Fluorinated heterocyclic compounds. A photochemical synthesis of 3-amino-5-perfluoroaryl-1,2,4-oxadiazoles

Article abstract of DOI:10.1016/S0040-4020(01)00524-5

A photochemical methodology for the synthesis of 3-amino- (or 3-N-substituted amino) 5-pentafluorophenyl-1,2,4-oxadiazoles is reported. Irradiation of 3-pentafluorobenzoylamino-4-methyl-1,2,5-oxadiazole (Furazan) at 254 nm in methanol and in the presence of ammonia, primary or secondary aliphatic amines produces 3-amino-, 3-(N-alkylamino)-, 3-(N,N-dialkylamino)-5-pentafluorophenyl-1,2,4-oxadiazoles. The photoreaction follows the fragmentation pattern of the furazan ring with the extrusion of acetonitrile and the formation of a counterpart fragment which the nitrogen nucleophile will capture. Depending on the nature of the reagent, displacement of a fluoride anion at the C(5)-pentafluorophenyl moiety of the first-formed oxadiazoles by the nitrogen nucleophile and/or the solvent also takes place. By the same photochemical approach, the synthesis of the 3-methoxy-5-pentafluorophenyl-1,2,4-oxadiazole is also described.

Full text of DOI:10.1016/S0040-4020(01)00524-5

TETRAHEDRON
Pergamon
Tetrahedron 57 *2001) 5865±5871
Fluorinated heterocyclic compounds. A photochemical synthesis
of 3-amino-5-per¯uoroaryl-1,2,4-oxadiazoles
a
Silvestre Buscemi, Andrea Pace, Rosa Calabrese, Nicolo Vivona and Pierangelo Metrangolo
a
a
a,p
b
Á
a
Á Á
Dipartimento di Chimica Organica `E. Paterno', Universita degli Studi di Palermo, Viale delle Scienze-Parco d'Orleans II,
I-90128 Palermo, Italy
bDipartimento di Chimica, Politecnico di Milano, Via Mancinelli 7, I-20131 Milan, Italy
Received 6 February 2001; revised 18 April 2001; accepted 10 May 2001
AbstractÐA photochemical methodology for the synthesis of 3-amino- *or 3-N-substituted amino) 5-penta¯uorophenyl-1,2,4-oxadiazoles
is reported. Irradiation of 3-penta¯uorobenzoylamino-4-methyl-1,2,5-oxadiazole *Furazan) at 254 nm in methanol and in the presence of
ammonia, primary or secondary aliphatic amines produces 3-amino-, 3-*N-alkylamino)-, 3-*N,N-dialkylamino)-5-penta¯uorophenyl-1,2,4-
oxadiazoles. The photoreaction follows the fragmentation pattern of the furazan ring with the extrusion of acetonitrile and the formation of a
counterpart fragment which the nitrogen nucleophile will capture. Depending on the nature of the reagent, displacement of a ¯uoride anion at
the C*5)-penta¯uorophenyl moiety of the ®rst-formed oxadiazoles by the nitrogen nucleophile and/or the solvent also takes place. By the
same photochemical approach, the synthesis of the 3-methoxy-5-penta¯uorophenyl-1,2,4-oxadiazole is also described. q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
In the context of our research dealing with ¯uorinated ®ve-
membered heterocycles, we became interested in the
synthesis of 1,2,4-oxadiazoles bearing at C*3) a functional
group which can confer speci®c properties on the ¯uori-
nated molecule. In this connection, it appears worthwhile
to note that 1,2,4-oxadiazoles have been receiving great
attention in the pharmaceutical industry.3,4 In fact, oxa-
diazoles have been described as peptidomimetics,3 or as
bioisosteres for amides and esters,4 and some 3-amino
derivatives have been found to act as potent and ef®cacious
muscarinic agonists.4a,b In this context we recently
reported5 a photochemical approach to 3-amino-, and
A growing interest in ¯uorinated heterocycles owing to
their applications in industrial or pharmaceutical areas
currently prompts development of new synthetic
methodologies for targeted compounds.1 Alongside the
direct ¯uorination or per¯uoroalkylation reactions,
widely applicable approaches to ¯uorinated heterocycles
exploit modi®cations of ¯uorinated precursors, or the
construction of the targeted structure by using ¯uorinated
fragments in cycloadditions or cyclocondensations.1 A very
promising methodology can also be recognized in the ring-
rearrangement reactions of suitable ¯uorinated hetero-
cycles, and among these reactions, a very soft strategy
would be photoinduced rearrangements of O±N bond
containing azoles.2
3-*N-alkylamino)-5-per¯uoroalkyl-1,2,4-oxadiazoles
*2)
by photolysis of 3-per¯uoroalkanoylamino-4-phenyl-1,2,5-
oxadiazoles *furazans) *1) at 313 nm in methanol and in the
presence of nitrogen nucleophiles such as ammonia, or
Scheme 1.
