Steric effects on the sydnones reactivity. New sydnones and pyrazoles

The sydnones 7a,b and 8a-c gave the corresponding pyrazoles 9a-e by 1,3-dipolar cycloaddition with dimethyl acetylenedicarboxylate (DMAD). The highly sterically hindered 3-(4,6-dibromo-2-methylphenyl)-4-iodosydnone ( 8d ) failed to react with DMAD on heating in boiling xylene. The iodination of sterically hindered sydnone 7b required more drastic reaction conditions than the sydnone 7a .


Introduction
][3][4][5] Sydnones can readily prepared by cyclodehydration of N-substituted-N-nitroso-aminoacids 1 with reagents such as acetic anhydride.The resulting compounds contain a mesoionic aromatic system which can be depicted with polar resonance structures.7][8][9] The reaction involves a 1,3dipolar cycloaddition of the sydnones, behaving like a cyclic azomethine imine, to the corresponding acetylene followed by carbon dioxide evolution and aromatization (Scheme 1).The present work describes the synthesis of new halogenated sydnones and their cycloaddition reaction to form pyrazoles.The halogen atoms are present in the benzene and/or heterocycle ring.The influence of steric effects on reactivity of sydnones is also discussed.
Recently 13 we obtained good results in the direct iodination of sydnone ring by using the reagent iodine monochloride/acetic acid.By using this method the sydnones 7a and 7b could be iodinated with this reagent in the presence of an equivalent of sodium acetate added to neutralize the hydrochloride acid formed in the reaction.Two new 4-iodosydnones 8c and 8d were obtained by this method.
The iodination of the sydnone 7b required large excess of iodine monochloride and a reaction time of 10 hrs., whereas the iodination of the sydnone 7a was complete in 1 hr.with only a slightly excess of iodination reagent.This was explained by steric hindering at the electrophilic center, C-4 in the sydnone ring.
The 13 C-NMR spectra of 4-iodosydnones showed a strong negative increment at C-4 (∆δ = 44.4,respectively 44.9 ppm).A shielding effect of 3-aryl group on C-4 was also apparent, provided that the aromatic ring was not strongly deviated from coplanarity by ortho substituents.A weak influence on polarization of the carbonyl group could also be observed with bromine and chlorine as 4-substituents.The transformation of sydnones 7a,b and 8a-c into halogenated pyrazoles 9a-e was performed by 1,3-dipolar cycloaddition reaction with DMAD.The 4-chloro-and 4-bromosydnones were found by Dickopp 14 to be unstable in non-polar solvents such that the corresponding pyrazoles were obtained in ethylene glycol upon reaction with excess DMAD.In our hands, 4-halogenosydnones 8a and 8b proved to be quite stable in xylene at reflux temperature and their reaction with a small excess of DMAD (1.2 molar ratio) led to the corresponding 5-halogenopyrazoles in yield of over 80%.In addition, 1-(4-Bromo-2methylphenyl)-3,4-dicarboethoxy-5-iodopyrazole (9f) was obtained by 1,3-dipolar cycloaddition between 4-iodosydnone 8c and diethyl acetylenedicarboxylate.By this method, six new pyrazoles 9a-f were obtained.
The 13 C-NMR spectra of 5-iodopyrazoles 9e and 9f showed about the same negative increments (∆δ = 45.6 and 45.8 ppm) for the signal of C-5 as in the case of the corresponding 4iodosydnones 8c and 8d.For the 4-iodopyrazoles 15 negative increments of ∆δ = 41.5-42.2 were measured.
The highly hindered 3-(4,6-dibromo-2-methylphenyl)-4-iodosydnone (8d) failed to react with DMAD (Scheme 2) or diethyl acetylenedicarboxylate for three days in boiling xylene.This finding could be explained by steric hinderance.The ortho substituents at benzene ring and the bulky iodine atom at C-4 in the sydnone ring does not allow the formation of the transition state the between sydnone 8d and acetylenic dipolarophiles.

Experimental Section
General Procedures. 1 H-and 13 C-NMR spectra were recorded with a Varian Gemini instrument at 300 and 75 MHz, chemical shifts being expressed in δ values relative to TMS as internal standard.All mps were taken with a micro-Boetius apparatus and are uncorrected.

General procedure for sydnones 7a and 7b
To a solution of 2 g NaOH in 30 mL of water were added 20 mmol N-arylglycine 6a,b and 1.4 g (21 mmol) of NaNO 2 .In the cooled solution 10 mL of HCl were dropped under stiring, the temperature maintened under 5 °C.The nitroso derivatives which separated as oils were extracted twice with CH 2 Cl 2 .The organic layer was dried on CaCl 2 and then the solvent was evaporated off.The residue was treated with 30 mL of acetic anhydride and 2 mL of pyridine and evaporated under reduced pressure on the water bath.The crude products 7a and 7b were recrystallized from ethanol as clourless crystals.

3-(4-Bromo-2-methylphenyl)-4-iodosydnone (8c).
A solution of 22 mmol (1.1 mL) of iodine monochloride in 10 mL of glacial acetic acid was added dropwise to a stirred mixture of 5.1 g (20 mmol) of sydnone 7a and 2.2 g (25 mmol) of dry sodium acetate and of 20 ml glacial acetic acid.Stirring was continued for 1 hr at 50˚C, after which the 4-iodosydnone was precipitated by the addition of water.The product was filtered off and throughly washed with water.Yield 82%; mp 197-8˚C (from ethanol);

General procedure for pyrazoles 9a-e
A mixture of 10 mmol sydnone (7a,b and 8a-c) and 1.55 g (12 mmol) of DMAD was refluxed in 30 mL xylene for 8 hrs.After removal of the solvent in vacuo, the pyrazoles 9a-e were crystallized from ethanol as clourless crystals.