A facile route for the synthesis of vinyl-substituted 1,3,4-oxadiazoles

Article abstract of DOI:10.1007/s11164-012-0852-y

An efficient synthesis of vinyl-substituted 1,3,4-oxadiazoles using o-nitrophenyl sulfoxide precursor via syn-elimination reaction using sodium acetate in THF is described. This method is cost effective as it uses cheap o-nitrothiophenol and can be used in the synthesis of vinyl intermediates during synthesis of bioactive compounds, which avoids the use of any toxic metals.

Full text of DOI:10.1007/s11164-012-0852-y

Res Chem Intermed
DOI 10.1007/s11164-012-0852-y
A facile route for the synthesis of vinyl-substituted
1,3,4-oxadiazoles
•
•
•
Santosh P. Pardeshi Sachin S. Patil Amar A. Patil
Vivek D. Bobade
Received: 21 July 2012 / Accepted: 3 October 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract An efficient synthesis of vinyl-substituted 1,3,4-oxadiazoles using
o-nitrophenyl sulfoxide precursor via syn-elimination reaction using sodium acetate
in THF is described. This method is cost effective as it uses cheap o-nitrothiophenol
and can be used in the synthesis of vinyl intermediates during synthesis of bioactive
compounds, which avoids the use of any toxic metals.
Keywords Vinyl 1,3,4-oxadiazole Á o-Nitrothiophenol Á b-Syn elimination Á
o-Nitrophenyl sulphoxide
Introduction
1,3,4-oxadiazoles are privileged structural units, not only in pharmaceutical
chemistry [1, 2] but also in pesticide chemistry [3, 4], polymer chemistry [5–7],
and material science [8–10]. Among 1,3,4-oxadiazoles, vinyl-substituted 1,3,4-
oxadiazoles are versatile intermediates used for the synthesis of complex natural
products and biologically active compounds, which are observed in a wide range of
pharmacological and therapeutic agents, such as antiallergic, antibacterial, and anti-
HIV [11, 12]. Some vinyl-substituted 1,3,4-oxadiazole derivatives play an important
role as useful additives in material chemistry [13, 14].
There are several synthetic approaches reported in the literature for the synthesis
of vinyl 1,3,4-oxadiazole. The most common approach involves the conventional
way of dehydration of acyl hydrazide (Route A) [15, 16]. This method has certain
drawbacks as it involves the synthesis of a,b-unsaturated hydrazide intermediate.
During the synthesis of a,b-unsaturated hydrazide, the predominant product is
pyrazolidinone due to hydrazinolysis and an undesired subsequent intramolecular
S. P. Pardeshi Á S. S. Patil Á A. A. Patil Á V. D. Bobade (&)
Department of Chemistry, HPT Arts and RYK Science College, Nasik, India
e-mail: v_bobade31@rediffmail.com
123

S. P. Pardeshi et al.
O
H
N
N
N
R
Route A
Route B
N
N
N
Ph
Se
R
R
H
R
O
O
O
7
Route C
N
N
Se
O
Scheme 1 Literature-reported methods for the synthesis of vinyl-substituted 1,3,4-oxadiazole
Michael-type cyclisation [17–19]. Another disadvantage of the cyclocondensation
method is the complicated isolation procedure and low yield because of the reactive
terminal double bond present in vinyl oxadiazole, which undergoes polymerization
at higher reaction temperatures [20]. A second approach involves syn elimination of
phenylselanylethyl-substituted oxadiazole (Route B) [21]. This approach has the
advantage over the conventional method, such as good yield and simple work-up
procedure. A third approach involves the use of polymer-bound selenopropionic
acid (Route C) [22] (Scheme 1). But both these approaches demand the use of
selenium metal which is carcinogenic and genotoxic and has little benefit in the
synthesis of bioactive compounds.
Results and discussion
Taking into account the pharmacological importance of vinyl oxadiazole interme-
diates, and as part of our continuing efforts on the development of new routes for the
preparation of biologically active heterocyclic compounds [23–26], we have
focused on the development of the synthesis of this nucleus which does not involve
any toxic metal.
From our careful study of all the reported literature routes, we have come to the
conclusion that we should introduce a non-metallic functional group that could be
used to mask the vinylic functionality, which can serve as a pro-vinyl intermediate
which can undergo syn-elimination to get vinyl-substituted oxadiazole.
Recently, in the literature, o-nitrophenyl sulfoxide was found to be an efficient
precursor for the synthesis of various alkenes [27] and vinylglycines [28] via syn-
periplanar b-elimination. We extended this methodology to develop a mild and
efficient process for the synthesis of vinyl oxadiazole via b-elimination reaction.
(Scheme 2).
We began the synthesis from ethyl b-bromo propionate, which condensed with
o-nitrothiophenol to form sulphide 3. Reaction of hydrazine hydrate with sulphide 3
gave hydrazide 4, which in turn acylated and cyclized in the presence of phosphorus
oxychloride to give nitrothiophenylethyl-1,3,4-oxadiazole 5. Compound 5 under-
went an oxidation reaction using m-chloroperbenzoic acid to form sulfoxide
123

