Endo-dig cyclization reactions

Samarium diiodide-induced ketyl couplings are of significant synthetic interest, and Reissig el al. have reported an elegant application of the reaction in the case of the precursor 18. Reaction of 18 with 2 equivalents of samarium diodide and HMPA gave the 2-benzazepine 19 from an S-endo-dig cyclization reaction of the ketyl radical from the... 

Interestingly, when the substrate was switched from benzene-1,2-dialkyne 90 to cA-enediyne 95, 6-endo-dig cyclization reaction pathway was observed. Two regioisomeric ort/zo-auroaryl cation intermediates 96 and 98 were proposed via dual gold-catalyzed 6-endo-dig cyclization model, which can be mutual isomerization via aryne-coordinated gold complex 97. Ort/zo-aurophenyl cation intermediates 98 could be trapped by a tethered hydroxy or sulfonamide group to deliver the seven-membered O- or AT-heterocycles 99 (Scheme 12.45) [48]. 

A unique method to generate the pyridine ring employed a transition metal-mediated 6-endo-dig cyclization of A-propargylamine derivative 120. The reaction proceeds in 5-12 h with yields of 22-74%. Gold (HI) salts are required to catalyze the reaction, but copper salts are sufficient with reactive ketones. A proposed reaction mechanism involves activation of the alkyne by transition metal complexation. This lowers the activation energy for the enamine addition to the alkyne that generates 121. The transition metal also behaves as a Lewis acid and facilitates formation of 120 from 118 and 119. Subsequent aromatization of 121 affords pyridine 122. 

The final cyclization manifold has been realized with a different ruthenium catalyst (Scheme 22). The cationic [Cp Ru(MeCN)3]PF6 induces exclusive endo-dig cyclization of both homopropargylic and bis-homopropargylic alcohols.29 73 The clean reaction to form a seven-membered ring is noteworthy for several reasons intramolecular exo-dig cyclization with bis-homopropargylic alcohols is not well established, the platinum-catalyzed case has been reported to be problematic,80 and the selectivity for seven-membered ring formation over the exo-dig cyclization to form a six-membered ring is likely not thermodynamic. The endo-dig cyclization manifold was thus significant evidence that a re-examination of alkyne hydrosilylation mechanisms is necessary (see Section 10.17.2). 

Another rhodium vinylidene-mediated reaction for the preparation of substituted naphthalenes was discovered by Dankwardt in the course of studies on 6-endo-dig cyclizations ofenynes [6]. The majority ofhis substrates (not shown), including those bearing internal alkynes, reacted via a typical cationic cycloisomerization mechanism in the presence of alkynophilic metal complexes. In the case of silylalkynes, however, the use of [Rh(CO)2Cl]2 as a catalyst unexpectedly led to the formation of predominantly 4-silyl-l-silyloxy naphthalenes (12, Scheme 9.3). Clearly, a distinct mechanism is operative. The author s proposed catalytic cycle involves the formation of Rh(I) vinylidene intermediate 14 via 1,2-silyl-migration. A nucleophilic addition reaction is thought to occur between the enol-ether and the electrophilic vinylidene a-position of 14. Subsequent H-migration would be expected to provide the observed product. Formally a 67t-electrocyclization process, this type of reaction is promoted by W(0)-and Ru(II)-catalysts (Chapters 5 and 6). 

A stereochemical study of the synthesis of unsaturated 1,4-aminoalcohols via the reaction of unsaturated 1,4-alkoxyalcohols with chorosulfonyl isocyanate revealed a competition between an retentive mechanism and an SnI racemization mechanism, with the latter having a greater proportion with systems where the carbocation intermediate is more stable.254 An interrupted Nazarov reaction was observed, in which a nonconjugated alkene held near the dienone nucleus undergoes intramolecular trapping of the Nazarov cyclopentenyl cation intermediate.255 Cholesterol couples to 6-chloropurine under the conditions of the Mitsunobu reaction the stereochemistry and structural diversity of the products indicate that a homoallylic carbocation derived from cholesterol is the key intermediate.256 l-Siloxy-l,5-diynes undergo a Brpnsted acid-promoted 5-endo-dig cyclization with a ketenium ion and a vinyl cation proposed as intermediates.257... 

