Stereochemistry benzyl amines

Imines, on the contrary, proved particularly reactive under these conditions (Fig. 4.34). For example, Jones and Selenski report that the introduction of one equivalent of methyl magnesium bromide to benzaldehyde 5 stirring at —78 °C in the presence of one and half equivalents of the imine that is derived from the condensation of benzyl amine and benzaldehyde proceeds immediately to the aminal 65 in 94% yield.27 Only the trans isomer is observed from this low-temperature cycloaddition. While the relative stereochemistry appears to be result of an exo transition state, we suspect that initial cis adduct from and endo addition may epimerize under these conditions. 

Thus, in contrast to an ionization process from a neutral substrate, which initially generates an intimate ion pair, deamination reactions generate a cation which does not have an anion closely associated with it. The stereochemistry of substitution is shown for four representative systems in Table 5.15. Displacement on the primary 1-butyl system is much less stereospecific than the 100% inversion observed on acetolysis of the corresponding brosylate (entry 1, Table 5.14). Similarly, the 2-butyl diazonium ion affords 2-butyl acetate with only 28% net inversion of configuration. Small net retention is seen in the deamination of 1-phenylethylamine. The tertiary benzylic amine 2-phenyl-2-butylamine reacts with 24% net retention. These results indicate that the lifetime of the carbocation is so short that a symmetrically solvated state is not reached. Instead, the composition of the product is determined by a nonselective collapse of the solvent shell. 

Two equivalents of the tertiary amine base are required, and a significant improvement in the diastereoselectivity was observed with TMEDA over DIPEA. Purification and further enrichment of the desired RRR isomer to >98% ee was achieved by crystallization. Oxidative removal of the chiral auxiliary followed by carbodiimide mediated amide formation provides (3-keto carboxamide 14 in good yield. Activation of the benzylic hydroxyl via PPha/DEAD, acylation, or phosphorylation, effects 2-azetidinone ring-closure with inversion of stereochemistry at the C4 position. Unfortunately, final purification could not be effected by crystallization and the side products and or residual reagents could only be removed by careful chromatography on silica. 

It is known that electrochemical reduction of oximes in protic media occurs in two steps the N—O bond is first reduced to form an imine and the latter is then reduced to afford a primary amine1,29. Tallec has shown that the amine from oxime 33 can be trapped intramolecularly (equation 16)35. Interestingly, the SS diastereomer predominates the chiral pyrrolidine ring derivative serves to control the stereochemistry of formation of the new benzylic chiral center. Electrochemical reductive cross-coupling of O-methyl oximes with carbonyl compounds in isopropanol at a tin cathode affords adducts (equation 17) which can be reduced further to 2-amino alcohols36. In this fashion, menthone could... 

Another effect of the coordination is that the benzylic cation is also stabilized [63]. This stabilization is explained by delocalization of the positive charge due to the interaction of the d-orbital of Cr with the 71-orbital of the benzylic carbon, caused by the coordination of Cr(CO)3. Facile stereospecific Friedel- Crafts-type cyclization of the complex of the optically active benzyl alcohol 248 gave the tetrahydrobenzazepine 249 with retention of the stereochemistry, and the free amine 250 with 98% ee was... 

Using the same procedure, phenyl-substituted alkenes can be aminated. For example, the photochemically promoted reaction of l,2-dihydro-4-phenylnaphthalene (3) with an amine in the presence of 1,4-dicyanobenzene (/ -DCNB) afforded the corresponding 2-amino-1 -phenyl derivatives 4, albeit in relatively low yield after 64-71% conversion of the alkene30. The stereochemistry of the product is dependent on the steric bulk of the amine, since the intermediate benzylic carbanion should undergo protonation from the less hindered face, that is, opposite to the amino group. The stereochemical assignment of 4 was based on chemical shifts and coupling constants for the methine protons in the H-NMR spectra. 

Bartoli et al. [31] reported the formation of enantiomerically pure amines and hydroxylamines from optically active nitroalkanes with allylic and benzylic Grignard reagents. The intermediate nitrones (see Table 3, entry 7) were mixtures of E- and Z-isomcrs from the protected nitroalkanes. Although the regiochemistry is complicated, the stereochemistry of the double bond was affected by the nature of the Grignard reagent. The major isomer was always the R-isomer. 

More recently, the same catalyst was used to produce cyclic amines with retention of stereochemistry from a simple linear aliphatic azide [53]. Treatment of a substituted aliphatic azide by complex 66 afforded the cyclized compound 75, by insertion of the nitrene moiety in allylic, benzylic, and even in the less reactive tertiary C—H bonds. The catalyst is inhibited by coordination of the product to the metal center. However, that can be avoided by using an in situ protecting agent (Boep is preferred over Fmoc-OSuc which leads to catalyst decomposition). 

Benzylic carbocations are also stabilized by complexation to chromium and a number of interesting reactions have been reported. Again, reaction of the carbocations with nucleophiles occurs from the exo face of the complex, relative to the metal. Carbocations are readily formed by treatment of benzylic alcohols with a strong acid, such as sulfuric acid, tetrafluoroboric acid, or borontrifluoride etherate. The cation can be trapped with water, alcohols, nitriles, and mono-or disubstituted amines to form alcohols, ethers, amides, and di- or trisubstituted amines respectively. Scheme 96 illustrates the formation of a benzylic carbocation followed by intramolecular trapping, resulting in a net inversion of stereochemistry. Benzylic acetates react with trimethyl aluminium introducing a methyl group from the opposite face of the metal. 

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