A-Halo acids

This reaction is of synthetic value in that a halo acids are reactive sub strates m nucleophilic substitution reactions... 

Nucleophilic substitution by ammonia on a halo acids (Section 19 16) The a halo acids obtained by halogenation of car boxylic acids under conditions of the Hell-Volhard-Zelinsky reaction are reac tive substrates in nucleophilic substitu tion processes A standard method for the preparation of a ammo acids is dis placement of halide from a halo acids by nucleophilic substitution using excess aqueous ammonia... 

The a halo acid is normally prepared by the Hell-Volhard-Zehnsky reaction (see Sec tion 19 16)... 

Preparation. The general preparation of y acids is by the hydrolysis of an a-halo acid or by the acid hydrolysis of the cyanohydrins of an aldehyde or a ketone. 

Substitution Reactions. Reaction with nitrous acid in dilute aqueous solutions yields the corresponding hydroxy acid or in solution containing a hydrohahc acid, the corresponding a-halo acid, with inversion in many cases. 

Various alkylating agents are used for the preparation of pyridazinyl alkyl sulfides. Methyl and ethyl iodides, dimethyl and diethyl sulfate, a-halo acids and esters, /3-halo acids and their derivatives, a-halo ketones, benzyl halides and substituted benzyl halides and other alkyl and heteroarylmethyl halides are most commonly used for this purpose. Another method is the addition of pyridazinethiones and pyridazinethiols to unsaturated compounds, such as 2,3(4//)-dihydropyran or 2,3(4//)-dihydrothiopyran, and to compounds with activated double bonds, such as acrylonitrile, acrylates and quinones. 

Bromination of the substituted butyric acid, 26, by the Hell-Volhardt-Zelinsky procedure affords the a-halo acid bromide (27). Reaction of this with urea affords directly bromisovalum (28). 

The tosylatc must come from alcohol (44), Disconnection Lo an epoxide (45) is no good as the amine will attack the wrong atom. Change of oxidation level to (46) is more hopeful as the a-halo acid (47) is easily made. Another possibility is to use naturally occurring a 1 an ine ( 48),... 

The second method of intramolecular cyclization to 2,5-DKPs involves formation of the Ni—Ce bond. This reaction entails acylation of glycinamide with an a-halo acid halide, followed by ring closure under basic conditions. ... 

The biochemical reduction of a, -unsaturated -haloaliphatic acids by means of Clostridium kluyveri yielded halogen-free satmated acids. The same products were obtained from saturated -halo acids. However, the same microorganism converted ix, -unsaturated a-halo acids to saturated a-halo acids with R configuration. Yields of reduction of a-fluoro-, a-chloro- and a-bromocrotonic acid ranged from 30% to 100% [330]. 

Fig. 14 Tandem Ugi-Sjj2 starting from a-halo acids...

The Hell-Volhard Zelinsky reaction is a method for forming a-halo acid. 

This is a synthetically useful procedure because the a-halo acids are useful starting materials for other reactions. For example, the addition of hydroxide ion leads to the replacement of the halogen with an -OH group. The reaction with ammonia replaces the halogen with -NH2. The reaction with cyanide ion, CN , converts the halide to a nitrile. Figure 12-33 illustrates this reaction. 

In contrast to thiomiinchnones, thioisomiinchnones (5) (l,3-thiazolium-4-olates) have received considerable attention over the past three decades, and a rich array of 1,3-dipolar cycloaddition chemistry is described in Section 10.2.5. These heterocycles were initially constructed by Potts (1,53,57) from thioamides and a-halo acid chlorides, an example of which is shown in Scheme 10.17 (58). 

One of the more important uses of thioureas has been in the preparation of 2-imino-4-thiazolidinones, first reported by Meyer135 and Andreasch,136 138 via reaction with a-halo acids or esters. This reaction has been covered by Brown139 in a review on 4-thiazolidinones which appeared in 19(51, and, therefore, will not be discussed in detail here. The corresponding reaction between a-halo acids or esters and scleno-ureas to produce 2-iminoselenazolidin-4-ones is also known and has been reviewed.77-78 Akerblom140 has attempted to clear up some of the confusion in the literature on whether 3-alkyl-2-iminothiazolidin-4-ones (63) or 2-alkylamino-2-thiazolin-4-ones (64) are formed from 1-alkyl-thioureas and chloroacetic acid. She found that the reaction in water... 

Scheme 6 Preparation of an /V-Hydroxvamino Acid by Halogen Displacement of an a-Halo Acid 29-301...

Preparation. The general preparation of u-hydroxy acids is by the hydrolysis of an a-halo acid or by Ihe acid hydrolysis of the cyanohydrins of an aldehyde or a ketone. 0-Hydroxy acids may be made by catalytic reduction of 0-keut esters followed by hydrolysis. 0-Hydroxy acids can also he prepared by ihe ReformaCsky reaction y-Hydroxy acids are seldom obtained in the free slate because of ihe case wilh which they form... 

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