Thiazole amination

Compounds containing two or more heterocyclic rings in entirely different positions are also known to be used in this field. For example, a nonsteroidal antiinflammatory drag meloxicam (Fig. 11.4) consists of an amide withbenzothiazine-dione acid and a thiazole amine component [29]. 

The Schiff base obtained is converted in good yield (60 to 80%) to amines by the action of Raney Ni (209). This reductive condensation provides a good synthetic method and was used to prepare thiazole analogs (62) of folic acid (Scheme 43) (210). These Schiff bases under... 

Acetamidothiazole is nitrated in the same way (58, 378, 379). 2-Acetamido-4-phenylthiazole is reported to be nitrated on C-5 (380) as opposed to 2-amino-4-phenylthiazole, where nitration occurs on the phenyl ring (381). This latter result is not consistent with the other data on electrophilic reactivity in most cases 2-amino-4-arylthiazole derivatives react with electrophilic reagents at the C-5 position (see Sections rV.l.B and D). Furthermore, N-pyridy]-(2)-thiazolyl-2-amine (178) is exclusively nitrated on the thiazole ring (Scheme 113) (132, 382). 

Because of their use in the rubber industry various sulfenamido thiazoles (131) have been prepared. They are obtained in good yields through the oxidation of A-4-thiazoline-2-thiones (130) in aqueous alkaline solution in the presence of an amine or ammonia (Scheme 66) <123, 166, 255, 286, 308, 309). Other oxidizing agents have been proposed (54, 148. 310-313) such as iodine (152), chlorine, or hydrogen peroxide. Disulfides can also be used as starting materials (3141. 

Thiazole disulfides react with amines in the presence of oxidizing agents to yield 2-sulfenamidothiazoles (314). Results obtained in the ben-zothiazole series (323) indicate that they could be used as starting material to obtain 2-halosulfothiazoles. 

Under appropriate conditions 2-amino-4-alkylthiazoles are alkylated in the 5-position 2-acetylamino-4-methylthiazole reacts with dimethyl-amine and formaldehyde to afford the corresponding Mannich base (113) (372). 2-Amino-4-methyl-thiazole is alkylated in the 5-position by heat-... 

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

Tschitschibabin amination of pyridine, the mechanism of which has been established as involving an intermediate charge distribution of the thiazole molecule as well as of the thiazolium ion. 

The thiazolyl radicals are, in comparison to the phenyl radical, electrophilic as shown by isomer ratios obtained in reaction with different aromatic and heteroaromatic compounds. Sources of thiazolyl radicals are few the corresponding peroxide and 2-thiazolylhydrazine (202, 209, 210) (see Table III-34) are convenient reagents, and it is the reaction of an alky] nitrite (jsoamyl) on the corresponding (2-, 4-, or 5-) amine that is most commonly used to produce thiazolyl radicals (203-206). The yields of substituted thiazole are around 40%. These results are summarized in Tables III-35 and IIT36. 

The Stephen s method allows the reduction of nitriles by stannous chloride in acid medium. If the amine chlorhydrate initially formed is hydrolyzed, the corresponding aldehyde is obtained (37, 91). Harington and Moggridge (37) have reduced 4-methyl-5-cyanothiazole by this method (Scheme 23). However, Robba and Le Guen (91) did not obtain the expected products with 4.5-dicyanothiazole and 2-methyl-4,5-dicyanothiazole. These compounds have been reduced with diisobutyl-aluminium hydride with very low yields (3 to 6%) (Scheme 24). In other conditions the reaction gives a thiazole nitrile aldehyde with the same yield as that of the dialdehyde. 

It is common practice in the mbber industry for a compounder to use combinations of several accelerators in developing a cure system. Typically these cure systems are comprised of a primary accelerator and one or more secondary types. Primary accelerators are generally the thiazole and sulfenamide classes the secondary types (kickers) are the thiurams, dithiocarbamates, guanidines, and to a much lesser extent, certain amines and the dialkylphosphorodithioates (20). 

Amines are insufficiently nucleophilic to react with most azoles which do not contain a ring oxygen, and the stronger nucleophile NH2 is required. When treated with amide ions, thiazoles can be aminated in the 2-position by NaNHa at 150 °C. Only TV-substituted condensed imidazoles such as 1-alkylbenzimidazole react in such Chichibabin reactions. Imidazoles are aminated by alkaline NH2OH. 

The relative ease of preparation of condensed thiazole derivatives is a consequence of facile thiazole ring closure, and therefore also benzothiazole amines with an amino group on the benzene ring (except for the weakly regioselective nitration of benzothiazoles) are very easily accessible and useful substrates for the Gould-Jacobs reaction. 

In general, the reaction mechanism of elastomeric polymers with vulcanisation reagents is slow. Therefore, it is natural to add special accelerators to rubber compounds to speed the reaction. Accelerators are usually organic compounds such as amines, aldehyde-amines, thiazoles, thiurams or dithio-carbamates, either on their own or in various combinations. 

Other common five-membered heterocyclic amines include imidazole and thiazole. Imidazole, a constituent of the amino acid histidine, has two nitrogens, only one of which is basic. Thiazole, the five-membered ring system on which the structure of thiamin (vitamin Bt) is based, also contains a basic nitrogen that is alkylated in thiamin to form a quaternary ammonium ion. 

NCS-carbon is shifted dowfield in the two first complexes. The amine complex shows a shift of the N—H signal which appears at 2.08 ppm in the free ligand and at 5.17 ppm when it is coordinated. The structure of the thiazole complex was studied by X-ray diffraction, confirming the almost linear coordination about the gold atom and showing that the ligands are almost co-planar. 

The first practical, large-scale synthesis of 2-amino-5-fluorothiazole 84 employs the reaction of dilithiated 2-butoxycarbonylaminothiazole 83 with A-fluorobenzenesulfonimide (NFSi) <06OPRD346>. This reaction generates a 70 15 mixture of the desired fluorinated thiazole 84 and the sulphone 85, and after three consecutive recrystallizations thiazole 84 is isolated in 35-40% yield. This procedure has been utilized to prepare multikilogram quantities of 84, which is a heterocyclic amine component of a series of glucokinase inhibitors. 

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. 

Organic accelerators of the thiazole class having delayed action and finding particular application in tyre compounds containing furnace blacks. Sulphenamides are manufactured from mercaptobenzothiazole by reaction with an amine, the nature of which determines the degree of delayed action. 

A direct procedure from isothiocyanates and amines using tetrabutylammo-nium thiocyanate (Bu4NSCN) and PhCH2NMe3Br3 affords functionalized 2-aminobenzo-l,3-thiazoles (Scheme 60).143... 

Strecker aldehyde are generated by rearrangement, decarboxylation and hydrolysis. Thus the Strecker degradation is the oxidative de-amination and de-carboxylation of an a-amino acid in the presence of a dicarbonyl compound. An aldehyde with one fewer carbon atoms than the original amino acid is produced. The other class of product is an a-aminoketone. These are important as they are intermediates in the formation of heterocyclic compounds such as pyrazines, oxazoles and thiazoles, which are important in flavours. 

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