Myers-Saito

Full -polarization in diradicals can give rise to zwitterionic products. First examples were studied in detail by Carpenter and coworker who investigated solvent effects on rates and product distribution in Myers-Saito cyclizations.64 Polar solvents and substitution patterns that stabilize either positive or negative charges (or both) favor the zwitterionic products. For example, the presence of a dimethylamino group leads to stabilization of cations and isolation of pyrrolo-quinolines, rather than pyrido-indoles from eneyne-carbodiimides, as reported by Wang and coworkers (Scheme 14).65... 

Zwitterionic Myers-Saito-type cyclization from reference65. 

The most obvious effect on cycloaromatization, as the name implies, is the formation of an aromatic system. By delocalizing electrons in an aromatic ring, the product gains a high degree of stability, which is reflected in the small endothermicity of the Bergman cyclization and the exothermicity of the Myers-Saito cyclization. Since the Schmittel and Schreiner cyclizations are not true cycloaromatization reactions per se, they do not have the beneficial effect of the formation of an aromatic system and are therefore much are more endothermic than their counterparts. 

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. 

The acetylene 27 became of interest since it undergoes a novel type of thermal cyclization reaction, later to be called the Myers or Myers-Saito cyclization (see Chapter 20 for a discussion of its relevance). The Z-diastereomer of 1,2,4-heptatrien-6-yne (27) was prepared by the sequence summarized in Scheme 5.33 [85]. 

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. 

J. Am. Chem. Soc. 1992, 114, 9369-9386 fora reinvestigation of the Myers-Saito cydization, seeTh. S. Hughes, B. K. Carpenter,/. Chem. Soc., Perkin Trans. 21999, 2291-2298. 

Since the double bond between C5 and C6 of the enynecumulene 169 is not required for the Myers-Saito cyclization, a large number of enyneallenes have been synthesized as model compounds for the neocarzinostatin chromophore and tested for DNA-cleaving activity in recent years, with the results having already been summarized extensively (cf. Chapter 20) [162]. 

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). 

Scheme 20.3 The Myers-Saito cyclization reaction of (Z)-l, 2,4-heptatrien-6-yne.

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 benzannulated enyne-allenes 48 were likewise synthesized in situ from coupling between 41b and the bromoallene 47 (Scheme 20.11) [39]. Under the reaction conditions, 48 presumably underwent a spontaneous cation-mediated Myers-Saito cyclization reaction with a concomitant 1,2-shift of the trimethylsilyl group to give the naphthalene derivatives 49. 

Scheme 20.11 Cation-mediated Myers-Saito cyclization reaction.

The use of l-iodo-9-fluorenone (59) for cross-coupling with phenylacetylene produced 60, which on treatment with 51 gave the benzannulated enyne-allenes 61 (Scheme 20.14) [43], Thermolysis of 61 in 1,4-CHD at 75 °C promoted the Myers-Saito cyclization reaction, leading to 63 in excellent yields. Again, the benzylic radical center in 62 is a stabilized triarylmethyl radical. 

The diketone 64 was also readily prepared from 59 as outlined in Scheme 20.15. Condensation between 64 and 2 equiv. of 51b gave 65 in excellent yield. Thermolysis of 65 in 1,4-CHD at 75 °C also promoted the Myers-Saito cyclization reaction to generate the biradical 66. The aryl radical center in 66 was then captured by the allenic moiety to form 67, having two stabilized triarylmethyl radical centers. Subsequent hydrogen-atom abstractions from 1,4-CHD then furnished 68. 

The benzannulated analog 115 was likewise synthesized from 114 (Scheme 20.24) [56, 63], However, unlike 109, thermolysis of 115 resulted in its slow decomposition without the formation of the cycloaromatized adduct 116. The lack of propensity for 115 to undergo the Myers-Saito cyclization reaction was attributed to unfavorable steric interactions between the diphenylphosphinyl group and the aryl ring of the benzannulated enyne-allene system, causing the allenic moiety to be rotated out of the plane defined by the aryl ring and preventing the cyclization reaction. 

The enyne-allenylphosphine oxides 120 and the benzannulated and naphthannu-lated analogs 121 and 122 having the diphenylphosphinyl group at the allenic terminus were readily prepared from the corresponding enediynyl propargylic alcohols 117,118 and 119 (Scheme 20.25) [64]. Without the unfavorable steric interactions, these conjugated derivatives smoothly underwent the Myers-Saito cyclization reaction. 

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. 

In addition to the sulfur-substituted enyne-allenes depicted in Schemes 20.18-20.20, the sulfoxide 141 was prepared by treatment of the enediynyl propargylic alcohol 108 with benzenesulfenyl chloride to induce a [2,3]-sigmatropic rearrangement (Scheme 20.29) [10]. The Myers-Saito cyclization of 141 occurs at 37 °C with a half-life of only 16 min. 

When 160 was heated at 150 °C in the presence of 1,4-CHD, the naphthalene derivative 163 was obtained in 45% yield (Scheme 20.32) [56, 67]. An initial [3,3]-sigmatro-pic rearrangement to form 161 followed by a Myers-Saito cyclization and hydrogen-atom abstractions from 1,4-CHD could account for the formation of 163. 

The use of the zinc-copper couple to effect the reduction of the methanesulfonate 168 with rearrangement furnished 169 (Scheme 20.34) [10]. Treatment of 168 with methylmagnesium bromide in the presence of copper(I) cyanide to induce an SN2 -type reaction produced the methylated adduct 170. The half-life of the Myers-Saito cyclization of 169 is 66 h at 37 °C, whereas that of 170 is 100 min. The faster rate of cyclization for 170 has been attributed to a steric effect favoring the requisite s-cis or twisted s-cis conformation. 

Similarly, exposure of 180 to trifluoroacetic acid also promoted an internal SN2 displacement reaction to form 181 (Scheme 20.37) [68], The Myers-Saito cyclization generated the biradical 182 and, subsequently, 183. As in the case of 55, the benzylic radical center in 182 is a stabilized triarylmethyl radical. Several related transformations to produce enyne-allenes have also been reported [69, 70]. 

In addition to the example depicted in Scheme 20.40 and examples involving a prototropic rearrangement [61], the use of trimethylsilyl trifluoromethanesulfonate to induce the transformation of 212 afforded 213 bearing a keto substituent at the allenic terminus (Scheme 20.44) [81]. Thermolysis of 213 promoted the Myers-Saito cyclization leading to 216. 

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... 

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

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