Alkylation of imines

The alkylation of imines by an alkyl halide to give an iminium salt will be illustrated by selected reactions over a period of years. A more complete survey is available (88). Decker and Becker (89) prepared a number of iminium salts (91, for example) by mixing methyl iodide and aromatic imines in benzene. 2,5-Dimethyl-2-pyrroline (92) has been alkylated and the... 

Scheme 1.11 provides some examples of alkylation of imine and hydrazone anions. Entries 1 and 2 involve alkylation of anions derived from IV-alkylimines. In Entry 1, two successive alkyl groups are added. In Entry 2, complete regioselectivity... 

Nitrones have been generally prepared by the condensation of /V-hydroxylamines with carbonyl compounds (Eq. 8.40).63 There are a number of published procedures, including dehydrogenation of /V,/V-disubstituted hydroxylamines, / -alkylation of imines, and oxidation of secondary amines. Among them, the simplest method is the oxidation of secondary amines with H202 in the presence of catalytic amounts of Na2W04 this method is very useful for the preparation of cyclic nitrones (Eq. 8.41).64... 

Scheme 6.18. Three-component Zr-catalyzed asymmetric alkylation of imines by alkylzincs leads to the formation of optically enriched amines not accessible by alternative methods such as catalytic hydrogenation.

To enhance the efficiency of the cyanide addition, these workers subsequently reported a three-component asymmetric synthesis of amino nitriles that avoids the use of the previously mentioned undesirable stannane [74], Thus, as illustrated in Scheme 6.23, treatment of the requisite aniline and aldehyde with HCN (toxic but cheap and suitable for industrial use) at —45°C in the presence of 2.5 mol% 65 leads to the formation of 67 with 86 % ee and in 80 % yield. As was mentioned above in the context of catalytic asymmetric three-component alkylations of imines (see Scheme 6.18), the in situ procedure is particularly useful for the less stable aliphatic substrates (cf. 71—73, Scheme 6.23). The introduction of the o-Me group on the aniline is reported to lead to higher levels of asymmetric induction, perhaps because with the sterically less demanding aliphatic systems, the imine can exist as a mixture of interconverting cis and trans isomers. 

J. J. Eddine, M. Cherqaoui, Chiral Quaternary Benzo-phenone Hydrazonium Salt Derivatives Efficient Chiral Catalysts for the Enantioselective Phase-Transfer Alkylation of Imines. Application to Synthesis of Chiral Primary Amines , Tetrahedron Asymmetry 1995, 6, 1225-1228. 

The scope of these reactions has not yet been thoroughly investigated. The examples listed in Table 4.17 suggest that azomethine ylides generated by intramolecular, carbene-mediated N-alkylation of imines enable convergent and fast... 

In contrast to earlier known imines, those imines derived from a-(methoxymethyl)benzene-ethanamine, which allow formation of a rigid chelate by additional coordination of the lithium with the methoxy group, enabled the preparation of a-alkylated cyclic ketones in very high enantiomeric excesses (90-99% ee)7,8. However, alkylations of imines derived from medium ring ketones were accomplished in 30-82% ee9. The alkylation of acyclic ketones was performed with enantiomeric excesses of more than 75 % and, in the case of the imine derived from 4-heptanone, proceeded with complete asymmetric induction10. 

Table 7. Chiral Auxiliaries Used in the Asymmetric Synthesis of Carbonyl Compounds by Alkylation of Imines...

In contrast to the variety of chiral auxiliaries which have been used in the asymmetric alkylation of imine-derived azaenolates (see Section 1.1.1.4.1Table 7), alkylations of the hydrazone analogues employ mainly (-)-(S)-l-amino-2-methoxymethylpyrrolidine (SAMP) and its opti-cal antipode (RAMP). r A oCH, O ... 

Additionally, 1,2-dihydroxyethylene dipeptide analogues without the C-terminal carboxylic acid have been used to obtain aspartyl proteases inhibitors.[641 These efforts include stereoselective alkylation of imines, one-pot reductive amination of epoxy ketones, ring opening of epoxides with sodium azide, diastereoselective dihydroxylation of allylic amines, and enzymatic resolution and stereocontrolled intramolecular amidation. 

The last five years have witnessed explosive advances in the development of catalytic enantioselective alkylation of imines. This chapter collects some of the important advances that have taken place during the past few years in catalytic enantioselective alkylation of imines. 

Catalytic Enantioselective Alkylation of Imines with Organozinc Reagents... 

Quite recently, there has been significant expansion and development in the alkylation of imines with organozinc reagents using chiral Lewis acid catalysts. In 2000, Tomioka and co-workers reported a copper(II)-chiral amidophos-phine 4-catalyzed asymmetric process for the addition of diethylzinc to N-sul-fonylimines (Scheme 2) [8]. Excellent enantioselectivities (90-94%) and yields (83-99%) were obtained in reactions of N-sulfonylimines derived from arylal-dehydes. 

Although several excellent examples of the catalytic asymmetric alkylation of imines have been reported, especially in the past few years, the scope of the reactions is still limited with regard to substrate generality, experimental simplicity, catalyst loading, and the enantiomeric purity of the isolated products. Research in this field has just started and further development can be expected in the near future. 

D. E. Bergbreiter and M. Newcombe (1983). Alkylation of imine and enamine salts , in Asymmetric Synthesis, Ed. J. D. Morrison. Orlando, Florida Academic Press. Vol. 2A, p. 243 D. Enders (1984). Alkylation of chiral hydrazones , in Asymmetric Synthesis. Ed. J. D. Morrison. Orlando, Florida Academic Press, Vol. 3, p. 275. 

Reductive carbonylation and alkylation of imines.3 This cobalt carbonyl catalyzes a reaction of imines with organoboranes and carbon monoxide that results in amides. / -Keto amides are obtained from a-keto imines by this reaction. 

Table 7.4 a,a-Dialkylamino acid derivatives by asymmetric alkylation of imines 40a and 40b utilizing salen-Cu(ll) complex 39c. 

Barbier-type C-alkylation of imines can be carried out with alkylstrontium halides generated from strontium metal and alkyl halide.38 IV-Alkylation competes, and RSrI is strongly nucleophilic, as shown by a-alkylation of imines derived from enolizable... 

A variation of the alkylation of imines has been developed188,189. The imine is first converted to the ambident ion by sodium hydride, sodium amide or lithium diisopropy-lamide and an alkylating agent is then added. 

Intramolecular alkylation of imines with cyclopropyl and cyclobutyl groups, such as 36, produces heterocyclic enamines 37190-192. 

Further evidence of these reactivity-steric sensitivity effects is evident in the alkylation of imines of medium-large ring ketones397 (Scheme 202). The larger rings are sign-... 

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