Regioselectivity of Deprotonations and Alkylations

There is no perfectly linear correlation between the basicity and nucleophilicity of carbanions [66], but higher basicity usually also implies higher nucleophilicity. Carbanions in which the negative charge is highly delocalized (e.g. diethylmalonate) will usually react more slowly with electrophiles than less extensively delocalized carbanions of similar basicity (e.g. malodinitrile) [66], 

Stoichiometric, irreversible formation of enolates from ketones or aldehydes is usually performed by addition of the carbonyl compound to a cold solution of LDA. Additives and the solvent can strongly influence the rate of enolate formation [23]. The use of organolithium compounds as bases for enolate formation is usually not a good idea, because these reagents will add to ketones quickly, even at low temperatures. Slightly less electrophilic carbonyl compounds, for example some methyl esters [75], can, however, be deprotonated by BuLi if the reactants are mixed at low temperatures (typically -78 °C), at which more metalation than addition is usually observed. A powerful lithiating reagent, which can sometimes be used to deproto-nate ketones at low temperatures, is tBuLi [76], 

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Alkylation of (diethoxyphosphoryl)methylcopper(I) and (dialkoxyphosphoryl)trimethylsilylalkyl-lithiums with a variety of alkyl iodides and bromides has been reported by Savignac and coworkers. Tsuge et al. have demonstrated the regioselective dipolar addition of (diethoxyphosphoryl)acetonitrile oxide with monosubstituted alkenes to yield the 3-[(diethoxyphosphoryl)methyl]-2-isoxazolines. The phosphonates can be deprotonated and alkylated in good yields. 

The chiral a-cyano allylamines prepared from ( )-3-phenylpropenal, potassium cyanide and (L)-ephcdrinc [(17 ,2S )-2-methylamino-l-phenylpropanol] hydrochloride as a mixture (1 1) of C-l epimers, were deprotonated using 2 equivalents of LDA in THF to give the dilithio compound37. Alkylation at C-3 afforded regioselectively a mixture of (E)- and (Z)-enamines in variable amounts depending on reaction conditions. Diastereoselectivity varied from moderate to excellent. Addition of HMPA and especially lithium iodide improved the diastereoselectivity. De-aggregation is proposed to be the reason for the effect of these additives. 

On reaction of the corresponding l-iminomethyl-l,2,5,6-tetrahydropyridine in situ alkylation was effected by deprotonation with butyllithium at — 78 °C in the presence of haloalkanes to again afford a regioisomeric mixture of 1 and 2 (n = 2). Regioselectivity in this case was much lower (about 2 1), but hydrazinolysis followed by hydrogenation in a similar manner afforded the chiral 2-alkylpiperidines with 91-96% ee. 

The regio- and stereoselectivity of enolate formation are essential for the control of alkylation reactions. The regioselectivity of ketone deprotonation has been extensively investigated and this important step in alkylation reactions has been discussed in many reviews (e.g., refs 1-4, 71) and textbooks (e.g., refs 5, 6). Therefore, this topic will be discussed here only in general terms. 

Although the regioselectivity of the alkylation reaction is independent of the nature and the steric bulk of the electrophile, it is dependent on the steric bulk of the base used for deprotonation. Lithium diisopropylamide (LDA) is superior for endo deprotonation, whereas exo dcprotonation is best achieved with the sterically hindered lithium 2,2,6,6-tetramethylpiperidide (LTMP)11,16. 

Allyl carbamates 19 are even more versatile, and the lithio derivatives 20 of allyl carbamates are the most important class of homoenolate equivalents.17 Lithiated allyl carbamates react reliably at the y-position with aldehydes and ketones but less regioselectively with alkylating and silylating agents. O-Benzyl carbamates 21 are readily deprotonated and can be quenched with electrophiles.17 20... 

On the other hand, lithium enolates derived from substituted endocyclic ketones have largely been exploited in the synthesis of steroids since the regioselectivity of their deprotonation can be controlled and high levels of 1,2- and 1,3-stereoselection occur9,418. The control is steric rather than electronic, with the attack directed to the less substituted ji-face of the enolate for conformationally rigid cyclopentanones, whereas stereoelectronic control becomes significant for the more flexible cyclohexanones. Finally, an asymmetric variant of the formation of a-branched ketones by hydration of camphor-derived alkynes followed by sequential alkylation with reactive alkyl halides of the resulting ketones was recently reported (Scheme 87)419. 

The previous cycloaddition reaction discussed is believed to proceed through an aldimine anion (19). Such delocalized anions can also be generated by treatment of suitable aldimines with a strong base. Subsequent cyclocondensation with a nitrile produces imidazoles [25-28]. The 2-azaallyl lithium compounds (19) are made by treatment of an azomethine with lithium diiso-propylamide in THF-hexane ( 5 1) (Scheme 4.2.9) [29. To stirred solutions of (19) one adds an equimolar amount of a nitrile in THF at —60°C. Products are obtained after hydrolysis with water (see also Section 2.3). If the original Schiff base is disubstituted on carbon, the product can only be a 3-imidazoline, but anions (19) eliminate lithium hydride to give aromatic products (20) in 37-52% yields (Scheme 4.2.9). It is, however, not possible to make delocalized anions (19) with R = alkyl, and aliphatic nitriles react only veiy reluctantly. Examples of (20) (Ar, R, R, yield listed) include Ph, Ph, Ph, 52% Ph, Ph, m-MeCeUi, 50% Ph, Ph, p-MeCeUi, 52% Ph, Ph, 3-pyridyl, 47% Ph, Ph, nPr, 1% [25]. Closely related is the synthesis of tetrasubstituted imidazoles (22) by regioselective deprotonation of (21) and subsequent reaction with an aryl nitrile. Even belter yields and reactivity are observed when one equivalent of potassium t-butoxide is added to the preformed monolithio anion of (21) (Scheme 4.2.9) [30]. 

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