate and molecular iodine as model substrates to search for appropriate
reaction conditions for the synthesis of bis-2-amino-1,3,4-oxadiazole 3a (Table 1). First, we evaluated the
Page 329
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
reaction by stirring the substrates in 1,4-dioxane at room temperature under conditions similar to those
previously reported (conventional conditions).38 It was found that the reaction afforded the bis-2-amino-1,3,4-
oxadiazole 3a (confirmed by NMR analysis) with a yield of 66% in 1 h (Table 1, entry 1). Increases in both
temperature and time slightly ameliorated the yield of the desired product (3a) (Table 1, entries 2, 3). In order
to further improve the yield and to decrease the reaction time, we attempted the same reaction under
ultrasound irradiation at room temperature and the results are shown in Table 1 (entries 4, 5). From these
results, it was observed that the ultrasound irradiation improved the product yield to a maximum of 88% of
the bis-2-amino-1,3,4-oxadiazole 3a within 10 minutes (Table 1, entry 5).
In spite of this satisfactory result, we have evaluated other conditions for optimizing an effective method
for this synthetic reaction. By varying the amount of oxidant in the above reaction, it was found that the
reaction yield increased with the increase in the amount of iodine from 2.0 to 2.3 equivalents and became
steady thereafter (Table 1, entries 7, 12, 13), establishing 2.3 equivalents of iodine as optimal for this protocol.
In the next experiment, in order to determine the efficiency of ultrasound heating in the model reaction, a
control run was undertaken using thermal heating under the same reaction conditions. It was found that when
o
the temperature during ultrasound irradiation was modulated, 60 C was the optimum temperature (Table 1,
entry 7). Moreover, on reducing the irradiation time to 5 min, the yield of the required product was decreased
and some starting material remained unreacted (Table 1, entry 6). The influence of irradiation frequency on
the reaction efficiency was also studied (Table 1, entries 7-11). Several ranges of irradiation frequencies (20-60
kHz) were studied on the model reaction. On screening, it was found that, when the irradiation frequency was
20 kHz (Table 1, entry 8), a low yield was obtained in 10 min. However, the reaction could not improve well in
the irradiation frequency of 60 kHz (Table 1, entry 11). In the frequency of 40 kHz, the yield of 3a was better
than that with 30 kHz within 10 min (96%, Table 1, entry 7). By increasing the irradiation frequency from 40 to
50 kHz (Table 1, entries 7, 10), there was no significant improvement in the reaction yield (95%, entry 10).
Eventually, the optimal conditions for the model reaction were identified as ultrasound irradiation of 40
kHz frequency at 60 oC for 10 min using 2.3 equiv of iodine and 1.0 mmol of bis-semicarbazone derivatives 2a-f
(Table 1, entry 7). After corroborating the feasibility of the model system, the scope of this synthesis was
evaluated by using a range of bis-semicarbazone derivatives 2b-f (Scheme 2, method 1). It was found that
sonication is superior to the conventional method as it generates in almost all cases nearly quantitative yields
of the desired products without the need for tedious purification steps.
Products 3a-f can also be obtained in one-pot synthesis without the isolation of intermediates 2a-f. Thus,
upon completion of the condensation of dialdehydes 1a-f and the semicarbazide hydrochloride under
ultrasound irradiation (monitored by TLC), the solvent was evaporated under reduced pressure and then the
remaining bis-semicarbazones 2a-f were redissolved in 1,4-dioxane, followed by the addition of potassium
o
carbonate and iodine and the reaction mixture was subjected to ultrasound irradiation at 60 C for an
additional 10 min to afford the required products (3a-f, Scheme 2, method 2). The structures of synthesized
1
bis-1,3,4-oxadiazole derivatives 3a-f were elucidated by elemental analysis, IR, H and 13C NMR data, and
1
high-resolution mass spectra. The H NMR spectrum of derivative 3a showed a signal at 2.25 ppm
corresponding to the CH3 group. The singlets at δ 7.17 and 7.51 ppm were due to the NH2 and aromatic
protons, respectively. 13C NMR spectra, C-2 and C-5 of the bis-1,3,4-oxadiazole moiety were observed around
164.1 and 157.8 ppm, respectively. The chemical shifts of the other carbons of the final bis-1,3,4-oxadiazoles
were as expected. The high-resolution mass spectra (HRMS) of the synthesized derivatives were in conformity
with the proposed structures.
Page 330
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
Table 1. Optimization of the reaction conditions for the synthesis of bis-2-amino-1,3,4-oxadiazole 3a under
conventional (Conv.) and ultrasound (US) methods
Entry
1
Method
Conv.
Conv.
Conv.
US
I2 (equiv.)
2.3
Time (min)
Temp. (oC)
Frequency (kHz)
Yield (%)
66
60
120
180
5
rt
rt
-
2
2.3
-
68
3
2.3
60
rt
-
76
4
2.3
40
40
40
40
20
30
50
60
40
40
83
5
US
2.3
10
5
rt
88
6
US
2.3
50
60
60
60
60
60
60
60
92
7
US
2.3
10
10
10
10
10
10
10
96
8
US
2.3
87
9
US
2.3
95
10
11
12
13
US
2.3
95
US
2.3
92
US
2.0
90
US
2.5
96
Scheme 2. Synthesis of bis-oxadiazole derivatives (3a-f) by different methods.
