Thermal and photochemical reactivity of β , γ -unsaturated oximes in the presence of SnCl 4

The thermal reaction of some symmetrically substituted β , γ -unsaturated oximes 2a-d in the presence of one equivalent of tin tetrachloride in toluene leads to the formation of 5,6-dihydro-4 H -1,2-oxazines 3a-d. The photochemical reaction follows a different path and yields 5-(diarylhydroxymethyl)-4,4-dimethyl-4,5-dihydroisoxazoles 6a, b. A cationic mechanism is proposed for the thermal cyclisation while the photochemical process is thought to involve an SET process.


Introduction
β,γ-Unsaturated oximes and their derivatives have provided a fruitful area of study over the past two decades.Our own recent studies have recorded 1 the photochemical cyclisation of such oximes under SET conditions using DCA and also a novel oxidative intramolecular cyclisation to yield peri-naphthisoxazoles. 2 However, the definitive earlier work by Armesto and his coworkers 3 demonstrated the usefulness of the photochemical reactions of such species in the discovery and subsequent study and development of the aza-di-π-methane rearrangement.In another account Armesto et al. 4 reported the photochemical transformations of some β,γunsaturated oximes in the presence of BF 3 etherate whereby a new reaction, the formation of dihydroisoxazoles, was observed.Subsequent to that study there have been few, if any, other reports of the reactivity of such systems in the presence of Lewis acid catalysts.Thus, it was of interest to investigate the thermal and photochemical reactivity of some of these oximes with

Results and Discussion
The aldehydes 1a-d required for the synthesis of the oximes 2a-d were readily prepared using a slight modification of the procedure developed by Zimmerman and Pratt. 5The oximes 2a-d were synthesized by conventional means using the method described earlier by Armesto and his coworkers. 6he thermal reaction of the β,γ-unsaturated oximes 2a-d in the presence of stoichiometric amounts of tin tetrachloride was investigated.The procedure adopted involved reaction of the unsaturated oxime 2a (0.66 mmol) at reflux in toluene (35 ml) with one equivalent of tin tetrachloride for about 20 h.The solution was allowed to cool to room temperature and poured into water (50 ml).Conventional work-up gave a semi-solid residue TLC analysis of which showed the presence of a new compound.This was isolated by conventional column chromatography (toluene/ethyl acetate 7:1).The isolated product exhibited 1 H NMR signals as singlets at δ 7.00 for an oximino hydrogen and at δ 2.65 for a methylene group.These resonances justify the assignment of the structure of the new product as the dihydrooxazine 3a.The others oximes 2c-d behaved similarly affording the dihydrooxazines 3c-d (Scheme 1).The yields of these new compounds are shown in the table.There are a few methods [7][8][9] described in the literature for the preparation of 5,6-dihydro-4H-1,2-oxazine derivatives.For example, Brandman and Conley 7 described the formation of 3methyl-4H-5,6-dihydro-1,2-oxazine in moderate yield by treatment of 5-chloro-2-pentanone with hydroxylamine hydrochloride in the presence of potassium carbonate while Zimmer and Reissig 8 used a hetero-Diels-Alder reaction between 1,1,1-trifluoro-2-nitroso-2-propene and electron-rich alkenes.In an earlier study Thoai et al. 9 described the formation of dihydro-1,2-isoxazoles by treatment of α,β-unsaturated oximes with sulphuric acid.Presumably, the oxime isomerises in the first step to the β,γ-unsaturated oxime and then cyclisation leads to the product.Under these conditions they 9 also obtained low yields of 5,6-dihydro-4H-1,2-oxazines.Our method seems to provide a more general route to these latter compounds.
The fact that dihydrooxazines are obtained from the thermal reaction of the oximes suggests that the most likely mechanism of cyclisation involves a cationic intermediate.The formation of carbocations by tin(IV) tetrachloride is well known. 10,11 hus, we suggest that tin tetrachloride behaves as a Lewis acid and complexes with the alkene double bond.This could involve the formation of a tin−carbon σ-bond and results in the production of a stabilized cation.For compounds 2a-d the resultant cation centre will be at C4 where it is stabilized by two aryl groups in 2a-c and by two alkyl groups in 2d.Cyclisation takes place by attack of the hydroxyl group of the oxime moiety.After the cyclisation step aqueous hydrolysis of the complex gives the final products 3a-d (Scheme 2).

