A generalized synthesis of 3-amino-5-aryl-, 3-amino-5-polyfluorophenyl-, and 3-amino-5-alkyl-1,2,4-oxadiazoles through ring-degenerate rearrangements

Article abstract of DOI:10.3987/com-02-9436

A generalized synthesis of 3-amino-5-aryl-, 3-amino-5-polyfluorophenyl- and 3-amino-5-alkyl-1,2,4-oxadiazoles has been developed starting from the 3-amino-5-methyl-1,2,4-oxadiazole as a common synthon. Aroylation or alkanoylation of this aminooxadiazole,

Full text of DOI:10.3987/com-02-9436

HETEROCYCLES, Vo. 57, No. 5, 2002, pp. 811 - 823, Received, 15th January, 2002
A GENERALIZED SYNTHESIS OF 3-AMINO-5-ARYL- , 3-AMINO-5-
POLYFLUOROPHENYL-, AND 3-AMINO-5-ALKYL-1,2,4-
OXADIAZOLES THROUGH RING-DEGENERATE
REARRANGEMENTS
Silvestre Buscemi,* Andrea Pace, Vincenzo Frenna, and Nicolò Vivona
Dipartimento di Chimica Organica “E. Paternò”, Università degli Studi di
Palermo, Viale delle Scienze-Parco d’Orleans II, I-90128, Palermo, Italy
E-mail: sbuscemi@unipa.it
Abstract - A generalized synthesis of 3-amino-5-aryl-, 3-amino-5-poly-
fluorophenyl- and 3-amino-5-alkyl-1,2,4-oxadiazoles has been developed
starting from the 3-amino-5-methyl-1,2,4-oxadiazole as a common synthon.
Aroylation or alkanoylation of this aminooxadiazole, followed by thermally-
induced ring-degenerate equilibration of resulting 3-acylamino compounds, and
final acid hydrolysis of the 3-acetylamino-5-aryl- (or 5-polyfluorophenyl-), or 3-
acetylamino-5-alkyl-1,2,4-oxadiazoles counterpart which is formed, gave the
expected 3-amino-5-substituted 1,2,4-oxadiazoles. In the case of some 3-
aroylamino compounds, yields of final 3-amino-5-aryloxadiazoles are higher
than that expected on the basis of the thermally-induced equilibrium
composition, since acid hydrolysis plays a significant role in the shift of the
equilibrium itself. Satisfactory direct procedures have also been described. As
expected, restrictions to the above methodology were found in the synthesis of
5-perfluoroalkyl derivatives.
INTRODUCTION
The synthesis of heterocyclic compounds represents an increasingly valuable goal in view of their large
range of applications as pharmaceuticals, agrochemicals and a variety of other products.1 To this aim,
efficient synthetic methodologies exploit ring-rearrangement reactions,2 and among these, several
examples regard rearrangements of O-N bond-containing azoles,2,3 which have been studied both from
mechanistic4 point of view and synthetic applications.3,5
In the course of our work on the synthesis and reactivity of fluorinated heterocyclic compounds,6,7 we
were interested in an efficient synthesis of 3-amino-5-polyfluoroaryl- and 3-amino-5-heteroaryl-1,2,4-
oxadiazoles. In the last years, since discovery of their applications in pharmaceuticals,8,9 oxadiazoles have
been receiving a growing interest; inter alia, some 3-amino derivatives have been found to act as

efficacious muscarinic agonists.9 In principle, different methods are available for the synthesis of these
functionalized oxadiazoles.10 A general approach considers the reaction of N-acylcyanamides with
hydroxylamine;11 other methods use N-aroyl-S-methylisothioureas as starting reagent,12 oxidative
cyclization of N-acylguanidines,13 and the reaction of N-hydroxyguanidine with acylating reagents in an
acylation/cyclodehydration pattern.9a-c A photochemical approach, also applicable to the synthesis of N-
substituted derivatives has been also pointed out.14,15 Moreover, this photochemical methodology has
been also applied for the synthesis of 3-amino- and 3-N-substituted amino-5-perfluoroalkyl-6 or 5-
perfluoroaryloxadiazoles.7
To contribute to the search of efficient methodologies for synthesis of these functionalized oxadiazoles,
we have now considered the 3-amino-5-methyl-1,2,4-oxadiazole (3)16 as a starting synthon to build 3-
amino compounds variously substituted at the C(5) of the ring. In fact, it appears noteworthy to consider
