Regioselectivity of Allylic Substitutions

The regioselectivity of the allylic substitution process depends heavily on the identity of the metal and its coordination sphere. To bypass the issue of regioselectivity, most of the substrates used to demonstrate activity and enantioselectivity of catalysts for allylic substitution generate symmetrical allyl intermediates. However, many synthetic applications would require a regioselective substitution process involving unsymmetrical allyl intermediates. The regioselectivity of allylic substitution arises from the position of attack of the nucleophile on the allyl intermediate. 

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In addition to enantiocontrol, the problem of regiocontrol arises in these reactions. There are various factors that influence the regioselectivity of allylic substitutions [3,4,13, 36, 37, 38, 39]. Electronic effects exerted by the catalyst and the allylic substituents, steric interactions between the nucleophile, the allyl system and the catalyst, and the relative stabilities of the Ti-olefin complexes formed after nucleophilic addition, can all play a role. The relative importance of these factors varies with the catalyst, the substrate, the nucleophile, the solvent and other reaction parameters and is difficult to predict. 

Fig. 16 Regioselective cathodic addition of allyl substituted allyl halides to carbonyl compounds [93].

Backvall [47] studied the chemo- and regioselectivity of the substitution of allylic chlorides in the presence of allylic acetates by Grignard reagents in the presence of a catalytic amount of Li2CuCl4 and showed that the reaction was chemoselective (the acetate function remains unchanged), and the regioselectivity was in favor of the Sn2 product. In the cyclic compound, the reaction was also nr/-selective [Eq. (25)]. 

Alvarez-IbaiTa. C. Csaky. A.G. Martin. M.El. Quiroga. M.L. Study of the asymmetrie synthesis of (Z)-y-substituted-0(,P-didehydroglutamate.s from V-alkylidene-glycinates. Tetrahedron 1999. 55 (23). 7319-7330. Yanagisawa, A. Yamada. Y. Yamamoto. H. Effect of crown ethers on the regioselectivity of allylation of benzaldehyde with allylic barium reagents. Synlett 1997. (9). 1090-1092. 

Much effort has been devoted to developing catalysts that control the enantioselectiv-ity of these substitution reactions, as well as the regioselectivity of reactions that proceed through unsymmetrical allylic intermediates. A majority of this effort has been spent on developing palladium complexes as catalysts. Increasingly, however, complexes of molybdenum, tungsten, ruthenium, rhodium, and iridium have been studied as catalysts for enantioselective and regioselective processes. In parallel with these studies of allylic substitution catalyzed by complexes of transition metals, studies on allylic substitution catalyzed by complexes of copper have been conducted. These reactions often occur to form products of Sj 2 substitution. As catalylic allylic substitution has been developed, this process has been applied in many different ways to the synthesis of natural products. ... 

Most allylic substitution reactions have been conducted witti derivatives of allylic alcohols, such as acetates, phosphates, and carbonates. These reactions occur with allyl electrophiles displaying a wide structural variation. The allylic electrophiles can be cyclic or acyclic, substituted with aliphatic or aromatic groups, substituted at one or both termini, and substituted or unsubstituted at the central carbon. As discussed in more detail below, these substituents affect the regioselectivity of the substitution process. 

The M6L4 coordination cage was also used as a protective group for control of the regioselectivity of nucleophilic substitution of aryl-substituted allylic chlorides [35]. Normally, both a and -y carbons of allylic chlorides can be the sites of reaction and attacked by nucleophile (Fig. 9.22). Therefore, two regioisomeric products are expected in this reaction. 

These two aspects, regioselectivity and stereoselectivity, are certainly the most important issues in the field of allylic substitutions. They have been shown to be influenced by the catalyst, the nucleophile, the leaving group, and by the constitutional as well as configurational details of the substrate. 

The allyl-substituted cyclopentadiene 122 was prepared by the reaction of cyclopentadiene anion with allylic acetates[83], Allyl chloride reacts with carbon nucleophiles without Pd catalyst, but sometimes Pd catalyst accelerates the reaction of allylic chlorides and gives higher selectivity. As an example, allylation of the anion of 6,6-dimethylfulvene 123 with allyl chloride proceeded regioselectively at the methyl group, yielding 124[84]. The uncatalyzed reaction was not selective. 

Furthermore, the regioselective hydrogenolysis can be extended to internal allylic systems. In this case, clean differentiation of a tertiary carbon from a secondary carbon in an allylic system is a problem. The regioselectivity in the hydrogenolysis of unsymmetrically substituted internal allylic compounds depends on the nature and size of the substituents. The less substituted alkene 596 was obtained from 595 as the main product, but the selectivity was only... 

