Despite the observed inability of the ene-allene-yne substrates to undergo the intramolecular [2 + 2 + 2] cycloaddition reaction, one variant of the ene-allene-yne substrates did take part in an unexpected cycloaddition reaction of potentially significant synthetic utility. Irradiation of ene-
allene-yne 1.60 containing a styrene moiety for 10 min at 225 °C in o-DCB resulted in the formation of naphthalene 1.61 in 68% yield; the expected alkylidene cyclobutene product 1.62 produced from a [2 + 2] cycloaddition reaction of the allene and alkyne, as well as the desired [2 + 2 + 2] cycloadduct 1.63 were not observed (Scheme 1.11). The isolated naphthalene is believed to form via a DDA reaction in which the styrene is acting as a diene and the ynone as a dienophile. Surprisingly, the allene which is often very reactive under thermal conditions in the presence of alkynes and alkenes, as previously demonstrated, did not partake in the reaction. This was evidenced by analysis of the crude reaction mixture by 1H NMR spectroscopy, which showed allene resonances at δ 4.7 and 5.3 that were similar to those of the starting material 1.60 (Figure 1.5). The disappearance of the olefinic resonances at δ 6.2 and 6.4 signified full conversion of the starting material to product, while the presence of distinct resonances in the aromatic region of the 1H NMR spectrum were diagnostic of formation of naphthalene 1.61. Overall, the 1H NMR spectrum of the crude reaction mixture was very clean and showed one product, the naphthalene 1.61. Conversion of 1.61 to a tosyl hydrazone 1.64 allowed for confirmation of the naphthalene structure by X-ray crystallography (Scheme 1.12).
Figure 1.5. 1H NMR analysis of DDA reaction.
1H NMR spectrum of styrene-yne 1.60 (top) and crude reaction mixture after microwave irradiation showing only
naphthalene product 1.61 (bottom)
Scheme 1.12. Confirmation of naphthalene structure.
The effectiveness and selectivity associated with the thermal conversion of styrene-yne 1.60 to naphthalene 1.61 was surprising for a number of reasons, the first being that the styrene is acting as a diene for the DDA reaction. Problems that can arise when employing styrene as a diene include a lack of regioselectivity, as well as undesired polymerization37 and [2 + 2] cycloaddition reactions.38 An example of the latter is observed in the intermolecular reaction of
trans-anethole (1.65) with tetracyanoethylene (1.66), where the dienophile reacts exclusively
with the styrene olefin to produce cyclobutanes 1.67 (Scheme 1.13).38a Similar [2 + 2] cycloaddition reactions are also associated with styrenes in intramolecular examples.38b To circumvent problems related to using styrene as a diene in DA reactions, intramolecular variants of the reaction can be utilized to control regioselectivity, and more reactive dienophiles can be employed to prevent undesired, competitive reactions. However, in the latter case, the desired cycloadducts are often obtained in low yields because the reactivity of these dienophiles leads to a second DA reaction with the newly formed diene of the first cycloadduct. This is depicted in the DA reaction of 1,1-diphenylethylene (1.68) and maleic anhydride (1.69), which generates the cycloadduct 1.70 in 42% yield (Scheme 1.14).39 While selectivity problems commonly accompany the use of styrene as a diene in DA reactions, no byproducts attributed to polymerization or [2 + 2] cycloaddition were observed in the DDA reaction of styrene-yne 1.60 (Scheme 1.11).
Scheme 1.14. Reactions of reactive dienophiles with styrenes
Another unique and unexpected aspect of the DDA reaction of styrene-yne 1.60 was the occurrence of a dehydrogenation during the reaction to produce the naphthalene 1.61. In traditional DDA reactions to produce naphthalenes, arylacetylenes are employed as dienes rather than styrenes because they have additional unsaturation that allows for the generation of the naphthalene products via aromatization of a cyclic allene intermediate (Scheme 1.2). When styrene is utilized instead of arylacetylene in the intramolecular DDA reaction, a tetraene intermediate is produced that subsequently aromatizes to the dihydronaphthalene product (Scheme 1.15).40 In order to form naphthalene, a second oxidative reaction must be performed to aromatize the dihydronaphthalene to naphthalene.41 However, in our thermal dehydrogenative dehydro-Diels-Alder (DDDA) reaction of styrene-yne 1.60, no oxidants were necessary to achieve exclusive formation of the naphthalene product 1.61, highlighting the novelty of this reaction (Scheme 1.11).