Keywords: ¯uorinated aminooxadiazoles; penta¯uorobenzoylaminofurazans; photochemistry; per¯uoroaryloxadiazoles.
Corresponding author. Fax: 139-091-596825; e-mail: nvivona@unipa.it
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020*01)00 524-5

5866
S. Buscemi et al. / Tetrahedron 57 32001) 5865±5871
primary aliphatic amines *Scheme 1). This photoreaction,
which had been previously reported for non-¯uorinated
systems,6 is explained by assuming a photoinduced ring
fragmentation2a,b into benzonitrile and a nitriloxide species
that the nucleophilic reagent will capture to give an N-acyl-
aminoamidoxime intermediate as a precursor of the ®nal
product. Unlike non-¯uorinated 5-alkyl-1,2,4-oxadiazoles,
Irradiations of compound 4 in the presence of a large excess
of methanolic ammonia allowed us to isolate both the
3-amino-5-penta¯uorophenyl-1,2,4-oxadiazole *6a) and
the 5-*2,3,5,6-tetra¯uoro-4-methoxyphenyl)- derivative 7a
in different ratios depending on the work-up procedure
*Scheme 2). In a typical experiment, allowing the photoly-
sate to stand for 24 h in the dark, 6a and 7a were isolated in
15 and 25% yields, respectively. Some minor products were
present; among these, signi®cative amounts of the penta-
¯uorobenzamide *likely arising from ammonolysis of
open-chain intermediates) were obtained. Monitoring the
photoreaction by TLC analyses, we observed that soon
after the irradiation only trace amounts of ®nal products
6a and 7a were present, whereas a signi®cant species *likely
the supposed N-acylaminoamidoxime 5a) was detected. *A
quick work-up procedure of the photolysate performed
immediately after irradiation allowed us to isolate 5a,
which, if kept in methanolic triethylamine, slowly gave 6a
and 7a together with other by-products.) On the other hand,
when the photolysate was allowed to stand for more than
24 h, yields of 6a decreased, whereas yields of 7a increased.
Consequently, the formation of the latter in the photo-
reaction can be explained by assuming a base-assisted
solvolysis taking place at the C*5)-penta¯uorophenyl ring
of the initially formed 6a, and this hypothesis was also
con®rmed by a separate reaction of 6a with methanolic
triethylamine. Solvolytic displacement of a ¯uoride anion
in 6a leading to 7a is activated by the electron-de®cient
oxadiazole heterocycle, as similar nucleophilic displace-
ment of ¯uoride does not take place in the penta¯uoro-
benzoylamino compound 4. When we tried to prepare the
3-aminooxadiazole 6a by non-photochemical methodology,
we found that attempts to achieve 6a by the acylcyanamide
route were unsuccessful. On the other hand, the penta-
¯uorobenzoylation/cyclodehydration route of N-hydroxy-
guanidine allowed us to obtain 6a in very low overall
yields.14
5-per¯uoroalkyl compounds
2 showed some photo-
reactivity, thus suggesting irradiation at low conversion of
starting material. For these reasons, yields of the isolated
oxadiazoles 2 were not excellent; however, this photo-
chemical methodology has advantages when compared
with the troublesome non-photochemical procedures.
In order to extend this photochemical methodology to the
synthesis of different ¯uorinated oxadiazoles, we have now
considered a similar approach for the synthesis of 5-penta-
¯uorophenyl-1,2,4-oxadiazoles bearing an amino, N-alkyl-
amino, or N,N-dialkylamino group at the C*3) of the ring.
Conventional methodologies7 for the synthesis of these
¯uoro-substituted compounds would present some
dif®culties. In fact, 3-aminooxadiazoles *but not their
N-substituted derivatives) are generally obtained by the
reaction of N-acylcyanamides with hydroxylamine followed
by heterocyclization of resulting intermediates.8 Other
methods *which have been also used for the preparation
of N-substituted derivatives) include the reaction of
N-aroyl-S-methylisothioureas9 with hydroxylamine, oxida-
tive cyclization of N-acylguanidines10 and the reaction of
N-hydroxyguanidine with acylating reagents in an acyl-
ation/cyclodehydration pattern.4a±c In some instances,11,12
3-*N-substituted amino)oxadiazoles have been obtained
from the corresponding 3-halo compounds by nucleophilic
displacement of the halide ion with primary or secondary
aliphatic amines. To realize our aim, we then looked at the
photolysis of 3-penta¯uorobenzoylamino compound 4
irradiated in the presence of ammonia, primary or secondary
aliphatic amines, relying on the regiochemistry of the
furazan ring breaking *which involves the O*1)±N*5)
bond and extrusion of acetonitrile) already observed2b,12
for un¯uorinated analogues.
