Phosphoramidite nucleophilic substitution reactions

Dahl suggested a kinetic model for the nucleophilic substitution reaction at tri-covalent phosphorus with a P-N bond with alcohols (Scheme 2.135) [41]. The reaction proceeds in the presence of an ammonium salt as a catalyst. In the first step, the phosphoramidite is protonated in a fast equilibrium (1). In the second step, replacement of the amino group takes place (2). This step is slow and is the rate-determining step. Regeneration of the catalyst in the last step closes the catalytic cycle (3). 

As previously discussed, activation of the iridium-phosphoramidite catalyst before addition of the reagents allows less basic nitrogen nucleophiles to be used in iridium-catalyzed allylic substitution reactions [70, 88]. Arylamines, which do not react with allylic carbonates in the presence of the combination of LI and [Ir(COD)Cl]2 as catalyst, form allylic amination products in excellent yields and selectivities when catalyzed by complex la generated in sim (Scheme 15). The scope of the reactions of aromatic amines is broad. Electron-rich and electron-neutral aromatic amines react with allylic carbonates to form allylic amines in high yields and excellent regio- and enantioselectivities as do hindered orlAo-substituted aromatic amines. Electron-poor aromatic amines require higher catalyst loadings, and the products from reactions of these substrates are formed with lower yields and selectivities. 

Several types of intramolecular allylic substitution reactions of carbon, nitrogen, and oxygen nucleophiles catalyzed by metalacyclic iridium phosphoramidite complexes have been reported. Intramolecular allylic substitution is much faster than the competing intermolecular process when conducted in the presence of iridium catalysts. Thus, conditions involving high dilution are not required. Intramolecular... 

The scope of reactions catalyzed by metalacychc iridium-phosphoramidite complexes is remarkably broad, but reactions with some substrates, such as allylic alcohols, prochiral nucleophiles, branched allylic esters, and highly substituted allylic esters, that would form synthetically valuable products or would lead to simpler symthesis of reactants occur with low yields and selectivities. In addition, iridium-catalyzed allylic substitution reactions are sensitive to air and water and must be conducted with dry solvents under an inert atmosphere. Several advances have helped to overcome some, but not aU of these challenges. 

A new phosphoramidite ligand (1 Y = OMe), gives high enantioselectivities (92-99% ee) and regioselectivities (99% S 2 ) in iridium-catalysed allylic substitution reactions of carbonates and acetates with carbanion or primary amine nucleophiles.6 The new ligand also leads to a faster rate of reaction than other phosphoramidite ligands. 

Preparative Methods the phosphoramidite ligand can be prepared by the nucleophilic substitution of phosphory 1 chloride (formed from the reaction of PCI3 and (S)-2,2 -binaphthol in presence of triethylamine) with (R,R)-bis(l-phenylethyl)amine. Purification recrystallization from diethyl ether/dichloro-methane. 

With the first nucleoside in place, we are ready to attach to it the second. For this purpose, the point of attachment, the 5 -OH, is deprotected with acid. Subsequent addition of a 3 -OH activated nucleoside effects coupling. The activating group is an unusual phosphoramidite [containing P(III)], which, as we shall see shortly, also serves as a masked phosphate [P(V)] for the final dinucleotide and is subject to nucleophilic substitution, not unlike PBrs (recall Sections 9-4 and 19-8). The displacement reaction is catalyzed and furnishes a phosphite derivative the catalyst is the, again unusual, aromatic heterocycle tetrazole, a tetrazacyclopentadiene related to pyrrole (Section 25-3) and imidazole (Section 26-1). Finally, the phosphorus is oxidized with iodine to the phosphate oxidation state. 

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. 

The 3-bromopropyl-substituted nucleoside phosphoramidite 244 has been prepared, with a view to its incorporation into oligonucleotides which would permit post-synthetic functionalization of the sugar moiety on the solid support by reaction with appropriate nucleophiles. ... 

In contrast, iridium complexes of phosphoramidite ligands catalyze the enantiose-lective formation of the branched allyUc substitution products with high enantiomeric excess. Takeuchi and Helmchen " - - - reported that iridium complexes, hke rhodium complexes, generate the chiral, branched product from reactions of mono-substituted aUylic acetates and carbonates with carbon and nitrogen nucleophiles (Equations 20.45-20.47). 

Over the last few years, the Ir-catalyzed allylic substitution has been investigated in several laboratories and was found to be well suited for applications in organic synthesis. Using this reaction, branched chiral allylic derivatives can be prepared with high selectivity from simple achiral monosubstituted allylic substrates (Scheme 11.1). The reaction has been carried out with C, N, O, and S nucleophiles. The very broad range of nucleophiles is impressive. Several reviews have appeared on the subject [1]. At present, the best catalysts are prepared from [Ir(cod)Cl]2 (cod, cycloocta-1,5-diene) [2, 3] or [Ir(dbcot)Cl]2 (dbcot, dibenzocyclooctatetraene) [4] and a chiral phosphoramidite by base-induced C-H activation. Reliable experimental procedures have been developed for the reaction [5]. 

The two diasteromeric allyliridium-phosphoramidite complexes formed in the allylic 5 2 substitution of /-substituted allylic acetates, benzoates, or carbonates, with amine nucleophiles have been synthesized and characterized by NMR and X-ray diffractions. Kinetic and stereochemical studies using deuterated substrates indicate that the reaction, which occurs with a retention of configuration, proceeds by the mechanism in Scheme 3. This iridium-catalysed reaction is compared to molybdenum- and palladium-catalysed reactions. 

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