One-pot synthesis of 3-benzoyl- and 3-acetyl-1,2,4-oxadiazole derivatives using iron(III) nitrate

Article abstract of DOI:10.1055/s-2005-869898

The reaction of nitriles and acetophenone with iron(III) nitrate at 80 °C gave the corresponding 3-benzoyl-1,2,4-oxadiazole derivatives. Moreover, in this reaction using acetone, the 3-acetyl-1,2,4-oxadiazole derivatives were obtained. Georg Thieme Verlag

Full text of DOI:10.1055/s-2005-869898

PAPER
1935
One-Pot Synthesis of 3-Benzoyl- and 3-Acetyl-1,2,4-Oxadiazole Derivatives
Using Iron(III) Nitrate
O
ne-Pot Synthesis
e
of 3-Benzo
n
yl- and 3-A
c
-
etyl-1,2,
i
4-Oxad
c
iazole De
rh
ivatives i Itoh,*a Hiroshi Sakamaki,a C. Akira Horiuchib
a
College of Science and Technology, Nihon University, 7-24-1 Narashinodai, Funabashi-shi, Chiba 274-8501, Japan
Fax +81(80)474695477; E-mail: k-itoh@chem.ge.cst.nihon-u.ac.jp
b
Department of Chemistry, Rikkyo (St. Paul’s) University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
Received 13 January 2005; revised 21 February 2005
182.5, 177.3 and 165.4 ppm, which were assigned to the
commonly known carbonyl carbon and carbons of the
1,2,4-oxadiazole ring, respectively. Therefore, compound
1a was identified to be 3-benzoyl-5-methyl-1,2,4-oxadi-
azole. These reaction conditions are summarized in
Table 1. In this reaction, acetonitrile (1) was employed as
the solvent because of its low reactivity in the 1,3-dipolar
cycloaddition (Table 1, entries 1–5). And the yields of the
products were based on amount of iron(III) nitrate since
this reaction required excess ketones and nitriles for
iron(III) nitrate. When acetophenone (5.0 mmol), acetoni-
trile (1; 4.5 mL) and Fe(NO3)3 (1.0 mmol) were em-
ployed, the corresponding 1,2,4-oxadiazole derivative 1a
in good yield of 95% (Table 1, entry 9).
Abstract: The reaction of nitriles and acetophenone with iron(III)
nitrate at 80 °C gave the corresponding 3-benzoyl-1,2,4-oxadiazole
derivatives. Moreover, in this reaction using acetone, the 3-acetyl-
1,2,4-oxadiazole derivatives were obtained.
Key words: ketones, nitriles, heterocycles, iron(III) nitrate, 1,2,4-
oxadiazole derivatives
1,2,4-Oxadiazole derivatives have been described as im-
portant bioisosteres for esters and amides to improve the
pharmacokinetics of drug candidates. In the literature, the
1,2,4-oxadiazole derivatives participate in antikineto-
plastid activity,1 b3 adrenergic receptor agonists,2 antiin-
flammatory properties,3 muscarinic agonists4 and
serotoninergic antagonists.5 The 1,2,4-oxadiazole deriva-
tives have been prepared by the cycloaddition of nitrile
oxides to amidoximes,6 treatment of acylated amidoximes
with bases such as NaH, NaOEt or pyridine,7 and the O-
acylation of amidoximes by an activated carboxylic acid
derivative such as esters5 or acid chlorides, followed by
cyclodehydration.8
N
O
Fe(NO3)3
O
R1
R2C
N
R2
+
N
R1
O
1–4
a–b
1: R2 = Me
a: R1 = Ph
b: R1 = Me
1a–4a, 1b–4b
2: R2 = Et
3: R2 = n-Pr
4: R2 = i-Pr
Recently, we reported the one-pot synthesis of 3-acetyl-
and 3-benzoylisoxazole derivatives using ammonium ce-
rium nitrate (CAN).9 The reaction of alkenes and alkynes
with CAN(IV) or CAN(III)–formic acid in acetone gave
the corresponding 3-acetylisoxazole derivatives, and the
same reactions in acetophenone yielded the 3-benzoyl-
isoxazole derivatives. We have proposed the reaction
mechanisms based on the formation of the nitrile oxides
mediated by Ce3+ or Ce4+ from ketones.10 Furthermore,
the reaction using non-toxic iron(III) nitrate afforded sim-
ilar isoxazole derivatives. We attempted to adapt the new
synthesis of 1,2,4-oxadizole derivatives using these reac-
tion systems.11,12 Now in this paper, we report a novel and
efficient one-pot synthesis of 3-benzyl- and 3-acetyl-
1,2,4-oxadiazole derivatives using iron(III) nitrate.