Synthesis of vinyl substituted 1,3,4-oxadiazoles
NO2
O
NO2
NO2
K2CO3
DMF
NH2NH2.H2O
Ethanol
OC2H5
O
O
+
NH2
Br
OC2H5
SH
S
N
S
H
1
2
3
4
NO2
S
RCOOH
POCl3
NO2
OH
NO2
N
N
N
N
m-CPBA
CH3COONa
THF 50 οC
N
N
+
R
R
S
O
O
R
S
O
O
6
7
8
5
Scheme 2 Synthesis of vinyl 1,3,4-oxadiazole
intermediate 6, which was followed by sulfenic acid syn-elimination to obtain vinyl-
substituted oxadiazoles 7 in good yield.
To optimize the reaction conditions for b-syn elimination reaction, precursor 6a
was used as model substrate. As a starting point, the b-syn elimination of p-
nitrophenyl sulfoxide 6a was carried out using sodium acetate in 10 volumes of
toluene at reflux temperature; it completed within 2 h but provided a low yield
(30 %). The reason for the low yield may be the higher temperature which leads to
polymerization of the vinyl oxadiazole. We then carried out this reaction at a
lower temperature using several solvents such as acetonitrile, dichloromethane,
1,4-dioxane, 1,2-dimethoxyethane, and THF, among which THF was found to be
the best with 75 % yield at 50 °C. It was also observed that when the reaction was
carried out at a higher temperature, the yield decreased considerably. We tested
several bases such as sodium carbonate, potassium carbonate, and sodium acetate,
of which sodium acetate provided better yields. Using the optimized reaction
conditions, we examined the scope of this reaction and the results are summarized in
Table 1. Electron-withdrawing substituted derivatives (6j) afforded product in 70 %
yield with a faster reaction rate, while electron-donating substituents (6b–e) gave
55–60 % yield. The halo-substituted aromatic compounds (6f–i) gave a moderate
Table 1 Vinyl-substituted 1,3,4-oxadiazoles
R
Product
Yield
Product
Yield
Product
Yield
C6H5
5a
5b
5c
5d
5e
5f
75
71
62
73
80
79
71
67
72
69
65
63
6a
6b
6c
6d
6e
6f
78
74
68
71
76
72
73
69
73
69
78
70
7a
7b
7c
7d
7e
7f
75
55
57
49
61
69
66
65
68
70
48
50
4-CH3 C6H4
4-OCH3 C6H4
Naphthyl
3-CH3 C6H4
4-F C6H4
4-Cl C6H4
4-Br C6H4
2-Br C6H4
4-NO2 C6H4
i-C3H7
5g
5h
5i
6g
6h
6i
7g
7h
7i
5j
6j
7j
5k
5l
6k
6l
7k
7l
CH3
123

