A-alkylated esters

The asymmetric alkylation of other prochiral enolates has also been studied, and good results have been obtained provided that the intermediate enolate is stabilised by conjugation. For example, the extended enolate derived from 15 has been trapped with a range of alkylating agents to give a-alkylated esters such as 16 in 98% ee (Scheme 5) [12]. 

Aminomcthylation of hctcroatoms (X-aminomcthylation in Table 6) is generally the easiest, whereas C-aminomethylation requires a great variety of experimental conditions. Indeed, the C—H moiety bound to a carboxyl group is among the less reactive systems, so that alkyl ketones require conditions A alkyl esters, which would be unstable under such conditions, have to be allowed to react with methyleneimmonium salts. Alkenes, as well as ferrocenyl derivatives, are also barely reactive. By contrast, the nitro group of nitroalkanes behaves as a very good activator of aminomcthylation, and phenols are readily aminomethylated. 

As will be described below, self-reproduction of chirality can be accomplished through alkylations of endocyclic as well as exocyclic enolates. It generally entails (i) production of a ring containing a temporary, auxiliary chiral center by derivatization of an optically active a-hydroxy or a-amino ester (ii) formation of an enolate by deprotonation at the original asymmetric a-carbon atom (iii) use of intramolecular chirality transfer to control the stereochemistry of alkylation of the enolate and (iv) generation of the chiral a-alkylated ester by hydrolysis. 

In the benzil-benzilic acid rearrangement, an a-diketone is treated with a base to give the sodium salt of an a-hydroxy carboxylic acid. In the Favorskii rearrangement, an a-halogenoketone is treated with an alkoxide anion to give the a-alkyl ester. This reaction may also be used to effect a ring contraction. 

Stereoselective synthesis of an a-alkylated ester has been carried out employing a polymer supported chiral oxazoline [13, 38]. An oxazoline bound ethyl moiety was alkylated with benzyl chloride to provide, after acid catalyzed detachment from the resin, an a-alkylated propionic acid ester in 43—48% yield and 56% ee. 

Decarboalkylation (5, 445-446). Japanese chemists have used this reaction for the synthesis of certain a-alkylated esters, ketones, and nitriles as illustrated in equations I-lll. 

Following up on the allylic oxidation and the interesting requirement of an ester solvent, the Yeung group attempted the allylic oxidation reaction in the absence of the alkene, and noticed some oxidation of the ester solvent. Development of this as its own reaction demonstrated the successful oxidation of a number of 0-alkyl and A-alkyl esters such as 23 and amides 24. The oxidation typically occurred on a methylene carbon on the alkoxy- or amino-carbon chain several carbons away from the ester center. Attempts to oxidize n-octane resulted in no reaction, further corroborating the necessity of carbonyl coordination to the iodine center. 

II. Esters, (a) Alkyl esters (for example, methyl esters), and (b) phena-cyl esters (for example, esters of p-bromophenacyl alcohol). 

CH OfiSj, H2C(S03H)2- a colourless, crystalline solid which readily absorbs water vapour decomposes on distillation. The potassium salt is prepared by heating methylene chloride with an aqueous solution of potassium sulphite under pressure at 150-I60" C. The free acid is obtained by decomposing the sparingly soluble barium salt with sulphuric acid. The aryl esters are very stable, but the alkyl esters decompose on heating to give ethers. Resembles malonic acid in some of its reactions. 

NOTE. Many esters reduce Fehling s solution on warming. This reduction occurs rapidly with the alkyl esters of many aliphatic acids, but scarcely at all with similar esters of aromatic acids (f.g., ethyl oxalate reduces, but ethyl benzoate does not). Note also that this is a property of the ester itself thus both methyl and ethyl oxalate reduce Fehling s solution very rapidly, whereas neither oxalic acid, nor sodium oxalate, nor a mixture of the alcohol and oxalic acid (or sodium oxalate), reduces the solution. 

Methyl p-toluenesulphonate. This, and other alkyl esters, may be prepared in a somewhat similar manner to the n-butyl ester with good results. Use 500 g. (632 ml.) of methyl alcohol contained in a 1 litre three-necked or bolt-head flask. Add 500 g. of powdered pure p-toluene-sulphonyl chloride with mechanical stirring. Add from a separatory funnel 420 g. of 25 per cent, sodium hydroxide solution drop by drop maintain the temperature of the mixture at 23-27°. When all the alkali has been introduced, test the mixture with litmus if it is not alkaline, add more alkali until the mixture is neutral. Allow to stand for several hours the lower layer is the eater and the upper one consists of alcohol. Separate the ester, wash it with water, then with 4 per cent, sodium carbonate solution and finally with water. Dry over a little anhydrous magnesium sulphate, and distil under reduced pressure. Collect the methyl p-toluenesulphonate at 161°/10 mm. this solidifies on cooling and melts at 28°. The yield is 440 g. 

If alkyl groups are attached to the ylide carbon atom, cis-olefins are formed at low temperatures with stereoselectivity up to 98Vo. Sodium bis(trimethylsilyl)amide is a recommended base for this purpose. Electron withdrawing groups at the ylide carbon atom give rise to trans-stereoselectivity. If the carbon atom is connected with a polyene, mixtures of cis- and rrans-alkenes are formed. The trans-olefin is also stereoseiectively produced when phosphonate diester a-carbanions are used, because the elimination of a phosphate ester anion is slow (W.S. Wadsworth, 1977). 

