Three-component reaction of N-isocyaniminotriphenylphosphorane (Ph 3PNNC), biacetyl, and a carboxylic acid in water

Article abstract of DOI:10.1080/10426507.2015.1091826

Reaction of N-isocyaniminotriphenylphosphorane with biacetyl in the presence of a carboxylic acid in water proceeds smoothly at RT (20-26°C) and neutral conditions to afford sterically congested 1,3,4-oxadiazole derivatives in high yields. The reaction pr

Full text of DOI:10.1080/10426507.2015.1091826

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
THREE-COMPONENT REACTION OF N-
ISOCYANIMINOTRIPHENYLPHOSPHORANE
(Ph3PNNC), BIACETYL AND A CARBOXYLIC ACID IN
WATER
Ali Jafari, Ali Ramazani, Hamideh Ahankar, Pegah Azimzadeh Asiabi, Fariba
Sadri & Sang Woo Joo
To cite this article: Ali Jafari, Ali Ramazani, Hamideh Ahankar, Pegah Azimzadeh
Asiabi, Fariba Sadri & Sang Woo Joo (2016): THREE-COMPONENT REACTION OF N-
ISOCYANIMINOTRIPHENYLPHOSPHORANE (Ph3PNNC), BIACETYL AND A CARBOXYLIC
ACID IN WATER, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2015.1091826
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1091826
Accepted author version posted online: 08
Jan 2016.
Submit your article to this journal
Article views: 7
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gpss20
Download by: [University of California, San Diego]
Date: 13 January 2016, At: 19:45

ACCEPTED MANUSCRIPT
THREE-COMPONENT REACTION OF N-ISOCYANIMINOTRIPHENYLPHOSPHORANE
(Ph3PNNC), BIACETYL AND A CARBOXYLIC ACID IN WATER
Ali Jafari1, Ali Ramazani*,1, Hamideh Ahankar2, Pegah Azimzadeh Asiabi1, Fariba Sadri3 and
Sang Woo Joo4
1Department of Chemistry, University of Zanjan, P O Box 45195-313, Zanjan, Iran,
2Department of Chemistry, Abhar Branch, Islamic Azad University, P O Box 22, Abhar, Iran
3Department of Chemistry, Payame Noor University, P O BOX 19395-4697 Tehran, Iran
4School of Mechanical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of
Korea, E-mail: swjoo@yu.ac.kr
*Corresponding Author E-mail: aliramazani@gmail.com
Abstract
Reaction of N-isocyaniminotriphenylphosphorane with biacetyl in the presence of a carboxylic
acid in water proceeds smoothly at RT (20--26°C) and neutral conditions to afford sterically
congested 1,3,4-oxadiazole derivatives in high yields. The reaction proceeds smoothly and
clearly under mild conditions and no side reactions were observed.
C
N
N
O
O
OH
O
N
H2O
N
H3C
CH3
+
Ph3P=O
+
R
OH
+
H3C
r.t., 12 h
CH3
O
O
Ph3P
R
Keywords
1
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
N-isocyaniminotriphenylphosphorane (Ph3PNNC); water; 1,3,4-oxadiazoles; aza-Wittig reaction;
carboxylic acid.
2
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
INTRODUCTION
In recent years, a great attention has been focused on the use of water as green solvent in various
organic reactions because there has been increasing recognition that water is an attractive
medium for many organic reactions.1 The aqueous medium is safe, non-toxic, not inflammable,
environmentally friendly, readily available, and cheap compared to organic solvents. Also,
protection and deprotection processes in organic synthesis can be simplified in aqueous media.
Water-soluble compounds can be reacted directly without the need of derivatization.
Recently, multicomponent reactions (MCRs) have become an important and powerful tool
in modern synthetic chemistry, because these reactions increase the efficiency by combining
several operational steps without any isolation of intermediates or changes of the reaction
conditions.2 Therefore, this principle is highly efficient in terms of time as well as resources.3
Among the multicomponent reactions, the most important reactions are those based on
isocyanides. Isocyanides with their prominent roles in multicomponent reactions and synthesis of
heterocycles in organic chemistry have received much attention in recent decades. Isocyanide-
based multicomponent reactions (abbreviated to IMCRs by Ugi and Dömling) due to their
synthetic potential, their inherent atom efficiency, convergent nature, ease of implementation,
and molecular diversity, have attracted attention because of the advantages that they offer to the
field of combinatorial chemistry.3,4
In the past decade, the intramolecular version of the aza-Wittig-type reaction has attracted
much attention because it has exhibited high potential for the synthesis of a wide variety of
nitrogen heterocycles, which can be attributed to the rapid progress in the preparation of
3
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
functionalized iminophosphoranes.5 Nucleophilicity at the nitrogen is an important and essential
factor for applying these iminophosphoranes as aza-Wittig reagents. Iminophosphoranes
(phosphazenes) are very important reagents in synthetic organic chemistry, especially in C-C and
C-N bonds formation; synthesis of naturally occurring products, compounds with biological and
pharmacological activity.5,6 According to the presence of two functional groups in N-
isocyaniminotriphenylphosphorane, this reagent can play new and effective role in
multicomponent reactions for the preparation of heterocyclic compounds.7 Recently, several
synthetic methods have been reported for the preparation of N-
isocyaniminotriphenylphosphorane.8,9 There are several reports on the use of 3 in the synthesis of
metal complexes.8 However, the organic chemistry of N-isocyaniminotriphenylphosphorane 3
remains almost unexplored. N-isocyaniminotriphenylphosphorane 3 is expected to have a
synthetic potential because it forms a reaction system in which the iminophosphorane group can
react with a reagent having a carbonyl functionality.7,8 In continuation of our interest in the
synthesis of organophosphorus compounds10, we studied the synthetic chemistry of the N-
isocyaniminotriphenylphosphorane 3.7
1,3,4-Oxadiazoles have attracted interest in medicinal chemistry as surrogates of
carboxylic acids, esters, and carboxamides.11 They have a wide range of pharmaceutical and
biological activities including antimicrobial, anti-fungal, anti-inflammatory, antihypertensive,
analgesic, antibacterial, hypoglycemic, antimalarial, antitubercular, antimycobacterial and
antidepressive effects.11 Several methods have been reported for the synthesis of 1,3,4-
oxadiazoles. These protocols are multi-step in nature.12 As part of our ongoing program to
develop efficient and robust methods for the synthesis of heterocyclic compounds,13 we wish to
4
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
report the preparation of 1,3,4-oxadiazole derivatives 4a-s by a three-component condensation
reaction of biacetyl 2, N-isocyaniminotriphenylphosphorane 3 and a carboxylic acid 2 in
excellent yields under neutral conditions in water14 (Scheme 1).
