Compounds, CH-acidic

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). 

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 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. 

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. 

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. 

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

Alkoxyallenes turned out to be excellent starting materials also for the synthesis of highly functionalized 1,3-dienes, two examples being depicted in Schemes 8.61 and 8.62. As described by Kantlehner et al., 1,3-dienes such as 238 were obtained from methoxyallene derivative 50 by condensation with CH-acidic compounds 237 [135]. Hoppe and co-workers explored the stereochemical course of the allene Claisen rearrangement under Johnson s conditions, e.g. the reaction of 239 with trimethyl orthoacetate, which furnished intermediate 240 followed by rearrangement to the isomeric dienes 241a,b [136],... 

The reaction of Bi2HnNH22 with chlorides of carboxylic acids proceeds not to carboxamides, as would have been expected, but to carboximido acids. Reaction of the amine takes place only when deprotonated with strong base. The high p KR value of the ammonium group makes reactions with CH-acidic compounds difficult, as the latter might be stronger acids than the Bi2HiiNH3. ... 

Anions of CH-acidic compounds (dimethyl malonate and nitromethane) can he linked to aromatics (benzene, toluene, naphthalene, and 1,4-dimethoxybenzene) when they are coelectrolyzed in methanol-sodium methoxide [167]. 

Bis-acceptor-substituted diazomethanes are most conveniently prepared by diazo group transfer to CH acidic compounds either with sulfonyl azides under basic conditions [949,950] or with l-alkyl-2-azidopyridinium salts [951] under neutral or acidic conditions [952-954]. Diazo group transfer with both types of reagents usually proceeds in high yield with malonic acid derivatives, 3-keto esters and amides, 1,3-diketones, or p, y-unsaturated carbonyl compounds [955,956]. Cyano-, sulfonyl, or nitrodiazomethanes, which can be unstable or sensitive to bases, can often only be prepared with 2-azidopyridinium salts, which accomplish diazo group transfer under neutral or slightly acidic reaction conditions. Other problematic substrates include amides of the type Z-CHj-CONHR and P-imino esters or the tautomeric 3-amino-2-propenoic esters, which upon diazo group transfer cyclize to 1,2,3-triazoles [957-959]. 

Scheme 62. Palladium-catalyzed cross-coupling of bicyclopropylidene derivatives with metal-lated or brominated CH-acidic compounds accompanied by an unprecedented ring opening [153]...

The preparation and properties of the dithiocarboxylic acids and their metal complexes have been reviewed several times.38"11 The formation of C—C bonds in the direct reaction of CS2 requires sufficiently nucleophilic carbon bases, directly or potentially accessible in the form of ambifunction-al phenoxides, organometalfic compounds, CH acidic compounds, enamines or ketimines. Carba-nions react with CS2 to give dithiocarboxylates. The preparation and purification of the adds is performed via their salts. Metal complexes are in general readily available. The bonding in these complexes is mostly of the type (27) but a bonding mode (28) is also found. Action of elemental sulfur upon heavy metal complexes of (29) aromatic dithiocarboxylic acids yields the perthio complexes (29) of these compounds. 

In the Mannich reaction, a carbonyl component usually formaldehyde, a secondary amine and a CH-acidic compound react together to form 3-aminoketones. The classical method for the formation of (3-aminoketones suffers from many disadvantages such as drastic reaction conditions, formation of undesired side products, little or no stereo-or regioselectivity and low yields. In 2000, Gadhwal and co-workers developed the first microwave-assisted Mannich protocol24 (Scheme 5.10). 

In the course of oxidation of the sulfonyl group in 32, lithium di isopropyl ami do is used to form the a-sulfonyl carbanion 33 This anion reacts with MOPH via complex 34 to give natural product 1. The MOPH complex utilized here is crystalline and stable to air over brief periods of time, so it is relatively convenient to employ. It has become a standard reagent tor a-hydroxylation of CH-acidic compounds.1 ... 

In the first part of this one-pot multi-component reaction a carbonyl group reacts with a CH-acidic compound. 

In addition to the cathodic hydrodimerization of activated olefins and the Kolbe reaction, the anodic dimerization of CH-acidic compounds is another possibility for the electrochemical C—C coupling. Monsanto 281 > has used the anodic dimerization of malonates in a laboratory synthesis of intermediates for useful sequestrants and detergency builders. 

An alternative solution to the workup issue relied on the attachment of CH-acidic compounds 64 to a soluble polymer support (PEG-4000). The approach improved the yields of the dihydropyrimidinones 66 by the use of a 2-fold excess of other components—urea and aldehyde in the microwave-assisted solvent-free cyclocondensation [118]. Another single-step approach towards 4,5-disubstituted pyrimidines was based on cyclocondensation of a variety of aromatic, heterocyclic and aliphatic ketones, formamide and HMDS as the ammonium source [119]. The high temperature (215 °C) required to effect the formation of pyrimidines was secured by microwave dielectric heating in sealed vessels (Scheme 45). 

More interestingly, Michael additions of CH-acidic compounds 139 onto the vinyl ketone — generated from 132 by action of the catalyst Triton B (0.08 equiv. in methanol) — smoothly afford adducts 140 in good yields (Eq. 57)83). Under these conditions methoxide acts as the desilylating agent as well as the base to form the corresponding carbanions. 

Pyrimido[5,4-c]-l,2,5-oxadiazinones (417) are suitable starting materials to construct annulated pyrazines. Reaction with carbanions derived from CH-acidic compounds, activated by two different electron-withdrawing functions, proceed in a regioselective manner by initial attack at the N—O bond. Triethyl phosphonoacetate, /f-ketophosphonates, nitro ketones, nitro esters, sulfonylacetates, and JV-acetoacetylglycine have been applied to form 6,7-disubstituted lumazines (418) (Equation (18)) <91H(32)79>. 

In another type of reaction, CH-acidic compounds in the presence of a strong base react with aldonitrones by C—C bond formation to form a hydroxylamine. Formed from the reaction of (78) and dimethyl malonate, the adduct (81) undergoes cyclization to an azlactone <71LA(748)143>. 

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