N-Isocyanimino-Triphenylphosphorane (Ph 3Pnnc) as an Efficient Reagent for the Preparation of Fully Substituted 1,3,4-Oxadiazoles via Intramolecular Aza-Wittig Reaction in Water

Article abstract of DOI:10.1080/10426507.2015.1054486

An efficient green protocol for the synthesis of 1,3,4-oxadiazoles derivatives via a one-pot three-component reaction of aromatic carboxylic acids, N-isocyanimino-Triphenylphosphorane and ester derivatives of 2-oxopropyl alcohol (2-oxopropyl benzoate, 2-oxopropyl-4-bromobenzoate and 2-oxopropyl acetate) in water at room temperature have been developed. The present methodology offers several advantages such as a simple procedure, high yields, environmental friendliness and the absence of any volatile and hazardous organic solvents.

Full text of DOI:10.1080/10426507.2015.1054486

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Phosphorus, Sulfur, and Silicon and the Related
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N-Isocyanimino-Triphenylphosphorane (Ph3Pnnc) As
An Efficient Reagent For The Preparation Of Fully
Substituted 1,3,4-Oxadiazoles Via Intramolecular Aza-
Wittig Reaction In Water
Ali Jafaria, Ali Ramazania, Pegah Azimzadeh Asiabia, Fariba Sadrib & Sang Woo Jooc
a Department of Chemistry, University of Zanjan, P O Box 45195-313, Zanjan, Iran
b Department of Chemistry, Payame Noor University, P O BOX 19395-4697 Tehran, Iran
c School of Mechanical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of
Korea
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Accepted author version posted online: 09 Jun 2015.
To cite this article: Ali Jafari, Ali Ramazani, Pegah Azimzadeh Asiabi, Fariba Sadri & Sang Woo Joo (2015): N-Isocyanimino-
Triphenylphosphorane (Ph3Pnnc) As An Efficient Reagent For The Preparation Of Fully Substituted 1,3,4-Oxadiazoles
Via Intramolecular Aza-Wittig Reaction In Water, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2015.1054486
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1054486
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ACCEPTED MANUSCRIPT
N-ISOCYANIMINO-TRIPHENYLPHOSPHORANE (Ph3PNNC) AS AN EFFICIENT
REAGENT FOR THE PREPARATION OF FULLY SUBSTITUTED 1,3,4-
OXADIAZOLES VIA INTRAMOLECULAR AZA-WITTIG REACTION IN WATER
Ali Jafari1, Ali Ramazani*,1, Pegah Azimzadeh Asiabi1, Fariba Sadri2 and Sang Woo Joo*,3
1Department of Chemistry, University of Zanjan, P O Box 45195-313, Zanjan, Iran,
*E-mail: aliramazani@gmail.com
2Department of Chemistry, Payame Noor University, P O BOX 19395-4697 Tehran, Iran
3 School of Mechanical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of
Korea, *E-mail: swjoo@yu.ac.kr
Abstract An efficient green protocol for the synthesis of 1,3,4-oxadiazoles derivatives via a one-
pot three-component reaction of aromatic carboxylic acids, N-isocyanimino-
triphenylphosphorane and ester derivatives of 2-oxopropyl alcohol (2-oxopropyl benzoate, 2-
oxopropyl-4-bromobenzoate and 2-oxopropyl acetate) in water at room temperature have been
developed. The present methodology offers several advantages such as a simple procedure, high
yields, environmental friendliness and the absence of any volatile and hazardous organic
solvents.
1
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O
O
O
DMF, 100 oC, 21 h
CH3
+
H3C
CH2Cl
R
O Na
R
O
O
C
N
O
N
O
N
N
H2O
Ar
CH3
+
ArCO2H +
+
Ph3PO
O
R
O
R
O
r.t., 1 h
OH
O
PPh3
Keywords N-isocyanimino-triphenylphosphorane; 1,3,4-oxadiazoles; water; aromatic carboxylic
acids; environmentally friendly; green solvent.
