Imines lithiated

In contrast to the amt-selective reaction of lithiated imines with aldehydes, titanated imines, prepared by transmetalation of the corresponding lithium azaenolates, give predominantly. sFH-adducts2. 

While the steric explanation is consistent with the observed selectivity, it nonetheless presents an incomplete explanation, as alkylation of 2-methyl-4-cyano-l,3-dioxane 17 also proceeded with very high syn-selectivity [11] (Eq. 5). The selective equatorial alkylation can be rationalized as an anfz-anomeric effect that disfavors axial alkylation of the ketene iminate through filled-shell repulsion. Simple lithiated nitriles are known to exist as ketene iminates, but it would be easy to rationalize the preference for equatorial alkylation by considering the relative stability of hypothetical equatorial and axial alkyllithium reagents, vide infra. Preferential equatorial alkylation was also observed by Beau... 

Imidazolidine-2-thiones functionalised on the four-position can be obtained by reaction of HN(CH3)R with n-butyllithium, followed by addition of carbon disulfide. The lithium thicarbamate can then by further lithiated and cyclisation occurs upon reaction of this species with an imine (S) [22],... 

Spectroscopic investigations of the lithium derivatives of cyclohexanone (V-phenylimine indicate that it exists as a dimer in toluene and that as a better donor solvent, THF, is added, equilibrium with a monomeric structure is established. The monomer is favored at high THF concentrations.110 A crystal structure determination was done on the lithiated A-phenylimine of methyl r-butyl ketone, and it was found to be a dimeric structure with the lithium cation positioned above the nitrogen and closer to the phenyl ring than to the (3-carbon of the imine anion.111 The structure, which indicates substantial ionic character, is shown in Figure 1.6. 

A thorough study of the factors affecting the rates of formation of lithiated imines from cyclohexanone imines has been carried out.117 Lithiation occurs preferentially anti to the /V-subsiiiueni and with a preference for abstraction of an axial hydrogen. 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

The temperature at which a cycloaddition reaction of a neopentylsilene takes place (detected by the elimination of LiCl) has turned out to be dependent on the reaction partners added as substrate. This implies that an interaction between the substrate and A or B or the substrate and C occurs somewhere along the reaction pathway depicted above. For the system Cl3SiCH=CH2/LiBut/R2C=NR it was observed that the imine initiates and supports the salt elimination from the species A/B. Based on the knowledge that silenes are stabilized by external donors [1] we conclude that with carbon unsaturated compounds x-donor interactions instead of cr-donor complexes may be possible as well for the lithiated species (D) as for the silene itself (E). 

The preparation of chiral isoquinoline derivatives continued to be investigated. Sulfanamide 59 was prepared by addition of a lateral lithiated o-toluonitrile with the corresponding sulfinimine. Treatment of 59 with MeLi followed by acidification afforded cyclic imine 60. Reduction of imine 60 with liAlHi/MejAl afforded the trans-1,3 derivative, and... 

Many other examples, even with less reactive imine precursors as electrophiles, demonstrate that this type of dihydropyrrole synthesis has a very broad range. Eqs 8.21-8.24 present selected examples of the addition of lithiated methoxyallene 42 to... 

The efficient addition-cyclization sequence described above could be successfully applied to the preparation of the polyhydroxylated y-amino acid (-)-detoxinine [73], The crucial key step in this fairly short synthesis is the chelate-controlled addition of lithiated benzyloxyallene 120 (R = Bn) to the chiral N-benzyl-substituted imine 121 as shown in Scheme 8.31. The required skeleton of the natural product was generated in good overall yield. 

Terminal trimethylsilylacetylenes are deprotonated at the propargylic position by using sBuLi to yield a lithiated species which undergoes transmetallation with ZnBr2 to afford the allenylzinc reagent (Eq. 9.125) [99]. Additions to a-alkoxyalde-hydes are relatively unselective (Table 9.48), whereas additions to a-alkoxy imines are highly anti selective (Eq. 9.126). 

Addition of the lithiated allene to an imine yielded a mixture of four diastereoisomers (ratio 68/17/12/3 68% ds) which was subjected to a silver nitrate induced cyclization. Product 145 derived from major diastereoisomer 144 was isolated and further converted to (-)-preussin (Scheme 36). 

This acidity means that even iodopyrimidines and iodopyrazines may be lithiated because hindered, non-nucleophilic lithium amide bases will deprotonate them. For example, the base 244, which is easily made by BuLi attack on the imine, deprotonates 243 a to N rather than ortho to and the lithiation of 245 with LiTMP is also successful (Scheme 121). ... 

