Dicarbonyl Compounds as Nucleophiles

This type of reaction was also investigated by Liu and Li using a meso-porous organosilica chiral nickel catalyst. This functionalised meso-porous organosilica, with chiral cyclohexanediamine-based nickel(ii) complex 6 incorporated within the silica framework, was prepared through 

In 2012, Wu et al reported a practical large-scale preparation of the antidepressant drug (i )-rolipram from isovanilline, the key step of which was an enantioselective nickel-catalysed conjugate addition of diethyl malonate to a functionalised nitroalkene. Using only 1 mol% of catalyst the reac- 

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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 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]. 

Zhi-Feng, L., Yong-Miao, S., Jia-Jun, Y., Hong-Wen, H., and Jian-Hua, X. (2008) Photoinduced three-component reactions of tetracyanobenzene with alkenes in the presence of 1,3-dicarbonyl compounds as nucleophiles. Journal of Organic Chemistry, 73, 8010-8015. 

In biosynthesis, pyruvic acid, a representative 1,2-dicarbonyl compound, is used as a key C2 and C3 donor unit. The use of related 1,2-dicarbonyl compounds, such as a-keto esters and ct-keto anilides, as nucleophiles in catalytic asymmetric synthesis, however, is rather limited due to their high reactivity as electrophiles. Chemoselective activation of 1,2-dicarbonyl compounds as nucleophiles is required to avoid undesired self-condensation reactions of 1,2-dicarbonyl compounds. Applications of 1,2-dicarbonyl compounds as donors in asymmetric Michael reactions remained unsolved until a recent report by Sodeoka et oL Indeed, these authors have described the first example of a diastereo- and... 

Kita et al. further developed PIFA-induced CDC reactions between phenyl ether derivatives and cyclic 1,3-dicarbonyl compounds as nucleophiles (Scheme 8.2). The reactions with 1 equiv. of PIFA in hexafluoro-2-propyl alcohol attach nucleophiles onto the ort/jo-position of para-substituted phenyl ethers to afford the dehydrogenative coupling products 8 in moderate yields. UV and electron spin resonance (ESR) spectroscopic studies support a reaction mechanism involving the formation of the charge-transfer complex 9 followed by the generation of the cation radical intermediate 10. This is the first example of the reaction of aromatic compounds with PIFA that involves the formation not of diatyliodonium(m) salt 11 but the cation radical intermediate 10 as a key intermediate. 

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. 

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyl compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of o /ocarbonyl compounds.. A strong, storically hindered base such as LD.A is needetl so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

The reaction of an enolate with an a,(3-unsaturated carbonyl compound yields a 1,5-dicarbonyl compound as a product. Two different reaction paths can be envisioned for synthesis of these compounds. The superior pathway is always that which employs the most acidic carbonyl partner (least basic enolate) as the nucleophile. 

A TMSOTf-initiated cyclization of the dicarbonyl substrate was invoked to explain the reactivity pattern [79]. Selective complexation of the less hindered carbonyl group activates it toward intramolecular nucleophilic attack by the more hindered carbonyl which leads to an oxocarbenium species. Subsequent attack by the enol ether results in addition to the more hindered carbonyl group. The formation of this cyclic intermediate also explains the high stereochemical induction by existing asymmetric centers in the substrates, as demonstrated by Eq. 52, where the stereochemistry at four centers is controlled. A similar reactivity pattern was observed for the bis-silyl enol ethers of / -diketones. The method is also efficient for the synthesis of oxabicyclo[3.3.1] substrates via 1.5-dicarbonyl compounds, as shown in Eq. 53. Rapid entry into more complex polycyclic annulation products is possible starting from cyclic dicarbonyl electrophiles [80]. 

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). 

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>. 

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]. 

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. ... 

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. 

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... 

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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