Fluoro heterocycles. A photochemical methodology for the synthesis of 3-amino- and 3-(N-alkylamino)-5-perfluoroalkyl-1,2,4-oxadiazoles

Article abstract of DOI:10.1016/S0040-4039(00)01375-7

A photochemical methodology for the synthesis of perfluoroalkyl-1,2,4-oxadiazoles has been described. 3-Amino- and 3-(N-alkylamino)-5-perfluoroalkyl-1,2,4-oxadiazoles have been prepared by irradiation of 3-perfluoroalkanoylamino-4-phenyl-1,2,5-oxadiazoles (furazans) at λ=313 nm in methanol and in the presence of ammonia or primary aliphatic amines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01375-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7977–7981
Fluoro heterocycles. A photochemical methodology for the
synthesis of 3-amino- and
3-(N-alkylamino)-5-perfluoroalkyl-1,2,4-oxadiazoles
Silvestre Buscemi, Andrea Pace and Nicolo` Vivona*
Dipartimento di Chimica Organica ‘E. Paterno`’, Universita` degli Studi di Palermo,
Viale delle Scienze-Parco D’Orleans II, 90128 Palermo, Italy
Received 5 June 2000; accepted 10 August 2000
Abstract
A photochemical methodology for the synthesis of perfluoroalkyl-1,2,4-oxadiazoles has been described.
3-Amino- and 3-(N-alkylamino)-5-perfluoroalkyl-1,2,4-oxadiazoles have been prepared by irradiation of
3-perfluoroalkanoylamino-4-phenyl-1,2,5-oxadiazoles (furazans) at u=313 nm in methanol and in the
presence of ammonia or primary aliphatic amines. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: perfluoroalkanoylamino-furazans; photolysis; perfluoroalkylheterocycles; oxadiazoles.
Fluorinated heterocycles are interesting compounds widely used in medicinal, agricultural and
polymer chemistry, and their synthesis represents a research area of growing interest.1 Although
the direct introduction of fluorine or perfluoroalkyl groups into heterocyclic structures can be
realized by fluorinating or perfluoroalkylating reagents, a widely used approach to fluorinated
heterocycles uses building-block strategies, e.g. by the formation of the heterocyclic ring from
fluorinated precursors.1 In this context, a very promising strategy can be recognized in
photochemical methodologies exploiting photoinduced rearrangements of suitable heterocyclic
structures, such as OꢀN bonds containing azoles.2 As part of a research program on the
synthesis and reactivity of fluorinated derivatives of five-membered heterocycles, we became
interested in realizing an efficient and general synthesis of 3-amino- and 3-(N-alkylamino)-5-
perfluoroalkyl-1,2,4-oxadiazoles. To this purpose, it is worthy to note that in the last few years
increasing efforts have been devoted to develop synthetic methods for targeting 1,2,4-oxadia-
zoles,3 and this is because 1,2,4-oxadiazole moieties have some interest in the pharmaceutical
industry.4 So, for 3-amino- or 3-(N-alkylamino)-5-alkyl-1,2,4-oxadiazoles, a new and quite
general synthetic approach exploits photochemical methodologies.2a,5 Thus, irradiation (at
* Corresponding author. Fax: +39 091 596825; e-mail: nvivona@unipa.it
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01375-7

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u=313 nm) of 3-alkanoylamino-4-phenyl-1,2,5-oxadiazoles (furazans) in methanol containing
ammonia, or primary aliphatic amines gave the mentioned compounds as a result of: (i)
photoinduced regioselective-breaking of the 1,2,5-oxadiazole ring involving extrusion of ben-
zonitrile; (ii) capture of the ring-cleaved intermediate by the added amine forming N-acyl-
aminoamidoximes which will undergo cyclo-dehydration into final products in the reaction
medium.5
On this basis, to realize our aim we decided to pursue this photochemical approach by
studying the photochemistry of 3-perfluoroalkanoylamino-4-phenylfurazans, with the assump-
tion that the perfluoroalkyl moiety would preserve the regioselective-breaking of the O(1)ꢀN(2)
bond of the furazan nucleus on one hand, and would favour the heterocyclization step, on the
other. In this communication we report preliminary results6 concerning irradiation of
perfluoroalkanoylamino-furazans 2 and 3 at u=313 nm in the presence of ammonia or some
primary aliphatic amines (see Scheme 1).
Scheme 1.
Compounds 2 and 3 have been prepared (in 80% yield) by a standard protocol,5 that is, by
the acylation reaction of the 3-aminofurazan (1)7 with the appropriate perfluoroacyl chloride
(for 2) or perfluoroanhydride (for 3).8,9 As for photochemical experiments,10 we observed that
the photochemistry of these substrates was significantly dependent on the concentration of the
amine and irradiation time. At variance with 3-amino- or 3-(N-alkylamino)-5-alkyl-1,2,4-oxadi-
azoles, the expected 5-perfluoroalkyl derivatives showed some photoreactivity under the reaction
conditions.
Therefore, irradiations had to be carried out at low conversion of starting material. Thus, a
typical irradiation of 2 (1 mmol) in methanol (200 mL) in the presence of, respectively,
ammonia, methylamine, n-propylamine, and n-octylamine (2.5 mmol) at u=313 nm for 60 min
gave the 3-amino- (5a) and 3-(N-alkylamino)-5-perfluoroalkyl-oxadiazoles (5b–d), respectively.
Similarly, irradiation of 3 for 90 min in the presence of methanolic ammonia or methylamine
gave oxadiazoles 5e and 5f, respectively (see Table 1). To compare, a sample of 5a was also
obtained, although in very low yields, by acylation and subsequent cyclodehydration of
N-hydroxyguanidine,11 exploiting conventional procedures.12
As mentioned above, the whole reaction goes through a thermal cyclo-dehydration of
N-acylamino-amidoxime intermediates 4. Following photolysis of 2 in the presence of methyl-
amine by HPLC, we found that when the irradiation was stopped, the concentration of final
oxadiazole 5b was low. By standing the photolysate in the dark for 24 h, the concentration of

