Nucleophilic addition allylic systems

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. 

Complexes 79 show several types of chemical reactions (87CCR229). Nucleophilic addition may proceed at the C2 and S atoms. In excess potassium cyanide, 79 (R = R = R" = R = H) forms mainly the allyl sulfide complex 82 (R = H, Nu = CN) (84JA2901). The reaction of sodium methylate, phenyl-, and 2-thienyllithium with 79 (R = R = r" = R = H) follows the same route. The fragment consisting of three coplanar carbon atoms is described as the allyl system over which the Tr-electron density is delocalized. The sulfur atom may participate in delocalization to some extent. Complex 82 (R = H, Nu = CN) may be proto-nated by hydrochloric acid to yield the product where the 2-cyanothiophene has been converted into 2,3-dihydro-2-cyanothiophene. The initial thiophene complex 79 (R = R = r" = R = H) reacts reversibly with tri-n-butylphosphine followed by the formation of 82 [R = H, Nu = P(n-Bu)3]. Less basic phosphines, such as methyldiphenylphosphine, add with much greater difficulty. The reaction of 79 (r2 = r3 = r4 = r5 = h) with the hydride anion [BH4, HFe(CO)4, HW(CO)J] followed by the formation of 82 (R = Nu, H) has also been studied in detail. When the hydride anion originates from HFe(CO)4, the process is complicated by the formation of side products 83 and 84. The 2-methylthiophene complex 79... 

Scheme 7.4 illustrates some of the important synthetic reactions in which organolithium reagents act as nucleophiles. The range of reactions includes S/v2-(ype alkylation (Entries 1 to 3), epoxide ring opening (Entry 4), and formation of alcohols by additions to aldehydes and ketones (Entries 5 to 10). Note that in Entry 2, alkylation takes place mainly at the 7-carbon of the allylic system. The ratio favoring 7-alkylation... 

In addition to alkoxides, carbonyl oxygens have occasionally been recruited to function as nucleophiles in allylic etherification processes. The cyclization reactions of ketones containing internal allylic systems occur through O-allylation under Pd catalysis to give rise to vinyl dihydrofurans203 or vinyl dihydropyrans (Equation (51))204,205 in good yields. 

In the examples presented so far, only two enantiomeric products have been possible in each case, since the substrates have all contained identical substituents on the Cl and C3 positions. However, a more complex situation occurs when the allyl system is unsymmetrically-substituted, as in 43a or 43b (Scheme 12).1161 Here, nucleophilic addition to the corresponding ri3-allyl intermediate 44 may afford an achiral, linear product 45, in addition to the pair of enantiomeric branched products 46. 

Although Helmchen et al. showed that asymmetric iridium-catalyzed allylic substitution could be achieved, the scope of the reactions catalyzed by iridium complexes of the PHOX ligands was limited. Thus, they evaluated reactions catalyzed by complexes generated from [lr(COD)Cl]2 and the dimethylamine-derived phosphoramidite monophos (Scheme 8) [45,51]. Although selectivity for the branched isomer from addition of malonate nucleophiles to allylic acetates was excellent, the highest enantiomeric excess obtained was 86%. This enantiomeric excess was obtained from a reaction of racemic branched allylic acetate. The enantiomeric excess was lower when linear allylic acetates were used. This system catalyzed addition of the hthium salts of A-benzyl sulfonamides to aUylic acetates, but the product of the reaction between this reagent and an alkyl-substituted linear aUylic acetate was formed with an enantiomeric excess of 13%. 

The palladium catalysed substitution reaction of allylic systems has also been utilised in the formation of five membered rings. Intramolecular nucleophilic attack of the amide nitrogen atom on the allylpalladium complex formed in the oxidative addition of the allyl acetate moiety on the catalyst led to the formation of the five membered ring (3.63.). In the presence of a copper(II) salt the intermediate pyrroline derivative oxidized to pyrrole.80... 

E.3.2.1. Deracemization of Acyclic Substrates When chiral allylic substrates generate meso 71-allyl intermediates, the two allylic termini of such intermediates are enantiotopic. Thus, enantioselectivity is derived from the regiochemistry of the nucleophilic addition (a vs. b), and the alkylation process corresponds to a deracemization event (Eq. 8E,2). One of the prototypical reactions, which has been studied in extensive detail, is the 1,3-diphenylallyl system. Since its introduction as a different mechanistic motif in contrast with the 1,1,3-triphenylallyl system, this reaction has become a benchmark for design and comparison of a variety of different ligands in recent years [73]. 

