Imines reactions with lithiated

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"" . 

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. 

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. 

In contrast to the chemical properties of enolates, azaenolates of imines exhibit a marked thermodynamic preference for the syn configuration at the C-N partial double bond (syn effect)2 due to the repulsion between the lone pair density at nitrogen and the 7t-electron density at the carbon. Thus, lithiation of imines derived from ketones occurs with strong regioselectiv-ity at the least substituted carbon, followed by a regioselective reaction with electrophiles exclusively at the carbon of the ambident azaalkyl moiety. 

The metallation of 3-methyl-4//-5,6-dihydro-l,2-oxazine has been shown to take place at the methyl group with hindered bases and at the methylene group with unhindered bases (81JA5916). Deprotonation of (753) with lithium dimethylamide at -65 °C followed by reaction with benzyl bromide gave (754) in 85% yield. This product was converted to enone (755) by reaction first with triethyloxonium tetrafluoroborate to produce an oxoiminium salt. The salt was stirred with trimethylamine and the resulting a,/3-unsaturated imine hydrolyzed with wet silica gel to the enone (Scheme 174). The lithiated derivative of (753) serves as a synthon for the unknown a-anion of methyl vinyl ketone. 

Lithiation of imines and acetylene Imines and acetylenes can be lithiated directly by reaction with metallic lithium in THF at 10° with phenanthrene as the hydrogen acceptor (it is converted into 1,2,3,4,5,6,7,8-octahydrophenanthrene). 

Based on their fluorination protocol, Cahard and co-workers have elaborated a convenient synthesis of a-fluoro-a-phenylglycin derivatives [18]. For example, upon reaction with reagent 24 racemic nitrile 23 was converted into the fluorinated derivative 25 with 94% enantiomeric excess. The corresponding ester derivatives of 23 gave rise to somewhat lower ees. This difference was contributed to the fact that a-lithiated nitriles can be in equilibrium with axial-chiral lithio ketene imines of low racemization barriers thus leading to a potential dynamic kinetic resolution. 

Reaction of (R)-(+)-tert-butyl ferf-butanethiosulfinate (52) with lithiated imine 53 gave 54 as a single isomer in 92% yield.39 The thiosulfinate 52 was prepared by asymmetric oxidation of rerf-butyldisulfide with H202 in the presence of a chiral vanadium complex. 

The structural analysis clearly shows that the reaction of lithiated 48 with aldehydes and imines occurs in the same stereochemical sense with respect to the configuration at the stereogenic center at Cl but in the opposite stereochemical sense with respect to the configuration at the stereogenic center at C2. 

Lithiation of compound 560 with s-BuLi-TMEDA in THF at —78 °C following an inverse addition protocol provided the anion 561. It reacts with primary alkyl iodides and triflates, silyl chlorides, diphenyl disulfide, epoxides, aldehydes, ketones, imines, acyl chlorides, isocyanates and sulfonyl fluorides to yield the expected compounds 562 (Scheme 152). The transmetallation of compound 561 with ZnBr2 allowed the palladium-catalyzed cross-coupling reaction with aryl and vinyl bromides837. When the reaction was quenched with 1,2-dibromotetrafluoroethane, the corresponding bromide 562 (X = Br) is obtained838. 

Alkylations of hydrazone anions derived from aldehydes and ketones are closely related to imine anion alkylations. Lithiated hydrazones are particularly powerful nucleophiles for alkylation reactions. The alkylated hydrazones may be cleaved with periodate, as shown below.The choice of solvent and base is critical to the success of hydrazone alkylations hexane-free medium is essential for complete metalation. °... 

The Ziegler-modified Ullmann reaction was used for the total synthesis of pyrrolophenanthridinium alkaloid tortuosine by L.A. Flippin and co-workers. First, A/-Boc-5-methoxyindoline was lithiated at C7 with s-BuLi in the presence of TMEDA, and then it was transmetallated to the corresponding organocopper species that smoothly underwent the Ullmann reaction with a 3-iodoaryl imine. The resulting biaryl product was treated with anhydrous HCI in chloroform, which promoted the cyclization followed by dehydration to give the natural product. 

Whitesell and Whitesell" have tabulated some of the many types of electrophilic reagents that C-al-kylate metallated imines. These are potent nucleophiles and undergo substitution reactions even with weakly electrophilic species such as epoxides and oxetanes. Lithiated ketimines and aldimines have been frequently used in reactions with alkylating agents containing latent 2-keto (or aldehydo) groupsor 3-keto (or aldehydo) groups. ... 

Stork overcame the dialkylation problem at the a-carbons in aldehydes by using imines. The obvious disadvantages of this method are the unstable starting materials (Schiff bases). Meyers and coworkers found that the stable commercial starting material 2,4,4,6-tetramethyl-5,6-dihydro-l,3-4A/-oxazine 43 can be used as a precursor for formation of various aldehydes. After lithiation of the methyl group in the 2 position it acts as an excellent nucleophile in reaction with various electrophiles E, and after reducing the double bond and hydrolysis the aldehyde group is formed (equation 15). 

Imines 20 formed from SAMP and enolisable aldehydes prefer an E-configuration across the C=N bond. Lithiation gives the aza-enolate 21 also with the E-configuration derived from the preferred conformation of 20. Reaction with an electrophile gives mostly the diastereoisomer 22. 

Following their earlier findings on the enantioselective allylzincation of cy-clopropenone acetals [43], Nakamura and co-workers investigated the same reaction with imines of aromatic aldehydes [44]. In an initial experiment, ( )-ben-zaldehyde N-phenyl imine (59) was treated with preformed chiral allylic zinc reagent 57a (R=z-Pr) obtained by mixing a lithiated bis(oxazoline) (55, R=z-Pr) with an allylic zinc bromide (56a) (Scheme 22). The allylation product was obtained in 95% yield, but the enantioselectivity was only 6% ee. Fortunately, the enantioselective allylzincation of Z- (i.e., cyclic) aldimines was more successful. 

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