Nucleophiles 1,3-dicarbonylic carbon

One of the first 1,3-dicarbonylic carbon nucleophiles added in asymmetric fashion to iminium activated enals was malonates. In 2006, Jorgensen et al. reported the reaction between malonates and enals catalyzed by catalyst 28 [20]. The final products 42 were obtained in good yields and excellent enantioselectivities. The only limitation of this methodology is that only aromatic enals could be used. To overcome this hmitation, Oriyama and coworkers employed catalyst 43 to promote the reaction between crotonaldehyde and malonates in moderate yields and enanti-oselectivities (Scheme 33.6) [21]. 

Alkenes in (alkene)dicarbonyl(T -cyclopentadienyl)iron(l+) cations react with carbon nucleophiles to form new C —C bonds (M. Rosenblum, 1974 A.J. Pearson, 1987). Tricarbon-yi(ri -cycIohexadienyI)iron(l-h) cations, prepared from the T] -l,3-cyclohexadiene complexes by hydride abstraction with tritylium cations, react similarly to give 5-substituted 1,3-cyclo-hexadienes, and neutral tricarbonyl(n -l,3-cyciohexadiene)iron complexes can be coupled with olefins by hydrogen transfer at > 140°C. These reactions proceed regio- and stereospecifically in the successive cyanide addition and spirocyclization at an optically pure N-allyl-N-phenyl-1,3-cyclohexadiene-l-carboxamide iron complex (A.J. Pearson, 1989). 

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... 

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>. 

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. 

Widenhoefer has developed methods for Pd-catalyzed addition of 1,3-dicarbonyl nucleophiles to alkenes [ 171-173]. Most of these reactions employ stoichiometric copper as the oxidant however, Yang and coworkers recently reported a modified procedure that employs cocatalytic lanthanide Lewis acids to achieve direct dioxygen-coupled turnover (Eq. 39) [174], The Lewis acid is thought to activate the carbon nucleophile, P-keto amide, toward attack on the tethered alkene. 

Related studies have recently been reported by the same author on propargyl steres reactions with dicarbonyl compounds or electron-rich arenes [135], to provide an atom-economical functionalization of carbon nucleophiles under catalytic conditions, using a very different method of addition catalyzed by Lewis acids [136]. 

Support-bound carbonyl compounds can be converted into alcohols by treatment with suitable carbon nucleophiles. Aldehydes react readily with ketones or other C,H-acidic compounds under acid- or base-catalysis to yield the products of aldol addition (Table 7.2). Some types of C,H-acidic compound, such as 1,3-dicarbonyl compounds, can give the products of aldol condensation directly (Section 5.2.2.2). 

Numerous examples of the preparation of tetramic acids from N-acylated amino acid esters by a Dieckmann-type cyclocondensation have been reported (Entries 7-9, Table 15.4). Deprotonated 1,3-dicarbonyl compounds and unactivated amide enolates can be used as carbon nucleophiles. In most of these examples, the ester that acts as electrophile also links the substrate to the support, so that cyclization and cleavage from the support occur simultaneously. The preparation of five-membered cyclic imi-des is discussed in Section 13.8. 

They are, however, reactive carbon nucleophiles. Examples of enolates include anionic derivatives of aldehydes, ketones, acid derivatives, and dicarbonyl compounds. 

Alkynyl(phenyl)iodonium salts can be used for the preparation of substituted alkynes by the reaction with carbon nucleophiles. The parent ethynyliodonium tetrafluoroborate 124 reacts with various enolates of /J-dicarbonyl compounds 123 to give the respective alkynylated products 125 in a high yield (Scheme 51) [109]. The anion of nitrocyclohexane can also be ethynylated under these conditions. A similar alkynylation of 2-methyl-1,3-cyclopentanedione by ethynyliodonium salt 124 was applied in the key step of the synthesis of chiral methylene lactones [110]. 

A -Acyliminium ion pools were found to react with various carbon nucleophiles. Scheme 5 summarizes reactions of the A -acyliminium ion pools with allylsilanes, silyl enol ethers, Grignard reagents, and 1,3-dicarbonyl compounds. ... 

Besides the Michael addition of heteroatomic nucleophiles initiating cyclocondensations, acceptor substituted unsaturated systems can also be reacted with carbon nucleophiles stemming from aldehydes in the sense of an umpolung, generally referred to as the Stetter reaction [244-246]. This process is organocatalytic and furnishes in turn 1,4-dicarbonyl compounds, intermediates that are well suited for Paal-Knorr cyclocondensations giving rise to furans or pyrroles. Among numerous heterocycles furans and pyrroles have always been the most prominent ones since they constitute important classes of natural products [247-249], of synthetic... 