We next examined irradiations of compound 4 in the
presence of methylamine and propylamine as representative
primary aliphatic amines. Irradiation of 4 in the presence of
methylamine and work-up of the photolysate after 24 h gave
7b and 8b. On the other hand, by working up the photolysate
soon after irradiation the expected 6b, 7b and 8b were
isolated. In turn, irradiations in the presence of propylamine
gave 6c and 7c, whereas 8c was not detected. Again, oxa-
diazoles 7b,c and 8b originate from solvolysis or aminolysis
of the ®rst formed oxadiazoles 6b,c *Scheme 2).
2. Results and discussion
Irradiations of the furazan 4, which was easily obtained by
penta¯uorobenzoylation of the 3-amino compound 3,13
were carried out at 254 nm in methanol and in the presence
of a slight excess of the nitrogen nucleophile. This choice
was a compromise to avoid competing reactions with the
nucleophilic solvent on one hand, and to minimize base-
promoted hydrolysis of intermediates, on the other. More-
over, because of the expected photoreactivity of the ®nal
oxadiazoles under experimental conditions, irradiations
have not been run for long times. For these reasons, depend-
ing on the reagent used, photochemical experiments were
carried out in different conditions so as to have ef®cient
synthetic results. Note that, differently from 4-phenyl
substituted furazans 1 *which were irradiated at 313 nm),
irradiations of the 4-methyl substituted furazan 4 were
carried out at 254 nm, and this is because of different
chromophores in the two furazan systems.
As for secondary amines, we studied irradiations in the
presence of dimethylamine, pyrrolidine and morpholine.
In a typical experiment, irradiation of 4 in the presence of
dimethylamine, and work-up of the photolysate soon after
irradiation, gave the expected 3-dimethylamino-5-penta-
¯uorophenyl-1,2,4-oxadiazole *6d) *24%) and the corre-
sponding p-dimethylamino substituted compound 8d
*45%). In turn, when the photolysate was worked up after
standing 24 h, no oxadiazole 6d was isolated, whereas
compound 8d was formed in about 68% yield. A similar
result was observed in the irradiation of 4 in the presence
of pyrrolidine: depending on the work-up procedure,
mixtures of compounds 6e, 7e and 8e, on one hand, or
compounds 7e and 8e, on the other, were obtained. Isolation

S. Buscemi et al. / Tetrahedron 57 32001) 5865±5871
5867
Scheme 2.
of the oxadiazole 6e *in about 28% yield) was realized by
neutralization of the photolysate with hydrochloric acid
soon after the irradiation, followed by column chromato-
graphy. Furthermore, irradiations of 4 in the presence of
morpholine, gave the 3-N-morpholinyl oxadiazole 6f
*35%) and the p-substituted compound 8f *17%).
To verify the possibility of exploiting this photochemical
approach for the synthesis of the 3-methoxy-5-penta¯uoro-
phenyloxadiazole *10), we then examined photolysis of the
furazan 4 in methanol only, relying on the nucleophilic
character of the solvent. *This behavior had been already
pointed out for non-¯uorinated analogues.2b) This irradia-
tion gave a mixture of components from which, after
standing of the photolysate for 24 h, we isolated the
O-acylamidoxime 9 [*50%); likely arising from the corre-
sponding N-acylamidoxime *5; ZˆOMe), or from a
carbodiimide species; see un¯uorinated analogues2b], but a
few percent of the oxadiazole 10 *Scheme 3). Low yields of
the oxadiazole component could be due to the competing
development of open-chain intermediates. On the other
hand, subsequent photoreactivity of the ®rst-formed
3-methoxyoxadiazole 10 under the reaction conditions
could also play a role. *A complete study on photo-
reactivities of ¯uorinated 1,2,4-oxadiazoles will follow.)
Nevertheless, the oxadiazole 10 was ef®ciently obtained
by thermal cyclodehydration of 9.
As for the structure of substituted compounds 7 and 8, 19F
NMR analyses unequivocally proved the entry of the
oxygen or nitrogen nucleophiles in the para position of
the penta¯uorophenyl ring. Two doublets with a coupling
constant of ca 20Hz were present in the spectra of all
compounds, as expected for the presence of two ortho posi-
tioned pairs of ¯uorine atoms, but with line broadening or
further few Hz splittings of these doublets resulting from the
para and meta couplings.15 Comparison with similarly
substituted tetra¯uorophenyl ring16 allowed the upper and
lower ®eld doublets *in the ranges 2153.2/2162.9 and
2138.1/2140.1 ppm, respectively) to be assigned to the
¯uorine atoms ortho and meta to the entering nucleophile,
respectively. At this stage we have not studied the in¯uence
of different parameters involved in the formation of these
substituted compounds, or the competition between
solvolysis and aminolysis reactions.
