Carboxylates synthesis from halides

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

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. 

The palladium-catalyzed Heck carbonylation reaction is a powerful means of generating amides, esters, and carboxylic acids from aryl halides or pseudohalides [28]. The development of rapid, reliable, and convenient procedures for the introduction of carbonyl groups is important for the development of high throughput chemistry in general and high-speed microwave-mediated chemistry in particular. Unfortunately, the traditional method of introducing carbon monoxide into a reaction mixture via a balloon or gas tube is not practical because of the special requirements of microwave synthesis. 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

Sandmeyer s synthesis of aromatic nitriles is far more elegant than the removal of water from the ammonium salts of carboxylic acids, which latter reaction is also applicable to benzene derivatives. In particular, the former synthesis permits of the preparation of carboxylic acids via the nitriles, and so provides a complete substitute for Kolbe s synthesis (alkyl halide and potassium cyanide), which is inapplicable to aromatic compounds. The simplest example is the conversion of aniline into benzoic add. The converse transformation is Hofmann s degradation (benzamide aniline, see p. 152). 

Suzuki and Stille couplings. For coupling of aryl chlorides with arylboronic acids the catalytic system contains (CyjPjjPdClj, CsF in NMP. co-Arylalkanoic acids are prepared by coupling of aryl halides with carboxylic esters bearing a 9-BBN substituent at the other terminus, and saponification. A biaryl synthesis from two different aryl halides is accomplished with in situ boronate formation which depends on the (dppfjPdClj catalyst. For access to aryl boronates either the coupling of aryl triflates with bis(pinacolato)diboron" or that of aryl iodides with pinacolborane may be employed. 

Monothioacetals 1,3-Oxathiolanes Thiolactams S extrusion, 59-60, 261 Thiols synthesis from haloalkanes, 169, 269 Thionation of lactones, 110-111 Thiones olefination of, 35 Thionocarbonates. See Carbonothioates Thionolactones, 110-111 Thionyl chloride prepn. of acyl halides, 143 prepn. of carboxylic esters, 347 prepn. of haloalkanes from alcohols, 32 Thiophenoi. See Benzenethiol Thiotosylatc. See Benzenesulfonothioic add... 

X" = NOj- From Amberlyst A-26 or Amberlite IRA 400 From Amberlite IRA 900 (C1-) by treatment with NaNO, soln. 3 Synthesis of nitroalkanes and alkyl nitrites from alkyl halides. - a-Nitro carboxylic esters from a-bromo esters alkyl-nitro compounds from primary, secondary and benzylic bromides (formation of nitrites was not detected). ... 

Nickel carbonyl-sodium alcohol Carboxylic acid esters and amides from halides Synthesis with addition of 1 C-atom... 

Lithium N-isopropylcyclohexylamide Carboxylic acid esters from halides Synthesis with addition of 2 C-atoms Modified malonic ester synthesis... 

We study the nomenclature, structure, and characteristic reactions of acid halides in Chapter 14. In this chapter, our concern is only with their synthesis from carboxylic acids. 

Carboxylic acids can he prepared from nitriles by heating with aqueous acid or base by a mechanism that we ll see in Section 15.7. Since nitriles themselves are easily made by Sn2 reaction of a primary or secondary alkyl halide with CN , the two-step sequence of cyanide displacement followed by nitrile hydrolysis is a good way to make a carboxylic acid from an alkyl halide (RBr RC=N RCO2H). Note that the product acid has one more carbon than the starting alkyl halide. An example occurs in one commercial route for the synthesis of the nonsteroidal anti-inflammatory drug ibuprofen. 

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