Ester by nucleophilic substitution

The cleavage of carbon-oxygen bonds in ethers or esters by nucleophilic substitution is frequently a useful synthetic transformation. 

Dimsylsodium (24) functions as a highly basic sulfur ylide. It can be used to convert phosphonium salts to phosphorus ylides for use in the Wittig reaction. Dimsylsodium also reacts with aldehydes and ketones by nucleophilic addition to form epoxides and with esters by nucleophilic substitution to yield p-ketosulfoxides (25) (Scheme 11). The p-ketosulfoxides (25) contain acidic a-hydrogens which can be readily removed to allow alkylation, and the products (26) suffer reductive desulfuration on treatment with aluminium amalgam to yield ketones (27) (Scheme 11) This procedure can, for instance, be applied to the conversion of ethyl benzoate to propiophenone (28) (Scheme 12). 

In addition to the methods described above, prenol (51) can be prepared from methyl-butynol (43) by rearrangement to prenal (52) using a titanium alkoxide/copper chloride catalyst [69, 70] followed by selective hydrogenation using a ruthenium rhodium tris( 7-sulfonatoyl)phosphine trisodium salt (TPPTS) catalyst [71, 72]. However, it is more usual to prepare the prenyl esters by nucleophilic substitution of a carboxylate anion on prenyl chloride [503-60-6] (56) which, in turn, is available through hydrochlorination of isoprene [78-79-5] (1). This hydrochlorination often employs copper ions as catalysts. These processes are shown in Fig. 8.14. 

The mechanisms by which sulfonate esters undergo nucleophilic substitution are the same as those of alkyl halides Inversion of configuration is observed m 8 2 reac tions of alkyl sulfonates and predominant inversion accompanied by racemization m 8 1 processes... 

Very important compounds are the carboxylic acids and their derivatives, which can be formally obtained by exchanging the OH group for another group. In fact, derivatives of this type are formed by nucleophilic substitutions of activated intermediate compounds and the release of water (see p. 14). Carboxylic acid esters (R-O-CO-R ) arise from carboxylic acids and alcohols. This group includes the fats, for example (see p.48). Similarly, a carboxylic acid and a thiol yield a thioester (R-S-CO-R ). Thioesters play an extremely important role in carboxylic acid metabolism. The best-known compound of this type is acetyl-coenzyme A (see p. 12). 

The two reaction modes of the Michael adducts 145 demonstrate two general principles for the possible preparation of ordinary size heterocyclic compounds from the chlorocyclopropylideneacetates 1,2. Thus, either the heterocycles 153 can be formed by Michael addition of a bidentate nucleophile 150 onto the chloro ester 1-Me and subsequent ring closure of the intermediate 151 [26] by nucleophilic substitution of the chlorine atom at the newly formed sp carbon center adjacent to both the carbonyl and the cyclopropyl group (Route B in Scheme 48). Alternatively, the intermediate 151 can cyclize by nucleophilic attack on the ester moiety to give heterocycles of type 152 (Route A in Scheme 48) [26]. 

As synthetic steps, the Michael additions of nitrogen nucleophiles were followed by nucleophilic substitutions of the chlorine atom with a primary amine and, finally, alkylations of the then secondary amino group with various alkyl bromides were performed just as previously developed for the chloro ester 1-Me in solution (see, e.g. Schemes 25,27,36 etc.). With differently substituted pyra-zoles as Michael addends, different primary amines and alkyl bromides, combinatorial libraries consisting of 8, 24 and 84 compounds were thus successfully prepared in ca. 60% yield and proved by the LC-MS technique to contain all the individual compounds in about equal amounts (Scheme 80) [127]. 

Ho and coworkers" have observed that the addition of small amounts of solid KCN (0.2 equivalents) can effectively accelerate the formation of hydroxamic acids 112 from methyl esters 111 (Scheme 58). The authors suggested that this reaction proceeds through an acylcyanide intermediate followed by nucleophilic substitution by 50% aqueous hydroxylamine at room temperature. The use and advantage of this methodology have been demonstrated for both solution-phase and solid-phase applications. 

The mechanism for the reactions with phosphorus halides can be illustrated using phosphorus tribromide. Initial reaction between the alcohol and phosphorus tribromide leads to a trialkyl phosphite ester by successive displacements of bromide. The reaction stops at this stage if it is run in the presence of an amine which neutralizes the hydrogen bromide that is formed.9 If the hydrogen bromide is not neutralized the phosphite ester is protonated and each alkyl group is successively converted to the halide by nucleophilic substitution by bromide ion. The driving force for cleavage of the C—O bond is the... 

