Allylic substrate

Treatment of allylic substrates ISO, possessing suitable leaving groups X in tlieir allylic positions, witli organocopper reagents may result eitlier in an S 2-type process fa-attack) or alternatively in an S 2 one fy-attack), giving tlie substitution products 151 and 152, respectively fSclieme G.30) [Ij]. 

For acyclic allylic substrates die situation is mote complex, since a larger number of reactive conformations, and betice corcesponding transition states, compete. Hius, mediyl ciimamyl derivatives 163 tX= O.Acj, upon treatment witli litliiiim dimetliylcuprate, mainly gave tlie S 2 substitution product 166 fentry 1, Tab. 6.6 and Sdieme 6.34) [80]. Hie preference for die S 2 product is expected, since de-conjugation of die alkene system is electronically imfavorable. 

Hie use of chiral catalysts as an approach to enantiomer icaliy enriched products by means of coppet-mediated substitution reactions is covered in this chapter. Reactions in which a chiral auxiliary resides in the leaving group of the substrate w ill also he dealt with, since these reactions provide direct and efBcient routes to single enantiomers of the desired products. Most studies so far have been concerned with allylic substrates, with a new chiral center being produced in the course of a selec-... 

S ]2 -selective reactions between primary allylic substrates and otganocoppet reagents testiU in the creation of new Chirality in previously aChital molecules, and it is tempting to try to take advantage of this for the development of enantioselective allylic substitution reactions. 

Allylic Substrates with Chiral Leaving Croups... 

Most asymmetric induction processes with Chital auxiliaries involve a stereo-differentiating reaction that affords one diastereomet as the primary product To obtain the desired enantiomer, the Chiral auxiliary must be removed Highly dia-stereoselective reactions between otganocoppet reagents and allylic substrates with... 

Hie use of tlie cliiral catalyst 19b for asymmetric allylic substitution of allylic substrates bas been studied in some deta d fSdieme 8.18) and, under ji-selective reaction conditions, asymmetric induction was indeed obtained [28, 34]. 

For the deprotonation of less acidic precursors, which do not lead to mesomerically stabilized anions, butyllithium/TMEDA in THF or diethyl ether, or the more reactive, but more expensive,. seobutyllithium under these conditions usually are the most promising bases. Het-eroatomic substitution on the allylic substrate, which docs not contribute to the mesomeric or inductive stabilization often facilitates lithiation dramatically 58. In lithiations, in contrast to most other metalations, the kinetic acidity, caused by complexing heteroatom substituents, may override the thermodynamic acidity, which is estimated from the stabilization of the competing anions. These directed lithiations59 should be performed in the least polar solvent possible, e.g.. diethyl ether, toluene, or even hexane. 

Table 1. Typical Examples of SN2 Reactions of Allylic Substrates ... 

In general, SnI rates at an allylic substrate are increased by any substituent in the 1 or 3 position that can stabilize the carbocation by resonance or hyper-... 

Triple bonds in the P position (in propargyl systems) have about the same effect as double bonds. Alkyl, aryl, halo, and cyano groups, among others, in the 3 position of allylic substrates increase Sn2 rates, owing to increased resonance in the transition state, but alkyl and halo groups in the 1 position decrease the rates because of steric hindrance. 

When electrophilic substitution is carried out at an allylic substrate, the product may be rearranged ... 

It is well known that allylic substrates are more reactive under solvolytic conditions than their saturated counterparts because of the delocalization of the positive charge in the developing carbonium ion over the tt system and the overlap of the empty p orbital with the double bond in the intermediate ion. 

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... 

Dimethylmalonate 75 coordinates to a Fe(CO)4 species, yielding a ferrate species 128. This coordinates the allylic substrate under decarbonylation and by nucleophilic attack at the double bond an allyliron-species 131 is generated which undergoes substitution of the ferrate 132 by a dimethylmalonte molecule 75. Although there is some evidence of this catalytically active ferrate 128, until now it could not be fully analytically characterized and therefore the structure presented above still remains a hypothesis. 

In 2006, these workers successfully expanded the previous study to several acyclic and cyclic allylic substrates (Scheme 1.17)." In all cases, the best enantioselectivity (up to 91% ee) was obtained by using the ligand that contained the more bulky sulfur substituent (t-Bu). The methodology was also applied to monosubstituted acyclic substrates but, however, this ligand proved to be inadequate in terms of regioselectivities, whereas a good enantioselectivity of up to 89% ee was obtained. 

Furanoside thioether-phosphinite ligand for Pd-catalysed allylic substitutions of acyclic and cyclic allylic substrates. 

Scheme 1.47 Arenethiolatocopper(I)-catalysed substitution reactions of RMgX with allylic substrates.

Grignard reagents with allylic substrates, providing the corresponding y-pro-ducts in enantioselectivities of up to 50% ee (Scheme 1.47). ... 

More recently, Backvall et al. have reported the use of arenethiolatocopper(I) as a catalyst for the analogous substitution reaction of Grignard reagents with allylic substrates. In this case, the crosscoupling reaction could occur in an a(SN2) or y(Sn2 ) manner, depending on the reaction conditions. In all cases, the y-product was isolated as the sole product with moderate to quantitative... 

Scheme 10.89 Arenethiolatocopper(I)-catalysed Grignard crosscouplings of allylic substrate.

Scheme 10.90 Cu-catalysed Grignard crosscouplings of allylic substrates with fer-rocenylthiolate ligands.

Regioselectivities that are usually high to excellent have been reported in novel palladium-catalyzed Heck arylation reactions with a variety of allylic substrates. The //-stabilizing effect of silicon enhanced regiocontrol in the internal arylation of allyl-trimethylsilane (Eq. 11.5) [18], and coordination between palladium and nitrogen... 

The presence of EWG on 2,4-dioxopentane-3-thione favours the formation of thiophilic adducts with different allyl substrates.178 In all cases the reaction affords single thiophilic ene adducts and formation of C=C occurs with high E stereoselectivity (Scheme 17). 

Due to the poor nucleophilicity of aliphatic alkoxides, the intermolecular O-allylation of aliphatic alcohols has been performed, for the most part, using a large excess of structurally simple primary alcohols (Equation (37))165 and/or unsubstituted allylic substrates.166,167 When allylic systems activated with an electron-withdrawing substituent were employed, only a slight excess of the alcohol was necessary to achieve complete stereospecificity, as exemplified by Equation (38).168,169... 

Related catalytic enantioselective processes It is worthy of note that the powerful Ti-catalyzed asymmetric epoxidation procedure of Sharpless [27] is often used in the preparation of optically pure acyclic allylic alcohols through the catalytic kinetic resolution of easily accessible racemic mixtures [28]. When the catalytic epoxidation is applied to cyclic allylic substrates, reaction rates are retarded and lower levels of enantioselectivity are observed. Ru-catalyzed asymmetric hydrogenation has been employed by Noyori to effect the resolution of five- and six-membered allylic carbinols [29] in this instance, as with the Ti-catalyzed procedure, the presence of an unprotected hydroxyl function is required. Perhaps the most efficient general procedure for the enantioselective synthesis of this class of cyclic allylic ethers is that recently developed by Trost and co-workers, involving Pd-catalyzed asymmetric additions of alkoxides to allylic esters [30]. 

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