Nucleophiles 1,3-dicarbonyl compounds

Concentrated sulfuric or perchloric acids induce polymerization of the cations, while dilute acids, e.g. perchloric acid in aqueous DMSO, cause hydrolysis to 1,4-dicarbonyl compounds. Nucleophilic attack by water probably takes place at the 2-position of protonated furan. Finally, in a reversion of the Paal-Knorr synthesis (see p 58), 2-hydroxy-2,3-dihydrofuran gives rise to the 1,4-dicarbonyl compound hexane-2,5-dione as shown. 

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.). 

Isoxazoles are susceptible to attack by nucleophiles, the reactions involving displacement of a substituent, addition to the ring, or proton abstraction with subsequent ring-opening. Isoxazolium salts are even more susceptible to attack by a variety of nucleophiles, providing useful applications of the isoxazole nucleus in organic synthesis. Especially useful is the reductive cleavage of isoxazoles, which may be considered as masked 1,3-dicarbonyl compounds or enaminoketones. 

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines denved from hexafluoroacetone... 

The chloride of triflic acid (trifluoromethanesulfonyl chloride) is an effective sulfonylating agent Like triflic anhydride, it usually reacts with alcohols and other nucleophiles with the formation of the corresponding derivatives of tnflic acid [69] However, in some reactions, it acts as a chlorinating reagent [98] The reactions of tnfluoromethanesulfonyl chloride with 1,3-dicarbonyl compounds or some carboxylic esters in the presence of a base result m the formation of chlonnated products in high yields (equation 49)... 

The formation of vinylogous amides from primary amines and -dicarbonyl compounds gives rise to hydrolyzable amine derivatives with greatly decreased nucleophilicity of the nitrogen function. Thus these derivatives have found some use as protecting groups in peptide syntheses 617-619). 

In the case of NH2OH with a sharp difference in the nucleophilicity of the two functions, the primary amino group reacts with the carbocation C-1 center. For example, the reaction of l-alkylaminoalk-l-en-3-ynes with hydroxylamine leads to selective synthesis of alkylisoxazoles (69ZOR1179). A preparative value of this method is evident because the use of dicarbonyl compounds as starting materials for the synthesis of alkylisoxazoles results in a mixture of isomers. 

The coupling reaction of arenediazonium ions with semidione radicals (12.84, obtainable by reduction of 1,2-diketones, 12.83) is also included here in the discussion of 1,3-dicarbonyl compounds, although it is a coupling with a nucleophilic radical and does not strictly belong in this context. The reaction (Scheme 12-43) was... 

In addition, Hashida et al. (1971 a) found a linear correlation between log k and the pof fifteen 1,3-dicarbonyl compounds. This indicates that in these cases the nucleophilicity and the basicity of the anions are closely related. The same result was obtained by Hashida et al. (1971b) for the azo coupling reactivity of substituted phenoxide ions. 

The process is assumed to take place by a chemoselective attack of the dianion 2-223 at the bromomethyl group of 2-221 and subsequent nucleophilic attack of the resultant monoanion 2-224 onto the epoxide moiety to give 2-225. Use of the sodium-lithium-salt 2-223 of the dicarbonyl compound 2-220, the reaction temperature as well as the Lewis acid LiC104, are crucial. The reaction seems to be quite general, since various 1,3-dicarbonyl compounds can be converted into the corresponding furans. 

As depicted in the following scheme, in the presence of sodium iodate and pyridine, several 5,6-dihydroxylated benzofuran derivatives were synthesized via an oxidation-Michael addition of P-dicarbonyl compounds to catechols in a one-pot procedure <06TL2615 06JHC1673>. A novel additive Pummerer reaction of 2-benzo[fc]furan sulfilimines with carbon nucleophiles derived from P-dicarbonyl compounds was also employed to the synthesis of 2,3-disubstituted benzo[b]furans <06TL595>. 

