Lithium amide bases, deprotonation with

Irradiation of matrix-isolated imidazole-2-carboxylic acid gave the 2,3-dihydro-imidazol-2-ylidene-C02 complex (31) characterized by IR spectroscopy and calculated to lie 15.9 kcal mol above the starting material. A series of non-aromatic nucleophilic carbenes (32) were prepared by desulfurization of the corresponding thiones by molten potassium in boiling THF. The most hindered of the series (32 R = Bu) is stable indefinitely under exclusion of air and water and can be distilled without decomposition. The less hindered carbenes slowly dimerize to the corresponding alkenes. Stable aminoxy- and aminothiocarbenes (33 X = O, S) were prepared by deprotonation of iminium salts with lithium amide bases. The carbene carbon resonance appears at 260-297 ppm in the NMR spectrum and an X-ray structure determination of an aminooxycarbene indicated that electron donation from the nitrogen is more important than that from oxygen. These carbenes do not dimerize. 

A regioselective deprotonation with amide base by preferential abstraction of the a-methylene hydrogen syn to the phenylaziridyl moiety in 116 and subsequent decomposition of the resulting monoanion furnishes, with extrusion of styrene and nitrogen, the alkyllithium 118. After abstraction of the amine proton, the c -alkene 117 is formed with regeneration of the lithium amide base for further use in the catalytic cycle. 

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

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). ... 

Chiral bis-lithium amide bases have been used for enantiotopic deprotonation of the sulfonium salt of 1,4-oxathiane 86. The anion undergoes an enantioselective thia-Sommelet rearrangement to afford the 3-substituted-1,4-oxathiane 87. Only bis-lithium amide bases were effective, giving products with high diastereoselectivity and with low to moderate enantioselectivity (Equation 13) <2003TL8203>. 

As shown by the last reaction in Scheme 5.23, the metalation of benzamides is complicated by several potential side reactions (Scheme 5.24). Thus, benzamides can also undergo ortho-metalation [181, 217-222] or metalation at benzylic positions [223-225], Ortho-metalation seems to be promoted by additives such as TMEDA, and benzylic metalation can be performed selectively with lithium amide bases [217,224], which are often not sufficiently basic to mediate ortho- or a-amino metalation. If deprotonation of the CH-N group succeeds, the resulting product might also undergo cydization by intramolecular attack at the arene [214, 216] (see also Ref. [226] and Scheme 5.27) instead of reacting intermolecularly with an electrophile. That this cydization occurs, despite the loss of aromatidty, shows how reactive these intermediates are. 

A dearomatising asymmetric cyclisation initiated by deprotonation with a chiral lithium amide base is discussed in section 5.4. 

Research by M. Majewski et al. showed that the enantioselective ring opening of tropinone allowed for a novel way to synthesize tropane alkaloids such as physoperuvine. The treatment of tropinone with a chiral lithium amide base resulted in an enantioslective deprotonation, which resulted in the facile opening of the five-membered ring to give a substituted cycloheptenone. This enone was subjected to the Wharton transposition by first epoxidation under basic conditions followed by addition of anhydrous hydrazine in MeOH in the presence of catalytic amounts of glacial acetic acid. 

Chiral lithium amide bases have been used successfully in the asymmetric deprotonation of prochiral ketones [55, 56]. WUliard prepared polymer-supported chiral amines from amino acid derivatives and Merrifield resin [57]. The treatment of cis-2,6-dimethylcyclohexanone with the polymer-supported chiral lithium amide base, followed by the reaction with TMSCl, gave the chiral silyl enol ether. By using polymeric base 96, asymmetric deprotonation occurred smoothly in tetrahydrofuran to give the chiral sUyl enol ether (, S )-102 in 94% with 82% ee (Scheme 3.28). 

A number of bases may be used for deprotonation, but the most important ones are lithium amide bases such as those illustrated in Figure 3.3. Although other alkali metals may be used with these amides, lithium is the most common. Amide bases efficiently deprotonate virtually all ctirbonyl compounds, and do so regioselectively with cyclic ketones such as 2-methylcyclohexanone i.e., C2 vs. C6 deprotonation) and stereoselectively with acyclic carbonyls (i.e., E(O)- vs. Z(O)- enolates. If the carbonyl is added to a solution of the lithium amide, deprotonations are irreversible and kinetically controlled [36-38]. Under such conditions, the con-... 

Interligand asymmetric induction. Group-selective reactions are ones in which heterotopic ligands (as opposed to heterotopic faces) are distinguished. Recall from the discussion at the beginning of this chapter that secondary amines form complexes with lithium enolates (pp 76-77) and that lithium amides form complexes with carbonyl compounds (Section 3.1.1). So if the ligands on a carbonyl are enantiotopic, they become diastereotopic on complexation with chiral lithium amides. Thus, deprotonation of certain ketones can be rendered enantioselective by using a chiral lithium amide base [122], as shown in Scheme 3.23 for the deprotonation of cyclohexanones [123-128]. 2,6-Dimethyl cyclohexanone (Scheme 3.23a) is meso, whereas 4-tertbutylcyclohexanone (Scheme 3.23b) has no stereocenters. Nevertheless, the enolates of these ketones are chiral. Alkylation of the enolates affords nonracemic products and O-silylation affords a chiral enol ether which can... 

The organic synthesis of alkaloids has a long history and numerous synthetic approaches of the tropane skeleton have been developed, from the classical synthesis of tropine by Willstatter at the beginning of the century and comprehensively reviewed by Holmes [46], to the most recent developments dealing with asymmetric deprotonation of tropinone, with chiral lithium amide bases for the enantioselective synthesis of a range of tropanes [47]. New synthetic methods are periodically reviewed and readers interested in this area may refer to specialized literature. 

