Didehydrotoluene

The ability of (Z)-l,2,4-heptatrien-6-ynes (enyne-allenes) and the benzannulated derivatives to undergo cyclization reactions under mild thermal conditions to produce biradicals has been the main focus of their chemical reactivities [1-5]. With the development of many synthetic methods for these highly conjugated allenes, a variety of biradicals are readily accessible for subsequent chemical transformations. Cyclization of the enyne-allene 1 could occur either via the C2-C7 pathway (Myers-Saito cyclization) leading to the a,3-didehydrotoluene/naphthalene biradical 2 [6-10] or via the C2-C6 pathway (Schmittel cyclization) producing the fulvene/benzofulvene biradical 3 [11] (Scheme 20.1). 

With the presence of two methyl substituents at the allenic terminus of 20a, the a,3-didehydrotoluene biradical 21 having a tertiary benzylic radical center was generated after cycloaromatization (Eq. 20.1). As a result, the half-life of the reaction is only -70 min at 37 °C, which is significantly shorter than that of 8. 

In the absence of 1,4-CHD, the biradical 55e undergoes an intramolecular 1,5-hydrogen shift to form 57, making it possible for an intramolecular radical-radical coupling to occur to produce 58 (Scheme 20.13). The fact that 58 was produced from 54e lends support to the formation of the a,3-didehydrotoluene biradical 55e as a transient reaction intermediate. It is also worth noting that the benzylic radical center in 55 is a stabilized triarylmethyl radical. 

Scheme 20.13 Intramolecular 1,5-hydrogen shift of an a,3-didehydrotoluene biradical.

Scheme 20.14 a,3-Didehydrotoluene biradicals having a triarylbenzylic radical center. 

The prototype of this reaction is the Myers-Saito reaction, the rearrangement of eneyneallene (Z)-hepta-l,2,4-triene-6-yne (70) to a,3-didehydrotoluene (71). This C2—C7 cyclization yields a benzylic 7i-conjugated a,7t-biradical and is therefore... 

The first isolation of a derivative of 71 was reported by Sander et al. in 1998. Irradiation of quinone diazide (73) with X > 475 nm in an argon matrix at 10 K quantitatively yields 2,6-dimethylcyclohexa-2,5-diene-l-one-4-ylidene (74). Short wavelength irradiation (X > 360 nm) converts 74 into the substituted a,3-didehydrotoluene derivative 75 (Scheme 16.22). Upon prolonged irradiation 76 and (presumably) 77 are formed by Myers cycloreversion. No evidence was found for the formation of bicyclic 78. ... 

Scheme 16.22. The first direct detection of a derivative of a,3-didehydrotoluene.

The cyclization of enyne-allenes was first reported by Myers and coworkers in the late 1980s [34], These reactions are energetically favorable and often proceed at ambient temperature. The parent (Z)-l,2,4-heptatrien-6-yne (101) cyclizes to afford a,3-didehydrotoluene 98 with a half-life of 30 min at 75 °C (Fig. 9). 

Protti S, Ravelli D, Mannucci B, Albini A, Fagnoni M (2012) a,n-Didehydrotoluenes by photoactivation of (chlorobenzyl)trimethylsilanes an alternative to enyne-allenes cyclization. Angew Chem Int Ed 51 8577-8580... 

Ravelli D, Protti S, Fagnoni M (2015) Photogenerated a, n-didehydrotoluenes from chlorophe-nylacetic acids at physiological pH. J Org Chem 80 852-858... 

The Myers cyclization of enyne-allenes under mild thermal conditions provides an easy access to the a,3-didehydrotoluene biradicals 10-18). Thermolysis of 22b in refluxing benzene generated the biradical 23 (Scheme 5). The phenyl radical center in 23 was then captured by the double bond intramolecularly, giving rise to the biradical 24. A subsequent 1,5-hydrogen shift produced the o-quinodimethane 25, which in turn underwent a [1,5] sigmatropic hydrogen shift to afford the indan 26. 

Other methods of forming six-mem bered rings include the Myers-Saito C -C cycloaromatization of enyne-allenes (Scheme 3.4) [25, 27, 29]. A possible pathway of enyne-allene 3.430 involves a,3-didehydrotoluene diradical 3.431. The acyclic enyne-allene 3.430 (Z-1,2,4-heptatrien-6-yne) undergoes the Myers-Saito cyclization at 37°C with ti/2 = 24 hours and at 75°C with tj/2 = 30 minutes to afford toluene [29]. The alternative Schmittel C -C cycloaromatization via diradical 3.432 is discussed in Section 3.3.3. 

Like the Bergman cyclization transforming enediynes to aromatic systems, the Myers-Saito cyclization of (Z)-l,2,4-heptatrien-6-ynes also proceeds via the formation of 3-a-didehydrotoluene diradicals 3.428. But in contrast to the Bergman cyclization, the acyclic enyne-allenes 3.444-3.446 react along the Myers-Saito route under conditions close to physiological ones (Scheme 3.7) [221,222]. Cyclic enyne-allenes react in a similar manner to their acyclic counterparts. The biological activity of neocarzinostatin [24, 27] is attributed to this reaction. 

Computational studies indicated that benzannulation decreases the activation barriers for both cyclizations. This effect is much more pronounced in the C -C compared with the C -C cyclization, mostly because of the fact that benzannulation stabilizes the fulvenyl diradical 10 kcal/mol more efficiently than the a,3-didehydrotoluene diradical, reducing the C -C cyclization barrier by 2.3 kcal/mol compared with that of the C -C reaction. 

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