Imines lithium salts

In principle, it would appear that the presence of bulky substituents R and E should kinetically favor the formation of nitrile imines. Lithium salts have been used for much of this work and it has been shown that this is generally the case [e.g., for 151 (X = S)] bulky electrophiles favor the nitrile imine (e.g., 153) while smaller analogues favor diazo compounds (e.g., 152). Reducing the size of the substituent on the diazo compound has a similar effect (e.g., 150 from 151) (X = lone pair). 

Lithium salts of ketone derivatives such as imines, oximes and hydrazones have also been used for directed aldol reactions (Scheme 103).374 375 A recent example involves triple coordination of lithium in a very rigid transition state, to lead to regiospecificity in the product (Scheme 104).376... 

Functionalization of tiglaldehyde. Anions of a,/5-unsaturated aldimines are known to react with electrophiles at both the a- and y-position. Thus, the lithium salt (1) of tiglaldehyde cyclohexylimine reacts with aldehydes to give, after acid hydrolysis of the imine, mainly the product of a-substitution. Addition of HMPT (1 equiv.) to the reaction followed by equilibration at 0° (2 hours) results mainly in formation of the product of y-subsitution. 

Similarly, the enamine salt 15 is obtained by lithiation of 14 (equation 5). In both cases the lower steric hindrance leads to higher stability of the enaminic system33 where the double bond is formed on the less substituted carbon. The Af-metalated enamines 11 and 15 are enolate analogs and their contribution to the respective tautomer mixture of the lithium salts of azomethine derivatives will be discussed below. Normant and coworkers34 also reported complete regioselectivity in alkylations of ketimines that are derived from methyl ketones. The base for this lithiation is an active dialkylamide—the product of reaction of metallic lithium with dialkylamine in benzene/HMPA. Under these conditions ( hyperbasic media ), the imine compound of methyl ketones 14 loses a proton from the methyl group and the lithium salt 15 reacts with various electrophiles or is oxidized with iodine to yield, after hydrolysis, 16 and 17, respectively (equation 5). 

Another use of imines is in a directed aldol condensation reaction, directing the condensation in a way that the aldehyde, after reacting with the base, will react with the other carbonyl compound, with no self-condensation. Imines, in contrast to their precursors, aldehydes, are too weak electrophiles to undergo self-condensation. However, after lithiation with LDA, the lithium salts 19 are sufficiently good nucleophiles to react... 

A study35,36 concerning the ambidentity of the lithium salts of imines resulted in the discovery that the lithium is bonded to the nitrogen, e.g. compare 8 (equation 3). However, the evolution of the products on the carbon or nitrogen is influenced by the nature of the electrophile reactants like methyl iodide that ionize with difficulty will form a six-centered transition state 21 where the C-alkylation product will be evolved after elimination of lithium iodide. In the same way, the intermediate in aldol condensation is 22. 

All the investigations that have been performed so far suffer from the fact that the deprotonation of the imines by strong bases gives metalation—after which an electrophilic reaction takes place on the less substituted a-carbon. Lithiation that does not depend on the degree of substitution on the a-carbon was developed by Wender and co workers3 9,40 using a,/ - unsaturated ketones 23 via 24, 25 and the lithium salt 26 (equation 7) or primary allyl imines via 29, 30 and the lithium salt 31 (equation 8). The products 27 and 32 are obtained after alkylation and hydrolysis. 

Another type of pre-formed reagent (28) has been used to carry out diastereose-lective Mannich reactions. The lithium salts 27 are treated with TiCU to give 28, which is then treated with the enolate of a ketone." ° The palladium catalyzed Mannich reaction of enol ethers to imines is also known." ° The reaction of silyl enol ethers and imines is catalyzed by HBF4 in aqueous methanol." ° Similarly, silyl enol ethers react with aldehydes and aniline in the presence of InCla to give the p-amino ketone." ° Imines react on Montmorillonite KIO clay and microwave irra-... 