this synthon an O-protected amidoxime in one hand, or an O,N-protected hydroxyguanidine, in the other,
both structures being precursors of the 1,2,4-oxadiazole nucleus.10
The construction of the new oxadiazole molecule from this synthon should involve ring-rearrangement
reactions of its N-acylamino derivatives according to the well known Boulton-Katritzky general
pattern.3,17 These peculiar rearrangements (which can be of ring-degenerate or fully-degenerate type18)
have been studied both from experimental19-21 and theoretical22 point of view. To our purposes it is
noteworthy to bear in mind that: i) the thermally-induced equilibration between 3-aroylamino-5-methyl-
oxadiazoles (at least when the aroyl moiety is meta- or para-substituted phenyl ring) and the
corresponding 3-acetylamino-5-aryl derivatives has been found to be significantly shifted toward the 5-
aryl substituted component as a result of its higher stabilization due to the diaryloid contribution;19,21 ii)
acidic hydrolysis of the 3-acylamino group to produce 3-amino compounds will proceed in different rate
depending on the nature of the acylamino group itself (that is, an alkanoylamino or an aroylamino group);
iii) finally, experimental conditions employed in the hydrolysis reaction could play a role in the overall
equilibrium composition.
On the basis of the above considerations, we planned and succeeded in the synthesis of 3-amino-5-
substituted oxadiazoles by realizing the following reaction steps: i) acylation of the 3-amino-5-methyl-
oxadiazole; ii) thermal equilibration of resulting 3-acylamino derivatives; iii) acid hydrolysis of the 3-
acetylamino components.
RESULTS AND DISCUSSION
Aroylation reactions of 3-amino-5-methyl-1,2,4-oxadiazole (3) and subsequent thermal equilibration
between a series of meta- and para-substituted 3-aroylamino compounds (1) and the corresponding

3-acetylamino counterpart (2) have been previously reported.19,21,23 When representative compounds
(1a-c) were equilibrated in refluxing ethanol, subsequent acid hydrolysis of the resulting equilibrium
mixture gave good yields of the corresponding 3-aminooxadiazoles (4) (see Table 1). In a synthetic
approach, there is no need to separate the 3-acetylamino component (2) from the reaction mixture; in fact,
apart from its much higher percentage, we observed that the acetylamino group is more easy to hydrolyze
than the aroylamino group. Interestingly, as shown for representative example a direct procedure starting
from compound (3) also gave good yields of the 3-aminooxadiazoles (4) (see Table 1).
Scheme 1
H
N
H
N
Ar
Me
N
N
∆
N
O
O
N
Me
Ar
O
O
1a-j
2a-j
+
EtOH / H
ArCOCl
75-80%
C6H6/Pyridine
H2N
NH2
N
N
N
N
Ar
Me
O
O
3
4a-j
1, 2, 4 a: Ar = Ph
b: Ar = p-CF3C6H4
f : Ar = 2-Furyl
g: Ar = 2-Thienyl
h: Ar = C6F5
i : Ar = 2,3,4,5-Tetrafluorophenyl
j : Ar = 2,3,4-Trifluorophenyl
c: Ar = m-CF3C6H4
d: Ar = o-NO2C6H4
e: Ar = o-CF3C6H4
In the case of the ortho-substituted 3-aroylamino derivatives (1d,e) or 3-heteroaroylamino compounds
(1f,g) the equilibrium composition shows a high concentration of the aroylamino- (or heteroaroylamino)
component, even predominant in the cases of 1d and 1f. However, acid hydrolysis of the resulting
equilibration mixture in ethanolic solution gave the 3-amino-5-aryl- (or 5-heteroaryl)-1,2,4-oxadiazoles in
high yields, too. This means that: i) the ring-rearrangement is an acid-catalysed process (that is, a
protonated starting ring could favor O-N bond fission); ii) hydrolysis of the 3-acetylamino component is
coupled with an equilibrium shift; iii) finally, the ring rearrangement reaction could take place on an
oxadiazoline species arising from an acid-catalysed nucleophilic addition of ethanol to the N(4)-C(5)
double bond of the oxadiazole nucleus. Clearly, this addition should take place in the 5-methyl-

oxadiazole component (1) easier than in the 5-aryloxadiazole counterpart (2).24 At this moment, however,
we have no evidences to corroborate one of these reaction pathways.
