2- Azaallyl anions

Closely related to the 1,4-additions of enolates are the reactions of 1- and 2-azaallyl anions. 

This method is complementary to the anti-selective Michael route to 3-substituted glutamates using 2-azaallyl anions derived from alkylidene protected glycine (see Section 1.5.2.4.1.1.). 

In general, metalated 2-azaallyl anions derived from imines of a-amino esters serve both as Michael donors and as 1,3-dipolar reagents the course of the reaction, as well as the stereochemical outcome depends upon the base and the reaction conditions82,83. 

Table 5. 3-Substituted Glutamates from the Addition of 2-Azaallyl Anions to Enones84...

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... 

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 deprotonation of Af-alkyl imines 1 with LDA to give 2-azaallyl anions 2 is a well-known reaction34 At least one stabilizing substituent R2 such as phenyl35 or alkoxycarbonyl36 at the carbon atom is necessary to achieve the deprotonation. The deprotonation of iV-benzylimines, which contain no acidic a-protons in the R1 group proceeds under relatively mild conditions37-38. 

The 2-azaallyl anions 2 obtained were used for 1,3-dipolar cycloadditions mostly to give five-membered rings 3, but reaction with electrophiles at the former A-alkyl carbon atom to give 4 has also been described. 

Heating /V-lithioaziridines provides 2-azaallyl anions, which undergo concerted cycloaddition reactions with certain alkenes and other anionophiles (Scheme 39) (74AG(E)627, B-88MI101-02). 

Figure 15.2. Formation of pyrrolidines by cycloaddition of 2-azaallyl anions to alkenes.

Table 15.5. Preparation of pyrrolidines from 2-azaallyl anions.

The azomethine-azomethine isomerization of 14 to 15 proceeds essentially intramolccular-ly (> 98 %), as shown by the reaction of ketimine 14h in a solution of triethylamine/methanol-r/4 (1 1), which gives 15h in 93% yield with less than 2% incorporation of deuterium in the product.14 The intermediate 2-azaallyl anion 12 apparently exists as a contact ion pair. 

Assuming a mechanism involving intermediate 2-azaallyl anion 12, substitution on the phenyl ring of the A-benzyl group should influence the rate of isomerization and the position of the equilibrium between 14 and 15. In order to test this, substituted A-benzylimines of benzyl trifluoromethyl ketone have been prepared and isomerized (see Table 4).1517... 

Azaallyl anion cycloadditions. Imines bearing one or more aryl groups are converted by LDA into 2-azaallyl anions. These anions undergo cycloaddition not only with activated alkenes,2 but can also undergo intramolecular cycloaddition with a double bond to form as-fused bicyclic pyrrolidines.3... 

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. 

The Pearson syntheses of (—)-augustamine and (—)-amabiline by a common strategy are very noteworthy. They brilliantly show how the awesome power of intramolecular 2-azaallyl anion-olefin cycloadditions can be marshalled for the rapid assembly of complex pyrrolidine alkaloids with excellent efficiency and atom economy. 

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