Scheme 1
On the basis of these reaction conditions, the reactions us-
ing several nitriles 2–4 were carried out (Scheme 1,
Table 2, entries 1–3). The corresponding 3-benzoyl-1,2,4-
oxadiazole derivatives 2a–4a were obtained in 44–95%
yields. Moreover, the reaction using acetone produced 3-
acetyl-5-methyl-1,2,4-oxadiazole (1b). The IR spectrum
of 1b showed absorptions at 1731, 1699 and 1601 cm–1.
The 1H NMR spectra exhibited a singlet at d = 2.70 (3 H,
CH3). The 13C NMR spectra exhibited signals at d = 188.8,
178.5 and 165.8 ppm, which were assigned to the com-
monly known carbonyl carbon and carbons of the 1,2,4-
oxadiazole ring, respectively. The reaction of acetone (5.0
mmol) and acetonitrile (1; 4.5 mL) with Fe(NO3)3 (1.0
The reaction of acetonitrile (1) and acetophenone with mmol) under reflux gave the corresponding 1,2,4-oxadi-
iron(III) nitrate at 80 °C afforded 3-benzoyl-5-methyl-
azole derivatives 1b in 61% yield (Table 2, entry 5). Also,
1,2,4-oxadiazole (1a) (Scheme 1). Compound 1a showed under the these reaction conditions, the similar 3-acetyl-
absorptions at 1713, 1681 and 1581 cm–1 in its IR spec- 1,2,4-oxadiazoles 2b–4b from nitrile 2–4 were obtained
trum. The 1H NMR spectrum showed a singlet at d = 2.71 in 25–62% yields (Table 2, entries 8–10). It seems that the
(3 H, CH3). The 13C NMR spectra exhibited signals at d = formation of the 3-benzoyl-1,2,4-oxadiazole derivatives
1a–4a from nitriles and acetophenone proceeds more
smoothly, compared with the formation of the 3-acetyl-
1,2,4-oxadiazole derivatives 1b–4b.
SYNTHESIS 2005, No. 12, pp 1935–1938
Advanced online publication: 18.05.2005
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DOI: 10.1055/s-2005-869898; Art ID: F00805SS
© Georg Thieme Verlag Stuttgart · New York

1936
K.-i. Itoh et al.
PAPER
Table 1 Reaction Conditions
Entrya
1
Acetophenone (mmol)
Acetonitrile (1) (mmol)
1.0
Fe(NO3)3 (mmol)
Time (h)
20
Product, Yield (%)b
4.5 mL
4.5 mL
4.5 mL
4.5 mL
4.5 mL
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
3.0
4.0
1.0
1.0
1a (traces)
1a (16)
1a (27)
1a (55)
1a (49)
1a (4)
2
10.0
20
3
20.0
18
4
40.0
18
5
50.0
18
6
4.5 mL
4.5 mL
4.5 mL
4.5 mL
4.5 mL
4.5 mL
4.5 mL
4.5 mL
4.5 mL
22
7
2.0
20
1a (27)
1a (72)
1a (95)
1a (69)
1a (48)
1a (25)
1a (94)
1a (80)
8
4.0
18
9
5.0
18
10
11
12
13
14
5.0
20
5.0
22
5.0
22
7.5
18
10.0
18
a Reaction conditions: Acetophenone, acetonitrile (1) and iron(III) nitrate were employed at 80 °C.
b Determined by GLC analysis using n-dodecane as internal hydrocarbon standard. Yields based on amount of iron(III) nitrate used.
Table 2 Reaction of Ketones and Nitriles with Iron(III) Nitrate
was employed, the corresponding 1,2,4-oxadiazoles 1a
was obtained in 78% yield (Table 3, entry 1). However,
the reaction using NaNO3, Mg(NO3)2 and NH4NO3 did
not proceed (Table 3, entries 2–4). Previously, we have
reported that CAN(IV) accelerates the enolization of ke-
tones.13 From these results, we proposed the reaction
mechanism in Scheme 2. In this reaction mechanism, the
enolization of ketones was accelerated by Fe(NO3)3 or
CAN(IV), followed by the nitration of ketones. The for-
mation of nitrile oxides proceeds via the acid-catalyzed
dehydration of a-nitroketones,10 and the 3-benzoyl- and 3-
acetyl-1,2,4-oxadiazole derivatives were obtained by the
1,3-dipolar cycloaddition to nitriles. Therefore, the yields
of the products were dependent on the stabilities of the ni-
trile oxides and the reactivity of nitriles in 1,3-dipolar cy-
cloaddition.
