Endo and regioselectivity in 1,3-dipolar cycloaddition of pyridazinium N -ylides with a non-symmetrical cyclic olefin

The 1,3-dipolar cycloaddition between pyridazinium N-ylides 3 and 3-methyl-N - phenylmaleimide was studied. In the case of pyridazinium phenacylides 4a-c the reaction was endo and regioselective, while in the case of carbomethoxymethylide 4d the cycloaddition gave two endo isomers in a 2:1 ratio. The stereochemistry of the adducts 6a-c and 7a,b was determined by NMR spectroscopy and confirmed by X-ray analysis for a representative compound, namely 6b .


Results and Discussion
The starting materials, pyridazinium bromides 3a-c were prepared by N-alkylation of pyridazine 1 with the corresponding 2-bromoacetophenones 2 in acetone at room temperature (Scheme 1).The quaternization of pyridazine with methyl bromoacetate was performed in ethyl acetate at reflux, giving the salt 3d.The structure of the new cycloimmonium bromide 3c was confirmed by elemental analysis and NMR spectroscopy.The protons H-3 and H-6 are strongly deshielded due to the vicinity of the two nitrogen atoms.Interestingly, in the 1 H-NMR spectra of 3a-d recorded in CDCl 3 and trifluoroacetic acid, the signals for the H-3 and H-6 protons from the pyridazine moiety appeared as eight lines (ddd) and as six lines (dt).The multiplicity of these protons is due to a long range coupling of H-3 with H-6 and was confirmed by a HH decoupling experiment.The value of this coupling constant was found to be 0.9 Hz.A similar para coupling was found between protons H-1 and H-4 for some phthalazinium salts. 15,16he monosubstituted heteroatomic N-ylides are generally unstable compounds.Therefore the N-ylides 4a-c were generated in situ by the reaction between the corresponding salts 3a-c and triethylamine in the presence of 3-methyl-N-phenylmaleimide as dipolarophile (Scheme 2).The cycloaddition reaction was performed in methylene chloride at room temperature.After 15 minutes, the reaction mixture was washed with water.The crude product was subjected to 1 H-NMR measurements, which indicated the formation of cycloadducts 6a-c as single regioisomers.
The regioselectivity of the cycloaddition between pyridazinium phenacylides 4a-c and 3methyl-N-phenylmaleimide 5 can be explained by steric repulsion between the methyl group in the maleimide (dipolarophile) and the COAr group in the ylide (1,3-dipole).The stereochemistry of the cycloadducts 6a-c was determined by 1 H-NMR spectroscopy, X-ray diffraction and checked by comparison with literature NMR and X-ray data for similar compounds.

Scheme 2
The chemical shifts of protons were assigned on the basis of values of coupling constants and HH-COSY.The protons H-6 and H-7 appear in the 1 H-NMR spectrum as two doublets with J = 1.1 Hz, the small value of the vicinal coupling constant indicating a trans configuration.The position of the methyl group on the pyrrolidine moiety was deduced from multiplicity of the signals for protons H-4a and H-7.Thus, H-4a appears as a doublet of doublets instead of a doublet of doublets of doublets, and H-7 as a doublet.The cis configuration of the methyl group with respect to the hydrogen atoms H-4a and H-6 was put in evidence by a NOEDIF experiment.Thus, irradiation of the 5-Me group results in an enhancement in differential spectra for protons H-4a and H-6.
The stereochemistry of the cycloadducts 6a-c shows that the cycloaddition reaction is endo and regioselective.From the trans configuration of the hydrogens on the carbon atoms C-4a and C-7, we can deduce that N-ylides 4a-c participate in the cycloaddition in the anti form.
The signal for H-4a appears as a doublet of doublets with a vicinal coupling constant of 5.4 Hz and an allylic one of J = 1.3 Hz.The large value of J 4,4a could be explained by a distortion of the tetrahydro-pyrrolopyridazine system.
The structural features of the tricyclic system in 6b reported above closely resemble those reported for the related compound endo-N-(4-methylphenyl)-3-(4-bromobenzoyl)-1-methyl-1,2,3,10b-tetrahydro-pyrrolo[2,1-a]phthalazine-1,2-dicarboximide, obtained by cycloaddition of a phthalazinium phenacylide and the non-symmetrical cyclic olefin 3-methyl-1-(4-methylphenyl) maleimide. 19otably, in the present study, the analogous reaction between methoxycarbonyl pyridazinium N-ylide 4d and 3-methyl-N-phenylmaleimide 5 gave a mixture of regioisomers 7a and 7b, in a ratio of 2:1 (Scheme 3).Unfortunately, the reaction was not complete and the separation of the isomers was unsuccessful.Nevertheless, the stereochemistry of the two regioisomers could be assigned by physical methods.The 1 H-NMR data (Figure 2) indicated that the major product, 7a, has a structure similar to those of compounds 6a-c.In the case of the compound 7b, the proton H-4a (δ = 5.04 ppm) appears as eight lines (ddd, J 4a,5 = 8.4 Hz, J 4,4a = 3.8 Hz, J 3,4a = 2.0 Hz), whereas H-5 is a doublet with J = 8.4 Hz.The large value of the coupling constant between H-5 and H-4a indicates a cis configuration.The proton H-7 appears as a sharp singlet (δ = 4.87 ppm).The difference in regioselectivity between the reactions of 4a-c and 4d can be explained by the increased steric hindrance of the benzoyl moiety as opposed to that of the methoxycarbonyl group.

Conclusions
The regioselectivity in the cycloaddition of pyridazinium N-ylides is determined by the nature of the substituent attached to the ylidic carbanion.Thus, when the substituent is COAr, the reaction is completely regioselective, whereas with COOMe as substituent, a mixture of stereoisomers was obtained.
From the stereochemistry of the compounds 6a-c and 7a,b it was possible to conclude that in the cycloaddition reaction the pyridazinium ylides 4a-c participate only in the anti form.

Experimental Section
General Procedures.Melting points were determined on a Boëtius hot plate and are uncorrected.The NMR spectra were recorded on a Varian Gemini 300 BB instrument, operating at 300 MHz for 1 H and 75 MHz for 13 C. Supplementary evidence was given by HETCOR and COSY experiments.

X-ray analysis of compound 6b
A crystal of dimensions 0.12 x 0.14 x 0.16 mm was mounted on a Nonius Kappa CCD diffractometer and cooled in a stream of nitrogen vapor during intensity data-collection.The latter was based on strategies suggested by program COLLECT 20 and involved φ-scans of 1-2° and ω-scans of 2°.DENZO-SMN 21 was used for data-reduction and unit cell refinement.Lorentz-polarization and empirical absorption corrections were applied to the intensity data and the structure was routinely solved by direct methods (SHELXS-97) 22 and refined by full-matrix least-squares against F 2 (SHELXL-97). 23All H atoms were located in difference electron density maps but were added in idealized positions in a riding model with U iso set at 1.2-1.5 times those of their parent atoms.All non-H atoms refined anisotropically.Weights of the form w = [σ 2 (F o 2 ) + (aP) 2 + bP] -1 with P = [max(F o 2 , 0) +2F c 2 ]/3 were employed in the refinement.

Figure 1 .
Figure 1.Perspective view of the molecular structure of compound 6b.

Figure 2 .
Figure 2. The signals for the representative protons of the regioisomer 7b.