RESULTS AND DISCUSSION
The sterically congested 2,5-disubstituted 1,3,4-oxadiazoles derivatives (4) were
synthesized via a one-pot three-component reaction of a carboxylic acid (1), biacetyl (2) and N-
isocyaniminotriphenylphosphorane (Ph3PNNC) (3) in water as a green solvent at RT (20--26°C)
in 12 h (Scheme 1). The N-isocyaniminotriphenylphosphorane (Ph3PNNC) 3 was prepared based
on reported procedure.8
We studied the synthesis of 1,3,4-oxadiazole 4a as a model reaction in several solvents
(Table 1). Isolated yield of the desired product (4a) was 95% when the reaction was carried out
in water as a solvent at RT (20--26°C) for 12 h (Table 1, entry 6). Consequently, water was
selected as the best reaction solvent. The results of this study are summarized in
One-pot three-component reaction of a carboxylic acid derivative (1 mmol) with biacetyl
(1 mmol) and N-isocyaniminotriphenylphosphorane (Ph3PNNC) (1 mmol) were investigated in
water at RT (20--26°C). The reaction proceeds smoothly and cleanly under mild conditions in
water that is considerable to be a green chemistry method. Products 4a-s are known and were
identified by comparing their physical and spectral data (mass spectral data, IR, 1H-NMR, and
13C-NMR spectroscopy) with those reported.15 A 13C-NMR spectrum and a 1H-NMR spectrum
are presented in the Figures 1 and 2. The E-stereochemistry of compounds 4m-p and 4r-s was
confirmed based on their H-H coupling constants (3JHH = 16.5-16.8 Hz).16
5
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
The proposed mechanism for the formation of product 4 is indicated in Scheme 2. On the
basis of the chemistry of isocyanides,17 it is reasonable to assume that the first step may involve
nucleophilic addition of the N-isocyaniminotriphenylphosphorane 3 to biacetyl 2, which
facilitates by its protonation with the acid 1, leading to the nitrilium intermediate 6. The
intermediate 6 may be attacked by the conjugate base of the acid 1 to form 1:1:1 adduct 7. The
adduct 7 may undergo an intramolecular aza-Wittig reaction15 of an iminophosphorane moiety
with the ester carbonyl group to afford the sterically congested 1,3,4-oxadiazole derivatives 4 by
removal of triphenylphosphine oxide 5 from the intermediate 8. (See Scheme 2).
EXPERIMENTAL
N-isocyaniminotriphenylphosphorane (Ph3PNNC) 3 was prepared based on reported
procedure.8 Other starting materials and solvents were obtained from Merck (Germany) and
Fluka (Switzerland) and were used without further purification. The progress of the reaction was
monitored by thin layer chromatography (TLC) technique. Melting points were measured on an
Electrothermal 9100 apparatus and are uncorrected. IR spectra were measured on a Jasco 6300
FT-IR spectrometer. 1H and 13C NMR spectra (CDCl3) were recorded on a BRUKER DRX-250
AVANCE spectrometer at 250.0 and 62.5MHz, respectively. Preparative layer chromatography
(PLC) plates were prepared from Merck silica gel (F254) powder. The Supplemental Materials
file contains sample 1H and 13C NMR spectra for products 4a-4s (Figures S 1 -- S 3*)
General Procedure for the synthesis of sterically congested 2,5-disubstituted 1,3,4-oxadiazoles
derivatives (4a-s)
6
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
A mixture of N-isocyaniminotriphenylphosphorane (1 mmol; 0.30 g), biacetyl (1 mmol;
0.1 mL) and a carboxylic acid (1 mmol; (1a: 0.122 g, 1b: 0.156 g, 1c: 0.201 g, 1d: 0.201 g, 1e:
0.201 g, 1f: 0.140 g, 1g: 0.140 g, 1h: 0.128 g, 1i: 0.136 g, 1j: 0.136 g, 1k: 0.172 g, 1l: 0.112 g,
1m: 0.162 g, 1n: 0.166 g, 1o: 0.182 g, 1p: 0.148 g, 1q: 0.162 g, 1r: 0.182 g, 1s: 0.178 g)) in H2O
(5 mL) was stirred at RT (20--26°C) for 12 h. The reaction mixture was extracted in
dichloromethane. The solvent was removed under reduced pressure, and the viscous residue was
purified by preparative layer chromatography (PLC) (silica gel powder, F254; petroleum ether-
ethyl acetate (4:1)). The characterization data16 of the compounds are given below:
3-Hydroxy-3-(5-phenyl-1,3,4-oxadiazol-2-yl)butan-2-one (4a, C12H12N2O3).
White crystals, yield 95%, mp: 104.1-106.0 ºC, 1H NMR (250.13 MHz, CDCl3) δ = 1.95 (s, 3H,
CH3), 2.36 (s, 3H, CH3CO), 4.69 (s, 1H, OH), 7.50--7.56 (m, 2CHarom of meta and CHarom of
para) and 8.05 (d, 3JHH = 6.5 Hz, 2CHarom of ortho) ppm. 13C NMR (62.53 MHz, CDCl3) δ =
23.25 (CH3), 23.71 (CH3CO), 75.73 (C-OH), 123.30 (1C of arom, ipso carbon), 127.11 (2CHarom
of ortho), 129.08 (2CHarom of meta), 132.13 (CHarom of para), 152.81, 152.84 (2C = N of
oxadiazole, C2 and C5), 204.56 (C = O) ppm. IR (KBr) (υmax, cm−1): 3230, 2986, 2848, 2360,
2344, 1725, 1608, 1482, 1293, 1155, 782.
3-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxybutan-2-one (4b, C12H11ClN2O3).
