Treatment of o -alkynylphenylsydnones with acids: a new route to 3-arylcinnolines

Treatment of o -alkynylphenylsydnones with triflic acid or trifluoroacetic acid provides a novel avenue to 3-arylcinnolines. With triflic acid the best results were obtained at room temperature with alkynylsydnones containing an electron-withdrawing group (or an H) whereas with TFA an electron-donating group and reflux conditions were required.


Introduction
Sydnones are dipolar, nonbenzenoid aromatic compounds, which are the most studied members of the class of heterocycles known as mesoionic. 1Since their first preparation in 1935, 2 on account of their intriguing structural, chemical and biological properties, 1 a large number of sydnones have been reported.The most common avenue to modification of their properties has been via substitution at the C-4 position and this has been achieved by electrophilic aromatic substitution, 3 lithiation 4,5 or other metallation 6,7 followed by reaction with an electrophile.
For some years, we have been interested in the preparation of fused-ring sydnones such as 2 with a view to exploring the modification of sydnone properties thus engendered. 8,9In this regard, it has been speculated by Coburn and O'Donnell that, in fused-ring sydnones, the stabilization achieved by the additional conjugation from the sydnone ring "might be of practical significance, since many of the simple sydnones with potentially useful biological activities lack thermal stability and frequently darken upon exposure to light and air". 10While, previously, sydno [3,4-a]quinoxalines were prepared by Coburn and O'Donnell using a lithiation protocol, 10 for us the most effective, general strategy to fused-ring sydnones has been to generate an electrophilic side-chain that can be trapped by the heteroaromatic sydnone ring.In this fashion, we have synthesized a sydno [4,3-c]benzotriazine, 9 several 4-arylaminosydno[3,4-a]quinoxalines, 8 and a limited number of 5-substituted sydno [3,4-a]quinazolines. 11,12 In order to explore further this concept, and extend the limited range of fused-ring sydnones available, we elected to examine the reactions of o-alkynylphenylsydnones 1 (prepared by Sonogashira coupling with o-iodophenylsydnone) 13 with various acids in the expectation that sydnoquinoline derivatives 2 would result.The present manuscript reports our findings from this study.

Results and Discussion
Our first effort to effect cyclization of the sydnone alkynes 1 to the desired sydnoquinolines 2 was to examine the efficacy of concentrated sulfuric acid in this regard.While reaction of 1a with sulfuric acid did lead to the corresponding fused-ring sydnone 2a (Table 1, entry 1) the extremely low yield led us to consider alternative avenues.We postulated that this issue could be alleviated by the use of an organic acid and, accordingly, we explored the use of trifluoromethanesulfonic acid (TfOH) and trifluoroacetic acid (TFA) as acid replacements.Unexpectedly, treatment of alkynylsydnones 1 with TfOH or TFA resulted in the isolation of 3-arylcinnolines 3 in 60-86% yield.With TfOH, the reaction was effected in 15 minutes at room temperature and the best results were obtained with those alkynylsydnones containing electron-withdrawing moieties (or an H) attached to the alkynyl aryl group (1a-c, entries 2-4).In contrast, TFA, the weaker acid, required reflux conditions for 3-6 hours and a donating group attached to the alkynyl aryl group (1d-f, entries 5-7) to effect the transformation.Undoubtedly, the mechanism of the reaction involves hydrolysis of the sydnone ring to a hydrazine, acid-catalyzed cyclization of the latter to the alkyne and subsequent oxidation in air.Acid-induced hydrazine formation from sydnones has been known since 1935, 2 however, the utility of ortho-substituted arylsydnones as masked hydrazines for heterocycle formation has been utilized only infrequently.Indeed, to the best of our knowledge, apart from our study of such transformations in 1992, 18 there has been no systematic examination of this concept.The present findings exhibit further the utility of stable, crystalline o-substituted arylsydnones as valuable precursors to useful heterocycles and, given the rather efficient avenues to the alkynylsydnone precursors, 13 may find considerable utility.
Substituted cinnolines often exhibit interesting bioactivity 19 and hitherto have been prepared by a variety of methods, primary among which are intramolecular cyclizations such as the von Richter synthesis (cyclization of an arenediazonium species onto an o-alkyne) 20 and avenues involving aryl hydrazines, 21 aryl hydrazones 22,23 and nitriles. 24More recently, valuable extensions to these routes have been developed using copper-catalyzed coupling protocols. 15,17n general, 3-arylcinnolines have been prepared using one or other of the aforementioned approaches 16,17 and methods for the synthesis of cinnolines, in general, have been reviewed. 25

Conclusions
A convenient synthesis of 3-arylcinnolines 3 from o-alkynyl sydnones 1 has been developed using either treatment with trifluoroacetic acid or triflic acid, depending on the nature of the alkynyl sydnone employed.A novel fused-ring sydnone 2a was obtained in low yield from one alkynylsydnone 1a.It is planned to examine further both synthetic avenues (to 2 or 3) in order to better delineate the scope and limitations of the procedures.

Experimental Section
General.The o-alkynylphenylsydnone 1 starting materials were prepared as reported previously. 13Melting points were determined on a Mel-Temp melting point device and remain uncorrected.Infrared spectra were performed on a KBr salt plate and were taken on a Nicolet 6700 FTIR.NMR spectra were obtained on a Bruker Advance 300 MHz NMR in CDCl3 and are reported relative to tetramethylsilane as an internal standard.Column chromatography was accomplished either manually or on an Isco CombiFlash Separator System Sg100c.Thin layer chromatographic assessments were performed on silica gel.Elemental analyses were determined by Midwest Microlab LLC, Indianapolis, Indiana.