S. P. Pardeshi et al.
yield at 65–69 %. We extended the scope of the reaction for aliphatic compounds
(6k–l), which provided a lower yield (48–50 %) and slower reaction.
Experimental
Chemicals were procured from Aldrich Chemical (Bangalore, India). Reactions
were monitored, and the purity of the products was checked by thin layer
chromatography (TLC). TLC was performed on Merck 60 F-254 silica gel plates
with visualization by UV light. Melting points were determined on a Buchi Melting
Point B-545 apparatus. The IR spectra (in KBr pellets) were recorded on a Hyper IR
1
spectrophotometer. H-NMR and 13C spectra were recorded on Bruker (300 and
75 MHz) spectrometer instruments, respectively, in DMSO-d6. Chemical shifts
were recorded in parts per million downfield from tetramethylsilane. Mass spectra
were recorded on a MS-3200Q trap spectrometer. Elemental analysis was performed
on a Carlo Erba CHNS-O 1108 Elemental analyzer.
General procedure for the synthesis of ethyl 3-(2-nitrophenylthio)propanoate, 3
To a stirred mixture of 2-nitrothiophenol (10 mol) in DMF, anhydrous potassium
carbonate (10 mmol) was added and stirred at room temparature for 6 h. The
reaction was monitored by TLC. The reaction mixture was filtered and the filtrate
was quenched in water. The product was extracted with ethyl acetate and dried over
magnesium sulfate. The solvent was evaporated to get the crude product. The crude
product was re-crystallized from ethanol. The yield was 70 %.
General procedure for preparation of 3-(2-nitrophenylthio)propanehydrazide, 4
To a stirred solution of ethyl 3-(2-nitrophenylthio)propanoate (10 mmol) in ethanol
(30 mL), hydrazine hydrate (25 mmol) was added and heated to reflux for 4 h. The
reaction was monitored by TLC. On cooling to 0 °C, the product separated out was
filtered, and washed with chilled ethanol. The yield was 80 %.
General procedure for preparation of 2-{2-[(2-nitrophenyl)sulphanyl]ethyl}-
5-substituted-1,3,4-oxadiazole, 5
The reaction mixture of 3-(2-nitrophenylthio)propanehydrazide (4) and carboxylic
acid (10 mmol) in phosphorus oxychloride (20 mL) was heated to reflux for 4 h,
monitored by TLC, then evaporated to dryness in vacuum to get the crude product.
The product was purified by column chromatography using silica gel and eluted
with ethyl acteate/hexane to afford pure product 5.
2-(4-Methoxyphenyl)-5-2-[2-(2-nitrophenylsulfanyl)ethyl]-1,3,4-oxadiazole (5c)
1H NMR (300 MHz, CDCl3) d 8.21 (m, 1H); 8.03 (d, J = 8.4 Hz, 2H), 7.27–7.56
(m, 3H), 7.04 (d, J = 8.4 Hz, 2H), 3.91 (s, 3H), 3.55 (t, 2H), 3.13 (t, 2H); 13C NMR
123

Synthesis of vinyl substituted 1,3,4-oxadiazoles
(75 MHz, CDCl3) d 166.3, 164.3, 161.8, 145.1, 135.8, 134.1, 130.0, 129.1, 128.0,
126.1, 116.2, 114.1, 54.9, 29.4, 27.7; MS (m/z): 358.4 (M?).
General procedure for the preparation of 2-(2-(2-nitrophenylsulfinyl)ethyl)-
5-substituted-1,3,4-oxadiazole, 6
To a stirred solution of thio compound 5 (10 mmol) in MDC (10 mL), was added
solution of m-CPBA (12 mmol) in MDC (5 mL) and the mixture was stirred for 3 h
at room temperature, was monitored by TLC, then quenched with 5 % sodium
bicarbonate solution. The organic layer was separated and the aqueous layer was
extracted with MDC. The combined organic layer was washed with brine, dried
over anhydrous sodium sulfate, and concentrated in vacuum. The product were
purified by column chromatography using silica gel and eluted with ethyl acteate/
hexane to afford pure product 6.
2-(4-Methoxyphenyl)5-{2-[2(2-nitrophenyl)sulfinyl]ethyl}-1,3,4-oxadiazole (6c)
1H NMR (300 MHz, CDCl3) d 8.30 (m, 1H), 8.03 (d, J = 8.4 Hz 2H), 7.71–7.76
(m, 3H), 7.04 (d, J = 8.4 Hz, 2H), 3.29 (m, 2H), 3.62 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 168.2, 162.3, 161.9, 144.8, 136.9, 134.8, 130.2, 128.1, 127.3, 125.3,
114.4, 113.5, 55.1, 47.6, 21.1; MS (m/z): 374.3 (M?).
General procedure for the preparation of 5-vinyl-2-substituted 1,3,4-oxadiazoles,
7
To a stirred mixture of sulfoxide 6 (10 mmol) in THF (20 mL), sodium acetate
(60 mmol) was added, and the mixture was heated to 50 °C for 4–8 h. The reaction
mixture was monitored by TLC. The reaction mixture was cooled to room
temperature, and the solid was removed by filtration through celite. The filtrate was
concentrated in vacuum to get the crude product. The product were purified by
column chromatography using silica gel and eluted with ethyl acteate/hexane (4:1)
to afford pure product 7.
5-Phenyl-2-vinyl-1,3,4-oxadiazole (7a)
Oil, [Lit 21]; 1H NMR (300 MHz, CDCl3) d 8.11–8.09 (m, 2H), 7.56–7.51 (m, 3H),
6.84–6.76 (m 1H,), 6.38–6.34 (d, 1H), 5.88–5.86 (d, 1H,); 13C NMR (75 MHz,
CDCl3) d 164.24, 163.64, 131.87, 129.09, 127.02, 124.92, 123.77, 120.05; IR tmax
(cm-1) 3,065, 2,927, 1,552, 1,536, 1,465, 780, 706, 690; MS (m/z): 173 (M?)Anal.
Calcd for C10H8N2O: C, 69.76 %, H, 4.68 %, N, 16.27 %; Found: C, 69.81 %, H,
4.78 %, N, 16.19 %.
5-(4-Methylphenyl)-2-vinyl-1,3,4-oxadiazole(7b)
Colourless oil, 1H NMR (300 MHz, CDCl3) d 1H NMR (300 MHz, CDCl3): d 7.99
(d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.78–6.71 (m, 1H), 6.59–5.96
123