White crystals, yield 93%, mp: 111.8-113.3 ºC, 1H NMR (250.13 MHz, CDCl3) δ = 1.95 (s, 3H,
CH3), 2.37 (s, 3H, CH3CO), 4.69 (s, 1H, OH), 7.49 (2CHarom of ortho (H3 and H5), 3JHH = 8.5
Hz), 7.99 (2CHarom of ortho (H2 and H6), 3JHH = 8.5) ppm. 13C NMR (62.53 MHz, CDCl3) δ =
23.30 (CH3), 23.72 (CH3CO), 75.75 (C-OH), 121.75 (1C of arom, ipso carbon of C1), 128.38
7
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
and 129.50 (4CH of arom, C2, C3, C5 and C6), 138.50 (1C of arom, ipso carbon of C4), 164.98,
165.54 (2C = N of oxadiazole, C2 and C5), 204.44 (C = O) ppm. IR (KBr) (υmax, cm−1): 3427,
2929, 2857, 2382, 2346, 1729, 1607, 1486, 1282, 1151, 838.
3-[5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxybutan-2-one (4c, C12H11BrN2O3).
White crystals, yield 90%, mp: 117-120 ºC, 1H NMR (250.13 MHz, CDCl3) δ = 1.95 (s, 3H,
CH3), 2.37 (s, 3H, CH3CO), 4.68 (s, 1H, OH), 7.65 (2CHarom of ortho (H3 and H5), 3JHH = 8.5
Hz), 7.92 (2CHarom of ortho (H2 and H6), 3JHH = 8.5) ppm. 13C NMR (62.53 MHz, CDCl3) δ =
23.30 (CH3), 23.70 (CH3CO), 75.74 (C-OH), 122.20 (1C of arom, ipso carbon of C1), 126.95
(1C of arom, ipso carbon of C4), 128.49 and 132.46 (4CH of arom, C2, C3, C5 and C6), 165.07,
165.60 (2 C of oxadiazole, C2 and C5), 204.40 (C = O) ppm. IR (KBr) (υmax, cm−1): 3433 (OH),
2926, 2857, 2361, 2343, 1727, 1603, 1405, 1274, 1152, 835.
3-[5-(3-Bromophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxybutan-2-one (4d, C12H11BrN2O3).
White crystals, yield 90%, mp: 102-104 ºC, 1H NMR (250.13 MHz, CDCl3) δ = 1.95 (s, 3H,
CH3), 2.37 (s, 3H, CH3CO), 4.71 (s,1H, OH), 7.39 (t, 3JHH = 7.7Hz, 1CH of arom, H5), 7.68 (d,
3JHH = 7.7Hz, CH of arom, H4), 7.99 (d, 3JHH = 8.0Hz, CH of arom, H6), 8.19 (s, CH of arom,
H2) ppm. 13C NMR (62.53 MHz, CDCl3) δ = 23.30 (CH3), 23.72 (CH3CO), 75.76 (C-OH),
123.12 (1C of arom, ipso carbon of C1), 125.10 (1C of arom, ipso carbon of C3), 125.64, 129.93,
130.66 and 135.12 (4 CH of arom, C2, C4, C5 and C6), 164.46 and 165.76 (2 C of oxadiazole,
C2 and C5), 204.37 (C = O) ppm. IR (KBr) (υmax, cm−1): 3355, 2957, 2848, 2359, 2343, 1726,
1552, 1466, 1221, 1157, 805.
3-[5-(2-Bromophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxybutan-2-one (4e, C12H11BrN2O3).
8
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Colorless oil, yield 88%, 1H NMR (250.13 MHz, CDCl3) δ = 1.95 (s, 3H, CH3), 2.37 (s, 3H,
CH3CO), 4.65 (s, 1H, OH), 7.25--7.57 (m, 2CHarom, H4 and H5); 7.75 (d, 3JHH = 7.5 Hz, CH of
arom, H3); 7.91 (d, 3JHH = 7.3 Hz, CH of arom, H2) ppm. 13C NMR δ = 23.14 (CH3), 23.78
(CH3CO), 75.69 (C-OH), 121.78 (1C of arom, ipso carbon of C1), 127.23 (1C of arom, ipso
carbon of C3), 127.63, 131.78, 132.84, 134.51 (4CH of arom, C3, C4, C5 and C6), 164.71 and
165.94 (2 C of oxadiazole, C2 and C5), 204.29 (C = O) ppm. IR (Neat) (υmax, cm−1): 3419, 2937,
2855, 2346, 2344, 1729, 1569, 1457, 1270, 1140, 768.
3-[5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxybutan-2-one (4f, C12H11FN2O3).
Yellow powder, yield 95%, mp: 93-95 ºC, 1H NMR (250.13 MHz, CDCl3) δ = 1.95 (s, 3H, CH3),
2.37 (s, 3H, CH3CO), 4.68 (s, 1H, OH), 7.16--7.26 (m, 2 Harom), 8.03--8.09 (m, 2 H arom) ppm.
13C NMR (62.53 MHz, CDCl3) δ = 23.27 (Me), 23.71 (CH3CO), 75.73 (C-OH), 116.47 (d, 2JCF =
22.0Hz, 2 CH of arom, C3 and C5), 119.62 (d, 4JCF = 3.7 Hz, C1 of arom, ipso carbon), 129.45
(d, 3JCF = 9.4 Hz, 2 CH of arom, C2), 165.00 (d, 1JCF = 249.9 Hz, C1 of arom, ipso carbon),
164.97 and 165.47 (2 C of oxadiazole, C2 and C5), 204.51 (C = O) ppm. IR (KBr) (υmax, cm−1):
3327, 2962, 2862, 2371, 2345, 1729, 1611, 1501, 1465, 1290. 1148, 850.
3-[5-(3-Fluorophenyl)-1,3,4-oxadiazol-2-yl]-3-hydroxybutan-2-one (4g, C12H11FN2O3).
White crystals, yield 95%, mp: 81-83 ºC, 1H NMR (250.13 MHz, CDCl3) δ = 1.95 (s, 3H, CH3),
2.37 (s, 3H, CH3CO), 4.71 (s, 1H, OH), 7.22-7.29 (m, 1CHarom, C4); 7.45-7.54 (m, 1CHarom, C5);
7.73-7.77 (m, 1CHarom, C2); 7.83-7.86 (m, 1CHarom, C6) ppm. 13C NMR (62.53 MHz, CDCl3) δ =
23.25 (Me), 23.70 (CH3CO), 75.75 (C-OH), 114.17 (d, 2JCF = 24.3Hz, CH of arom, C4), 119.27
(d, 2JCF = 21.3Hz, CH of arom, C2), 122.88 (d, 4JCF = 3.1Hz, CH of arom, C6), 125.14 (d, 3JCF =
9
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
8.2Hz, C of arom, C1, ipso carbon), 130.96 (d, 3JCF = 8.2Hz, CH of arom, C5), 162.78 (d, 1JCF =
248.1Hz, C of arom, C3, ipso carbon), 164.79 and 165.73 (2C = N of oxadiazole, C2 and C5),
204.37 (C = O) ppm. IR (KBr) (υmax, cm−1): 3422, 2927, 2857, 2359, 2343, 1725, 1596, 1470,
1268, 1121, 869.