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INTRODUCTION
Iminophosphoranes are important reagents in organic chemistry, especially in the
production of naturally occurring products, compounds with biological and pharmacological
activity.1 In the last few years, several preparative procedures have been reported for the
preparation and synthetic applications of iminophosphoranes.1 It is expected N-isocyanimino-
triphenylphosphorane (Ph3PNNC) will have synthetic potential because it develops a reaction
system in which the iminophosphorane group can react with a reagent having a carbonyl
functionality.1
One important aspect of green chemistry is the elimination of solvents in chemical
processes or the replacement of hazardous solvents with relatively benign solvents. Water being
the most environmentally benign, cleanest, cheapest, nonflammable, and naturally occurring
solvent having high specific heat capacity is the primary choice. Moreover, in water significant
rate enhancement was observed in many reactions,2 because of hydrophobic interactions that
induce a favorable aggregation of polar components in water.2
Multicomponent reactions (MCRs), with three or more reactants that are combined in a
one-pot procedure to give a single product, have become increasingly popular during the last
decade.3-10 They are economically and environmentally advantageous because multi-step
syntheses produce considerable amounts of waste mainly due to complex isolation procedures
often involving expensive, toxic, and hazardous solvents after each step. MCRs are perfectly
suited for combinatorial library syntheses, thus are finding increasing use in the discovery
process for new drugs and agrochemicals.11 They provide a powerful tool toward the one-pot
synthesis of diverse and complex compounds as well as small and drug-like heterocycles.12
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MCRs that involve isocyanides are by far the most versatile reactions in terms of scaffolds and
number of accessible compounds.13,14
The 1,3,4-oxadiazoles are an important class of heterocycles, which possess
pharmaceutical and biological activities, such as antimicrobial,15-17 antimycobacterial,18 anti-
inflammatory,19 anti-allergic,20 antifungal and genotoxic activities.21 Several methods have been
developed to synthesize 1,3,4-oxadiazoles.15-21 These protocols are multistep in nature.22-24 In
recent years, we have established a one-pot method to synthesize 1,3,4-oxadiazoles from N-
isocyanimino-triphenylphosphorane.25-29 In the continuation of our ongoing program to develop
water-promoted organic synthesis,30 we report herein an efficient green protocol for the synthesis
of 1,3,4-oxadiazoles via
a
one-pot three-component reaction of N-isocyanimino-
triphenylphosphorane, aromatic carboxylic acids and ester derivatives of 2-oxopropyl alcohol
(2-oxopropyl benzoate, 2-oxopropyl 4-bromobenzoate and 2-oxopropyl acetate) in water at room
temperature.
RESULTS AND DISCUSSION
In our initial research, 3a, 4a, and 5 were selected as representative reactants in order to
optimize the reaction conditions (Scheme 1). We conducted the one-pot, three component
condensation reaction of 3a, 4a, and 5 in the presence of various solvents. We examined the
effect of different solvents such as CH2Cl2, DMF, THF, CH3CN, water and EtOH on a model
reaction at room temperature. The results are listed in Table 1 and show that CH2Cl231 and water
as solvents gave the best results (Table 1, entries 5 and 6). The reaction failed to give fairly poor
yields in DMF, THF, CH3CN and EtOH (Table 1, entries 1–4). Water has been selected as a
suitable solvent for the reaction, because of its environmentally friendly nature.30
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The reaction of carboxylic acid derivatives
4
with ester derivatives of
2-oxopropyl benzoate
N-isocyanimino-triphenylphosphorane in
room temperature to produce
and triphenylphosphine oxide (Scheme 1).
The reaction proceeds smoothly and cleanly under mild conditions and no
2-oxopropyl
alcohol
3
(2-oxopropyl
and
4-bromobenzoate,
and
2-oxopropyl
acetate)
5
a
1:1:1 ratio
was conducted in water at
disubstituted 1,3,4-oxadiazoles
6
7
side
(Ph3PNNC)
of 2-oxopropyl
reactions
were
observed.
