Fluorinated heterocyclic compounds: an assay on the photochemistry of some fluorinated 1-oxa-2-azoles: an expedient route to fluorinated heterocycles

Abstract

Photoinduced heterocyclic rearrangements of ON bond-containing azoles have been claimed in the synthesis of target fluorinated heterocyclic compounds. In this context, the photochemical behavior of some fluorinated 1,2,4-oxadiazoles has been investigated. Irradiations of 3-amino-5-perfluoroalkyl-1,2,4-oxadiazoles at λ=313 nm in methanol gave open-chain products arising from a reaction of the nucleophilic solvent with either the first formed ring-photolytic species or with a nitrilimine moiety generated from it. Differently, irradiations in methanol with the presence of triethylamine (TEA) followed competing phototransposition pathways leading to the ring-isomers 2-amino-5-perfluoroalkyl-1,3,4-oxadiazoles (major component) and the ring degenerate isomers 5-amino-3-perfluoroalkyl-1,2,4-oxadiazoles (minor component). On the other hand, 3-amino-5-polyfluorophenyl-1,2,4-oxadiazoles underwent ring-photoisomerization into 1,3,4-oxadiazoles when irradiations were carried out at λ=254 nm. In turn, the irradiation of the 3-phenyl-5-perfluoroheptyl-1,2,4-oxadiazole at λ=254 nm in methanol gave the solvolysis product, but no ring-isomerization was observed. Some mechanistic considerations are reported, and some applications in the synthesis of target fluorinated 1,3,4-oxadiazoles are claimed.

Introduction

Fluorinated heterocyclic compounds are widely employed in pharmaceuticals, agrochemicals, and new materials, and their synthesis constitutes an increasingly valuable research area [1], [2], [3], [4]. On the other hand, requirements for the photostability and/or photodegradation pattern of commercial fluorinated products under sunlight raise the question of the photoreactivity of fluorinated heterocycles. Little material about this interesting matter has been reported; in the recent literature, an example can be recognized in the photochemistry of fluoroquinolone antibiotics [5], [6], [7].

With respect to the synthetic aspects, a general and convenient approach to fluorinated heterocycles often utilizes a building-block strategy for the construction of the heterocyclic moiety from fluorinated acyclic precursors, rather than the direct introduction of fluorine or fluorinated groups in the heterocyclic structure [1], [2], [3], [4]. In this context, heterocyclic rearrangements [8], [9], [10], [11], [12], [13] and, among them, photoinduced rearrangements [14], [15], [16], [17] of ON bond containing azoles [18], [19], [20], [21], [22], [23] appear to be a promising strategy for the synthesis of target compounds. In this context, we recently reported [24] the synthesis of 3-amino- (or 3-N-alkylamino-)-5-perfluoroalkyl-1,2,4-oxadiazoles (2) by photolysis of some 3-perfluoroalkanoylamino-4-phenyl-1,2,5-oxadiazoles (furazans) (1) at λ=313 nm in methanol and ammonia or primary aliphatic amines (Scheme 1). This photoreaction, which had been also reported for unfluorinated substrates [19], has been explained by assuming a photoinduced fragmentation of the furazan moiety leading to benzonitrile and an acylamino-nitriloxide species that is then captured by the nucleophilic reagent (ZH in the Scheme 1). A subsequent heterocyclization reaction of the resulting open-chain intermediate (3) will then give the final product.

Regarding the application of this photochemical methodology in the synthesis, we have observed that unlike the corresponding 5-alkyl substituted derivatives, the 3-amino- (or 3-N-alkylamino)-5-perfluoroalkyl-1,2,4-oxadiazoles (2) showed some photoreactivity under the photoreaction conditions used. As a consequence, low photoconversion of starting material was needed in the synthetic procedure, thus leading to modest yields of the final products [24]. However, if compared with some troublesome non-photochemical methodologies [25], [26], our photochemical approach appears to be a rather general method for the synthesis of these target fluorinated oxadiazoles.

