One-pot, four-component synthesis of fully substituted 1,3,4-oxadiazole derivatives from (Isocyanoimino)triphenylphosphorane, a primary amine, an aromatic carboxylic acid, and chloroacetone

Article abstract of DOI:10.1002/hlca.201000356

The 1:1 imine intermediate 7 generated by the addition of a primary amine 2 to chloroacetone (1) is trapped by (isocyanoimino)triphenylphosphorane (4) in the presence of an aromatic carboxylic acid 3 and leads to the formation of the corresponding iminoph

Full text of DOI:10.1002/hlca.201000356

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Helvetica Chimica Acta – Vol. 94 (2011)
One-Pot, Four-Component Synthesis of Fully Substituted 1,3,4-Oxadiazole
Derivatives from (Isocyanoimino)triphenylphosphorane, a Primary Amine,
an Aromatic Carboxylic Acid, and Chloroacetone
by Ali Ramazani*a), Fatemeh Zeinali Nasrabadia), and Yavar Ahmadib)
a) Chemistry Department, Zanjan University, P.O. Box 45195-313, Zanjan, Iran
(phone: þ 98-241-5152572; fax: þ 98-241-5152477; e-mail: aliramazani@yahoo.com)
b) Young Researchers Club, Zanjan Branch, Islamic Azad University, Zanjan, Iran
The 1:1 imine intermediate 7 generated by the addition of a primary amine 2 to chloroacetone (1) is
trapped by (isocyanoimino)triphenylphosphorane (4) in the presence of an aromatic carboxylic acid 3
and leads to the formation of the corresponding iminophosphorane intermediate 9 (Scheme 2). The 1,3,4-
oxadiazole derivatives 5 are then formed via an intramolecular aza-Wittig reaction of the iminophos-
phorane intermediate 9. The reactions were completed under neutral conditions at room temperature.
The fully substituted 1,3,4-oxadiazole derivatives 5 were produced in high yields (Table).
Introduction. – In recent years, several synthetic methods have been reported for
the preparation of (isocyanoimino)triphenylphosphorane (¼ N-(triphenylphosphora-
nylidene)isocyanamide; CNꢀN¼PPh3; 4) [1][2]. There are several reports on the use of
4 in the synthesis of metal complexes [1][2]. However, application of 4 in the synthesis
of organic compounds is fairly rare [3 – 13]. As part of our ongoing program to develop
efficient and robust methods for the preparation of organic compounds [14 – 28], we
sought to develop a convenient preparation of fully substituted 1,3,4-oxadiazole
derivatives 5a – 5q. Herein, we report a four-component reaction, which, starting from
readily available chloroacetone (1), affords fully substituted 1,3,4-oxadiazole deriva-
tives 5a – 5q (Scheme 1).
Scheme 1. Four-Component Synthesis of 1,3,4-Oxadiazoles 5 (see Table)
Results and Discussion. – The 1:1 imine intermediate (¼ N-alkylideneamine
intermediate) generated by the condensation reaction of chloroacetone (1) with
primary amines 2 is trapped by 4 in the presence of aromatic carboxylic acids 3 and
leads to the formation of 1,3,4-oxadiazole derivatives 5 and Ph3P¼O (6; Scheme 1 and
Table). The reaction proceeds smoothly and cleanly under mild and neutral conditions,
and no side reactions were observed. The structures of the products were deduced from
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 94 (2011)
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Table. Synthesis of 2,5-Disubstituted 1,3,4-Oxadiazole Derivatives 5a – 5q from Chloroacetone (1), Primary
Amine 2, and Carboxylic Acid 3 in the Presence of (Isocyanoimino)triphenylphosphorane (4)
R
Ar
Product
Yield
[%]a)
M.p. [8] IRb) [cmꢀ1
]
Bn
Ph
5a 85
82 – 84 1608, 1449
Bn
Bn
Bn
Bn
4-BrꢀC6H4
4-MeOꢀC6H4
4-MeꢀC6H4
4-ClꢀC6H4
Ph
5b 87
99 – 101 1602, 1482
5c
77
oil
1616, 1496
1618, 1499
1608, 1486
1609, 1449
5d 78
70 – 72
80 – 82
71 – 73
5e 75
4-Methyl-
benzyl
5f
76
4-Methoxy- 4-BrꢀC6H4
5g 75
95 – 97
1605, 1478
benzyl
Bn
4-NCꢀC6H4
5h 75
oil
1656, 1494

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Helvetica Chimica Acta – Vol. 94 (2011)
Table (cont.)
R
Ar
Ph
Product
Yield M.p. [8] IRb) [cmꢀ1
]
[%]a)
2-Chlorobenzyl
5i
82
65 – 67
1609, 1475
Bn
3,4-Me2C6H3
5j
70
oil
1617, 1455
1612, 1499
1614, 1499
Bn
4-FꢀC6H4
5k 80
77 – 79
4-Fluorobenzyl
4-MeꢀC6H4
5l
70
oil
Furan-2-ylmethyl
4-ClꢀC6H4
2-BrꢀC6H4
5m 80
79 – 81
1609, 1485
Bn
5n 86
oil
1602, 1455
1612, 1471
3,4-Dichorobenzyl Ph
5o 85
73 – 75

