Imine and Hydrazone Anions

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... 

Ketone dilithio-c /S-dianions (30, formed by treatment of /3 -stannylketones, RCOCH2-CH2SnBuCl2, with 4 equiv. of BuLi) react with imines and hydrazone selectively at the /3-anion portion to give dilithium enolate amides (31).82 Subsequent reaction with electrophiles gives y-amino ketones and related heterocycles. 

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. °... 

The synthetic uses of hydrazones and oximes for carbon-bond formation differ little from those of imines as their anions represent enolate equivalents except for certain methods that have been developed for asymmetric induction. Conversely, the formal replacement of the carbon substituent of imines by a heteroatom (nitrogen for hydrazones and oxygen for imines) opens reaction pathways such as the Beckmann rearrangement of oximes and the Wolff-Kishner and Shapiro reductions of hydrazones that have no analogy in the chemistry of imines. 

Many of the same features of imine and imine anion structure previously discussed (Section 4.1.3.2) are apparent with hydrazones and their anions and with oxime ether anions. A number of investigations of the structure of A A -dialkylhydrazone and oxime ether anions as well as oxime dianions have been carried out. Most notable are the experimental studies of Collum and Clardy, " and the theoretical treatment by Glaser and Streitwieser. As might be expected, and as was observed for lithiated imine anions iyida supra), lithiated hydrazones exist in the solid as aggregates, with two lithiums coordinated to the aza anion system (Figure 3). ... 

The application of hydrazone and oxime anions for carbon-carbon bond formation generally offers no advantages to the use of imine anions and, significantly, the hydrolysis of the hydrazone or oxime products to form the product carbonyl group is substantially more difficult than is the cleavage of an imine. The notable exception is in the area of asymmetric induction where powerful direction has been obtained with chiral hydrazone anions. This area has been explored fully by Enders following initial observations of Enders and Corey.2 Enders has recently reviewed these contributions. ... 

Cathodic reduction consists of electron supply from the cathode, followed by acquisition of protons by anionically charged substrates. Thus, ready accessibility of the reductive electron transfer processes leads to a variety of reactions, including reductive abstraction of halogens [13, 14], reduction of alcohols to alkanes [15], reduction of imines, oximes, and hydrazones to the corresponding amines [16], and conversion of nitro groups to the corresponding nitroso, hydroxy amino, and amino groups [17]. In... 

The SAMP and RAMP hydrazone anions also undergo Michael additions with excellent asymmetric induction at the electrophilic carbon. (Note that the configuration of the imine is unimportant— the LDA deprotonates exclusively at the methyl group.)... 

Organomagnesium compounds react with imines, prepared from 3-methoxy-2-naphth-aldehydes by a 1.4-addition mechanism. This reaction can be performed with high diastere-oselectivity. The method was applied for the synthesis of optically pure S-tetralones . Vinyhnagnesium bromide reacts as an acceptor with a ketone dimethyl hydrazone zincate 207, yielding a 1,1-bimetallic species, which can be reacted sequentially with two different electrophiles (equations 131 and 132) . The reaction proceeds via a metalla-aza-Claisen rearrangement, where the dimethylhydrazone anion behaves as an aza-allylic system . 

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). 

The use of hydrazines as chiral auxiliaries was initiated by Enders and coworkers [315]. They have developed the chemistry of hydrazones derived from epimeric 1 -amino-2-methoxymethylpyrrolidines 1.76, Samp and Ramp [161, 169, 253, 261, 315, 316], These compounds are commercially available, or they can easily be prepared from (S)-prolinol 1.64 (R = CH2OH) or (R)-glutamic add [261]. Hydrazones have some advantages over their related imine derivatives. First, they are formed in quantitative yield even from sterically hindered ketones. Second, their derived anions are often more reactive than the related aldehyde or ketone enolates. 

---