Cyanides chain extension

Chain extension by means of the reaction of alkyl halides with cyanide is frequently alluded to but rarely employed, mainly because of the long reaction times and poor yields usually encountered. The use of DMSO as a solvent has greatly simplified the procedures and improved the yields of many ionic reactions, and the conversion of alkyl chlorides to nitriles is a good example. 

This extension, known as the Amdt-Eistert procedure,1 is useful if the relationship between functional groups is unhelpful in the TM but becomes helpful if the chain is retrosynthetically shortened. Other methods, such as cyanide displacement, also increase the chain length by one carbon and we saw a chain extension by two carbon atoms in the last chapter. The disconnections are strange both C-C bonds between R and CO are made in the reaction so we must disconnect both 5a. You might like to think of this as a reconnection strategy (chapter 26) or as an extrusion of a CH2 group. 

Cyanide ion is a good small nucleophile and displaces tosylate from primary carbon atoms and adds one carbon atom Lo the chain. As the cyanide (nitrile) group can be converted directly to a carboxylic acid or ester (Chapter 14) this sequence is a useful chain extension. 

The cyanohydrin chain extension results when a sugar is treated with sodium cyanide. The resulting cyanohydrin is then hydrolyzed to the corresponding carboxylic acid, resulting in a one-carbon... 

This method, known as the Arndt-Eistert procedure, is useful when the relationship between the carbonyl groups in the TM is unhelpful but becomes helpful when the chain length is shorter. We saw an example in Chapter 28 where cyanide ion was used as the chain extension reagent. Diazomethane is a more sophisticated version, needing fewer steps. The disconnection is to remove the car bene. 

Three papers describing chain-extensions by use of C-6-aldehydes have been published the diacetonegalactose-derived dialdose 31 was extended by two carbons to give the acetamido-dideoxy-octosulose derivative 33 via intermediate 32 by consecutive treatment with potassium cyanide in the presence of ammonia,... 

The bicyclic compound 86 has been made from p-D-galactopyranosyl cyanide tetraacetate by chain extension of the aglycon and cyclization. It was then used to introduce a pyrimidine... 

Cyanide ion ( C = N ) The negatively charged carbon atom of cyanide ion IS usually the site of its nucleophilic character Use of cyanide ion as a nucleophile permits the extension of a carbon chain by carbon-carbon bond formation The product is an alkyl cyanide or nitrile... 

Among the classic methods for the extension of the aldose chain by one carbon atom from the reducing end [9J, the Kiliani-Fischer cyanohydrin synthesis [10] is a milestone in carbohydrate chemistry. However after 110 years from discovery and numerous applications [11], including the preparation of carbon and hydrogen isotopically labeled compounds for mechanistic and structural studies [12], there are still several drawbacks that make the method impractical. These are the low and variable degree of selectivity and the harsh reaction conditions that are required to reveal the aldose from either the aldonic acid or directly from the cyanohydrin. Synthetic applications that have appeared in recent times confirmed these limitations. For instance, a quite low selectivity was registered [13] in the addition of the cyanide ion to the D-ga/acfo-hexodialdo-l,5-pyranose derivative 1... 

The classical procedure for the reaction involves heating the alkyl halide (usually the chloride or bromide) with sodium or potassium cyanide in metha-nolic or ethanolic solution. The method is clearly of value for the extension of the carbon chain by one carbon atom, since the cyano group may be converted into a carboxyl group by hydrolysis (Section 5.11.2, p. 671) or into an amino-methyl group (—CH2-NH2) by reduction (Section 5.16.1, p. 771), or into a formyl group by controlled reduction to the imine followed by hydrolysis (Section 5.7.4, p. 594). ... 

Extensive work by Cheah (121, 122, 123, 128, 130), mainly with M. expansa, has shown that large cestodes possess a cytochrome chain which differs from the mammalian system in being branched and possessing multiple terminal oxidases (Fig. 5.11). One branch resembles the classical chain with cytochrome a3 as its terminal oxidase. The terminal oxidase of the alternative pathway, which branches at the level of rhodoquinone or vitamin K, is an o-type cytochrome. Cytochrome o is an autoxidisable b-type cytochrome which is commonly found in micro-organisms, parasitic protozoa and plants. The classical chain constitutes about 20% of the oxidase capacity in cestodes and cytochrome o is quantitatively the major oxidase. Cyanide-insensitive respiration - i.e. where oxygen uptake occurs in the presence of cyanide - is characteristic of most helminths (39). Cytochrome o binds cyanide much less strongly than cytochrome a3, and it seems reasonable, therefore, to equate cyanide-insensitive respiration with the non-classical pathway. 

Kiliani-Fischer synthesis. Extension of the carbon atom chain of aldoses by treatment with cyanide. Hydrolysis of the cyanohydrins followed by reduction of the lactone yields the homologous aldose. 

Extension of the carbon chain of an aldose from the carbonyl by one unit at a time can be carried out fairly readily by the Kiliani reaction. A cyanhydrin is formed by addition of cyanide ion, followed by reduction and hydrolysis (in either order) historically, the sugar was unprotected, and the cyanohydrin was hydrolysed to the sugar lactone, and then reduced with sodium amalgam (Figure 1.4). Because a new asymmetric centre is formed, two epimeric sugars result (epimers are diastereomers that differ in the configuration of only one carbon). 

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