Alkyl halides 1.1- allyl metals

Lithiated (and also potassiated) allylic ethers and tertiary amines undergo mainly y-attack by primary alkyl halides. The preference for C-y is particularly strong with the metallated allylic ethers H2C=CHCH2Ot-Bu and H2C=CHCH2OSiEt3 [6,7]. Selectivities in reactions with sec-alkyl halides, allylic and cyclohexyl halides are often considerably lower than with primary alkyl halides [6,8]. Metallated allylic sulfides show mainly a-attack by primary alkyl halides [2,8,17]. 

Figure 1 shows typical organophosphorus substrates, which usually act directly, or after activation at a metal center, as nucleophiles. Most include a reactive P-H bond, which, for P(V) substrates, is involved in an important tautomerization equilibrium which interconverts four- and three-coordinate compounds 1 and 2. The source of electrophilic carbon for C-P bond formation is usually unsaturated (alkynes, alkenes, aldehydes, etc), or contains a good leaving group (aryl and alkyl halides, allyl acetates). 

Pyrroles do not react with alkyl halides in a simple fashion polyalkylated products are obtained from reaction with methyl iodide at elevated temperatures and also from the more reactive allyl and benzyl halides under milder conditions in the presence of weak bases. Alkylation of pyrrole Grignard reagents gives mainly 2-alkylated pyrroles whereas N-alkylated pyrroles are obtained by alkylation of pyrrole alkali-metal salts in ionizing solvents. 

Metallocorroles (M = Cu, Ni or Pd) can also be alkylated under the same conditions as the metal-free corroles23,24 to give the N2i-alkylated products together with a small amount of C3 alkylated product ( f = Pd). Allyl halides or bulky alkyl halides react with nickel corroles also at the 3-position. 

Asymmetric Allylation. One of the recent new developments on this subject is the asymmetric allylation reaction. It was found that native and trimethylated cyclodextrins (CDs) promote enantiose-lective allylation of 2-cyclohexenone and aldehydes using Zn dust and alkyl halides in 5 1 H2O-THF. Moderately optically active products with ee up to 50% were obtained.188 The results can be rationalized in terms of the formation of inclusion complexes between the substrates and the CDs and of their interaction with the surface of the metal. 

Monoanions derived from nitroalkanes are more prone to alkylate on oxygen rather than on carbon in reactions with alkyl halides, as discussed in Section 5.1. Methods to circumvent O-alkylation of nitro compounds are presented in Sections 5.1 and 5.4, in which alkylation of the a.a-dianions of primary nitro compounds and radial reactions are described. Palladium-catalyzed alkylation of nitro compounds offers another useful method for C-alkylation of nitro compounds. Tsuj i and Trost have developed the carbon-carbon bond forming reactions using 7t-allyl Pd complexes. Various nucleophiles such as the anions derived from diethyl malonate or ethyl acetoacetate are employed for this transformation, as shown in Scheme 5.7. This process is now one of the most important tools for synthesis of complex compounds.6811-1 Nitro compounds can participate in palladium-catalyzed alkylation, both as alkylating agents (see Section 7.1.2) and nucleophiles. This section summarizes the C-alkylation of nitro compounds using transition metals. 

The benzotriazole 109 reacts with alkyl or allyl halides in the presence of bismuth(III) chloride and metallic aluminium to give the homoalkylated amines 110 in high yields119. 

Tab. 10.8 summarizes the application of rhodium-catalyzed allylic etherification to a variety of racemic secondary allylic carbonates, using the copper(I) alkoxide derived from 2,4-dimethyl-3-pentanol vide intro). Although the allyhc etherification is tolerant of linear alkyl substituents (entries 1-4), branched derivatives proved more challenging in terms of selectivity and turnover, the y-position being the first point at which branching does not appear to interfere with the substitution (entry 5). The allylic etherification also proved feasible for hydroxymethyl, alkene, and aryl substituents, albeit with lower selectivity (entries 6-9). This transformation is remarkably tolerant, given that the classical alkylation of a hindered metal alkoxide with a secondary alkyl halide would undoubtedly lead to elimination. Hence, regioselective rhodium-catalyzed allylic etherification with a secondary copper(l) alkoxide provides an important method for the synthesis of allylic ethers. 

Whereas allyl, benzyl and propargyl electrophiles are among the most reactive towards Pd, Ni and other transition metals, ordinary alkyl halides and related alkyl electrophiles that are not /3, -unsaturated are among the least reactive carbon electrophiles with respect to oxidative addition to Pd or Ni. Most of the alkyl derivatives are also associated... 

Finally, the hybridization of the carbon atom also has a marked effect on its willingness to attach to the transition metal. Allyl or benzyl halides undergo oxidative addition faster than aromatic or vinyl halides. The least reactive are alkyl halides which require the use of nickel(O)9 complexes or highly active catalyst systems.10 If we start from an optically active substrate, then the oxidative addition usually proceeds in a stereoselective manner. 

Etherification. The reaction of alkyl halides with sugar polyols in the presence of aqueous alkaline reagents generally results in partial etherification. Thus, a tetraallyl ether is formed on reaction of D-mannitol with allyl bromide in the presence of 20% sodium hydroxide at 75°C (124). Treatment of this partial ether with metallic sodium to form an alcoholate, followed by reaction with additional allyl bromide, leads to hexaallyl D-mannitol (125). Complete methylation of D-mannitol occurs, however, by the action of dimethyl sulfate and sodium hydroxide (126). A mixture of tetra- and pentabutyloxymethyl ethers of D-mannitol results from the action of butyl chloromethyl ether (127). Completely substituted trimethylsilyl derivatives of polyols, distillable in vacuo, are prepared by interaction with trimethylchlorosilane in the presence of pyridine (128). Hexavinylmannitol is obtained from D-mannitol and acetylene at 25.31 MPa (250 atm) and 160°C (129). 

Benzyl methyl ether or allyl methyl ethers can be selectively metalated at the benzylic/allylic position by treatment with BuLi or sBuLi in THF at -40 °C to -80 C, and the resulting organolithium compounds react with primary and secondary alkyl halides, epoxides, aldehydes, or other electrophiles to yield the expected products [187, 252, 253]. With allyl ethers mixtures of a- and y-alkylated products can result [254], but transmetalation of the lithiated allyl ethers with indium yields y-metalated enol ethers, which are attacked by electrophiles at the a position (Scheme 5.29). Ethers with ft hydrogen usually undergo rapid elimination when treated with strong bases, and cannot be readily C-alkylated (last reaction, Scheme 5.29). Metalation of benzyl ethers at room temperature can also lead to metalation of the arene [255] (Section 5.3.11) or to Wittig rearrangement [256]. Epoxides have been lithiated and silylated by treatment with sBuLi at -90 °C in the presence of a diamine and a silyl chloride [257]. 

Buu-Hoi, N. P. Demerseman, P. Zinc chloride-catalyzed benzylations of phenols and naphthols./. Org. Chem. 1955, 20, 1129—1134. Curtin, D. Y. Crawford, R. J. Wilhelm, M. Factors controlling position of alkylation of alkali metal salts of phenols, benzyl and allyl halides./. Am. Chem. Soc. 1958, 80, 1391— 1397. 

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