The reaction of (N-isocyanimino) triphenylphosphorane with an electron-poor α-haloketone in the presence of aromatic carboxylic acids: A novel three-component reaction for the synthesis of disubstituted 1,3,4-oxadiazole derivatives

Article abstract of DOI:10.1002/hc.20626

Reactions of electron-poor α-haloketones with (N-isocyanimino) triphenylphosphorane in the presence of aromatic carboxylic acids proceed smoothly at room temperature and in neutral conditions to afford disubstituted 1,3,4-oxadiazole derivatives in high yi

Full text of DOI:10.1002/hc.20626

Heteroatom Chemistry
Volume 21, Number 6, 2010
The Reaction of (N-isocyanimino)
triphenylphosphorane with an Electron-poor
α-Haloketone in the Presence of Aromatic
Carboxylic Acids: A Novel Three-Component
Reaction for the Synthesis of Disubstituted
1,3,4-oxadiazole Derivatives
Ali Ramazani,1 Yavar Ahmadi,1 Morteza Rouhani,1 Nahid Shajari,1
and Ali Souldozi2
1Chemistry Department, Zanjan University, P.O. Box 45195-313, Zanjan, Iran
2Chemistry Department, Islamic Azad University–Urmia Branch, P.O. Box 969, Urmia, Iran
Received 16 March 2010; revised 9 June 2010
material. The development of novel MCRs is receiv-
ABSTRACT: Reactions of electron-poor α-
ing growing interest from industrial chemistry re-
haloketones with (N-isocyanimino) triphenylphos-
search groups and represents a challenge for organic
phorane in the presence of aromatic carboxylic acids
chemists [1,2]. The drive toward the ideal synthesis
proceed smoothly at room temperature and in neutral
embracing the step count, ideally just one, and yield,
conditions to afford disubstituted 1,3,4-oxadiazole
ideally 100%, has been pursued aggressively since
ꢀ
C
derivatives in high yields.
2010 Wiley Periodicals,
scientists began to construct molecules. Of course,
there are many other factors that affect these two
aspects of synthesis, including cost; starting mate-
rial availability; safety; environmental concerns; and
overall ease of the process, including work-up and
purification [3]. The nature of the synthesis project
also plays a role. Complex molecule total synthe-
sis is often driven by step count while showcasing
innovative chemistry. Traditional structure-activity
relationship evaluations in medicinal chemistry typ-
ically involve the preparation of an advanced inter-
mediate that can be analogued readily to introduce
the molecular diversity necessary to prepare a collec-
tion, or library, of structurally related compounds.
One strategy that potentially meets the goals of to-
tal synthesis and library production is MCR chem-
istry, in which three or more starting materials are
brought together in a highly convergent approach to
rapidly build up molecular structure and complexity
[4].
Inc. Heteroatom Chem 21:368–372, 2010; View this article
online at wileyonlinelibrary.com. DOI 10.1002/hc.20626
INTRODUCTION
Multicomponent reaction (MCR) is a chemical reac-
tion where three or more compounds react to form
a single product. By definition, MCRs are those re-
actions whereby more than two reactants combine
in a sequential manner to give highly selective prod-
ucts that retain majority of the atoms of the starting
Correspondence to: Ali Ramazani; e-mail: aliramazani@gmail
.com.
Contract grant sponsor: Zanjan University.
Contract grant sponsor: Iran National Science Foundation.
c
ꢀ
2010 Wiley Periodicals, Inc.
368

Reaction of (N-isocyanimino)triphenylphosphorane with an α-Haloketone 369
SCHEME 1 Three-component synthesis of disubstituted 1,3,4-oxadiazole derivatives 4 (Table 1).
1,3,4-Oxadiazoles have attracted interest in
medicinal chemistry as surrogates of carboxylic
acids, esters, and carboxamides. They are an im-
portant class of heterocyclic compounds that have
a wide range of pharmaceutical and biological ac-
tivities including antimicrobial, antifungal, anti-
inflammatory, and antihypertensive [5–9].
