Synthesis of hydronaphthalenes through coupling of enyne carbonyl compounds that contain pendant alkene groups with Fischer carbene complexes

Abstract

The coupling of enyne carbonyl compounds that contain pendant alkene groups with Fischer carbene complexes to afford furans that contain pendant alkene groups is described. Subsequent intramolecular Diels-Alder reactions are effective in select cases, resulting in hydronaphthalene systems after dehydration. Although the Diels-Alder event is thermodynamically unfavorable, the overall transformation of alkene-furans to dihydronaphthalenes is a favorable process.

Introduction

Recently, a novel synthesis of hydrophenanthrenes (e.g. 5, Scheme 1) involving the coupling of 2-alkynylbenzoyl systems (e.g. 1) with γ,δ-unsaturated Fischer carbene complexes (e.g. 2) was reported.¹ This reaction proceeds through a series of tandem events that eventually lead to the formation of an isobenzofuran ring system containing a pendant alkene group (3), which undergoes intramolecular Diels-Alder reaction and oxanorbornene ring opening to afford the observed product 5. In this manuscript, attempts to effect an analogous process using simple furans (e.g. 7a) generated from non-aromatic enyne carbonyl compounds (e.g. 6a) is reported.² The net conversion represents construction of two new ring systems in a single reaction event. This latter process is considerably more challenging than generation of oxanorbornene 4 from isobenzofuran 3 since the Diels-Alder step involves furans and not isobenzofurans. Examples of successful intramolecular Diels-Alder reactions have been reported for simple furans,³ however they appear to be less reliable relative to analogous reactions involving isobenzofurans. Most of the high-yielding reactions involve activated systems such as electron-deficient alkenes,⁴ allenes,⁵ or a favorable gem dialkyl effect.⁶ Six-membered ring forming intramolecular furan Diels-Alder reactions involving unactivated alkenes are often low-yielding,⁷ although several high-yielding processes have been reported.⁸ The net transformation is a unique construction of a hydronaphthalene⁹ from two five-carbon pieces where both components contribute at least one carbon to both of the newly-formed rings.

Scheme 1.

Results and Discussion

Enyne-carbonyl compounds were readily prepared using the synthetic routes depicted in Scheme 2. Haloformylation of either cyclohexanone or cyclopentenone¹⁰ to afford the β-bromoenal derivative 10, followed by Sonogashira coupling afforded the enyne-aldehyde derivative 6. Subsequent desilylation and/or synthetic manipulation of the aldehyde carbonyl group led to additional enyne-carbonyl systems.

Scheme 2.

In the initial studies, the carbene alkyne coupling reactions were conducted in dioxane. As noted in Scheme 3, there is NO reason for optimism concerning the Diels-Alder reactions of 7b–i. The carbene coupling reaction provides the vinylfuran derivatives 7b–i, which do not undergo Diels-Alder reactions in any of the systems depicted. Extended heating at reflux results in a slow decomposition process. Heating at higher temperatures also results in decomposition. Hydrolysis affords a more robust compound, furan-ketones 13a–i that is also thermally inert with respect to the Diels-Alder reaction.

Scheme 3.

The reaction depicted in Scheme 4 is the only evidence of possible successful execution of the original objective. In this reaction, a low yield of a secondary cyclization product, hexahydrophenanthrene 14a, was observed. Compound 14a hypothetically results from dehydration of Diels-Alder adduct 8a, which was not observed under these conditions. Two of the examples in Scheme 3 bear remarkable similarity to this system, the five-membered analog 7b and the hydrolysis product 13b, yet no Diels-Alder derived products were observed in these relatively similar systems. Greater focus was thus placed on 7a since it is only system where there is any remote glimmer of success.

Scheme 4.

Computational evaluation (DFT-B3LYP, 6-31G*) of selected Diels-Alder reactions reveal that all of these reactions will be difficult (see Scheme 5). Although most of the simple intramolecular Diels-Alder events are exothermic, all are very slightly endergonic when entropic considerations are taken into consideration. Even though the cyclohexane-fused system 7a was the only system where there is any hint of the Diels-Alder event, there is very little energetic difference in the five- and six-membered ring systems (7a,b). Hydrolysis of enol ether 7d to the ketone 13d results in a less favorable intramolecular Diels-Alder reaction. Successful Diels-Alder reaction in the five-membered ring alkene-tethered system (conversion of 13g to 15g) is very highly unlikely. The tandem Diels-Alder reaction and dehydration process (conversion of 7a to 14a and water) is however highly exothermic and exergonic.

Scheme 5.

The calculations suggest that successful cyclization might be achieved if the Diels-Alder reaction is coupled with the dehydration step. Tandem Diels-Alder reaction followed by oxanorbornene ring opening and/or aromatization is a feature in many examples of the highly successful amidofuran-based intramolecular Diels-Alder reactions.¹¹ A likely mechanism for the dehydration step is depicted in Scheme 6, and involves ionization of the C-O bond as a key step. Optimization of this process would ideally involve a high boiling and highly polar solvent, thus DMF was employed for the Diels-Alder reaction. Complete conversion of the furan to the desilylated hydrophenanthrene derivative 18a occurred upon heating the compound to reflux in DMF. The idea condition for this process involves performing the carbene-alkyne coupling in dioxane at 85 °C followed by replacing the dioxane with DMF and heating to 145 °C for 10 h, which affords the hydrophenanthrene 18a in 60% yield¹² accompanied by a trace of the aromatized compound 19a. Since the thermodynamics for Diels-Alder reaction of five-membered ring analog 7b are basically identical, this analog was subjected to similar reaction conditions. This process resulted in the five-membered ring fused adduct 18b, also accompanied by a trace of aromatized compound 19b.¹³

Scheme 6.

In summary, we have demonstrated that the net [5+5]-cycloaddition of 2-alkynylbenzaldehydes and γ,δ-unsaturated carbene complexes can be extended to non-aromatic enyne-aldehyde systems. The simple Diels-Alder step of the tandem reaction was unsuccessful, however can be conducted if conditions favoring a Diels-Alder dehydration sequence were employed, resulting in the direct formation of dihydronaphthalene derivatives.