Desulfonylation of equally substituted allylic sulfones with NaBH4 and LiBHEt3 usually yields a mixture of regioisomeric alkenes[406,407]. However, the regioselective attack of the less substituted side of the unsymme-trically substituted allylic system with LiEtjBH has been utilized for the removal of the allylic sulfone group in synthesis of the polyprenoid 658[408],... 

Depending on the substrate and the other reaction parameters, very higli re-gioselectivilies towards either a or y suhstilution can he obtained. In cetLain cases, the regioselectivity can easily he switclied between the two modes by changing the reaction conditions [11]. Compared to, for example, palladiumiO)-catalyzed allylic substitution reactions, the possibility of switching between S j2 and S j2 selectivity... 

Allylstannanes can be prepared by treatment of allyl halides with trialkyl- or triaryltin lithium reagents. Displacement of primary allyl halides tends to be regioselective for formation of the less substituted allylstannane, and takes place with useful retention of double-bond geometry14-16. 

Nanaomycin A 103 and deoxyfrenolicin 108 are members of a group of naphthoquinone antibiotics based on the isochroman skeleton. The therapeutic potential of these natural products has attracted considerable attention, and different approaches towards their synthesis have been reported [65,66]. The key step in the total synthesis of racemic nanaomycin A 103 is the chemo-and regioselective benzannulation reaction of carbene complex 101 and allylacety-lene 100 to give allyl-substituted naphthoquinone 102 after oxidative workup in 52% yield [65] (Scheme 47). The allyl functionality is crucial for a subsequent intramolecular alkoxycarbonylation to build up the isochroman structure. However, modest yields and the long sequence required to introduce the... 

Trost and Hachiya [140] studied asymmetric molybdenum-catalyzed alkylations. Interestingly, they noticed that the regioselectivity of this transformation performed with a non-symmetric allylic substrate varied according to the nature of the metal Pd-catalyzed substitutions on aryl-substituted allyl systems led to attack at the less substituted carbon, whereas molybdenum catalysis afforded the more substituted product. They prepared the bis(pyridylamide) ligand 105 (Scheme 55) and synthesized the corresponding Mo-complex from (C2H5 - CN)3Mo(CO)3. With such a catalyst, the allylic... 

Aregioselective catalytic system for the allylic substitution of non-symmetric allyl carbonates by carbon and nitrogen nucleophiles based on [ Bu N][Fe(NO)(CO)3] and PPhj was developed (Scheme 2.26). The high regioselectivity was ascribed to the slow a-allyl- to Jt-aUyl-isomerisation relative to the rate of substitution. However, the use of high excess of the pro-nucleophile and DMF solvent are drawbacks on the atom efficiency and functional group tolerance of the system. 

The directive effect of allylic silyoxy groups has also been examined. The reactions are completely regioselective for 1,3-oxygen substitution. The reaction of... 

The idea of Hoveyda with co-workers to employ their peptide ligands (e.g., 295) as chiral inductors in allylic substitutions with dialkylzincs turned out to be very rewarding.399-401 As a result of meticulous screening of numerous optically active ligands, copper salts, and substrates under various conditions, they achieved excellent results for aliphatic alkenes. Particularly, allylic substitution products with tertiary 297 and quaternary 299 carbon centers were obtained regioselectively and with 78-96% ee (Scheme 151).401... 

As shown in Scheme 2.21 Id, starting with N-allyl carbohydrate-nitrones (469), a series of chiral six- (470) and seven-membered(471) TV-heterocycles were synthesized (Scheme 2.227). A very interesting and useful aspect of this cycloaddition is the control of regioselectivity by the substitution at the nitrogen atom. Therefore, it is possible to direct reactions towards the syntheses of preferred six- or seven-membered heterocycles from carbohydrate derivatives (722). 

Several classes of silyl ethers have been shown to be excellent substrates for the C-H insertion chemistry of donor/ acceptor-substituted carbenoids.81 Effective C-H insertions predominantly occur at methylene sites. Primary sites are not sufficiently activated electronically while tertiary sites are sterically too crowded. Rl -DOSP -catalyzed functionalization of the allyl silyl ether 3 resulted in a highly diastereoselective transformation, leading to the formation of the /3-hydroxyester 4 in 94% yield and 82% ee (Equation (17)).81 This example illustrates the regioselectivity of this chemistry, because 3 contains two allylic sites but only the methylene site adjacent to the siloxy group was functionalized. Even better substrates are the commercially available tetraalkoxysilanes such as 5, because with these substrates, the high diastereoselectivity was retained while the enantioselectivity was increased (Equation (18)).81... 

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