Enol or Enolate Alkylation and Acylation

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

Several important reactions of arenols involve aromatic substitution of arenolate ions with carbon electrophiles. In a sense, these reactions are alkylation and acylation reactions as discussed for arenes (Sections 22-4E and 22-4F). In another sense, they are alkylation and acylation reactions of enolate anions and therefore could give rise to products by C- and O-alkyla-tion, or C- and O-acylation (Section 17-4). Thus ... 

It is this equilibrium which renders difficult the explanation of the course of the reactions which take place when metallic sodium or sodium ethoxide and then alkyl or acyl halide are added to these compounds. At first it was thought that the sodio compound formed with acetoacetic ester was CH3.CO.CHNa.COOC2H5, because the reaction with alkyl and acyl halides always yielded a C-derivative, CH3.CO.CHR.COOC2H5. The first example of a different course of reaction was found in the formation of an O-derivative—/3-carhethoxyhydroxycrotonic ester from sodio-acetoacetic ester and chloroformic ester (J. pr., [2], 37, 473 B., 25,1760 A., 277, 64). This could only be explained by assigning an enol formula to the sodium salt—... 

Enamines are the stable products of a similar reaction between secondary amines (such as pyrrolidine or morpholine) and aldehydes and ketones.218 These vinylamines are reactive reagents of value in synthesis they function as specific enol equivalents of carbonyl compounds, readily undergoing alkylation and acylation processes (e.g. Section 5.9.2, p. 632). 

Many alkylation and acylation reactions are most effective using anions of /3-dicarbonyl compounds that can be completely deprotonated and converted to their enolate ions by common bases such as alkoxide ions. The malonic ester synthesis and the acetoacetic ester synthesis use the enhanced acidity of the a protons in malonic ester and acetoacetic ester to accomplish alkylations and acylations that are difficult or impossible with simple esters. 

In contrast, /3-dicarbonyl compounds such as malonic ester and acetoacetic ester are more acidic than alcohols. They are completely deprotonated by alkoxides, and the resulting enolates are easily alkylated and acylated. At the end of the synthesis, one of the carbonyl groups can be removed by decarboxylation, leaving a compound that is difficult or impossible to make by direct alkylation or acylation of a simple ester. 

So far, most of the reactions presented in the book that are useful in synthesis have made C-O, C-N, or C-halogen bonds and only a few (Wittig, Friedel-Crafts, and reactions of cyanides and alkynes) make C-C bonds. This limitation has severely restricted the syntheses that we can discuss in this chapter. This is by design as we wanted to establish the idea of synthesis before coming to more complicated chemistry. The next four chapters introduce the main C-C bond-forming reactions in the chemistry of enols and enolates. You met these valuable intermediates in Chapter 21 but now you are about to see how they can be alkylated and acylated and how they add directly to aldehydes and ketones and how they do conjugate addition to unsaturated carbonyl compounds. Then in Chapter 30 we return to a more general discussion of synthesis and develop a new approach in the style of the last synthesis in this chapter. 

The enamine reaction provides an alternative method for selective alkylation and acylation of aldehydes and ketones. The enamine group is both a protecting group for carbonyl compounds and a directing or activating group for further elaboration. Note the relationship between enolates and enamines ... 

Synthesis of trifluoromethylated compounds 152 has been achieved via ester-enolate [2,3]-Wittig and [3,3]-lreland-Claisen rearrangements. Perfluorocyclo-butane phosphonium ylides, e.g. 153, have been used as a masked fluoride anion source in their reactions with alcohols and carboxylic acids which lead to alkyl-and acyl-fluorides. Ylides 153 are also reported to cleave Si-C and Si-O bonds, cause dimerisation of fluoro-olefins, and also react with acid chlorides or other activated aromatic compounds under halogen exchange. ... 

This chapter introduced the use of enolates and/or enamines as nucleophiles in several reactions, including aldol reactions, Claisen condensations and Michael additions, alkylations, and acylations. We can also use LDA to generate the enolate anions and perform the same reactions, as shown here for cyclohexanone and a few specific electrophiles. Similar reactions are possible for aldehydes and esters with a-hydrogens. The synthetic versatility of this approach has made LDA a very popular and important reagent in modem synthetic organic chemistry. 

The synthesis of barbiturates is relatively simple and relies on reactions that are now familiar enolate alkylations and nucleophilic acyl substitutions. Starting with diethyl malonate, or malonic ester, alkylation of the corresponding enolate ion with simple alkyl halides provides a wealth of different disubstituted malonic esters. Reaction with urea, (H2N)2C=0, then gives the product barbiturates by a twofold nucleophilic acyl substitution reaction of the ester groups with the -NH2 groups of urea (Figure 22.7). Amobarbi-tal (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal) are typical examples. 

Due to the nonaromatic character of the oxepin system the oxepinones do not usually form stable enol structures. By O-acylation or O-alkylation, however, the enol forms can be stabilized as enol esters and ethers, respectively. A large number of substituted 1-benzoxepins have been synthesized by this route. Acetylation of l-benzoxepin-3(2//)-ones 1 and l-benzoxepin-5(2/T)-ones 3 was readily achieved with acetic anhydride in the presence of an appropriate base such as pyridine, triethylamine or sodium acetate.t5,t6 t72 176... 

The reaction between acyl halides and alcohols or phenols is the best general method for the preparation of carboxylic esters. It is believed to proceed by a 8 2 mechanism. As with 10-8, the mechanism can be S l or tetrahedral. Pyridine catalyzes the reaction by the nucleophilic catalysis route (see 10-9). The reaction is of wide scope, and many functional groups do not interfere. A base is frequently added to combine with the HX formed. When aqueous alkali is used, this is called the Schotten-Baumann procedure, but pyridine is also frequently used. Both R and R may be primary, secondary, or tertiary alkyl or aryl. Enolic esters can also be prepared by this method, though C-acylation competes in these cases. In difficult cases, especially with hindered acids or tertiary R, the alkoxide can be used instead of the alcohol. Activated alumina has also been used as a catalyst, for tertiary R. Thallium salts of phenols give very high yields of phenolic esters. Phase-transfer catalysis has been used for hindered phenols. Zinc has been used to couple... 

Hydrolysis of enol esters 0-83 Reduction of acyl halides 0-84 Reduction of carboxylic acids, esters, or anhydrides 0-85 Reduction of amides 0-95 Alkylation and hydrolysis of imines, alkylation of aldehydes 0-97 Alkylation and hydrolysis of dithi-anes... 

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