Table 1
Irradiation of 3-alkanoylamino-4-phenylfurazans (2, 3): preparation of 3-amino- and 3-(N-alkylamino)-5-perfluoroalkyl-1,2,4-oxadiazoles 5a–f8
Substrate
RNH2 (R) Product Yield (%)
Mpa (°C) 1H NMR (DMSO-d6/TMS) l, J (Hz)
MS m/z
2
2
2
H
CH3
n-C3H7
5a
5b
5c
40
50
45
103
59
38
7.15 (s)b
453 (M+), 134, 69, 58
467 (M+), 119, 72, 69, 42
495 (M+), 466, 169, 126, 69,
43
2.80 (d, 3H, J=5)c, 7.60 (q, 1H, J=5)b
0.99 (t, 3H, J=7), 1.64–1.74 (m, 2H), 3.27 (q, 2H,
J=7), 4.62 (broad, 1H)d
2
3
3
n-C8H17
H
5d
5e
5f
40
30
30
54
71
49
0.89 (t, 3H, J=7), 1.29–1.40 (m, 10H), 1.59–1.71 (m, 565 (M+), 466, 196, 69, 43
2H), 3.26–3.34 (m, 2H), 4.57 (t, 1H, J=6)b,d
7.14 (s)b
253 (M+), 234, 196, 169, 134,
119, 69, 58
CH3
2.82 (d, 3H, J=5)c, 7.63 (broad, 1H)b
267 (M+), 239, 196, 169, 119,
69, 42
a Crystallization solvent: light petroleum (fraction boiling between 40 and 60°C).
b Exchangeable with D2O.
c Singlet in the presence of D2O.
d In CDCl3.

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5b increases as a result of thermal evolution of the supposed N-acylamidoxime 4. On this basis,
experimental conditions allowed us to isolate oxadiazoles 5a–f with yields in the range of
30–50% (30–40% of starting material being recovered) by simply standing the photolysate for 24
h before the usual work-up procedure. Nevertheless, these yields could be further optimized by
varying irradiation or standing conditions.
Although at first glance yields do not appear excellent, if compared with troublesome
non-photochemical procedures, this photochemical approach can be considered a general and
efficient method for the synthesis of 3-amino-, and, particularly, of 3-(N-alkylamino)-5-
perfluoroalkyl-1,2,4-oxadiazoles (with a chosen length of the chain both at the N-alkyl moiety
and at the perfluoroalkyl group); moreover, it opens new and promising strategies in the
synthesis of perfluoroalkyl-heterocycles. A complete study on the photoreactivity of 3-
perfluoroalkanoylamino-furazans irradiated in the presence of aliphatic amines, as well as on the
photoreactivity of 5-perfluoroalkyl-1,2,4-oxadiazoles formed will follow.
Acknowledgements
The Authors are indebted to Professor Tullio Caronna (Politecnico di Milano) for useful
discussions. Financial support from Italian MURST within the National Research Project
‘Fluorinated Compounds: Synthetic Targets and Advanced Applications’ is gratefully
acknowledged.
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1
nm (log m=4.0); H NMR (DMSO-d6) l: 7.42–7.78 (m, 5H), 12.8 (br s, 1H); Mass e/z: 557 (M+), 527, 119, 104,
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1
umax=251 nm (log m=3.7); H NMR (DMSO-d6) l: 7.59–7.79 (m, 5H), 12.9 (br s, 1H); mass e/z: 357 (M+), 327,
169, 119, 104, 77, 69.

7981
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