The
N-isocyanimino-triphenylphosphorane
5
was prepared based on
a
reported procedure.32 Ester derivatives
alcohol
3
(2-oxopropyl
acetate) were
4-bromobenzoate,
prepared based
2-oxopropyl
on known
benzoate,
and
2-oxopropyl
procedures.33
6a: R=Ph, Ar=3,5-diMeC6H4; 6b: R=Ph, Ar=4-MeC6H4; 6c: R=Ph, Ar=3,4-diMeC6H4; 6d:
R=Ph, Ar=4-ClC6H4; 6e: R=Ph, Ar=4-BrC6H4; 6f: R=CH3, Ar=3-MeC6H4; 6g: R=Ph, Ar=3-
MeC6H4; 6h: R=Ph, Ar=4-EtC6H4; 6i: R=CH3, Ar=4-MeC6H4; 6j: R=4-BrC6H4, Ar=4-ClC6H4;
6k: R=4-BrC6H4, Ar=4-BrC6H4; 6l: R=4-BrC6H4, Ar=4-MeC6H4; 6m: R=4-BrC6H4, Ar=3-
ClC6H4
1
The structures of the products were deduced from their IR, H, 13C NMR and
Mass (Mass spectra were obtained only for the 6a and 6b) spectra. For
example the ¹H NMR spectrum of 6a consisted of two singlet for the 3 CH3
(δ=1.85 and 2.33 ppm), a broad singlet for the OH (δ= 4.36), an AB-quartet
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for CH2 aliphatic at δ=4.65 and 4.71 ppm (J = 11.50 Hz) and a multiplet at δ
= 7.12-7.99 ppm for the aromatic H. The aryl groups exhibited characteristic
signals in the aromatic region of the spectrum. The 1H decoupled 13C NMR
spectrum of 6a showed 15 distinct resonances; partial assignment of these
resonances is given in the experimental section. The 1H and 13C NMR spectra
of compounds 6b–m were similar to those of 6a, except for the aromatic and
aliphatic
moieties,
which
exhibited
characteristic
signals
with
appropriate
chemical shifts.31
The suggested mechanism for the formation of products 6a-m is presented in Scheme 2.
On the basis of the chemistry of isocyanides, it is reasonable to assume that the first step may
involve nucleophilic addition of the N-isocyanimino-triphenylphosphorane 5 to the ester
derivative of 2-oxopropyl alcohol 3, which is facilitated by its protonation with the acid, leading
to nitrilium intermediate 8. This intermediate may be attacked by the conjugate base of the acid
to form 1:1:1 adduct 9. This adduct may undergo and intramolecular aza-Wittig reaction of the
iminophosphorane moiety with the ester carbonyl to afford the isolated sterically congested
1,3,4-oxadiazoles derivatives 6 by removal of triphenylphosphine oxide 7 from intermediate
10.31
EXPERIMENTAL
The
N-isocyanimino-triphenylphosphorane
(Ph3PNNC)
5
was
prepared based on
a
reported procedure.32 Ester derivatives of 2-oxopropyl
alcohol
3
(2-oxopropyl
acetate) were
4-bromobenzoate,
2-oxopropyl
on known
benzoate,
and
2-
oxopropyl
prepared
based
procedures.33 Other
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starting materials and solvents were obtained from Merck (Germany) and
Fluka (Switzerland) and were used without further purification. The progress
of
the
reaction
Melting
was
points
monitored
were
by
thin
layer
on
chromatography
Electrothermal
(TLC)
9100
technique.
measured
an
apparatus and are uncorrected. IR spectra were measured on a Jasco 6300 FT-
IR spectrometer. 1H and 13C NMR spectra were measured (CDCl3 solution)
with
a
BRUKER DRX-250 Avance spectrometer at 250.0 and 62.5 MHz,
FINNIGAN-MATT 8430 mass
respectively. Mass spectra were recorded on
a
spectrometer operating at an ionization potential of 20 eV. Preparative layer
chromatography (PLC) plates were prepared from Merck silica gel (F254)
powder.