Several methods have been reported in the lit-
erature for the synthesis of 1,3,4-oxadiazoles. These
protocols are multistep in nature [10–15]. The most
general method involves the cyclization of dia-
cylhydrazides with a variety of reagents, such as
thionyl chloride, phosphorus oxychloride, or sulfu-
ric acid, usually under harsh reaction conditions.
Few reliable and operationally simple examples have
been reported for the one-step synthesis of 1,3,4-
oxadiazoles, especially from readily available car-
boxylic acids and acid hydrazides [16–21].
In recent years, several synthetic methods
have been reported for the preparation of (N-
isocyanimino)triphenylphosphorane (CNNPPh3) 3
[22–23]. There are several reports on the use of
(N-isocyanimino)triphenylphosphorane (CNNPPh3)
3 in the synthesis of metal complexes [22–23]. How-
ever, application of 3 in the synthesis of organic
compounds is fairly rare [24–31]. As part of our on-
going program to develop efficient and robust meth-
ods for the preparation of heterocyclic compounds
[24–31], we sought to develop a convenient prepa-
ration of disubstituted 1,3,4-oxadiazole derivatives
4a-k. Herein, we report a hitherto unknown, one-
pot, three-component reaction, which, starting from
readily available electron-poor α-haloketones 2, af-
fords disubstituted 1,3,4-oxadiazole derivatives 4a-k
(Scheme 1).
also used acetone 6a and acetophenone 6b instead
of electron-poor α-haloketones 2 in this reaction,
but no corresponding products 4 were observed. In
both the cases, 2-aryl-1,3,4-oxadiazoles 7 and triph-
enylphosphine oxide 5 were observed, as has been
previously reported [25], and the acetone 6a and ace-
tophenone 6b were recovered unreacted at the end
of reaction (Scheme 2). As indicated in Table 1, the
reactions proceeded efficiently with an electron-poor
ketone 2 and electron-rich ketones such as acetone
6a and acetophenone 6b are not suitable starting
materials in these reactions (Scheme 2).
The structures of the products were deduced
1
from their IR, Mass, H NMR, and 13C NMR spec-
tra. The mass spectra of these compounds displayed
molecular ion peaks at the appropriate m/z values.
1
The H NMR spectrum of 4a consisted of a singlet
for the CH3 (δ = 1.93), a hydroxy hydrogen atom
(δ = 4.51), exchangeable by D2O and two doublet
3
for the aromatic protons (δ = 7.50 and 7.99, JHH
=
8.5 Hz). The 1H decoupled 13C NMR spectrum of 4a
showed nine distinct resonances, partial assignment
of these resonances is given in the Experimental sec-
tion. The 1H and 13C NMR spectra of compounds 4b-
k were similar to those of 4a, except for the aromatic
and aliphatic moieties, which exhibited characteris-
tic signals with appropriate chemical shifts.
TABLE
1 Synthesis of Disubstituted 1,3,4-oxadiazole
Derivatives 4 (Scheme 1)
4
Ar
R1
R2
%Yielda,b
a
b
c
d
e
f
g
h
i
4-ClC6H4
3-ClC6H4
4-BrC6H4
3-FC6H4
C6H5
4-MeC6H4
3-MeOC6H4
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CH2Cl
CHCl2
CH2Cl
CH2Cl
85
83
84
85
85
87
88
84
85
88
87
RESULTS AND DISCUSSION
The carboxylic acid derivative 1 with electron-
poor α-haloketones 2 and (N-isocyanimino) triph-
enylphosphorane 3 in CH2Cl2 react together in a
1:1:1 ratio at room temperature to produce dis-
ubstituted 1,3,4-oxadiazole derivatives 4 and triph-
enylphosphine oxide 5 (Scheme 1 and Table 1). The
reaction proceeds smoothly and cleanly under mild
conditions, and no side reactions were observed. We
C6H5
C6H5
4-MeC6H4
j
k
CH2Cl
CH2Cl
aWe also used acetone 6a and acetophenone 6b instead of electron-
poor ketone 2 in this reaction, but no corresponding products 4 were
observed (Scheme 2).
bIsolated yields.