S. P. Pardeshi et al.
(m, 2H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3): d 174.2, 168.6, 141.4, 129.4,
128.5, 127.2, 123.8, 120.5, 21.4; MS: m/z 133(100), 187.2 (M?); IR tmax (cm-1
)
3,063, 2,981, 1,540, 1,311, 1,290, 835, 696, 600; MS (m/z): 184 (M?); Anal. Calcd
for C11H10N2O: C, 65.34 %, H, 4.98 %, N, 13.85 %; Found: C, 65.50 %, H,
5.08 %, N, 17.00 %.
5-(4-Methoxyphenyl)-2-vinyl-1,3,4-oxadiazole(7c)
1
Off white solid, mp: 79–81 °C, [Lit 22: 80–82 °C]; H NMR (300 MHz, CDCl3) d
7.84 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H,), 6.67–6.59 (m, 1H), 6.19–5.68
(m, 2H), 3.71 (s, 3H,). 13C NMR (75 MHz, CDCl3): d163.61, 162.68, 161.94,
128.20, 124.02, 119.53, 115.61, 114.01, 54.99; IR tmax (cm-1) 3,063, 2,981, 1,540,
1,311, 1,290, 835, 696, 600; MS (m/z): 203.2 (M?); Anal. Calcd for C11H10N2O2: C,
65.34 %, H, 4.98 %, N, 13.85 %; Found: C, 65.50 %, H, 5.08 %, N, 17.00 %.
2-(Naphthalen-2-yl)-5-vinyl-1,3,4-oxadiazole (7d)
1
Off white solid, mp: 79–81 °C; H NMR (CDCl3) d 8.08–7.99 (m, 2H), 7.64–7.60
(m, 2H), 7.57–7.53 (m, 1H), 7.42–7.40 (d, J = 8.4 Hz, 1H,), 7.26–7.19 (m, 1H),
6.16–6.00 (m, 2H), 5.34–5.31 (m, 1H); 13C NMR (75 MHz, CDCl3) d 164.4, 160.3,
134.34, 130.66, 130.06, 129.75, 128.59, 128.37, 127.44, 126.74, 125.42, 120.82; IR
tmax (cm-1) 3,063, 2,981, 1,540, 1,311, 1,290, 835, 696, 600; MS (m/z): 223.1
(M?); Anal. Calcd for C14H10N2O: C, 75.66 %, H, 4.54 %, N, 12.60 %; Found: C,
75.70 %, H, 4.62 %, N, 12.75 %.
Conclusion
In summary, we have described a new method for the synthesis of vinyl-substituted
1,3,4-oxadiazole using o-nitro phenyl sulfoxides as an efficient synthetic precursor.
The advantage of this new method is the use of a very mild condition for b-syn
elimination which avoids the polymerization of the vinyl group of synthesized
vinyl-substituted oxadiazole. This method is cost effective as it uses cheap o-
nitrothiophenol and can be used in synthesis of vinyl intermediates during synthesis
of bioactive compounds, which avoids the use of any toxic metals.
Acknowledgments The authors are grateful to the University of Pune and IIT Mumbai, India, for
providing facilities for spectral studies of compounds. Financial support from CSIR, New Delhi is
gratefully acknowledged.
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