In conclusion, all the results described in this paper, together
with those previously reported,5 show that this unprece-
dented photochemical approach17 appears as an ef®cient

5868
S. Buscemi et al. / Tetrahedron 57 32001) 5865±5871
Scheme 3.
methodology for the synthesis of 1,2,4-oxadiazoles bearing
a per¯uorinated aryl moiety at C*5) and an amino, N-alkyl-
amino, N,N-dialkylamino or a methoxy group at C*3).
Although yields were not excellent *they could be improved
by optimizing experimental conditions), these results appear
to be of some signi®cance in view of troublesome non-
photochemical procedures for the synthesis of these
compounds. Moreover, they open new synthetic strategies
toward targeted ¯uorinated structures, by exploiting photo-
induced rearrangements of suitable ¯uorinated heterocyclic
precursors.
chromatography and then by crystallization from benzene
containing light petroleum. Yield 70%; mp 184±1868C. IR:
3240, 3200, 3180, 3095, 1690 cm21. 1H NMR *DMSO-d6):
d 2.83 *s, 3H), 12.39 *s, 1H). MS m/z: 293 *2) *M1), 250
*11), 195 *100), 167 *13), 117 *30), 93 *4). Anal. Calcd for
C10H4F5N3O2: C, 40.97; H, 1.38; N, 14.33. Found: C, 41.10;
H, 1.50; N, 14.45.
3.2. General procedure for irradiation of compound 4 in
the presence of nitrogen nucleophiles
To a solution of compound 4 *0.5 g; 1.7 mmol) in anhydrous
methanol *300 mL) the appropriate nitrogen nucleophile
was added [i.e. methanolic ammonia *5 mL; 30mmol),
methanolic methylamine *1.1 mL; 8.5 mmol), propylamine
*0.7 mL; 8.5 mmol), methanolic dimethylamine *1.5 mL;
8.5 mmol), pyrrolidine *0.7 mL; 8.5 mmol), and morpholine
*0.75 mL; 8.5 mmol)]. The mixture was apportioned into six
quartz tubes and then irradiated for 1.5 h. The photolysates
were then worked up as reported below. After removal of
the solvent under reduced pressure at room temperature, the
residue was chromatographed. Amounts of untractable
materials or minor components were discarded.
3. Experimental
3.1. Material and methods
Melting points were determined with a Ko¯er hot-stage
apparatus and are uncorrected. IR spectra *Nujol) were
determined with a Perkin±Elmer 257 instrument, H NMR
1
spectra were recorded on a Bruker 250E spectrometer, and
19F NMR on a Bruker AV 500 instrument *bd stands for
broad doublet). GC/MS determinations were carried out
by using a VARIAN STAR 3400 CX/SATURN 2000
system. Flash chromatography was performed by using
mixtures of ethyl acetate and light petroleum *fraction boil-
ing in the range of 40±608C) in varying ratios. Freshly
prepared saturated methanolic ammonia, ethanolic *33%)
methylamine and dimethylamine *Fluka), propylamine
*Aldrich), and freshly distilled pyrrolidine or morpholine
*Aldrich) were used. Photochemical reactions were carried
out in anhydrous methanol *Romil Co.) in quartz vessels, by
using a Rayonet RPR-100 photoreactor, equipped with 16
Hg-lamps irradiating at 254 nm *RPR-25378) and a merry-
go-round apparatus.
3.2.1. Irradiation of compound 4 in the presence of
ammonia. The photolysate was left to stand for 24 h in
the dark. Chromatography of the residue returned starting
material *0.1 g; 20%), and gave the 3-amino-5-penta¯uoro-
phenyl-1,2,4-oxadiazole *6a) *0.064 g; 15%), the 3-amino-
5-*2,3,5,6-tetra¯uoro-4-methoxyphenyl)-1,2,4-oxadiazole
*7a) *0.11 g; 25%), and then some amounts of penta¯uoro-
benzamide *0.036 g; 10%), mp 146±1478C.
Compound 6a had mp 174±1758C *from light petroleum).
1
IR: 3400, 3330, 3240 cm21. H NMR *DMSO-d6): d 6.76
*s). MS m/z: 251 *79) *M1), 194 *35), 117 *59), 93 *21), 58
*100). Anal. Calcd for C8H2F5N3O: C, 38.26; H, 0.8; N,
16.73. Found: C, 38.40; H, 1.0; N, 16.90.
3.1.1. 3-Penta¯uorobenzoylamino-4-methylfurazan +4).
Compound 4 was prepared by reacting 3-amino-4-methyl-
furazan *3)13 *3 g, 30mmol) with penta¯uorobenzoyl
chloride *7.6 g, 33 mmol) in anhydrous benzene *100 mL)
containing pyridine *2.7 mL, 33 mmol). Addition of the acyl
chloride *diluted in 50mL of anhydrous benzene) was made
slowly and with stirring, and then the mixture was left at
room temperature for 24 h. After removal of the solvent
under reduced pressure, the residue was worked-up with
water and then ®ltered. The crude mixture was puri®ed by
Compound 7a had mp 192±1938C *from light petroleum).
