2-Azaallyl anions generation

Azaallyl anions, generated by treatment of arylmethylidene(arylmethylamines) with lithium diisopropylamide (LDA), react with 2-halogenopyridines to give a variety of substituted [l,7]naphthyridines (Scheme 47) <1995J(P1)2643>. 

The azaallylic anion generated from the substrate 15 underwent alkylation to provide the intermediate 16, which could be cyclized to the 1-pyrrolines 17. Treatment of the latter with methoxide eventually gave the pyrrole 18 (Scheme 2) <2001JOC53>. 

Azaallyl anion cycloadditions (13, 163).4 Nonstabilized 2-azaallyl anions (1) are readily generated by transmetallation of N-(trialkylstannyl)methylimines, prepared as shown in equation I, with a base such as butyl- or methyllithium. The... 

The use of lithium amides to metalate the a-position of the N-substituent of imines generates 2-azaallyl anions, typically stabilized by two or three aryl groups (Scheme 11.2) (48-62), a process pioneered by Kauffmann in 1970 (49). Although these reactive anionic species may be regarded as N-lithiated azomethine ylides if the lithium metal is covalently bonded to the imine nitrogen, they have consistently been discussed as 2-azaallyl anions. Their cyclization reactions are characterized by their enhanced reactivity toward relatively unactivated alkenes such as ethene, styrenes, stilbenes, acenaphtylene, 1,3-butadienes, diphenylacetylene, and related derivatives. Accordingly, these cycloaddition reactions are called anionic [3+2] cycloadditions. Reactions with the electron-poor alkenes are rare (54,57). Such reactivity makes a striking contrast with that of N-metalated azomethine ylides, which will be discussed below (Section 11.1.4). 

Note that Pearson has extended the classical anionic [3 + 2] cycloadditions to allow the generation of nonstabilized 2-azaallyl anions, and has successfully applied this methodology to the held of alkaloid total synthesis. A key discovery was that (2-azaallyl)stannanes are capable of undergoing tin-lithium exchange to generate the nonstabilized anions (63-76), which can be trapped either intramole-cularly or intermolecularly with unactivated alkenes to produce pyrrolidines, often in a stereoselective fashion. Thus, a variety of 2-azaallyl anions are accessible by his method. A few examples of Pearson s contributions are illustrated in Scheme 11.3 (70,76). 

N-Unsubstituted azomethine ylides may be generated thermally (79), and the N-metalated, 2-azaallyl anion versions may be generated by action of nonmetalhc bases such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) on certain imines (80). Although they are assumed to show similar chemical properties, these two species usually show different reaction patterns, as shown in Scheme 11.7, where the regio-and stereoselectivities of the cycloadditions are quite different (24,78-80). Metala-tion of (alkylideneamino)acetonitriles can be performed with metallic bases other than LDA. Thus, butyllithium, ethylmagnesium bromide, and magnesium bromide-diisopropylamide are also effective (78). The N-magnesioazomethine... 

In more recent times, 2-azaallyl anions have been much more conveniently generated by the transmetallation of 1-aminoalkylstannanes. Thus for the forward synthesis of (—)-augustamine, this would mean that the 2-azaallylstannane 5 would be the key intermediate needed. 

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. 

Diaryl-2-thiazolines (331) are synthesized by reaction of l,3-diaryl-2-azaallyl anions (330) with 0-ethyl thiocarboxylates (Scheme 83). The anions (330) are generated in situ from imines <95SL809>. 

Pentasubstituted 2-fluoropyridines 66 were prepared by the reaction of perfluor-oalkene 65 with A-silyl-l-azaallyl anion 64, generated by coupling of a functional silane 62 and aryl/alkyl nitrile 63 using -BuLi in tetrahydrofurane" (Scheme 6.22). 

Reaction of vinyltrimethylsilane with the nonstabUized 2-azaallyl anion (19), generated in situ from the (2-azaallyl)stannane (18) (eq 10), produces, after quenching with Mel, the p5nrolidine (20) as a single diastereomer in 77% yield (eq 11). Some evidence suggests that the cycloaddition is stepwise and that the W-conformation of the anion predominates in the cycloaddition sequence. 

The previous cycloaddition reaction discussed is believed to proceed through an aldimine anion (19). Such delocalized anions can also be generated by treatment of suitable aldimines with a strong base. Subsequent cyclocondensation with a nitrile produces imidazoles [25-28]. The 2-azaallyl lithium compounds (19) are made by treatment of an azomethine with lithium diiso-propylamide in THF-hexane ( 5 1) (Scheme 4.2.9) [29. To stirred solutions of (19) one adds an equimolar amount of a nitrile in THF at —60°C. Products are obtained after hydrolysis with water (see also Section 2.3). If the original Schiff base is disubstituted on carbon, the product can only be a 3-imidazoline, but anions (19) eliminate lithium hydride to give aromatic products (20) in 37-52% yields (Scheme 4.2.9). It is, however, not possible to make delocalized anions (19) with R = alkyl, and aliphatic nitriles react only veiy reluctantly. Examples of (20) (Ar, R, R, yield listed) include Ph, Ph, Ph, 52% Ph, Ph, m-MeCeUi, 50% Ph, Ph, p-MeCeUi, 52% Ph, Ph, 3-pyridyl, 47% Ph, Ph, nPr, 1% [25]. Closely related is the synthesis of tetrasubstituted imidazoles (22) by regioselective deprotonation of (21) and subsequent reaction with an aryl nitrile. Even belter yields and reactivity are observed when one equivalent of potassium t-butoxide is added to the preformed monolithio anion of (21) (Scheme 4.2.9) [30]. 

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