Reactions of some annelated 2-aminothiophenes with two naphthoquinones

2-Amino-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carbonitrile ( 1 ) and three 3-aminobenzopyrano[3,4-c ]thiophenes ( 2a-c ) were reacted with 2,3-dichloro-1,4-naphthoquinone ( 3a ) and the parent 1,4-naphthoquinone ( 3b ) in solution at reflux temperature. While from 1 only products of addition/dehydrogenation and chlorine substitution, respectively, were obtained, Diels-Alder addition of 2a-c to 3b followed by hydrogen sulfide elimination led to the polycycles 10a-c .


Introduction
A detailed examination of the chemical literature shows that in recent years the synthesis of quinonoid natural products has drawn a lot of attention.The application of the Diels-Alder reaction has been so far very useful for this purpose.The consequence is a growing interest in the scope of this reaction.To the best of our knowledge, in contrast to furan [1][2][3][4][5][6][7] and other dienes [8][9][10][11][12] , very little has been reported on the [4+2]-cycloaddition of quinones and other cycloenones to thiophenes in general and 2-aminothiophenes in particular.
Direct addition of dienophiles in general [13][14][15] and quinonoid dienophiles in particular across the butadiene fragment of the thiophene ring system in a [4+2]-mode seems to be rare.Three cases of cycloaddition of 1,4-naphthoquinone to [c]anellated 2-aminothiophenes have been reported recently by Al-Saleh et al. 16 .When these components were refluxed in ethanol, [4+2]cycloaddition across the thiophene ring occurred followed by hydrogen sulfide elimination.
When, however, the components were subjected to microwave irradiation in the presence of a few drops of acetic acid, the 1,4-dihydroxynaphthalen-2-yl residue was introduced to the hitherto unsubstituted carbon atom α to sulfur in the thiophene ring 16 .The other successful [4+2]cycloadditions of thiophenes with quinones reported in the literature deal either with reactions in which the sulfur atom in the thiophene reagent is activated through oxidation with peracids 5 , prior to or during the reaction, or with cases in which side chains partly or totally act as diene components. 17,18e recently reported 19 the preparation of the condensed benzoxepin 4 from the thienocoumarin 2a and 2,3-dichloro-1,4-naphthoquinone (3a) in refluxing THF in the presence of triethylamine, as the so far only successful reaction from several attempts to induce reactions between 2a and numerous quinones.

Scheme 1
This discovery prompted us to reexamine in this work some of the reactions of 2a with quinones under somewhat modified reactions conditions and to extend the study to other 2aminothiophenes such as 1 and 2b,c.

