Schmittel cyclization

There are also some rare domino sequences where two anionic and two radical reactions are combined (Scheme 2.152) [347]. According to a report of the Wang group, thionyl chloride is able to promote a succession of reactions by an initial formation of a chlorosulfite 2-673 of the tertiary alcohol 2-672, followed by an SN-type reaction to produce the chloroallene 2-674. A Schmittel cyclization reaction [348] then generates... 

Product stabilization is much more pronounced when the enediyne or ene-yne-allene starting materials are not already part of an aromatic system, since forming an aromatic system constitutes a much higher degree of stabilization than expanding an aromatic system (Fig. 24). Conjugation of the radical center provides additional stabilization to the 71-radical formed by the Myers-Saito and Schmittel cyclizations. 

Schmittel cyclization, 4f 30, see also Cycloaromatization reactions Schreiner cyclization, f 30, see also Cycloaromatization reactions Sensitizers, singlet oxygen, 233-234, 235-236... 

Many of the allenic parent systems mentioned in Schemes 5.1-5.3 have been of interest in mechanistic studies. Thus, the Z-isomer of 27 can either cyclize by the Myers-Saito route to the aromatic diradical 339 or under the so-called Schmittel cyclization conditions to yield the fulvene diradical 338 (Scheme 5.51) [141], both processes being discussed thoroughly in Chapters 13 and 20. 

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). 

Thermolysis of 44 produced products derived from the Myers-Saito cyclization reaction. However, when 43 having a trimethylsilyl substituent at the acetylenic terminus was subjected to heating in the presence of 1,4-CHD at 70 °C for 3 h, the 1H-cyclobut[a]indene 46 was produced. A reaction mechanism involving an initial Schmittel cyclization to generate the benzofulvene biradical 45 followed by an intramolecular radical-radical coupling was proposed to account for the formation of the formal [2 + 2]-cycloaddition product 46. 

The propargylic alcohol 102, prepared by condensation between 100 and the lithium acetylide 101, was efficiently reduced to the hydrocarbon 103, which on treatment with potassium tert-butoxide was isomerized to the benzannulated enyne-allene 104 (Scheme 20.22) [62], At room temperature, the formation of 104 was detected. In refluxing toluene, the Schmittel cyclization occurs readily to generate the biradical 105, which then undergoes intramolecular radical-radical coupling to give 106 and, after a prototropic rearrangement, the llJ-f-benzo[fo]fluorene 107. Several other HJ-f-benzo[fo]fluorenes were likewise synthesized from cyclic aromatic ketones. 

Scheme 20.26 Schmittel cyclization reactions of benzannulated enyne-allenes.

The presence of a sterically demanding tert-butyl or trimethylsilyl group at the acetylenic terminus also makes the Schmittel cyclization the preferred pathway (Scheme 20.27) [65], This observation has been attributed to the emergence of severe non-bonded steric interactions in the naphthalene biradicals derived from the Myers-Saito cyclization. 

Scheme 20.27 Schmittel cyclization reactions of tert-butyl- and trimethylsilyl-substituted enyne-allenes.

Treatment of the propargylic alcohol 144, readily prepared from condensation between benzophenone (143) and the lithium acetylide 101, with thionyl chloride promoted a sequence of reactions with an initial formation of the chlorosulfite 145 followed by an SNi reaction to produce in situ the chlorinated and the benzannulated enyne-allene 146 (Scheme 20.30) [62], A spontaneous Schmittel cyclization then generated the biradical 147, which in turn underwent a radical-radical coupling to form the formal [4+ 2]-cycloaddition product 148 and subsequently, after a prototropic rearrangement, 149. The chloride 149 is prone to hydrolysis to give the corresponding 11 H-bcnzo h fluoren-ll-ol 150 in 85% overall yield from 144. Several other llff-benzo[fc]fluoren-ll-ols were likewise synthesized from benzophenone derivatives. 

