Prins-type

The synthesis of different substituted finans by cyclization of 4-pentynones using potassium tert-butoxide in DMF was reported <96TL3387>. Dihydrofuran 32 can be prepared by a destannylative acylation of l-[(2-methoxyethoxy)methoxy]-2-(phenylsulfonyl)-2-(tributylstannyl)-cyclopropane. Treatment of 32 with BFj-EtjO yields 3-acyUurans via an intramolecular Prins-type reaction of the resulting oxonium ion intermediate <96TL4585>. 

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]. 

Scheme 21 Plausible mechanism for Prins-type cyclization promoted by iron(III) halides...

As an extension of this work, the same authors explored such methodology for the synthesis of 2,6-disubstituted dihydropyrans using secondary homopropargylic alcohols (Scheme 10, route E). Surprisingly, the treatment of pent-4-yn-2-ol and 3-methylbutanal in the presence of FeCls led to unsaturated ( )-(3-hydroxyketone and ( )-a,p-unsaturated ketone in 2.5 1 ratio and 65% yield, without any trace of the expected Prins-type cyclic product (Scheme 22) [36]. To test the anion influence in this coupling, FeCE and FeBrs were used in a comparative study for the reaction of pent-4-yn-2-ol (R = R" = H, = Me) and several aldehydes. A range of aldehydes except for benzaldehyde was transformed into unsaturated (3-hydroxy-ketones in moderate to good yields. 

Scheme 28 Halide exchange with halogenated solvents during the acetylenic Prins-type cyclization...

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]. 

Cho et al. reported a indium trichloride-catalyzed intramolecular Prins-type reactions of compounds having both the functionalities of homoallyl alcohol and acetal moiety. The intramolecular Prins cycliza-tions were performed using indium trichloride in chloroform or 25%... 

Mascarenas developed a synthetic method to 1,5-oxygen-bridged medium-sized carbocycles through a sequential ruthenium-catalyzed alkyne-alkene coupling and a Lewis-acid-catalyzed Prins-type reaction (Eq. 3.45). The ruthenium-catalyzed reaction can be carried out in aqueous media (DMF/H20 = 10 1).181... 

Another attractive domino approach starts with an aldol reaction of preformed enol ethers and carbonyl compounds as the first step. Rychnovsky and coworkers have found that unsaturated enol ethers such as 2-237 react with different aldehydes 2-238 in the presence of TiBr4. The process consists of an aldol and a Prins-type reaction to give 4-bromotetrahydropyrans 2-239 in good yields, and allows the formation of two new C-C-bonds, one ring and three new stereogenic centers (Scheme 2.56) [131]. In the reaction, only two diastereomers out of eight possible isomers were formed whereby the intermediate carbocation is quenched with a bromide. 

Scheme 2.56. Aldol/Prins-type/addition sequence.

A fourfold anionic sequence which is not initiated by a Michael but an aldol reaction has been reported by the group of Suginome and Ito (Scheme 2.129) [295]. In this approach, the borylallylsilane 2-573 reacts selectively in the presence of TiCl4 with two different aldehydes which are added sequentially to the reaction mixture. First, a Lewis acid-mediated allylation of the aldehyde with 2-573 takes place to form a homoallylic alcohol which reacts with the second aldehyde under formation of the oxenium ion 2-574. The sequence is terminated by a Prins-type cyclization of 2-574 and an intramolecular Friedel-Crafts alkylation of the intermediate 2-575 with formation of the fraws-1,2-be rizoxadeca lines 2-576 as single diastereomers. 

Tetrahydropyrans hydroxylated at the 4-position have good synthetic value [113]. Although many synthetic methods have been reported [17-23,114,115], the search for potential alternate approaches and the development of eco-friendly and high-yielding reactions resulted in the development of a method that poses less problems for the environment. Synthesis of tetrahydropyranol derivatives can be achieved through the Prins-type cyclization reaction of homoallylic alcohols with aldehydes using bismuth triflate as catalyst in [bmim]PF6 solvent system [108] (Fig. 22). 

