Esters alkyl halide carbonylation

The lithium derivatives described above react with electrophiles such as alkyl halides, carbonyl compounds, and thiocarbonyl compounds, resulting in the corresponding 3-substituted derivatives (190). Hydrolysis of these products by dilute acid as described in Section B,1 gives the new nonproteinogenic amino acid ester (191) along with the original amino acid ester used as the chiral auxiliary. The chemical yields are above 80% (83MI1). 

The cyclic a-lithio-l,3-dithiane S-oxide 406 was generated from compound 392 with n-BuLi at —10 °C and reacted with deuterium oxide, alkyl halides, carbonyl compounds and esters to afford the corresponding products 407 as mixture of diastereomers (Scheme 106)605 - 607. (V-Acyl imidazoles were better acylating agents than esters608. However, compound 406 has not been employed properly as acyl anion. Intermediate... 

The direct replacement of chlorine in 2-chlorotetrahydrothiophene by means of MeSH leads to low yields of (339). However, reaction with diphenylacetic acid and EtjN gives the diphenylacetic ester which can be converted to (339) in excellent yield by MeSH. Alternatively, 2-mercaptotetra-hydrothiophene can be prepared by the thiourea method (CHEC-I) and methylated to give (339) <92CB1641>. Deprotonation of (339) with Bu"Li at —30°C gives the 2-lithio derivative this reacts with a variety of electrophiles (alkyl halides, carbonyl compounds) to form (340) (Scheme 69). 

NaOCHjCHa. White solid (Na in EtOH). Decomposed by water, gives ethers with alkyl halides reacts with esters. Used in organic syntheses particularly as a base to remove protons adjacent to carbonyl or sulphonyl groups to give resonance-stabilized anions. 

Particularly alkyl halides which have a perfluoroalkyl group at the /3-position undergo smooth carbonylation. Probably the coordination of fluorine to form a five-membered chelate ring accelerates the reaction. Double carbonylation to give the a-keto amide 915 is possible in Et NH with the fluorine-bearing alkyl iodide 914[769,770]. The ester 917 is obtained by the carbonylation of the /3-perfluoroalkyl iodide 916 in ethanol. 

The A-phthalimidomalonic ester 8 can be further alkylated at the malonic carbon center with most alkyl halides, or with an o ,/3-unsaturated carbonyl compound thus offering a general route to a-amino acids 9. 

One of the oldest and best known carbonyl alkylation reactions is the malonic ester synthesis, a method for preparing a carboxylic add from an alkyl halide while lengthening the carbon chain by two atoms. 

Ethyl 3-oxobutanoate, commonly called ethyl acetoacetate or ace tome tic ester, is much like malonic ester in that its ct hydrogens are flanked by two carbonyl groups. It is therefore readily converted into its enolate ion, which can be alkylated by reaction with an alkyl halide. A second alkylation can also be carried out if desired, since acetoacetic ester has two acidic a hydrogens. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Another method for the conversion of alkyl halides to carboxylic esters is treatment of a halide wifh nickel carbonyl, Ni(CO)4, in the presence of an alcohol... 

Olefination Reactions Involving Phosphonate Anions. An important complement to the Wittig reaction involves the reaction of phosphonate carbanions with carbonyl compounds 253 The alkylphosphonic acid esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are generated by treating alkylphosphonate esters with a base such as sodium hydride, n-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.254... 

Domino transformations combining two consecutive anionic steps exist in several variants, but the majority of these reactions is initiated by a Michael addition [1]. Due to the attack of a nucleophile at the 4-position of usually an enone, a reactive enolate is formed which can easily be trapped in a second anionic reaction by, for example, another n,(5-urisalurated carbonyl compound, an aldehyde, a ketone, an inline, an ester, or an alkyl halide (Scheme 2.1). Accordingly, numerous examples of Michael/Michael, Michael/aldol, Michael/Dieckmann, as well as Michael/SN-type sequences have been found in the literature. These reactions can be considered as very reliable domino processes, and are undoubtedly of great value to today s synthetic chemist... 

Carbonylation of alkyl halides to yield esters and lactones (Table 8.5)... 

Selected examples of the conversion of alkyl halides into ethyl esters using cobalt carbonyl complexes... 

A new free-radical carbonylation strategy, employing S -phenyl chlorothioformates and alkyl halides, has been developed. Reaction with (Eu3Sn)2 furnishes the corresponding S -phenyl esters in moderate yields (Scheme 30). 

This method is of quite general applicability and the carbonyl compound may be an aldehyde, a ketone, or an ester. Similarly, the halide may be chloride, bromide, or iodide although yields are generally lower with iodides. Alkyl and aryl halides react with equal facility and the alkyl halide may be primary, secondary, or tertiary. A few examples of the yields obtained with a variety of reagents are given in Table I (the yields quoted are obtained by g.l.c. analysis of the reaction mixture using an internal standard ). 

Treatment of sodium and potassium nitronates with alkyl halides typically results in the formation of oximes and carbonyl compounds by cleavage of the N—O bond (11). In one case, however, reaction of w-butyl bromide with the potassium salt of nitro ester 191 does afford the -butyl nitronate (192, Eq. 2.14) (154). 

The first successful preparation of lithium ethyl acetate was using the base lithium hexam-ethyldisilazanide12,14 at — 78 CC in tetrahydrofuran. The much greater stability of the lithium salt as compared to the previously prepared13 sodium ethyl acetate was noted and used in the reaction with carbonyl compounds12. The attack of alkyl halides as electrophiles on the lithium salts of esters, prepared by the action of lithium cyclohexylisopropylamide on the esters at low temperatures in tetrahydrofuran, furnished the a-alkylated products in yields of 50 -90%16,17. 

Several methods, all based on carbon monoxide or metal carbonyls, have been developed for converting an alkyl halide to a carboxylic acid or an acid derivative with the chain extended by one carbon.1603 When an alkyl halide is treated with SbCl5-S02 at -70°C, it dissociates into the corresponding carbocation (p. 166). If carbon monoxide and an alcohol are present, a carboxylic ester is formed by the following route 1604... 

Enol Ethers and Esters 0-15 O-Alkylation of carbonyl compounds with diazo alkanes 0-17 Transetherification 0-20 Reaction between acyl halides and active hydrogen compounds 0-23 Transesterification 0-24 Acylation of vinylic halides 0-94 Alkylation with ortho esters 0-107 O-Acylation of 1,3-dicarbonyl compounds... 

Trialkylaluminums, 21 By geminal alkylation of carbonyl groups Dichlorodimethyltitanium, 216 From reduction of alkyl halides, alkyl sulfonates and similar compounds From acetates or other esters Triphenylsilane, 334 From alcohols... 

---