Table 1. Equilibration between 3-Acylaminooxadiazoles (1) and (2)
or (5) and (6). Preparation of 3-Aminooxadiazoles (4) and (7).
Starting
Compound
Equilibrium compositiona Compound (4) or (7)
[1]/[2] or [5]/[6]
(%)b
1a
1b
1c
1d
1e
1f
1g
1h
3
9/91c
14/86c
17/83c
78/22d
58/42d
80/20d
42/58d
80/20d
4a 90 (70)
4b 90
4c 75
4d 75
4e 90 (60)
4f 75 (60)
4g 75
4h 75 (60)
4i
4j
7a
7b
7c
(60)
(60)
(50)
(50)
(50)
3
5a
5b
5c
40/60e
36/64e
40/60e
_________________________________________________
a
Composition (%) of the equilibrium mixture for the ring-
degenerate rearrangements 1
2 or 5
6.
b
Yields of isolated product from acid hydrolysis of the
equilibrium mixture. In parenthesis, yields in the direct
(one-pot) procedure from 3 as starting material.
Values from equilibration in methanol at 40 °C. Ref.21
Values from equilibration in methanol at 40 °C. This work.
Values from equilibration on melting compounds (5) at 120 °C.
c
d
e
On the basis of the above results and pursuing our studies on fluorinated heterocyclic compounds, we
have then extended this methodology for the synthesis of 3-amino-5-polyfluorophenyoxadiazoles. In this
respect, we note that the pentafluorophenyl derivative (4h) was recently7 obtained (with modest yields,
indeed) by a photochemical procedure (irradiation of 3-pentafluorobenzoylamino-4-methylfurazane in the
presence of ammonia). When 3-pentafluorobenzoylamino-5-methyloxadiazole (1h) has been equilibrated
in methanol, the composition of the mixture (20% of 2h versus 80% of 1h) reflected a balance between
the electron withdrawing character of the pentafluorophenyl moiety, which will largely stabilize the
carbamoyl function, and the rather meagre stabilization due to the diaryloid effect.21 However, acid
hydrolysis of this mixture, in spite of its actual composition, gave the expected 3-amino compound (4h)
in 75% yields, thus corroborating the ring-degenerate equilibrium shift under hydrolytic conditions.

Acceptable results (60% of final yields) have been also obtained by adopting a direct (one-pot) procedure
where the first step was the aroylation of the amino compound (3) with the pentafluorobenzoyl chloride.
Furthermore, a similar procedure allowed us to obtain 3-amino-5-polyfluorophenyl-1,2,4-oxadiazoles
(4i,j) in 60% yields. These results appear noteworthy in view of the fact that our attempts to obtain the
pentafluorophenyloxadiazole (4h) by conventional routes were frustrating. In fact, the acylcyanamide
method was unsuccessful, while the acylation/dehydration of hydroxyguanidine gave 4h in a low yields.7
Aiming to value restrictions of the above procedure, we then tested to synthesize 3-amino-5-
alkyloxadiazoles. Thus, alkanoylation of 3 with some representative alkanoyl chlorides in benzene
containing pyridine gave the 3-alkanoylaminooxadiazoles (5a-c). The ring-degenerate equilibration
between 5a-c and counterparts (6a-c) was analytically realized on melting compounds (5) at 120 °C. The
equilibrium composition (by NMR spectral technique; see Table 1) showed a moderate predominance of
the 5-alkyl component, thus indicating to some extent a stabilization effect of a 5-alkyl group in the
respect of the 5-methyl substituent. Although we were unable to isolate the 3-acetylamino component (6)
from the equilibration mixture, acid hydrolysis of these mixtures [also obtained in preparative scale by
refluxing compounds (5) in ethanol] allowed us to isolate both the starting 3-amino compound (3) (40%)
and the expected 3-amino-5-alkyloxadiazoles (7a-c) in 50% yields following a direct (one-pot) procedure.