Page 331
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
Encouraged by the success of bis-2-amino-1,3,4-oxadiazoles synthesis, we sought to further extend the
scope of this practical approach by replacing semicarbazide hydrochloride with thiosemicarbazide aiming to
prepare bis-2-amino-1,3,4-thiadiazoles 5a-f (Scheme 3). Upon completion (monitored by TLC) of the
condensation of thiosemicarbazide and the corresponding dialdehydes 1a-f, the solvent was evaporated under
reduced pressure and the remaining bis-thiosemicarbazones 4a-f were redissolved in 1,4-dioxane, followed by
o
the treatment with molecular iodine and potassium carbonate. Stirring the resulting mixture at 60 C under
ultrasound irradiation for 10 min produced the desired bis-2-amino-1,3,4-thiadiazoles 5a-f in excellent yields
(85-95%).
Scheme 3. Synthesis of bis-thiadiazole derivatives 5a-f.
Although the preparation of bis-tetrazoles (6a-f) under ultrasonic irradiation, to the best of our
knowledge, has not been reported in the existing literatures until date, synthesis of relevant mono-tetrazoles
have been achieved by several methods, for example, one-pot reactions for tetrazole synthesis have been
carried out by using aldehydes, ammonia and iodine.39-41 However, the use of ammonia should be avoided in
order to prevent the generation of hydrazoic acid and nitrogen triiodide monoamine (explosive) which are
formed from the reaction of ammonia with sodium azide and iodine, respectively. In order to prevent the
formation of these dangerous and undesirable by-products, Khalid Mohammed Khan et al.42 developed a
method that included the replacement of iodine and ammonia with hydroxylamine and phosphorus pentoxide
under thermal conditions for nitrile formation followed by addition of sodium azide for the synthesis of a
number of tetrazoles, but this method had some shortcomings such as long reaction times and poor yields.
Scheme 4. Synthesis of bis-tetrazole derivatives (6a-f).
Page 332
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
Our first approach to the synthesis of novel bis-tetrazoles commenced using the conventional
method, with the reaction in DMF under reflux of the dialdehydes 1a-f and hydroxylamine hydrochloride
followed by addition of phosphorus pentoxide (Schemes 4, 5).
These reactions yielded the corresponding dinitriles (8a-f, not isolated), which on reaction with sodium
azide afforded bis-tetrazoles (6a-f) but in poor yields (Table 2) and their purification was difficult.
Notwithstanding this outcome, we explored other conditions for the above reaction in order to obtain
optimum conditions for this protocol. Under ultrasound irradiation, the synthesis of bis-tetrazoles (6a-f) was
o
achieved by the addition of hydroxylamine hydrochloride in DMF to dialdehydes (1a-f) and heating (70 C)
under ultrasound irradiation (40 kHz) for 25 min to generate the corresponding oximes (7a-f). Phosphorus
pentoxide was then added and the resulting mixture was heated under ultrasound irradiation for another 15
min. Finally, sodium azide was added to the formed bis-nitriles (8a-f) and the obtained mixture was heated for
another 15 min followed by acidic work-up, furnished the required products (6a-f, Scheme 4) in excellent
overall yields (88-95%, Table 2). This synthetic process comprises a new protocol for the synthesis of this class
of bis-tetrazoles (6a-f). These derivatives displayed IR, HRMS, NMR spectra and elemental analyses consistent
with the assigned structures (partial assignments are given in the Experimental section).
Scheme 5. Proposed intermediates in the synthesis of bis-tetrazoles (6a-f).
Table 2. Comparison results with different conditions in the synthesis of bis-tetrazoles (6a-f)
Entry Products
Time (min)
Conv.
Yield (%)
Conv.
(6a-f)
US
55
55
55
75
75
55
US
95
93
90
92
88
89
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
180
180
200
200
180
180
46
51
37
43(50)43
46
52
Conclusions
A powerful one-pot protocol has been developed to provide a rapid synthesis of bis-2-amino-1,3,4-oxa-
diazoles, bis-2-amino-1,3,4-thiadiazoles, and bis-tetrazoles from easily available starting materials. The use of
Page 333
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
ultrasonic irradiation effectively speeds up the reaction to produce higher yields within shorter reaction times
than with conventional heating. These notable features make the present protocol appropriate for
automation in a high-throughput synthesis of hybrid compounds which can be of potential use for medicinal
chemistry purposes.
Experimental Section
General. Starting materials were commercially available and were used without further purification. Silica gel
1
G [E-Merck] was used for thin layer chromatography (TLC). H and 13C NMR spectra were recorded using
Bruker UltraShield spectrometer at 400 and 100 MHz, respectively. Splitting patterns are designated as singlet
(s), doublet (d), triplet (t), doublet of doublet (dd), doublet of triplet (dt), triplet of triplet (tt) quartet (q),
broad (br). Splitting patterns that could not be interpreted or easily visualized are written as multiplet (m).
High resolution mass spectra (HRMS) measurements were recorded on a Bruker Daltonics microTOF
spectrometer. IR spectra were recorded on a Perkin-Elmer Spectrum One spectrometer, using samples
prepared as KBr discs. Sonication was done in a SY5200DH-T ultrasound cleaner with an output power of 250
W and frequency range of 20-60 kHz. The reaction vial was placed in the maximum energy area in the
cleaner.44 Water was added or removed in order to control the bath temperature.
General procedure for the synthesis of bis-semicarbazones (2a-f)
Conventional Method. A 10 mL ethanolic solution of dialdehydes (1a-f) (1 mmol) was added dropwise to an
aqueous solution of semicarbazide hydrochloride (2 mmol) and sodium acetate (2.5 mmol). The mixture was
stirred well at room temperature for 2h (the reaction was monitored by TLC). The obtained solid was filtered,
washed with chilled aqueous ethanol (3x5 mL), and dried to afford the desired products (2a-f).
