CH-acid

A wide vanety of nucleophiles, such as 1-alkylpyrroles, furans, thiophenls [51], phenols [52], anilmes [55, 54], indoles [55], CH-acidic compounds [56, 57], as well as organolithium [56], Gngnard [57, 59], organocadmiura, and organozmc compounds [56], undergo C-hydroxyalkylation with trifluoropynivates to yield derivatives of a-trifluoromethyi a-hydroxy acids. 

The thioimidates obtained from peifluorinated nitnles and methylmercaptan can be transformed into thiohydroxyimidates on treatment with hydroxylamine [64] CH-acidic compounds, such as methylketones [63, 66], nitroalkanes [67], and enamines [d jradd to peifluorinated nitnles in the same way (equation 6). 

Tnfluoroacetic anhydride is an efficient dehydrating reagent [46, 47] In the presence of pyndine, it smoothly dehydrates amides and aldoximes to the correspond ing nitriles [46] and adducts of CH-acids and 1,2,3-indantnone [47] (equation 20)... 

In some cases, a simple carbonyl reaction with the CH-acidic cyclopenta-dienes in the presence of a base gave a convenient entry to special types of azafulvalenes. Starting from the appropriate cyclic carbonylic and thiocar-bonylic systems respectively, or their acetals, the following azafulvalenes... 

To complete this section, we note the cleavage of electron-rich DTDAFs by CH-acidic five-membered heterocycles of the oxazolidine, thiazolidine, and imidazolidine types (64BSF2857). 

The high reactivity of monosubstituted acetylenes in many reactions (acetylenic condensation, Favorsky reaction, Mannich reaction, oxidative coupling, etc.) is determined by their acidity (7IMI1 83MI1). The literature data on the thermodynamic CH acidity of these compounds are rather scarce. 

The thermodynamic CH acidity of terminal acetylenes in the series of A-alkylpyrazoles was studied (83IZV466). These equilibrium CH acidity measurements were performed in DMSO by the method of remetallation (75ZOB1529). It reveals some regularities concerning the influence of the ring structure, the nature of other substituents, and the position of the ethynyl group on the acidity of ethynyl pyr azoles. 

The scheme shows that the influence of substituents on CH acidity in ethynylpy-razoles is not additive as compared with benzene derivatives (84IZV923), and its value depends, for each substituent, on the nature of other groups in different positions of the azole. 

The increasing CH acidity in the ethynylpyrazole series points to the advantageous inductive nature of this influence. Although the data are rather scarce, some correlation is observed between the ethynyl group values and (T constants of substituents in heterocycles (Fig. 3). 

It is known that diacetylenes (in Favorsky s reaction, for example) are 1000-fold more active than monoacetylenes. It is of interest to consider how the accumulation of triple bonds will affect the compound acidity. However, in the literature there are no data on the CH acidity of diacetylenic compounds. We were the first to estimate the p/ifa of a monosubstituted diacetylene, 4-butadiynyl-l,3,5-trimethylpyrazole, to be about 24-26 log units. Unfortunately, the authors (83IZV466) have failed to determine the acidity of the diyne more accurately owing to the side processes of remetallization that complicate control over reaction. 

Compounds of the type HC=C—CH=CHXR are not involved in a primary reaction with weak nucleophiles such as CH acids meanwhile, a final (secondary) cyclization with participation of active methylene groups happens to be feasible. Evidently, in most cases the energy gain in the heteroaromatic system realization is the decisive factor (81UK1252). 

It is believed (54IZV47 72JPR353) that in the first stage the intermediate 282 is formed due to the addition of the CH acid to the enamine moiety with subsequent elimination of amine. The enol form of the intermediate 282 undergoes cyclization in two fashions, depending on the nature of substituent X. In the case of the ester (X = OMe) the attack is directed to the cyano group to form substituted 3-methoxycarbonyl-I//-pyridin-2-one (283) or its tautomer (2-hydroxy-3-methoxycarbonylpyridine). With the amide (X = NH2) intramolecular condensation leads to 3-cyano-l//-pyridin-2-one and its hydroxy tautomer (284). 

Acetylene and terminal alkynes are CH-acidic compounds the proton at the carbon-carbon triple bond can be abstracted by a suitable base. Such a deprotonation is the initial step of the Glaser reaction as well as the Eglinton... 

The Japp-Klingemann reaction is a special case of the aliphatic diazo coupling. For a successful reaction, the dicarbonyl substrate 2 should bear a sufficiently CH-acidic hydrogen. 

The term Knoevenagel reaction however is used also for analogous reactions of aldehydes and ketones with various types of CH-acidic methylene compounds. The reaction belongs to a class of carbonyl reactions, that are related to the aldol reaction. The mechanism is formulated by analogy to the latter. The initial step is the deprotonation of the CH-acidic methylene compound 2. Organic bases like amines can be used for this purpose a catalytic amount of amine usually suffices. A common procedure, that uses pyridine as base as well as solvent, together with a catalytic amount of piperidine, is called the Doebner modification of the Knoevenagel reaction. 

The formation of Zj -adducts—e.g. 8 by a consecutive Michael addition reaction, is observed in some cases. This reaction is formulated as a 1,4-addition of a second molecule of the CH-acidic starting material 2 to the initially formed a ,/3-unsaturated carbonyl compound 3 ... 

