Organolithium reagents, addition amination

Addition of Grignard and organolithium reagents to imines 2. derived from enantiomerically pure (S)-valinol (1), provides a-substituted phenethylamines 3 in moderate to good yield and excellent diastereoselectivity (in each case only one diastereomer can be detected by NMR)15. By appropriate selection of imine and organometallic reagent both diastereomeric amines are accessible (see also refs 16 and 17). 

Table 5. Addition of Organolithium Reagents R2Li to Oxime Ethers 4 and Reduction of the Resulting Alkoxyamines 5 to Amines 6"...

Dimethylpyrimido[4,5-f]pyridazine-5,7-dione 23 and its derivatives undergo attack at both C-3 and C-4. Under conditions of kinetic control, addition occurs preferentially at the more electron-deficient C, whereas thermodynamic control conditions, or the use of bulkier nucleophiles, favor addition at the less hindered position 3. This duality is illustrated by the addition of Grignard and organolithium reagents to C of 3-chloro analogue 24 (Equation 9), whereas stabilized nucleophiles such as the anion of nitromethane add at C-3 (Scheme 10) <2000CHE975>. Displacement of the 3-chloride occurs also upon treatment of 24 with amines (Equation 10) <2000CHE1213>. 

Diastereoselective 1,2- and 1,4-Additions of Chiral Aminals. The organolithium reagent derived from a chiral bromoaminal and BuLi adds to pentanal to afford an optically active lactol. Subsequent oxidation affords the optically active lactone with 88% ee (eq 3). ... 

Although (1) itself has not been shown to be useful in the stereospecific 1,2-addition of organometaiiic reagents to carbonyl compounds, closely related amines, such as (/ )-(ct-methoxymethylbenzyl)-(5)-(a-methylbenzyl)amine, have been used to direct the addition of organolithium reagents to benzalde-hyde with up to 95% stereoselectivity (eq 12). ... 

The complexes (5,5)-(Phebox)Pt(OTf) and [(5,5)-(Phebox)Pt(H20)](BF4) react with A -phenylbenzaldimine to afford the corresponding chiral aldimine complexes. Addition of organolithium reagents gives, after work-up, the corresponding enantio-merically enriched amines (Sch. 34) [145],... 

A(-(Arylthiomethyl)amines, which are easily prepared and reportedly have better shelf stability than the corresponding )V-(alkoxymethyl)amines, have also been utilized to prepare tertiary amines. Alkenyl cuprate addition to )V,A -diethylphenylthiomethylamine produces allylic amines in high yield (entry 1, Table 6). Both alkenyl groups of the cuprate react. 5-(Dialkylaminomethyl) dithiocarbamates (entry 2, Table 6), sulfonates (entry 3, Table 6) and amides also generate iminium salts in situ. Of a variety of amides examined, imides such as dialkylaminomethyl-succinimides (entry 4, Table 6) and -phthali-mides provide the best overall yields. Organolithium reagents are rarely utilized in aminomethylation reactions. However, )V-chloromethylamines condense readily with lithiated anisole derivatives (entry S, Table 6). ... 

Iminium salts bearing a labile trimethylsilyl group can be generated in situ and undergo nucleophilic addition (see Sections 1.12.4.2 and 1.12.7.3). Bis(trimethylsilyl)methoxymethylamine (75), for example, has been used as a formaldehyde equivalent for the preparation of primary amines. Cyclic imines, such as 3,4-dihydroquinolines, react with trimethylsilyl triflate (TMS-OTf) to provide reactive labile iminium salts (55), which condense with picoline anions. The addition of nonstabilized Grignard and organolithium reagents to acyclic aromatic ketimines and aldimines, however, is often not facilitated by the presence of TMS-OTf ... 

On a small scale, it is convenient to add the carboxylic acid to two equivalents of LDA10 or other lithium amide, but larger experiments can be performed by addition of an available organolithium reagent to a suspension of a preformed salt containing equivalent or lesser molar amounts of the amine.12,13 Diisopropylamine reacts more rapidly than carboxylate salts with n-butyllithium. When LDA so formed abstracts a proton from the carboxylate-salt, the amine produced can react again with addi-... 

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