1.3- Dicarbonyl compounds from nitriles

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Pyrroles from 1,4-dicarbonyl compounds and ammonia isoxazolines from olefins and nitrile oxides. 

In the presence of bis(acetylacetonato)nickel, a-dicarbonyl compounds readily add at the nitrile group of 4-R-substituted l,2,5-oxadiazole-3-carbonitriles 219 to form enaminofurazans 220. The adducts obtained from 4-amino-3-cyanofurazan underwent intramolecular cyclization upon heating with acetic acid in ethanol to give furazano[3,4- ]pyridine 221 derivatives in high yields (Scheme 51) <2001RCB1280>. 

The three-carbon component in this subgroup is either a /3-dicarbonyl compound or a /3-keto nitrile. The N and C-N components in the reactions with /3-dicarbonyl compounds come from formamide, a nitrile, a thiocyanate, or a cyanamide <1994HC(52)1>. 

Regarding ozonation processes, the treatment with ozone leads to halogen-free oxygenated compounds (except when bromide is present), mostly aldehydes, carboxylic acids, ketoacids, ketones, etc. [189]. The evolution of analytical techniques and their combined use have allowed some researchers to identify new ozone by-products. This is the case of the work of Richardson et al. [189,190] who combined mass spectrometry and infrared spectroscopy together with derivatization methods. These authors found numerous aldehydes, ketones, dicarbonyl compounds, carboxylic acids, aldo and keto acids, and nitriles from the ozonation of Mississippi River water with 2.7-3 mg L 1 of TOC and pH about 7.5. They also identified by-products from ozonated-chlorinated (with chlorine and chloramine) water. In these cases, they found haloalkanes, haloalkenes, halo aldehydes, haloketones, haloacids, brominated compounds due to the presence of bromide ion, etc. They observed a lower formation of halocompounds formed after ozone-chlorine or chloramine oxidations than after single chlorination or chlorami-nation, showing the beneficial effect of preozonation. 

Carbanions from hydrocarbons, nitriles, ketones, esters, TV./V-dialkyl acetamides and thioamides, and mono and dianions from (3-dicarbonyl compounds are some of the most common nucleophiles through which a new C-C bond can be formed. This C-C bond formation is also achieved by reaction with aromatic alkoxides. Among the nitrogen nucleophiles known to react are amide ions to form anilines however, the anions from aromatic amines, pyrroles, diazoles and triazoles, react with aromatic substrates to afford C-arylation. 

The problem of regioselectivity remains. Monosubstituted alkynes usually react cleanly using the HOMO of the alkyne and the LUMO of the nitrile oxide. The product is exactly that type of isoxazole (72 or 73) that was so difficult to make from dicarbonyl compounds and hydroxylamine. Here regioselectivity is controlled because the two substituents (R1 and R2) are on different reagents. Conditions are very mild. 

From 1,3-Dicarbonyl Compounds (or Synthons) and 3-Amino-Enones or -Nitriles Pyridines are formed from the interaction between a 1,3-dicarbonyl compound and a 3-amino-enone or 3-amino-acrylate 3-cyano-2-pyridones result if cyanoacetamide is used instead of an amino-enone. 

Still another powerful method for the regeneration of carbonyl compounds from dialkylhydrazones is copper-catalyzed hydrolysis. The reagents that have been tested for this purpose are 2% aqueous cop-per(II) acetate solution at pH 4, copper(II) chloride in 0.05M phosphate buffer and 75% tetrahydrofu-ran/water, and copper(II) sulfate pentahydrate . Under the conditions of the hydrolysis, no reaction is observed in the absence of the copper(II) ion. Typical yields are 85-100%. Other functional groups like a-dicarbonyl, a-tricarbonyl, acetal and aldehydic formyl groups were not affected by this hydrolysis procedure. Nitrile formation in the case of aldehyde dimethylhydrazones was not a significant side reaction. However, reaction times ranged from 1 to 15 h. The reaction is believed to be nonoxidative in nature rather, the copper is believed to activate the C=N bond and catalyze hydrolysis. The dimethylhydrazine produced during hydrolysis also complexes irreversibly with the copper(II) ion to drive the reaction to completion. 

From 1,3-dicarbonyl compounds and 3-amino-enones or -nitriles... 

The hydrazones 22 derived from partially protected o-ribose or o-glucose exist in equilibrium with the corresponding cyclic structures (Fig. 4). Subsequent cyclization of the respective hydrazine residue with 1,3-dicarbonyl compounds or unsaturated nitriles gave the pyrazoles 23 and 24 [51-55]. To-sylation of the isopropylidene derivative 23 gave the pyrazolium tosylate 26 via the intramolecular cyclization of 25 [54]. 

Trifluoroacetamidine (585) is most widely used for the principal synthesis of pyrimidines. Compound 585 can be prepared from ethyl trifluoroacetate by ammo-nolysis, followed by dehydration with P2O5 and reaction with ammonia (Scheme 124) [335,336]. Amidine 585 has been introduced into reaction with various p-dicarbonyl compounds and their synthetic equivalents (Table 27), including p-ketoesters (Entries 1-6), in particular p-ketopyruvates (Entry 3) and a-alkoxymethylene-p-ketoesters (Entries 4-6), p-enaminocarbonyl compounds (Entries 7-9), malonic acid derivatives (Entry 10), fluorinated p-diketones (Entry 11), vinamidinium salts (Entry 12), a,p-unsaturated nitriles with leaving group at p position (Entries 13-15) and other bis-electrophiles (Entries 16, 17). Usually, the reaction gives moderate yields of the target 2-CF3-pyrimidines (ca. 50 %). 

Reaction of the stabilized anions derived from )3-dicarbonyl compounds and related analogs (Table 23-1) with a,)3-unsaturated carbonyl compounds leads to 1,4-additions. This transformation, an example of Michael addition (Section 18-11), is base catalyzed and works with a,j8-unsaturated ketones, aldehydes, nitriles, and carboxylic acid derivatives, all of which are termed Michael acceptors. 

Some of the most common nucleophiles through which a new CC bond can be formed are carbanions from hydrocarbons, nitriles, ketones, esters, N,N-dialkyl acetamides and thioamides, and mono- and dianions from 3-dicarbonyl compounds. The synthesis of indoles, isocarbostyrils, isoquinolines, benza-zepines, binaphthyls, etc. and an important number of natural products has been achieved by ring closure reactions of carbanions with suitable substrates through the Sgj.jl mechanism. Several reviews have been published in relation to aromatic Sgj,l reactions and to the synthetic applications of the process. - ... 

---