Ultrasound Method. A mixture of dialdehydes (1a-f) (1 mmol), semicarbazide hydrochloride (2 mmol) and
sodium acetate (2.5 mmol) in aqueous ethanol (15 mL) was irradiated in the water bath of the ultrasonic
cleaner at room temperature. To optimize time, the tests were implemented with several times (2, 5, 7, 10,
and 15 min) and 5 min was selected as optimum time, also with increasing time from 5 to 15 min no changes
were observed in the formed products. After completion of the reaction (confirmed TLC), the obtained solid
was filtered off, washed with chilled aqueous ethanol (3x5 mL) and dried to afford the desired products (2a-f),
which in all cases were essentially pure semicarbazones.
2,2'-[(2-Hydroxy-5-methyl-1,3-phenylene)bis(methanylidene)]bis(hydrazine-1-carboxamide) (2a).45 Yield
98%; light yellow solid; mp 197-199 oC; 1H NMR (400 MHz, DMSO): δ 10.67 (s, 1H, OH), 10.30 (s, 2H, NH), 8.11
(s, 2H, CH=N), 7.48 (s, 2H, ArH), 6.43 (s, 4H, NH2), 2.24 (s, 3H, CH3). 13C NMR (100 MHz, DMSO): δ 156.6 (C=O),
152.9 (ArC), 139.0 (CH=N), 129.3, 128.6, 121.0 (ArC), 20.4 (CH3). IR (KBr, cm-1): νmax 3264 (br, NH2, NH& OH),
1676 (C=O) cm-1. HRMS (EI) for (M - H)+: calcd. 277.1044; found 277.1061. Anal. Calcd. for C11H14N6O3: C,
47.48; H, 5.07; N, 30.20. Found: C, 47.51; H, 5.12; N, 30.16%
2,2'-[(5-Bromo-2-hydroxy-1,3-phenylene)bis(methanylidene)]bis(hydrazine-1-carboxamide) (2b). Yield 95%;
o
1
yellow solid; mp 231-233 C; H NMR (400 MHz, DMSO): δ 11.10 (s, 1H, OH), 10.43 (s, 2H, NH), 8.10 (s, 2H,
CH=N), 7.88 (s, 2H, ArH), 6.53 (s, 4H, NH2). 13C NMR (100 MHz, DMSO): δ 156.8 (C=O), 153.5 (ArC), 139.1
(CH=N), 129.2, 128.9, 123.1 (ArC). IR (KBr, cm-1): νmax 3213 (br, NH2, NH, OH), 1660 (C=O) cm-1. HRMS (EI) for
(M - H)+: calcd. 341.0070; found 340.9992. Anal. Calcd. for C10H11BrN6O3: C, 35.00; H, 3.23; N, 24.49. Found: C,
35.11; H, 3.35; N, 24.52%.
Page 334
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
3,5-Bis-[(2-carbamoylhydrazono)methyl]-4-hydroxybenzoic acid (2c). Yield 95%; light yellow solid; mp 205-
207 oC; 1H NMR (400 MHz, DMSO): δ 11.91 (s, 1H, OH), 10.45 (s, 2H, NH), 8.21 (s, 2H, CH=N), 8.16 (s, 2H, ArH),
6.46 (s, 4H, NH2). 13C NMR (100 MHz, DMSO): δ 167.2, 158.4 (2 C=O), 138.7 (CH=N), 129.9, 122.7, 121.1 (ArC).
IR (KBr, cm-1): νmax 3199 (br, NH2, NH& OH), 1693, 1672 (C=O) cm-1. HRMS (EI) for (M - H)+: calcd. 307.0769;
found 307.0785. Anal. Calcd. for C11H12N6O5: C, 42.86; H, 3.92; N, 27.26. Found: C, 42.80; H, 4.05; N, 27.33%.
2,2'-[1,4-Phenylenebis(methanylidene)]bis(hydrazine-1-carboxamide) (2d). Yield 97%; light yellow solid; mp
o
1
221-224 C; H NMR (400 MHz, DMSO): δ 10.33 (s, 2H, NH), 8.18 (s, 2H, CH=N), 8.09 (s, 4H, ArH), 6.32 (s, 4H,
NH2). 13C NMR (100 MHz, DMSO): δ 157.5 (C=O), 139.7 (CH=N), 136.33, 129.9 (ArC). IR (KBr, cm-1): νmax 3205
(br, NH2 & NH), 1671 (C=O) cm-1. HRMS (EI) for (M - H)+: calcd. 247.0948; found 247.0945. Anal. Calcd. for
C10H12N6O2: C, 48.38; H, 4.87; N, 33.85. Found: C, 48.41; H, 4.80; N, 33.99%.
2,2'-[(1H-Pyrazole-3,5-diyl)bis(methanylidene)]bis(hydrazine-1-carboxamide) (2e). Yield 92%; white solid; mp
o
1
262-264 C; H NMR (400 MHz, DMSO): δ 14.11 (s, 1H, NH), 10.47 (s, 2H, NH), 8.12 (s, 2H, CH=N), 7.17 (s, 1H,
Pyrazole-C4), 6.44 (s, 4H, NH2). 13C NMR (100 MHz, DMSO): δ 158.1 (C=O), 138.9 (CH=N), 135.7, 109.2,
(Pyrazole-C3,4). IR (KBr, cm-1): νmax 3159 (br, NH2 & NH), 1688 (C=O) cm-1. HRMS (EI) for (M - H)+: calcd.
237.0850; found 237.0849. Anal. Calcd. for C7H10N8O2: C, 35.30; H, 4.23; N, 47.04. Found: C, 35.25; H, 4.33; N,
47.11 %.
