Azaallyl anions, cycloaddition

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... 

This cycloaddition can be performed with either the amino acid, the aldehyde, or the electron-poor alkene linked to the support. Intramolecular azaallyl anion cycloadditions have been used to prepare polycyclic systems on solid phase (Entries 5 and 7, Table 15.5). 

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... 

Peal997 Pearson, W.H. and Clark, R.B., Solid Phase Synthesis of Pyrrolidines Via 2-Azaallyl Anion Cycloadditions widi Alkenes, Tetrahedron Lett., 38 (1997) 7669-7672. 

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... 

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.

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. 

Cycloaddition of nonstabilized 2-azaallyllithiums (2-azaallyl anions) and azomethine ylides with alkenes to form pyrrolidines and its application to alkaloid total synthesis 03SL903. 

Azaallyl anions with lithium as the cation have been found to undergo efficient and often stereoselective [3 + 2] cycloadditions both inter- and intramolecularly with a wide range of olefins11. This transformation amounts to a very versatile synthesis of substituted pyrrolidines... 

Highly reactive non-stabilized 2-azaallyl anions (48) have been found to react with alkenes by efficient 3 + 2-cycloaddition to form 1-pyrrolines (50) after loss of LiX from intermediate (49)7 The 1-pyrrolines are deprotonated under the reaction conditions to give 1-metalloenamines which can be trapped by electrophiles. 

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. 

Also, a [3+2] cycloaddition reaction of thioketene -oxides with 2-azaallyl anions 76 affords ionic cycloadducts, which after acidification give the heterocycle 77 . 

The anionic [2+3] cycloaddition of l,3-diphenyl-2-azaallyl lithium 325 with DCC gives the cycloadduct 326, which reacts with another equivalent of E)CC to form the final product 327 ... 

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]. 

Among the cycloaddition reactions which lead to imidazole products is the [3 + 2] cycloaddition of imines to 2-azaallenyl radical cations (derived from azirines by photolysis) which yields 1-substituted imidazoles <91AG(E)1336,93CB543). Similar addition of 2-azallyl anions (made by deprotonation of A-alkylated Schilf bases) to aromatic nitriles can give rise to either 3-imidazolines or imidazoles depending on the substitution pattern in the azaallyl species (229) <83CB492>. These reactions have been reviewed (Scheme 164) <90CHE1>. 

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