Stable Vicinal Bisketene Equivalents for Aryne Diels–Alder Reactions

Abstract

2,5-Bis(tert-butyldimethylsilyloxy)thiophenes are introduced as bench-stable Diels–Alder dienes for reaction with arynes as dienophiles. Ring-opening of the cycloadducts can be achieved via TBAF-promoted desilylation, providing convergent redox-neutral access to a library of substituted naphthoquinones. Strategically, this two-step sequence represents the application of stable vicinal bisketene equivalents as Diels–Alder dienes. Extension to anthraquinone is also demonstrated, in this case via mild autoxidation of a readily accessible cyclohexenyl-fused derivative.

Graphical Abstract

Thiophenes are inefficacious Diels–Alder dienes as consequence of their high aromatic character.¹ As a result, elevated temperatures or pressures are typically necessary for reactivity, even when employing highly activated dienophiles such as maleimides or maleic anhydride.² While Lewis acids have been shown to enable reactivity under mild conditions, yields remain modest.³ Furthermore, thiophene/Lewis acid complexation has been observed to engender a switch from Diels–Alder to Friedel–Crafts selectivity.^3a Of particular relevance to the present study, even ultra-reactive dienophiles such as arynes appear to be problematic substrates. In total, only four reaction platforms of this nature have been disclosed, each proceeding via reductive desulfurization of the direct cycloadduct to generate the corresponding naphthalene (comprehensive summary provided in Scheme 1a).⁴ Despite several methods of aryne generation having been implemented within these studies (e.g., metal-halogen exchange,⁵ pyrolysis,⁶ and intramolecular hexadehydro-Diels–Alder reaction⁷), yields tend to be low (2–62%, most below 50%), and the thiophene is uniformly used in excess.

Scheme 1.

(a) Known thiophene-aryne Diels–Alder reactions. (b) Aryne Diels–Alder reactions of 2,5-bis(silyloxy)-furans/pyrroles as motivation for evaluating thiophenes.

In 2020, our group introduced 2,5-bis(tert-butyldimethylsilyloxy)furans as vicinal bisketene equivalents for application as dienes across a variety of Diels–Alder settings (Scheme 1b).⁸ Within this report, arynes were demonstrated to be competent dienophiles, enabling convergent redox-neutral access to a variety of substituted naphthoquinones. The corresponding silyloxypyrroles also proved effective, in this case leading to benzo-fused para-iminoquinones.⁹ Several years later we disclosed an optimized and independently reproduced procedure illustrating this chemistry can be conducted in excellent yield, and on multigram scale, while employing only a small excess of furan.¹⁰ Herein we describe our recent efforts to expand this chemistry to 2,5-bis(tert-butyldimethylsilyloxy)thiophenes as Diels–Alder dienes.

The present study commenced with a comparative stability assessment of several 2,5-bis(silyloxy)furans and their thiophene counterparts (Scheme 2a).¹¹ In line with our previous observations,^{8, 10, 12} larger silyl groups confer an improved stability profile (compare 1 vs. 2 and 4 vs. 5). Notably, while more electron-rich furan derivatives are less stable (compare 2 vs. 3), this trend is not observed for thiophenes 5 and 6. In fact, when bulky tert-butyldimethylsilyl functionality is incorporated, the resulting thiophenes are completely bench-stable and no special precautions need to be taken during preparation, purification, or storage.¹³ Of note, cyclohexyl-fused derivative 6 is a crystalline solid that has been prepared on greater than 10-gram scale.

Scheme 2.

(a) Stability of 2,5-bis(silyloxy)-furans/thiophenes. (b) Diels–Alder/ring-opening reaction development.

