Thiazoles, amidation

Metribuzin heterocyclic nitrogen, triazine Metsulfovax heterocyclic nitrogen thiazole, amide Metsulfuron-methyl sulfonyl urea Mevinphos phosphoro organic, phosphate ester Mexacarbate carbamate Mirex halogenated hydrocarbon Molinate thiocarbamate Monalide amide... 

Piroxicam (84, Feldene in the US), a non-selective COX inhibitor with both analgesic and antipyretic properties, is one of the most used NSAIDs and serves as prototype of the oxicam family. This drug is utilized to relieve the symptoms of arthritis, menstrual pains or cramps and fever. It is also used in veterinary medicine to treat certain neoplasias expressing COX receptors, such as bladder, colon and prostate cancers. Variation on the structure of piroxicam has produced several other analogues with the benzene ring replaced by a thiophene ring and/or derivatives of the amide moiety, including meloxicam (85, a thiazole amide), isoxicam (86, an isoxazole amide), tenoxicam (87a, a thiophene derivative) and lornoxicam (87b, a chlorothiophene derivative). 

Cohen F, Koehler MFT, Beigeron P et al (2010) Antagonists of inhibitor of apoptosis proteins based on thiazole amide isosteres. Bioorg Med Chem Lett 20 2229-2233... 

This reaction, thoroughly studied for 2-aminopyridine (14, 15), has received less attention in the case of the thiazole nucleus. 2-Amino-4-methylthiazole is formed when 4-methylthiazole is heated with sodium amide for 15 hr at 150°C (16). This reaction was used to identify 2-amino-4-butylthiazok (17). 

Similarly, coupling 2-aminothiazole with 2-dimethylaminoethylchloride in the presence of sodium amide yields 2-(2-dimethyla.minoethylamino)-thiazole (42) (186, 187). 

The O-S exchange method in presence of a-halogenated carbonyl compound is a very good one for thiazole compounds. The thioamide is prepared in situ by the action of amide upon phosphorus pentasulphide with solvent. The a-halogenated aldehyde reacts directly. But the O-Se exchange cannot be performed with a-halogenated carbonyl compounds because of the apparition of phosphoric acid. (Scheme 3), The C-Se bond is very sensitive to add pH. 

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. 

When chloroacetaldehyde is condensed with higher thioamides prepared from amides and phosphorus pentasulfide according to Schwarz s method (222), 2-substituted thiazoles are obtained (4, 10,"22, 175). 

In the reverse reaction, thioheteroaryl amides reacted under reflux in alcohol with haloketones or aldehydes to give the corresponding 2-heteroarylthiazole derivatives (238, 271, 482, 550, 751, 765, 776, 781). 2,2 -Bithiazoles (4,4 -disubstituted) have been obtained in 80 to 90% yield by cyclocondensation of 1 mole rubeanic acid with 2 moles of a-bromoketones in polyphosphoric acid at 95 to 135 C (780). Some multiheteroaryl substituted thiazoles have been also reported (704). 

Thiazolium salts with alkyl (103, 722), arylalkyl (116), aryl (305), or heteroaryl (96) substituents on the nitrogen have been also prepared by this procedure. As in the thiazole series, N-substituted thioamides can be formed directly in the reaction mixture from phosphorus pentasulfide and N-substituted amides (127). These methods are important in the synthesis of thiamine 102 (vitamin Bj) (Scheme 45). 

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. 

In most other reactions the azolecarboxylic acids and their derivatives behave as expected (cf. Scheme 52) (37CB2309), although some acid chlorides can be obtained only as hydrochlorides. Thus imidazolecarboxylic acids show the normal reactions they can be converted into hydrazides, acid halides, amides and esters, and reduced by lithium aluminum hydride to alcohols (70AHC(12)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show the normal range of reactions. 

Simple isothiazole-4-carboxylic acids have been made from the corresponding nitriles, which are available in turn from the halogeno derivatives, or directly by the olefin route.5-Aminoiso-thiazole-4-esters and -nitriles are readily obtained by the thioamide route. The 4-acids behave normally and form acid chlorides, esters, amides, and hydrazides. In contrast to the 5-series... 

Reaction of /3-carbonyl amides with the Lawesson s reagent under microwave irradiation gave thiazoles in acceptable yields [37]. The reaction was the same one previously reviewed for the synthesis of thiophenes and was also employed for the preparation of thiadiazoles (Scheme 10, X = NH, Y = CH). 

In NRPs and hybrid NRP-PK natural products, the heterocycles oxazole and thiazole are derived from serine and cysteine amino acids respectively. For their creation, a cyclization (or Cy) domain is responsible for nucleophilic attack of the side-chain heteroatom within a dipeptide upon the amide carbonyl joining the amino acids [61]. Once the cyclic moiety is formed, the ring may be further oxidized, to form the oxazoline/thiazoline, or reduced, to form oxazolidine/thiazolidine (Figure 13.20). For substituted oxazoles and thiazoles, such as those... 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

A series of 2-(thiazol-5-yl)acetamides and acetates 35a/b has been prepared in one pot from the reactions of benzotriazolylthione derivatives 32 with A,A-dimethyl-4-A ,A -bis(trimethylsilyl)aminobut-2-yne amide 31a and ethyl 4-A,A-bis(trimethylsilyl)aminobut-2-ynoate 31b, respectively <06TL8661>. Presumably, the initial adducts 33a/b undergo intramolecular thia-Michael addition to give 34a/b, which isomerize to thiazoles 35a/b. 

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. 

The endothiopeptide amides have been converted into the corresponding 4H-l,3-thiazol-5-ones or 4/f-l,3-thiazol-5-imines in the presence of ( )- 10-cam-phorsulfonic acid (CSA) (Scheme 22).44 46... 

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