Heteroatom Chemistry DOI 10.1002/hc

370 Ramazani et al.
SCHEME 2 Electron-rich ketones such as acetone 6a and acetophenone 6b are not suitable starting materials in the
three-component synthesis of 1,3,4-oxadiazol derivatives.
SCHEME 3 Proposed mechanism for the formation of disubstituted 1,3,4-oxadiazole derivatives 4.
A mechanistic rationalization for this reaction is
provided in Scheme 3. On the basis of the chemistry
of isocyanides [4], it is reasonable to assume that
the first step may involve nucleophilic addition of
the (N-isocyanimino)triphenylphosphorane 3 to the
electron-poor ketone 2, which facilitates by its proto-
nation with the acid 1, leading to nitrilium interme-
diate 8. This intermediate may be attacked by conju-
gate base of the acid 9 to form 1:1:1 adduct 10. This
adduct may undergo intramolecular aza-Wittig [32]
reaction of iminophosphorane moiety with the ester
carbonyl to afford the isolated disubstituted 1,3,4-
oxadiazoles 4 by removal of triphenylphosphine ox-
ide 5 from intermediate 11.
EXPERIMENTAL
Starting materials and solvents were obtained from
Merck (Germany) and Fluka (Switzerland) and were
used without further purification. Melting points
were measured on an Electrothermal 9100 appa-
ratus and are uncorrected. IR spectra were mea-
1
sured on a Jasco FT-IR 6300 spectrometer. H and
13C NMR spectra were measured (CDCl3 solution)
with a BRUKER DRX-250 AVANCE spectrometer at
250.0 and 62.5 MHz, respectively. Mass spectra were
recorded on a FINNIGAN-MAT 8430 mass spectrom-
eter operating at an ionization potential of 70 eV.
Elemental analyses were performed using a Heraeus
CHN-O-Rapid analyzer. The results agreed favorably
with the calculated values.
CONCLUSIONS
GENERAL PROCEDURE FOR THE
PREPARATION OF COMPOUNDS 4a-k;
GENERAL PROCEDURE EXEMPLIFIED
FOR 4a
We believe that the reported method offers a mild,
simple, and efficient route for the preparation of dis-
ubstituted 1,3,4-oxadiazole derivatives. Its ease of
work-up, high yields, and fairly mild reaction condi-
tions make it a useful addition to modern synthetic
methodologies. Other aspects of this process are un-
der investigation.
To
a
stirred solution of (N-isocyanimino)
triphenylphosphorane (1 mmol) and 1,1, 1-
trifluoroacetone (1 mmol) in CH2Cl2 (7 mL) was
Heteroatom Chemistry DOI 10.1002/hc

Reaction of (N-isocyanimino)triphenylphosphorane with an α-Haloketone 371
added dropwise a solution of 4-chlorobenzoic acid
225 (100), 197 (14), 183 (55), 155 (29), 102 (33), 75
(32), and 43 (71).
(1 mmol) in CH2Cl2 (5 mL) at room temperature
over 15 min. The mixture was stirred for 4 h. The
solvent was removed under reduced pressure, and
the viscous residue was purified by flash column
chromatography (silica gel; petroleum ether–ethyl
acetate (2:1)). The solvent was removed under
reduced pressure and the products were obtained.