2,2'-[Methylenebis-(6-hydroxy-3,1-phenylene)bis(methanylidene)]bis(hydrazine-1-carboxamide) (2f). Yield
96%; white solid; mp 242-244 oC; 1H NMR (400 MHz, DMSO): δ 11.67 (s, 1H, OH), 10.44 (s, 2H, NH), 8.18 (s, 2H,
CH=N), 7.41 (d, J 7.4 Hz, 2H, Ar), 7.32 (s, 2H, Ar), 6.99 (d, J 7.4 Hz, 2H, Ar), 6.45 (s, 4H, NH2), 4.09 (s, 2H, CH2).
13C NMR (100 MHz, DMSO): δ 159.1 (C=O), 152.7 (ArC), 138.8 (CH=N), 133.5, 131.4, 120.1, 117.4 (ArC), 40.5
(CH2). IR (KBr, cm-1): νmax 3184 (br, NH2, NH& OH), 1684 (C=O) cm-1. HRMS (EI) for (M - H)+: calcd. 369.1318;
found 369.1320. Anal. Calcd. for C17H18N6O4: C, 55.13; H, 4.90; N, 22.69. Found: C, 55.09; H, 4.98; N, 22.74%.
Synthesis of derivatives 3a-f and 5a-f
A mixture of dialdehydes 1a-f (1 mmol), semicarbazide hydrochloride or thiosemicarbazide (2mmol) and
sodium acetate (2 mmol, added only in case of semicarbazide hydrochloride) in aqueous ethanol (75%, 10 mL)
was sonicated for 5 min. Then the solvent was evaporated under reduced pressure, and the resulting residue
was redissolved in 1,4-dioxane (10 mL), followed by addition of potassium carbonate (3 mmol) and iodine (2.3
o
equiv.) in sequence. The reaction mixture was sonicated again at 60 C for about 10 min (monitored by TLC).
After cooling to ambient temperature, 5% Na2S2O3 (30 mL) was added and the mixture was extracted with
CH2Cl2/MeOH (6:4, 3x15 mL). The combined organic layer was dried over anhydrous magnesium sulfate and
concentrated. Upon standing at room temperature, the corresponding bis-1,3,4-oxa(thia)diazoles were
precipitated in pure form which is then washed with chilled ethanol, filtered and dried.
o
1
2,6-Bis-(5-amino-1,3,4-oxadiazol-2-yl)-4-methylphenol (3a). Yield 93%; white solid; mp 221-223 C; H NMR
(400 MHz, DMSO): δ 10.64 (s, 1H, OH), 7.51 (s, 2H, ArH), 7.17 (br, s, 4H, NH2), 2.25 (s, 3H, CH3). 13C NMR (100
MHz, DMSO): δ 164.1, 157.8, 152.6, 129.1, 128.3, 120.8 (ArC), 20.3 (CH3). IR (KBr, cm-1): νmax 3164 (br, NH2 &
OH). HRMS (EI) for (M - H)+: calcd. 277.1044; found 277.1061. Anal. Calcd. for C11H10N6O3: C, 47.48; H, 5.07; N,
30.20. Found: C, 47.51; H, 5.12; N, 30.16%.
o
1
2,6-Bis-(5-amino-1,3,4-oxadiazol-2-yl)-4-bromophenol (3b). Yield 98%; yellow solid; mp 255-257 C; H NMR
(400 MHz, DMSO): δ 11.12 (s, 1H, OH), 7.85 (s, 2H, ArH), 7.24 (br, s, 4H, NH2). 13C NMR (100 MHz, DMSO): δ
164.4, 158.4, 153.1, 129.6, 129.0, 123.6 (ArC). IR (KBr, cm-1): νmax 3199 (br, NH2 & OH). HRMS (EI) for (M + Na)+:
calcd. 360.9665; found 360.9662. Anal. Calcd. for C10H7BrN6O3: C, 35.42; H, 2.08; N, 24.78. Found: C, 35.40; H,
2.12; N, 24.83%.
Page 335
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
o
1
3,5-Bis-(5-amino-1,3,4-oxadiazol-2-yl)-4-hydroxybenzoic acid (3c). Yield 89%; yellow solid; mp 267-269 C; H
NMR (400 MHz, DMSO): δ 12.88 (br, s, 1H, CO2H), 11.94 (s, 1H, OH), 8.13 (s, 2H, ArH), 7.44 (br, s, 4H, NH2). 13C
NMR (100 MHz, DMSO): δ 167.6 (CO2H), 164.9, 158.0, 130.3, 123.1, 121.9 (ArC). IR (KBr, cm-1): νmax 3157 (br,
NH2 & OH), 1687 (C=O). HRMS (EI) for (M + Na)+: calcd. 327.0457; found 327.0453. Anal. Calcd. for C11H8N6O5:
C, 43.43; H, 2.65; N, 27.63. Found: C, 43.40; H, 2.72; N, 27.56%.
o
1
5,5'-(1,4-Phenylene)bis-(1,3,4-oxadiazol-2-amine) (3d). Yield 95%; yellowish solid; mp 277-280 C; H NMR
(400 MHz, DMSO): δ 7.93 (s, 4H, ArH), 7.32 (s, 4H, NH2). 13C NMR (100 MHz, DMSO): δ 165.6, 159.8, 135.6,
129.4 (ArC). IR (KBr, cm-1): νmax 3184 (br, NH2 & OH). HRMS (EI) for (M)+: calcd. 244.0711; found 244.0708.