Entrya Nitriles Ketones
Mol
equiv
Time
(h)
Product,
Yield (%)b
1
2
2
3
4
1
1
1
1
2
3
4
Acetophenone
Acetophenone
Acetophenone
Acetone
5.0
5.0
5.0
2.5
5.0
7.5
10.0
5.0
5.0
5.0
20
20
22
18
16
16
14
16
16
18
2a (95)
3a (95)
4a (44)
1b (47)
1b (61)
1b (50)
1b (44)
2b (62)
3b (61)
4b (25)
3
4
5
Acetone
6
Acetone
7
Acetone
8
Acetone
9
Acetone
In conclusion, this method using non-toxic and inexpen-
sive iron(III) nitrate is simple, efficient and clean for pro-
ducing 3-benzoyl- and 3-acetyl-1,2,4-oxadiazole
derivatives.
10
Acetone
a Reaction conditions: Acetophenone (5.0 mmol), nitriles 2–4 (4.5
mL) and iron(III) nitrate (1.0 mmol) were employed at 80 °C. Acetone
(2.5–10.0 mmol), nitriles 1–4 (4.5 mL) and iron(III) nitrate (1.0
mmol) were employed under reflux.
The IR spectra were recorded using a Jasco FT-IR 230 spectrome-
ter. The 1H and 13C NMR spectra were measured using a JEOL GSX
400 model spectrometer in CDCl3 solutions with TMS used as the
internal standard. Gas chromatographic analyses were performed
using a GC-column (DB-1, 25 m) attached to a Shimazu GC-14A
instrument. The HRMS were recorded at 75 eV using a JEOL JMS-
01SG-2 instrument.
b Determined by GLC analysis using n-dodecane as internal hydrocar-
bon standard. Yields based on amount of iron(III) nitrate used.
In order to investigate the reaction mechanism, the reac-
tions of acetophenone and acetonitrile (1) with several
metal nitrates were carried out (Table 3). When CAN(IV)
Synthesis 2005, No. 12, 1935–1938 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 3-Benzoyl- and 3-Acetyl-1,2,4-Oxadiazole Derivatives
1937
Fe(NO3)3
or
OH
O
CAN(IV)
R1
R1
Acceleration
Fe3+, Ce4+
H+, NO3
–
N
O
H+
– H2O
O
O
R2C
N
R1
C
N
O
R2
NO2
N
R1
R1
O
Scheme 2 Reaction mechanisms
HRMS: m/z [M] calcd for C11H10N2O2: 202.0742; found [M]+:
202.0749.
Table 3 Application of Some Metal Nitrates
Entrya
Metal nitrate
CAN(IV)
NaNO3
Time (h)
Product (%)b
1a (78)
3-Benzoyl-5-propyl-1,2,4-oxadiazole (3a)
Yellow oil.
IR (NaCl): 1712, 1679, 1580 cm–1.
1H NMR (CDCl3): d = 8.28–8.33 (m, 2 H), 7.46–7.62 (m, 3 H), 3.01
(t, J = 7.56 Hz, 2 H), 1.90–1.99 (m, 2 H), 1.07 (t, J = 7.56 Hz, 3 H).
13C NMR (CDCl3): d = 183.0, 171.3, 165.6, 135.1, 134.6, 130.6,
128.7, 28.4, 20.1, 13.6.
HRMS: m/z [M] calcd for C12H12N2O2: 216.0899; found [M]+:
216.0898.
1
3
4
5
18
30
30
30
No reaction
No reaction
No reaction
Mg(NO3)2
NH4NO3
a Reaction conditions: Acetophenone (5.0 mmol), acetonitrile (1; 4.5
mL) and metal nitrate (1.0 mmol) were employed at 80 °C.
b Determined by GLC analysis using n-dodecane as internal hydro-
carbon standard. Yields based on amount of metal nitrate used.
3-Benzoyl-5-isopropyl-1,2,4-oxadiazole (4a)
Yellow oil.
IR (NaCl): 1711, 1677, 1569 cm–1.
Reaction of Acetonitrile (1) and Acetophenone with Iron(III)
Nitrate; Typical Procedure
1H NMR (CDCl3): d = 8.27–8.30 (m, 2 H), 7.46–7.61 (m, 3 H),
3.34–3.41 (m, 1 H), 1.50 (d, J = 6.83 Hz, 6 H).