Both dimethylphenylphosphine-borane (107) and -sulfide (108) are enantio-selectively deprotonated by a lithiumalkyl (—)-sparteine complex as demonstrated by subsequent reaction with electrophiles to give products with e.e. values of 80-87% (Scheme 8). Oxidative coupling of (109) in the presence of copper(II) pivalate gives the (S. S)-isomer (110) as the major product. Asymmetric metalla-tion and silylation of diphenylphosphinyl ferrocene (111) using the chiral lithium amide base derived from di(l-methylbenzyl)amine has been reported to give an... 

The reactions of ( )-(371) with lithium amide bases, e.g. LiNEt2 in THF, give rise to two products after protonation i.e., (372) (major) and (373). ° It has been concluded that the reduction product (372) arose primarily by a route involving electron transfer from the base to (371). The amide product was formed in a competing isomerization reaction involving simultaneous deprotonation and ring-opening to the anion of (373). 

The diastereoselective lithiation of 74 shows that ferrocenes bearing electron-withdrawing directors of lithiation are sufficiently acidic to allow deprotonation with lithium amide bases. By replacing LDA with a chiral lithium amide, enantioselectivity can be achieved in some cases. The phosphine oxide 82, for example, is silylated in 54% ee by treatment with N-Hthiobis(a-methylbenzyl)amine 83 in the presence of Me3SiCl (Scheme 20) [58]. 

Aggarwal and Olofsson have developed a direct asymmetric a-arylation of prochiral ketones using chiral lithium amide bases and diaryliodonium salts [881]. In a representative example, the deprotonation of cyclohexanone derivative 684 using chiral Simpkins (/ ,/ )-base followed by reaction with the pyridyl iodonium salt gave the arylated product 685 in 94% ee (Scheme 3.275). This reaction has been employed in a short total synthesis of the alkaloid (-)-epibatidine [881]. 

The in situ quench (ISQ) technique [47] involves premixing of a hthium amide base (usually LDA or LTMP) and the electrophile at low temperature before addition of the arene. As soon as the orf/io-lithio anion forms, it can immediately react with the electrophile. The inverse addition protocol is equally productive, that is, a mixture of the arene and the electrophile is treated with a lithium amide base. The electrophile must be either unreactive to or react nondestructively with the lithium amide base, which therefore drastically limits useful base-electrophUe combinations. This concept was introduced by Martin for cyanobenzene deprotonation-sUylation sequences [47]. Low concentrations of aryllithiums lead to increased functional group tolerance. The ISQ technique was extended to a number of electrophiles that are compatible with lithium amide bases, including TMSCl, MejSnCl, B(OiPr)j [125, 126], benzaldehyde, Mel, EtI, and Me S. ... 

Asymmetric transformation mediated by chiral lithium amide bases has been used to advantage in an enantioselective pathway for formation of 8-oxanorcocaines (22) by deprotonation of 8-oxabicyclo[3.2.1]octan-3-one (21) and subsequent carbomethoxy-lation reaction with methyl cyanoformate (Scheme 2) ... 

Enantioselective deprotonation has been reviewed " and further explored " for cyclic ketones and for L-dihydroorotate ° and alkyl carbamates.Conformationally rigid chiral lithium amide bases, based on 1,3-disubstituted tetrahydroisoquinoline, deprotonate 4-r-butylcyclohexanone with high enantioselectivity (81%... 

The preparation of enantiopure or enriched complexes possessing planar chirality has been accomplished either by resolution of racemic mixtures or by asymmetric syntheses. Reported methods for the resolution of planar chirality include both chemical and kinetic resolution procedures, whilst reported asymmetric syntheses of enantiomerically pure or enriched benchrotrenic complexes include enantioselective ort/io-deprotonations with chiral lithium amide bases, and the transfer of side chain chirality onto the arene ring mediated by diastereoselective orf/io-nucleophilic additions and o/tfeo-metalations. 

Further work on the preparation of chiral a-amino-acids reported in the past year (see also the section on asymmetric hydrogenation) includes an extension of the utility of anions derived from lactim ethers (228) in the synthesis of such compounds by condensations with aldehydes and ketones chiral inductions are somewhat lower than in the alkylations of (228) reported previously (4, 320). Enzyme-mediated hydrolysis of 5(4H)-oxazolones by chymotrypsin or subtilisin gives a-acylamino-acids with good enantiomeric enrichments, especially if the substrate carries bulky substituents. Schiff s bases of a-amino-esters can be enriched enantiomerically to an extent of up to 70% by sequential deprotonation with a chiral lithium amide and protonation with an optically pure tartaric acid. ... 

Calorimetric study of enolate formation and aldol additions performed by Arnett and coworkers revealed the deprotonation with lithium amid bases to be a highly exothermic process. To give an example, the deprotonation of ketones like pinacolone or cyclohexanone with LiHMDS in THF resulted in negative AH values around 10 kcal mol L The stronger base LDA reacts even in a more exothermic manner cf. Ref. [1]. One can therefore postulate a reactant-like transition state in the deprotonation step accordii to Hammonds postulate. 

Enantioselective ethoxycarbonylation has recently been attempted via deprotonation of Wbenzylidenebenzylamine with two equivalents of a chiral lithium amide base and quenching with ethyl chloroformate levels of asymmetric induction were low but higher than those obtained using other chloroformates (eq 4). 

---