Results and Discussion
Compound 1 reacts with 3a in refluxing toluene in the presence of triethylamine to give in poor yield the aminoquinone 5 (Scheme 2).The latter reaction can be considered as the result of a nucleophilic addition of the amino group of 1a to C-2 of 3a followed by elimination of a molecule of HCl trapped by triethylamine.It is worth mentioning that in the absence of triethylamine no reaction took place.
By reacting 1 with 3b in boiling dioxane, the aminoquinone 6 (Scheme 2) was obtained in low yield after purification by preparative layer chromatography.Structures 5 and 6 were assigned on the basis of their IR and mass spectral data.
Reaction of 1 with 3b in refluxing glacial acetic acid gave no addition to the thiophene ring.Besides the N-acetylation product 7, the product 8 of the known ARKAT cyclohexadehydrotrimerization 20 of 1,4-naphthoquinone (3b) was obtained (Scheme 2).This compound crystallizes as a green-yellow, high melting (mp > 360°C) powder from acetic acid.In the IR spectrum, the absorption bands of the carbonyl groups are seen at ν = 1691 and 1668 cm -1 .In the mass spectrum, besides the molecular ion at m/z = 468 (100%), characteristic fragmentations are observed at m/z = 440 (37%), 412 (49%), 356 (18%), 328 (13%) and 300 (11%) corresponding to the elimination of 1x CO, 3x CO, 4x CO, 5x CO and 6x CO, respectively.According to the literature 21 , the reaction of 1,4-naphthoquinone (3b) with 1 cannot be considered as a simple nucleophilic addition, because hydrogen is finally eliminated.From recent kinetic and mechanistic studies 22 , the quinone-amine reactions lead primarily to a chargetransfer-complex intermediate which is subsequently dehydrogenated (either by another molecule of quinone or by oxygen) to final products (aminoquinones) such as 6 (Scheme 2).
The reactions of 2a-c with 1,4-naphthoquinone (3b) in refluxing DMF gave the polycycles 10a-c as the results of Diels-Alder additions across the thiophene rings of 2a-c with subsequent aromatization and H 2 S elimination (intermediates 9 could not be isolated, Scheme 3).Because of their very poor solubility in DMSO-d 6 , not all the NMR data were obtained for compounds 10ac, the structures of which were nevertheless supported by their elemental analyses, IR and mass spectral data.Furthermore, the more soluble N-trifluoroacetyl derivative 10d, prepared from 10c and trifluoroacetic acid anhydride, provided all the analytical and spectroscopic data in agreement with the assigned structures.
Compound 10d crystallizes as an orange powder melting at 274-276 °C from ethyl acetate.The gross formula C 27 H 12 NO 5 F 3 , deduced from the combustion analysis results, was confirmed by the mass spectrum, which exhibited a molecular ion at m/z = 487 (83%).The peaks at m/z = 418 (100%) and 390 (13%), respectively, were attributed to the ion-fragments (M +. -CF 3 ) +. , (M +. -COCF 3 ) +. .The 1 H-NMR spectrum exhibits in the range 11.93-7.59ppm a series of signals corresponding to twelve protons.The assignment of 1 H-and 13 C( 1 H)-NMR data for 10d was done by comparison with those of its precursor 2c and with simulated values as displayed in table 1.The normal 13   The reactions of 2-aminothiophenes 2a-c with 1,4-naphthoquinone (3b) under reflux in DMF gave the polycondensed compounds 10a-c and were rationalized in terms of [4+2]cycloaddition followed by H 2 S release (scheme 3).This study has confirmed previous findings 23,24 on the ability of [3,4-c] benzopyranoanellated 2-aminothiophenes such as 2a-c to react as electron rich dienes in a [4+2]-mode through their C-3, C-4 bonds, towards electron poor dienophiles such as 1,4-naphthoquinone (3b).Both quinones used in this study are formally electron poor olefins and, at the same time, α,β-unsaturated carbonyl compounds, oxidants, and electron acceptors.The halogenated quinone 3a is also a vinylene homologous acid chloride.All these properties show up in the encountered results depending on the nature of the reaction and reaction partner.
As previously found 24 , compound 1 is not a good diene since establishing a double bond between its C-3 and C-3a does not profit from a gain in conjugation, the NH 2 group thus is nucleophilic and reacts with 2,3-dichloronaphthoquinone as with an acid chloride.If a Diels-Alder reaction would occur with 1, carbon 7a would become a quaternary carbon.This result is often difficult to achieve.The salient feature in the Diels-Alder additions of 3b to 2a-c is the relation of the polycyclic products 10 to the class of the important tetracycline and anthracycline antibiotics 25 , which show great promise for the treatment of various tumors and the synthesis of which has exerted a huge influence on the application and development of Diels-Alder chemistry.

Experimental Section
General Procedures.All the elemental and spectroscopic analyses were performed in the chemistry department analytical center of Gerhard-Mercator-Universität Duisburg, Duisburg (Germany).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 Bruker WM ARKAT 300 and DRX 500 instruments, with TMS as internal standard.Coupling constants in brackets 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, using a direct inlet system.Combustion analyses were carried out with a CHN + O/S elemental analyzer "CARLO ERBA'' Model 1106.Simulated 1 H-and 13 C( 1 H)-NMR-spectra were performed using ACD NMR spectral simulation software.