Carbon nucleophiles enamines

These Fp-alkene complexes react with a variety of other nucleophiles,3 5 including water, alcohols, amines,3 6 phosphines, and thiols as well as carbon nucleophiles (enamines, organocuprates, enolates),3 2,3l8 and dialkyl cadmium reagents.3 9 Diene complexes such as 487 were converted to the corresponding cationic complexes (488), for example, and reaction with malonate gave 489. The iron complex was removed with trimethylamine N-oxide (Me N-O) to give 490.320... 

Carbon nucleophiles enamines Michael addition of cyclohexanone and other cyclic ketones to chalcones Ar CH=CHCOAr, catalysed by the pyrrolidine-based phthalimide and/or 1,8-naphthalimide (316) (30mol%) in the presence of PhC02H (10mol%), neat at 20 C, has been found to exhibit good stereoselectivity (<99 1 dr, <96% ee) Similar results were obtained with the C2-sytnmetric tetraamine (317) as 0 catalyst (20 mol%) with <99 1 dr and 93% ee in the presence of 4-Me0-C6H4C02H (20 mol%) (neat, r.t.). Here, a mechanism has been proposed, based on the ESI-MS study of the intermediates. ... 

The enamine 315 as a carbon nucleophile reacts with 7r-allylpalladium complexes to give allyl ketones after hydrolysis[265],... 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As deseribed in Chapter 3, Seetion 3, Tt-allylpalladium complexes react with soft carbon nucleophiles such as maionates, /3-keto esters, and enamines in DMSO to form earbon-carbon bonds[2, 3], The characteristie feature of this reaction is that whereas organometallic reagents are eonsidered to be nucleophilic and react with electrophiles, typieally earbonyl eompounds, Tt-allylpalladium complexes are electrophilie and reaet with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

The preparation of enamines will be discussed in Chapter 8, and their application as carbon nucleophiles in synthesis is discussed in Chapter 1 of Part B. 

In addition to enolate ions, other kinds of carbon nucleophiles also add to a jjS-iinsaturated acceptors in Michael-like reactions. Among the most important such nucleophiles, particularly in biological chemistry, are enamines, which are... 

As the following resonance structures indicate, enamines are electronically similar to enolate ions. Overlap of the nitrogen lone-pair orbital with the double-bond p orbitals leads to an increase in electron density on the a carbon atom, making that carbon nucleophilic. An electrostatic potential map of N,N-6imethyl-aminoethvlene shows this shift of electron density (red) toward the a position. 

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1 illustrates the tendency for reaction to proceed through the more stable enolate. Entries 2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are comparable in acidity to (i-ketocslcrs (see Table 1.1) and are often excellent nucleophiles for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9 is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10 shows an enamine as the carbon nucleophile. All of these reactions were done under equilibrating conditions. 

The focus of Chapters 1 and 2 is enolates and related carbon nucleophiles such as silyl enol ethers, enamines, and imine anions, which can be referred to as enolate equivalents. 

Also alkynylcarbene complexes can react as Michael acceptors with nucleophiles, forming 1,3-dien-l-ylcarbene complexes (Figure 2.17). Both carbon nucleophiles, such as, e.g., enamines [246-249], and non-carbon nucleophiles, such as imidates [250], amines [64,131,251], aliphatic alcohols [48,79,252], phenols [252], and thiols [252] can add to the C-C triple bond of alkynylcarbene complexes. Further reactions of the C-C triple bond of alkynylcarbene complexes include 1,3-dipolar [253,254], Diels-Alder [64,234,238,255-258] and [2 -i- 2] cycloadditions [259 -261], intramolecular Pauson-Khand reactions [43,262], and C-metallation of ethynylcarbene complexes [263]. 

When trifluoroacetaldehyde ethyl hemiacetal [F3CCH(OH)OEt] is treated with enamines in hexane at room temperature, it provides a source of the aldehyde under mild conditions. Subsequent reaction with the enamine can be used to prepare -hydroxy-/ -trifluoromethyl ketones, F3CCH(OH)CH2COR. The enamine plays successive roles as base, ammonium counterion, and then carbon nucleophile as the sequence proceeds. 

The most prominent property of enamines is that the ( -carbon can behave as a carbon nucleophile. 

The nucleophilicity of the carbon of enamines makes them particularly useful reagents in organic synthesis because they can be acylated, alkylated, and used in Michael addition. 

The reaction of tnfluoromethyl-substituted N-acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enamines [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomtnle [2,41], 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 derived from hexafluoroacetone... 

How can the imine behave as the carbon donor in addition to the aldehyde carbonyl of glyceraldehyde 3-phosphate It is unlikely to do so directly, but it can rearrange to an enamine which, as we will explain in Section 17-4B, can act as a carbon nucleophile ... 

By using the neutral enamine as the carbon nucleophile rather than an eno-late anion, the biological system avoids the need for strongly basic reaction conditions in aldol addition. 

Several important biological reactions utilize enamine intermediates as carbon nucleophiles in C-C bond-forming reactions. One example is discussed in Section 17-3F. 

Examine the electrostatic potential map of each nucleophile enamine, silyl enol ether, lithium enolate and enol) with emphasis on the face of the nucleophilic alkene carbon. Rank the nucleophiles from most electron rich to least electron rich. What factors are responsible for this order (Hint For each molecule, consider an alternative Lewis structure to that given above that places a negative charge on the nucleophilic carbon.)... 

This section describes the additions of stabilized carbon nucleophiles, such as cyanide, malonate, ketone enolates, enamines, etc., to alkenic ir-systems. These reactions are highly useful in organic synthesis since they are all carbon-carbon bond-forming reactions, and therefore have been used extensively in organic chemistry. 

The reaction of 7i-allylpalladium chloride (3) with carbon nucleophiles such as malonate, acetoacetate and enamines was discovered in 1965 [3]. This reaction constitutes the basis of stoichiometric as well as catalytic 7i-allylpalladium chemistry. 

Mechanistically, the antibody aldolases resemble natural class I aldolase enzymes (Scheme 4.7) [52]. In the first step of a condensation reaction, the s-amino group of the catalytic lysine reacts with a ketone to form a Schiffbase. Deprotonation of this species yields a nucleophilic enamine, which condenses with electrophilic aldehydes in a second step to form a new carbon-carbon bond. Subsequent hydrolysis of the Schiffbase releases product and regenerates the active catalyst. 

Because of the importance of carbon nucleophiles in synthesis, organic chemists have spent considerable effort developing others in addition to the enolate anions that have already been described. Several of these other carbon nucleophiles are presented in this and the following section. This section describes the use of enamines. 

Potentiometric measurements indicate that in water-DMSO the 3-aminothiophenes 197 undergo protonation exclusively at the nitrogen with dilute acid. But on treatment with the superelectrophile 4,6-dinitrobenzofuroxan (DNBF) they react as carbon nucleophiles giving rise directly to the corresponding C-adducts. The 3-aminothio-phenes are thus shown to possess strong enaminic character <1998CJC937>. 

In addition ta molate iona. other kinds of carbon nucleophiles add unaatarated acceptors in th Michael reaction greatly extending the usefulness ami versatility of the procew. Among (he most important such nucleophiles are eruimines- Recall from Section 19 9 that enamines are reedily prepared by reaction between a ketone and a socondary amine ... 

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