The characterization data of the compounds are
given below:
2-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-1,1,
1-trifluoro-2-propanol (4a): White crystals; mp:
145.5–147.1◦C; Yield: 85%. IR (KBr) (νmax, cm−1):
3281, 1607, 1488, 1159, 1095, 716. 1H NMR
1,1,1-Trifluoro-2-[5-(3-fluorophenyl)-1,3,4-oxadia-
zol-2-yl]-2-propanol (4d): Yellow crystals; mp: 95.1–
97.0◦C; Yield: 85%. IR (KBr) (νmax, cm−1): 3280,
1
1605, 1165, 1087, 776. H NMR (CDCl3, 250 MHz):
δH 1.93 (s, 3H, CH3), 4.34 (s, 1H, OH, exchanged
by D2O addition), 7.23–7.88 (m, 4H, arom). 13C
NMR (CDCl3, 62.5 MHz): δC 20.48 (CH3), 72.33 (q,
2
2 JCF = 32.1 Hz, C CF3), 114.60 (d, JCF = 24.5 Hz,
2
CH, arom), 119.93 (d, JCF = 20.8 Hz, CH, arom),
4
123.33 (d, JCF = 3.8 Hz, CH, arom), 123.90 (q,
3
1 JCF = 285.6 Hz, CF3), 125.11 (d, JCF = 8.2 Hz, C,
arom), 131.44 (d, 3 JCF = 8.2 Hz, CH, arom), 163.14 (d,
1 JCF = 248.5 Hz, C, arom), 164.47 and 165.85 (2C N).
Anal. Calcd for C11H8F4N2O2 (276.2): C, 47.84; H,
2.92; N, 10.14%. Found: C, 47.90; H, 2.95; N,
10.11. MS: m/z (%) (EI) 276 (M+, 7), 207 (9), 165
(22), 123 (100), 95 (63), 75 (30), 69 (18), and 42
(68).
(CDCl3,250 MHz): δH 1.93 (s, 3H, CH3), 4.51 (s, 1H,
3
OH, exchanged by D2O addition), 7.50 (d, JHH
=
3
8.5 Hz, 2H, arom), 7.99 (d, JHH = 8.5 Hz, 2H,
arom).13C NMR (CDCl3, 62.5 MHz): δC 20.46 (CH3),
72.32 (q, 2 JCF = 32.2 Hz, C CF3), 121.76 and 139.22
1
(2C, arom), 123.90 (q, JCF = 286.1 Hz, CF3),128.80
and 129.96 (4CH, arom), 164.19 and 166.03 (2C N).
Anal. Calcd for C11H8ClF3N2O2 (292.6): C, 45.15; H,
2.76; N, 9.57%. Found: C, 45.22; H, 2.71; N, 9.50. MS:
m/z (%) (EI) 294 ([M+ + 2], 24), 292 (M+, 54), 225
(27), 223 (63), 183 (33), 181 (100), 139 (62), 111 (51),
74 (51), 62 (26), and 43 (84).
1,1,1-Trifluoro-2-(5-phenyl-1,3,4-oxadiazol-2-yl)-
2-propanol (4e): White crystals; mp: 120.0–121.4◦C;
Yield: 85%. IR (KBr) (νmax, cm−1): 3320, 1560, 1156,
1084, 708. 1H NMR (CDCl3, 250 MHz): δH 1.94
(s, 3H, CH3), 5.08–5.35 (br. s, 1H, OH; exchanged
by D2O addition), 7.41–7.68 (m, 3H, arom), 8.04
3
2-[5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-1,1,
1-trifluoro-2-propanol (4b): Yellow crystals; mp:
87.0–88.8◦C; Yield: 83%. IR (KBr) (νmax, cm−1): 3477,
1561, 1478, 1159, 1105, 720. 1H NMR (CDCl3,
250 MHz): δH 1.93 (s, 3H, CH3), 4.29 (s, 1H, OH, ex-
changed by D2O addition), 7.35–8.12 (m, 4H, arom).
13C NMR (CDCl3, 62.5 MHz): δC 20.52 (CH3), 72.34 (q,
(d, JHH = 7.0 Hz, 2H, arom). 13C NMR (CDCl3,
2
62.5 MHz): δC 21.22 (CH3), 72.92 (q, JCF = 32.1 Hz,
C CF3), 123.81 (C, arom), 124.65 (q, 1 JCF = 286.2 Hz,
CF3), 128.17, 130.15 and 133.46 (5CH, arom), 165.04
and 167.35 (2C N). Anal. Calcd for C11H9F3N2O2
(258.2): C, 51.17; H, 3.51; N,10.85%. Found: C, 51.15;
H, 3.55; N, 10.81. MS: m/z (%) (EI) 258 (M+, 9), 189
(16), 147 (25), 105 (81), 90 (9), 77 (100), 63 (14), and
43 (53).
