Enyne-allenes, cyclization

In view of this background, it is the aim of this chapter to organize the fundamentals of radical additions to 1,2-dienes and to present its state of the art in organic synthesis. All aspects of enyne allene cyclizations [19, 20] have been omitted since this topic is addressed in Chapter 20. In order to simplify the mechanistic discussion, the positions and Jt-bonds of allenes have been consistently numbered using the nomenclature outlined in Figure 11.1. 

To improve the thermal tandem [3,3]-sigmatropic rearrangement-enyne allene cyclization, Grissom et al.65 focused their attention on the transformation of 2-propynylvinyl ethers to allenes using silver salts as catalysts. The tetrafluoroborate proved to be the most effective, quantitatively yielding the expected aflenyl aldehyde (Scheme 3.42). However, isomerization problems appeared in some cases (see Scheme 3.33). 

PraU, M. Wittkopp, A. Schreiner, P. R. Can fulvenes form from enediynes A systematic high-level computational study on parent and benzannelated enediyne and enyne—allene cyclizations, 7. Phys. Chem. A 2001,105, 9265-9274. 

Singleton carried out a combined experimental/computational/MD study of the enyne-allene cyclization problem. First, he determined that the experimental KIE for the cyclization of 60 is 1.43. This value is smaller than that usually found for concerted ene reactions, where kg/kjj is often greater than... 

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... 

Even in 1989 the mechanism of reactions concerning enyne-allene and cumulene-enyne bond systems, known as the Myers-Saito cycloaromatization, had been thoroughly investigated [3,17,18,267,268]. Thermal cycloaromatization of the enyne-allene 3.535 (Myers-Saito C -C ) to give naphthalene 3.536 competes with the Schmittel C -C enyne-allene cyclization to give indene 3.537 [18] (Scheme 3.34). Since the discovery of these cyclizations, they have been intensively studied, in particular. 

Ring strain effects may also influence the regioselectivity of enyne-allene cyclizations (C -C vs. C -C ). Cyclopent-enyne-allene underwent exclusively Myers-Saito cyclization. Upon exchange of the cyclopentene by a cyclohexene or cycloheptene, the C -C cyclization becomes preferred because the ring strain differences do not override the effect of the phenyl group at the alkyne terminus. 

Substitution at the inner locus of the allene unit will strongly influence enyne-allene cyclizations because of steric and electronic effects. Enyne-allenes with the methyl substituent at the inner allene atom undergo cyclization at room temperature, whereas unsubstituted compounds are stable below 80°C. Computations (DFT) demonstrated that methyl substitution enhances the equilibrium concentration of the reactive s-cis conformer with respect to that of the s-trans conformer. 

The reactive structural element for the Myers cyclization is an enyne allene, the heptatrienyne 6, which reacts to form a diradical species 7 ... 

Wang s approach for the synthesis of enyne-allenes focused on ene-allenyl iodide 45 (Scheme 14.12) [24]. Palladium-catalyzed Sonogashira reaction of 45 with terminal alkynes 46 (R= Ph or CH2OH) proceeded smoothly under mild reaction conditions in the presence of the cocatalyst cuprous iodide and n-butylamine. The initially formed enyne-allene 47b with substituent R= CH2OH cyclized spontaneously to the corresponding a-methylstyrene derivative 48. 

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). 

The enyne-allene 12 having a methyl substituent at the allenic terminus was likewise prepared from the corresponding enediynyl propargylic alcohol 11 (Scheme 20.4). The presence of a methyl group accelerates the rate of cyclization by approximately sixfold and 12 cyclizes with a half-life of -3.6 min at 78 °C. The formation of a more stable secondary benzylic radical is apparently responsible for the rate enhancement. 

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. 

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 benzannulated analogs were also found to behave in a similar fashion. Attachment of a pendent olefin to the benzannulated enyne-allene system as depicted in 89 allowed the aryl radical in 90 to be captured in a 5-exo radical cyclization reaction leading to 91 and then the dihydrobenz[e]indene 92 (Scheme 20.20) [55, 56]. 

Scheme 20.20 Tandem enyne-allene and radical cyclizations.

Scheme 20.21 Synthesis and cyclization of a 10-membered ring enyne-allene.

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. 

Synthesis and cyclization of phosphorus-substituted enyne-allenes. 

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. 

Scheme 20.26 Schmittel cyclization reactions of benzannulated enyne-allenes.

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

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. 

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. 

Scheme 20.30 Synthesis and cyclization of chlorinated enyne-allenes.

Synthesis and cyclization of enyne-allenes via a [3,3]-sigmatropic rearrangement. 

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]. 

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. 

Cascade Radical Cyclizations of Biradicals Generated from Enyne-Allenes 1119... 

---