SUBSTITUTED THIOPHENES AS DIENOPHILES IN DIELS-ALDER REACTIONS

Claudia Della Rosa, María Kneeteman, Elisa Paredes, Pedro M. E. Mancini*

Área Química Orgánica- Departamento de Química- Facultad de Ingeniería Química, Universidad Nacional del Litoral. Santiago del Estero 2829 – 3000 Santa Fe, Argentina.

FAX: +54-342-4571162. *E-mail: pmancini@fiqus.unl.edu.ar

Abstract. Dienophilic behavior of substituted thiophenes towards normal electron demand Diels-Alder reactions is studied under thermal conditions. While a-nitrated thiophenes act as dienophile before isoprene and Dansihefsky’s diene, their b-nitrated isomers did not undergo cycloaddition through their Ca-Cb bond. Formation of pyrrolyl-thiophenes are observed in reactions of nitrothiophenes with isoprene. Acyl-substitution on thiophenes showed to be inefficiency towards Diels-Alder reactions.

Keywords: thiophenes, dienophiles, Diels-Alder

Introduction

It is known that thiophenes can act as dienes in Diels-Alder (DA) reactions.¹ However only a few examples can be found where thiophenes act as dienophiles. Thus it has been reported that they react with diene partners such us hexaclorocyclopentadiene,² dimethyl 1,2,4,5-tetrazine-3,6-dicarboxilate³ and masked o-benzoquinones⁴ through DA reactions with inverse electron demand.

We have previously informed studies on the dienophilic character of other aromatic systems like substituted indoles⁵ and naphthalenes⁶ in DA reactions with normal electron demand. In this opportunity we would like to explore the behavior of thiophenes substituted with electron-withdrawing groups in thermal reactions with dienes.

Results and Discussion

The study was carried out employing as dienophiles 2-nitrothiophene (1a), 3-nitrothiophene (2a), thiophen-2-carboxylic methyl ester (1b), thiophen-3-carboxylic methyl ester (2b), 2-nitro-thiophen-5-carboxylic methyl ester (3a) and 4-nitro-thiophen-2-carboxylic methyl ester (3b). trans-1-Methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefsky’s diene) and isoprene were chosen as diene partners.

a-Nitro substituted thiophenes, 1a and 3a, reacted through their nitrated bond with Danishefsky’s diene (2 equiv. of diene, 120^oC, 72 h) to give the 5-hydroxybenzothiophene (22%) and methyl 5-hydroxy-benzothiophen-3-carboxylic methyl ester (45%) respectively, resulting from thermal extrusion of nitrous acid and methanol followed by a further aromatization of the primary cycloadduct (Scheme 2). A higher temperature (150^oC, 72 h) improved the yield of these cycloadditions (1a ® 25%, 3a ® 50%).  

In contrast to the previous thiophenes, b-nitro substituted 2a and 3b only afforded traces of products when they were exposed to Danishefsky’s diene, showing lower reactivity toward the cycloaddition. This is in good agreement with semiempirical calculations that predict lower LUMOs for 1a and 3a than those for 2a and 3b.

On the other hand, when isoprene was used, 3a (12 equiv. of diene, 150^oC, 72 h) gave the corresponding benzothiophene 6 (6%) and pyrrol 7 (17%) (Scheme 3). Rate 7/6 (22% and 8%) was essentially kept at 180^oC during 72 h. The formation of pyrroles by reaction of the diene with a nitro group was already observed in experiments with nitronaphthalenes.^6c It is assumed that these nitroaromatic compounds can react through the heterodienophilic fragment NO by a hetero Diels-Alder reaction (HDA) affording the 1,2-oxazine that rearranged into the corresponding pyrroles under thermal conditions. The mechanism for the conversion of this type of heteroadduct into pyrroles by thermal⁷ and fotochemical⁸ activation was first proposed for the transformation of cycloadducts from nitrosobenceno.

Compound 3b gave with isoprene pyrrol 8 (12 equiv of diene, 150^oC, 72 h, 15%; 180^oC, 72 h, 20%) while 1a and 2a gave traces of pyrroles 9 and 10, respectively (detected by TLC).^6c The above-mentioned results evidenced that a second electron-withdrawing group on thiophene nucleus notoriously enhanced the yield of pyrroles.

Reactions using esters 1b and 2b with Danishefsky’s diene were also carried out under thermal conditions but they did not undergo cycloaddition, showing the inefficiency of acyl substitution on thiophene towards DA reactions.

Acknowledgement

This research was supported by CAI+D and Doctoral Grant Programs at Universidad Nacional del Litoral.

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