Azomethines nucleophilic addition reactions

With heterocycles containing an sp--nitrogen atom, a totally different problem can occur, namely nucleophilic addition of the base to the azo-methine (C=N) bond. The use of very sterically hindered bases such as lithium tetramethylpiperidide (LiTMP) can prevent this type of addition in certain cases, but bases of this sort tend to be expensive and not suitable for general use. However, two different approaches to overcoming the problem of azomethine addition have been developed over the years, both relying on the fact that the addition is temperature dependent, and that by enabling metalation reactions to be performed at low temperatures, the desired carbanion formation can often be achieved. 

QUINAPHOS ligands are usually synthesized in a one-pot-procedure from readily available 8-substituted quinolines [8] via nucleophilic addition of a lithium reagent [9] to the azomethinic double bond and direct quenching of the resulting 1,2-dihydroquinoline amide 1 with a phosphorochloridite derived from enantio-merically pure binaphthol (1) or from 3,3 -di-t-butyl-5,5 -dimethoxybiphenyl-2,2 -diol (m) [10] (Scheme 2.1.5.1, Method A). Alternatively, the anion 1 can be reacted with an excess (in order to avoid multiple substitution) of phosphorous trichloride to obtain the corresponding phosphorous dichloridite 2, which can be isolated (Scheme 2.1.5.1, Method B). In a second step, 2 is converted into 4 by reaction with the desired diol in the presence of triethylamine. 

Evidently, the stability of 3-hydroxy-3,4-dihydroisoquinolines 137, formed as the result of heterocyclization, is also determined by the anne-lated benzenoid ring. The lower tendency toward aromatization for these compounds, compared to monocyclic analogs, leads to the ability of 137 to react as a cyclic azomethine. The addition of a molecule of nucleophile to the C=N bond causes opening of the isoquinoline ring and formation of a new ring system (for instance, a-naphthols 141 in alkaline aqueous solutions). Such conversions occur even under conditions of the recyclization reaction of 2-benzopyrylium salts, namely, on heating 137 in alcoholic ammonia a mixture of isoquinoline 138 and a-naphthylamine 140 results (88MI1). 

Another type of mechanism operates in the synthesis of amino acids by electrore-ductive coupling of alkyl halides with Schiff bases in DMF in these reactions the alkyl halide chosen is reduced at less negative potentials than the azomethine derivative of an a-ketoester, and the coupling is proposed to be a nucleophilic addition of an alkyl anion [Eq. (7)] to the azomethine compound, [Eq. (8)] the benzyl group is afterward reductively removed [32,33] ... 

The general modes of reactivity concerning nucleophilic or electrophilic additions to the polarized C=N bond are indicated in Scheme 2. Nucleophilic reagents can add to the carbon atom of the azomethine linkage (a reaction that is promoted by coordination of the oxime, in particular via the N-atom), whereas electrophilic reagents can attack the O- or the N-sites. 

Each of the approaches reported thus far to these rare ring systems appears rather promising. The nucleophilic addition/cyclization and [3,3]-rearrangement routes appear potentially well-suited for the rather general preparation of substituted analogues. The azomethine ylide route will presumably be somewhat limited in scope, given the basic reaction motif and its structural requirements, while the bicyclic thione rearrangement route will perhaps be of some use for the preparation of specialty compounds related to (54). 

This study prompted us to examine stmcturally distinct azomethine imines. The reaction of a C,A-cyclic azomethine imine not fused to the aromatic ring, which was generated in situ from 37 in the presence of a base, was conducted with t-butyl isocyanide (35a) to afford a cyclized product 38 in 81% yield (Eq. 11.15). On the other hand, the AJV -cyclized azomethine imine 11a, which geometrically could not afford the iminoxadiazinone derivatives, did not react with the isocyanide 35a even under dichloromethane reflux conditions (Eq. 11.16). These results suggested that the direction of the amidocarbonyl oxygen was crucial to promote the nucleophilic addition of isocyanide. 

The polarographic method, as is now known, makes it possible to ascertain the differences in properties and the structural characteristics of the C = N bond, and can be used for comparative investigation of carbonyl compound derivatives. Polarographic data hence allow characterization of reactivity of azomethine compounds in such simple reactions as nucleophilic additions of an electron. However, in the course of application of polarography it was possible to find certain limitations, arising either from chemical reactions of the azomethines in the investigated solutions or from their adsorbability at the dropping mercury electrode. 

It is of some interest to speculate briefly oonocming the nature of the peracid-imine reaction. It xb quite possible that this reaction is analogous to the epoxidation of olefins with peracids and involves a similar oydks transition state (X). An equally attractive if less obvious possibility is that the imine reaction proceeds through addition of the peracid to the azomethine followed by internal nucleophilic displace ment of the basic nitrogen atom on the peroxide bond. This reaction... 

Besides the 1,3-dipolar cycloaddition of azomethine ylides to C60, the Bingel cycloprop anation reaction is widely used for regioselective functionalization of fullerenes. In principle, this versatile modification involves the generation of carbon nucleophiles from a-halo esters and their subsequent addition to C60 [19]. The addition takes place exclusively on double bonds between two six-membered rings of the fullerene skeleton, yielding methanofullerenes. As shown in Scheme 2, addition of diethylbromomalonate to C60, in the presence of an auxiliary base... 

While the abstraction of protons adjacent to the carbon-nitrogen double bond of imines/imine derivatives has been utilized for tiie regioselective generation of azaallyl anions (which are useful in asymmetric ketone synthesis), it competes with and often prevents the addition of nucleophiles to imines. For this reason, imine additions often involve azomethines (e.g. benzylidineanilines) which are not capable of enolization. Many potentially useful additions, however, involve substrates capable of proton abstraction. By avoiding in certain instances some of the structural features of imines/imine derivatives and the reaction conditions responsible for proton abstraction, products resulting from this serious side reaction can be minimized. 

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