Intramolecular Prins reaction

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

The chain of atoms can include an oxygen atom. When the enophile is a carbonyl group, the reaction is a Prins reaction 6.16, which is usually acid-catalysed and not pericyclic, except perhaps in gas phase reactions like the intramolecular example 6.17 6.19 with a plausible transition structure... 

Triflic acid has been successfully used in the stereocontrolled synthesis of substituted tetrahydropyrans. 2,4,6-Trisubstituted tetrahydropyrans have been synthesized by an intramolecular Prins reaction-pinacol sequence694 [Eq. (5.250)]. 

Homoallenic alcohols 8 yield 3,4-dimethylidenetetrahydropyrans in a Prins reaction with aldehydes <03CC346> and an intramolecular Prins cyclisation occurs in water using a Lewis acidic surfactant <03OL4521>. Application of the Prins reaction to alkynols instead of alkenols yields 5,6-dihydro-2//-pyrans (Scheme 10) <03OL1979>. 

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. 

Kocovsky, P., Ahmed, G., SrogI, J., Maikov, A. V., Steele, J. New Lewis-Acidic Molybdenum(ll) and Tungsten(ll) Catalysts for Intramolecular Carbonyl Ene and Prins Reactions. Reversal of the Stereoselectivity of Cyclization of Citronellal. J. Org. Chem. 1999, 64, 2765-2775. 

Bi(III) is an efficient catalyst for the formation of tetrahydropyran-4-ols from homoallylic alcohols by the Prins reaction application to styrenes leads to 1,3-dioxanes <05SC1177> cr i-2,6-Disubstituted tetrahydropyrans are selectively formed in a Bi-mediated intramolecular oxa-conjugate addition of a,P-unsaturated ketones 10 the actual catalyst is considered to be the Bronsted acid derived from the Bi salt <05TL5625>. cat. BiXa... 

The next step is a simple electrophilic attack by another molecule of formaldehyde on the alkene - in other words a simple Prins reaction 215 - showing the regioselectivity we expect to produce the secondary benzylic cation 216. The second molecule of formaldehyde has added onto the opposite side from the first. The resulting cation is perfectly placed for an intramolecular Friedel-Crafts alkylation 216 of the benzene ring. This is again a stereoselective reaction giving the more stable anti diastereoisomer 214. This sequence involves three successive C-C bondforming reactions and the stereochemistry is simply controlled by the preference for the more stable anti product. 

In connection with a synthesis of the hydroazulenic sesquiterpene kessanol (304), Knoevenagel condensation of photocitral-A (302) with ethyl cyanoacetate was found to give (303) as a single isomer. The following sequence includes an intramolecular Prins reaction initiated with SnCU. In Isobe s synthesis of vemolepin (307) the two carbons of the -y-iactone are introduced by a Knoevenagei condensation. Reaction of ketone (305) with di-f-butyl maionate followed by treatment with DBU affords (306), which is transformed to the a,a -dihydroxy compound (308). Hydrolysis of the esters foliowed by decarboxy-iation, formation of the y-lactone, Mannich reaction and elimination yields vemolepin (307 Scheme 58).3"... 

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. 

The intramolecular Prins reaction can be divided into three types8a depending on the mechanism of the cvclization step and each pathway results in a different product. Several studies involving the Prins reaction in ring-closure processes of larger systems failed37. 

By way of review, the Prins reaction (Scheme 8.20) comprises addition of a carbonyl group to an olefin followed by capture of a nucleophile by the other end of the double bond (20-1). A side reaction consists of addition of carbonyl oxygen (20-2). Yet another photolysis, this one on 19-5, severs the bond between the carbonyl and the adjacent quaternary carbon atom to the unsaturated aldehyde 21-1 (Scheme 8.21) this is admixed with the product of 21-2 from addition via oxygen. Treatment of the mixmre of these products with mild acid leads to intramolecular Prins condensation of the aldehyde in 21-1 with the C13-C14 double bond. Capture of a nucleophile, in this case water, from the less hindered face installs the critical 14a-hydroxyl function. The (9-addition product 21-2 presumably cycles back to 21-1, which the goes on to product. The 12)8-hydroxy product predominates over its 12a-isomer in a 2 1 ratio. 

