Alkylation of Enolates and Other Carbon Nucleophiles PDF

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```markdown ## Your role - You are a tool to convert images and documents into a structured markdown format. - Transcribe text. - Keep all important facts, figures etc. - Remove unnecessary spacing and punctuation. - Summarize any messy text but stay very true to the original text. - If text is not visible on truncated, you can guess what it might say when confident in order to return a complete sentence. - Avoid returning incomplete sentences and tables - Convert any math formula into LaTeX format, for example: $f(x) = -4(x + 3)­­­­2 + 2$. - Do not include the image or links to an image. - Instead, do your best job at describing the image. - If the image is of a piece of paper or a book, ignore background objects and focus on the text. - Format text using markdown headings, lists and tables - Do you best job of converting tables and diagrams into markdown, or describing them in detail. - Always write in the same language as the text in the image or document. ## Alkylation of Enolates and Other Carbon Nucleophiles ### Introduction Carbon-carbon bond formation is the basis for the construction of the molecular framework of organic molecules by synthesis. One of the fundamental processes for carbon-carbon bond formation is a reaction between a nucleophilic and an electrophilic carbon. The focus in this chapter is on enolates, imine anions, and enamines, which are carbon nucleophiles, and their reactions with alkylating agents. Mechanistically, these are usually $S_N2$ reactions in which the carbon nucleophile displaces a halide or other leaving group with inversion of configuration at the alkylating group. Efficient carbon-carbon bond formation requires that the $S_N2$ alkylation be the dominant reaction. The crucial factors that must be considered include: (1) the conditions for generation of the carbon nucleophile; (2) the effect of the reaction conditions on the structure and reactivity of the nucleophile; and (3) the regio- and stereo-selectivity of the alkylation reaction. The reaction can be applied to various carbonyl compounds, including ketones, esters, and amides. ``` O || Z C H + R'CH2-X --> Z C R' | | | || R R R O ``` Z=R, RO, R₂N, enolate alkylation These reactions introduce a new substituent $\alpha$ to the carbonyl group and constitute an important method for this transformation. In the retrosynthetic sense, the disconnection is between the a-carbon and a potential alkylating agent. There are similar reactions involving nitrogen analogs called *imine anions*. The alkylated imine can be hydrolyzed to the corresponding ketone, and this reaction is discussed in Section 1.3. ``` R' H2O \ | R-N + RCH2-X --> R-N --> O | | || R1 CH2R CH2R ` R2 R2 R2 ``` Either enolate or imine anions can be used to introduce alkyl a-substituents to a carbonyl group. Because the reaction involves a nucleophilic substitution, primary groups are the best alkylating agents, with methyl, allyl, and benzyl compounds being particularly reactive. Secondary groups are less reactive and are likely to give lower yields because of competing elimination. Tertiary and aryl groups cannot be introduced by an $S_N2$ mechanism. ### 1.1 Generation and Properties of Enolates and Other Stabilized Carbanions #### 1.1.1. Generation of Enolates by Deprotonation The fundamental aspects of the structure and stability of carbanions were discussed in Chapter 6 of Part A. In the present chapter we relate the properties and reactivity of carbanions stabilized by carbonyl and other EWG substituents to their application as nucleophiles in synthesis. As discussed in Section 6.3 of Part A, there is a fundamental relationship between the stabilizing functional group and the acidity of the C-H groups, as illustrated by the pKa data summarized in Table 6.7 in Part A. These pKa data provide a basis for assessing the stability and reactivity of carbanions. The acidity of the reactant determines which bases can be used for generation of the anion. Another crucial factor is the distinction between *kinetic* or *thermodynamic control of enolate formation by deprotonation* (Part A, Section 6.3), which determines the enolate composition. Fundamental mechanisms of $S_N2$ alkylation reactions of carbanions are discussed in Section 6.5 