Ketones, 2-substituted deprotonation, alkylation

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at —12°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioseiectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2BOSO2CF3, at low temperatures (D A. Evans, 1979). Both types of trans-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

The requirement that an enolate have at least one bulky substituent restricts the types of compounds that give highly stereoselective aldol additions via the lithium enolate method. Furthermore, only the enolate formed by kinetic deprotonation is directly available. Whereas ketones with one tertiary alkyl substituent give mainly the Z-enolate, less highly substituted ketones usually give mixtures of E- and Z-enolates.7 (Review the data in Scheme 1.1.) Therefore efforts aimed at increasing the stereoselectivity of aldol additions have been directed at two facets of the problem (1) better control of enolate stereochemistry, and (2) enhancement of the degree of stereoselectivity in the addition step, which is discussed in Section 2.1.2.2. 

Alkyltriphenylphosphonium halides are only weakly acidic, and a strong base must be used for deprotonation. Possibilities include organolithium reagents, the anion of dimethyl sulfoxide, and amide ion or substituted amide anions, such as LDA or NaHMDS. The ylides are not normally isolated, so the reaction is carried out either with the carbonyl compound present or with it added immediately after ylide formation. Ylides with nonpolar substituents, e.g., R = H, alkyl, aryl, are quite reactive toward both ketones and aldehydes. Ylides having an a-EWG substituent, such as alkoxycarbonyl or acyl, are less reactive and are called stabilized ylides. 

Compound 211 and several related compounds are readily accessible by stereospecific deprotonation of the appropriate optically active carbamic esters with 5-BuLi/TMEDA ° . Much of the knowledge about the stereochemical course of substitution in benzyUithium derivatives was obtained from experiments with these compounds. Only the reaction with proton acids, aliphatic aldehydes, ketones or esters as electrophiles proceed with retention for alkyl, silyl and stannyl halides, acid chlorides. 

Few reports describe reactions of substituents at the benzene ring of benzotriazoles. The facile deprotonation of the methyl group in N-Boc-7-methyl-1-aminobenzotriazole (403) with butyllithium followed by reactions with electrophiles gives substituted products (404) (Scheme 78). The electrophile can be an alkyl halide, an aldehyde or a ketone, and the Boc group is removed by brief exposure to CF3CO2H in CH2CI2 <93TL6935>. 1-Acetylbenzotriazole (405) is hydrolyzed to form 3-(177-5-hydroxybenzotriazol-6-yl)propionic acid (406), which is then converted (Scheme 79) to... 

Analogous N/C substituted allenylidenes [M =C=C=CPh(NMeR) (CO)5] (M = Cr, W R= H, Me, Et) are obtained by using C-ethynylimines HC = CC(=NMe)Phinstead of propynoic acid amides. 0/C-, 0/0-, and N/S-substituted allenylidenes are also accessible from ethynyl ketones HC = CC(=0)R, propynoic acid esters HC=CC(=0)0R and propynethioic acid amides HC=CC(=S)NR2, respectively, after sequential deprotonation and the corresponding alkylation (representative examples are shown in Figure 2.2) [4a, 9]. 

Monocyclic tetrahydrophosphorin derivatives can be prepared, for example by dehydration of tertiary alcohols which are available by the action of lithium alkyls on 4-oxophos-phorinane derivatives (equation (16)). P- Oxidation and dehydrogenation of the ketone with Se02 is also possible (equation (17)) (66AG(E)588). Electrophilic substitution in position 2 (6) of phosphorinane 1-oxides and 1-sulfides can be achieved by a Wittig-Horner a-deprotonation, e.g. equation (18) (72BSF(2)402l, 79CJC723). 

A new method of kinetically controlled generation of the more substituted enolate from an unsymmetrical ketone involves precomplexation of the ketone with aluminium tris(2,6-diphenylphenoxide) (ATPH) at —78°C in toluene, followed by deprotonation with diisopropylamide (LDA) highly regioselective alkylations can then be performed.22 ATPH has also been used, through complexation, as a carbonyl protector of y./)-unsaturated carbonyl substrates during regioselective Michael addition of lithium enolates (including dianions of /i-di carbonyl compounds).23... 

The enolate A or the nitronate A, respectively, initially adds to the C=0 double bond of the aldehyde or the ketone. The primary product in both cases is an atkoxide, D, which contains a fairly strong C,H acid, namely, of an active-methylene compound or of a nitroalkane, respectively. Hence, intermediate D is protonated at the atkoxide oxygen and the C-fi atom is deprotonated to about the same extent as in the case of the respective starting materials. An OH-substituted enolate C is formed (Figures 13.52 and 13.53), which then undergoes an Elcb elimination, leading to the condensation product B. The Knoevenagel condensation and the aldol condensation have in common that both reactions consist of a sequence of an enolate hydroxy alkylation and an Elcb elimination. 

Although the acetoacetic ester synthesis and the malonic ester synthesis are used to prepare ketones and carboxylic acids, the same alkylation, without the hydrolysis and decarboxylation steps, can be employed to prepare substituted /3-ketoesters and /3-diesters. In fact, any compound with two anion stabilizing groups on the same carbon can be deprotonated and then alkylated by the same general procedure. Several examples are shown in the following equations. The first example shows the alkylation of a /3-ketoester. Close examination shows the similarity of the starting material to ethyl acetoacetate. Although sodium hydride is used as a base in this example, sodium ethoxide could also be employed. 

Additionally, acetylene itself is a useful two-carbon building block but is not very convenient to handle as it is an explosive gas. Trimethylsilyl acetylene is a distillable liquid that is a convenient substitute for acetylene in reactions involving the lithium derivative as it has only one acidic proton. The synthesis of this alkynyl ketone is an example. Deprotonation with butyl lithium provides the alkynyl lithium that reacted with the alkyl chloride in the presence of iodide as nucleophilic catalyst (see Chapter 17). Removal of the trimethylsilyl group with potassium carbonate in methanol allowed further reaction on the other end of the alkyne. 

Knochel and coworkers have reported the use of lithiated /V,/V-dialkylurcas (such as 47), which have proved to be useful for enantioselective deprotonation and alkylation of ketones. Enantioselectivities up to 88% were achieved across a range of 4-substituted cyclohexanones in the absence of HMPA. On addition of HMPA, both yield and enantioselectivity were lowered (Scheme 31)71,72. 

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. 

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. 

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