A novel gold catalyzed example of three-component addition was recently reported by Shi et al. (Equation 8.44) [106]. Terminal aryl alkynes, alcohols and 2-(arylmethy-lene) cyclopropylcarbinols provided an intermolecular tandem hydroalkoxylation/ Prins-type reaction to form 3-oxabicyclo[3.1.0]hexanes from simple materials and under mild conditions, catalyzed by the system AuClPPh3/AgOTf. The proposed mechanism for this reaction is shown in Scheme 8.19. 

Formaldehyde reacts with isoeugenol [l-(3-methoxy-4-hydroxyphenyl)propene] in alkaline medium to give a 1,3-dioxane derivative via an unusual Prins-type reaction.192... 

An intramolecular Prins-type cyclization of a-acetoxy acetals 239 is catalyzed by (7-PrO)2Ti(NTf)2 and provides a stereoselective route to 2,6- A-substituted 3,6-dihydropyrans 240 (Equation 107, Table 5) <2004BKC1625>. 

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 acid-mediated Prins type cyclization of enol ether 328 followed by basic hydrolysis of the intermediate trifluoro-acetate provides a key step during synthetic studies toward leucascandrolide A (Equation 139) <20010L755>. The acid-promoted Prins cyclization of enol ethers attracts much attention <20030L1499, 2004HCA2750, 2005OL2683>. 

Kinetics of isomerization of glyceraldehyde to dihydroxyacetone—and the formation of pyruvaldehyde from both— have been studied in sub- and super-critical water. Formaldehyde reacts with isoeugenol [l-(3-methoxy-4-hydroxyphenyl)propene] in alkaline medium to give a 1,3-dioxane derivative via an unusual Prins-type reaction. The potential-energy surface for the equihbriimi, HCO - - HCN H2CO - - CN, has been calculated by ab initio methods. 

It may be clear that this reaction involves the formation of one C-C and one C-0 bond during the linking of three molecules I, II, and methanol from the solvent. The combination of an expectedly strong electrophile such as the pyrrolinium ion (I) and a very mild nucleophile represented here by isopropylene, falls within the familiar framework of a Prins -type reaction. That process has a protonated form of a carbonyl derivative as the electrophile, usually an aldehyde of which the iminium ion would be a nitrogen homolog. However, in contrast with the classical Prins reaction whereby 1,3-dioxanes result by the inclusion of a second mole of the electrophile, in the present reaction 1 mol of methanol is incorporated instead. 

Yang, J., Viswanathan, G. S., Li, C.-J. Highly effective synthesis of 4-halotetrahydropyrans via a highly diastereoselective in situ Prins-type cyclization reaction. Tetrahedron Lett. 1999,40,1627-1630. 

The tnCl3-mediated, tin(lV)-catalyzed Prins-type couphng of allylphenols with carbonyl compounds gives oxepanes as a mixture of diastereomers (Scheme 8.119)... 

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. 

Ene reactions are carried out thermally (100-300C,C) or with Lewis acid catalysis under anhydrous conditions. Usually, ene reactions are concerted but recent investigations suggest that some are stepwise processes (Lewis acid catalyzed) and proceed via an intermediate Jt-complex9. In this section only Prins-type reactions will be described ene reactions are discussed in Section D.1.6.2. 

A cyclopentanol system is prepared by treating the rigid aldehyde 5 with Lewis acids22. In the presence of titanium(IV) chloride the chlorinated tricycle 6 is formed exclusively in 80-90% yield (Prins-type product), with chlorine in an axial position and a hydroxyl group in the /3-configuration. In a tin(IV) chloride mediated reaction the ene product 7 can be obtained in 42 % yield with the hydroxyl group in the /3-position. 

A 1-endo reaction forming a Prins-type product has been described43. The cyclization of acid chloride 19 leads to a mixture of the chlorides 20 a consecutive dehydrohalogenation results in the cycloheptenone 21 in about 67% overall yield. 

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