Phosphoramidites allylic alkylation

Table 9.1 Allylic alkylations with dimethyl malonate using (phosphoramidite)-lr complexes as catalysts.

Some monophosphines are also revealed to work as reasonably effective ligands. Imamoto and Tsuruta prepared and applied P-chirogenic monophosphines 38 to the allylic alkylation (up to 96% ee) (Equation (7)). Nelson and Hilfiker found that monophosphines 39 bearing a tricarbonyl(arene)chromium moiety work as effective chiral ligands (up to 92% ee) (Equation (7)). " Some monophosphines 40-42 bearing a binaphthyl moiety and some mono-dentate phosphoramidites 43-45 work as quite effective chiral ligands (Equation (7)). Several other monophosphines 46-48 applied to the asymmetric allylic alkylation are summarized in Scheme 5 39,39a-39h... 

Eneouraged hy Bandini s pioneering studies, You and co-workers introduced indolyl carbonates 180 into Ir-catalyzed intramolecular asymmetric allylic alkylation reactions. Interestingly, spiroindolenine derivatives 181 are obtained in 50-98% yields with up to >99/1 dr and 97% ee (Scheme 6.83). Chiral phosphoramidite ligand (/ ,/ a)-170d (Me-THQphos), newly developed by the You group, was responsible for excellent reactivity, diastereo- and enantioselectivity of this process. 

An asymmetric allylic alkylation (AAA) route to substituted allylic boronates relies on the influence of phosphoramidite ligand 90, together with 2 mol% copper thiophenecarboxylate and a Grignard reagent in DCM at -78 These Sn2 ... 

Malda H, van Zijl AW, Arnold LA, Feringa BL (2001) Enantioselective copper-catalyzed allylic alkylation with dialkylzincs using phosphoramidite ligands. Org Lett 3 1169-1171... 

Fananas-Mastral M, Perez M, Bos PH, Rudolph A, Harutyimyan SR, Feringa BL (2012) Enantioselective synthesis of tertiary and quaternary stereogenic centers copper/ phosphoramidite-catalyzed allylic alkylation with organolithiiun reagents. Angew Chem Int... 

Asymmetric allylic alkylation reactions of geminal disubstituted allylic electrophiles have been studied by the group of Feringa. In 2010, they reported that the use of the phosphoramidite ligand in the Cu-catalysed reaction between... 

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... 

In analogy with the Ir-catalyzed allylic alkylations described in the previous section, chiral phosphoramidite ligands derived from BINOL have shown excellent potential in copper-catalyzed asymmetric 8 2 substitutions [93], Alexakis recognized that ligand 86 in the presence of CuBr effects enantio-selective displacement with simple Grignard reagents (Scheme 14.16) [9]. Thus, the reaction between chloride 96 and MeMgBr in the presence of... 

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 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. 

Reactions of allylic electrophiles with stabilized carbon nucleophiles were shown by Helmchen and coworkers to occur in the presence of iridium-phosphoramidite catalysts containing LI (Scheme 10) [66,69], but alkylations of linear allylic acetates with salts of dimethylmalonate occurred with variable yield, branched-to-linear selectivity, and enantioselectivity. Although selectivities were improved by the addition of lithium chloride, enantioselectivities still ranged from 82-94%, and branched selectivities from 55-91%. Reactions catalyzed by complexes of phosphoramidite ligands derived from primary amines resulted in the formation of alkylation products with higher branched-to-linear ratios but lower enantioselectivities. These selectivities were improved by the development of metalacyclic iridium catalysts discussed in the next section and salt-free reaction conditions described later in this chapter. 

Unstabilized enolates react with allylic carbonates in the presence of metalacyclic iridium-phosphoramidite catalysts. Although ketones and aldehydes have not yet been used directly as pronucleophiles with this catalyst system, silyl enol ethers [80] and enamines [81] react with linear allylic carbonates to form, after workup, p-branched, y-8 unsaturated ketones (Scheme 13). Both methods form products in high yield, branched selectivity, and enantioselectivity for a range of cinnamyl and alkyl-substituted allylic carbonates. However, the silyl enol ethers derived from aliphatic ketones reacted in lower yields than enamines derived from the same ketones. 

Asymmetric allylation of cinnamyl halides, alkylation of alkynyl epoxides, and 1,4-addition of nitro olefins" are also successfully demonstrated by combination of an organozinc reagent and a chiral copper phosphoramidite. 

The Syj2 alkylation of acyclic allyl halides by a Grignard reagent catalysed by copper (I) thiophene carboxylate and a phosphoramidite ligand forms a 50 50 mixture of the (Z) and (E) allylic product in high yields (85 to >99%) with 74-94% ee The actual substitution is thought to be a stereospecific anti-Sf 2 mechanism on the Si enantiotopic face of the a- and/or jr-allyl-copper complex(es). 

High yielding preparations of 2 -C> allylribonucleosides have been described, by allylation of 3, 5 -0-Tips derivatives. Again, phosphoramidites were made for incorporation into oligonucleotides. The uridine derivative 226 was also made by alkylation of a Tips... 

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