Scheme 2
H
N
H
N
R
Me
N
N
∆
N
O
O
N
Me
R
O
O
5a-c
6a-c
+
RCOCl
C6H6/Pyridine
EtOH / H
75-80%
H2N
N
3
+
3
N
R
O
7a-c
5, 6, 7
a. R = n-Pr
b: R = t-Bu
c: R = n-C
H
11 23

Table 2. Physical and Analytical Data for 3-Acylaminooxadiazoles (1, 2, 5, 6).
_____________________________________________________________________________________________________________
Compounda mpb
(°C)
IR(nujol)
1H NMR (DMSO-d6/TMS),
Molecular Formula Anal. Calcd/(Found)
ν (cm-1)
δ (ppm) J (Hz)
(Solvent of Crystallization)
C
H
N
_____________________________________________________________________________________________________________
1d
1e
1f
145
138
129
125
164
163
124
151c
137
128
72
3230, 3180,
3100, 1680
2.62 (s, 3H), 7.79-8.29 (m, 4H), C10H8N4O4
11.86 (s, 1H) (benzene)
48.39 3.25 22.57
(48.20) (3.20) (22.60)
3220, 3170,
3100, 1690
2.63 (s, 3H), 7.75-7.94 (m, 4H), C11H8N3O2F3
11.77 (s, 1H) (benzene)
48.72 2.97 15.49
(48.60) (2.90) (15.40)
3220, 3160,
3100, 1680
2.62 (s, 3H), 6.74.8.14 (m, 3H), C8H7N3O3
11.40 (s, 1H) (benzene)
49.75 3.65 21.75
(49.60) (3.50) (21.60)
1g
1h
2d
2e
2f
3220, 3160,
3080, 1660
2.63 (s, 3H), 7.18-8.21 (m, 3H), C8H7N3O2S
45.93 3.37 20.08
(45.80) (3.50) (20.20)
11.57 (s 1H)
(benzene)
3230, 3180,
3100, 1690
2.64 (s, 3H), 12.34 (s, 1H)
C10H4N3O2F5
(benzene)
40.97 1.38 14.33
(40.80) (1.50) (14.10)
3230, 3180,
3100, 1680
2.19 (s, 3H), 7.80- 8.29 (m, 4H), C10H8N4O4
11.38 (s, 1H) (Ethyl acetate)
48.39 3.25 22.57
(48.30) (3.20) (22.50)
3200, 3180,
3100, 1690
2.18 (s, 3H), 7.60-8.13 (m, 3H), C11H8N3O2F3
48.72 2.97 15.49
(48.50) (2.80) (15.30)
11.39 (s, 1H)
(benzene)
3220, 3190,
3130, 1690
2.21 (s, 3H), 6.73-7.89 (m, 3H),
11.28 (s, 1H)
2g
2h
5a
3220, 3190,
3100, 1690
2.17, (s, 3H), 7.18-8.20 (m, 3H), C8H7N3O2S
45.93 3.37 20.08
(45.80) (3.50) (20.30)
11.28 (s, 1H)
(benzene)
3220, 3160,
3100, 1680
2.20 (s, 3H),
11.55 (s, 1H)
C10H4N3O2F5
(benzene)
40.97 1.38 14.33
(40.80 (1.20) (14.20)
3260, 3200,
3120, 1690
0,93 (t, 3H, J = 7), 1.63 (q, 2H,
J = 7), 2.41 (t, 2H, J = 7), 2.59
(s, 3H), 11.01 (s, 1H)
C7H11N3O2
(benzene)
49.70 6.55 24.84
(49.80) (6.60) (24.70)
5b
5c
81
85
3230, 3180,
3100, 1690
1.39 (s, 9H), 2.39 (s, 3H),
11.06 (s, 1H)
C8H13N3O2
(benzene)
52.45 7.15 22.94
(52.20) (6.90) (22.70)
3240, 3180,
3100, 1690
0.91 (t, 3H, J = 7), 1.20-1.40
(m, 18H),2.41 (t, 2H, J = 7),
2.58 (s, 3H),10.95 (s, 1H)
C15H27N3O2
(benzene)
64.03 9.67 14.93
(64.10) (9.60) (14.80)
6a
82
3220, 3180,
3100, 1680
0.95 (t, 3H, J = 7), 1.75 (m, 2H), C7H11N3O2
49.70 6.55
24.84
2.12 (s, 3H), 2.88 (t, 2H, J = 7),
(benzene)
(49.70) (6.50) (24.80)
11.04 (s, 1H)
6b
6c
123
90
3240, 3180,
3100, 1690
1.41 (s, 9H), 2.11 (s, 3H),
11.11 (s, 1H)
C8H13N3O2
(benzene)
52.45 7.15
22.94
(52.30) (7.20) (22.90)
3240, 3180,
3100, 1690
0.89 (t, 3H, J = 7), 1.20-1.40
(m, 18H), 2.12 (s, 3H), 2.86 (t,
2H, J = 7), 11.00 (s, 1H)
C15H27N3O2
(benzene)
64.03 9.67 14.93
(64.10) (9.50) (14.80)
_____________________________________________________________________________________________________________
a For compounds (1a-c) and (2a-c), see ref.21
b Melting points can be affected by the thermally induced rearrangement.
