Nucleophilic Allylic Alkylation

Alkylation of allylic acetates (formates or chlorides) with the dimethyl malonate anion is catalyzed by sodium tricarbonyl(nitroso)iron90. The nucleophile attacks the less hindered site... 

The reaction of 4-(phenylsulfonyl)azetidin-2-one (128) with nucleophiles such as dialkylcopper lithium and Grignard reagents gives 4-alkyl, 4-allyl, 4-vinyl or 4-ethynyl-azetidinon-2-one (129) in good yields (equation 99)83. The yields of several azetidin-2-ones obtained by this method are given in Table 10. The reaction apparently proceeds through an intermediate azetin-2-one 131 derived from the five-membered coordination complex (equation 100). 

Chiral pyridine-based ligands were, among various Ar,AT-coordinating ligands, more efficient associated to palladium for asymmetric nucleophilic allylic substitution. Asymmetric molybdenum-catalyzed alkylations, especially of non-symmetric allylic derivatives as substrates, have been very efficiently performed with bis(pyridylamide) ligands. 

Years earlier, Nicholas and Ladoulis had found another example of reactions catalyzed by Fe2(CO)9 127. They had shown that Fe2(CO)9 127 can be used as a catalyst for allylic alkylation of allylic acetates 129 by various malonate nucleophiles [109]. Although the regioselectivites were only moderately temperature-, solvent-, and substrate-dependent, further investigations concerned with the reaction mechanism and the catalytic species were undertaken [110]. Comparing stoichiometric reactions of cationic (ri -allyl)Fe(CO)4 and neutral (rj -crotyl ace-tate)Fe(CO)4 with different types of sodium malonates and the results of the Fe2(CO)9 127-catalyzed allylation they could show that these complexes are likely no reaction intermediates, because regioselectivites between stoichiometric and catalytic reactions differed. Examining the interaction of sodium dimethylmalonate 75 and Fe2(CO)9 127 they found some evidence for the involvement of a coordinated malonate species in the catalytic reactions. With an excess of malonate they... 

Allyl acetates are more commonly used as electrophiles for the palladium-catalyzed allylic alkylation than allylic nitro compounds.20 However, the reaction of allylic nitro compounds has found wider applications. Allylic nitro compounds are readily available by nitration of alkenes. The regio- and stereoselective introduction of electrophiles and nucleophiles into alkenes is possible as outlined in Eq. 7.19. In fact, this strategy is applied to the synthesis of terpenoids.21... 

The scope of allylic electrophiles that react with amines was shown to encompass electron-neutral and electron-rich ciimamyl methyl carbonates, as well as furan-2-yl and alkyl-substituted allylic methyl carbonates. An ort/io-substituted cinnamyl carbonate was found to react with lower enantioselectivity, a trend that has been observed in later studies of reactions with other nucleophiles. The electron-poor p-nitrocinnamyl carbonate also reacted, but with reduced enantioselectivity. Allylic amination of dienyl carbonates also occur in some cases with high selectivity for formation of the product with the amino group at the y-position over the s-position of the pentadienyl unit [66]. Arylamines did not react with allylic carbonates under these conditions. However, they have been shown to react in the presence of the metalacyclic iridium-phosphoramidite catalysts that are discussed in Sect. 4. 

For further details of this reaction, the reader is referred to Chapter 9. The catalytic allylation with nucleophiles via the formation of Ti-allyl metal intermediates has produced synthetically useful compounds, with the palladium-catalyzed reactions being known as Tsuji-Trost reactions [31]. The reactivity of Ti-allyl-iridium complexes has been widely studied [32] for example, in 1997, Takeuchi idenhfied a [lrCl(cod)]2 catalyst which, when combined with P(OPh)3, promoted the allylic alkylation of allylic esters 74 with sodium diethyl malonate 75 to give branched... 

Takemoto and his co-workers developed asymmetric allylic alkylation of allylic phosphates with (diphenyl-iminolglycinates as carbon-centered nucleophiles (Equation (56))/" " In this reaction system, use of optically active bidentate phosphites 142 bearing an (ethylthio)ethyl group as chiral ligands promotes the allylic alkylation, and chiral /3-substituted a-amino acids are obtained with an excellent enantioslectivity. 

Allylic alkylationThis Pd(0) complex, in combination with a small quantity of bis(diphenylphosphino)ethane, is more effective than PdIPfQ.HOjL for alkylation of allylic acetates with the anion of dimethyl malonate. It also permits use of sodium cyclopentadienide as a nucleophile. 

Allylic amination of allyl halides can also be achieved using lithium and potassium bis(trimethylsilyl)amides [34] and potassium 1,1,3,3-tetramethyldisilazide [35] as the nucleophiles. It has been found that for the reaction of alkyl-substituted allyl chlorides using lithium bis(trimethylsilyl)amides as the nucleophile the allylic amination proceeds smoothly in a SN2 fashion to give /V,Af-disilylamines in high yields when silver(I) iodide was used as an additive. Other metal complexes such as copper ) iodide and other silver(I) salts can also be used as additives for the reaction. 

Finally, Table 8.1 lists three primary alkyl chlorides—allyl chloride, benzyl chloride, and chloroacetone—that react considerably faster than other primary alkyl chlorides. This increase in reaction rate is due to resonance stabilization of the transition state. Each of these compounds has a pi bond adjacent to the reactive site and forms a transition state that is conjugated. The p orbital that develops on the electrophilic carbon in the transition state overlaps with the p orbital of the adjacent pi bond. The stabilization due to the conjugated transition state results in a significantly faster reaction. The transition state for the reaction of allyl chloride with a nucleophile is shown as follows ... 

New versatile Pd-catalyzed alkylation of indoles 523 via nucleophilic allylic substitution provides 3-allylindoles 524 in good to excellent yields (Scheme 107) <20040L3199 and references therein>. The regioselectivity of the reaction... 

Thiophene sulfonium salts have also been used for alkylation of phenols, thiophenols, and other nucleophiles (Equation 70) <2001T2871>. Ylides generated from THT and alkyl or allyl halides are known to react with aldehydes to form oxiranes. However, a modified procedure has been developed in which only a catalytic amount of THT is used for the preparation of vinyloxiranes from allyl bromides and aldehydes. In most of the cases, a m-/ra r-mixture of vinyloxiranes was obtained. Optically pure C2-symmetric /ra r-2,5-dimethyltetrahydrothiophene has also been used for the asymmetric version of this reaction, but the enantioselectivity was poor (25% ee) (Equation 71) <2003CC2074>. 

AUylic alkylations. This complex in combination with 2,2 -bipyridyl (bpy) catalyzes nucleophilic alkylation of allylic acetates and carbonates, but is less active than molybdenum or palladium catalysts. The displacement occurs with retention of configuration, as with Mo and Pd catalysts. However, alkylation occurs almost entirely at the more substituted end of the allylic group, regardless of the nucleophile. 

Catalytic allylic alkylation with Pd is one of the most powerfiil techniques to come out of the development of organotransition metal reagents for organic synthesis. Especially powerfiil is the versatility in the reactants a wide range of allyl species with electronegative allylic substituents and essentially every type of nucleophile. Allylic alkylation using metals other than Pd are known but have been less commonly applied to organic synthesis. 

The Pd-catalyzed C-3 alkylation of indoles via nucleophilic allylic substitution on allylic carbonates and acetates has been described [90]. Two clever indole ring syntheses involving oxidative cyclization are illustrated below [91]. 

---