Acylation of Nucleophilic Carbon

Enolate anions and other nucleophilic carbon species are acylated when addition to a carbonyl group is followed by elimination of one of the carbonyl substituents. A classic example of this type of reaction pattern is the base-catalyzed 

Modern workers have often chosen sodium hydride and a small amount of alcohol as the catalyst system. It is probable that the effective catalyst is actually the sodium alkoxide formed by reaction of the alcohol released in the condensation with sodium hydride. The sodium alkoxide is also no doubt the active catalyst in reactions 

The preparation of diethyl benzoylmalonate (entry 12) represents the use of an acid anhydride, a function in which it is much more reactive than an ester, as the acylating agent. The reaction must be carried out in nonnucleophilic solvents to prevent solvolysis of the anhydride from competing with the desired reaction. Other limitations on the use of highly reactive acylating agents, such as acid anhydrides and acid chlorides, in reactions with enolates derive from the fact that O-acylation may be the dominant reaction. The magnesium salt of diethyl malonate (entries 12 and 

14) has proved to be a satisfactory substrate in these reactions, in part because it is soluble in nonnucleophilic solvents such as ether. Low temperatures permit successful acylation of lithium enolates with acid chlorides (entry 16). 

Since the jS-ketoaldhydes that result from acidification exist with the formyl group extensively enolized, the compounds are often referred to as hydroxymethylene derivatives. The formation of the product is governed by thermodynamic control therefore, the dominant product expected from unsymmetrical ketones can be predicted on the basis of considerations of relative stability. Once formed, hydroxymethylene compounds have several synthetic uses. A hydroxymethylene group can be converted to methyl via reaction with a mercaptan followed by reduction.  

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The alkylation of carbon nucleophiles by SN2-type processes is an important transformation in the synthesis of organic compounds. The generation and alkylation of such nucleophiles are described in this chapter. Alkylation and acylation of nucleophilic carbon species by other mechanisms are discussed in Chapter 2. 

The conversion of alcohols to esters by O-acylation and of amines to amides by N-acylation are fundamental organic reactions. These reactions are the reverse of the hydrolytic procedures discussed in the preceding sections. Acylation of nucleophilic carbon is also important, but this topic is deferred until Part B, Chapter 2, where the synthetic aspects of the reaction can be emphasized. 

The conjugate base of an alkyne is an alkyne anion (older literature refers to them as acetylides), and it is generated by reaction with a strong base and is a carbanion. It funetions as a nucleophile (a source of nucleophilic carbon) in Sn2 reactions with halides and sulfonate esters. Acetylides react with ketones, with aldehydes via nucleophilic acyl addition and with acid derivatives via nucleophilic acyl substitution. Acetylides are, therefore, important carbanion synthons for the creation of new carbon-carbon bonds. Some of the chemistry presented in this section will deal with the synthesis of alkynes and properly belongs in Chapter 2. It is presented here, however, to give some continuity to the discussion of acetylides. 

Under these circumstances, the overall transformation results in the acylation of the carbon nucleophile. An important group of these reactions involves acylation by esters, in which case the leaving group is alkloy or aryloxy. The self-condensation of esters is known as the Claisen condensation." Ethyl acetoacetate, for example. 

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. 

Nucleophilic acyl substitution (Sections 20 4 20 6 and 20 12) Acylation of am monia and amines by an acyl chloride acid anhydride or ester is an excep tionally effective method for the for mation of carbon-nitrogen bonds... 

Ketenes undergo rapid addition by nucleophilic attack at the sp-carbon atom. The reaction of tertiary amines and acyl halides, in the absence of nucleophiles, is a general preparation for ketenes. ... 

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]. 

One such compound, bropirimine (112), is described as an agent which has both antineo-plastic and antiviral activity. The first step in the preparation involves formation of the dianion 108 from the half ester of malonic acid by treatment with butyllithium. Acylation of the anion with benzoyl chloride proceeds at the more nucleophilic carbon anion to give 109. This tricarbonyl compound decarboxylates on acidification to give the beta ketoester 110. Condensation with guanidine leads to the pyrimidone 111. Bromination with N-bromosuccinimide gives bropirimine (112) [24]. 

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. 

In the first step, a resin-bound secondary amine is acylated with bromoacetic acid, in the presence of N,N-diisopropylcarbodiimide. Acylation of secondary amines is difficult, especially when coupHng an amino acid with a bulky side chain. The sub-monomer method, on the other hand, is facilitated by the use of bromoacetic acid, which is a very reactive acylating agent Activated bromoacetic acid is bis-reactive, in that it acylates by reacting with a nucleophile at the carbonyl carbon, or it can alkylate by reacting with a nucleophile at the neighboring ah-phatic carbon. Because acylation is approximately 1000 times faster than alkylation, acylation is exclusively observed. 

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

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. 

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