IR: 3380, 3320, 3230 cm21. 1H NMR *DMSO-d6): d 4.25 *s,
3H), 6.69 *s, 2H). 19F NMR *CDCl3): d 2138.10*bd, 2F,
Jˆ20.8 Hz), 2157.84 *bd, 2F, Jˆ19.5 Hz). MS m/z: 263
*90) *M1), 206 *100), 163 *11), 117 *25), 58 *31). Anal.
Calcd for C9H5F4N3O2: C, 41.08; H, 1.92; N, 15.97.
Found: C, 41.20; H, 2.0; N, 16.10.

S. Buscemi et al. / Tetrahedron 57 32001) 5865±5871
5869
In a further experiment, a sample of 4 *0.25 g) in methanol
*150mL) containing methanolic ammonia *4 mL) appor-
tioned in three tubes was irradiated for 1 h and then the
solvent was removed soon after the irradiation. A quick
chromatography, after discarding ®rst fractions containing
mixtures of the starting material and oxadiazole components
*see before), gave almost pure 5a *0.1 g; 43%); mp 93±988C
*dec). IR: 3480, 3340, 3250, 1720 cm21. 1H NMR *DMSO-
d6): d: 7.43 *br s, 2H), 9.48 and 10.84 *2s, 2H). A sample of
5a in methanolic triethylamine at room temperature slowly
gave 6a and 7a *by HPLC and GC±MS).
propylamino)-5-*2,3,5,6-tetra¯uoro-4-methoxyphenyl)-1,2,
4-oxadiazole *7c) *0.16 g; 30%).
Compound 6c had mp 48±498C *from light petroleum). IR:
3320cm 21. 1H NMR *DMSO-d6): d 0.96 *t, 3H, Jˆ7.4 Hz),
1.61 *m, 2H), 3.14 *m, 2H), 7.39 *t, 1H, Jˆ5.7 Hz). MS m/z:
293 *10) *M1), 264 *100), 195 *82), 167 *26), 117 *51).
Anal. Calcd for C11H8F5N3O: C, 45.06; H, 2.75; N, 14.33.
Found: C, 45.20; H, 2.90; N, 14.50.
Compound 7c had mp 78±808C *from light petroleum). IR:
3290cm 21. 1H NMR *DMSO-d6): d 0.99 *t, 3H, Jˆ7.4 Hz),
1.61 *m, 2H) 3.14 *m, 2H), 4.25 *s, 3H), 7.39 *t, 1H,
Jˆ5.7 Hz). 19F NMR *CDCl3): d 2138.27 *bd, 2F,
Jˆ22.1 Hz), 2157.85 *bd, 2F, Jˆ19.3 Hz). MS m/z: 30 5
*7) *M1), 276 *41), 207 *100), 163 *9), 117 *15). Anal.
Calcd for C12H11F4N3O2: C, 47.22; H, 3.63; N, 13.77.
Found: C, 47.30; H, 3.70; N, 13.90.
A sample of 6a was obtained by reacting equimolar
amounts of N-hydroxyguanidine *crude free base freshly
prepared from S-methylisothiourea and hydroxylamine)18
with penta¯uorobenzoyl chloride. In our hands, the usual
work-up procedure allowed to isolate 6a in very low
yields.14
3.2.2. Irradiation of compound 4 in the presence of
methylamine. The photolysate was left to stand for 24 h.
Chromatography of the residue returned starting material
*0.1 g; 20%), and gave at ®rst the 3-*N-methylamino)-5-
*2,3,5,6-tetra¯uoro-4-methoxyphenyl)-1,2,4-oxadiazole
*7b) *0.14 g; 30%) and then the 3-*N-methylamino)-5-
*2,3,5,6-tetra¯uoro-4-N-methylaminophenyl)-1,2,4-oxa-
diazole *8b) *0.14 g; 30%).
3.2.4. Irradiation of compound 4 in the presence of
dimethylamine. The photolysate was left to stand for
12 h. Chromatography of the residue returned starting
material *0.075 g; 15%), and gave 3-*N,N-dimethylamino)-
5-*2,3,5,6-tetra¯uoro-4-N,N-dimethylaminophenyl)-1,2,4-
oxadiazole *8d) *0.35 g; 68%).
Compound 8d had mp 73±748C *from light petroleum). 1H
NMR *DMSO-d6): d 3.03 and 3.11 *2s, 12H). 19F NMR
*CDCl3): d 2139.48 *bd, 2F, Jˆ19.4 Hz), 2153.23 *bd,
2F, Jˆ18.8 Hz). MS m/z: 304 *57) *M1), 220 *100), 192
*17), 152 *7), 117 *4). Anal. Calcd for C12H12F4N4O: C,
47.37; H, 3.98; N, 18.41. Found: C, 47.5 0; H, 3.90; N,
18.50.
