A-halo compounds

The most widely used method for the synthesis of thiazoles (see Chapter 4.19) is of this type and involves the reaction of a-halo compounds (Y = halogen in Scheme 2) with a reactive component containing an —C(=S)— structural entity. Reaction of the a-... 

The formation of derivatives of this type by free-radical attack has been mentioned previously (see section E above). The most common route to vinylogous halo ketones is by halogenation of dienol acetates or ethers. Both free halogen and A -halo compounds may be employed, and this approach has frequently been used to obtain 6 (axial) halo compounds ... 

The mechanism and stereochemistry of halogenation, physical methods / 273 Dihalogenation / 276 The use of A-halo compounds / 280 The use of other reagents / 282 The oxidation of halohydrins / 283 Vinylogous a-halo ketones / 284... 

This reaction, which was carried out for the first time by Tschitschibabin in 1927, involves the quaternization of a 2-substituted pyridine (106) by an a-halo compound (107) followed by intramolecular cyclization of the quaternary salt (108) with a mild base (Scheme 15). 

Oxidation of aldoses by hypoiodite can also be used for preparative purposes.7 Other types of halogen oxidants, especially A-halo compounds, are useful. For example, A -bromocarbamide was recommended by Kiss8 as a selective and convenient reagent for oxidizing benzylated sugars to their corresponding aldonolactones in yields exceeding 90%. Another example is the use of A-iodosuccinimide and tetrabutylammonium iodide.9... 

The only examples of reactions in this category relates to A-oxides of ring heteroatoms (see Section 7.23.4.1) which on reaction with POCl3 or POBr3 form the a-halo compound typical examples are given in Table 2. 

Triazole pesticides are made by reaction between 1.2.4 triazole and a halo-compound... 

Aryl ortho thioesters, which can be readily prepared from the corresponding acid chlorides or methyl esters, react with A-halo compounds, such as 1,3-dibromo-5,5-dimethylhydantoin (DBH) or A-bromosuccinimide, and hydrogen fluoridc/pyridine to give aromatic trifluoromethyl compounds,i.e. formation of... 

The most widely used method for the synthesis of thiazoles (see Chapter 4.19) is of this type and involves the reaction of a-halo compounds (Y = halogen in Scheme 2) with a reactive component containing an N—C(=S)— structural entity. Reaction of the a-bromoketone (65) with the primary thioamide (66) in hot benzene gave the intermediate hydroxy compound (67), which could be isolated in certain instances but in most cases underwent dehydration to form the thiazole (68). The diversity in the substituents capable of being introduced into the resultant thiazole by this procedure is illustrated in Chapter 4.19. Especially noteworthy in this respect is the reaction of the bromopyruvaldehyde oxime (69) with thiourea in methanol at room temperature. Neutralization with sodium carbonate resulted in the isolation of the 2-aminothiazole-4-carbaIdehyde oxime (70) in 39% yield (73JOC806). 

Halogeno-1,2,4-triazoles are reductively dehalogenated with red phosphorus and hydriodic acid (05la(343)i) but, unlike A/ halo compounds, not by bisulfite (67zci84). 

This approach was discussed in Chapter 6. The synthesis of the spasmolytic Diphepanol (28) is an example. Disconnection of one or both phenyl groups gives a-amino carbonyl compounds which can be made from the corresponding a-halo compounds (see Chapter S). Halogenation of both (29) and (30) is regioselective as the other side of the carbonyl group cannot enolise. 

All A-halo compounds can be readily determined by analysis based on their oxidizing action. They liberate two equivalents of iodine from acidified potassium iodide solution almost instantaneously (1 mmole of A-monohalo compound is equivalent to 20 ml of O.In-thiosulfate solution). The liberation of iodine from hydrogen iodide involves production of the amine or amide parent of the halo compound. Sodium sulfite and hydrogen sulfide also reduce N-halo compounds. UV and IR spectroscopic methods have been worked out for determination of JV-halo compounds.399... 

Bailey, A.R. Banks, R.E. A-Halo compounds. Part 8. Perfluoro-A-chloropiperidine. 

Reaction of dialkyl phosphorodithioic acids with a halo compound in the presence of PTC and alkali... 

With a hydrocarbon of low reactivity, hydrogen atom abstraction by Cl dominates but, with a more reactive hydrocarbon, Br can be the major hydrogen atom abstracting species. Thus, with PhCH2CH3 k(a)/k(P) per hydrogen atom is 116, characteristic of Br attack rather than attack by Cl or the complexed chlorine atom the ratio of the a-halo compounds is about 10 1 in favor of the bromide. ... 

Scheme 9.103. The Hofmann rearrangement, which results in the loss of carbon dioxide (CO2) and the production of an amine from oxidation of an amide with bromine (Br ) or chlorine (CI2).The oxidation produces the A -halo-compound, which, on treatment with base, undergoes rearrangement to generate the N-alkylisocyanate (cyclohexylisocyanate in this case). Treatment of the Af-alkyhsocyanate with water, produces the transient carbamic acid. The carbamic acid undergoes spontaneous decarboxylation in water to carbon dioxide (CO2) and cyclohexylamine (Chapter 10). Details of the Hofinann rearrangement will be discussed subsequently. But see Hofmann, A. W. Chem. Ber., 1881,7 /, 2725.

Referring to the short list of reactions that Prof. Whitesides considered foolproof. Prof. Heathcock remembered that in his work several amines could not be acylated easily. He wondered whether any of Prof. Whitesides amines ever underwent diacylation Did his a-halo compounds ever reduce instead of... 

Kinetically controlled addition of hydrogen halide to acylaminoacrylic ester leads to a-halo-a-acylamino-propionic acid ester (76), which gradually rearranges in the reaction solution into the p-halo-derivative 236, 241, 301). The a-halo compound can be captured with mercaptans, alcohols or water, forming the appropriate a-substituted a-acylamino-propionic acid esters (77) 197,199). 

---