c Lit.,25 mp 151°C.
Because of the expected structure-depending reactivity of 3-acylaminooxadiazoles towards the ring-
degenerate interconversions,2b,3c,21 it was not surprising that this approach was not applicable to the
synthesis of 3-amino-5-perfluoroalkyl compounds. In fact, the representative 3-perfluorooctanoylamino

compound (8) remained unchanged both on melting at 120 °C and on refluxing in ethanol; obviously, this
result reflects the low nucleophilicity of the carbamoyl oxygen in inducing the ring O-N bond fission.27
On the other hand, acetylation of the 3-amino-5-perfluoroheptyloxadiazole (10) did not give the
acetylamino compound (9) since the reaction directly gave the counterpart oxadiazole (8) as a result of
the ring-rearrangement of the oxadiazole (9) soon after it is formed; in this case, both the nucleophilicity
of the carbamoyl oxygen and the powerful electron withdrawing character of the perfluoroalkyl moiety
would play a decisive role.
Table 3. Physical and Analytical Data for 3-Aminooxadiazoles (4) and (7).
_________________________________________________________________________________________________________________
Compound mp IR(nujol) 1H NMR (DMSO-d6/TMS),
(°C) δ (ppm), J (Hz)
ν (cm-1)
MS
Molecular Formula
Anal. Calcd/(Found)
m/z (%)
(Solvent of Crystallization)
C
H
N
_________________________________________________________________________________________________________________
4a
4b 188
170a
3320, 3190 6.60 (s, 2H), 8.00-8.25
(m, 4H)
229 (M+) (72), 172
(100), 145 (37)
C9H6N3O F3
(Ethanol)
47.17 2.64 18.34
(47.20) (2.60) (18.10)
4c
149
3320, 3190 6.59 (s, 2H), 7.82-8.35
(m, 4H)
229 (M+) (61), 172
(100), 145 (38)
C9H6N3OF3
(Ethanol)
47.17 2.64 18.34
(47.10) (2.50) (18.20)
4d 190
3380, 3320, 6.65 (s, 2H), 7.94-8.20
3240, 3180 (m, 4H)
206 (M+) (2), 134
(100), 104 (88)
C8H6N4O3
(Ethanol)
46.61 2.93 27.18
(46.50) (2.90) (27.60)
4e
4f
145
3360. 3170 6.59 (s, 2H), 7.91-8.07
(m, 4H)
229 (M+) (42), 172
(40), 152 (100)
C9H6N3OF3
(Ethanol)
47.17 2.64 18.34
(47.10) (2.60) (18.30)
163b 3320, 3180 6.51 (s, 2H), 6.84-8.12
(m, 3H)
151 (M+) (100), 121
(6), 94 (79)
4g
150c 3360, 3320, 6.49 (s, 2H), 7.32-8.05 167 (M+) (86), 137
C6H5N3OS
(Ethanol)
43.11 3.01 25.13
(43.20) (2.90) (25.00)
3220, 3190 (m, 3H)
(6),110 (100)
4h 175d
4i
190
3360, 3330, 6.67 (s, 2H), 8.05
3240, 3200 (m, 2H),
233 (M+) (99), 176 (83)
C8H3N3OF4
41.22 1.30 18.02
(41.10) (1.20) (18.10)
156 (24)99 (31), 58 (100) (benzene)
4j
193
101e
74
3340, 3240 6.62 (s, 2H), 7.55-8.00 215 (M+) (83), 158 (100), C8H4N3O F3
44.66 1.87 19.53,
(44.50) (1.80) (19.50)
3200
(m, 2H)
138 (23), 81 (25), 58 (46) (benzene)
7a
7b
3360, 3340, 1.37 (s, 9H), 6.25
3240, 3190 (s, 2H)
141 (M+) (22), 126 (17), C6H11N3O
51.05 7.85 29.76
(51.00) (7.80) (29.80)
111 (16)
(benzene)
7c
65f
3340, 3300, 0.91 (t, 3H, J = 7),
3220, 3180 1.25-1.40 (m, 18H),
2.75 (t, 2H, J = 7)),
239 (M+) (3), 223 (10),) C13H25N3O
112 (100) (benzene)
65.23 10.53 17.55
(65.30) (10.40) (17.50)
6.22 (s, 2H)
______________________________________________________________________________________________________
a Lit.,11a mp 169-170 °C.