Compound 7b had mp 132±1338C *from light petroleum).
IR: 3340cm 21 1H NMR *DMSO-d6): d 2.81 *d, 3H,
.
Jˆ4.8 Hz), 4.25 *s, 3H), 7.20*q, 1H, Jˆ4.8 Hz). 19F
NMR *CDCl3): d 2138.29 *bd, 2F, Jˆ20.8 Hz), 2157.95
*bd, 2F, Jˆ20.0 Hz). MS m/z: 277 *42) *M1), 207 *39), 117
*22), 72 *41), 42 *100). Anal. Calcd for C10H7F4N3O2: C,
43.33; H, 2.55; N, 15.16. Found: C, 43.40; H, 2.70; N, 15.30.
In a further experiment, the solvent was removed soon after
the irradiation. Chromatography of the residue, besides
starting material *0.075 g; 15%), gave 3-*N,N-dimethyl-
amino)-5-penta¯uorophenyl-1,2,4-oxadiazole *6d) *0 .11 g;
24%) and then 8d *0.23 g; 45%).
Compound 8b had mp 192±1948C *from light petroleum).
IR: 3320cm 21 1H NMR *DMSO-d6): d 2.78 *d, 3H,
.
Jˆ5.0Hz), 3.11 *d, 3H, Jˆ3.0Hz), 6.9±7.1 *m, 2H). 19F
NMR *CDCl3): d 2139.80*bd, 2F, Jˆ19.4 Hz), 2162.92
*bd, 2F, Jˆ22.0Hz). MS m/z: 276 *100) *M1), 206 *59), 178
*10), 138 *18), 117 *14), 83 *42), 42 *87). Anal. Calcd for
C10H8F4N4O: C, 43.49; H, 2.92; N, 20.29. Found: C, 43.40;
H, 2.90; N, 20.20.
Compound 6d had mp 53±548C *from light petroleum). 1H
NMR *CDCl3): d 3.09 *s). MS m/z: 279 *68) *M1), 195 *28),
167 *4), 117 *35), 42 *100). Anal. Calcd for C10H6F5N3O: C,
43.02; H, 2.17; N, 15.05. Found: C, 43.10; H, 2.30; N,
15.20).
In a further experiment, the solvent was removed soon after
the irradiation. Chromatography of the residue gave, besides
starting material *0.1 g; 20%), gave 3-*N-methylamino)-5-
penta¯uorophenyl-1,2,4-oxadiazole *6b) *0.08 g; 18%) and
then 7b *0.05 g; 10%) and 8b *0.10 g; 20%).
3.2.5. Irradiation of compound 4 in the presence of
pyrrolidine. The photolysate was left to stand for 12 h.
Chromatography of the residue returned starting material
*0.075 g; 15%), and gave 3-*N-pyrrolidinyl)-5-*2,3,5,6-
tetra¯uoro-4-methoxyphenyl)-1,2,4-oxadiazole *7e) *0.054
g; 10%), and then 3-*N-pyrrolidinyl)-5-*2,3,5,6-tetra¯uoro-
4-N-pyrrolidinylphenyl)-1,2,4-oxadiazole *8e) *0.36 g; 60%).
Compound 6b had mp 89±928C *from light petroleum). IR:
3280cm 21. 1H NMR *DMSO-d6): d 2.83 *d, 3H, Jˆ5.0Hz),
7.26 *q, 1H, Jˆ5.0Hz). MS m/z: 265 *54) *M1), 195 *56),
167 *7), 117 *42), 93 *12), 72 *38), 42 *100). Anal. Calcd for
C9H4F5N3O: C, 40.77; H, 1.52; N, 15.85. Found: C, 40.70;
H, 1.60; N, 16.0.
1
Compound 7e had mp 75±788C *from light petroleum). H
NMR *CDCl3): d 1.95±2.04 *m, 4H), 3.48±3.54 *m, 4H),
4.20*s, 3H). MS m/z: 317 *44) *M1), 250 *7), 207 *100), 162
*6),117 *25). Anal. Calcd for C13H11F4N3O2: C, 49.22; H,
3.49; N, 13.25. Found: C, 49.30; H, 3.60; N, 13.40).
3.2.3. Irradiation of compound 4 in the presence of
propylamine. The photolysate was left to stand for 12 h.
Chromatography of the residue returned starting material
*0.1 g; 20%), and gave 3-*N-propylamino)-5-penta¯uoro-
phenyl-1,2,4-oxadiazole *6c) *0.15 g; 25%), and 3-*N-
Compound 8e had mp 161±1638C *from light petroleum).