A 6-endo-dig cyclization of the homopropargylic alcohol 182 is achieved by careful manipulation of the ruthenium catalyst and reaction conditions to afford the 3,4-dihydropyran 183 (Equation 83) <2002JA2528>. Likewise, alkynols 184 undergo rhodium(i) mediated 6-< 4o-selective cyclizations to afford 3,4-dihydropyrans in good yield (Equation 84) <2003JA7482>. 

In contrast to the process catalyzed by platinum complexes the ruthenium-catalyzed reaction gives endo-dig cyclization in this case to provide seven-mem-bered ring products even though the exo-dig process would form the more favorable six-membered ring. In all reactions only a single product isomer is observed [116]. 

In contrast to the 5-endo-trig anionic cyclization reactions, rarely observed, there are several examples in which 5-endo-dig processes are involved. Hence 2,3-disubstituted benzofurans, benzothiophenes and indoles 374 have been synthesized starting from triflu-oroethyl ethers, thioethers and anilines 373, respectively, and alkyllithium compounds. A 5-endo-dig carbolithiation reaction on 375, generated by two successive eliminations, one substitution and one ortho-lithiation reactions, is proposed to account for the formation of the corresponding 2-lithiated heterocycles. Further reaction of these intermediates with electrophiles affords compounds 374 (Scheme 98)159. In the case of thioether 373 (X = S) a bromine substituent must be present at the ortho position. 

A gold(I)-catalyzed domino reaction sequence involving pentenynyl tosylamides led to the formation of 2,3-disubstituted pyrroles containing a quaternary center in the 2-substituent <07OL3181>. The mechanism of the reaction involved a 5-endo-dig cyclization followed by an aza-Claisen rearrangement. 

This cyclization reaction is not restricted to sulfone-stabilized carbanions. Indeed, phosphorus ylides, ester- and ketone-enolates participate also in the 5-endo-dig carbometallation reaction [17a]. The synthesis of fused bicyclo as well as spirobicyclo derivatives can be accomplished via the intramolecular carbometallation reactions of various stabilized carbanions with alkoxyacetylenes [17a]. Moreover, some asymmetric... 

Parsons and coworkers [54] explored the possibility of a 0-endo dig cyclization for the construction of germacranes. Reaction of the vinyl bromide 224 with BujSnH and AIBN furnished uncyclized reduction product 226 as the major prod-... 

The methodology has been extended [68] to the total synthesis of the alkaloid lennoxanine 267 starting from the enamide 266. Subsequently an alternative methodology was also developed for lennoxanine 267 based on a 10-endo dig cyclization. The IQ-endo dig radical cyclization of the TMS-protected acetylene 268 generated the tricyclic compound 269, which was further cyclized and transformed into lennoxanine 267. The 0-endo dig radical cyclization reaction (268 269) with free acetylene was found to generate an E,Z mixture of olefins. 

A final example serves to both highlight the potential for further developments of 5-endo-dig cyclizations and to encourage a search for novel electrophilic triggers reaction of the alkynyl hydroxylamines 273 with zinc iodide and DMAP in dichloromethane delivers excellent yields of the isoxazolines 274 . It therefore seems very likely that 5-endo cyclizations in general, those already developed and new versions to come, will make many useful contributions to synthetic organic methodology. 

The Saegusa indole synthesis involves the strong-base promoted cyclization of ort/ o-tolylisocyanides to indoles (Scheme 1) [1-5], Thus the Saegusa indolization resembles the Madelung indole synthesis. The reaction proceeds by a 5-endo-dig cyclization of 2 to form indole (equation 1). The isocyanide anion 2 was alkylated and subsequently cyclized to form 3-substituted indoles (equation 2). The quenching of 2 with epoxides yielded tryptophols (equation 3 and 4 and 5). Reaction of the ultimately formed N-lithioindole with electrophiles gave Af-substituted indoles (equation 4). 

A further example for a metal-initiated reaction sequence providing an indole-inspired NP-based complex scaffold was reported by Van der Eycken and coworkers [7]. In this case, a Ugi reaction provided the desired substrate for the sequence of cyclization reactions initiated by the activation of the acetylene with a gold catalyst. The Ugi four-component reaction employed the indole-carboxaldehyde 12, the nitrile 13, amine 14, and carboxyhc acid 15 and led to the formation of the intermediate 16. In the presence of a gold(I) catalyst, instead of the expected indoloazepinone that could be formed via an endo-dig cyclization, a tetracyclic spiroindoline 17 was formed diastereoselectively (Scheme 13.3). 

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