Diels–Alder reactivity was probed using thiophene 6 as limiting reagent and iodo triflate 7 as benzyne precursor (complete optimization details provided in the Supporting Information). While lithium-iodide exchange¹⁴ provided the desired cycloadduct 8 in 55% NMR yield, attempts to improve the reaction were unsuccessful. Transitioning to the less basic/nucleophilic TMSCH₂MgCl proved beneficial,¹⁵ enabling access to 8 in 95% NMR yield and without the need for dry ice/acetone cooling. Subsequent treatment with either TBAF or LiAlH₄ provided naphthoquinone 9 in excellent yield. Attempts to observe and/or isolate thioketone 10, the presumed precursor to 9, were unsuccessful.

The scope of the two-step Diels–Alder/ring-opening sequence is presented in Scheme 3. While we found it most convenient to submit the direct cycloadducts to the resulting ring-opening reaction in either crude or semi-purified form, Diels–Alder NMR yields proved informative and are presented alongside the isolated naphthoquinone yields. With respect to quinone formation, TBAF was ultimately selected as reagent of choice, given its slightly higher yield and milder reaction conditions.

Scheme 3.

Scope of the Diels–Alder/ring-opening sequence.

Aryne scope was explored using cyclohexyl-fused thiophene 6 (Scheme 3). Diels–Alder yields ranged from good to excellent (67–95%, most ≥80%), with no obvious trend between aryne substitution pattern and yield. Conversion of the cycloadducts into their corresponding naphthoquinones proved efficient, with an average yield of 84% across these eight examples. Highlights include fluorine (14), trifluoromethyl (15), and methoxy (16 and 17) incorporation.

Thiophene scope proved less general. While cyclopentyl fused quinone 18 was accessible in 82% yield, a significant drop in yield was observed for the synthesis of 19. Monosubstituted 2,5-bis(silyloxy)thiophenes underperform relative to their bis-substituted counterparts (20 and 21). However, given their furan congeners tend to exhibit a user-friendly stability profile (e.g., compound 2 in Scheme 2a) and excellent yields in aryne cycloadditions (e.g., our 2023 work summarized in Scheme 1b),¹⁰ we simply recommend their application in these settings.

Finally, a small collection of unsuccessful substrates is presented (22–24). Likely, each of the corresponding thiophene precursors and/or their direct aryne cycloadducts are sensitive toward TMSCH₂MgCl, and perhaps alternate benzyne generation techniques may prove more productive in these cases. Nevertheless, it is worth highlighting that their respective thiophenes remain bench stable, even with direct heteroatom substitution (23), thus creating an excellent platform for future experimentation in the present context or beyond.

To round out this study we elected to explore the synthesis of anthraquinones via the same general Diels–Alder/ring-opening strategy. In principle, this could be achieved via a simple switch from thiophenes to isobenzothiophenes. However, this family of heterocycle tend to be significantly less stable than their direct thiophene analogs.¹⁶ Mindful of this trend, we reasoned that the readily accessible cyclohexenyl derivative 25 may serve as a convenient precursor to the corresponding isobenzothiophene via a mild oxidation procedure. While exploratory experiments directed toward the oxidation of 25 were unsuccessful,¹⁷ we fortuitously discovered that simply submitting this diene to our standard aryne Diels–Alder/TBAF conditions yielded anthraquinone 27, proceeding via facile autoxidation during the ring-opening process.

In summary, herein we introduce 2,5-bis(tert-butyldimethylsilyloxy)thiophenes as a new class of Diels–Alder diene. This family is significantly more stable than their direct furan counterparts, which is of particular significance when considering the application of more electron-rich variants. We have demonstrated that fully substituted 2,5-bis(tert-butyldimethylsilyloxy)thiophenes react efficiently in aryne Diels–Alder reactions—a rare example of this general reactivity mode. Cycloadduct treatment with TBAF yields substituted naphthoquinones, thus representing the development of stable vicinal bisketene equivalents as Diels–Alder dienes. Overall, these new thiophenes serve as a nice complement to our previously reported family of 2,5-bis(tert-butyldimethylsilyloxy)furans.

Supplementary Material

Yes.

Scheme 4.

A synthetic equivalent of an isobenzothiophene.