1H NMR *CDCl3): d 1.92±2.05 *m, 8H), 3.48±3.53 *m, 4H),
3.68±3.76 *m, 4H). 19F NMR *CDCl3): d 2140.06 *bd, 2F,

5870
S. Buscemi et al. / Tetrahedron 57 32001) 5865±5871
Jˆ20.8 Hz), 2157.78 *bd, 2F, Jˆ20.8 Hz). MS m/z: 356
*100) *M1), 287 *16), 246 *56), 176 *16), 149 *7). Anal.
Calcd for C16H16F4N4O: C, 53.93; H, 4.53; N, 15.72.
Found: C, 53.80; H, 4.40; N, 15.80.
*71), 117.*42), 44 *100). Anal. Calcd for C9H5F5N2O3: C,
38.04; H, 1.77; N, 9.86. Found: C, 38.20; H,1.90; N, 9.70.
A sample of 9 *0.13 g) was kept in an oil-bath at 1208C for
6 h. Chromatography of the residue returned starting
material *0.065 g; 50%) and gave 10 *0.040 g; 33%).
In a further experiment, soon after the irradiation the
photolysate was neutralized with few drops of hydrochloric
acid and then the solvent was removed. Chromatography of
the residue returned starting material *0.05 g; 10%), and
Acknowledgements
gave 3-*N-pyrrolidinyl)-5-penta¯uorophenyl-1,2,4-oxa-
diazole *6e) *0.15 g; 28%), 7e *0.08 g; 15%) and 8e
*0.24 g; 40%).
Financial support from Italian MURST within the National
Research Project `Fluorinated Compounds: Synthetic
Targets and Advanced Applications' is gratefully acknowl-
edged.
1
Compound 6e had mp 85±868C *from light petroleum). H
NMR *CDCl3): d 2.01 *t, 4H, Jˆ7.4 Hz), 3.49 *t, 4H,
Jˆ7.4 Hz). MS m/z: 305 *85) *M1), 287 *76), 258 *11),
195 *57), 117 *42), 68 *100). Anal. Calcd for
C12H8F5N3O: C, 47.22; H, 2.64; N, 13.77. Found: C,
47.30; H, 2.50; N, 13.90.
References
1. *a) Silvester, M. J. Aldrichimica Acta 1991, 24, 31. *b) Burger,
K.; Wucherpfennig, U.; Brunner, E. Adv. Heterocycl. Chem.
1994, 60, 1 and references cited therein. *c) Furin, G. G.
Target in Heterocyclic Systems, Attanasi, O. A., Spinelli, D.,
3.2.6. Irradiation of compound 4 in the presence of
morpholine. The photolysate was left to stand for 24 h,
and then neutralized with hydrochloric acid. After removal
of the solvent, chromatography of the residue returned start-
ing material *0.1 g; 20%), and gave 3-*N-morpholinyl)-5-
penta¯uorophenyl-1,2,4-oxadiazole *6f) *0.19 g; 35%) and
3-*N-morpholinyl)-5-*2,3,5,6-tetra¯uoro-4-N-morpholinyl-
phenyl)-1,2,4-oxadiazole *8f) *0.11 g; 17%).
Á
Eds.; Societa Chimica Italiana: Roma, 1998; Vol. 2, p 355.
2. *a) Vivona, N.; Buscemi, S. Heterocycles 1995, 41, 2095.
*b) Buscemi, S.; Vivona, N.; Caronna, T. J. Org. Chem.
1995, 60, 4096. *c) Buscemi, S.; Vivona, N.; Caronna, T.
J. Org. Chem. 1996, 61, 8397. *d) Vivona, N.; Buscemi, S.;
Asta, S.; Caronna, T. Tetrahedron 1997, 53, 12629.
*e) Buscemi, S.; Pace, A.; Vivona, N.; Caronna, T.; Galia,
A. J. Org. Chem. 1999, 64, 7028.
1
Compound 6f had mp 80±818C *from light petroleum). H
NMR *CDCl3): d 3.52 *t, 4H, Jˆ4.7 Hz), 3.80*t, 4H,
Jˆ4.7 Hz). MS m/z: 321 *17) *M1), 306 *24), 195 *61),
149 *100), 117 *30). Anal. Calcd for C12H8F5N3O2: C,
44.87; H, 2.51; N, 13.08. Found: C, 44.90; H, 2.50; N, 13.10.
3. Inter alia: *a) Borg, S.; Estenne-Bouhtou, G.; Luthman, K.;
Csoregh, I.; Hesselink, W.; Hacksell, U. J. Org. Chem. 1995,
60, 3112. *b) Young, J. R.; DeVita, R. J. Tetrahedron Lett.
1998, 39, 3931. *c) Hebert, N.; Hannah, A. L.; Sutton, S. C.
Tetrahedron Lett. 1999, 40, 1.
Compound 8f had mp 126±1288C *from light petroleum).
