Novel Burgess reagent mediated C-to-N aryl migration reaction in nitrones

Abstract

Nitrones undergo useful transformations with Burgess reagent. The reaction ostensibly involves a [3 + 2] annulation across a σ-bond followed by rearrangement involving C-to-N aryl migration. On the basis of available experimental evidence, plausible mechanisms for the rearrangement and the overall conversion have been proposed.

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Burgess reagent (1) is a versatile reagent in organic synthesis^1,2 and its reactivity with a number of nucleophilic functional groups like alcohols, epoxides,^3,4 1,2-diols,^5–8 thiols,^9,10 oximes¹¹ etc. are well documented. Newer applications^12–26 of the reagent as well as several modified forms of the reagent with improved thermal stability¹¹ are being reported. Now, chiral versions of the reagent are also known²⁶ enabling extensive use in organic natural product syntheses.

Burgess reagent (1) shows unexpected reactivity with N-oxides and the results are interesting and applicable in synthesis of several heterocyclic compounds, particularly those with pharmaceutical applications. A recent report shows an unexpected N-demethylation of oxymorphone and oxycodone-N-oxide using Burgess reagent to the corresponding oxazolidines providing a direct synthetic route to naltrexone, naloxone, and other antagonists from oxymorphone.²⁴ This report prompted us to investigate the reaction between nitrones and Burgess reagent. Nitrones being N-substituted 1,3-dipolar systems undergo [3 + 2] cycloaddition reactions with a variety of carbon–carbon, carbon–nitrogen, carbon–sulphur, nitrogen–phosphorus multiple bonded systems to give various heterocyclic systems.^27–33 Burgess reagent can be considered as a 1,2-dipole and hence can participate in a formal [3 + 2] annulation reaction with elimination of triethylamine with a complimentary 1,3-dipole to yield the corresponding five-membered heterocycle. Nitrones exhibit remarkable nucleophilicity^32,34 and hence are expected to react with Burgess reagent to give 1,2,3,5-oxathiadiazolidine intermediates B (Fig. 1) in what may formally be regarded as a [3 + 2] annulation reaction across a σ-bond³¹ (nitrogen–sulfur bond in this case).

Fig. 1 A Formal [3 + 2] annulation of Burgess reagent across a sigma bond.

With a view to verify [3 + 2] annulation hypothesis and to exploit its synthetic potential, we examined the reaction of four structurally diverse nitrones^35–38 such as N-diphenylmethylene-N-pheylnitrone (2), N-fluorenylidene-N-pheylnitrone (3), (Z)-N-phenylmethylene-N-phenylnitrone (4a) and (Z)-N-(9-anthracenyl)methylene-N-phenylnitrone (4b) with Burgess reagent (Fig. 2).

Fig. 2 Nitrones used in the present study of Burgess reagent mediated C-to-N migration reaction.

Reaction between N-diphenylmethylene-N-phenylnitrone (2) and Burgess reagent (1) was conducted in a 1 : 3 molar ratio in dry dichloromethane at room temperature. The product precipitated on adding hexane was identified as methyl (diphenylamino)(phenyl)methylenecarbamate (6, Scheme 1). In a repeat run, careful work up of the reaction mixture under absolutely moisture free conditions afforded, in addition to 6, triethylamine–sulphur trioxide complex as colorless needles. Generation of 6 in the reaction between 2 and Burgess reagent mandates carbon to nitrogen aryl group migration. This rearrangement is reminiscent of a similar C-to-N aryl migration observed in the chlorosulfonyl isocyanate mediated transformation of nitrones^39,40 and Beckmann rearrangement of oximes. Though Burgess reagent is known to exhibit myriad reactivity, this is the first example for a C-to-N aryl migration promoted by this versatile reagent. Plausible mechanism for the C-to-N aryl migration reaction is provided in Scheme 1. Structure of carbamate 6 was further confirmed by chemical transformations. Acid hydrolysis of 6 gave diphenylamine (7) along with 8 in quantitative yields (Scheme 2).

Scheme 1

Scheme 2

In order to establish the generality of the novel C-to-N aryl migration observed by us, we examined the reaction of N-fluorenylidene-N-pheylnitrone (3) with Burgess reagent. In this case also, C-to-N aryl migration leading to ring expanded product 12 was observed. Carbmate 12 precipitated out on addition of dry hexane to the reaction mixture. It was separated, purified and characterized on the basis of spectral and analytical data and chemical transformations. Hydrolysis of 12 using dil. HCl gave 5-phenylphenanthridin-6(5H)-one (11) in high yields as the only isolable product.

In continuation, we examined the reaction of (Z)-N-arylmethylene-N-phenylnitrones (4a, b) with Burgess reagent. In this case, the carbamate intermediates 13a, b could not be isolated and the corresponding diarylamines 7a, b were the only isolable products (Scheme 3). Though we could not isolate the carbmate intermediate 13a, b generation of diarylamines 7a, b is consistent with the C-to-N aryl migration pathway proposed by us. It may be noted that C-to-N hydrogen migration is an alternative possibility here. In order to check this possibility, we carried out careful GC-MS analysis of the reaction mixture. GC-MS analysis ruled out aniline generation in the reaction of 4a, b with Burgess reagent and hence the alternative C-to-N hydrogen migration possibility.

Scheme 3

Conclusions

On the basis of the results obtained in the reaction of Burgess reagent with different nitrones, we demonstrated that the novel C-to-N aryl migration in the Burgess reagent–nitrone reaction is a general reaction as well. It appears that 1,2,3,5-oxathiadiazolidine intermediates generated through a [3 + 2] annulation pathway is a possible intermediate in the aryl migration reaction. Another striking feature of this rearrangement is the remarkable migratory aptitude observed here. In the case of 2 and 3, migratory aptitude cannot be ascertained. However, with 4a, b exclusive aryl group migration is observed. The migratory aptitude observed can be explained in two different ways: (i) the more electron rich group migrates; (ii) the syn group migrates. Mechanism of aryl group migration appears different from the one operating in Beckmann rearrangement.⁴¹ Observed migratory aptitude is consistent with the involvement of a cyclic intermediate.^39,40 Detailed analysis of migratory aptitude is currently underway in our laboratory.

Acknowledgements

This work was supported by the Council of Scientific and Industrial Research, Government of India (no. 01/(1989)/05/EMR-II). Spectral and analytical data were collected at STIC, CUSAT funded by DST. We acknowledge Jayakumar and Amrutha for partial experimental assistance. STS gratefully acknowledges CSIR, India for financial assistance in the form of a Senior Research Fellowship.

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Footnote

† Electronic supplementary information (ESI) available: See DOI: 10.1039/c4ra06835a

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