3-Hydroxy-3-[5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl]butan-2-one (4h, C10H10N2O3S).
White crystals, yield 88%, mp: 70-72 ºC, 1H NMR (250.13 MHz, CDCl3) δ = 1.92 (s, 3H, CH3),
2.35 (s, 3H, CH3CO), 4.80 (s, 1H,OH), 7.11--7.19 (m, 1CHthiophene, C4), 7.56 (d, 3JHH = 4.7 Hz,
1CHthiophene, C5), 7.75 (d, 3JHH = 3.2Hz, 1CH thiophene, C3) ppm. 13C NMR (62.53 MHz, CDCl3) δ
= 23.56, 24.08 (2 CH3), 76.05 (C-OH), 124.68 (1C of thiophene, C2, ipso carbon), 128.54,
130.85, 131.12 (3 CH of thiophene, C3, C4 and C5), 162.30 and 165.20 (2 C = N of oxadiazole,
C2 and C5), 204.90 (C = O) ppm. IR (KBr) (υmax, cm−1): 3246, 2924, 1724, 1602, 1418, 1353,
727.
3-Hydroxy-3-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]butan-2-one (4i, C13H14N2O3).
Yellow powder, yield 89%, mp: 97-99 ºC; 1H NMR (250.13 MHz, CDCl3) δ = 1.92 (s, 3H, CH3),
2.34 (s, 3H, CH3), 2.39 (s, 3H, CH3), 4.91 (s, 1H, OH), 7.27 (d, 3JHH = 8.0Hz, 2 CHarom, H3 and
H5), 7.89 (d, 3JHH = 8.0Hz, 2 CHarom, H2 and H6) ppm. 13C NMR (62.53 MHz, CDCl3) δ = 21.93
(CH3), 23.52 (CH3), 24.10 (CH3), 76.10 (C-OH), 120.71 (1C of arom, C1, ipso carbon), 127.33
and 130.05 (4CH of arom, C2, C3, C5 and C6), 143.07 (1C of arom, C4, ipso carbon), 165.56,
166.17 (2 C = N of oxadiazole, C2 and C5), 205.13 (C = O) ppm. IR (KBr) (υmax, cm−1): 3422,
2921, 1728, 1612, 1498, 1362, 826.
3-Hydroxy-3-[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]butan-2-one (4j, C13H14N2O3).
10
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
White crystals, yield 88%, mp: 75-77 ºC, 1H NMR (250.13 MHz, CDCl3) δ = 1.92 (s, 3H, CH3),
2.35 (s, 3H, CH3), 2.39 (s, 3H, CH3), 4.92 (s, 1H,OH), 7.26--7.38 (m, 2 CHarom, C4 and C5),
7.75--7.89 (m, 2CHarom, C1 and C6) ppm. 13C NMR (62.53 MHz, CDCl3) δ = 21.53 (CH3), 23.51
(CH3), 24.10 (CH3), 76.12 (C-OH), 123.34 (1C of arom, C1, ipso carbon), 124.52, 127.83,
129.24 and 133.23 (4CH of arom, C2, C4, C5 and C6), 139.26 (1C of arom, C3, ipso carbon),
165.74 and 166.16 (2 C = N of oxadiazole, C2 and C5), 205.10 (C = O) ppm. IR (KBr) (υmax
,
cm−1): 3421, 2926, 1728, 1609, 1458, 1377, 806.
3-Hydroxy-3-[5-(naphthalene-2-yl)-1,3,4-oxadiazol-2-yl]butan-2-one (4k, C16H14N2O3).
White crystals, yield 86%, mp: 120-122 ºC, 1H NMR (250.13 MHz, CDCl3) δ = 1.99 (s, 3H,
CH3), 2.40 (s, 3H, CH3), 4.79 (s, 1H, OH), 7.54--7.61 (m, 2 CHarom, H6 and H7), 7.87--7.91 (m,
2 CHarom, H5 and H8), 7.95 (d, 3JHH = 8.6 Hz, 1CHarom, H3), 8.11 (d, 3JHH = 8.6 Hz, 1CHarom, H4),
8.54 (s, 1CHarom, H1) ppm. 13C NMR (62.53 MHz, CDCl3) δ = 23.67 (CH3), 24.13 (CH3), 76.18
(C-OH), 120.82 (1C of arom, C2, ipso carbon), 123.47, 127.55, 128.13, 128.31, 128.56, 129.24,
129.46 (7CH of arom, C1, C3, C4, C5, C6, C7 and C8), 133.07 and 135.19 (2 C of arom, C4a
and C8a), 165.83 and 166.30 (2C = N of oxadiazole, C2 and C5); 205.01 (C = O) ppm. IR (KBr)
(υmax, cm−1): 3448, 2923, 1725, 1577, 1458, 1362, 755.
3-[5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl]-3-hydroxybutan-2-one (4l, C10H10N2O4).
White crystals, yield 85%, mp: 100-101 ºC, 1H NMR (250.13 MHz, CDCl3) δ = 1.94 (s, 3H,
CH3), 2.35 (s, 3H, CH3), 4.66 (s, 1H, OH), 6.56--6.63 (m, 1CHfuran, H4), 7.19 (d, 3JHH = 3.2Hz,
1CHfuran, H3), 7.65 (s, CHfuran, H5) ppm. 13C NMR (62.53 MHz, CDCl3) δ = 23.64 (CH3), 24.02
(CH3), 76.02 (C-OH), 112.61 and 115.28 (2CH of furan, C3 and C4); 146.46 (1CH of furan, C5),
11
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
139.20 (1C of furan, C2, ipso carbon); 163.01 and 165.08 (2C = N of oxadiazole, C2 and C5),
204.62 (C = O) ppm. IR (KBr) (υmax, cm−1): 3423, 2924, 1722, 1636, 1458, 1370, 752.
