Acylation carbon nucleophiles

As with the tetrahedral mechanism at an acyl carbon, nucleophilic catalysis (p. 427) has been demonstrated with an aryl substrate, in certain cases. 

Carboxylic acid and its derivatives undergo nucleophilic acyl substitution, where one nucleophile replaces another on the acyl carbon. Nucleophilic acyl substitution can interconvert all carboxylic acid derivatives, and the reaction mechanism varies depending on acidic or basic conditions. Nucleophiles can either be negatively charged anion (Nu ) or neutral (Nu ) molecules. 

Substitution (SnI or Sn2) is the major reaction of nucleophiles in which one functional group is replaced by another (nucleophilic aliphatic substitution). Nucleophiles can also form a new bond to an acyl carbon (nucleophilic acyl addition). Both of these retrosynthetic transforms are represented by the C-Nuc species, where Nuc = CN , AcQ-, RO , N3-, CO2-, etc. and X = Cl, Br, I, OAc, OSO2R, and so on for Sn2 reactions. In nucleophilic acyl substitutions, the nucleophile is usually a carbon, nitrogen or oxygen species. 

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 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 reaction of tnfluoropymvates or their acyl imines with carbon nucleophiles offers a convenient route to a-tnfluornmethyl substituted a-hydroxy or a-ammn acids Reduction of the keto or immo function yields 3,3,3-tnfluorolac-tates or 3,3,3-tnfluoroaIanine esters [32]. 

When a Br nsted base functions catalytically by sharing an electron pair with a proton, it is acting as a general base catalyst, but when it shares the electron with an atom other than the proton it is (by definition) acting as a nucleophile. This other atom (electrophilic site) is usually carbon, but in organic chemistry it might also be, for example, phosphorus or silicon, whereas in inorganic chemistry it could be the central metal ion in a coordination complex. Here we consider nucleophilic reactions at unsaturated carbon, primarily at carbonyl carbon. Nucleophilic reactions of carboxylic acid derivatives have been well studied. These acyl transfer reactions can be represented by... 

The net effect of the addition/elimination sequence is a substitution of the nucleophile for the -Y group originally bonded to the acyl carbon. Thus, the overall reaction is superficially similar to the kind of nucleophilic substitution that occurs during an Sn2 reaction (Section 11.3), but the mechanisms of the two reactions are completely different. An SN2 reaction occurs in a single step by backside displacement of the Leaving group a nucleophilic acyl substitution takes place in two steps and involves a tetrahedral intermediate. 

Nucleophilic substitution at an alkyl carbon is said to alkylate the nucleophile. For example, the above reaction between RI and NMe3 is an alkylation of tri-methylamine. Similarly, nucleophilic substitution at an acyl carbon is an acylation of the nucleophile. 

Acylation of carbon nucleophiles can also be carried out with more reactive acylating agents such as acid anhydrides and acyl chlorides. These reactions must... 

These carbon nucleophiles react with acyl chlorides220 or acyl imidazolides.221 The initial products decarboxylate readily so the isolated products are (3-ketoesters. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Catalytic site of lipase is known to be a serine-residue and lipase-catalyzed reactions are considered to proceed via an acyl-enzyme intermediate. The mechanism of lipase-catalyzed polymerization of divinyl ester and glycol is proposed as follows (Fig. 3). First, the hydroxy group of the serine residue nucleophilically attacks the acyl-carbon of the divinyl ester monomer to produce an acyl-enzyme intermediate involving elimination of acetaldehyde. The reaction of the intermediate with the glycol produces 1 1 adduct of both... 

EM). The initiation is a nucleophilic attack of water, which is probably contained in the enzyme, onto the acyl carbon of the intermediate to produce m-hy-droxycarboxylic acid (n= 1), the shortest propagating species. In the propagation stage, the intermediate is nucleophilically attacked by the terminal hydroxyl group of a propagating polymer to produce a one-unit-more elongated polymer chain. 

Reactions of allylzinc halides with carbon nucleophiles are rare examples of uncatalyzed transformations of organo-zinc compounds. Allylzinc bromide, formed in situ, reacted with a number of structurally diverse acyl chlorides furnishing the corresponding ketones 222 in high yields (Scheme 129).330 No isomerization to the corresponding a,(3-unsaturated ketones was observed under the conditions used (RT, 5min-6h). 

There are three possible active sites in a,(3-unsaturated acylzirconocene chlorides with respect to nucleophiles, namely the (3-unsaturated carbon, the acyl carbon, and the Zr—chlorine bond. The reactions of a, (3-unsaturated acylzirconocene chlorides with nucleophiles indicate bimodal reactivity (nucleophilic or electrophilic) at both the acyl and P-carbons (Scheme 5.37) [40],... 

The asymmetric Mannich addition of carbon nucleophiles to imines catalyzed by the cyclohexane-diamine catalysts has developed significantly in the past decade. List and co-workers reported the asymmetric acyl-cyanantion of imines catalyzed by a cyclohexane-diamine catalyst [103], Using a derivative of Jacobsen s chiral urea catalyst, the authors optimized reaction conditions and obtained chiral iV-acyl-aminonitriles in high yield and enantioselectivities (Scheme 51). The scope of the reaction was explored with both aliphatic and aromatic imines, providing good to high selectivities for a variety of substrates. 

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