Imines, carbanions, reaction with

The reductive couphng of imines can follow different pathways, depending on the nature of the one-electron reducing agent (cathode, metal, low-valent metal salt), the presence of a protic or electrophihc reagent, and the experimental conditions (Scheme 2). Starting from the imine 7, the one-electron reduction is facihtated by the preliminary formation of the iminiiim ion 8 by protonation or reaction with an electrophile, e.g., trimethylsilyl (TMS) chloride. Alternatively, the radical anion 9 is first formed by direct reduction of the imine 7, followed by protonation or reaction with the electrophile, so giving the same intermediate a-amino radical 10. The 1,2-diamine 11 can be formed from the radical 10 by dimerization (and subsequent removal of the electrophile) or addition to the iminium ion 8, followed by one-electron reduction of the so formed aminyl radical. In certain cases/conditions the radical 9 can be further reduced to the carbanion 12, which then attacks the... 

It is assumed that the mechanism proceeds via activation of the imine by the ruthenium catalyst (structure 169), followed by reaction with ethyl diazoacetate to generate a metal-bound ylide intermediate. Intramolecular ruthenium- assisted attack of the carbanion 170 onto the iminium ion provides the corresponding aziridine with moderate to high // selectivity. Imines bearing electron-donating groups (R2) showed significant rate enhancement. 

However, difluoromethylation occurs when nucleophiles intercept difluoro-carbene generated under basic conditions, providing a route to difluoromethyl-ethers of phenols [33] and thiophenols [34]. The reaction with phosphite anion leads to the corresponding difluoromethyl phosphonate (see Sect. 2.3.2) while nucleophilic carbanions such as alkynes [35] also undergo formal alkylation, as do malonates [36,37]. An -difluoromethylaziridine was reported in a reaction with a glycine imine [38]. The scope of the established chemistry is summarised in Fig. 1. Bromodifluoromethylation occurs with a similar range of nucleophiles [39,40], and also with carbonyl-stabilised carbanions such as malonates [41,42]. 

The macrocyclization reaction proceeds by an analogous route when bifunctional methylene compounds, e.g., diethylmalonate, were used as cross-linking agents [133]. In this case as with nitromethane, the attacking imine carbanion is also formed under basic conditions. The diethoxycarbonylethylamine resulting from the addition of the carbanion to the coordinated imine undergoes two intramolecular condensations to a produce macrobicyclic structure (Scheme 107). 

Another type of reaction relying on the same fundamental mechanism involves organolithium compounds <85JA4700>. The general scheme is depicted in Equation (29). The vinyl carbanion product isomerizes rapidly even at — 70 °C, hence a mixture of ( ) and (Z) isomers is obtained upon reaction with electrophiles. This kind of chemistry has been used to prepare some unusual phos-phino-l,2,3-butatrienes (Equation (30)) <92SL635>. Formally involving an hydride ion and related to the same scheme is the reaction of a phosphirene imine with a borane complex (Equation (31)) <94CB313>. 

Carbonyl compounds and imines are the electrophilic partner of isocyanides in the Passerini-3CR and the Ugi-4CR, respectively. Other highly electrophilic multiple bonds, such as in dimethyl acetylenedicarboxylate (DMAD), are also known to react with isocyanides. The initially formed 1 1 zwitterionic species having carbanion, carbene character can undergo further reaction with DMAD and isocyanides in different molar ratios, leading to a variety of heterocyclic systems (Scheme 5.32) [69]. 

F.ii. Hydrazone Carbanions. Corey and Endersl introduced an alternative to Wittig s imine-carbanion methodology discussed in Section 9.4.F.i. Changing the imine to a hydrazone unit led to a more controllable and useful reaction. A,A-Dimethylhydrazone 313 was formed by reaction of 2-methylcyclo-hexanone and dime thy Ihydrazine. Subsequent reaction with LDA was followed by addition of methyl... 

Diastereoselectivity is also observed in reactions of carbanions derived from imines and hydrazones, when those species contain a chiral center or a chiral auxiliary (sec. 9.4.F). Asymmetric imines can be used, and chiral oxazoline derivatives have also been prepared and used in the alkylation sequence (sec. 9.3.A). Meyers showed that chiral oxazoline 478 could be alkylated to give the ethyl derivative, 479. A second alkylation generated the diastereomeric product 480, and hydrolysis provided the chiral lactone (481) in 58% yield and with a selectivity of 70% ee for the (R) enantiomer. 53 As pointed out in Section 9.4.F.ii, hydrazone carbanions can be used for alkylation or condensation reactions. In a synthesis of laurencin. Holmes -l prepared the asymmetric hydrazone 483 (prepared by Enders by reaction of cycloheptanone and the chiral hydrazine derivative called SAMP, 482-A-amino-(2S)-(methoxymethyl)pyrrolidine)- - and showed that treatment with LDA and reaction with iodomethane gave an 87% yield of the 2-ethyl derivative in >96% de. Ozonolysis cleaved the SAMP group to give (/ )-2-ethylcycloheptane (484) in 69% yield. The enantiomer of 482 is also known (it is called RAMP, A-amino-(27 )-(methoxymethyl)pyrrolidine). 

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