Anal. Calcd. for C10H8N6O2: C, 49.18; H, 3.30; N, 34.41. Found: C, 49.22; H, 3.24; N, 34.35 %.
o
5,5'-(1H-Pyrazole-3,5-diyl)bis-(1,3,4-oxadiazol-2-amine) (3e). Yield 90%; yellow solid; mp 301-304 C; 1H NMR
(400 MHz, DMSO): δ 14.24 (s, 1H, NH), 7.21 (s, 4H, NH2), 7.18 (s, 1H, Pyrazole-C4). 13C NMR (100 MHz, DMSO):
δ 166.4, 161.3, 135.3, 109.8, (Pyrazole-C3,4). IR (KBr, cm-1): νmax 3122 (br, NH2). HRMS (EI) for (M + Na)+: calcd.
257.0512; found 257.0516. Anal. Calcd. for C7H6N8O2: C, 35.90; H, 2.58; N, 47.85. Found: C, 35.98; H, 2.50; N,
47.92%.
o
1
4,4'-Methylenebis-[2-(5-amino-1,3,4-oxadiazol-2-yl)phenol] (3f). Yield 89%; yellow solid; mp 296-299 C; H
NMR (400 MHz, DMSO): δ 11.58 (s, 1H, OH), 7.44 (d, J 7.4 Hz, 2H, Ar), 7.33 (m, 6H, Ar + NH2), 7.01 (d, J 7.4 Hz,
2H, Ar), 4.11 (s, 2H, CH2). 13C NMR (100 MHz, DMSO): δ 164.7, 162.0, 152.6, 134.3, 131.6, 121.4, 119.6 (ArC),
40.4 (CH2). IR (KBr, cm-1): νmax 2199 (br, NH2 & OH). HRMS (EI) for (M)+: calcd. 366.1079; found 366.1076. Anal.
Calcd. for C17H14N6O4: C, 55.74; H, 3.85; N, 22.94. Found: C, 55.70; H, 3.92; N, 23.05%.
o
1
2,6-Bis-(5-amino-1,3,4-thiadiazol-2-yl)-4-methylphenol (5a). Yield 95%; yellow solid; mp 311-313 C; H NMR
(400 MHz, DMSO): δ 10.66 (s, 1H, OH), 7.53 (s, 2H, ArH), 7.60 (br, s, 4H, NH2), 2.26 (s, 3H, CH3). 13C NMR (100
MHz, DMSO): δ 175.2, 163.3, 152.6, 129.7, 128.5, 121.2 (ArC), 20.6 (CH3). IR (KBr, cm-1): νmax 3177 (br, NH2 &
OH). HRMS (EI) for (M - H)+: calcd. 305.0281; found 305.0279. Anal. Calcd. for C11H10N6OS2: C, 43.13; H, 3.29;
N, 27.43. Found: C, 43.19; H, 3.20; N, 27.51%.
o
1
2,6-Bis-(5-amino-1,3,4-thiadiazol-2-yl)-4-bromophenol (5b). Yield 93%; yellow solid; mp 288-290 C; H NMR
(400 MHz, DMSO): δ 11.20 (s, 1H, OH), 7.83 (s, 2H, ArH), 7.47 (br, s, 4H, NH2). 13C NMR (100 MHz, DMSO): δ
171.4, 164.2, 152.3, 129.1, 128.7, 122.7 (ArC). IR (KBr, cm-1): νmax 3214 (br, NH2 & OH). HRMS (EI) for (M - H)+:
calcd. 368.9229; found 368.9225. Anal. Calcd. for C10H7BrN6OS2: C, 32.35; H, 1.90; N, 22.64. Found: C, 32.30;
H, 1.99; N, 22.57%.
o
3,5-Bis-(5-amino-1,3,4-thiadiazol-2-yl)-4-hydroxybenzoic acid (5c). Yield 91%; yellow solid; mp 323-326 C; 1H
NMR (400 MHz, DMSO): δ 12.90 (br, s, 1H, CO2H), 11.99 (s, 1H, OH), 8.17 (s, 2H, ArH), 7.60 (br, s, 4H, NH2). 13C
NMR (100 MHz, DMSO): δ 173.5, 167.9 (CO2H), 162.6, 158.8, 132.5, 125.0, 123.2 (ArC). IR (KBr, cm-1): νmax 3186
(br, NH2 & OH), 1689 (C=O). HRMS (EI) for (M - H)+: calcd. 335.0024; found 335.0020. Anal. Calcd. for
C11H8N6O3S2: C, 39.28; H, 2.40; N, 24.99. Found: C, 39.18; H, 2.47; N, 24.83%.
5,5'-(1,4-Phenylene)bis-(1,3,4-thiadiazol-2-amine) (5d).46 Yield 95%; white solid; mp 291-293 oC; 1H NMR (400
MHz, DMSO): δ 7.83 (s, 4H, ArH), 7.10 (s, 4H, NH2). 13C NMR (100 MHz, DMSO): δ 175.2, 163.2, 135.1, 129.5
(ArC). IR (KBr, cm-1): νmax 3195 (br, NH2). HRMS (EI) for (M)+: calcd. 276.0255; found 276.0251. Anal. Calcd. for
C10H8N6O2: C, 43.47; H, 2.92; N, 30.41. Found: C, 43.52; H, 2.86; N, 30.33%.
o
1
5,5'-(1H-Pyrazole-3,5-diyl)bis-(1,3,4-thiadiazol-2-amine) (5e). Yield 88%; light yellow solid; mp 311-314 C; H
NMR (400 MHz, DMSO): δ 14.33 (s, 1H, NH), 7.40 (s, 4H, NH2), 7.21 (s, 1H, Pyrazole-C4). 13C NMR (100 MHz,
DMSO): δ 174.0, 161.5, 136.0, 111.2, (Pyrazole-C3,4). IR (KBr, cm-1): νmax 3265 (br, NH2). HRMS (EI) for (M +
Na)+: calcd. 289.0059; found 289.0056. Anal. Calcd. for C7H6N8S2: C, 31.57; H, 2.27; N, 42.08. Found: C, 31.50;
H, 2.32; N, 42.13%.
