C-H-Acidic Compounds

Walther et al. improved the Na0Ph/C02 system by tuning the role of the solvent, such that the carboxylation of acetone was carried out selectively by sodium phenoxide with N-methyl-caprolactam under 0.1 MPa C02 to afford 3-ketoglutaric acid in 65% yield [34]. The same authors reported the conversion of acetyl-naphthalene (acetonaphthone) to acetyl-naphthalene carboxylic acid with 84% yield, and of cyclohexanone to cyclohexane-2,6-dicarboxylic acid in 56% yield. 

Most other reported catalytic systems rely on the use of strong nucleophiles such as 1,3-diphenyl urea (DPU), diazabicyclo[5.4.0]undec-7-ene (DBU) [37], diphenyl carbodiimide (DPC) [38] and anilides [39] to activate 0O2 and acidic substrates. 

Reactive Organometallic Derivatives in the Synthesis of Carboxylic Acids 

From an historical point of view, the production of carboxylic acids from C02 and reactive organometallic derivatives dates back almost as far as the Kolbe-Schmitt 

The development of new methods by which to conduct versatile carboxylations with C02 has long been the subject of many research projects. One method chosen to overcome this reactivity problem was to generate a transient, milder organome- 

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Class (2) reactions are performed in the presence of dilute to concentrated aqueous sodium hydroxide, powdered potassium hydroxide, or, at elevated temperatures, soHd potassium carbonate, depending on the acidity of the substrate. Alkylations are possible in the presence of concentrated NaOH and a PT catalyst for substrates with conventional pX values up to - 23. This includes many C—H acidic compounds such as fiuorene, phenylacetylene, simple ketones, phenylacetonittile. Furthermore, alkylations of N—H, O—H, S—H, and P—H bonds, and ambident anions are weU known. Other basic phase-transfer reactions are hydrolyses, saponifications, isomerizations, H/D exchange, Michael-type additions, aldol, Darzens, and similar... 

C-H acidic compounds do not possess any basic properties. But they can form anions in the presence of strong bases, and these possess sufficiently strong nucleophilic properties to be able to add to a polarized carbonyl group. Examples are listed in Table 6. 

Table 6 Reaction of carbonyl compounds (aldehydes, ketones) with C-H acidic compounds, a selection.

Finally, the synthesis of allenyl ketones is also possible by carbonylation if carbonates 103 are treated with C-H acidic compounds 104 such as /3-diketones or derivatives of malonic ester to yield products of type 105 [143],... 

The attack of carbon nucleophiles such as Grignard reagents [116, 235, 236], cuprates [183, 237-242] and C-H acidic compounds [212] on allenes 155 leads generally to the non-conjugated products 158. However, it was observed early that 158 is the product of a kinetically controlled reaction also in these cases, whereas the thermodynamically more stable product 159 is formed at longer reaction times or subse-... 

The heterocycles 205 are accessible by addition of the reagents NuH2, acting as double nucleophiles, to the diallenes 204 [104]. Compound 206 can also be prepared by this method and C,H-acidic compounds can serve as double nucleophiles as well. 

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

Azo couplings with C-H acidic compounds such as barbituric acids (40) or pyrazolones (304) proceed equally quantitatively in the solid state. However, in some combinations a basic catalyst has to be added in the form of gaseous trimethylamine in order to speed up the reaction. The free azo dyes occur in the hydrazono form after washing away the unavoidable stoichiometric salts [99-100] (Scheme 46). The prescription should be carefully followed for safety... 

The Bingel reaction is not restricted to C-H-acidic carbonyl compounds such as malonates. Various other substrates have also been used. Some C-H-acidic compounds, which were successfully subjected to the Bingel reaction, are shown in Table 3.1. 

Most C,H-acidic compounds can be condensed with aldehydes or ketones to yield alkenes. Some of these reactions have also been realized on insoluble supports, with either the C,H-acidic (nucleophilic) reactant or the electrophilic reactant linked to the support. Some illustrative examples are listed in Table 5.6. Polystyrene-bound malonic esters or amides, cyanoacetamides, nitroacetic ester [95], and 3-oxo esters undergo Knoevenagel condensation with aromatic or aliphatic aldehydes. Catalytic amounts of piperidine and heating are generally required, although reactive substrates can react at room temperature. 

Support-bound carbonyl compounds can be converted into alcohols by treatment with suitable carbon nucleophiles. Aldehydes react readily with ketones or other C,H-acidic compounds under acid- or base-catalysis to yield the products of aldol addition (Table 7.2). Some types of C,H-acidic compound, such as 1,3-dicarbonyl compounds, can give the products of aldol condensation directly (Section 5.2.2.2). 