3-Hydroxy-3-{5-[(E)-2-(4-methylphenyl)-1-ethenyl]-1,3,4-oxadiazol-2-yl}-2-butanone (4m,
C15H16N2O4).
White powder, yield 95%, m.p 125-127°C, 1H NMR (CDCl3, 250 MHz): δ = 1.92 (s, 3H, CH3),
2.35 (s, 3H, CH3), 2.38 (s, 3H, CH3), 4.70 (s, 1H, OH), 6.95 (d, 3JHH = 16.5 Hz, CH, olefinic
hydrogen, H2), 7.21 (d, 2H, 3JHH = 7.5 Hz, CHarom, H3 and H5), 7.43 (d, 2H, 3JHH = 7.5 Hz,
CHarom, H2 and H6), 7.53 (d, 3JHH = 16.5 Hz, CH, olefinic hydrogen, H1) ppm. 13C NMR (CDCl3,
62.5 MHz): δ = 21.47 (CH3), 23.24 (CH3), 23.75 (CH3), 75.72 (C-OH), 108.20 (1CH, olefinic
carbon, C1) and 140.20 (1CH, olefinic carbon, C2); 127.58 and 129.77 (4CH of arom, C2, C3,
C5 and C6), 131.71 (1C of arom, C1); 140.69 (1C of arom, C4); 164.67 and 165.56 (2C = N of
oxadiazole, C2 and C5); 204.65 (C = O) ppm. IR (KBr) (υmax, cm−1): 3298, 2998, 2918, 1723,
1644, 1532, 1363, 1180, 833.
3-{5-[(E)-2-(4-Fluorophenyl)-1-ethenyl]-1,3,4-oxadiazol-2-yl}-3-hydroxy-2-butanone (4n,
C14H13FN2O3).
White powder, yield 93%, m.p 84-86°C, 1H NMR (CDCl3, 250 MHz): δ = 1.87 (s, 3H, CH3),
2.35 (s, 3H, CH3), 4.70 (s, 1H, OH), 6.92 (d, 3JHH = 16.5 Hz, CH, olefinic hydrogen, H2), 7.01-
7.55 (m, 5H, 4 CHarom and 1 olefinic CH (H2)) ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 23.25
(CH3), 23.74 (CH3), 75.74 (C-OH), 109.02 (1CH, olefinic carbon, C1) and 138.89 (1CH, olefinic
carbon, C2); 116.22 (d, 2JCF = 28.3 Hz, 2 CH of arom, C3 and C5); 129.44 (d, 3JCF = 8.2 Hz, 2CH
of arom, C2 and C6), 130.70 (1C of arom, C1); 162.50 (d, 1JCF = 240.3 Hz, 1C of arom, C4);
12
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
164.85 and 165.22 (2C = N of oxadiazole, C2 and C5), 204.60 (C = O) ppm. IR (KBr) (υmax
,
cm−1): 3372, 2923, 1731, 1670, 1529, 1505, 1163, 818.
3-{5-[(E)-2-(4-Chlorophenyl)-1-ethenyl]-1,3,4-oxadiazol-2-yl}-3-hydroxy-2-butanone
(4o, C14H13ClN2O3).
White powder, yield 90%, m.p 148-150°C, 1H NMR (CDCl3, 250 MHz): δ = 1.92 (s, 3H, CH3),
2.35 (s, 3H, CH3), 4.67 (s, 1H, OH), 6.97 (d, 3JHH = 16.8 Hz, CH, olefinic hydrogen, H2), 7.25 -
7.54 (m, 5H, 4CHarom and 1 olefinic hydrogen H1) ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 23.26
(CH3), 23.72 (CH3), 75.72 (C-OH), 109.84 (1CH, olefinic carbon, C1) and 138.76 (1CH, olefinic
carbon, C2); 128.73 and 129.34 (4CH of arom, C2, C3, C5 and C6);132.90 (1C of arom, C1);
136.15 (1C of arom, C4); 164.85 and 165.12 (2C = N of oxadiazole, C2 and C5), 204.51 (C = O)
ppm. IR (KBr) (υmax, cm−1): 3363, 2921, 1726, 1648, 1523, 1406, 1152, 815.
3-Hydroxy-3-{5-[(E)-2-phenyl-1-ethenyl]-1,3,4-oxadiazol-2-yl}-2-butanone (4p,
C14H14N2O3).
White powder, yield 85%, m.p 79-81°C, 1H NMR (CDCl3, 250 MHz): δ = 1.93 (s, 3H, CH3),
2.36 (s, 3H, CH3), 4.69 (s, 1H, OH), 7.01 (d, 3JHH = 16.5 Hz, CH, olefinic hydrogen, H2), 7.40-
7.60 (m, 6H, 5CHarom and 1 olefinic hydrogen H1) ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 23.26
(CH3), 23.73 (CH3), 75.71 (C-OH), 109.28 (1CH, olefinic carbon, C1); 140.22 (1CH, olefinic
carbon, C2); 127.60 and 129.05 (4CH, ortho and meta carbons of Ph group); 130.24 (1CH, para
carbon of Ph group); 134.41 (1C of arom, ipso carbon, C1); 164.95 and 165.35 (2C = N of
13
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
oxadiazole, C2 and C5); 202.6 (C = O) ppm. IR (KBr) (υmax, cm−1): 3311, 2923, 1726, 1649,
1528, 1449, 1150, 759, 693.
3-Hydroxy-3-{5-[(E)-1-methyl-2-phenyl-1-ethenyl]-1,3,4-oxadiazol-2-yl}-2-butanone (4q,
C15H16N2O3).
Yellow viscous oil, yield 96%, 1H NMR (CDCl3, 250 MHz): δ = 1.93 (s, 3H, CH3), 2.36 (s, 3H,
CH3), 2.39 (s, 3H, CH3), 4.66 (s, 1H, OH), 7.36 -7.51 (m, 6H, 5CHarom and 1 olefinic hydrogen
H2) ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 14.56 (CH3), 23.25 (CH3), 23.75 (CH3), 75.75 (C-
OH), 128.52 and 129.59 (4CH, ortho and meta carbons of Ph group); 135.25 and 135.38 (2CH,
1CH of para carbon of Ph group and 1 CH of olefinic carbon, C2); 120.90 (1CH, olefinic carbon,
C1); 139.56 (1C of arom, ipso carbon, C1); 167.83 and 170.00 (2C = N of oxadiazole, C2 and
C5), 204.68 (C = O) ppm. IR (Neat) (υmax, cm−1): 3298, 2994, 2926, 1720, 1601, 1526, 1447,
1093, 713, 695.