Page 336
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
4,4'-Methylenebis-[2-(5-amino-1,3,4-thiadiazol-2-yl)phenol] (5f). Yield 85%; light yellow solid; mp 195-198 oC;
1H NMR (400 MHz, DMSO): δ 11.66 (s, 1H, OH), 7.47 (d, J 7.4 Hz, 2H, Ar), 7.43 (s, 4H, NH2), 7.38 (s, 2H, Ar), 7.11
(d, J 7.4 Hz, 2H, Ar), 4.13 (s, 2H, CH2). 13C NMR (100 MHz, DMSO): δ 173.9, 161.5, 151.8, 135.4, 132.3, 121.2,
120.2 (ArC), 40.8 (CH2). IR (KBr, cm-1): νmax 3223 (br, NH2 & OH). HRMS (EI) for (M)+: calcd. 398.0624; found
398.0629. Anal. Calcd. for C17H14N6O2S2: C, 51.24; H, 3.54; N, 21.09. Found: C, 51.20; H, 3.45; N, 21.16%.
Synthesis of derivatives 6a-f
Dialdehydes (1a-f, 1 mmol) and hydroxylamine hydrochloride (2 mmol) were dissolved in dry DMF (10 ml). The
o
reaction mixture was sonicated at 70 C for 25 min under nitrogen. After completion of the reaction (as
monitored by TLC), the reaction mixture was cooled to room temperature and 2.5 mmol of phosphorus
o
pentoxide was added. The sonication was continued at 70 C for another 15 min (till the disappearance of
o
oximes). Sodium azide (2 mmol) was added to the resulting mixture and then sonicated at 70 C for 15 min.
After cooling to ambient temperature, 20 g of ice-water mixture was added and the pH of the medium was
adjusted to be around 3 by addition of HCl (3 N). The mixture was extracted with CH2Cl2/MeOH (7:3, 3 x 15
mL). The organic layers were collected, washed with brine solution (3x10 mL), dried over anhydrous
magnesium sulfate and evaporated under reduced pressure to afford a pure white solid of the desired
products 6a-f.
o
1
4-Methyl-2,6-di-(1H-tetrazol-5-yl)phenol (6a). Yield 95%; white solid; mp 316-319 C; H NMR (400 MHz,
DMSO): δ 10.78 (s, 1H, OH), 7.59 (s, 2H, ArH), 2.29 (s, 3H, CH3). 13C NMR (100 MHz, DMSO): δ 155.7, 152.1,
129.9, 129.3, 121.7 (ArC), 20.9 (CH3). IR (KBr, cm-1): νmax 3173 (br, NH & OH). HRMS (EI) for (M)+: calcd.
244.0824; found 244.0820. Anal. Calcd. for C9H8N8O: C, 44.26; H, 3.30; N, 45.88. Found: C, 44.20; H, 3.39; N,
45.96%.
o
1
4-Bromo-2,6-di-(1H-tetrazol-5-yl)phenol (6b). Yield 93%; white solid; mp 192-193 C; H NMR (400 MHz,
DMSO): δ 11.31 (s, 1H, OH), 7.85 (s, 2H, ArH). 13C NMR (100 MHz, DMSO): δ 154.6, 152.0, 129.5, 128.3, 121.5
(ArC). IR (KBr, cm-1): νmax 3244 (br, NH & OH). HRMS (EI) for (M)+: calcd. 307.9774; found 307.9771. Anal. Calcd.
for C8H5BrN8O: C, 31.09; H, 1.63; N, 36.25. Found: C, 31.13; H, 1.69; N, 36.33%.
o
1
4-Hydroxy-3,5-di-(1H-tetrazol-5-yl)benzoic acid (6c). Yield 90%; white solid; mp 302-303 C; H NMR (400
MHz, DMSO): δ 12.97 (br, s, 1H, CO2H), 11.86 (s, 1H, OH), 8.22 (s, 2H, ArH). 13C NMR (100 MHz, DMSO): δ
167.9 (CO2H), 158.0, 156.7, 132.0, 126.4, 122.5 (ArC). IR (KBr, cm-1): νmax 3286 (br, NH & OH), 1678 (C=O).
HRMS (EI) for (M)+: calcd. 274.0566; found 274.0564. Anal. Calcd. for C9H6N8O3: C, 39.42; H, 2.21; N, 40.87.
Found: C, 39.34; H, 2.27; N, 40.94%.
o
1
1,4-Di-(1H-tetrazol-5-yl)benzene (6d).43 Yield 92%; white solid; mp 300-302 C; H NMR (400 MHz, DMSO): δ
8.24 (s, 4H, ArH). 13C NMR (100 MHz, DMSO): δ 154.5, 128.0, 127.7 (ArC). IR (KBr, cm-1): νmax 3208 (NH). HRMS
(EI) for (M)+: calcd. 214.0718; found 214.0714. Anal. Calcd. for C8H6N8: C, 44.86; H, 2.82; N, 52.32. Found: C,
44.93; H, 2.77; N, 52.40%.
o
1
5,5'-(1H-Pyrazole-3,5-diyl)bis-(1H-tetrazole) (6e). Yield 88%; white solid; mp 199-202 C; H NMR (400 MHz,
DMSO): δ 14.27 (s, 1H, NH), 7.26 (s, 1H, Pyrazole-C4). 13C NMR (100 MHz, DMSO): δ 158.4, 136.7, 113.7,
(Pyrazole-C3,4). IR (KBr, cm-1): νmax 3244 (NH). HRMS (EI) for (M)+: calcd. 204.0623; found 204.0619. Anal.