b Lit.,25 mp 163 °C.
c Lit.,26 mp 160-162 °C
d Lit.,7 mp 174-175 °C.
e
Lit.,15 mp 101 °C.
f Lit.,11b,e,13 does not report mp for 7c prepared by the acylcyanamide method11b,e or by oxidative cyclization.13

Scheme 3
H
N
H
N
H2N
C7F15
Me
∆
N
N
MeCOCl
Pyridine
N
N
O
O
N
N
Me
C7F15
C7F15
O
O
O
8
10
9
In conclusion, the use of the 3-amino-5-methyl-1,2,4-oxadiazole synthon as a O,N-protected N-
hydroxyguanidine could represent a generalized and efficient methodology for the synthesis of 3-amino-
5-substituted 1,2,4-oxadiazoles; moreover, this approach appears of some significance for those targeted
3-aminooxadiazoles (e.g., 5-polyfluoroaryl-substituted compounds) which would be hard to obtain by
literature methods.
EXPERIMENTAL
General: Melting points were determined on a Reichart-Thermovar hot-stage apparatus and are
1
uncorrected. IR spectra (Nujol) were determined with a Perkin Elmer 257 instrument; H-NMR spectra
were recorded on a Bruker AC 250 E spectrometer, and GC/MS determinations were carried out by using
a VARIAN STAR 3400 CX/SATURN 2000 system. Flash chromatography was performed by using
silica gel (Merck, 0.040-0.063 mesh) and mixtures of EtOAc and light petroleum (fraction boiling in the
range 40-60°C) in varying ratios. Reagents and solvents were used as received from Aldrich.
Compound (3) has been prepared by a modification of the literature method.16 Thus, a mixture of freshly
purified cyanamide (9.5 g, 0.22 mol) and hydroxylamine hydrochloride (14.7 g, 0.22 mol) in dry ethanol
(100 mL) was refluxed for 8 h. After removal of the solvent under reduced pressure, potassium acetate
(30 g, 0.31 mol) and then acetic anhydride (50 mL, 0.53 mol) were added to the syrupy residue. The
resulting mixture was gently refluxed (30 min) and then poured into ice-water (300 g). The solution was
made strongly basic with solid sodium hydroxide (about 45 g) and then kept at 80 °C (boiling water-
bath) for 45 min. After cooling, repeated extraction with ether (6 x 100 mL) and removal of the solvent
gave 3-amino-5-methyl-1,2,4-oxadiazole (3) (8 g; 36%) which was crystallized from benzene (mp 119-
121 °C; lit.,16 mp 117-119 °C).
1
Analytical determinations of the equilibration mixtures were carried out by H-NMR spectral technique,
by integrating the methyl singlets in the δ ranges 2.39-2.65 [characteristic of the C-5 methyl of 3-
aroylamino compounds (1) or 3-alkanoylamino compounds (5)] and 2.11-2.25 ppm [characteristic of the

methyl group of the acetylamino moiety in compounds (2) or (6)], respectively. Compositions at
equilibrium are expressed in % of the two isomers (within 1-2%).