By a similar approach it was possible to synthesize also the 5-pentafluorophenyl-1,2,4-oxadiazoles (5) (Scheme 2) [27]. In this photoreaction, displacement of the fluoride anion from the C(5) pentafluorophenyl moiety of the first formed oxadiazoles by the solvent and/or the nitrogen nucleophile also takes place, thus affording a series of 1,2,4-oxadiazoles, (6 and 7) , respectively, that contain a para-substituted tetrafluorophenyl moiety at C(5). In the context of photochemical strategies for the synthesis of heterocyclic compounds, photoinduced rearrangements of certain 1,2,4-oxadiazoles have been also considered. In fact, the photochemistry of 1,2,4-oxadiazole heterocycle is characterized by the photoinduced cleavage of the ring ON bond, providing open-chain species which develops into different products depending on the nature and position of substituents, as well as on the presence of a reagent in the photoreaction medium [20], [21], [22], [23], [28]. Several examples of these photoreactivities have been reported, and synthetic applications have been pointed out [20], [21], [22], [23]. To introduce our present work, we need to recall that a particular case of photoreactivity of the 1,2,4-oxadiazole heterocycle is represented by the ring-photoisomerization into 1,3,4-oxadiazoles by a “ring contraction–ring expansion” pattern [28], [29], [30], [31]. This ring-photoisomerization was found to be restricted to those oxadiazoles bearing an XH group at C(3) and favored by the addition of a base in the photoreaction medium [30]. Thus, upon irradiation of the 3-amino-5-phenyl-1,2,4-oxadiazoles (8) at λ=254 nm in methanol, yields of the ring-photoisomers 9 increased when irradiations were carried out in the presence of triethylamine (TEA) [30] (Scheme 3). A first-glance hypothesis to explain the effect of the base suggests the involvement of the anionic form of starting 3-amino compound (at least in the excited state) as the key-intermediate undergoing ring-cleavage at ON bond level. Subsequent processes will be ring-closure into a diazirine and then ring-expansion into 1,3,4-oxadiazole ring, the latter being favored by the base-catalysis.

Interestingly, in the case of 5-alkyl-3-amino-1,2,4-oxadiazoles (10), two competing ring-photoisomerization pathways have been pointed out [31]. In fact, irradiation of compounds 10 in methanol in the presence of TEA (at λ=254 nm) gave both the expected 1,3,4-oxadiazole (11) and the ring-degenerate isomers 3-alkyl-5-amino-1,2,4-oxadiazoles (12) (Scheme 4). Formation of compounds 12 should imply an internal “cyclization isomerization” route which involves initial formation of a N(2)C(5) bond in the starting 3-amino oxadiazole in its anionic form. This means that, once an XH group is present at C(3), the nature of the substituent at C(5) of the oxadiazole ring determines the preferred route. In the presence of an alkyl substituent we observe the occurrence of both the “ring contraction–ring expansion” and the “internal-cyclization isomerization”, while the “ring contraction–ring expansion” pathway is the only route preferred when a phenyl group is present. Various parameters could be invoked to explain this finding. An intriguing hypothesis considers different stabilization of key-intermediates (a diazirine in one hand, and a bicyclic species in the other) as driving-force in the development of the first-formed oxadiazole-anion. (see the case of fluorinated substrates in the Scheme 7).

On the basis of the above photoreactivities, we now looked at the photochemical behavior of some fluorinated 1,2,4-oxadiazoles. In this context, we wish to note that in the last years, 1,2,4-oxadiazole derivatives have been receiving much attention by virtue of their pharmaceutical applications [32], [33], [34], [35], [36], [37], [38], [39], [40]. In this paper, we will consider the photochemistry of 3-amino-5-perfluoroalkyl- and 3-amino-5-polyfluorophenyl-1,2,4-oxadiazoles in view of developing methodologies for the synthesis of the corresponding fluorinated ring isomers, namely the 1,3,4-oxadiazoles. In addition, the question as to how the fluorinated group affects photoreactivity of the 1,2,4-oxadiazole heterocycle will also be addressed.