1
2 JCF = 32.1 Hz, C CF3), 123.91 (q, JCF = 285.6 Hz,
CF3), 124.87 and 135.71 (2C, arom), 125.64, 127.48,
130.92 and 132.87 (4CH, arom), 164.53 and 165.62
(2C N). Anal. Calcd for C11H8ClF3N2O2 (292.6): C,
45.15; H, 2.76; N, 9.57%. Found: C, 45.09; H, 2.80;
N, 9.50. MS: m/z (%) (EI) 292 (M+, 4), 223 (5), 138
(33), 113 (19), 110 (32), 91 (19), 74 (55), 69 (48), and
42 (100).
1, 1, 1-Trifluoro-2-[5-(4-methylphenyl)-1, 3, 4-
oxadiazol-2-yl]-2-propanol (4f): Yellow crystals;
mp: 111.7–113.6◦C; Yield: 87%. IR (KBr) (νmax
,
cm−1): 3238, 1502, 1160, 1109, 725. 1H NMR
(CDCl3,250 MHz): δH 1.92 and 2.42 (2s, 6H, 2CH3),
5.08–5.35 (br. s, 1H, OH; exchanged by D2O addi-
3
2-[5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl]-1,1,
1-trifluoro-2-propanol (4c): White crystals; mp:
153.6–155.5◦C; Yield: 84%. IR (KBr) (νmax, cm−1):
tion), 7.30 (d, JHH = 7.9 Hz, 2H, arom), 7.92 (d,
3 JHH = 7.9 Hz, 2H, arom). 13C NMR (CDCl3,
62.5 MHz): δC 20.55 and 22.02 (2CH3), 72.26 (q,
2 JCF = 32.1 Hz, C CF3), 120.40 and 143.53 (2C,
1
3237, 1602, 1484, 1158, 1078, 727. H NMR (CDCl3,
1
250 MHz): δH 1.93 (s, 3H, CH3), 4.16 (s, 1H, OH; ex-
arom), 124.02 (q, JCF = 285.6 Hz, CF3), 127.49
changed by D2O addition), 7.68 (d, 3 JHH = 8.0 Hz, 2H,
and 130.20 (4CH, arom), 164.08 and 166.88 (2C N).
Anal. Calcd for C12H11F3N2O2 (272.2): C, 52.94; H,
4.07; N, 10.29%. Found: C, 52.87; H, 4.09; N, 10.35.
MS: m/z (%) (EI) 272 (M+, 100), 203 (84), 161 (79),
160 (76), 136 (19), 119 (66), 91 (84), 77 (14), 65 (21),
and 43 (31).
3
arom), 7.93 (d, JHH = 8.0 Hz, 2H, arom). 13C NMR
2
(CDCl3, 62.5 MHz): δC 20.44 (CH3), 72.32 (q, JCF
=
32.1 Hz, C CF3), 122.21 and 127.67 (2C, arom),
1
123.88 (q, JCF = 286.2 Hz, CF3), 128.90 and 132.93
(4CH, arom), 164.19 and 166.14 (2C N). Anal. Calcd
for C11H8BrF3N2O2 (337.1): C, 39.19; H, 2.39; N,
8.31%. Found: C, 39.13; H, 2.43; N, 8.24. MS: m/z
(%) (EI) 338 ([M+ + 2], 65), 336 (M+, 64), 269 (64),
1,1,1-Trifluoro-2-[5-(3-methoxyphenyl)-1,3,4-oxa-
diazol-2-yl]-2-propanol (4g): Yellow crystals; mp:
80.0–81.5◦C; Yield: 88%. IR (KBr) (νmax, cm−1):
Heteroatom Chemistry DOI 10.1002/hc

