Nucleophilic aliphatic allylic systems

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... 

Rhodium catalysts have also been used with increasing frequency for the allylic etherification of aliphatic alcohols. The chiral 7r-allylrhodium complexes generated from asymmetric ring-opening (ARO) reactions have been shown to react with both aromatic and aliphatic alcohols (Equation (46)).185-188 Mechanistic studies have shown that the reaction proceeds by an oxidative addition of Rh(i) into the oxabicyclic alkene system with retention of configuration, as directed by coordination of the oxygen atom, and subsequent SN2 addition of the oxygen nucleophile. 

A two-component bimetallic catalytic system has been developed for the allylic etherification of aliphatic alcohols, where an Ir(i) catalyst acts on allylic carbonates to generate electrophiles, while the aliphatic alcohols are independently activated by Zn(n) coordination to function as nucleophiles (Equation (48)).194 A cationic iridium complex, [Ir(COD)2]BF4,195 and an Ru(n)-bipyridine complex196 have also been reported to effectively catalyze the O-allylation of aliphatic alcohols, although allyl acetate and MeOH, respectively, are employed in excess in these examples. 

Whilst the method described above appears very elegant, Weix and Hartwig expressed their discontent about the allylations of aliphatic silyl enol ethers and developed an alternative system using enamines as nucleophiles. Once the considerable initial difficulties had been overcome, these authors were able to present a procedure that gave excellent results (Scheme 9.16) [50]. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Pd(0)/phosphine complexes, or their precursors, in the presence of a suitable co-base, have also been shown to promote, in good yields (66-100%), the formation of allylic carbamates from various primary and secondary aliphatic amines, pressurized C02 and allylic chlorides, in THF, at ambient temperature [87a]. The choice of the added co-base (Base), used for generating the carbamate salt RR NC02 (BaseH)+, was found to be critical for high yields of O-allylic urethanes. The use of a guanidine (CyTMG) or amidine (DBU) base was optimal for this system (see also Section 6.3.1). ft is assumed that this chemistry passes catalytically through a mechanism similar to that illustrated in Scheme 6.19. This involves nucleophilic attack by carbamate anion on a (tt-allyl) palladium species, formed by the oxidative addition of the allylic chloride to a palladium(O) intermediate. 

A very simple method for the allylation of alcohols with allylsilane was reported. Different Lewis acids (AICI3, Sc(OTf)3, Bi(OTf)3...) had been examined for this reaction but catalytically these were inefficient. Bismuth(III) chloride was proved to be the best catalyst. The reaction of benzhydrol or its derivatives with silyl nucleophile in the presence of 1 mol% at room temperature afforded the desired alkenes in good yields without any side product. A higher temperature was needed to allylate other alcohols such as phenylethanol. Aliphatic alcohols were not suitable for this system (Equation 3) [25d]. 

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