Phenols attached to insoluble supports can be etherified either by treatment with alkyl halides and a base (Williamson ether synthesis) or by treatment with primary or secondary aliphatic alcohols, a phosphine, and an oxidant (typically DEAD Mitsu-nobu reaction). The second methodology is generally preferred, because more alcohols than alkyl halides are commercially available, and because Mitsunobu etherifications proceed quickly at room temperature with high chemoselectivity, as illustrated by Entry 3 in Table 7.11. Thus, neither amines nor C,H-acidic compounds are usually alkylated under Mitsunobu conditions as efficiently as phenols. The reaction proceeds smoothly with both electron-rich and electron-poor phenols. Both primary and secondary aliphatic alcohols can be used to O-alkylate phenols, but variable results have been reported with 2-(Boc-amino)ethanols [146,147]. 

Nucleophiles other than hydride can be added to support-bound imines to yield amines. These include C,H-acidic compounds, alkynes, electron-rich heterocycles, organometallic compounds, boronic acids, and ketene acetals (Table 10.9). When basic reaction conditions are used, stoichiometric amounts of the imine must be prepared on the support (Entries 1-3, Table 10.9). Alternatively, if the carbon nucleophile is stable under acidic conditions, imines or iminium salts might be generated in situ, as, for instance, in the Mannich reaction. Few examples have been reported of Mannich reactions on insoluble supports, and most of these have been based on alkynes as C-nucleophiles. 

Aldehydes and ketones are usually prepared on insoluble supports by the acylation of arenes, C,H-acidic compounds, or organometallic reagents. Alcohols or other substrates can also be converted into carbonyl compounds by oxidation (Figure 12.1). Linkers that enable the generation of aldehydes and ketones upon cleavage from a support are considered in Section 3.14. 

C-Acylations of C,H-acidic compounds have also been realized on insoluble supports. The few examples that have been reported include the C-acylation of support-bound ester enolates with acyl halides [9], Claisen condensations of polystyrene-bound ketones with benzoic acid esters, the C-acylation of nitriles with acyl nitriles or anhydrides, and the C-acylation of phosphonates with acyl halides (Entries 5-9, Table... 

To avoid the formation of ketenes by alkoxide elimination, ester enolates are often prepared at low temperatures. If unreactive alkyl halides are used, the addition of BU4NI to the reaction mixture can be beneficial [134]. Examples of the radical-mediated a-alkylation of support-bound a-haloesters are given in Table 5.4. Further methods for C-alkylating esters on insoluble supports include the Ireland-Claisen rearrangement of O-allyl ketene acetals (Entry 6, Table 13.16). Malonic esters and similar strongly C,H-acidic compounds have been C-alkylated with Merrifield resin [237,238]. 

Thioamides are suitable intermediates for the preparation of amidines, thiazoles, and thiophenes. Thioamides have mainly been prepared on insoluble supports by C-acylation of enamines or C,H-acidic compounds with isothiocyanates (Entries 1-3,... 

The few thiophene syntheses reported in which the formation of the heterocycle is realized on an insoluble support (Entries 1-3, Table 15.10) are based on the intramolecular addition of C,H-acidic compounds to nitriles (Thorpe-Ziegler reaction), or on the Gewald thiophene synthesis. The mechanism of these cyclizations is outlined in Figure 15.6. In thiophene preparations performed on solid phase, the required a-(cya-... 

Apart from halides, pseudohalides and acetates, FeCl3 is able to activate hydroxyl groups in a similar manner. Hence various substitutions of hydroxyl groups have been developed, e.g. the condensation of alcohols or phenols with diphenylmethanol to give DPM-protected alcohols [Equation (7.4), Scheme 7.11] [15] or the direct coupling of allylic or benzylic alcohols with C—H-acidic compounds [Equation (7.5)] [16]. 

Table 13.1 lists the pK values of C,H-acidic compounds with a variety of electron acceptors. It shows that multiple substitution by a given acceptor enhances the acidity of the o -H atom more than monosubstitution. Table 13.1 also shows that the nitro group is the most activating substituent. One nitro group causes the same acidity of an a-H atom as do two carbonyl or two ester groups. 

The equilibrium constant Keq of the respective deprotonation equilibrium shows whether a base can deprotonate a C,H-acidic compound quantitatively, in part, or not at all ... 

Rules of Thumb Regarding the Position of the Equilibria of C,H-Acidic Compounds... 

For every rule, there is an exception or so they say. Sometimes this is also true in chemistry. It appears, for example, that the pvalues of carboxylic acid esters vary more widely than is allowed or acknowledged by Table 13.1. This does not justify, though, the abandonment of the above mentioned rules of thumb for estimating the position of the deprotonation equilibrium of C,H-acidic compounds. As it were, one structural effect on the C,H acidity of carboxylic acid esters has so far been totally ignored, namely the effect of the conformation that the substructure C-0-C=0 adopts in relation to the highlighted bond (printed in boldface), i.e., which dihedral angle occurs between the C-O and the C=0 bond. 

Tab. 13.2 Survey of the Deprotonation Ability of C,H-Acidic Compounds. The ease of deprotonation of C,H-acidic compounds depends on (a) the type and number of the electron-withdrawing groups in the substrate and (b) on the base employed...

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