Reactions of thiazoles and fused derivatives

A practical synthesis of L-869,298, a potent phosphodiesterase-4 (PDE4) inhibitor, involves two regioslective deprotonations of thiazole at the 2- and 5-positions 05JOC3021 . Treatment of thiazole with LiHMDS gives clean formation of the C-2 anion, which reacts with hexafluoroacetone, and the resulting lithium alkoxide 105 is protected as the MOM ether 106. Deprotonation of 106 at the 5-position with n-BuLi followed by addition of nitrile 107 furnishes ketone 108, a key intermediate for the synthesis of L-869,298. 

5-iodo thiazole adducts 112a and 112b, respectively, again without epimerization. 

Easy access to a series of 5-substituted 4-bromo-2-thiazolamine derivatives 116 is based on the halogen dance (HD) reaction 05JOC567 . Treatment of 4-bromothiazole 113 with 

3 equiv of EDA at 0 °C brings about full conversion to the HD product 115, which is trapped with various electrophiles to give the 5-substituted thiazoles 116. For example, 4-bromo-5-trimethylsilyl-thiazole 118 is obtained in 74% yield when 113 is exposed to EDA followed by addition of TMSCl as the electrophile. The HD reaction is completely blocked when thiazole 113 is added to a solution of 3.3 equiv of EDA in the presence of TMSCl at -80 °C, and the corresponding normal, anti-HD product product 117 is formed exclusively. 

In the process of the HD studies on bromothiazole 113, methylation of amide nitrogen was attempted 05JOC567 . Deprotonation with sodium hydride or EDA and subsequent quenching with methyl iodide or dimethyl sulfide (DMS) leads to the exclusive methylation 

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. 

A mild and efficient a-heteroarylation of simple esters and amides via nucleophilic aromatic substitution has been described 06OL1447 . Treatment of 2-chloro-benzo[//Jthiazole 99 with tert-butyl propionate in the presence of NaHMDS under nitrogen furnishes tert-butyl 2-(benzo[c(jthiazol-2-yl)propanoate 100. When the same reaction is preformed initially under nitrogen and then exposed to air, the hydroxylation product 101 is obtained. This method offers two desirable features that are either complementary or improvements to the palladium-catalyzed a-arylation reactions. First, heteroaryl chlorides 

The palladium- and copper-mediated C-2 arylation of thiazole with 4-iodoanisole under ligandless and base-free conditions provides 2-(4-methoxyphenyl)thiazole in good yield 06EJOC1379 . However, the scope of this selective C-2 arylation has not been disclosed. 

A cobalt-catalyzed method for arylation of heteroarenes including thiazole and benzothiazole was reported in 2003 030L3607 . According to this report, the direct C-5 arylation of thiazole with iodobenzene was carried out in the presence of cobalt catalyst [Co(OAc)2/IMes] and cesium carbonate, and a complete reversal of arylation from C-5 to C-2 was observed with the bimetallic Co/Cu/IMes system. This report has been retracted as the laboratory of the senior author has not been able to reproduce the key results disclosed in the communication 06OL2899 . 

A parallel synthesis of a library of 2-aryl-6-chlorobenzothiazoles 112 involves a regioselective palladium-catalyzed Suzuki coupling reaction of 2,6-dichlorobenzothiazole 111 with arylboronic acids (1.1 equiv) under microwave irradiation 06TL3091 . When excess phenylboronic acid is used, Pd(PPh3)4 still provides 2-phenyl-6-chlorobenzothiazole exclusively, while 2-dicyclohexylphosphinobiphenyl 113 generates 2,6-diphenylbenzothiazole as the major product. 

Two methodologies for the direct C-2 arylation of thiazoles have been reported. The first one is mediated by both palladium and copper 07T1970 . Thus, the C-2 arylation of thiazole and benzothiazole with aryl iodides is carried out using copper iodide (2 equiv.) and a catalytic amount of palladium acetate under base-free conditions. The other method involves copper-catalyzed arylation with aryl iodides in the presence of lithium t-butoxide 07JA12404 . In general, reactions with lithium tert-butoxide provide better yields than those with potassium fert-butoxide. In addition, arylation with phenyl bromide, chloride or tosylate fails to provide any desired arylation products. 

In addition to 4-alkenylthiazoles 104, A-methylenethiazol-2-amine derivatives are also utilized in the Diels-Alder reactions with sulfene 112 07JCR127 . Cycloaddition of (E)-N-benzylidene-4-phenylthiazol-2-amines 111 with sulfene 112, generated in situ from methanesulfonyl chloride in the presence of triethyl amine, provides a mixture of regioisomers 113 and 114 in moderate yields. 

