Lithium diisopropylamide imines

Chiral oxazolidines 6, or mixtures with their corresponding imines 7, are obtained in quantitative yield from acid-catalyzed condensation of methyl ketones and ( + )- or ( )-2-amino-l-phcnylpropanol (norephedrine, 5) with azeotropic removal of water. Metalation of these chiral oxazolidines (or their imine mixtures) using lithium diisopropylamide generates lithioazaeno-lates which, upon treatment with tin(II) chloride, are converted to cyclic tin(II) azaenolates. After enantioselective reaction with a variety of aldehydes at 0°C and hydrolysis, ft-hydroxy ketones 8 are obtained in 58-86% op4. 

Table 10 shows examples of. vvn-sclcctive enolate condensations with imines using different types of enolates. All enolates used in these experiments were prepared based on the corresponding lithium enolate by treatment with different Lewis acids, where the lithium enolates themselves were generated with lithium diisopropylamide (LDA) at — 78 °C. 

Ethyl (bornylideneamino)acetate (2) and the imines of (-)-(lf ,2, 5 )-2-hydroxy-3-pinanone and glycine, alanine and norvaline methyl esters were particularly successful as Michael donors. The chiral azaallyl anions, derived from these imines by deprotonation with lithium diisopropylamide in THF at — 80 C, add to various a,/i-unsaturated esters with modest to high diastereoselectivity (see Section 1.5.2.4.2.2.5.). Thus, starting with the imine 2, (R1 = CH,) and ethyl ( )-2-butcnoate, the a,/i-dialkylated glutamate derivative 3 is obtained as a single diastercomer in 90% yield91-92. 

In 2001, Sierra and coworkers have reported that ethyl 3-ferrocenylpropanoate reacting with an excess of lithium diisopropylamide (LDA) afforded an enolate that condensed with imine the resulting reaction mixture contained the expected 2-azetidinone as a cisltrans mixture (3 1), and the unexpected 3-hydroxy p-lactam [136]. The ferrocene moiety was linked to the p-lactam ring at the C-3 position, (Scheme 51). 

The deuteriated (97%) imines 363 and 365, and the hydrazone 364 have been prepared396-399 by treating 2,6,6-trideuterio-2-methylcyclohexanone and 2,2,6,6-tetradeuteriocyclohexanone with the corresponding deuteriated ammonium salts (RND3CI) and used in the KIE studies of the metalation of the above C=N compounds with lithium diisopropylamide (LDA) in THF, in N, N, N A -tetramethyl ethylenediamine (TMEDA) and in dimethylethylamine (DMEA) solvents (equation 200). The rates, d[imine]/dt of that of imines 363 and 364 metalation are zero order with respect to [THF], [TMEDA]... 

However for the formation of optically active a-alkyl aldehydes, the imine or hydrazone routes have proved of considerable value.122 In the preparative example123 the aldehydes propanal and octanal are converted with (S)-( — )-2-amino-l-methoxy-3-phenylpropane (14) into the imines (15) and (16) respectively. Treatment with lithium diisopropylamide then yields the corresponding lithioenamines [only the (fs)-isomers are formulated, since the (Z)-isomers would be less stable]. These intermediates have a topography which determines the subsequent direction of attack by the alkyl halide (see also Section 5.11.7, p. 688). In the formulation below, this stereoselection is from above the plane of the paper and leads to the (/ )- and (S)-2-methyloctanals respectively. 

Evans and Domeier189,438 have described a general method for the synthesis of a variety of cyclic enamines from imine anions. An imine was added to a cooled ( — 30 °C) solution of lithium diisopropylamide in THF and, after 15 min, l-chloro-2-iodoethane (or l-chloro-3-iodopropane) was added in one portion (equation 28). This method was used by Bruno and coworkers439. 

The approach of leveraging chirality at the imine nitrogen to impart enantioselectivity has also been used to advantage in the preparation of chiral heterosubstituted aziridines. Thus, when 2-(l-chloroethyl)-4-methyl-thiazole 671 is deprotonated with lithium diisopropylamide (LDA) and treated with the chiral aldimine 670, the aziridinyl thiazole derivative 672 is produced in excellent yield and diastereoselectivity (Scheme 164) <2004T1175>. 

Examples of amines serving as hydride donors are scarce (for a special case, see Section 1.3.3.S.3). That this reaction is possible is exemplified by a side reaction that occurs when simple aldehydes are treated with lithium diisopropylamide (46) reduction of the aldehyde with formation of an imine (47) occurs (equation 25). ... 

