Homopropargyl alcohols, cyclization

In the case of terminal alkynes having oxygenated functions in the linear chain (Scheme 10, route D), Martin, Padron, and coworkers found that homopropargylic alcohols reacted properly, yielding 2-substituted dihydropyrans as sole products, probably via a Prins-type cyclization. This cyclization provides a new approach toward 2-alkyM-halo-5,6-dihydro-2//-pyrans through a concomitant C-C and C-O bond formation (Scheme 21) [35]. 

Several ways to suppress the 2-oxonium-[3,3]-rearrangements might be envisioned. Apart from the introduction of a bulky substituent R at the aldehyde (Scheme 23) a similar steric repulsion between R and R might also be observed upon introduction of a bulky auxiliary at R. A proof-of-principle for this concept was observed upon by using of a trimethylsilyl group as substituent R in the alkyne moiety (Scheme 25, R = TMS). This improvement provided an efficient access to polysubstituted dihydropyrans via a silyl alkyne-Prins cyclization. Ab initio theoretical calculations support the proposed mechanism. Moreover, the use of enantiomerically enriched secondary homopropargylic alcohols yielded the corresponding oxa-cycles with similar enantiomeric purity [38]. 

Scheme 25 Silyl alkyne-Prins cyclization of secondary homopropargylic alcohols and aldehydes using FeXs as a promoter...

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). 

The excellent ability of late transition metal complexes to activate alkynes to nucleophilic attack has made them effective catalysts in hydroamination reactions. The gold(l)-catalyzed cyclizations of trichloroacetimidates 438, derived from homopropargyl alcohols, furnished 2-(trichloromethyl)-5,6-dihydro-4f/-l,3-oxazines 439 under exceptionally mild conditions (Equation 48). This method was successfully applied to compounds possessing aliphatic and aromatic groups R. With R = Ph, cyclization resulted in formation of 439 with complete (Z)-stereoselectivity <2006OL3537>. 

Trichloroacetimidates derived from tetrahydrofuran homopropargyl alcohols were cyclized by mercury(ll) trifluoro-acetate-induced hydroamination to the corresponding 5,6-dihydro-4/7-l,3-oxazine derivatives with excellent stereoselectivity <1998CC761>. 

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>. 

An iron(m)-catalyzed Prins-type cyclization between a homopropargylic alcohol and an aliphatic aldehyde provides 2-alkyl-3-halo-3,6-dihydropyrans in excellent yield (Equation 113). The solvent and the catalyst equally contribute to the halogen observed in the product therefore, a straightforward choice of catalyst and solvent provides a route to either monochlorinated 252 or monobrominated 3,6-dihydropyrans 253 (Equation 113). Indium compounds have also shown potential as catalysts for this process, with high yields also obtained <20030L1979>. 

An intramolecular Heck-carbonylation/cyclization of the vinyl iodide 881 provides the 5,6-dihydropyran-2-one 882 during a total synthesis of manoalide (Equation 354) <1997CC1139>. The reaction of but-3-yn-l-ol with diaryl sulfides and carbon monoxide in the presence of a palladium(O) catalyst leads to a novel thiolactonization and hence arylthiosubstituted 5,6-dihydropyran-2-one 883 (Equation 355). Similar results are obtained with diaryl diselenides (Equation 355) <1997JOC8361>. Hydrozirconation of O-protected homopropargylic alcohols followed by carbonyla-tion and quenching with iodine provides a simple route to 5,6-dihydropyran-2-ones <1998TA949>. 

Eq. 3.7 shows the cyclization of the xanthate ester (20) formed from homopropargyl alcohol, through 5-exo-dig manner of the formed carbon-centered radical. This reaction is not a deoxygenation reaction of alcohol, but the cyclization of the carbon-centered radical formed from the addition of Bu3Sn to the thiocarbonyl-sulfur atom, onto the side-chained triple bond to form thionolactone, the hydrolysis of which readily creates lactone (21) [21-23]. 

Oxidative cyclization. Homoallylic and homopropargylic alcohols are converted to y-lactols and y-lactones, respectively. 

Although not electrophile-driven, it should be borne in mind that base-induced cyclizations of homopropargylic alcohols are useful methods. Thus, exposure of alcohol 261 to potassium r-butoxide in dimethyl sulfoxide delivers an excellent yield of the dihydrofuran 262 <89CC1371>. In much the same way, ort/to-alkynyl anilines 263 can be converted into 2-substituted indoles 264 <00AG(E)2488>. 

Borylsilylation of 1-octyne with 120 provided the alkenylboronate 121 in high yield using Pd(OAc)2 and bulky isocyanide (1,1,3,3-tetramethylbutyl isocyanide, XVll-6) as a ligand. The product 121 was subjected to Suzuki coupling catalyzed by PdCBCdppf) [36], Under similar conditions, no intermolecular bis-silylation of internal alkynes took place. However, intramolecular bis-silylation of disilanyl ether of homopropargylic alcohol proceeded smoothly with 5-exo-dig cyclization [36a]. 

A successful and highly selective Prins cyclization was also reported for the homopropargylic alcohol 236 in the presence of an aldehyde [78]. 

Scheme 10 y-Butyrolactones from oxidative cyclization of homopropargyl alcohols through Ru vinylidenes... 

Scheme 11 5-Valerolactones and dihydropyrans from oxidative cyclization and cycloisomerization of bis-homopropargyl alcohols...

Recently, Wang et al. reported anovel palladium-catalyzed sequential Sonogashira/ carbopalladative cyclization/Suzuki reactions involving multiple carbon-carbon bond formation using protected homopropargyl alcohol 155 under mild conditions [59] (Scheme 6.40). Various indene derivatives 156 could be constructed efficiently with good yields in this transformation. Moreover, this reaction has a wide tolerance of various substituents in the substrates. 

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