3-Aroylamino-5-methyl-1,2,4-oxadiazoles (1): The aroylamino compounds (1a-c) have been already
described in our previous papers.19,21,23 Similarly, aroylamino compounds (1d-h) have been prepared by
reacting 3-amino-5-methyl-1,2,4-oxadiazole (3) with the appropriate aroyl chloride according to this
previous procedure. Thus, in the cases of 1d-g, the aroyl chloride (0.012 mol) was added to a solution of
the amino compound (3) (1 g, 0.01 mol) in anhydrous benzene (150 mL) containing pyridine (0.95 g,
0.012 mol), and the mixture was allowed to stand at rt (with stirring) for about 10 days, following the
course of the reaction by TLC analysis. In the case of 1h, because of the high reactivity of the
pentafluorobenzoyl chloride, the reagent was previously diluted in anhydrous benzene (50 mL) and then
added to the amino substrate slowly under stirring. The mixture was then allowed to stand for 24 h. For
all reactions, the solvent was removed under reduced pressure and the residue was worked up with water
and filtered off. The crude material was then suitably purified by column chromatography or by
crystallization, affording the aroylamino compounds (1) in 75-80% yields. If necessary, analytical sample
(checked by NMR spectrometry) was recrystallized. Selected physical and spectral data for compounds
(1d-h) prepared are reported in Table 2.
Analytical equilibration between the 3-aroylaminooxadiazoles (1a-c) and the corresponding 3-
acetylamino derivatives (2a-c) has been already reported.21 Similarly, samples of the aroylamino
compounds (1d-h) (0.018 mmol) in CD3OD (1 mL) were mantained in NMR tubes at 40 °C until constant
mixture composition between the two isomers (Table 1). For preparative purposes, the equilibration can
be realized by refluxing the aroylamino compounds in ethanol (see after). In the representative case of 1h,
the equilibration has been also attained by refluxing 2h in ethanol. Analytical samples of compounds (2d-
h) have been obtained by acetylation of the corresponding 3-aminooxadiazoles (4) with acetyl chloride in
pyridine, working up by conventional procedures (Table 2).
Synthesis of 3-Amino-5-aryl-1,2,4-oxadiazoles (4): A sample of the 3-aroylamino compound (1) (2.5
mmol) in ethanol (100 mL) was refluxed for 10 h (to reach equilibration between 1 and 2). Concentrated
hydrochloric acid (1 mL) was then added and the mixture was refluxed for additional 8 h (12 h in the
cases of 1f and 1h), monitoring the hydrolysis by TLC analyses. After neutralization with aqueous (20%)
potassium hydroxide, the solvent was removed under reduced pressure and the residue chromatographed
to give the 3-aminooxadiazoles (4) (see Table 3). To avoid base-induced nuclephilic substitution at the
C(5)-polyfluorophenyl moiety, in the case of synthesis of 4h-j the final hydrolysis mixture was not
neutralized.

In a typical one-pot procedure, to a sample of 3 (0.5 g, 5 mmol) in dry benzene (100 mL) containing
pyridine (0.45 mL, 5.5 mmol) benzoyl chloride (0.65 mL, 5.5 mmol) was added and the mixture was
refluxed for 8 h. The solvent was removed under reduced pressure and then ethanol (100 mL) was added
to the residue and boiling continued for an additional 10 h. The hydrolysis step then follows as above:
after addition of concentrated hydrochloric acid (1 mL), the mixture was refluxed (8 h) and then
neutralized with aqueous (20%) potassium hydroxide; after removal of the solvent, chromatography
(eluant: light petroleum/ EtOAc 5:1) of the residue gave 3-amino-5-phenyl-1,2,4-oxadiazole (4a) (0.57 g,
70%).
A similar procedure was also representatively tested for the preparation of compounds (4e, 4f) and the
pentafluorophenyl derivative (4h), and then applied successfully for the preparation of 5-
polyfluorophenyl substituted oxadiazoles (4i,j) (see Table 1).