372 Ramazani et al.
1
REFERENCES
3475, 1607, 1468, 1147, 1080, 862. H NMR (CDCl3,
250 MHz): δH 1.93 (s, 3H, CH3), 3.88 (s, 3H, OCH3),
4.61–4.84 (br. s, 1H, OH; exchanged by D2O addi-
tion), 7.11 (d, 3 JHH = 8.2 Hz, 1H, arom), 7.42 (t, 3 JHH
= 7.9 Hz, 1H, arom), 7.58 (s, 1H, arom) 7.62 (d, 3 JHH
= 8.0 Hz, 1H, arom). 13C NMR (CDCl3, 62.5 MHz): δC
21.13 (CH3), 56.53 (OCH3), 72.91 (q, 2 JCF = 32.1 Hz,
C CF3), 112.86, 119.79, 120.54 and 131.32 (4CH,
arom), 124.92 and 160.94 (2C, arom), 124.61 (q, 1 JCF
= 286.2 Hz, CF3), 156.87 and 156.97 (2C N). Anal.
Calcd for C12H11F3N2O3 (288.2): C, 50.01; H, 3.85;
N, 9.72%. Found: C, 49.93; H, 3.87; N, 9.79. MS: m/z
(%) (EI) 288 (M+, 9), 219 (4), 177 (9), 135 (23), 107
(10), 92 (5), 77 (14), 58 (24), and 43 (100).
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propanol (4h): White crystals; mp: 83.5–84.7◦C;
Yield: 84%. IR (KBr) (νmax, cm−1): 3274 (br), 1655,
1
1560, 1125, 1083, 706. H NR (CDCl3, 250 MHz):
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2-propanol (4i): White crystals; mp: 99.3–101.4◦C;
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1558, 1132, 779. 1H NMR (CDCl3, 250 MHz): δH
1.96 (s, 3 H, CH3), 4.40 (s, OH, exchanged by D2O
addition), 6.12 (s, 1 H, CHCl2), 7.53–8.05 (m, 5
H, arom). 13C NMR (CDCl3, 62.5 MHz): δC 22.11
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(C, arom), 127.14, 129.14 and 132.24 (5 CH, arom),
165.64 and 166.02 (2C N).
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δH 4.12 (1 s, 4 H, 2 CH2Cl), 4.36 (1 s, OH, exchanged
by D2O addition), 7.53–8.05 (m, 5 H, arom). 13C
NMR (CDCl3, 62.5 MHz): δC 46.90 (2 CH2Cl), 73.28
(CH aliphatic), 123.05 (C, arom), 127.18, 129.16 and
132.33 (5 CH, arom), 164.70 and 165.80 (2C N).
1,3-Dichloro-2-[(5-(4-methylphenyl)-1,3,4-oxadi-
azol-2-yl]-2-propanol (4k): White crystals; mp:
160–161.2◦C; Yield: 87%. IR (KBr) (νmax, cm−1):
3106 (br), 1615, 1554, 1186, 1067, 781. 1H NMR
(CDCl3, 250 MHz): δH 1.82 (1 s, 3 H, CH3), 1.91 (1
s, OH, exchanged by D2O addition), 3.90 and 4.04
(AB-quartet, 2 JHH = 11.5 Hz, 4H, 2 CH2Cl), 7.50–8.04
(m, 4 H, arom). 13C NMR (CDCl3, 62.5 MHz): δC
24.59 (CH3), 51.70 (2 CH2Cl), 71.11 (CH aliphatic),
123.41 and 132.68 (2C, arom), 127.05, 128.82 and
132.04 (4 CH, arom), 165.42 and 167.59 (2C N).
[29] Ramazani, A.; Salmanpour, S.; Souldozi, A. Phospho-
rus Sulfur Silicon Relat Elem 2010, 185, 97.
´
[30] Souldozi, A.; Ramazani, A.; Slepokura, K.; Lis, T. Z
Naturforsch 2007, 62b, 835.
[31] Ramazani, A.; Rezaei, A. Org Lett 2010, 12, doi:
10.1021/ol100931q.
[32] Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197.
Heteroatom Chemistry DOI 10.1002/hc