Laterally lithiated tertiary amides are more prone to self-condensation than the anions of secondary amides, so they are best lithiated at low temperature (—78 °C). N,N-Dimethyl, diethyl (495) and diisopropyl amides have all been laterally lithiated with aUcyllithiums or LDA, but, as discussed in Section I.B.l.a, these functional groups are resistant to manipulation other than by intramolecular attack" . Clark has used the addition of a laterally lithiated tertiary amide 496 to an imine to generate an amino-amide 497 product whose cyclization to lactams such as 498 is a useful (if rather low-yielding) way of building up isoquinoline portions of alkaloid structures (Scheme 194) ". The addition of laterally lithiated amines to imines needs careful control as it may be reversible at higher temperatures. ... 

These reactions have been used in the synthesis of aikaioids such as corydalic acid methyi ester 502 (Scheme i95). Isoiated from Corydalis incisa, 502 is derived from a proposed biosynthetic intermediate in the route to the tetrahydroprotoberberine aikaioids. The 1,2,3,4-tetrasubstituted ring of 502 demands control by an ortholithiation strategy, and the synthetic route proposed by Clark and Jahangir employs a lateral lithiation of 503 and addition to an imine as the key disconnection at the centre of the molecule. 

The directing effect of the amide group can then be used a second time in the lateral lithiation of 503 to give an organolithium 507 which adds to the imine 508 in a stereoselective manner, probably under thermodynamic control (imine additions of laterally lithiated amides appear to be reversible). Warming the reaction mixture to room temperature leads to a mixture of 509 and some of the (ultimately required) cyclized product... 

Aldehydes can also be laterally lithiated if protected as imidazolidines (527) or as imines (528)". With imines, LUMP must be used to prevent nucleophilic addition to C=N (Scheme 207). 

The naphthalene-catalyzed (3%) lithiation of carbamoyl or thiocarbamoyl chlorides 91 in the presence of carbonyl componnds or imines as electrophiles in THF at temperatnres ranging between —78 to 20 °C led to the expected fnnctionalized amides or thioamides 92 after hydrolysis (Scheme 39) . ... 

Another type of acyllithium synthons was generated in situ from chloroimines. The naphthalene-catalyzed (4%) lithiation of chloroimines 93 in THF at —78 °C was followed by filtration of the excess of lithium, being then treated with an electrophile and finally hydrolyzed, to yield functionalized imines 94 (Scheme 40) . ... 

A particular case for the generation of a y-substimted organolithium compound, derived from an imine, was used for the synthesis of 2-substituted pyrrolidines. DTBB-catalyzed (5%) lithiation of y-chloro imines 196 yielded, after hydrolysis, 2-substituted pyrrolidines 198, including nomicotine (R = H, R = 3-pyridyl). The corresponding y-nitrogenated organolithium intermediate 197 was probably involved (Scheme 68). ... 

Phenone imines 587 were lithiated with lithium and a catalytic amount of naphthalene (8%) in the presence of different carbonyl compounds as electrophiles in THF at temperatures ranging between —78 and room temperature, giving, after hydrolysis with water, the corresponding 1,2-aminoalcohols 588 (Scheme 154). ... 

When, instead of aldehydes, A-tosyl imine 196 is used as an electrophile in a reaction with lithiated methoxyallene 183, allenyl imines 197 result. As shown in Scheme 26, they can be converted into pyrrole derivatives 198 and 199"" . 

Gaul and Seebach showed that lithiated methylthiomethyl-substituted chiral oxazolidi-nones react with aldehydes, ketones, imines and chalcones (Scheme 41). In this case, the oxazolidinone is derived from diphenylvalinol. The products, with two new asymmetric centers, are formed in good yield and excellent diastereoselectivity.A detailed mechanistic study of this and related systems, using computational methods, IR and NMR... 

However, the syn and anti isomers of imines are easily thermally equilibrated. They cannot be prepared as single stereoisomers directly from ketones and amines so this method cannot be used to control regiochemistry of deprotonation. By allowing lithiated ketimines to come to room temperature, the thermodynamic composition is established. The most stable structures are those shown below, which in each case represent the less substituted isomer. 

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). 

Titanium ylides are generated from imine esters with titanium isopropoxide chlorides and amines or by transmetalation of the N-lithiated ylides (90,91). The regioselectivity of their reactions with methyl acrylate is opposite to that normally observed (90). A transition state is proposed in Scheme 11.13 to explain this alternative regioselectivity. Intramolecular cycloadditions of the titanium ylides offer a synthetic application of this regioselectivity. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

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