3-Alkanoylamino-5-methyl-1,2,4-oxadiazoles (5): To a sample of 3 (0.5 g, 5 mmol) in dry benzene (100
mL) containing pyridine (0.45 mL, 5.5 mmol) the alkanoyl chloride (5.5 mmol) was added and the
mixture was refluxed for 8 h. After removal of the solvent under reduced pressure, the residue was
worked up with water. In the case of 5c the product separated was filtered off and crystallized. In the
cases of 5a,b the mixture was neutralized with solid sodium hydrogen carbonate and extracted with
EtOAc (3 x 50 mL) which was washed with water and dried (Na2SO4). The organic solvent was removed
and the residue crystallized. (see Table 2).
The equilibration between 3-alkanoylaminooxadiazoles (5) and the corresponding 3-acetylamino
derivatives (6) was reached by melting compounds (5) in an oil-bath at 120 °C for 90 min and cheked by
1H-NMR spectral technique (Table 1). Analytical samples of 6 have been obtained by acetylation of the
3-amino compounds (7) (2.5 mmol) with acetyl chloride (0.2 mL, 2.7 mmol) in dry benzene (50 mL)
containing pyridine (0.2 mL, 2.7 mmol) under reflux (4 h), by using conventional procedures (Table 2).
Preparative scale equilibration between compounds (5) and (6) has been achieved by refluxing
compounds (5) (5 mmol) in ethanol (100 mL) for 12 h. An analytical sample of the resulting equilibration
mixture (after removing of the solvent and 1H-NMR spectral analysis of the residue) confirmed the above
composition.
Synthesis of 3-Amino-5-alkyl-1,2,4-oxadiazoles (7): To a sample of 3 (0.5 g, 5 mmol) in anhydrous
benzene (100 mL) containing pyridine (0.45 mL, 5.5 mmol) suitable alkanoyl chloride (5.5 mmol) was
added and the mixture was refluxed for 8 h. The solvent was removed under reduced pressure and then
ethanol (100 mL) was added to the residue allowing to reflux for additional 12 h. The hydrolysis step then
follows as above: after addition of concentrated hydrochloric acid (1 mL), the mixture was refluxed (4 h)
and then neutralized with aqueous (20%) potassium hydroxide; after removing of the solvent,

chromatography (eluant: light petroleum/ EtOAc 1:1) of the residue gave at first the 3-amino-5-alkyl-
1,2,4-oxadiazole (7a-c) (50%) (see Tables 1 and 3) and then starting amino compound (3) (0.2 g, 40%).
3-Perfluorooctanoylamino-5-methyl-1,2,4-oxadiazole (8): To a sample of 3 (0.5 g, 5 mmol) in dry
benzene (100 mL) containing pyridine (0.5 mL, 6 mmol) the perfluorooctanoyl chloride (1.5 mL, 6
mmol) diluted in dry benzene (30 mL) was added slowly under stirring, and then the mixture was left at rt
for 48 h. After removal of the solvent under reduced presure, the residue was worked-up with water and
filtered giving compound (8) (2.1 g, 86%), mp 98-100 °C (from benzene). Compound (8) had IR cm-1
1
3250, 3200, 3100, H NMR (DMSO-d6) δ 2.63 (s, 3H), 13.00 (s, 1H). Anal. Calcd for C11H4N3O2F15. C,
26.68; H, 0.81; N, 8.49. Found: C, 26.50; H, 0.90; N, 8.30.
Compound (8) remained unchanged after: i) refluxing (4 h) in ethanol; ii) melting at 120 °C (2 h).
Attempts to intercept compound (9) (by 1H-NMR spectral analysis) failed. Treating compound (10)6 (0.15
g) with a slight excess of acetyl chloride (0.2 mL) in pyridine (5 mL) at rt (24 h), removal of the solvent
under reduced pressure and chromatography directly gave 8 (60%). Similarly, after refluxing compound
(10) with a slight excess of acetyl chloride in benzene containing pyridine (16 h), removal of the solvent
and chromatography gave 8 (70%).
ACKNOWLEDGEMENT
The authors are indebted to prof. D. Spinelli (University of Bologna) for useful criticism and Mr. M.
Cascino (University of Palermo) for valuable technical assistance. The financial support from Italian
MIUR within the National Research Project “Fluorinated Compounds: Synthetic Targets and Advanced
Applications” and CNR is gratefully acknowledged.
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