1H NMR *CDCl3): d 3.40±3.43 *m, 4H), 3.51±3.55 *m, 4H),
3.80±3.86 *m, 8H). 19F NMR *CDCl3): d 2138.49 *bd, 2F,
Jˆ21.3 Hz), 2157.85 *bd, 2F, Jˆ17.8 Hz). MS m/z: 388
*88) *M1), 374 *65), 262 *50), 204 *46), 117 *6), 86 *85),
56 *100). Anal. Calcd for C16H16F4N4O3: C, 49.49; H, 4.15;
N, 14.43. Found: C, 49.40; H, 4.10; N, 14.50.
4. See, e.g.: *a) Saunders, J.; Macleod, A. M.; Merchant, K.;
Showell, G. A.; Snow, R. J.; Street, L. J.; Baker, R.
J. Chem. Soc., Chem. Commun. 1988, 1618. *b) Saunders,
J.; Cassidy, M.; Freedman, S. B.; Harley, E. A.; Iversen,
L. L.; Kneen, C.; Macleod, A. M.; Merchant, K. J.; Snow,
R. J.; Baker, R. J. Med. Chem. 1990, 33, 1128. *c) Street,
L. J.; Baker, R.; Book, T.; Kneen, C. O.; Macleod, A. M.;
Merchant, K. J.; Showell, G. A.; Saunders, J.; Herbert, R. H.;
Freedman, S. B.; Harley, E. A. J. Med. Chem. 1990, 33, 2690.
*d) Watjen, F.; Baker, R.; Engelstoff, M.; Herbert, R.;
MacLeod, A.; Knight, A.; Merchant, K.; Moseley, J.;
Saunders, J.; Swain, C. J.; Wong, E.; Spinger, J. P. J. Med.
Chem. 1989, 32, 2282. *e) Orlek, B. S.; Blaney, F. E.; Brown,
F.; Clark, M. S. G.; Hadley, M. S.; Hatcher, J.; Riley, G. J.;
Rosenberg, H. E.; Wadsworth, H. J.; Wyman, P. J. Med.
Chem. 1991, 34, 2726. *f) Diana, G. D.; Volkots, D. L.;
Nitz, T. J.; Bailey, T. R.; Long, M. A.; Vescio, N.; Aldous,
S.; Pevear, D. C.; Dutko, F. J. J. Med. Chem. 1994, 37, 2421.
*g) Messer, Jr., W. S.; Abuh, Y. F.; Liu, Y.; Periyasamy, S.;
Ngur, D. O.; Edgar, M. A. N.; Zl-Assadi, A. A.; Sbeih, S.;
Dunbar, P. G.; Roknich, S.; Rho, T.; Fang, Z.; Ojo, B.; Zhang,
H.; Huzl III, J. J.; Nagy, P. I. J. Med. Chem. 1997, 40, 1230.
5. Buscemi, S.; Pace, A.; Vivona, N. Tetrahedron Lett. 2000, 41,
7977.
3.2.7. Irradiation of compound 4 in methanol. A solution
of compound 4 *0.5 g) in methanol *300 mL) was appor-
tioned in six quartz tubes and then irradiated for 1.5 h.
The photolysate was left to stand for 24 h and then the
solvent was removed. Chromatography of the residue,
besides some amounts of minor components *discarded),
returned starting material *0.115 g; 27%), and gave
3-methoxy-5-penta¯uorophenyl-1,2,4-oxadiazole
*10)
*colorless oil which solidi®ed under freezing) *0.020 g;
4%) and then the O-penta¯uorobenzoylamidoxime *9)
*0.25 g; 52%).
Compound 10 had 1H NMR *CDCl3) d 4.15 *s). MS m/z 266
*100) *M1), 208 *67), 195 *86), 181 *45), 117 *38). Anal.
Calcd for C9H3F5N2O2: C, 40.62; H, 1.14; N, 10.53. Found:
C, 40.50; H, 1.10; N, 10.40.
6. Buscemi, S.; Vivona, N.; Caronna, T. Synthesis 1995, 917.
7. *a) Clapp, L. B. Adv. Heterocycl. Chem. 1976, 20, 65.
*b) Kraatz, U. Houben-Weyl E 8c, Heteroarenes III/3, Georg
Thieme: Stuttgart, 1994; p 409.
Compound 9 had mp 102±1038C *from light petroleum): IR
1
3400, 3530, 1740 cm21. H NMR *DMSO-d6) d 3.75 *s,
3H), 6.64 *s, 2H). MS m/z 284 *3) *M1), 221 *16), 195

S. Buscemi et al. / Tetrahedron 57 32001) 5865±5871
5871
8. *a) Westphal, G.; Schmidt, R. Z. Chem. 1974, 14, 94.
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14. A quite ef®cient synthesis of 6a has been realized by using the
3-amino-5-methyl-1,2,4-oxadiazole as an O,N-protected
hydroxyguanidine *Buscemi, S. et al. unpublished results).