While DDDA reactions of styrenes to produce naphthalenes are rare, previous examples have been reported that demonstrate variable yields and selectivity. In 1971, Klemm et al. were the first to discover the DDDA reaction by refluxing styrene-yne 1.71 in acetic anhydride to produce naphthalene lactone 1.72 in low yield (Scheme 1.16, A).42 Klemm later improved upon this methodology in the synthesis of arylnaphthalene lactams 1.74 by reflux of the styrene-yne 1.73 in xylenes; however, the yield of the naphthalene product was moderate at best (Scheme 1.16, B).43 More recently, Chackalamannil et al.44 and Ruijter et al.45 have also employed the DDDA reaction of styrene-ynes 1.75 and 1.78 to the synthesis of naphthalene lactones 1.76 and lactams 1.79, respectively (Scheme. 1.16, C and D). These reactions showed limited success because only low to moderate yields of the naphthalene were obtained, and also because the naphthalene was generated as a mixture with dihydronaphthalene that was inseparable by column chromatography. A common feature of each of these reactions was the incorporation of heteroatoms into the styrene-yne tether in the form of esters or amides.
Scheme 1.16. Previous DDDA reactions of styrene-ynes.
Previous reactions reported low yields of naphthalene and mixtures of dihydronaphthalene and naphthalene products
Despite the poor yields and selectivity initially associated with DDDA reactions, two additional reports highlight the ability of this methodology to generate naphthalenes exclusively and in high yields, but only when the alkynyl terminus of the precursor is substituted with a trimethylsilyl (TMS) moiety. Terashima et al. were the first to show selective formation of cyclopentenone-fused naphthalenes 1.82 from styrene-ynes 1.81 with the intention of employing this reaction in the synthesis of fredericamycin A (Scheme 1.17, A).46 In 2011, Matsubara et al. also reported exclusive production of naphthalenes 1.84 from styrene-ynes 1.83 that contained heteroatoms within the styrene-yne tether, as well as a TMS-substituted alkyne (Scheme 1.17,
B).47 Exchange of the TMS of 1.83 for an ester or phenyl substituent resulted in the formation of a mixture of naphthalene and dihydronaphthalene substrates with dihydronaphthalene being the major product. Based upon these results, Matsubara et al. proposed that the silyl substituent was key to the exclusive production of the naphthalenes, and that this bulky substituent promoted a dehydrogenative retro-Diels-Alder reaction and loss of hydrogen gas from the initial DA cycloadduct to yield the naphthalene.47
Scheme 1.17. DDDA reactions of TMS-substituted styrene-ynes.
DDDA reactions of TMS-substituted styrene-ynes produced naphthalenes exclusively
Of significant note, Matsubara also performed the DDDA reaction with a styrene-yne containing an unsubstituted all carbon tether to generate the naphthalene 1.84b in 86% yield (Scheme 1.17, B). However, this reaction required harsh conditions of 250 °C for 48 h in order to complete. The reaction time observed in this case is considerably longer than that determined for our DDDA reaction of styrene-yne 1.60, containing a similar styrene-yne tether, in which
naphthalene 1.61 was formed after only 10 min of microwave irradiation at 225 °C (Scheme 1.11). Additionally, comparing our initial result to the other aforementioned DDDA reactions, we achieved selective production of naphthalene in high yield when an electron-withdrawing carbonyl moiety was appended to the alkyne terminus of the styrene-yne 1.60; no dihydronaphthalene product was observed. This is in contrast to the proposal by Matsubara that a TMS group on the alkyne promotes exclusive production of naphthalene,47 and also to the results of Chackalamannil, where an electron-withdrawing ester on the alkyne terminus of the styrene- yne 1.75 gave mixtures of naphthalene and dihydronaphthalene products.44