Six-coordinate mono-Cp chloride complex 355 containing two mono-anionic, o/7/w-substituted phenoxy-imine [0, . ]-r pc ligands was obtained by salt metathesis involving the reaction of CpZrCI (DME) and the lithium salt of the ligand in THF (Scheme 77).269 If the centroid of the Cp ring is considered as a single coordination site, the molecular structure of this complex can be described as octahedral, with a tram (O-O), as (N-N), and as (Cl-Cp)... 

Dimethoxy-3,6-dihydropyrazine (109), prepared by methylation of 2,5-piperazinedione with trimethyloxonium tetrafluoroborate, is susceptible to lithiation because the protons at C-3 and C-6 are activated by adjacent imine moieties. The lithium salt of this bislactim ether reacts with the 2-chloro-l-phenylsulfonyl alkene (110) to give the 3-substituted pyrazine (111) (Scheme 25) <89JCS(P1)453>. The bislactim ether from piperazinedione cyclo(L-Val—Gly) is lithiated with butyl-lithium and then treated with ketones, alkyl halides, or others to form, nearly stereospecifically, ran5-3-isopropyl-6-substituted piperazinediones due to the steric influence of the isopropyl group <828866, 838673). Similar stereoselective syntheses have been achieved in reactions starting from cyclo(L-Val—D,L-Ala) <828864, 918939). Acid hydrolysis of these products affords chiral a-amino acids. 

Among monoamines, both enantiomers of 1-phenylethylamine and their derivatives play a prominent role. They are commercially available, but can also be prepared by resolution of the racemate, obtainable by Leuckart- Wallach reaction of acetophenone1, with malic acid2 or, more conveniently, with tartaric acid in methanol3. They are used as chiral additives for the addition of zinc alkyls to aldehydes in Section D. 1.3.1.4., as copper complexes for the synthesis of biaryls in Section B.2., as lithium salts for enantioselective deprotonation in Section C., and as imines in Sections D.1.1.1.3.1., D.1.1.1,4.. D.1.4.4., D.1.5.2., D.1.5.8., D. 1.6.1.2.1., D.2.3.I., and D.8. A general procedure for the synthesis of imines from carbonyl compounds and primary amines, with many examples of both chiral carbonyl compounds and chiral amines is given in reference 4. 

A -Substituted bornyl- and isobornylamines 17-19 are best obtained by reduction of the imines formed from camphor and a suitable amine4, either by isolation of the imine or in situ formation. The substituted amines were used as the lithium salt for enantioselective deprotonation and elimination reactions (Section C ). In almost all cases, the exo-amines (isobornylamines) are formed however, using (S)-l-phenylethylamine as the starting amine, the selectivity is reversed and the enob-amine (bornylamine) is obtained. 

Interestingly, the cycloaddition reaction proceeded cleanly even without any acid, as long as lithium perchlorate or other lithium salts were added. Alternatively, stirring the imine 307 in ethyl acetate with Florisil at 50°C also led to the formation of the cycloadduct 308 in 82% yield. The final conversion of 308 to ( )-ebuma-monine (309) required the isomerization of the double bond using deoxygenated 6.0 M sulfuric acid in refluxing ethanol. 

Nitrones have also been used as electrophiles toward 67, though the diastereo-selectivities of the reactions were less satisfactory than those with the corresponding imines [59,60]. Addition of one equivalent of the lithium salt of quini-dine (72) improves the diastereoselectivity dramatically for various 3,4-dihydr-oisoquinohne N-oxides 71 (Scheme 21) [60]. The formation of a facial discrimi-... 

Methoxyallyl bromide monoalkylates acids, nitriles, esters, ketones, dialkyl-amides, enamines, and imines in 44—96% yield, e.g. alkylation of the lithium salt of imines followed by hydrolysis gives 1,4-diones (Scheme 21). ... 

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