Aside from alcohols, other oxygen nucleophiles have also participated in hydroalkoxylation reactions with alkynes. The most common of these are 1,3-dicarbonyl compounds, whose enol oxygens are readily available to add to alkynes. Cyclization reactions of this type have been carried out under Pd(0) catalysis with various aryl or vinyl iodides or triflates, often in the presence of CO, affording the corresponding furan derivatives (Equation (95)).337-340 A similar approach employing cyclic 1,3-diketones has also been reported to prepare THFs and dihydropyrans under Pd, Pt, or W catalysis.341 Simple l-alkyn-5-ones have also been isomerized to furans under the influence of Hg(OTf)2.342... 

When the monosodium salts of uracil and similar pyrimidines react with diphenyl phosphorochloridate, phosphorylation takes place on oxygen unless other suitable nucleophilic centres are present and free.69 The reaction between the sodium salt of a 1,3-dicarbonyl compound and diethyl phosphorochloridothionate yields the Z-vinylphosphorothionate if the tetrabutylammonium salt is employed, the product has E geometry. This phenomenon has been interpreted in terms of the shape of the... 

Catalysed alkylation of tosylmethylisocyanate (TOSMIC) [63, 64] has extended its versatility in the preparation of l, 4-dicarbonyl compounds and as a l, 3-dipolar precursor for the synthesis of heterocyclic compounds. The alkylation reactions should not be conducted in carbon disulphide, as nucleophilic attack by the methylene group on the carbon disulphide leads, after ring closure and S-alkylation, to a 4-alkylthio-1,3-thiazole system [65]. 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Hydroxycoumarin can be considered as an enol tautomer of a 1,3-dicarbonyl compound conjugation with the aromatic ring favours the enol tautomer. This now exposes its potential as a nucleophile. Whilst we may begin to consider enolate anion chemistry, no strong base is required and we may formulate a mechanism in which the enol acts as the nucleophile, in a simple aldol reaction with formaldehyde. Dehydration follows and produces an unsaturated ketone, which then becomes the electrophile in a Michael reaction (see Section 10.10). The nucleophile is a second molecule of 4-hydroxycoumarin. 

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

The majority of recent contributions for the conjugate addition of C-H acids to a,p-unsaturated carbonyl compounds catalysed through iminium ion intermediates have come from the laboratories of Jprgensen. The ease with which 1,3-dicarbonyl compounds and nitroalkanes can be deprotonated, together with the soft nature of the nucleophile mean this is a particularly facile reaction which conveniently leads to useful precursors for further synthetic manipulation. 

The only reactions of 2-diazobenzimidazole with nucleophiles involved the coupling with a-chloro-dicarbonyl compounds that gave the chlorohy-drazones (82MI2) and the reaction with nitrite in the presence of copper sulfate which led to the 2-nitrobenzimidazole (65AAC469). 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

Compounds whose structures are similar to (3-dicarbonyl compounds also have active hydrogens. These compounds have a CH2 sandwiched between two electron-withdrawing groups, some examples of which are in Figure 15-21. The loss of a hydrogen ion from the sandwiched carbon leaves an anion, which can then behave as a nucleophile similar to other nucleophiles seen in this chapter. 

On the basis of previous results, the Rueping group started to study alkylations with activated alkenes and nucleophiles other than arenes. Recently, Lewis- and Brpnsted-acid-catalyzed hydroalkylation procedures with 1,3-dicarbonyl compounds as nucleophiles have been developed [69, 70]. These reactions primarily utilized Pd... 

The catalytic efficiency of bifunctional thiourea 12 turned out to be mainly limited to (pre)nucleophiles such as CH-acidic 1,3-dicarbonyl compounds and... 

The use of other 1,3-dicarbonyl compounds as nucleophilic species was also investigated in this reaction. In particular, unsymmetrical diketones were tested in the condensation, giving rise to mixtures of C-glycosides [111, 114]. 

Nucleophilic additions were studied using the same TSIL with pyrrolidine and thiophenol as models. As with the Diels-Alder reaction above, the reaction gave the required adducts which were then transesterified to give the final products. Heck coupling catalyzed by a transition metal and the Stetter reaction, Scheme 30, to prepare 1,4-dicarbonyl compounds were also studied by the same group using similar TSILs. 

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