The divergent method is illustrated in Fig. 2-22 for the synthesis of polyamidoamine (PAMAM) dendrimers [Tomalia et al., 1990]. A repetitive sequence of two reactions are used—the Michael addition of an amine to an a,P-unsaturated ester followed by nucleophilic substitution of ester by amine. Ammonia is the starting core molecule. The first step involves reaction of ammonia with excess methyl acrylate (MA) to form LXIII followed by reaction with excess ethylenediamine (EDA) to yield LXIV. LXV is a schematic representation of the dendrimer formed after four more repetitive sequences of MA and EDA. 

Carboxylates are stable to anhydrous hydrogen fluoride,30 but as described above, how ever, hemiacetal esters are readily cleaved and fluorinated by anhydrous hydrogen fluoride or 70% hydrogen fluoride/pyridine, this method has been widely applied in the synthesis of glycosyl fluorides from glycosyl esters for reviews see refs 29, 34, 277-279. 288, 289. Furthermore, p-toluene- or methanesulfonates (but not trifluoroacetates) of primary alcohols arc fluorinated by nucleophilic substitution using tctrabutylammonium hydrogen fluoride. This procedure is less suitable for secondary alcohols because of the considerable number of elimination products 306 for example, formation of 1 compared to 2.306... 

Reactions of 5f/-2-methyl-l,2,4-triazepino[2,3- ]benzimidazol-4-one 71, prepared by reaction of 1,2-diaminobenz-imidazole 72 with acetoacetic ester 73, with different reagents was described, in the search of new heterocycles with biological activity <2002CHE598>. When lactam 71 was treated with aromatic aldehydes in boiling 1-BuOH with addition of piperidine 74, 577-3-arylidene-2-methyl-l,2,4-triazepino[2,3- ]benzimidazol-4-ones 75a-c were obtained (Scheme 7). Coupling lactam 71 with phenyldiazonium chloride 76 in dioxane afforded the 3-phenylazo-substituted tricycle 77. When 71 was treated with phosphorus pentasulfide 78 in boiling dioxane or pyridine, its thio analog 79 was obtained. The reaction proceeded most efficiently when lactam 71 was refluxed with twofold excess of 78 in dry dioxane. These thiones 79 react with ammonia and amines by nucleophilic substitution. When 79 was refluxed with ammonia, benzylamine, piperidine, or morpholine, the 4-amino-substituted tricycles 80a-d were obtained. All the described compounds were identified by NMR, mass spectrometry, and IR spectroscopy. 

The /f-alkoxy ester 111 is formed by nucleophilic substitution of 114 with alkoxide. Formation of 109, the esters 111, and 112 can be regarded as the nucleophilic addition to alkenes promoted by Pd(II). 

Functional Group Transformation Alcohols can be prepared by nucleophilic substitution of alkyl halides, hydrolysis of esters, reduction of carboxylic acids or esters, reduction of aldehydes or ketones, electrophilic addition of alkenes, hydroboration of alkenes, or substitution of ethers. 

Esters can also be converted by nucleophilic substitution from one type of ester to another and this process is called transesterification. For example, a methyl ester can be dissolved in ethanol in the presence of an acid catalyst and converted to an ethyl ester (Following fig.). 

Sulfonic acids, like sulfuric acid, are much stronger acids than carboxylic acids. However, their chemical behavior resembles that of carboxylic acids in many other respects. Sulfonic acids form the same type of derivatives, sulfonyl chlorides, esters, amides, and so on, as do carboxylic acids. These derivatives are intercon-verted by nucleophilic substitution reactions that resemble those of carboxylic acid derivatives. 

Diphenylphosphates 46a and 46b were shown to be excellent substrates for the synthesis of functionalized tetrahydroazocines by nucleophilic substitution. Thus, phenyl ester 46a underwent carbonylation at atmospheric pressure in the presence of Pd(OAc)2 (Scheme 15 <1998CC1757>). 

Esters react by nucleophilic substitution. In a Claisen reaction, an enoiate is the nucleophile that adds to the carbonyl group. 

Sulfinate esters (18) are isomeric with sulfones, but have very different properties. Cyclic sulfinate esters (sultines) (21) can be conveniently prepared by the action of sulfuryl chloride on t-2 butyl hydroxyalkyl sulfoxides (20) (Scheme 13). The most common reaction of sulfinate esters is nucleophilic substitution at sulfur with consequent sulfur-oxygen bond cleavage (Scheme 13). 

Aryl thionoesters (54a) may be prepared by nucleophilic substitution reactions of aryl thiocarbonyl halides with alcohols or phenols for instance, thiobenzoyl chloride (58) condenses with phenol to yield the diaryl ester (54a) (Scheme 30). 

Aminolysis of epoxides is also promoted by high pressure or silica gel catalysis. For example, 2V-(p-hydroxyalkyl)glycine esters have been prepared in high yields by nucleophilic substitution at 1.0 GPa or under silica gel catalysed conditions of various epoxides with a stoichiometric amount of tert- butyl glycinate. 

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