Treatment of the acetylenic ketones 186 with lithium dialkylcuprates and trapping the resultant enolates with acetic anhydride produced the enyne-allene 187 (Scheme 20.39) [72], Regeneration of the oxyanion-substituted enyne-allene system using methyllithium at -20 °C led to the formation of either the indanones 188 or the ben-zofluorenones 189 through a Schmittel cyclization reaction. 

Thermolysis of 219a and 219b produced the benzofulvenes 221 as expected. However, the formation of 222 from 219c can best be accounted for by regarding the biradical 220a as the carbene 220b to allow an intramolecular C-H insertion reaction. The presence of a carbonyl group in 219 also permits the use of samarium(II) iodide, samarium(III) chloride, boron trifluoride and trifluoroacetic acid to promote the Schmittel cyclization reaction. 

Figure 16.5. Myers-Saito versus Schmittel cyclization. ...

In the experimental thermolysis of 59, no Schmittel product was detected. Computational estimates for the activation enthalpy for the Schmittel cyclization of 59 range from 31 to 35 kcal mol , significantly higher than the barrier for the Myers-Saito cyclization of 20-22 kcal mol . Furthermore, the Schmittel cyclization is predicted to be endothermic (AH = -I-IO - -I-19 kcal mol ), while the Myers-Saito cyclization is exothermic. Therefore, the Myers-Saito cyclization of 59 is both theamodynamically and kinetically favored over the Schmittel reaction. 

The switch from Myers-Saito to Schmittel cyclization occurs with phenyl or bulky groups attached to the alkynyl position of the enyne-allene. Engels compared the Myers-Saito and Schmittel cyclization for the parent reaction with R=H, phenyl, and f-butyl (Fignre 4.15) at B3LYP/6-31G. The activation enthalpy for the Myers-Saito reaction increases from 21.4 kcal mol" when R=H to 26.7 kcal mol" for R=phenyl, and 27.9 kcal mol for R=f-butyl. Conversely, the phenyl group decreases the activation enthalpy for the Schmittel reaction from 29.0 to... 

This (7,o-diradical lacks the benzylic radical stabilization found in 61, and therefore cyclization of 68 is less exothermic than that of 59. Musch and Engels note that the Schmittel cyclization (AG (CCSD(T)/cc-pVDZ) = 18.6 kcal mol ) of 68 is favored over the Myers-Saito cyclization (AG (CCSD(T)/cc-pVDZ) = 21.1 kcal mor ). This is opposite to the case for the open chain analog 69, where the barrier for Myers-Saito cyclization is 9.7 kcal mol below the barrier for the Schmittel cyclization. However, fusing a cyclopentane ring with the eneyne-butatriene (70) favors the Myers-Saito cyclization over the Schmittel cyclization, AG (UB3LYP/6-31G(d) = 22.2 versus 22.8 kcal mol . Since neocarzinostatin chromophore follows the Myers-Saito pathway exclusively, nature has carefully balanced many factors in creating this system. 

In an analogy to the relationship between Myers-Saito and Schmittel cyclization, Schreiner proposed another cyclization path of an endiyne, C, -Cj, as an alternative to the Cj-Cg Bergman cyclization (Figure 4.17). For the case where the terminal group is a hydrogen atom (38 40), the barrier is 27.1 kcal mol ... 

Schreiner, P. R. Prall, M. Myers-Saito versus —C ( Schmittel ) cyclizations of parent and monocyclic enyne-aUenes challenges to chemistry and computation, J. Am. Chem. Soc. 1999,121, 8615-8627. 

S akai, S. Nishitani, M. Theoretical studies on Myers-S aito and Schmittel cyclization mechanisms of hepta-l,2,4-triene-6-yne, 7. Phys. Chem. A2010,114,11807-11813. 

Scheme 29. Fulvenes from Schmittel cyclization of enyne-allenes...

This reaction is related to the Myers-Saito Cyclization and Schmittel Cyclization. 

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