General procedure for the preparation of sterically congested 1,3,4-oxadiazoles (6a-m) in
water
A mixture of N-isocyanimino-triphenylphosphorane (1 mmol, 0.302 g), ester derivative
of 2-oxopropyl alcohol (2-oxopropyl benzoate, 2-oxopropyl 4-bromobenzoate and 2-oxopropyl
acetate) (1 mmol; 0.116 g (R=CH3), 0.178 g (R=Ph) and 0.257 g (R=4-BrC6H4)) and carboxylic
acid (1 mmol; 0.150 g (Ar=3,5-diMeC6H4), 0.136 g (Ar=4-MeC6H4), 0.150 g (Ar=3,4-
diMeC6H4), 0.157 g (Ar=4-ClC6H4), 0.201 g (Ar=4-BrC6H4), 0.136 g (Ar=3-MeC6H4), 0.150 g
(Ar=4-EtC6H4) and 0.157 g (Ar=3-ClC6H4)) in water (5 mL) was stirred at room temperature for
60 min. After the completion of the reaction, the product was extracted in dichloromethane. The
solvent was removed under reduced pressure, and the viscous residue was purified by preparative
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layer chromatography (PLC) (silica gel (F254) powder; petroleum ether-ethyl acetate (4:1). The
characterization data of the compounds (6a-m) are given below:
2-[5-(3,5-Dimethylphenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxypropyl benzoate (6a)
1
Yellow oil; Yield 85%; IR (neat): 3490 (s), 1725 (s), 1274 (s), 714 (m) cm-1. H NMR
(250 MHz, CDCl3): δ= 1.85 and 2.33 (2 s, 9H, 3CH3), 4.36 (br s, 1H, OH), 4.65, 4.71 (AB
quartet, J = 11.50 Hz, 2H, CH2 aliphatic), 7.12-7.99 (m, 8H, H-Ar). 13C NMR (62.5 MHz,
CDCl3): δ 21.16, 23.53 (3CH3), 69.82 (C aliphatic), 70.35 (CH2 aliphatic), 123.09, 129.18,
138.77 (4C arom), 124.68, 128.44, 129.77, 133.42, 133.69 (8CH arom), 165.74, 166.19 (2C of
oxadiazole), 167.76 (C of benzoate group). EI ms: m/z: 352 (M+), 217 (13.55), 167 (17.47), 149
(85.35), 132 (23.59), 104 (100), 91 (33.43), 77 (72.80), 43 (91.28).
2-Hydroxy-2-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]propyl benzoate (6b)
White crystals; Yield 87%; m. p.; 115.6-116.9 °C, IR (KBr): 3317 (s), 2954 (m), 1728
1
(s), 1500 (m), 1282 (s), 711 (m) cm-1. H NMR (250 MHz, CDCl3): δ 1.84 and 2.41 (2 s, 6H,
2CH3), 4.0 (br s, 1H, OH), 4.63, 4.72 (AB quartet, J = 11.37 Hz, 2H, CH2 aliphatic), 7.29-7.99
(m, 9H, H-Ar). 13C NMR (62.5 MHz, CDCl3): δ 21.69, 23.51 (2CH3), 69.83 (C aliphatic), 70.43
(CH2 aliphatic), 120.59, 129.10, 142.62 (3C arom), 126.95, 128.49, 129.78, 129.81, 133.50 (9CH
arom), 165.64, 166.15 (2C of oxadiazole), 167.75 (C of benzoate group). EI ms: m/z: 338 (M+),
203 (18.08), 166 (83.81), 149 (64.30), 122 (31.18), 105 (72.16), 91 (27.54), 77 (72.66), 57
(62.76), 43 (100).
2-[5-(3,4-Dimethylphenyl)-1,3,4-oxadiazol-2-yl]- 2-hydroxypropyl benzoate (6c)
Yellow oil; Yield 83%; IR (neat): 3450 (s), 2953 (m), 1726 (s), 1453 (m), 1274 (s), 713
1
(m) cm-1. H NMR (250 MHz, CDCl3): δ 1.84, 2.28 and 2.30 (3 s, 9H, 3CH3), 4.22 (br s, 1H,
8
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13
OH), 4.64, 4.71 (AB quartet, J = 11.37 Hz, 2H, CH2 aliphatic), 7.19-7.99 (m, 8H, H-Ar). C
NMR (62.5 MHz, CDCl3): δ 19.69, 20.02, 23.52 (3CH3), 69.83 (C aliphatic), 70.38 (CH2
aliphatic), 120.83, 129.15, 137.55, 141.33 (4C arom), 124.51, 127.92, 128.46, 129.78, 130.24,
130.44 (8CH arom), 165.72, 166.20 (2C of oxadiazole), 167.57 (C of benzoate group).