3-{5-[(E)-2-(3-Chlorophenyl)-1-ethenyl]-1,3,4-oxadiazol-2-yl}-3-hydroxy-2-butanone
(4r, C14H13ClN2O3).
White powder, yield 86%, m.p 62-64°C, 1H NMR (CDCl3, 250 MHz): δ = 1.93 (s, 3H, CH3),
2.36 (s, 3H, CH3), 4.69 (s, 1H, OH), 7.01 (d, 3JHH = 16.5 Hz, = CH, olefinic hydrogen H2); 7.36 -
7.52 (m, 5H, CHarom and 1 olefinic hydrogen H1) ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 23.28
(CH3), 23.73 (CH3), 75.72 (C-OH), 110.71 (1CH, olefinic carbon, C1); 135.10 (1CH, olefinic
carbon, C2); 125.71, 127.41, 130.11 and 130.29 (4CH of arom, C2, C4, C5 and C6); 136.20 and
138.58 (2C of arom, ipso carbons, C1 and C3); 162.83 and 164.95 (2C = N of oxadiazole, C2
14
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
and C5), 204.87 (C = O) ppm. IR (KBr) (υmax, cm−1): 3274, 2923, 1728, 1650, 1528, 1426, 1110,
840, 789, 691.
3-Hydroxy-3-{5-[(E)-2-(3-methoxyphenyl)-1-ethenyl]-1,3,4-oxadiazol-2-yl}-2-butanone
(4s, C15H16N2O4).
White powder, yield 88%, m.p 70-72°C, 1H NMR (CDCl3, 250 MHz): δ = 1.93(s, 3H, CH3),,
2.35 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.73 (s, 1H, OH), 6.91-7.35 (m, 5H, 4CHarom and 1
olefinic hydrogen H2), 7.52 (d, 3JHH = 16.5 Hz, CH, olefinic hydrogen H1) ppm. 13C NMR
(CDCl3, 62.5 MHz): δ = 23.26 (CH3), 23.76 (CH3), 55.31 (OCH3), 75.75 (C-OH), 109.57 (1CH,
olefinic carbon, C1);140.12 (1CH, olefinic carbon, C2); 112.54 (1 CH, arom. C2), 116.05 (1 CH,
arom. C4), 120.25 (1 CH, arom. C6), 130.04 (1 CH, arom. C5); 135.77 (C of arom, ipso carbon,
C1); 159.98 (C of arom, ipso carbon, C3); 164.87 and 165.31 (2 C = N of oxadiazole, C2 and
C5), 204.61 (C = O) ppm. IR (KBr) (υmax, cm−1): 3236, 3004, 2922, 1730, 1650, 1580, 1466,
1108, 876, 795, 687.
CONCLUSION
An efficient green procedure for the synthesis of sterically congested 2,5-disubstituted
1,3,4-oxadiazoles (4)15 via a one-pot three-component reaction of a carboxylic acid (1), biacetyl
(2) and N-isocyaniminotriphenylphosphorane (Ph3PNNC) (3) in water as a green reaction solvent
at RT (20--26°C) for 12 h has been developed. The remarkable features of this green
methodology include high yield of products, cheap and non-toxic solvent, short reaction time,
15
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
operational simplicity, environmentally benign and the absence of any volatile or hazardous
organic solvents.
ACKNOWLEDGEMENTS
This work is funded by the grant NRF-2015-002423 of the National Research Foundation of
Korea.
16
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
REFERENCES
[1] (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159--164. (b) Breslow, R.; Anastas, P. T. and
Williamson, T. C, Eds.; Oxford Press: New York, 1998, ch. 13. (c) DeSimone, J. M.; Gonsalves,
R.; Shenoy, S. Eur. J. Med. Chem. 2000, 35, 267-271. (d) Otto, S.; Engberts, J. B. F. N. Org.
Biomol. Chem. 2003, 1, 2809-2820. (e) Pirrung, M. C.; Sarma, K. D.; J. Am. Chem. Soc. 2004,
126, 444-445. (f) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K.
B. Angew. Chem. Int. Ed. 2005, 44, 3275-3279.
[2] (a) Zhu, J.; Bienayme, H. Eds.Wiley.Weinheim. 2005. (b) Henkel, B.; Sax, M.; Dmling, A.
Tetrahedron Lett. 2003, 44, 3679--3682. (c) Waller, R. W.; Diorazio, L. J.; Taylor, B. A.;
Motherwell, W. B.; Sheppard, T. D. Tetrahedron. 2010, 66, 6496-6507. (d) Yavari, I.; Hossaini,
Z.; Sabbaghan, M. Mol Divers. 2006, 10, 479-482. (f) Yavari, I.; Bayat, M. J.; Sirouspour, M.;
Souri, S. Tetrahedron. 2010, 66, 7995-7999. (g) Bayat, M.; Imanieh, H.; Zabarjad Shiraz, N.;
Shah Qavidel, M. Monatsh Chem. 2010, 141, 333-338. (h) Ramazani, A.; Ahmadi, Y.; Mahyari,
A. Synth. Commun. 2011, 41, 2273-2282. (i) Venkata, S.R, C.; Vedula Rajeswar, R. J. Sulfur
Chem. 2010, 31, 545-550. (j) Ramazani, A.; Mahyari, T. A.; Rouhani, M.; Rezaei, A.
Tetrahedron Lett. 2009, 50, 5625-5627. (k) Ramazani, A.; Rezaei, A.; Mahyari, A. T.; Rouhani,
M.; Khoobi, M. Helv. Chim. Acta 2010, 93, 2033--2036.
[3] Ramazani, A.; Mahyari, A. Helv. Chim. Acta 2010, 93, 2203--2209.
[4] (a) Kazemizadeh, A. R.; Ramazani, A. Arkivoc 2008, xv, 159-165. (b) Kazemizadeh, A. R.;
Ramazani, A. J. Braz. Chem. Soc. 2009, 20, 309-312.
17
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
[5] Palacios, F.; Aparicio, D.; Rubiales, G.; Alonso, C.; de los Santos, J. M. Curr. Org. Chem.
2009, 13, 810-828.