Bergbreiter and Newcomb have shown that the benzylamine imine of 3-pentanone is deprotonated by lithium diisopropylamide selectively at the benzylic position of a 2-azaallyllithium system that slowly isomerizes by a protonation-deprotonation sequence to afford the 1-azaallyl system (equation 46). ... 

Lithium Diisopropylamide, 526 Trimethylsilyl Enol Ether, 526 Enamines, 526 Imines, 527... 

Table I, examination of which provides ample support for the generality of the process. It is noteworthy that increased branching at the carbon a to the imine function leads to decreased yields of the desired adducts (12) the reason for this failure has not been addressed, but reversion by retroaldolization is one likely possibility. The base that was typically employed to effect the deprotonation of the intermediate aldimines was lithium diisopropylamide, since alkyllithiums were found to add to the carbon-nitrogen double bond of the aldimines. Wittig observed in a number of instances that the overall yields of a,3-un-saturated carbonyl compounds obtained according to this procedure were better than by the corresponding classical Wittig reaction. Interestingly, the anion derived from the r-butylimine of isobutyraldehyde reacts with selected a,3-unsaturated ketones to give 1,4-adducts, whereas the corresponding hydrazone anions add to such ketones to provide the 1,2-adducts. ...

Chiral enolates in which the auxiliary is in the ester portion provide still another route to optically active lactams. Early results indicated that little asymmetric induction was obtained with menthyl enolates. Use of the enolate obtained from 24 did lead to high levels of asymmetric induction. Treatment of 24 with lithium diisopropylamide in tetrahydrofuran, followed by addition of imine 25, gives cf -/(-lactam 26 in 79% yield and 91%ee98. Optically active /3-lactams can be prepared by addition of chiral iron enolates (see Section D.l. 1.1.3.2.) to imines99-101. Addition of aluminum enolate 27 to imine 28, followed by oxidative cyclization with iodine and an amine, affords /(-lactam 29 in 54% yield and >95% ee. 

Imine aliphatischer Amine init wenigstens einem H-Atom in a-Stellung bilden mit starken Basen (z. B. Lithium-diisopropylamid, Butyl-lithium) regioselektiv a-Carbanionen188. Die-se lassen sich ebenfalls mit Kohlendioxid bzw. Kohlensaurc-dicstern elektrophil substituie-ren182-189- 191 z.B.182 ... 

An efficient procedure for the synthesis of isoxazoles suitable for a multi-kilogram scale is shown in Scheme 1. An imine 1 is converted into its lithium derivative 2 by the action of lithium diisopropylamide, and an ester is added, The product 3 is treated with aqueous or methanolic hydroxylamine and the resulting oxime 4 (which exists largely as the hemiacetal 4a) is dehydrated to the isoxazole 5 with concentrated sulfuric acid. <97S439>. 5-Alkoxyisoxazoles and /VTV-disubstituted 5-isoxazolamines 6 (R = OMe, NMe2 or NMePh) rearrange to the azirines 7 in the presence of iron(II) chloride <97710911>. 

A-Chloroamines (e.g. 14), on treatment with strong bases such as potassium Fbutoxide or lithium diisopropylamide (LDA), give 2-aza-allyl anions (15) that can undergo r4s -I- tt2s cycloadditions with alkenes to give pyrrolidines. Imines can also be accessed by dehydrochlorination of (14), under modified conditions. ... 

In one approach, an imine moiety was generated in situ by reaction of a methoxy carbamate with lithium diisopropylamide. This imine was then condensed with an ester enolate to give the amino-ester, protected as a carbamate. Reaction of 4,70 with lithium diisopropylamide gave imine 4.71, for example. Subsequent reaction with... 

Dialkylformamides and EDA (lithium diisopropylamide) react to give carbamoyl anions (42, with contributions from C-lithiated anion and 0-lithiated carbene forms). Addition of such anions to chiral Al-sulfinyl aid- and ket-imines provides a-amino amides. The method avoids the unmasking of the nucleophile found in other approaches. i C-NMR confirms the unusual nature of the carbon of the anion (42). 

The isolation of the non-cyclic amino(aryl)carbenes and amino(alk-yl)carbenes demonstrated that singlet carbene centres can be sufficiently stabilized by only one a-nitrogen atom. In 2005, Bertrand and co-workers succeeded in preparing the first cyclic alkyl(amino)carbenes (CAACs Scheme 1.15). The precursor for CAAC 108 was obtained from an imine by deprotonation with LDA (LDA = lithium diisopropylamide) and subsequent reaction with 1,2-epoxy-2-methylpropane to give 106, which was converted into cyclic aldiminium salt 107 by reaction with trifluoromethanesulfonic acid... 

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