of Part A. A review of this material may prove helpful. A primary consideration in the generation of an enolate or other stabilized carbanion by deprotonation is the choice of base. In general, reactions can be carried out under conditions in which the enolate is *in equilibrium* with its conjugate acid or under which the reactant is *completely converted* to its conjugate base. The key determinant is the amount and strength of the base. For complete conversion, the base must be derived from a substantially weaker acid than the reactant. Stated another way, the reagent must be a stronger base than the anion of the reactant. Most current procedures for alkylation of enolates and other carbanions involve complete conversion to the anion. Such procedures are generally more amenable to both regiochemical and stereochemical control than those in which there is only a small equilibrium concentration of the enolate. The solvent and other coordinating or chelating additives also have strong effects on the structure and reactivity of carbanions formed by deprotonation. The nature of the solvent determines the degree of ion pairing and aggregation, which in turn affect reactivity. Table 1.1 gives approximate pKa data for various functional groups and some of the commonly used bases. The strongest acids appear at the top of the table and the strongest bases at the bottom. The values listed as $pK_{ROH}$ are referenced to water and are appropriate for hydroxylic solvents. Also included in the table are pK values determined in dimethyl sulfoxide ($pK_{DMSO}$). The range of acidities that can be measured directly in DMSO is greater than that in protic media, thereby allowing direct comparisons between weakly acidic compounds to be made more confidently. The pK values in DMSO are normally larger than in water because water stabilizes anions more effectively, by hydrogen bonding, than does DMSO. Stated another way, many anions are more strongly basic in DMSO than in water. This relationship is particularly apparent for the oxy anion bases, such as acetate, hydroxide, and the alkoxides, which are much more basic in DMSO than in protic solvents. At the present time, the $pK_{DMSO}$ scale includes the widest variety of structural types of synthetic interest.¹ The pK values collected in Table 1.1 provide an ordering of some important **Table 1.1. Approximate pK Values from Some Compounds with Carbanion Stabilizing Groups and Some Common Bases** | Compound | pKROH | pKDMSO | Base | pKROH | pKDMSO | |-----------------|-------|--------|----------------|-------|--------| | O₂NCH₂NO₂ | 3.6 | | CH₃CO₂⁻ | 4.2 | 11.6 | | CH₃COCH₂NO₂ | 5.1 | | | | | | CH₃CH₂NO₂ | 8.6 | 16.7 | HCO₃⁻ | 6.5 | | | CH₃COCH₂COCH₃ | 9 | | | | | | PhCOCH₂COCH₃ | 9.6 | | PhO⁻ | 9.9 | 16.4 | | CH₃NO₂ | 10.2 | 17.2 | | | | | CH₃COCH₂CO₂C₂H₅ | 10.7 | 14.2 | CO₃²⁻ | 10.2 | | | NCCH₂CN | 11.2 | 11.0 | (C₂H₅)₃N | 10.7 | | | PhCH₂NO₂ | | 12.3 | (CH₃CH₂)₂NH | 11 | | | CH₂(SO₂CH₃)₂ | 12.2 | 14.4 | | | | | CH₂(CO₂C₂H₅)₂ | 12.7 | 16.4 | | | | | Cyclopentadiene | 15 | | CH₃O⁻ | 15.5 | 29.0 | | PhSCH₂COCH₃ | | 18.7 | HHO⁻ | 15.7 | 31.4 | | CH₃CH₂CH(CO₂C₂H₅)₂| 15 | | C₂H₅O⁻ | 15.9 | 29.8 | | | | | | | 20.8 | | PhSCH₂CN | | 23.9 | (CH₃)₂CHO⁻ | | 30.3 | | (PhCH₂)₂SO₂ | | | (CH₃)₃CO⁻ | 19 | 32.2 | | PhCOCH₃ | 15.8 | 24.7 | | | | | PhCH₂COCH₃ | 19.9 | | | | | | CH₃COCH₃ | 20 | 26.5 | | | | | CH₃CH₂COCH₂CH₃ | | 27.1 | | | | | Fluorene | 20.5 | 22.6 | | | | | PhSO₂CH₃ | | 29.0 | [(CH₃)₃Si]₂N⁻ | 30b | | | PhCH₂SOCH₃ | 25 | | | | | | CH₃CN | | 31.3 | | | | | Ph₂CH₂ | | 32.2 | NH₂⁻ | 35 | 41 | | Ph₃CH | 33 | 30.6 | CH₃SOCH₂⁻ | 35 | 35.1 | | | | | (CH₃CH₂)₂N⁻ | 36 | | | PhCH₃ | | 43 | | | | | CH₄ | | 56 | | | | a. From F. G. Bordwell, Acc. Chem. Res., 21, 456 (1988). b. In THF; R. R. Fraser and T. S. Mansour, J. Org. Chem., 49, 3442 (1984). 