Calcd. for C5H4N10: C, 29.42; H, 1.97; N, 68.61. Found: C, 29.47; H, 1.90; N, 68.55%.
4,4'-Methylenebis-[2-(1H-tetrazol-5-yl)phenol] (6f). Yield 89%; white solid; mp 187-189 oC; 1H NMR (400 MHz,
DMSO): δ 11.29 (s, 1H, OH), 7.45 (d, J 7.4 Hz, 2H, Ar), 7.42 (s, 2H, Ar), 7.07 (d, J 7.4 Hz, 2H, Ar), 4.17 (s, 2H,
CH2). 13C NMR (100 MHz, DMSO): δ 154.2, 151.4, 135.1, 133.2, 122.5, 120.9 (ArC), 41.2 (CH2). IR (KBr, cm-1):
νmax 3273 (br, NH & OH). HRMS (EI) for (M)+: calcd. 336.1081; found 336.1084. Anal. Calcd. for C15H12N8O2: C,
53.57; H, 3.60; N, 33.32. Found: C, 53.65; H, 3.54; N, 33.27%.
Page 337
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
References
1. Kostyuchenko, A. S.; L. Yurpalov, V.; Kurowska, A.; Domagala, W.; Pron, A.; Fisyuk, A. S. Beilstein J. Org.
Chem. 2014, 10, 1596-1602.
https://doi.org/10.3762/bjoc.10.165
2. Gaonkar, S. L.; Rai, K. M. L.; Prabhuswamy, B. Eur. J. Med. Chem., 2006, 41, 841-846.
https://doi.org/10.1016/j.ejmech.2006.03.002
3. Amir, M.; Shikha, K. Eur. J. Med. Chem. 2004, 39, 535-545.
https://doi.org/10.1016/j.ejmech.2004.02.008
4. Schulz, B.; Orgzall, I.; Freydank, A.; Xü, C. Adv. Colloid Interface Sci. 2005, 116, 143-164.
https://doi.org/10.1016/j.cis.2005.03.007
5. Qu, S.; Lu, Q.; Wu, S.; Wang, L.; Liu, X. J. Mater. Chem. 2012, 22, 24605-24609.
https://doi.org/10.1039/c2jm35002e
6. Damaceanu, M. -D.; Bruma, M.; Schulz, B. Polymer 2012; 53, 5258-5267.
https://doi.org/10.1039/c2jm35002e
7. Ma, J.; Li, Z.; Zong, Y.; Men, Y.; Xing, G. Tetrahedron Lett. 2013, 54, 1348-1351.
https://doi.org/10.1016/j.tetlet.2012.12.128
8. Maslat, A. O.; Abussaud, M.; Tashtoush, H.; Al-Talib, M. Pol. J. Pharmacol. 2002, 54, 55-59.
9. Vereshchagin, L. I.; Petrov, A. V.; Kizhnyaev, V. N.; Pokatilov, F. A.; Smirnov, A. I. Russ. J. Org. Chem. 2006,
42, 1049-1055.
https://doi.org/10.1134/S1070428006070219
10. Joseph, L.; George, M.; Mathews, P. J. Pharm. Chem. Biol. Sci. 2015, 3, 329-345.
11. Wang, G.-X.; Sun, B.-P.; Ru, Z.-L. Synth. Commun. 2008, 20, 3577-3581.
https://doi.org/10.1080/00397910802228495
12. Ostrovskii, V. A.; Trifonov, R. E.; Popova, E. A. Russ. Chem. Bull. Int. Ed. 2012, 61, 768-780.
https://doi.org/10.1007/s11172-012-0108-4
13. Koldobskii, G. I.; Ostrovskii, V. A. Usp. Khim. 1994, 63, 847-865.
https://doi.org/10.1070/RC1994v063n10ABEH000119
14. Wittenberger, S. J.; Donner, B. G. J. Org. Chem., 1993, 58, 4139-4141.
https://doi.org/10.1021/jo00067a058
15. Kashani, E.; Pesyan, N. N.; Sahin, E. J. Chin. Chem. Soc. 2015, 62, 959-967.
https://doi.org/10.1002/jccs.201500257
16. Maleki, A.; Sarvary, A. RSC Adv. 2015, 5, 60938-60955.
https://doi.org/10.1039/C5RA11531K
17. Sreedhar, B.; Kumar, A. S.; Yadav, D. Tetrahedron Lett. 2011, 52, 3565-3569.
https://doi.org/10.1016/j.tetlet.2011.04.094
18. Coca, A.; Turek, E. Tetrahedron Lett. 2014, 55, 2718-2721.
https://doi.org/10.1016/j.tetlet.2014.03.049
19. Prajapti, S. K.; Nagarsenkar, A.; Babu, B. N. Tetrahedron Lett. 2014, 55, 3507-3510.
https://doi.org/10.1016/j.tetlet.2014.04.089
20. Kumar, S.; Kumar, A.; Agarwal, A.; Awasthi, S. K. RSC Adv. 2015, 5, 21651-21658.
https://doi.org/10.1039/C4RA13461C
21. Kant, R.; Singh, V.; Agarwal, A. C. R. Chimie 2016, 19, 306-313.
https://doi.org/10.1016/j.crci.2015.11.016
Page 338
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
22. Patel, K. D.; Prajapati, S. M.; Panchal, S. N.; Pate, H. D. Synth. Commun. 2014, 44, 1859-1875.
https://doi.org/10.1080/00397911.2013.879901
23. Kandemir, H.; Ma, C.; Kutty, S. K.; Black, D. S.; Griffith, R.; Lewis, P. J.; Kumar, N. Bioorg. Med. Chem. 2014,
22, 1672-1679.