[6] (a)Palacios, F.; Retana, O.; Marigorta, E.; Rodriguez, M.; Pagalday, J. Tetrahedron 2003, 59,
2617-2623. (b) Huang, N.; Liang, Y.; Ding, M.; Fu, L.; He, H. Bioorg. Med. Chem. Lett. 2009,
19, 831-833.
[7](a) Ahankar, H.; Ramazani, A.; Ahmadi, Y. Phosphorus, Sulfur, Silicon Relat. Elem. 2014,
189, 914-923. (b) Souldozi, A.; Ramazani, A. Tetrahedron Lett. 2007, 48, 1549-1551. (c)
Ahankar, H.; Ramazani, A.; Amini, I.; Ahmadi, Y.; Souldozi, A. Heteroat. Chem. 2011, 22, 612-
616. (d) Javanbani, H.; Ramazani, A.; Joo, S. W.; Ahmadi, Y.; Azizkhani, V.; Azimzadeh
Asiabi, P. Iran. Chem. Commun. 2015, 3, 310-322. (e) Shajari, N.; Kazemizadeh, A. R.;
Ramazani, A. J. Serb. Chem. Soc. 2012, 77, 1175--1180. (f) Ramazani, A.; Souldozi, A. Arkivoc
2008, xvi, 235-242. (g) Ramazani, A.; Abdian, B.; Nasrabadi, F. Z.; Shajari, N.; Ranjdoost, Z.
Bull. Korean Chem. Soc. 2012, 33, 3701-3705. (h) Ramazani, A.; Zeinali Nasrabadi, F.; Karimi,
Z.; Rouhani, M. Bull. Korean Chem. Soc. 2011, 32, 2700-2704. (i) Ramazani, A.; Ahmadi, Y.;
Tarasi, R. Heteroat. Chem. 2011, 22, 79-84. (j) Ramazani, A.; Zeinali Nasrabadi, F.; Ahmadi, Y.
Helv. Chim. Acta 2011, 94, 1024-1029. (k) Ramazani, A.; Salmanpour, S.; Souldozi, A.
Phosphorus, Sulfur, Silicon Relat. Elem. 2010, 185, 97-102. (l) Ramazani, A.; Shajari, N.;
Tofangchi Mahyari, A.; Khoobi, M.; Ahmadi, Y.; Souldozi, A. Phosphorus, Sulfur, Silicon
Relat. Elem. 2010, 185, 2496-2502. (o) Ramazani, A.; Rouhani, M.; Zeinali Nasrabadi, F.;
Gouranlou, F. Phosphorus, Sulfur, Silicon Relat. Elem. 2015, 190, 20-28. (p) Rouhani, M.;
Ramazani, A.; Joo, S. W. Ultrason. Sonochem. 2015, 22, 391-396. (q) Rouhani, M.; Ramazani,
A.; Joo, S. W. Ultrason. Sonochem. 2014, 21, 262--267. (r) Ramazani, A.; Ahmadi, Y.; Karimi,
18
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Z; Rezaei, A. J. Heterocyclic Chem. 2012, 49, 1447-1451. (s) Valizadeh Holagh, M.;
Maharramov, A. M.; Allahverdiyev, M. A.; Ramazani, A.; Ahmadi, Y.; Souldozi, A. Turk. J.
Chem. 2012, 36, 179-188. (t) Ramazani, A.; Karimi, Z.; Souldozi, A.; Ahmadi, Y. Turk. J. Chem.
2012, 36, 81-91. (u) Ramazani, A.; Khoobi, M.; Torkaman, A.; Zeinali Nasrabadi, F.;
Forootanfar, H.; Shakibaie, M.; Jafari, M.; Ameri, A.; Emami, S.; Faramarzi, M. A.; Foroumadi,
A.; Shafiee, A. Eur. J. Med. Chem. 2014, 78, 151--156. (v) Ramazani, A.; Fattahi, N.; Rezaei,
A.; Zeinali Nasrabadi, F. Chemija 2012, 23, 255--261. (w) Ramazani, A.; Rezaei, A; Ahmadi, Y.
Phosphorus, Sulfur Silicon Relat. Elem. 2012, 187, 22--31. (x) Ramazani, A.; Zeinali Nasrabadi,
F.; Karimi, Z.; Rouhani, M. Synth. Commun., 2013, 43, 1818--1830. (y) Ramazani, A.; Souldozi,
A.; Ghadimi, R.; Ahmadi, Y.; Azizkhani, V.; Azimzadeh Asiabi, P. Org Chem: An Indian Journal
2015, 11, 229-233. (z) Ramazani, A.; Kalhor, R.; Rezaei, A; Karimi, Z. Heteroat. Chem. 2012,
23, 315-321.
[8] (a) Stolzenberg, H.; Weinberger, B.; Fehlhammer,W. P.; P¨uhlhofer, F. G.; Weiss, R. Eur. J.
Inorg. Chem. 2005, 21, 4263-4271. (b) Chiu, T.W.; Liu, Y. H.; Chi, K. M.; Wen,Y. S.; Lu, K. L.
Inorg. Chem. 2005, 44, 6425-6430.
[9] Ramazani, A.; Momeni-Movahhed, A.; Gouranlou, F. Phosphorus Sulfur Silicon Relat. Elem.
2002, 177, 903-907.
[10] (a) Pakravan, P.; Ramazani, A.; Noshiranzadeh, N.; Sedrpoushan, A. Phosphorus Sulfur
Silicon Relat. Elem. 2007, 182, 545-549. (b) Ramazani, A.; Rahimifard, M.; Souldozi, A.
Phosphorus Sulfur Silicon Relat. Elem. 2007, 182, 1-5. (c) Ramazani, A.; Rahimifard, M.;
Noshiranzadeh,N.; Souldozi, A. Phosphorus Sulfur Silicon Relat. Elem. 2007, 182, 413-417. (d)
Ramazani, A.; Noshiranzadeh, N.; Ghamkhari, A.; Ślepokura, K.; Lis, T. Helv. Chim. Acta 2008,
19
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
91, 2252-2261. (e) Ramazani, A.; Amini, I.; Massoudi, A. Phosphorus Sulfur Silicon Relat.
Elem. 2006, 181, 2225-2229.
[11] (a) Holla, B. S.; Gonsalves, R.; Shenoy, S. Eur. J. Med. Chem. 2000, 35, 267-271. (b) Chen,
Q.; Zhu, X. H.; Jiang, L. L.; Liu, Z.M.; Yang, G. F. Eur. J. Med. Chem. 2008, 43, 595-603. (c)
Amir, M.; Shikha, K. Eur. J. Med. Chem. 2004, 39, 535-545.