2-[5-(4- Chlorophenyl)-1,3,4-oxadiazol-2-yl]- 2-hydroxypropyl benzoate (6d)
White crystals; Yield 85%; m. p.; 123.3-124.7 °C, IR (KBr): 3397 (s), 2953 (m), 1726
1
(s), 1607 (m), 1486 (m), 1281 (s), 708 (m) cm-1. H NMR (250 MHz, CDCl3): δ 1.84 (s, 3H,
CH3), 3.87 (br s, 1H, OH), 4.64, 4.72 (AB quartet, J = 11.37 Hz, 2H, CH2 aliphatic), 7.30-7.98
13
(m, 9H, H-Ar). C NMR (62.5 MHz, CDCl3): δ 23.52, (CH3), 69.75 (C aliphatic), 70.45 (CH2
aliphatic), 121.86, 129.04, 138.29 (3C arom), 128.26, 128.51, 129.44, 129.76, 133.57 (9CH
arom), 165.66, 166.22 (2C of oxadiazole), 167.98 (C of benzoate group).
2-[5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl]- 2-hydroxypropyl benzoate (6e)
White crystals; Yield 84%; m. p.; 138.1-139.8 °C, IR (KBr): 3377 (s), 2954 (m), 1725
1
(s), 1601 (m), 1281 (s), 1081 (m), 709 (m) cm-1. H NMR (250 MHz, CDCl3): δ 1.84 (s, 3H,
CH3), 3.87 (br s, 1H, OH), 4.64, 4.72 (AB quartet, J = 11.37 Hz, 2H, CH2 aliphatic), 7.30-7.98
13
(m, 9H, H-Ar). C NMR (62.5 MHz, CDCl3): δ 23.52, (CH3), 69.74 (C aliphatic), 70.45 (CH2
aliphatic), 122.29, 126.76, 129.15 (3C arom), 128.38, 128.51, 129.76, 132.40, 133.57 (9CH
arom), 165.64, 166.75 (2C of oxadiazole), 168.79 (C of benzoate group).
2-Hydroxy-2-[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]propyl acetate (6f)
Yellow oil; Yield 85%; IR (neat): 3491 (s), 2967 (m), 1748 (s), 1555 (m), 1246 (s), 1052
(m), 722 (m) cm-1. 1H NMR (250 MHz, CDCl3): δ 1.75, 2.06 and 2.42 (3 s, 9H, 3CH3), 4.11 (br
9
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s, 1H, OH), 4.36, 4.54 (AB quartet, J = 11.50 Hz, 2H, CH2 aliphatic), 7.36-7.85 (m, 4H, H-Ar).
13C NMR (62.5 MHz, CDCl3): δ 20.76, 21.35, 23.47 (3CH3), 69.28 (C aliphatic), 70.21 (CH2
aliphatic), 123.24, 139.03 (2C arom), 124.15, 127.50, 129.02, 132.87 (4CH arom), 165.56,
167.72 (2C of oxadiazole), 170.80 (C of acetate group).
2-Hydroxy-2-[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]propyl benzoate (6g)
Yellow oil; Yield 87%; IR (neat): 3327 (s), 2964 (m), 1726 (s), 1448 (m), 1255 (s), 710
1
(m) cm-1. H NMR (250 MHz, CDCl3): δ 1.84 and 2.37 (2 s, 6H, 2CH3), 4.20 (br s, 1H, OH),
4.65, 4.71 (AB quartet, J = 11.87 Hz, 2H, CH2 aliphatic), 7.32-7.98 (m, 9H, H-Ar). 13C NMR
(62.5 MHz, CDCl3): δ 21.28, 23.53 (2CH3), 69.81 (C aliphatic), 70.37 (CH2 aliphatic), 123.22,
129.16, 138.93 (3C arom), 124.15, 127.47, 128.45, 128.93, 129.77, 132.78, 133.43 (9CH arom),
165.59, 166.19 (2C of oxadiazole), 167.89 (C of benzoate group).