1. F. G. Bordwell, Acc. Chem. Res., 21, 456 (1988). is $NO_2$ > COR > CN ≈ $CO_2R$ > $SO_2R$ > SOR > Ph ≈SR > H > R. Familiarity with the relative acidity and approximate pKa values is important for an understanding of the reactions discussed in this chapter. There is something of an historical division in synthetic procedures involving carbanions as nucleophiles in alkylation reactions. As can be seen from Table 1.1, $\beta$-diketones, $\beta$-ketoesters, malonates, and other compounds with two stabilizing groups have pKa values slightly below ethanol and the other common alcohols. As a result, these compounds can be converted completely to enolates by sodium or potassium alkoxides. These compoththe second EWG is extraneous to the overall purpose of the synthesis and its in carbanion alkylation reactionremoval requires an extra step. After 1960, procedures using entirely aprotic solvents, especially THF, and amide bases, such as lithium di-isopropylamide (LDA) were developed. dialkylamines have a pKa around 35. These conditions permit the conversion of monofunctional compounds with pK > 20, especially ketones, esters, and amides, completely to their enolates. Other bases that are commonly used are the anions of hexaalkyldisily amines, especially hexamethyldisilazane. The lithium, sodium, and potassium salts are abbreviated LiHMDS, NaHMDS, and KHMDS. The disilylamines have a pK around 30.4 The basicity of both dialkylamides and hexaalkyldisilylamides tends to increase with branching in the alkyl groups. The more branched amides also exhibit greater steric discrimination. An example is lithium tetramethylpiperidide, LiTMP, which is sometimes used as a base for deprotonation. Other strong bases, such as amide anion (-NH2), the conjugate base of DMSO (sometimes referred to as the "dimsyl" anion), and triphenylmethyl anion, are capable of effecting essentially complete conversion of a ketone to its enolate. Sodium hydride and potassium hydride can also be used to prepare enolates from ketones, although the reactivity of the metal hydrides is somewhat dependent on the means of preparation and purification of the hydride.7 By comparing the approximate pK values of the bases with those of the carbon acid of interest, it is possible to estimate the position of the acid-base equilibrium for a given reactant-base combination. For a carbon acid C−H and a base B-H, $K_{a(c-H)} = \frac{[C-][H+]}{[C-H]}$ and $K_{a(B-H)} = \frac{[B-][H+]}{[B-H]}$ at equilibrium $\frac{K_{a(C-H)}}{K_{a(B-H)}} = \frac{[C-H]}{[C-]} / \frac{[B-H]}{[B-]}$ for the reaction $C−H+B^- = B-H+C^-$ By kinetic control when the product composition is determined by the relative rates of the competing proton abstraction reactions. ``` _O || Ka R2C-C CH2R + B Kb ` -0 R2C=CCH2R' A (A) Ka --( --) (B) Kb -0 R2CHC=CHR' B ``` Kinetic control of isomeric enolate composition By adjusting the conditions of enolate formation, it is possible to establish either kinetic or thermodynamic control. Conditions for kinetic control of enolate formation are those in which deprotonation is rapid, *quantitative*, and *irreversible*. This requirement is met experimentally by using a very strong base such as LDA or LiHMDS in an aprotic solvent in the absence of excess ketone. Lithium is a better counterion than sodium or potassium for regioselective generation of the kinetic enolate, as it maintains a tighter coordination at oxygen and reduces the rate of proton exchange. Use of an aprotic solvent is essential because protic solvents permit enolate equilibration by reversible protonation-deprotonation, which gives rise to the thermodynamically controlled enolate composition. Excess ketone also catalyzes the equilibration by proton exchange. Scheme 1.1 shows data for the regioselectivity of enolate formation for several ketones under various reaction conditions. A consistent relationship is found in these and related data. Conditions of kinetic control usually favor formation of the less- substituted enolate, especially for methyl ketones. The main reason for this result is that removal of a less hindered hydrogen is faster, for steric reasons, than removal of a more hindered hydrogen. Steric factors in ketone deprotonation are accent uated by using bulky bases. The most widely used bases are LDA, LiHMDS, and NaHMDS. Still more hindered disilylamides such as hexaethyldisilylamide and bis (dimethylphenylsilyl)amide may be useful for specific cases. The equilibrium ratios of enolates for several ketone-enolate systems are also shown in Scheme 1.1. Equilibrium among the various enolates of a ketone can be established by the presence of an excess of ketone, which permits reversible proton transfer. Equilibration is also favored by the presence of dissociating additives such as HMPA. The composition of the equilibrium enolate mixture is usually more closely balanced than for kinetically