Reactions of three [ c ]annelated 2-aminothiophenes with electron poor olefins

A series of electron poor alkenes [maleic acid derivatives 3a-d , dimethyl maleate ( 4 ), ethyl acrylate ( 5a ), phenyl vinyl sulfone ( 5b )] undergo [4+2]-cycloaddition to the thiophene moiety of benzopyrano[3,4-c]annelated 2-aminothiophenes 1a,b and 2 . The primary adducts tend to release hydrogen sulfide, in this way the fused thiophene ring is replaced by a fused benzene ring bearing the amino group and any new substituents introduced by the dienophile. With maleic anhydride ( 3a ) and dichloromaleic anhydride ( 3b ) acylation of the amino group competes with the [4+2]-cycloaddition to the thiophene ring. The cycloaddition of the monosubstituted alkenes 5a,b follows a head-to-head regioselectivity as predicted from FMO-considerations.


Introduction
Among the three common five-membered fully unsaturated heterocycles, furan derivatives [1,2] have been shown to readily undergo (π 4 +π 2 )-Diels-Alder additions.Pyrrole does so less readily and then usually only with electrophilic dienophiles, and sometimes Michael addition occurs instead [1,2] .Thiophene derivatives in contrast are generally more reluctant towards such cycloadditions because of their higher resonance energy [3] .The few examples of cycloadditions of certain substituted thiophenes to dienophiles refer either to reactant couples in which the thiophene compound is electron rich [1,2,[4][5][6][7][8]10] or to cases in which the sulfur atom in the thiophene reagent is oxidized prior to or during the reaction [9,11] . Sine 2-aminosubstitution does increase

Results and Discussion
In refluxing toluene 1b reacted with 3a to give the cycloadduct 6 in quantitative yield.A similar result obtained in refluxing glacial acetic acid was recently reported by Elnagdi et al. [12]

Scheme 1
From the reaction of substrate 2 with 3a in refluxing toluene, the N-acylated product 7 and the mixture of the bicyclic adducts 8 and 9 (scheme 1), were obtained.The latter may result from the hydrolysis of 8.The amide was obtained pure, whereas 8 and 9 were obtained as a mixture in the ratio 1:1.8 (on the basis of 1 H NMR data).
The reaction of 3b with 2 in refluxing toluene, gave the N-acylated product 11 (scheme 1).The constitution of 11 was confirmed by the elemental analysis, the mass-spectrum and all the other spectroscopic data.
Compounds 1a,b and 2 also add dimethyl maleate (4) under reflux in absence of solvent to afford the phthalate derivatives 13a-c (scheme 3) in yields of 33-96%.The preparation, the elemental and spectroscopic data of compound 13a were reported earlier. [8] Phenylvinylsulfone (5a) and ethylacrylate (5b) gave with the substrates 1a,b and 2 in boiling N,N-dimethylformamide respectively, the addition products 14a-c (scheme 4).
Products 14a-c were obtained in yields of 36%, 72% and 92% respectively, as the only regioisomers.The other possible regioisomers 15a-c, were ruled out on the basis of 1 H NMR experiments which clearly settled the differences with their counterparts 14 as follows.For 15, two more weakly coupled signals integrating for one proton each should be expected in the low field region, but two more strongly coupled (J > 8 Hz) doublets of one proton each from local AB-systems were however exhibited in this region in each case.
In the case of compound 14b, the strong chelation of the amino protons, enhanced by the ortho position of the ethoxycarbonyl group is clearly exhibited in the 1 H NMR spectrum, which shows two broad D 2 O-exchangeable signals for one proton each at δ = 8.93 and δ = 8.67 ppm.This is suggestive of a conformation in solution, in which the σ bond  linking carbone-4 to the amino group is blocked.Such details can not be encountered in the isomer 15b.For the transformation of the annelated thiophene rings into benzene rings, a mechanism operating in at least two steps, consisting of : (i) [4+2]-cycloaddition to the butadiene fragment of the thiophene, (ii) extrusion of hydrogene sulfide, should always be envisaged.A similar process has also been suggested by Elnagdi et al [12,13a-d,14-16] , for analogous transformations.It should be pointed out that both parts of the reaction can even proceed in several steps, in which : -the concerted [4+2]-cycloaddition (scheme 5), leading to the bicyclic intermediate 20, first takes place; -the epithio-bridge in [4+2]-cycloadduct 20, then opens to afford the thiolate, which subsequently undergoes H 2 S-extrusion to give the final product I (Scheme 5).
The H 2 S-extrusion is consistent with a recent observation of Elnagdi et al [16] .The addition of diethylmaleate to compound 17, gave the product 16, whereas the addition of diethylfumarate to the same heterocycle afforded instead the condensation product 18.
The formation of the latter product, proceeds by attack -SH or -S -on the ester group of the pyridazine ring.[4+2]-Cycloadditions of unsymmetrical electron poor alkenes are highly regioselective, as illustrated in this work by the formation of the products 14.Other authors found some related examples [13a-c, 14,15] .
These results are well rationalized by the Frontier-Molecular-orbital polarization and the principle of the perturbation theory [17,18] .For a [4+2]-cycloaddition reaction to even take place, a gain of conjugation should be affordable in the primary adduct.The condensed 2aminothiophenes 1a,b and 2 fulfill this requirement.
It should also be pointed out that the amino group lone pair in 1b and 2 is highly delocalised due to conjugation with the pyrane C=O group and therefore this amino group is only weakly nucleophilic.This may explain why maleic anhydride does not readily react with this group, and it requires a more electrophilic anhydride (as dichloromaleic anhydride) to attack it.The C=NH in 1a may show the same trend in abstracting electron density from the amino group, but clearly less than C=O, so it allows acylation of the amino group more readily.At the same time it is more easily replaced than the oxo group oxygen, and thus condensative dimmers may be found in some cases. [19]RKIVOC 2006 (x) 90-101 20  21 Experimental Section General Procedures.All the elemental and spectroscopic analyses were performed in the chemistry department analytical center of Gerhard Mercator Universität-GH-Duisburg, Duisburg (FRG).All the melting points were determined with a Reichert Thermovar microscope and are uncorrected.The IR and the UV spectra were measured with Perkin-Elmer 983 and 554 spectrophotometers, respectively. 1H and 13 C( 1 H) NMR spectra were recorded on WM 300 and 500 instruments, with TMS as internal standard.Coupling constants are reported in Hertz.Mass spectra were obtained on Varian MAT 311A and AMD 604 instruments by Electron Impact Ionization (EI) at 18 eV or 70 eV, on direct inlet system.Combustion analyses were carried out with a CHN + O/S elemental analyser "CARLO ERBA'' MOD.1106.Simulated 1 H and 13 C( 1 H) NMR spectra were performed with an ACD NMR spectra simulation programme.2-Aminothiophene derivatives 1a,b and 2 were prepared according to known procedures [20,21] .