2-[5-(4-Ethylphenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxypropyl benzoate (6h)
White crystals, Yield 87%; m. p.; 240.1-241.3 °C, IR (KBr): 3369 (s), 2977 (m), 1725
(s), 1282 (s), 1084 (m), 706 (m) cm-1. 1H NMR (250 MHz, CDCl3): δ 1.25 (t, J=7.2 Hz, 3H, CH3
of Et), 1.84 (s, 3H, CH3), 2.69 (q, J= 7.2 Hz, 2H, CH2 of Et), 4.18 (br s, 1H, OH), 4.64, 4.71 (AB
quartet, 2H, J=11.50 Hz, CH2 aliphatic), 7.29-7.98 (m, 9H, H-Ar). 13C NMR (62.5 MHz, CDCl3):
δ 15.16, 23.52 (2CH3), 28.89 (CH2 of Et), 69.79 (C aliphatic), 70.38 (CH2 aliphatic), 120.86,
129.23, 148.75 (3C arom), 127.07, 128.42, 128.53, 129.75, 133.36 (9CH arom), 165.59, 166.16
(2C of oxadiazole), 167.66 (C of benzoate group).
2-Hydroxy-2-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]propyl acetate (6i)
Yellow oil, Yield 86%; IR (neat): 3473 (s), 1748 (s), 1501 (m), 1255 (s), 1052 (m), 727
1
(m) cm-1. H NMR (250 MHz, CDCl3): δ 1.74, 2.05 and 2.42 (3 s, 9H, 3CH3), 4.11 (br s, 1H,
10
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OH), 4.36, 4.53 (AB quartet, J =11.12 Hz, 2H, CH2 aliphatic), 7.29 (d, J = 7.75 Hz, 2H, H-Ar),
7.91 (d, J = 7.75 Hz, 2H, H-Ar). 13C NMR (62.5 MHz, CDCl3): δ 20.76, 21.70, 23.47 (3CH3),
69.27 (C aliphatic), 70.16 (CH2 aliphatic), 120.60, 142.66 (2C arom), 126.95, 129.80 (4CH
arom), 165.54, 167.55 (2C of oxadiazole), 170.79 (C of acetate group).
2-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxypropyl-4-bromobenzoate (6j)
White crystals; Yield 83%; m. p.; 168.3-169.8 °C, IR (KBr): 3386 (s), 1725 (s), 1621
1
(m), 1467 (m), 1256 (s), 711 (m) cm-1. H NMR (250 MHz, CDCl3): δ 1.83 (s, 3H, CH3), 3.30
(br s, 1H, OH), 4.62, 4.72 (AB quartet, J = 11.12 Hz, 2H, CH2 aliphatic), 7.47 (d, J = 7.75 Hz,
2H, H-Ar), 7.53 (d, J = 7.87 Hz, 2H, H-Ar), 7.82 (d, J = 7.75 Hz, 2H, H-Ar), 7.95 (d, J = 7.87
13
Hz, 2H, H-Ar). C NMR (62.5 MHz, CDCl3): δ 23.86 (CH3), 69.07 (C aliphatic), 69.60 (CH2
aliphatic), 122.51, 127.73, 128.14, 137.29 (4C arom), 128.79, 130.11, 131.69, 132.39 (8CH
arom), 163.94, 165.02 (2C of oxadiazole), 168.81 (C of 4-bromobenzoate group).
2-[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxypropyl-4-bromobenzoate (6k)
White crystals; Yield 82%; m. p.; 173.4-174.7 °C, IR (KBr): 3352 (s), 2991 (m), 1727
1
(s), 1556 (m), 1487 (m), 1266 (s), 714 (m) cm-1. H NMR (250 MHz, CDCl3): δ 1.83 (s, 3H,
CH3), 3.61 (br s, 1H, OH), 4.63, 4.72 (AB quartet, J = 11.37 Hz, 2H, CH2 aliphatic), 7.55 (d, J =
8.50 Hz, 2H, H-Ar), 7.67 (d, J = 8.50 Hz, 2H, H-Ar), 7.83 (d, J = 8.50 Hz, 2H, H-Ar), 7.88 (d, J
13
= 8.5 Hz, 2H, H-Ar). C NMR (62.5 MHz, CDCl3): δ 23.85 (CH3), 69.06 (C aliphatic), 69.58
(CH2 aliphatic), 122.82, 126.21, 128.15, 138.12 (4C arom), 128.90, 131.69, 132.39, 133.02 (8CH
arom), 164.06, 165.02 (2C of oxadiazole), 168.81 (C of 4-bromobenzoate group).
