Alkyne-Prins cyclization

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...

In both oxa- and aza-alkyne Prins cyclization an unexpected halide exchange with halogenated solvents presumably caused by the vinyl cation intermediates was observed [37]. From a synthetic point of view, it is important to use the correct combination of FeXs and X-containing solvent in order to avoid the undesired halide scrambling (Scheme 28). 

In furtherance of these smdies, the reaction scope was broadened by employing homopropargylic amines to give the corresponding aza-cycles (Scheme 26) [39, 40]. Hence, the alkyne aza-Prins cyclization between homopropargyl tosyl amines... 

A plausible mechanism for this new alkyne aza-Prins cyclization is outlined in Scheme 27. Thus, reaction of the homopropargyl tosyl amine with an aldehyde promoted by ferric halide generates the W-sulfonyl iminium ion. This intermediate evolves to the corresponding piperidine, via the vinyl carbocation. Ah initio theoretical calculations support the proposed mechanism. 

Scheme 27 Plausible mechanism of the alkyne aza-Prins cyclization promoted by iron(III)...

Anhydrous iron(III) halides catalyse coupling of alkynes and aldehydes.211 Simple terminal alkynes, R CH, react with aldehydes, R2CHO, to give ( ,Z)-1,5-dihalo-1,4-dienes (55). In contrast, non-terminal arylalkynes give ( ,)-o, /3-unsaturated ketones. The catalysts also promote standard Prins cyclization of homoallylic alcohols. Studies of intermediates and of alkyne hydration - together with calculations - all support FeX3 complex formation with alkyne as the activating step. 

Prins cyclizations, which proceed by intramolecular addition of alkenes to oxocarbenium ions, provide a simple, efficient method for the stereoselective synthesis of carbocycles and cyclic ethers [77]. Halosilanes and (la) have been used for Prins cyclizations not only as Lewis acids but also as heteroatom nucleophiles. For instance, in the presence of MesSil or MesSiBr, and lutidine, mixed acetals (26) are efficiently cyclized to 4-halotetrahydropyrans (27) with high diastereoselectivity [78]. The halide is introduced into the axial site of the C(4) position. The proposed mechanism for the MesSiBr-promoted reaction involves the initial formation of a-bromoethers (28) from (26). Solvolysis of (28) provides the intimate ion pair (29). Cyclization to the chair transition structure (30) and proximal addition of the bromide produces the observed axial adduct (27). The role of lutidine is to suppress a less selective HBr-promoted cyclization (Scheme 9.23). Acetals bearing an alkyne or allene moiety also undergo the halosilane-promoted cyclization to form haloalkenes [79, 80]. 

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]. 

Coverage in this chapter is restricted to the use of alkenes or alkynes as enophiles (equation 1 X = Y = C) and to the use of ene components in which a hydrogen is transferred. Coverage in Sections 1.2 and 1.3 is restricted to ene components in which all three heavy atoms are carbon (equation 1 Z = C). Thermal intramolecular ene reactions of enols (equation 1 Z = O) with unactivated alkenes are presented in Section 1.4. Metallo-ene reactions are covered in the following chapter. Use of carbonyl compounds as enophiles, which can be considered as a subset of the Prins reaction, is covered in depth in Volume 2, Chtqiter 2.1. Addition of enophiles to vinylsilanes and allylsilanes is covered in Volume 2, Chapter 2.2, while addition of enophiles to enol ethers is covered in Volume 2, Chapters 2.3-2.S. Addition of imines and iminium compounds to alkenes is presented in Volume 2, Part 4. Use of alkenes, aldehydes and acetals as initiators for polyene cyclizations is covered in Volume 3, Chapter 1.9. Coverage of singlet oxygen, azo, nitroso, S=N, S=0, Se=N or Se=0 enophiles are excluded since these reactions do not result in the formation of a carbon-carbon bond. 

Lopez, F., Castedo, L. and Mascarenas, J.L. (2002) Atom-efficient assembly of 1,5-oxygen-bridged medium-sized carbocycles by sequential combination of a Ru-catalyzed alkyne-alkene coupling and a Prins-type cyclization. Journal of the American Chemical Society, 124, 4218-4219 Lopez, F., Castedo, L. and Mascarenas, J.L. (2005) Practical asymmetric approach to medium-sized carbocycles based on the combination of two Ru-catalyzed transformations and a Lewis add-induced cydization. Organic Letters, 7, 287—290. 

The ene and Prins reactions are not mechanistically distinct. Coverage will therefore be organized by the nature of the carbonyl compound, with intermolecular reactions presented first, followed by intramolecular reactions. The emphasis will be on material published since the field has been reviewed " and on examples demonstrating the stereo-, regio- and chemo-selectivity of these reactions. Coverage is restricted to the addition of carbonyl and thiocarbonyl compounds to simple alkenes. Addition of carbonyl compounds to vinylsilanes, allylsilanes and enol ethers is covered in the following chapters. Addition of imines and iminium compounds to alkenes is presented in Part 4 of this volume. Ene reactions with alkenes and alkynes as enophiles are covered in Volume 5, Chapter 1.1. Use of aldehydes and acetals as initiators for polyene cyclizations is covered in Volume 3, Chapter 1.6. 

Starting from tetrahydrocyclopenta[f)]furan-2-one 342, enyne 343, the substrate for the domino reaction, was prepared in 12 steps and with an overall yield of 45%. Exposure of 343 to the electron-rich gold(I) complex (t-Bu)2P(o-biphenyl)AuCl at room temperature afforded cis-hydrindanone 344 in 78% yield as a single stereoisomer (Scheme 14.54). The postulated mechanism involved Au(I) activation of the alkyne to initiate the cationic olefin cyclization of 346 to give carbocation 347, which then underwent a pinacol rearrangement to the final product 344. An originally attempted Lewis acid-catalyzed domino Prins/pinacol rearrangement of... 

This formal [2h-2h-2] alkyne/alkene/carbonyl cycloaddition proceeds through the opening of the cyclopropyl carbene intermediate 1-4 by the carbonyl group to form oxonium cation 1-5, which undergoes nucleophilic attack by the vinylgold intermediates in a Prins-type cyclization to give tetrahydropyranyl cation 1-6. 

Moreover, spiroketals are produced from tandem hydroalkoxylation of 4-alkynols (Scheme 15) [130]. Starting from diynediols, bis-spiroketals are obtained using Au (I) as catalysts [131]. Furthermore, Barluenga et al. reported the formation of spirocychc compounds in a tandem alkyne hydroalkoxylation [4 -1- 2] cycloaddition reaction [132, 133], together with a tandem intramolecular hydroalkoxylation of a triple bond followed by a Prins-type cyclization [129]. 

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