The Chemistry of α,β-Ditosyloxy Ketones: A New and Convenient Route to 4,5-Diarylisoxazoles from α,β-Chalcone Ditosylates

Abstract

The reaction of a,b-chalcone ditosylates with hydroxylamine hydrochloride under suitable conditions leads to a 1,2-aryl shift, thereby providing a new route to 4,5-disubstituted isoxazoles.The present study is in connection with our ongoing interest in the synthetic potential of a,b-ditosyloxyketones in the synthesis of 4,5-diarylisoxazoles. The chemistry of a,b-chalcone dibromides has been well explored, 1 and the reactivity mode of a,b-chalcone ditosylates 1 has been studied recently in our research group. The aim of this study is to explore the potential of a,b-chalcone ditosylates 1 in heterocyclic synthesis with particular emphasis on comparison with their dibromo analogues. In our preliminary study it was reported that the reaction of a,bchalcone ditosylates 1 with various reagents such as phenylhydrazine hydrochloride, semicarbazide hydrochloride, and thiosemicarbazide under suitable conditions leads to a 1,2-aryl shift, thereby providing a novel route to 1,4,5-trisubstituted pyrazoles 2 (Equation 1). 2 These results have shown that the reactivity pattern of a,b-chalcone ditosylates 1 is quite different from that of a,bchalcone dibromides, which are known to give pyrazolines 1j,3 under similar reaction conditions. Prompted by the foregoing observations and coupled to our interest in the synthesis of heterocyclic compounds, we became interested in investigating the reactivity of a,b-chalcone ditosylates 1 with hydroxylamine hydrochloride with the hope of developing a convenient approach to the synthesis of 4,5-diarylisoxazoles. As consequence of this investigation, we report herein a novel and convenient route to 4,5-diarylisoxazoles, for which previous synthetic and structural studies are limited.In the last decade it has been reported that 4,5-diarylisoxazole derivatives can act as potential therapeutic agents for the treatment of cancer, 4 novel inhibitors of cyclooxygenase-2 with analgesic and anti-inflammatory activities, 5 and can also inhibit metastasis of breast cancer cell lines. These compounds also have potential for the treatment of angiogenesis-related diseases including cancers, rheumatoid arthritis, and psoriasis. 6 Various derivatives of a,b-chalcone ditosylates 1a-o were prepared by treatment of the respective chalcones with hydroxy(tosyloxy)iodobenzene (HTIB) according to the method developed by Rebrovic and Koser 7 (Scheme 1 and Table 1). 2,8,9 We first examined the reaction of a,b-chalcone ditosylates 1 with hydroxylamine hydrochloride. Thus a,b-chalcone ditosylate 1a (0.001 mol) was heated with hydroxylamine hydrochloride (0.002 mol) in the presence of sodium acetate (0.002 mol) in ethanol (25 mL). The reaction afforded a single colourless solid product in 72% yield, which was characterised as 4,5-diphenylisoxazole (4a) on the basis of its physical and spectroscopic data (IR, 1 H NMR, mass). The IR spectrum of the product showed the disappearance of a peak at 1680 cm -1 arising from the carbonyl group of a,b-chalcone ditosylate 1a. The 1 H NMR spectrum showed a sharp singlet at d = 8.2 ...

Oxidative Rearrangement via 1,2-Aryl Migration using Hydroxy(tosyloxy)iodobenzene in a Polar Aprotic Solvent

“…At this stage it is important to mention that our previous investigations [42][43][44] that reported a vicinal structure for the ditosyloxy ketone 3 can also be justified in terms of the geminal ,-ditosyloxy ketone structure 2, as shown in Scheme 5.…”

“…As a result, in many previous investigations, our research group assumed that the structure of the ditosyloxy ketones corresponded to that of the vicinal ,-ditosyloxy ketone 3 (Scheme 3). [42][43][44] Scheme 3 Reported syntheses of pyrazoles 4, isoxazoles 5, -aryl -keto dialkylacetals 6, and desoxybenzoins 7, assuming that the structure of the ditosyloxy ketone was that of the vicinal ,-ditosyloxy ketone 3…”

Organohypervalent Iodine Reagents in the Synthesis of Bioactive Heterocycles

“…The key intermediates, α,β-chalcone ditosyslates, obtained by the treatment of appropriate chalcones 57 with HTIB, were reacted with hydroxylamine hydrochloride to furnish 4,5-diarylisoxazoles in good yields (Scheme 10) [26]. The key intermediates, α,β-chalcone ditosyslates, obtained by the treatment of appropriate chalcones 57 with HTIB, were reacted with hydroxylamine hydrochloride to furnish 4,5-diarylisoxazoles in good yields (Scheme 10) [26].…”

Chalcones as Versatile Synthons for the Synthesis of 5- and 6-membered Nitrogen Heterocycles

“…4,5-Disubstituted isoxazoles can also be obtained in a two-step synthesis starting from the tosylation of chalcones to give the corresponding , -ditosylate derivatives and subsequent reaction with hydroxylamine to afford the desired isoxazoles (Scheme 9) [101]. A similar approach involves the reaction of , -dibromo-chalcones with hydroxylamine hydrochloride in ethanol and using KOH as base [102][103][104].…”