https://doi.org/10.1016/j.bmc.2014.01.025
24. Dornelles, L.; Rodrigues, O. E. D.; Heck, E. F.; Bender, C. R.; Cansian, M. B.; Schwab, R. S.; Filho, W. A. S.
Arkivoc 2015, (vii) 131-144.
http://dx.doi.org/10.3998/ark.5550190.p009.310
25. Bretanha, L. C.; Teixeira, V. E.; Ritter, M.; Siqueira, G. M.; Cunico, W.; Pereira, C. M. P.; Freitag, R. A.
Ultrason. Sonochem. 2007, 18, 704-707.
https://doi.org/10.1016/j.ultsonch.2010.09.016
26. Hu, Y.; Li, C. -Y.; Wang, X. -M.; Yang, Y. -H.; Zhu, H. -L. Chem. Rev. 2014, 114, 5572-5610.
https://doi.org/10.1021/cr400131u
27. Singh, S. J.; Rajamanickam, S.; Gogoi, A.; Patel, B. K. Tetrahedron Lett. 2016, 57, 1044-1047.
https://doi.org/10.1016/j.tetlet.2016.01.083
28. Zarei, M. Tetrahedron 2017, 73, 1867-1872.
https://doi.org/10.1016/j.tet.2017.02.042
29. Zhang, D. W.; Zhang, Y. M.; Li, J.; Zhao, T. Q.; Gu, Q.; Lin, F. Ultrason. Sonochem. 2017, 36, 343-353.
https://doi.org/10.1016/j.ultsonch.2016.12.011
30. Sarwono, A.; Man, Z.; Muhammad, N.; Khan, A. S.; Hamzah, W. S. W.; Abdul Rahim, A. H.; Ullah, Z.;
Wilfred, C. D. Ultrason. Sonochem. 2017, 37, 310-319.
https://doi.org/10.1016/j.ultsonch.2017.01.028
31. Wood, R. J.; Lee, J.; Bussemaker, M. J. Ultrason. Sonochem. 2017, 38, 351-370.
https://doi.org/10.1016/j.ultsonch.2017.03.030
32. Hart, E. J.; Henglein, A. J. Phys. Chem. 1985, 89, 4342-4347.
https://doi.org/10.1021/j100266a038
33. Muthoosamy, K.; Manickam, S. Ultrason. Sonochem. 2017, 39, 478-493.
https://doi.org/10.1016/j.ultsonch.2017.05.019
34. Arafa, W. A. A.; Shaker, R. M. Arkivoc 2016, (iii), 187-201.
http://dx.doi.org/10.3998/ark.5550190.p009.464
35. Arafa, W. A. A.; Shaker, R. M.; Rabeh, S. A. Heterocycles 2016, 92, 1224-1243.
https://doi.org/10.3987/COM-16-13479
36. Arafa W. A. A.; Badry, M. G. J. Chem. Res. 2016, 40, 385-392.
https://doi.org/10.3184/174751916X14639296902648
37. Arafa, W. A. A.; Karkas, M. D.; Lee B.-L.; Åkermark, T.; Liao, R.-Z.; Berends, H.-M.; Messinger, J.; Siegbahn,
P. E. M.; Åkermark, B. Phys. Chem. Chem. Phys. 2014, 16, 11950 -11964.
https://doi.org/10.1039/c3cp54800g
38. Niu, P.; Kang, J.; Tian, X.; Song, L.; Liu, H.; Wu, J.; Yu, W.; Chang, J. J. Org. Chem. 2015, 80, 1018-1024.
https://doi.org/10.1021/jo502518c
39. Shie, J. -J.; Fang, J. -M. J. Org. Chem. 2003, 68, 1158-1160.
https://doi.org/10.1021/jo502518c
40. Shie, J. -J.; Fang, J. -M. J. Org. Chem. 2007, 72, 3141-3144.
https://doi.org/10.1021/jo026407z
Page 339
©ARKAT USA, Inc

Arkivoc 2017, v, 327-340
Arafa, W. A. A. et al.
41. Reddy, M. B. M.; Pasha, M. A. Synth. Commun. 2011, 41, 2081-2085.
https://doi.org/10.1021/jo0625352
42. Khan, K. M.; Fatima, I.; Saad, S. M.; Taha, M.; Voelter, W. Tetrahedron Lett. 2016, 57, 523-524.
https://doi.org/10.1080/00397911.2010.497593
43. Tao, J.; Ma, Z. -J.; Huang, R. -B.; Zheng, L. -S. Inorg. Chem. 2004, 43, 6133-6135.
https://doi.org/10.1016/j.tetlet.2015.12.067
44. Nascentes, C. C.; Korn, M.; Sousa, C. S.; Arruda, M. A. Z. J. Braz. Chem. Soc. 2001, 12, 57-63.
https://doi.org/10.1021/ic0492946
45. Lohar, S.; Sinha, S.; Ghosh, S.; Das, D. Spectrochim. Acta, Part A 2016, 155, 75-80.
https://doi.org/10.1590/S0103-50532001000100008
46. Darehkordi, A.; Ghazi, S. J. Chem. 2013, 2013, 1-8, ID 857956
https://doi.org/10.1155/2013/857956
Page 340
©ARKAT USA, Inc