It is well known that addition of benzothiazole to dimethyl acetylenedicarboxylate (DMAD) leads to the formation of zwitterion 115. This intermediate can be trapped with various aryl aldehydes, according to a recent study 07TL4391 . Thus, heating a solution of benzothiazole, DMAD and aryl aldehyde 116 in toluene generates oxazinobenzothiazole 117 as a single isomer in moderate yield. 

The palladium-catalyzed decarboxylative coupling of allyl 2-(benzo[c(jthiazol-2-yl)acetates 118 provides a facile approach to 2-(but-3-enyl)benzo[c(jthiazoles 122 07JA4138 . The reaction is initiated by nucleophilic attack of Pd(0) on the allyl ester to give Pd-7t-allyl complex 119, which undergoes nucleophilic attack at the less substituted allylic carbon from the benzothiazole nitrogen to produce 120. Decarboxylative dearomatization leads to intermediate 121, and a subsequent aza-Cope rearrangement driven by rearomatization affords the final product 122 and accounts for the unusual regioselectivity. This appears to be the first report of a tandem allylation/aza-Cope reaction driven by decarboxylative dearomatization/ rearomatization. 

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In an attempt to synthesize fused aromatic systems of a pentalene-like structure, Boekelheid and Fedoruk (332) submitted the dicyanomethyl ylide of thiazole (77) to the addition reaction with dimethyl acetylenedi-carboxylate (DMA). They unexpectedly observed the formation of a fused six-membered (80) rather than a five-membered-ring (78). This ylide (77) was readily afforded by the reaction of thiazole (73) with tetracyanoethylene oxide and then put into reaction with DMA. The initially formed thiazolopyrrole derivative (78) is strongly polarized by the gcm-dicyano group, and its pyrrole ring is spontaneously cleaved with proton elimination. The ring dosure of the intermediate (79) leads to the final stable derivative of 5-FT-thiazolo[3,2-a]pyridine (80). More recently. 

Reactions of thiocarbonyl ylides with nitriles are scarce. Simple nitriles do not undergo bimolecular cycloaddition (171). There is, however, a single example of an intramolecular case that was reported by Potts and Dery (24c,62). By analogy to the intramolecular cycloaddition with acetylenic dipolarophiles (Scheme 5.40), the primary product derived from the reaction of a thiocarbonyl ylide with a nitrile group undergoes a subsequent elimination of phenylisocyanate to give the fused 1,3-thiazole (131). 

A series of imidazo[2,l-6]thiazole derivatives 71 has been prepared through a catalyst-free three-component reaction in water <07TL7263>. Reaction of isocyanides 66, aryl aldehydes 67, and 2-aminothiazoles 65 in water at 70 °C produces the fused aminothiazoles 71 in good yields. 

Pyrazole-, Thiazole-, and Imidazole-fused Thiophens and Related Systems.— The behaviour of thieno- and selenolo-t-3,2-i/]pyrazoles in formylation and bromina-tion reactions has been studied. In contrast to benzo[fe]thiophen, a substituent is directed into the a-position of the condensed thiophen ring. 2-Mercapto-thieno[3,2-prepared from 2-chloro-3-nitrothiophen and sodium disulphide followed by carbon disulphide. A benzo-fused system was prepared similarly from 3-bromo-2-nitrobenzo[6]thiophen. Derivatives of... 

Many reactions in heterocyclic multistep syntheses involve thermal condensations. Among these, the Niementowski reaction is the most common method for synthesis of the 31-f-quinazolin-4-one ring. It involves the fusion of anthranilic acid (or a derivative, e.g. 2-aminobenzonitrile) vith formamides or thioamides (or their S-methyl derivatives) and usually needs high temperatures and requires lengthy and tedious conditions. Recently, Besson and coworkers studied the possibilities offered by this reaction and explored the preparation of novel bioactive heterocycles (e.g. 38, 39, and 40 in Scheme 9.11) in which the quinazoline skeleton is fused with thiazole, indole or benzimidazole rings [50a-c]. 

The synthesis of thiazolo[4,5-d]pyrimidines has been successfully accomplished by various methods. 4-Amino-5-ethoxycarbonylthiazole derivative has been cyclized to thiazolo[4,5-d]pyrimidine by its reaction with phenyl isothiocyanate [87], Many 4-amino-5-carbamoylthiazole derivatives have been cyclized to the corresponding thiazolo[4,5-d]pyrimidines using triethyl orthoformate/acetic anhydride mixture [88-91], Moreover, 4-amino-5-cyano thiazoles have been used to prepare the same fused ring system via their reaction with triethyl orthoformate, followed by treatment of the intermediate with hydrogen sulfide, guanidine, amines, and isothiocyanates [92, 93], Other thiazolo[4,5-d]pyrimidines have been obtained from 4-amino-5-cyano, carbamoyl, or ethoxycarbonyl thiazoles via cyclization with acetic anhydride [94] or formic acid [95],... 

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