Allylic substitution fundamentals

Transition metal-catalyzed allylic substitution with phenols and alcohols represents a fundamentally important cross-coupling reaction for the construction of allylic ethers, which are ubiquitous in a variety of biologically important molecules [44, 45]. While phenols have proven efficient nucleophiles for a variety of intermolecular allylic etherification reactions, alcohols have proven much more challenging nucleophiles, primarily due to their hard, more basic character. This is exemphfied with secondary and tertiary alcohols, and has undoubtedly limited the synthetic utihty of this transformation. 

Unsaturated fluorinated compounds are fundamentally different from those of hydrocarbon chemistry. Whereas conventional alkenes are electron rich at the double bond, fluoroal-kenes suffer from a deficiency of electrons due to the negative inductive effect. Therefore, fluoroalkenes react smoothly in a very typical way with oxygen, sulfur, nitrogen and carbon nucleophiles.31 Usually, the reaction path of the addition or addition-elimination reaction goes through an intermediate carbanion. The reaction conditions decide whether the product is saturated or unsaturated and if vinylic or allylic substitution is required. Highly branched fluoroalkenes, obtained from the fluoride-initiated ionic oligomerization of tetrafluoroethene or hexafluoropropene, are different and more complex in their reactions and reactivities. 

Thanks to the fundamental studies of Tsuji, Trost, and others, palladium-catalyzed allylic substitution has become a versatile, widely used process in organic synthesis [40]. The search for efficient enantioselective catalysts for this class of reactions is an important goal of current research in this field [41]. It has been shown that chiral phosphine ligands can induce substantial enantiomeric excesses in Pd-catalyzed reactions of racemic or achiral allylic substrates with nucleophiles [42]. Recently, promising results have also been obtained with chiral bidentate nitrogen ligands [43]. We have found that palladium complexes of neutral aza-semicorrin or methylene-bis(oxazoline) ligands are effective catalysts for the enantioselective allylic alkylation of l,3-diphenyl-2-propenyl acetate or related substrates with dimethyl malonate (Schemes 18 [25,30] and 19 [44]). 

A significant contribution to the use of iridium precursors for allylic alkylations has been provided by Takeuchi and co-workers, who demonstrated how the selectivity achieved by using iridium catalysts complements that obtained with palladium complexes. Fast combinatorial colorimetric screening has been used to individuate Ir(l) catalysts active for the allylic substitution reaction. Fundamental advancements in this field were achieved by Helmchen and co-workers who obtained high regio- and enantioselectivity in asymmetric allylic alkylations of achiral or racemic substrates with chiral phosphinooxazolines and phosphoramidites as... 

This procedure illustrates a fundamentally new method for constructing substituted tetrahydrofurans.5-10 This practical method assembles the tetrahydrofuran ring from allylic diol and carbonyl components and in the process forms three ring bonds C(2)-C(3), C(4)-C(5) and 0-C(5). Both aldehydes (eq 1) and ketones (illustrated in the present procedure) can be employed as the carbonyl component. Although it is often convenient to isolate the acetal intermediate, conversion to the 3-acyltstrahydrofuran can also be accomplished in many cases by the direct reaction of the diol and carbonyl components.8 High ds stereoselectivity (at least 20 1) is observed in the preparation of tetrahydrofurans that contain single side chains at carbons 2 and 5 (eq 1). The kinetically controlled product also has the cis relationship of these side chains and the 3-acyl substituent. 

Although the application of carboalumination to the synthesis of natural products is still in its infancy, a few preliminary results shown in Scheme 1.50 [167,168,171,172] suggest that it promises to become a major asymmetric synthetic reaction, provided that (i) the singularly important case of methylalumination can be made to proceed with S90% ee, and (ii) satisfactory and convenient methods for enantiomeric and diastereo-meric separation/purification can be developed. In this context, significant increases in ee in the synthesis of methyl-substituted alkanols from around 75 % to 90—93 % achieved through some strategic modifications are noteworthy (Scheme 1.50) [168]. Shortly before the discovery of the Zr-catalyzed enantioselective carboalumination, a fundamentally discrete Zr-catalyzed asymmetric reaction of allylically heterosubstituted alkenes proceeding via cyclic carbozirconation was reported, as discussed later in this section. 

But before 1980, the foundations for essentially all modern synthetic radical reactions had been laid, sometimes by synthetic organic chemists but more often by physical organic chemists. Kharasch reactions (now often called atom transfer reactions) were known since the 1930s and 1940s, and tributyltin hydride was introduced in the 1960s. In the 1970s, SnAc reactions and redox chain aromatic substitutions (Minisci reactions) were already topical, and allylations with allyl-tributylstannane were first described. In short, there were a number of ways to generate and trap radicals on the one hand, and a number of fundamental transformations of radicals such as addition and cyclization to multiple bonds on the... 

The Diels-Alder reaction is a thermal cycloaddition involving 1,3-dienes and alkenes, and [3+21-cyclo-addition reactions involve a Ji bond and a 1,3-dipole. The Cope, oxy-Cope, and Claisen rearrangements are thermal, intramolecular reactions of 1,5-dienes. [2+2]-Cycloadditions usually involve reaction between two alkenes, or certainly two Ji bonds. A reaction that is different from any seen so far occurs with certain alkenes and allylic systems. In its fundamental form, it is "the indirect substituting of a compound with a double bond... 

Alkyl halides are usually considered to be less suitable for double carbonylation because of the possibility of the direct reaction of alkyl halides with nucleophiles and of instability of alkyl-transition metal complexes involved in the catalytic process. However, allylic halides were found amenable to double carbonylation promoted by zerovalent palladium complex. It is well known that allylic halides undergo ready oxidative addition with a Pd(0) species to produce Tj -allylpalladium halide complexes. Thus, it was reasoned that the double carbonylation process might be realized if CO insertion into the aUyl-palladium bond proceeds before attack of amine on the 17 -allylpaUadium halide takes place. On the basis of fundamental studies on the behavior of i7 -allylpalladium halide complexes with CO and secondary amines, double carbonylation processes of substituted aUyl halides to give a-keto amides in high yields have recently been achieved (Eqs. 15 and... 

Hoffmann has investigated a fundamentally different approach for enan-tioselective allylation [56] and crotylation [57-60] in which the stereogenic center that dictates the stereochemical outcome of the reaction resides within the allyl fragment. Thus, asymmetric crotylations with the chiral chloro-substituted ( )-crotyl reagent 46 typically exceed 90% ee (Scheme... 

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