A mixture of acetonitrile (1; 4.5 mL), acetophenone (0.6008 g, 5.0
mmol) and iron(III) nitrate (0.4040 g, 1.0 mmol) was stirred at 80
°C for 18 h. The reaction mixture was filtered, extracted with
EtOAc (50 mL) and washed with aq NaHCO3 solution (2 × 2.0 mL),
sat. aq NaCl (2 × 2.0 mL) and H2O (2 × 2.0 mL). This solution was
dried over Na2SO4 and concentrated in a vacuum, followed by ace-
tophenone removal by reduced pressure distillation. The resulting
oil was chromatographed on silica gel. Elution with hexane–EtOAc
(4:1) gave 3-benzoyl-5-methyl-1,2,4-oxadiazole (1a) as a yellow oil
(0.1504 g).
13C NMR (CDCl3): d = 183.1, 171.1, 165.5, 135.2, 134.5, 130.6,
128.7, 27.6, 20.1.
HRMS: m/z [M] calcd for C12H12N2O2: 216.0899; found [M]+:
216.0892.
Reaction of Acetonitrile (1) and Acetone with Iron(III) Nitrate;
Typical Procedure
A mixture of acetonitrile (1; 4.5 mL), acetone (0.2904 g, 5.0 mmol)
and iron(III) nitrate (0.4040 g, 1.0 mmol) was stirred under reflux
for 16 h. The reaction mixture was filtered, extracted with EtOAc
(50 mL) and washed with aq NaHCO3 solution (2 × 2.0 mL), sat. aq
NaCl (2 × 2.0 mL) and H2O (2 × 2.0 mL). This solution was dried
over Na2SO4 and concentrated in a vacuum. The resulting oil was
chromatographed on silica gel. Elution with hexane–EtOAc (4:1)
gave 3-acetyl-5-methyl-1,2,4-oxadiazole (1b) as a yellow oil
(0.0504 g).
3-Benzoyl-5-methyl-1,2,4-oxadiazole (1a)
Yellow oil.
IR (NaCl): 1713, 1681, 1581 cm–1.
1H NMR (CDCl3): d = 8.25–8.27 (m, 2 H), 7.50–7.68 (m, 3 H), 2.71
(s, 3 H).
13C NMR (CDCl3): d = 182.5, 177.3, 165.4, 134.7, 134.3, 130.3,
3-Acetyl-5-methyl-1,2,4-oxadiazole (1b)
Yellow oil.
IR (NaCl): 1731, 1699, 1601 cm–1.
1H NMR (CDCl3): d = 2.70 (s, 6 H).
13C NMR (CDCl3): d = 188.8, 178.5, 165.8, 27.8, 12.4.
HRMS: m/z [M] calcd for C5H6N2O2: 126.0429; found [M]+:
128.4, 12.0.
HRMS: m/z [M] calcd for C10H8N2O2: 188.0586; found [M]+:
188.0583
3-Benzoyl-5-ethyl-1,2,4-oxadiazole (2a)
Yellow oil.
IR (NaCl): 1711, 1679, 1577 cm–1.
1H NMR (CDCl3): d = 8.25–8.30 (m, 2 H), 7.46–7.61 (m, 3 H), 3.06
(q, J = 7.68 Hz, 2 H), 1.49 (t, J = 7.68 Hz, 3 H).
126.0433.
3-Acetyl-5-ethyl-1,2,4-oxadiazole (2b)
Yellow oil.
IR (NaCl): 1738, 1688, 1599 cm–1.
13C NMR (CDCl3): d = 183.0, 165.6, 154.3, 135.3, 134.6, 130.6,
128.7, 20.3, 10.7.
Synthesis 2005, No. 12, 1935–1938 © Thieme Stuttgart · New York

1938
K.-i. Itoh et al.
PAPER
1H NMR (CDCl3): d = 3.02 (q, J = 7.56 Hz, 2 H), 2.70 (s, 3 H), 1.45
(t, J = 7.56 Hz, 3 H).
13C NMR (CDCl3): d = 189.1, 182.7, 165.7, 27.8, 20.3, 10.6.
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3-Acetyl-5-propyl-1,2,4-oxadiazole (3b)
Yellow oil.
IR (NaCl): 1733, 1691, 1589 cm–1.
1H NMR (CDCl3): d = 2.96 (t, J = 7.44 Hz, 2 H), 2.70 (s, 3 H), 1.86–
1.95 (m, 2 H), 1.04 (t, J = 7.44 Hz, 3 H).
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HRMS: m/z [M] calcd for C7H10N2O2: 154.0742: found [M]+:
154.0733.
3-Acetyl-5-isopropyl-1,2,4-oxadiazole (4b)
Yellow oil.
IR (NaCl): 1732, 1694, 1593 cm–1.
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Acknowledgment
This work was partially supported by the Frontier Project ‘Environ-
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Synthesis 2005, No. 12, 1935–1938 © Thieme Stuttgart · New York