Scheme 2
The involvement of a stabilized carbocation has support from the outcome of the thermal cyclisation of oxime 4 under the same conditions as those used above.In this instance the phenyl group at C3 will stabilize the cation centre.This postulate is confirmed by the isolation, in low yield, of a compound identified as the dihydroisoxazole 5.

5
Clearly, the thermal cyclisation of the 4,4-disubstituted oximes affording dihydrooxazines is different to the reaction observed in the photochemical transformation of oxime 2a in the presence of BF 3 etherate.Under these conditions 2a is trnasformed into the dihydroisoxazole 6a..In view of this disparity it was important to establish if irradiation in the presence of SnCl 4 followed the same path to a dihydroisoxazole.Irradiation using the conditions described in the experimental did give the same dihydroisoxazole 6a in a similar yield to that reported 4 in the earlier study.The same cyclisation mode was observed for oxime 2c that gave the dihydroisoxazole 6b.It is tempting to assume that the reactions observed with SnCl 4 follows a Single Electron Transfer (SET) mechanism.In the example with BF 3 etherate it was assumed that the Lewis acid complexed with the oximino group.However, with SnCl 4 it seems likely that the complex formed with the Lewis acid involves the double bond.This has precedence in the thermal reactions.A possible mechanism that accounts for the formation of the dihydroisoxazoles under the conditions used here is shown in Scheme 3.

Scheme 3
It seems logical that the formation of the hydroxylated products must involve the formation of a cation centre at the diarylmethyl site as shown in Scheme 3.

Conclusions
The experiments described above show that dihydrooxazines can be synthesized readily in reasonable yields by the use of SnCl 4 under thermal conditions.The cyclisations are readily accounted for by a cationic mechanism.When the oxime/SnCl 4 mixture in benzene is irradiated a different reaction path is followed and involves a SET.This cyclisation yields dihydroisoxazole derivatives.

Experimental Section
General Procedures.IR spectra were recorded on a Nicolet 205 spectrophotometer and UV/VIS spectra on a Perkin-Elmer Lambda 16 spectrometer. 1H and 13 C NMR spectra (CDCl 3 as solvent and TMS as internal standard) were recorded on a Bruker AM-200 at 200 MHz and 50 MHz, respectively.Mass spectra were recorded on a VG 70-S spectrometer using Datasystem 11-250J.Elemental analyses were carried out on a Carlo Erba Model 1106.Melting points were measured on an Electrothermal apparatus and are uncorrected.TLC was carried out on glass plates using Silica gel 60 F 254 (Merck).

Synthesis of oximes
The general synthesis of the oximes was carried out as described by Armesto and his coworkers. 6Thus, 13.7 mmol of the enal was reacted with 20.0 mmol of hydroxylamine hydrochloride in pyridine (3 ml) and ethanol (60 ml).The mixture was heated at reflux for 4 h.The oxime was obtained following work-up and column chromatography using diethyl ether/hexane gradient elution.

General conditions for irradiation of oximes with SnCl 4
In the examples reported 250 mg (0.94 mmol) of the oxime was dissolved in 250 ml benzene and an equivalent amount of SnCl 4 (0.94 mmol) was added.The irradiations were carried out in an immersion well apparatus fitted with a Pyrex filter and using a 400 W medium pressure Hg arc lamp.Argon was purged through the solution for 30 min before and during the irradiation.The times of irradiation varied from 0.5 -3.0 h.The mixtures reactions were quenched in 100 ml water.After conventional work-up the product was isolated by column chromatography using gradient elution with diethyl ether/hexane.Irradiation of 4,4-diphenyl-2,2-dimethylbut-3-enal oxime (2a).Irradiated for 3 h.Chromatography gave the dihydroisoxazole 6a (67 mg, 26 %) and recovered starting material 2a (84 mg, 41 %).