Helvetica Chimica Acta – Vol. 94 (2011)
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Table (cont.)
R
Ar
Ph
Product
Yield
M.p. [8]
IRb) [cmꢀ1
1614, 1452
]
[%]a)
3-(Trifluoromethyl)-
benzyl
5p
5q
77
oil
Allyl
Ph
70
oil
1649, 1451
a) Yield of isolated 5. b) Two main absorptions in KBr.
their IR, 1H- and 13C-NMR, and mass spectra. For example, the 1H-NMR spectrum of
5a consisted of an AB pattern for the H-atoms of the CH2Cl group (d(H) 3.69 and 3.75
(2J(H,H) ¼ 12.0 Hz)), and a second AB pattern for the H-atoms of the PhCH2 group
(d(H) 3.96 and 4.07 (2J(H,H) ¼ 11.5 Hz)), a s for NH (d(H) 2.22), and a s for Me (d(H)
1.77). The Ar groups exhibited characteristic signals in the aromatic region of the
1
spectrum. The H-decoupled 13C-NMR spectrum of 5a showed 14 distinct signals;
1
partial assignment of these signals is given in the Exper. Part. The H- and 13C-NMR
spectra of compounds 5b – 5q were similar to those of 5a, except for the aromatic
moieties, which exhibited characteristic signals with appropriate chemical shifts.
A mechanistic pathway for the reaction is provided in Scheme 2. On the basis of the
chemistry of isocyanides, it is reasonable to assume that the first step may involve the
Scheme 2. Proposed Mechanism for the Formation of Sterically Congested 1,3,4-Oxadiazole Derivatives
5

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Helvetica Chimica Acta – Vol. 94 (2011)
formation of imine 7 by the condensation reaction of chloroacetone (1) with the
primary amine 2. The next step may involve nucleophilic addition of (isocyanoimino)-
triphenylphosphorane (4) to the imine intermediate 7, which is facilitated by its
protonation with the carboxylic acid 3, leading to nitrilium intermediate 8. This
intermediate may be attacked by the conjugate base of the carboxylic acid to form the
1:1:1 adduct 9. The intermediate 9 then undergoes an intramolecular aza-Wittig
reaction [3 – 13] of the iminophosphorane moiety with the ester C¼O group to afford
the isolated sterically congested 1,3,4-oxadiazole derivative 5 by removal of Ph3P¼O
(6) from intermediate 10.
We also used 1,1-dichloroacetone, 1,3-dichloroacetone, 2-chloroacetophenone, 2-
bromoacetophenone, trifluoroacetone, and 2,2-dichlorobutyrophenone instead of
chloroacetone 1 in this reaction, but no corresponding products 5 were observed. In
all the cases, several colored products were detected by TLC monitoring.
Conclusions. – We believe that the reported method offers a mild, simple, and
efficient route for the preparation of fully substituted 1,3,4-oxadiazol derivatives of
type 5. Ease of workup, high yields, and fairly mild reaction conditions make it a useful
addition to modern synthetic methodologies. Other aspects of this synthetic process are
under investigation.
This work was supported by the Zanjan University and the Iran National Science Foundation
(INSF).
Experimental Part
General. (Isocyanoimino)triphenylphosphorane (¼ N-triphenylphosphoranylidene)isocyanamide;
4) was prepared based on reported procedures [1][2]. Other starting materials and solvents were
obtained from Merck (Germany) and Fluka (Switzerland) and were used without further purification.
Reaction monitoring by TLC and NMR (no by-products formed). Prep. TLC: plates coated with Merck
silica gel F254 powder. M.p.: Electrothermal-9100 apparatus; uncorrected. IR Spectra: Jasco-6300 FT-IR
spectrometer; ˜n in cmꢀ1. 1H- and 13C-NMR Spectra (CDCl3): Bruker-DRX-250-Avance spectrometer; at
250.0 and 62.5 MHz, resp.; in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. MS: Finnigan-
Matt-8430 mass spectrometer operating at an ionization potential of 20 eV; in m/z (rel. %). Elemental
analyses: Heraeus CHN-O-Rapid analyzer.
General Procedure. To a magnetically stirred soln. of primary amine 2 (1 mmol), chloroacetone (1;
1 mmol), and (isocyanoimino)triphenylphosphorane (4; 1 mmol) in CH2Cl2 (5 ml) was added dropwise a
soln. of benzoic acid derivative 3 (1 mmol) in CH2Cl2 (5 ml) at r.t. over 15 min. The mixture was stirred
for 12 h. The solvent was evaporated and the viscous residue purified by prep. TLC (silica gel F254
,
petroleum ether/AcOEt 4 :1). Purified 5a – 5q were obtained as yellow powders or yellow oils. For yields,
m.p., and IR of 5a – 5q, see Table1).
N-Benzyl-N-[2-chloro-1-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amine (¼a-(Chloromethyl)-
a-methyl-5-phenyl-N-(phenylmethyl)-1,3,4-oxadiazol-2-methanamine; 5a): Yellow powder. IR (KBr):
3456, 3269, 2927, 1608, 1449, 1069. 1H-NMR (CDCl3): 1.77 (s, Me); 2.23 (s, NH); 3.69, 3.76 (AB, 2J ¼ 12.3,
2
CH2Cl); 3.96, 4.07 (AB, J ¼ 11.5, PhCH2); 7.24 – 8.07 (m, 10 arom H). 13C-NMR (CDCl3): 22.53 (Me);
47.82, 50.24. (2 CH2); 57.58 (CNH); 127.00, 127.31, 128.27, 128.51, 129.07, 131.8 (10 CH); 123.70, 139.33
(2 C); 165.24, 167.77 (2 C¼N). EI-MS: 327 (Mþ), 187 (16), 149 (33), 105 (70), 91 (100), 76 (29), 43 (54).
Anal. calc. for C18H18ClN3O (327.81): C 65.95, H 5.53, N 12.82; found: C 65.83, H 5.49 N 12.77.
1
)
Supplementary material (characterization data of 5b – 5q) may be obtained upon request from the
senior author A. R

Helvetica Chimica Acta – Vol. 94 (2011)
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Received September 16, 2010