If the substrate contains two identical substituents at one terminus of the allylic position such as shown in Scheme 8E.26, the it-allyl intermediate can undergo enantioface exchange via the formation of a a-palladium species at that terminus. This process should occur faster than the nucleophilic addition, which is the enantio-determining step (fc, > 2[Nu ] and 2[Nu ]). Thus, enantioselection can be derived from the relative rate of the nucleophilic addition to each diastereomer the relative stabilities of the two diastereomeric complexes need not have a direct effect on the enantioselectivity (Curtin-Hammett conditions). Although the achiral allylic isomer 120 is expected to follow the same kinetic pathway as the racemic substrate 119, the difference between the results from the two systems often gives an indication as to the origin of enantioselection—complexation or ionization versus nucleophilic addition. 

In addition to the formation of 70 by the usual nucleophilic attack at the terminal carbon of allylic system, the substituted cyclopropanes 72 are formed by the attack at... 

The excellent control observed with the P,S- and certain N,S-ligands is believed to be mainly electronic in origin [85-88, 90-92, 94, 95]. When a tt-allyl system possesses two different coordinating atoms, the nucleophilic attack is expected to occur trans to the better Jt-acceptor, since the electronic density of the allylic system is lowest at this position. In these cases, the phosphorus and the nitrogen atoms are better Jt-acceptors than the sulfur which is a good donor but weak acceptor. In some cases, the sulfur atom is considered to be the better acceptor [90]. In addition, it has been proposed that the selectivity arises from subtle steric interactions that predispose attack on the allyl unit of the reaction intermediate with a preferred reaction trajectory [93]. 

Palladium-catalyzed heteroannulation is illustrated by synthesis of substituted l//-benzo[rf]azonine 227, which was prepared from allene and tosylamide-containing aryl halide (Equation 26). The reaction was suggested to proceed by addition of an arylpalladium compound to the allene to generate a 7i-allylpalladium intermediate, which subsequently undergoes nucleophilic displacement of palladium at the less-hindered end of the 7i-allyl system <1998JOC6859>. 

Stereoselective, conjngate allylation of more remote positions nsing aUyl trimethylsilane and TiCU is possible. Further transformation by nucleophilic addition and ringclosing metathesis affords fused polycychc ring systems (Scheme 88). Stabilized anions and organocopper see Copper OrganometaUic Chemistry) reagents also participate in Michael-type additions to complexed Q, /3-unsaturated aromatic enones. 

While good procedures are available for the initial oxidative addition to give allyl-PdX complexes, and the nucleophile addition has been folly developed, this process has not been amenable to catalysis. The Pd is reduced to Pd° during the basic pathway, and no compatible reoxidation system has been defined. 

The principally practicable route to allyl vinyl ethers by alkenation of allyl formates, has not yet been exploited in this context. In another approach, the nucleophilic addition of allylic alcohols to alkynic esters, one observes the exclusive formation of franr-enol ethers 2 the stereochemical information is lost, however, after the rearrangement, due to enolization of the formed formylacetic acid derivatives. On the other hand the nucleophilic addition of allyl alcohols to acceptor-substituted allenes like allenic sul-fones or phosphonates offers a novel route with fascinating potential. " Such systems that are readily... 

The direct nucleophilic attack of anilines occurs at both termini of the allylic system of the cationic 73-allylpalladium(II) complex 16 generated by oxidative addition of allylic compounds to a Pd(0) complex. 

The reaction scheme for substrates 16 bearing different substituents at the two allylic termini is more complex (Scheme 12). In this case 16 and the enantiomer ent-l6 are converted to different allyl complexes 18 and 19 with opposite absolute configuration at the allyl C-atoms. NucleophiHc addition to 18 with soff nucleophiles leads to the regioisomers 20 and 21 whereas 19 affords the corresponding enantiomeric products ent-20 and ent-2l. The two allyl complexes 18 and 19 cannot interconvert by a K-O-K process which solely results in syn-anti isomerization. Isomerization of 18 to 19 would be possible by Pd(0)-catalyzed allyl transfer (see Sect. 2.2.3) or a mechanism proposed for allyUc acetates involving metal-centered addition of acetate to the allyl system with retention... 

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