controlled conditions. In general, the more highly substituted enolate is the preferred isomer, but if the alkyl groups are sufficiently branched as to interfere with solvation, there can be exceptions. This factor, along with $CH_3/CH_3$ steric repulsion, presumably accounts for the stability of the less-substituted enolate from 3-methyl-2-butanone (Entry 3). **Scheme 1.1. Composition of Enolate Mixtures Formed under Kinetic and Thermodynamic Control** | Entry | Ketone | Kinetic Conditions | Thermodynamic Conditions | | :---: | :-----: | :-----------------: | :-----------------------: | | 1 | CH3CH2CCH3 | 71% | 16% | | 2 | CH3(CH2)3CCH3 | 100% | 12% | | 3 | (CH3)2CHCCH3 | 99% | 88% | | 4b | (CH3)2CHCCH2CH3 | 40% | 2% | | 5 | PhCH2CCH3 | 14% | 2% | | 6 | CH3CCH3 | 99% | 26% | | 7 | PhCH2CO | 0% | 35% | | 8 | | | | | 9 | | | | The acidifying effect of an adjacent phenyl group outweighs steric effects in the case of 1-phenyl-2-propanone, and as a result the conjugated enolate is favored by both kinetic and thermodynamic conditions (Entry 5). ``` O O || || PhCH2 - C = CH2 PhCHC=0 | | CH3 CH3 ``` For cyclic ketones conformational factors also come into play in determining enolate composition. 2-Substituted cyclohexanones are kinetically deprotonated at the C(6) methylene group, whereas the more-substituted C(2) enolate is slightly favored at equilibrium (Entries 6 and 7). A 3-methyl group has a significant effect on the regiochemistry of kinetic deprotonsation but very little effect on the thermodynamic stability of the isomeric enolates (Entry 8). Many enolates can exist in both E- and Z-geometry. The synthetic importance of LDA and HMDS deprotonation has led to studies of enolate stereochemistry under various conditions. In particular, the stereochemistry of some enolate reactions depends on whether the E- or Z-isomer is involved. Deprotonation of 2-pentanone was examined with LDA in THF, with and without HMPA. C(1) deprotonation is favored under both conditions, but the Z:E ratio for C(3) deprotonation is sensitive to the presence of HMPA. More Z-enolate is formed when HMPA is present. ``` CH3 CH3 \ / CH3---C==CH2 C==CH / \ CH3 CH3 ``` Z-enolate E-enolate **Ratio C(1):C(3) deprotonation Ratio Z:E for C(3) deprotonation** 0° C, THF alone 7.9 0.20 -60°C, THF alone 7.1 0.15 0° C, THF-HMPA 8.0 1.0 -60°C, THF-HMPA 5.6 3.1 These and other related enolate ratios are interpreted in terms of a tight, reactant- like cyclic TS in THF and a looser TS in the presence of HMPA. The cyclic TS favors the E-enolate, whereas the open TS favors the Z-enolate. The effect of the HMPA is to solvate the $Li^+$ ion, reducing the importance of $Li^+$ coordination with the carbonyl oxygen. ``` R' R' / / H O-Li+ H---N \ // | \ R C Li =0 \ CH3 | CH3 H E-enolate R' / R' / / -----N---H Li+O Z-enolate / | // R---C Li+ R \ CH3 CH3 cyclic TS open TS ``` The Z-selectivity seems to be associated primarily with reduced basicity of the amide anion. It is postulated that the shift to Z-stereoselectivity is the result of a looser TS, in which the steric effects of the chair TS are reduced **Table 1.2. Stereoselectivity of . . .** | Reactant | Base | THF (hexane) (Z:E) | THF (23% HMPA) (Z:E) | |------------|----------------------|----------------------|------------------------| **Ketones** | | | | | CH3CH2COCH2CH3 | LDA | 30:70 | NA | | CH3CH2COCH(CH3)2 | LDA | 20:80 | NA | | | LITMP | 34:66 | NA | | | LIHMDS | 56:44 | NA | | CH3CH2COC(CH3)3 | LDA | <2:98 | NA | |CH3CH2COC(CH3)3 | LIHMDS | >98:2 | | | C6H5CH2COCH3 | LDA | 4:96 | NA | Trimethylsilyl enol ethers can also be cleaved by tetraalkylammonium fluoride (Entry 2) The driving force for this reaction is the formation of the very strong Si-F bond, which has a bond energy of 142 kcal/mol.31 These conditions, too, lead to enolate equilibration. Such enantioselective deprotonations depend upon kinetic selection between prochiral such diomerie hydrogens and the chiral base, arising from differences in diastereomeric or en transition Example transition structors proposed deprotonation, by base D. This structure includes chloride 1.1.3. Other Means of Generating Enolates Reactions other than deprotonation can be used to generate specific enolates under conditions in which lithium enolates do not equilibrate with regio- and stereoisomers. Several methods are shown in Scheme 1.2.