2-Hydroxy-2-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]propyl-4-bromobenzoate (6l)
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White crystals; Yield 86%; m. p.; 154.3-155.6 °C, IR (KBr): 3324 (s), 2959 (m), 1725
1
(s), 1510 (m), 1286 (s), 714 (m) cm-1. H NMR (250 MHz, CDCl3): δ 1.70 and 2.36 (2 s, 6H,
2CH3), 4.26 (br s, 1H, OH), 4.51, 4.60 (AB quartet, J = 11.12 Hz, 2H, CH2 aliphatic), 7.10-7.85
(m, 8H, H-Ar). 13C NMR (62.5 MHz, CDCl3): δ 21.58, 23.88 (2CH3), 68.99 (C aliphatic),
69.61(CH2 aliphatic), 120.88, 128.13, 128.87, 142.71 (4C arom), 126.92, 130.43, 131.69, 132.38
(8CH arom), 164.75, 165.01 (2C of oxadiazole), 168.35 (C of 4-bromobenzoate group).
2-[5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxypropyl-4-bromobenzoate (6m)
White crystals; Yield 87%; m. p.; 164.3-165.6 °C, IR (KBr): 3391 (s), 1726 (s), 1634
1
(m), 1550 (m), 1464 (m), 1256 (s), 710 (m) cm-1. H NMR (250 MHz, CDCl3): δ 1.84 (s, 3H,
CH3), 3.36 (br s, 1H, OH), 4.63, 4.71 (AB quartet, J = 11.37 Hz, 2H, CH2 aliphatic), 7.39-7.95
13
(m, 8H, H-Ar). C NMR (62.5 MHz, CDCl3): δ 23.51 (CH3), 69.86 (C aliphatic), 70.45 (CH2
aliphatic), 124.95, 127.95, 128.81, 135.24 (4C arom), 125.08, 126.92, 130.47, 131.22, 131.90,
132.11 (8CH arom), 164.35, 165.47 (2C of oxadiazole), 168.06 (C of 4-bromobenzoate group).
CONCLUSION
In summary, we have developed an efficient environmentally friendly protocol for the synthesis
of 1,3,4-oxadiazoles via
a
one-pot, three-component reaction of N-isocyanimino-
triphenylphosphorane, aromatic carboxylic acids and ester derivatives of 2-oxopropyl alcohol (2-
oxopropyl benzoate, 2-oxopropyl-4-bromobenzoate and 2-oxopropyl acetate) in water at room
temperature. The remarkable features of this “green” methodology include good yield of
products, inexpensive and non-toxic solvent, simple procedure, environmental friendliness and
the absence of any volatile or poisonous organic solvents.
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Table 1 Effect of different solvents for the synthesis of 6a at room temperature a
Entry
Solvent
DMF
Time (min)
Yield (%) b
150
150
90
60
53
81
55
87
85
1
2
3
4
5
6
THF
CH3CN
EtOH
150
60
CH2Cl2
Water
60
a
Reaction conditions: 3a (1 mmol), 4a (1 mmol) and 5 (1 mmol) in 5 mL solvent at room
temperature
b Isolated yield
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O
O
O
DMF, 100 oC, 21 h
CH3
+
H3C
CH2Cl
R
O Na
R
O
2
1
O
3
C
N
O
N
N
N
Ar
H2O
3
+
ArCO2H +
O
R
O
+ Ph3PO
r.t., 1 h
4
OH
7
PPh3
6a-m
5
Scheme 1 Synthesis of ester derivatives of 2-oxopropyl alcohol 3 (2-oxopropyl 4-
bromobenzoate, 2-oxopropyl benzoate and 2-oxopropyl acetate) and three-component synthesis
of disubstituted 1,3,4-oxadiazoles 6a-m in water (See Experimental part).
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O
HO
CH3
H3C
O
O
+
HO
Ar
Ph3P
N
N
C
_
C
4
+
O
Ph3P
N
N
O
R
_
O
5
O
R
Ar
O
3
8
+
Ph3P
CH3
OH
Ph3P
N
H3C
N
N
N
N
N
_
O
OH
O
Ph3PO
CH3
OH
+
O
O
Ar
O
O
Ar
O
7
Ar
O
O
R
6
R
O
O
R
9
10
Scheme 2 Proposed mechanism for the formation of disubstituted 1,3,4-oxadiazoles 6a-m in
water.
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