J-unsaturated ester is formed from a terminal alkyne by the reaction of alkyl formate and oxalate. The linear a, /J-unsaturated ester 5 is obtained from the terminal alkyne using dppb as a ligand by the reaction of alkyl formate under CO pressure. On the other hand, a branehed ester, t-butyl atropate (6), is obtained exclusively by the carbonylation of phenylacetylene in t-BuOH even by using dppb[10]. Reaction of alkynes and oxalate under CO pressure also gives linear a, /J-unsaturated esters 7 and dialkynes. The use of dppb is essen-tial[l 1]. Carbonylation of 1-octyne in the presence of oxalic acid or formic acid using PhiP-dppb (2 I) and Pd on carbon affords the branched q, /J-unsatu-rated acid 8 as the main product. Formic acid is regarded as a source of H and OH in the carboxylic acids[l2]. 

One effective method for synthesis of tryptophan derivatives involves alkylation of formamido- or acetamido- malonate diesters by gramine[l,2]. Conversion to tryptophans is completed by hydrolysis and decarboxylation. These reactions were discussed in Chapter 12. An enolate of an a-nitro ester is an alternative nucleophile. The products can be converted to tryptophans by rcduction[3,4],... 

Alkylethers (269), R2 = alkyl, are obtained by the action of phosphorus pentasulfide on alkyl esters of a-acylamino acids (64, 334, 711) by means of the GabriePs synthesis (Section II.4), while aryl ethers (269), = aryl,... 

An advantage that sulfonate esters have over alkyl halides is that their prepara tion from alcohols does not involve any of the bonds to carbon The alcohol oxygen becomes the oxygen that connects the alkyl group to the sulfonyl group Thus the configuration of a sulfonate ester is exactly the same as that of the alcohol from which It was prepared If we wish to study the stereochemistry of nucleophilic substitution m an optically active substrate for example we know that a tosylate ester will have the same configuration and the same optical purity as the alcohol from which it was prepared... 

Among compounds other than simple alkyl halides a halo ketones and a halo esters have been employed as substrates m the Gabriel synthesis Alkyl p toluenesul fonate esters have also been used Because phthalimide can undergo only a single alkyl ation the formation of secondary and tertiary amines does not occur and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines... 

Acrolein, acrylamide, hydroxyalkyl acrylates, and other functional derivatives can be more hazardous from a health standpoint than acryhc acid and its simple alkyl esters. Furthermore, some derivatives, such as the alkyl 2-chloroacrylates, are powerful vesicants and can cause serious eye injuries. Thus, although the hazards of acryhc acid and the normal alkyl acrylates are moderate and they can be handled safely with ordinary care to industrial hygiene, this should not be assumed to be the case for compounds with chemically different functional groups (see Industrial hygiene Plant safety Toxicology). 

Optically active 2-arylalkanoic acid esters have been prepared by the Friedel-Crafts alkylation of arenes with optically active a-sulfonyloxy esters (40). Friedel-Crafts alkylation of ben2ene with (5)-methyl 2-(chlorosulfonyloxy)- or 2-(mesyloxy)propionate proceeded with predorninant inversion of configuration (<97%) to give (5)-methyl 2-phenylpropionate. 

Methacrylic acid polymer is iasoluble ia the monomer, which may result ia the plugging of transfer lines and vent systems. Polymers of the lower alkyl esters are often soluble ia the parent monomer and may be detected by an iacrease ia solution viscosity. Alternatively, dilution with a nonsolvent for the polymer such as methanol results ia the formation of haze and can be used as a diagnostic tool for determining presence of polymer. 

Naphthol is mainly used in the manufacture of the insecticide carbaryl (59), l-naphthyl A/-methyicarbamate/ iJ-2j5 - (Sevin) (22), which is produced by the reaction of 1-naphthol with methyl isocyanate. Methyl isocyanate is usually prepared by treating methylamine with phosgene. Methyl isocyanate is a very toxic Hquid, boiling at 38°C, and should not be stored for long periods of time (Bhopal accident, India). India has developed a process for the preparation of aryl esters of A/-alkyl carbamic acids. Thus l-naphthyl methylcarbamate is prepared by refluxing 1-naphthol with ethyl methylcarbamate and POCl in toluene (60). In 1992, carbaryl production totaled > 11.4 x 10 t(35). Rhc ne-Poulenc, at its Institute, W. Va., facihty is the only carbaryl producer in United States. 

For continuing polymerization to occur, the ion pair must display reasonable stabiUty. Strongly nucleophilic anions, such as C/ , are not suitable, because the ion pair is unstable with respect to THE and the alkyl haUde. A counterion of relatively low nucleophilicity is required to achieve a controlled and continuing polymerization. Examples of anions of suitably low nucleophilicity are complex ions such as SbE , AsF , PF , SbCf, BE 4, or other anions that can reversibly coUapse to a covalent ester species CF SO, FSO, and CIO . In order to achieve reproducible and predictable results in the cationic polymerization of THE, it is necessary to use pure, dry reagents and dry conditions. High vacuum techniques are required for theoretical studies. Careful work in an inert atmosphere, such as dry nitrogen, is satisfactory for many purposes, including commercial synthesis. 

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