Allylic substitution regioselectivity

Copper(I) chloride with Grignard reagents can be a very powerful synthetic tool in organic synthesis, as in /-selective allylic substitutions, regioselective Sn2 substitution to... 

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. 

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... 

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... 

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 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... 

The synthesis of lycorane (13) by Mori and Shiba-saki121 is breathtaking for its use of three consecutive Pd catalyzed C-C bond forming reactions. Thus, Pd-catalyzed asymmetric allylic substitution of a benzoate in meso 7 in the presence of the chiral bisphos-phine 8 leads to the regioselective formation of 10 in 40 % ee It is easy to overlook this low level of enantioselectivity when we are faced with the subsequent elegant Pd-catalyzed reactions Pd-catalyzed intramolecular animation is followed by a Pd-catalyzed Heck coupling to afford 12, which is then readily converted to the target molecule... 

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

Scheme 6.36. Regioselective allylic substitution of Z carbamate 170 with a silylcuprate reagent.

Calb et al. have thoroughly investigated the use of allylic electrophiles containing heterocyclic leaving groups in regioselective allylic substitution (Scheme 8.7) [22]. 

Initial studies on the application of these catalysts to allylic substitution reactions showed that the arenethiolate moiety functions as an excellent nontransferable group, and that the regioselectivity can be completely reversed by suitable changes in the reaction parameters [33]. If the reaction between geranyl acetate and n-BuM gl was carried out inTHFat—30°C with fast addition of the Grignard reagent to the reaction mixture, complete a selectivity was obtained. Raising the tempera-... 

Allylic acetates in conjunction with phosphinooxazolines (PHOX) as chiral ligands were used for the first asymmetric Ir-catalyzed allylic substitution (Scheme 9.7) [5]. The reaction was slow, compared to that catalyzed by the [lr(COD)Cl]2/P(OPh)3 system or the parent complex [lr(COD)Cl]2, although both regioselectivity and enantioselectivity were very high. The aminations were generally slow, yet quite interesting results were achieved in intramolecular aminations nevertheless [17, 18] in particular, a very strong influence of halide salts was found. 

Allylic substitutions with nonstabilized C-nucleophiles are an important domain of organocopper chemistry [51]. However, on close inspection of the literature, it becomes apparent that regioselectivity in favor of the branched allylic alkylation products is only obtained with alkyl copper compounds, while aryl copper compounds mainly give the linear alkylation products. This observation was an incentive for Alexakis et al. [52] to probe the reactions of aryl zinc hahdes in the Ir-catalyzed allylic substitution (Scheme 9.18). 

Evans and Nelson reexamined the rhodium-catalyzed allylic substitution reaction, in which they demonstrated that a triorganophosphite-modified Wilkinson s catalyst facilitates the allylic alkylation of secondary and tertiary aUyhc carbonates with excellent regioselectivity (Eq. 2). This work provided a convenient method for the construction of ternary and quaternary allylic products [11]. Additionally, they demonstrated that the modification of Wilkinson s catalyst with triorganophosphites serves to increase the re-... 

Scheme 7.15] or S -type mechanism [Equation (7.9)]. Depending on the nature of the nucleophile and catalyst employed, the subsequent nucleophilic substitution of the metal can follow either via a-elimination [path A, Equations (7.8) and (7.9), Scheme 7.15], via an SN2 reaction (path B) or via an SN2 -type reaction (path C). For reasons of clarity, only strictly concerted and stereospecific SN2- or SN2 -anti-type mechanistic scenarios are shown in Scheme 7.15. The situation might, however, be complicated if, e.g., the initial S l -anti ionization event is competing with an Sn2 -syn reaction. Erosion in stereo- and regioselectivity can be the result of these competing reactions. Furthermore, fluxional intermediates such as 7t-allyl Fe complexes are not shown in Scheme 7.15 for reasons of clarity. These intermediates are known for a variety of late transition metal allyl complexes and will be referred to later. Moreover, apart from these ionic mechanisms, radicals might also be involved in the reaction. So far no distinct mechanistic study on allylic substitutions has been published.

A new phosphoramidite ligand (1 Y = OMe), gives high enantioselectivities (92-99% ee) and regioselectivities (99% S 2 ) in iridium-catalysed allylic substitution reactions of carbonates and acetates with carbanion or primary amine nucleophiles.6 The new ligand also leads to a faster rate of reaction than other phosphoramidite ligands. 

The regioselective and enantiospecific allylic substitution of alkyl-substituted allyl benzoates and carbamates with (Me2PhSi)2Zn and Cul has been shown to occur by an oxidative addition - reduction elimination mechanism rather than an SN2 mechanism.16... 

The regioselectivity of bimolecular allylic substitutions, on the other hand, is often easier to control, and can sometimes be reversed by slight modification of the starting materials or reaction conditions. In uncatalyzed, bimolecular substitutions the nucleophile will usually add to the sterically less demanding site of the allylic system (Scheme 4.53). 

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