Imines anions, alkylation

Alkylations of hydrazone anions derived from aldehydes and ketones are closely related to imine anion alkylations. Lithiated hydrazones are particularly powerful nucleophiles for alkylation reactions. The alkylated hydrazones may be cleaved with periodate, as shown below.The choice of solvent and base is critical to the success of hydrazone alkylations hexane-free medium is essential for complete metalation. °... 

Ornithine decarboxylase is a pyridoxal dependent enzyme. In its catalytic cycle, it normally converts ornithine (7) to putrisine by decarboxylation. If it starts the process with eflornithine instead, the key imine anion (11) produced by decarboxylation can either alkylate the enzyme directly by displacement of either fluorine atom or it can eject a fluorine atom to produce viny-logue 12 which can alkylate the enzyme by conjugate addidon. In either case, 13 results in which the active site of the enzyme is alkylated and unable to continue processing substrate. The net result is a downturn in the synthesis of cellular polyamine production and a decrease in growth rate. Eflornithine is described as being useful in the treatment of benign prostatic hyperplasia, as an antiprotozoal or an antineoplastic substance [3,4]. 

There are similar reactions involving nitrogen analogs called imine anions. The alkylated imines can be hydrolyzed to the corresponding ketone, and this reaction is discussed in Section 1.3. 

Just as enamines are more nucleophilic than enol ethers, imine anions are more nucleophilic than enolates and react efficiently with alkyl halides. One application of imine anions is for the alkylation of aldehydes. 

Ketone imine anions can also be alkylated. The prediction of the regioselectivity of lithioenamine formation is somewhat more complex than for the case of kinetic ketone enolate formation. One of the complicating factors is that there are two imine stereoisomers, each of which can give rise to two regioisomeric imine anions. The isomers in which the nitrogen substituent R is syn to the double bond are the more stable.114... 

One of the potentially most useful aspects of the imine anions is that they can be prepared from enantiomerically pure amines. When imines derived from chiral amines are alkylated, the new carbon-carbon bond is formed with a bias for one of the two possible stereochemical configurations. Hydrolysis of the imine then leads to enantiomerically enriched ketone. Table 1.4 lists some examples that have been reported.118... 

In a related approach, Whitesell and Whitesell191 and others192 have examined the alkylation of the analogous imine anions (108) where bulky ligands about the metal are in a chelated form. 

Ketones can be prepared by addition of Grignard reagents to nitriles, followed by hydrolysis of the initially formed imine anion. Many ketones have been made in this manner, though when both R groups are alkyl, yields are not high. Yields... 

Imine anions are superior to the corresponding enolate anions of the parent carbonyl compounds in alkylation reactions because they give only monoalkylated products of predictable regioselectivity. They can be prepared from aldehyde imines as well as from ketone imines by deprotonation with EtMgBr, LDA, or t-BuLiA ... 

The effect of steric strain in the imine anion assures good regiochemical control for alkylation. ... 

Imines derived from benzylamine and a,3-unsaturated ketones which represent 1-azadiene systems can be isomerized to the corresponding 2-azadienes with potassium t-butoxide. Addition of r-butyl-lithium occurs smoothly to afford simple imine anions that undergo alkylation in the usual fashion. 3S The two examples provided in Scheme 17 illustrate the power of this method to provide either a,a- or a,a -substitution. On the other hand, reaction of similar 1-azadiene systems with Grignard reagents results in addition to form the imine anion directly (equation 44). This example represents one of the early contributions to asymmetric induction in this area and will be elaborated in Section 4.1.3.5. 

The synthetic implications of carbon-carbon bond formation via imine anions gained additional significance with the first report by Horeau of asymmetric induction in the alkylation of the anion derived from isobomylamine and cyclohexanone. However, the degree of stereochemical control in the formation of 2-meAylcyclohexanone by this process (72% ee) was below the synthetically useful level. Additionally, incorporation of other alkyl groups afforded even lower levels of asymmetric induction. Further studies by Yamada with a variety of chiral amines did not improve on these results. ... 

Similar studies have been carried out for control of absolute stereochemistry in the alkylation of aldehydes via imine anions. Fraser examined the reactions of the imine anion derived from a-phenylethyl-amine with lithium as the counterion where optimum conditions aftbrded approximately 70% optical... 

The basic concept, although most likely not the detailed mechanism, of the Enders asymmetric induction follows from the chelation-controlled asymmetric alkylation of imine anions introduced by Meyers and Whitesell. The hydrazones derived from either the (5)- or the (/ )-enantiomer of iV-amino-2-methoxymethylpyrrolidine (SAMP and RAMP, derived from the amino acid proline) can be converted to anions that undergo reaction with a variety of electrophiles. After hydrolysis of the product hydrazones, the alkylated ketones can be obtained with good to excellent levels of optical purity (Scheme 19). 

Recent research by Bergbreiter, Newcomb, Meyers and their respective coworkers has shown that a variety of factors, such as the base, the temperature of deprotonation, and the size of the substituent on nitrogen, control the structure of the metallated imine and ultimately the regiochemistry of the alkylation reaction. In contrast to metal enolates, where the more-substituted species is usually the more thermodynamically stable, less-substituted sy/i-metallated ketimines, e.g. (89), are the most thermodynamically stable of the possible isomers of unsymmetrical systems. An explanation for the greater stability of syn imine anions compared with anti imine anions has been presented by Houk, Fraser and coworkers. ... 

Ironically, species such as (89 M Li) are also the major isomers obtained when unsymmetrical ke-timines are deprotonated with LDA at -78 There is a kinetic preference for deprotonation anti to the substituent on nitrogen. At very low temperatures, deprotonations with LDA occur at the less-substituted carbon atom via the less stable (Z)-imine. Rearrangements then occur to the syn, less-substituted imine, which is in turn alkylated. On the other hand, deprotonations conducted at -23 to 0 C with LDA are faster than imine isomerization and the imine anion mixture composition reflects the ( ) (Z) ratio of the starting imine. Anti-syn imine anion isomerization occurs to give predominately the more-substituted fyn-metallated imine (cf. 90), which then undergoes alkylation. These results are summarized in Scheme 46 using the f-butylimine of 2-butanone as an example. 

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