Cyclization Prins

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]. 

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... 

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

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)...

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). 

FeX3 was also found to be an excellent promoter in the classical Prins cycliza-tion (Scheme 10, route H), with the observation of a satisfactory reaction between 3-buten-l-ol and several aldehydes, affording the corresponding c/s-4-halo-2-alkyl tetrahydrop3Tans in good yields [Eq. (1) in Scheme 32] [35], In a similar manner, the methodology can be extended to the piperidine synthesis through an aza-Prins cyclization [Eq. (2), Scheme 32] [41],... 

Whereas the Prins-type cyclizations reported in this and the preceeding chapter were performed using stoichiometric amounts of Fe salts as Lewis acids, a breakthrough in the field of catalysis was reported in 2009 when the first iron-catalyzed Prins- and aza-Prins cyclization was reported. The catalytic system, which is obtained by combining catalytic amounts of an iron salt with trimethylsilyl halides as a halide source, is widely applicable and promotes the construction of substituted six-membered oxa- and aza-cycles (Scheme 33) [44]. 

Scheme 33 The catalytic Prins cyclization leading to oxa- and aza-cycles...

Scheme 34 Plausible mechanism for the iron-catalyzed Prins cyclization...

Scheme 35 Stereoselective Prins cyclization by iron(III)-catalyzed W-acyliminium ion cyclization...

Aubele et al. studied the aqueous Prins cyclization using cyclic unsaturated acetals as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cyclizations proceed efficiently inside Lewis acidic micelles (of cerium salt) in water. A variety of vinyl- and aryl-substituted tetrahydropyrans with excellent stereocontrol was obtained (Eq. 3.26).113... 

The Prins cyclization can also be coupled with a ring-contraction pinacol rearrangement, as illustrated in Scheme 1.6. This allows a smooth conversion of alkyl-idene-cyclohexane acetal 1-16 to single bond-joined cyclohexane cyclopentane aldehyde 1-17 [le]. 

Scheme 2.57. Aldol/Prins cyclization of 2-240 and an aldehyde promoted by BF3OEt2.

The scheme below depicts the novel use of a carbonyl ene cyclization (A, Lewis acid-catalyzed) and a closely related Prins cyclization (B, Brpnsted acid-catalyzed) to generate predominantly trans (cyclization condition A) or cis (cyclization condition B), di and tri substituted piperidines 160 and 161 <06JOC2460 06OBC51>. Of note, in the formation of di-substituted derivatives, R1 = H and R2 = Ph, no reaction occurs under cyclization condition B and the cis isomer 160 is obtained exclusively under cyclization condition A. In the case of tri-substituted derivatives, when bulky substituents at the 2-position (R1 = f-Bu or Ph) are present the trans diastereomer 161 is obtained almost exclusively under cyclization condition A, while no diastereoselectivity is seen under cyclization condition B. 

Williams JT, Bahia PS, Snaith JS (2002) Synthesis of 3,4-disubstituted piperidines by carbonyl ene and prins cyclizations a switch in diastereoselectivity between Lewis and Bronsted acid catalysts. Org Lett 4 3727-3730... 

Aza-Prins Cyclization of Epoxides with Homoallylic Amines. 234... 

Fig. 3 Aza-Prins cyclization of epoxides with N-protected homoallylic amines...

The formation of the products could be explained by hemiacetal formation followed by Prins cyclization and subsequent Ritter amidation. A tentative reaction mechanism to realize the cis selectivity is given in Fig. 20 and could be explained by assuming the formation of an (L )-oxocarbenium ion via a chair-like transition state, which has an increased stability relative to the open oxocarbenium ion owing to electron delocalization. The optimal geometry for this delocalization places the hydrogen atom at C4 in a pseudoaxial position, which favors equatorial attack of the nucleophiles. 

New hydrophobic Brpnsted acidic ionic liquids (HBAILs) have been prepared and used as organic catalysts of dehydration reactions in water, e.g. Prins cyclization of styrene derivatives with aqueous formaldehyde, to give 1,3-dioxanes.183... 

Syn- and anti -selective halo-Prins cyclizations of 8,s-unsaturated ketones to give 1,3-halohydrins have been catalysed by Lewis acids, with syn selectivity correlating (g) with acid strength.184... 

Prins cyclization reaction of scalemic homoallylic alcohols (26) with aldehydes (R CIIO), carried out in the presence of an acid catalyst (HX), affords tetrasub-stituted tetrahydropyrans (27) (99% ee) with high stereoselectively in good yields... 

A new mechanism for loss of optical purity in Prins cyclizations has been elucidated using 2H and 13C labelling, supported by structural modification and calculations. 

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. 

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