The direct hydration of Empetal gives only a very poor yield of the desired product because of competing side reactions. These illustrate an important principle in organic chemistry, viz. if an intramolecular reaction can occur to form a 5- or 6-membered ring, then it will usually take precedence over intermolecular reactions. An example in this instance is the intermolecular Prins reaction shown in Figure 3.2. 

Reviews have appeared on the use of the Wittig reaction in industrial practice, the Claisen rearrangement, synthetic applications of the retro-Diels-Alder reaction, organo-palladium intermediates for the alkylation and arylation of olefins, the Prins reaction to give 1,3-dienes, and intramolecular [4 + 2] (Diels-Alder) and [3 + 2] cycloadditions.An interesting discussion of the regiospecificity of the Diels-Alder reaction in terms of frontier orbital overlap favours the Woodward-Katz concept. Useful alkyne and polyene coupling reactions are described in reviews on the chemistry of vitamin the synthesis of insect sex... 

The process from the FMC company involves as the pivotal step an intramolecular stereoselective [2 + 1 [-cycloaddition. In a Prins reaction [94] of chloral and isobutene, followed by an isomerisation, a racemic, trichloromethyl-substituted aUyl alcohol is obtained. Reaction with the isocyanate from (R)-naphthylethyl-amine enables separation ofthe diastereomers by crystallisation. The carbamate is cleaved by trichlorosilane/triethylamine, thus permitting the recycling of the chiral auxiliary. The optically pure (R)-aUyl alcohol is reacted with diketene, to produce the / -keto-ester. After diazo transfer and basic cleavage, the diazoacetate is obtained catalysed by a copper salt, this is converted in a [2 + 1 ]-cyclo-addition into a bicyclic lactone. The Boord reaction (discovered by Cecil E. Boord in 1930) [95] finally gives (IR)-cis-permethric acid. [96]... 

The acid-promoted Prins reaction between a homoaUyhc alcohol and an aldehyde is a weU-estabhshed synthesis of tetrahydropyrans (Scheme 4) [ 14,15]. While substituted tetrahydropyrans are often assembled by cyclizations forming a C - O bond, the Prins reaction undergoes cyclization by C - C bond formation. The Prins reaction of the silyl-modified substrates [16], which can be regarded as the intramolecular Hosomi-Sakurai reaction, is effectively activated by the allylsilane unit. The stereochemistry of the 2,6-cfs-form produced in the case of the exo-allylsilane unit is elucidated by the 6-membered transition state model, hi the cyclization of the ewdo-aUylsilane substrates, since the silyl group would be fixed on the axial position of the 6-membered transition states, the tetrahydropyrans with both 2,6-cis and fraws-forms can be synthesized (Panek Sect. 3.3.9). This type of cychzation was also... 

Rychnovsky reported synthesis of Leighton s macrolide 201 of leucascandrolide A, wherein the key reaction is the Mukaiyama aldol-Prins cascade reaction (Sect. 2.4). In this cascade reaction, oxonium cation, required for the Prins reaction, is prepared by a Lewis acid-mediated Mukaiyama aldol reaction of alkyl vinyl ether with aldehyde. Usually, alkyl vinyl ethers are not suitable for Mukaiyama-aldol, because of oligomerization of the resulting oxonium cation. Rychnovsky resolved this issue by trapping the cation with an intramolecular nucleophile, which resulted in Prins cyclization. 

The reported structure of cycloseychellene has been shown to be erroneous by a total synthesis that features intramolecular versions of the Claisen rearrangement and Prins reaction (Scheme 15)/ ... 

The most obvious synthesis of Lyral is to hydrate the double bond of Myrac Aldehyde (61) under acidic conditions. However, the aldehyde group is sensitive to acid and undergoes an intramolecular Prins reaction if this is attempted. It is therefore necessary to protect the aldehyde function prior to hydration, and this can be done by formation of an enamine or oxazolidine that can be removed by hydrolysis when hydration is complete [84, 85]. 

Cyclization via Prins-Type Reactions The intramolecular Prins reaction has been recognized as a powerful method to assemble six- and seven-membered rings from homoallylic alcohols and simple aldehydes under acid catalysis [28]. However, the competing 2-oxo-Cope rearrangement prior to cyclization could lead to a product with partial or total racemization when enantiomerieally enriched secondary alcohols are used [29]. Increasing the nueleophilicity of the alkene reagent... 

Scheme 4.17 Synthesis of 2,7-disubstituted-3-vinylidene oxepanes via the intramolecular Prins reaction.

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