The Koenigs-Knorr Reaction

Although secondary alkyl halides are generally unsatisfactory in the phase transfer catalyzed Williamson ether synthesis, the more reactive a-haloethers are as useful as, and more reactive than, simple alkyl halides. Thus the Koenigs-Knorr reaction has been successfully executed under phase transfer conditions [10]. a-2-Bromo-3,4,5,6- 

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Although the Koenigs-Knorr reaction appears to involve a simple backside S 2 displacement of bromide ion by alkoxide ion, the situation is actually more complex. Both a and /3 anomers of tetraacetyl-o-glucopyranosyl bromide give the same /3-glycoside product, implying that they react by a common pathway. 

The participation shown by the nearby acetate group in the Koenigs-Knorr reaction is referred to as a neighboring-group effect and is a common occurrence... 

The synthesis93 of N-(2,4-dinitrophenyl)-3-0-(tetra-0-acetyl-/ -D-glu-copyranosyl)-L-threonine methyl ester (131) involved a two-step procedure. First, formation of the intermediate, L-threonine orthoester 130 was achieved by treatment of tetra-O-acetyl-a-D-glucopyranosyl bromide (128) with the methyl ester of N-(2,4-dinitrophenyl)-L-threonine94 (129) under the conditions of the Koenigs-Knorr reaction (see next paragraph), and this was then converted into the L-threonine glycoside 131. 

Carbohydrate orthoesters, first reviewed by Pacsu more than 60 years ago [8], were reported by Fischer et al. [9] as by-products of the Koenigs-Knorr reaction [3] of acetobromo-L-rhamnose (1) with methanol. Orthoacetate 3 was isolated along with the expected a- and P-methyl rhamnosides 2 (Scheme 5.2). However, its true structure was assigned only 10 years later by several research groups [10-12]. 

A number of glycosides were available to Fischer by way of the Koenigs-Knorr reaction and his own glycoside synthesis, which involves treatment of... 

A second method is based on the abnormal course of the Koenigs-Knorr reaction with fluoroalkyl alcohols. Indeed, when there are two or three methylenes between the Rf group and the hydroxyl, the reaction does not lead to substitution of the anomeric bromide but instead affords an orthoester. In the presence of mercuric bromide, this orthoester can undergo a rearrangement into an (9-fluoroalkyl glycoside (Figure 6.47). 

K. Igarashi, The Koenigs-Knorr reaction, Adv. Carbohydr. Chem. Biochem. 34 243 (1977). 

The Koenigs-Knorr reaction will yield exclusively 1,2-trans glycosides, especially when insoluble silver salts are used as promoters. 

The effect of hydrogen bonding in the Koenigs Knorr reaction. 

Despite its wide application in glycoside synthesis, the Koenigs-Knorr reaction suffers from several disadvantages (i) the glycosyl halides are unstable, (ii) excess toxic heavy metals are needed to activate the donor, and (iii) a desiccant (to absorb any liberated water) and an acid acceptor (to absorb the liberated hydrogen halide and can be a promoter itself) are often needed to increase the yield and suppress side reactions. 

The acylglycosyl halide, the alcoholic compound and a solvent have been used in every case where the Koenigs-Knorr reaction has been carried out. Koenigs and Knorr68 and Ness, Fletcher and Hudson60-90... 

Helferich, Bohm and Winkler1 have reported that the use of iodine catalyzed the Koenigs-Knorr reaction, which was exceedingly slow when calcium chloride was used as an internal desiccant. This catalyst has since been used by a number of other workers.79 111-114 The work of Talley, Reynolds and Evans79 on the synthesis of the orthoester type of oligosaccharides, indicated that the presence of iodine favored the formation of a normal biosidic linkage, whereas the absence of iodine favored the formation of an orthoester linkage. 

The examples of the Koenigs-Knorr reaction are too numerous to discuss in detail. The compounds which have been prepared by this reaction will be listed in table VII and only a few will be discussed at this point. 

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