Virtually any aldehyde or ketone and any CH-acidic methylene compound can be employed in the Knoevenagel reaction however the reactivity may be limited due to steric effects. Some reactions may lead to unexpected products from side-reactions or from consecutive reactions of the initially formed Knoevenagel product. 

A large number of aldehydes and structurally different CH-acidic methylene compounds can be employed in such a domino-Knoevenagel + hetero-Diels-Alder reaction. 

The condensation reaction of a CH-acidic compound—e.g. a ketone 3—with formaldehyde 1 and ammonia 2 is called the Mannich reaction, the reaction products 4 are called Mannich bases. The latter are versatile building blocks in organic synthesis, and of particular importance in natural products synthesis. 

There have been extensive investigations on the reaction mechanism. In most cases the reaction proceeds via initial nucleophilic addition of ammonia 2 to formaldehyde 1 to give adduct 5, which is converted into an iminium ion species 6 (note that a resonance structure—an aminocarbenium ion can be formulated) through protonation and subsequent loss of water. The iminium ion species 6 then reacts with the enol 7 of the CH-acidic substrate by overall loss of a proton ... 

As solvent an alcohol—often ethanol—as well as water or acetic acid can be used. The reaction conditions vary with the substrate various CH-acidic compounds can be employed as starting materials. The Mannich bases formed in the reaction often crystallize from the reaction mixture, or can be isolated by extraction with aqueous hydrochloric acid. 

With an unsymmetrical ketone as CH-acidic substrate, two regioisomeric products can be formed. A regioselective reaction may in such cases be achieved by employing a preformed iminium salt instead of formaldehyde and ammonia. An iminium salt reagent—the Eschenmoser salt—has also found application in Mannich reactions. ... 

As enolate precursors can be used CH-acidic carbonyl compounds such as malonic esters, cyanoacetic esters, acetoacetic esters and other /3-ketoesters, as well as aldehydes and ketones. Even CH-acidic hydrocarbons such as indene and fluorene can be converted into suitable carbon nucleophiles. 

The overall process is the addition of a CH-acidic compound to the carbon-carbon double bond of an o ,/3-unsaturated carbonyl compound. The Michael reaction is of particular importance in organic synthesis for the construction of the carbon skeleton. The above CH-acidic compounds usually do not add to ordinary carbon-carbon double bonds. Another and even more versatile method for carbon-carbon bond formation that employs enolates as reactive species is the aldol reaction. 

Certain starting materials may give rise to the non-selective formation of regioisomeric enolates, leading to a mixture of isomeric products. Furthermore a ,/3-unsaturated carbonyl compounds tend to polymerize. The classical Michael procedure (i.e. polar solvent, catalytic amount of base) thus has some disadvantages, some of which can be avoided by use of preformed enolates. The CH-acidic carbonyl compound is converted to the corresponding enolate by treatment with an equimolar amount of a strong base, and in a second step the a ,/3-unsaturated carbonyl compound is added—often at low temperature. A similar procedure is applied for variants of the aldol reaction. 

The methyl groups of 2,4-dimethyl-3//-l, 5-benzodiazepine are CH acidic reaction with benzal-dehyde gives a mixture of mono- and distyryl derivatives 13 and 14.256... 

Similar results are observed in the conjugative addition of CH-acidic methylene compounds with the metal derivatives of 2-nitro-5,10,15.20-tetraphenylporphyrin (6). The nickel porphyrin 6 (M = Ni) yields with an excess of dimethyl malonate the cyclopropane derivative 7 whereas the copper porphyrin 6 (M — Cu) forms with two equivalents of malononitrile the bisadduct 8.111... 

Most diazotized heteroaromatic amines undergo normal coupling reactions with common aromatic coupling components, as well as with CH acidic compounds (review Butler, 1975). 

Other compounds with reactive methylene and methyl groups are completely analogous to the nitroalkanes. Compounds with ketonic carbonyl groups are the most important. Their simplest representatives, formaldehyde and acetone, were considered for many decades to be unreactive with diazonium ions until Allan and Podstata (1960) demonstrated that acetone does react. Its reactivity is much lower, however, than that of 2-nitropropane, as seen from the extremely low enolization equilibrium constant of acetone ( E = 0.9 x 10-7, Guthrie and Cullimore, 1979 Guthrie, 1979) and its low CH acidity (pK = 19.1 0.5, Guthrie et al., 1982). ... 

The cyclocondensation of an aldehyde, CH-acidic ketone and ammonia provides symmetrical l,4-dihydropyridine-3,5-dicarboxylate derivatives of pharmacological importance, often called Hantzsch 1,4-dihydropyridines (1,4-DHPs) following its original invention over a century ago (Scheme 4) [44,45]. The 1,4-DHP motif is found in a number of chemotherapeutic agents for... 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

In the presence of base, bifunctional CH acids, CH2XY, react with CS2 to form a dithio acid or a 1,1-ethenedithiolate. The formation of the latter depends on the electron-withdrawing nature of X and Y, and the base used. The proposed mechanism is as follows. 

For a monograph on very weak acids, see Reutov, O.A. Beletskaya, I.P. Butin, K.P. CH-Acids Pergamon NY, 1978. For other discussions, see Cram, D.J. Furulamentals of Carbanion Chemistry Academic Press NY, 1965, p. 1 Streitwieser Jr., A. Hammons,... 

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