Several classes of carbon nucleophiles have been successfully used in these systems, reflecting the utility of Reissert chemistry for derivatizing azines via carbon-carbon bond formation. Apart from cyanide anion, other classes of carbon nucleophiles have been explored. For instance, addition of indole (51) to A-acyla-zinium salts proceeds selectively at the a-position (Scheme 9). Pyrrole, quinolines and isoquinolines all behave similarly [73-76]. A related reaction, yielding adduct 70 (Scheme 12b) has also been described. In this case, azine activation is promoted by Vilsmeier reagents (generated by reaction of amides with POCI3) [77]. p-Dicarbonyls are reactive inputs in this chemistry, and dialkyl malonates 53... 

There is one example in which part of the amidine system is a C—N bond in a heterocyclic ring. The enamino ketone condensation products (42) of 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl compounds cyclize in basic medium to form 60-80% yields of imidazoles. The driving force for this reaction is provided by the well-established, general attack of a nucleophilic centre in the side-chain at N-2 of the heterocyclic ring, but it is unusual in that a carbon nucleophile (rather than an oxygen or nitrogen species) is implicated (Scheme 23). 

In addition to their reactions with trlmethylsilyl enol ethers, (propargyl1um)Co2(C0)g complexes react with a variety of other mild carbon nucleophiles including activated aromatic compounds, g-dicarbonyl compounds, other enol derivatives (enol acetates and ketones directly), allylsilanes, and alkyl- and alkynyl-aluminum reagents. These reactions provide a flexible means to introduce the synthetically versatile propargyl function. Key features of propargylations using these complexes are 1) ready... 

Aryllead, vinyllead, and alk-l-ynyllead tricarboxylates behave as aryl, vinyl and alkynyl cation equivalents to react with a variety of nucleophiles, especially soft carbon nucleophiles such as T -dicarbonyl compounds, phenols, and nitroalkanes. In these reactions, unique regioselectivity is obtained in which there is a preference for the generation of quaternary carbon centers. This aspect of reactivity has been put to use in a number of natural product syntheses and can result in the formation of highly hindered structures. 

Unstable viriyUead triacetates, generated in situ, react wifh soft carbon nucleophiles such as //-dicarbonyl compounds to give moderate to good yields of C-viny-lated products (Scheme 13.15). Thus, there is considerable potential for use of this vinylation in organic synthesis [12e, 41b]. 

N-Acyliminium ion pools react with various carbon nucleophiles as summarized in Scheme 5.16. For example, allylsilanes, silyl enol ethers, Grignard reagents, and 1,3-dicarbonyl compounds serve as good nucleophiles. Aromatic and heteroaromatic compounds also react as nucleophiles with N-acyliminium ion pools to give Friedel-Crafts-type alkylation products.N-Acyliminium ions are known to serve as electron-deficient 4n components and undergo [4 -F 2] cycloaddition with alkenes and alkynes. Usually these reactions take place very quickly, and therefore N-acyliminium ion pools serve as effective reagents for flash chemistry. 

In the case of carbon nucleophiles, the behaviour depends on the nature of the substrate. P-Dicarbonyl enolates react with alkynyliodonium salts to afford a transient carbene, which evolves either by migration towards alkynyl-substituted product, or by insertion towards cyclopentene... 

In a series of outstanding papers, Pinhey et al have shown that aryllead tricarboxylates react with soft nucleophiles to afford C-arylation products. These aryllead derivatives behave as aryl cation equivalents in reactions which involve a ligand coupling mechanism (see section 7.5).9 2 ju most cases, the reactions proceed in chloroform at 40-60 C in the presence of pyridine as a base with a ratio of substrate to organolead derivative to pyridine of 1 1 3. The substrates which easily undergo C-arylation include phenols, p-dicarbonyl compounds and their vinylogues, a-cyanoesters, a-hetero-substituted ketones, enamines and nitroalkanes. A very limited number of non-carbon nucleophiles has also been reported to react. 

Carbon nucleophiles can also add to the double bond. For example, addition of the enolate derived from acetone leads to a 3-ketophosphonate, which can be viewed as a masked form of a 1,4-dicarbonyl compound (equation 98) " ... 

Similar to Cr(CO)3 complexes, less stabilized carbon nucleophiles such as MeLi and acetone enolate add irreversibly at the position ortho to chloride in (chlo-robenzene)FeCp [84]. Nucleophiles stabilized by a nitro, p-dicarbonyl, or related groups add reversibly with ultimate formation of a substitution product [66, 85]. Ketoarene complexes 35 can be prepared by addition of a malonate derivative followed by acid-induced decarboxylation [86]. 

Few examples of non-catalytic alkenylations of carbon nucleophiles have been published. For example, enolate anions derived from various 1,3-dicarbonyl compounds can be vinylated with cyclohexenyl or cyclopentenyl iodonium salts 715 to afford products 716 (Scheme 3.286) [964]. 

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