[12] (a) Baxendale, I. R.; Ley, S. V.; Martinelli, M. Tetrahedron 2005, 61, 5323-5349. (b)
Coppo, F. T.; Evans, K. A.; Graybill, T. L.; Burton, G. Tetrahedron Lett. 2004, 45, 3257-3260.
(c) Brain, C. T.; Paul, J. M.; Loong, Y.; Oakley, P. J. Tetrahedron Lett. 1999, 40, 3275-3278. (d)
Wang, Y.; Sauer, D. R.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 105-108.
[13] (a) Souldozi, A.; Ramazani, A.; Bouslimani, N.; Welter, R. Tetrahedron Lett. 2007, 48,
2617-2620. (b) Souldozi, A.; Ramazani, A. Phosphorus Sulfur Silicon Relat. Elem. 2009, 184,
3191-3198. (c) Souldozi, A.; Ramazani, A. Phosphorus Sulfur Silicon Relat. Elem. 2009, 184,
2344-2350. (d) Ramazani, A.; Nasrabadi, F. Z.; Abdian, B.; Rouhani, M. Bull. Korean Chem.
Soc. 2012, 33, 453-458. (e) Souldozi, A.; S´ lepokura, K.; Lis, T.; Ramazani, A. Z. Naturforsch.
2007, 62b, 835-840. (f) Ramazani, A.; Rezaei, A. Org. Lett. 2010, 12, 2852-2855. (g) Ramazani,
A.; Ahmadi, Y.; Rouhani, M.; Shajari, N.; Souldozi, A. Heteroatom Chem. 2010, 21, 368-372.
(h) Ramazani, A.; Nasrabadi, F. Z.; Malekzadeh, A. M.; Ahmadi, Y. Monatsh Chem. 2011, 142,
625-630. (i) Ramazani, A.; Ahmadi, Y.; Zeinali Nasrabadi, F. Z. Naturforsch. 2011, 66b, 184-
190. (j) Ramazani, A.; Shajari, N.; Mahyari, A.; Ahmadi, Y. Mol. Divers. 2011, 15, 521-527.
[14] (a) Sadri, F.; Ramazani, A.; Massoudi, A.; Khoobi, M.; Tarasi, R.; Shafiee, A.; Azizkhani,
V.; Dolatyari, L.; Joo, S. W. Green Chem. Lett. Rev. 2014, 7, 257--264. (b) Sadri, F.; Ramazani,
A.; Massoudi, A.; Khoobi, M.; Azizkhani, V.; Tarasi, R.; Dolatyari, L.; Min, B.-K. Bull. Korean
20
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Chem. Soc. 2014, 35, 2029-2032. (c) Vessally, E.; Ramazani, A.; Yaaghubi, E. Monatsh Chem
2011, 142, 1143--1147.
[15] (a) Ramazani, A.; Abdian, B.; Zeinali Nasrabadi, F.; Rouhani, M. Phosphorus Sulfur Silicon
Relat. 2013, 188, 642-648. (b) Ramazani, A.; Rouhani, M.; Rezaei, A.; Shajari, N.; Souldozi, A.
Helv. Chim. Acta. 2011, 92, 282-288.
[16] G. Hägele, personal communication, quoted from “Analysis of 1D NMR Spectra. A
Practical Approach to Simple and Complex Spectral Structures” by Gerhard Hägele and Michael
Engelhardt. August 19, 2015. Bruker Corporation, Rheinstetten, Germany. In press.
[17] Dömling, A.; Ugi, I. Angew. Chem. Int Ed Engl. 2000, 39, 3168-3210.
21
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Table 1 Solvent effect in the synthesis of the sterically congested 1,3,4-oxadiazole 4a
Entry Solvent
Time (h) Yield 4a(%) a, b
EtOH
24
24
24
26
24
15
63
72
85
44
52
95
1
2
3
4
5
6
MeOH
CH2Cl2
Toluene
CH3CN
Water
aReaction conditions: N-isocyaniminotriphenylphosphorane (1.0 mmol), biacetyl (1.0 mmol) and
benzoic acid (1.0 mmol) in solvent (5 mL) at RT (20--26°C).
bIsolated yields.
22
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Figure 1: 13C NMR spectrum of 4d
23
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Figure 2: 1H NMR spectrum of 4m
24
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
4
5
R
N
3
N
O
2
1
O
HO
H2O
CH3
RCO2H
1
+
Ph3P=O
5
N
C
Ph3P N
+
+ H2C
CH3
O
r.t, 12 h
O
2
CH3
4
3
Ar, Furan-2-yl, Naphtalen-2-yl, Thiophen-2-yl and (E)-ArC=C
R=
Scheme 1 Three-component synthesis of sterically congested 2,5-disubstituted 1,3,4-oxadiazoles
in water. 4a: R = C6H5; 4b: R = 4-ClC6H4; 4c: R = 4-BrC6H4; 4d: R = 3-BrC6H4; 4e: R = 2-
BrC6H4; 4f: R = 4-FC6H4; 4g: R = 3-FC6H4; 4h: R = Thiophen-2yl; 4i: R = 4-MeC6H4; 4j: R = 3-
MeC6H4; 4k: R = naphthalen-2-yl; 4l: R = furan-2-yl; 4m: R = 4-Me(E)-ArCH = CH; 4n: R = 4-
F(E)-ArCH = CH; 4o: R = 4-Cl(E)-ArCH = CH; 4p: R = (E)-ArCH = CH; 4q: R = (E)-ArCH =
CMe; 4r: R = 3-Cl(E)-ArCH = CH; 4s: R = 3-MeO(E)-ArCH = CH.
25
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
R
O
R
HO
2
O
O
O
H3C
PPh3
O
CH3
H3C
Ph3P
N
N
C
N
N
C
O
3
H3C
OH
6
2
PPh3
O
O
OH
N
O
N
OH
N
O
N
H3C
O
N
R
H3C
HO
N
H3C
O
R
H3C
+
Ph3P=O
5
CH3
O
O
CH3
R
8
7
PPh3
4
Scheme 2. The proposed mechanism for the formation of sterically congested 2,5-disubstituted
1,3,4-oxadiazole derivatives 4 in water.
26
ACCEPTED MANUSCRIPT