Synthesis of fused thiazoles

A series of 2-arylbenzothiazoles 41 has been synthesized via microwave irradiation of 1 1 mixture of ortho-nm i noth iophenol s 39 and alkyl or aryl acylacetonitriles 06JHC1609 . This reaction appears to be more efficient than that of ort/20-aminothiophenols with (3-ketoesters to form substituted benzothiazoles reported previously 05H(65)2119 . 

The Jacobson thioanilide radical cyclization chemistry has been extensively used for the synthesis of benzothiazoles as shown by the preparation of 4-fluoro-2-(3,4-dimethoxy-phenyl)benzothiazole 47 06JMC179 . The harsh reaction conditions (K3Fe(CN)6, NaOH, 

90°C) can be overcome by using the Dess-Martin periodinane (DMP) (CH2CI2, 25°C) 06JOC8261 . The reaction probably proceeds via thiyl radical 50, which undergoes 1,5-homolytic radical cyclization followed by aromatization of radical 51 to give 2-arylthiazole 52. 

A modified Pictet-Spengler reaction has been applied to the synthesis of thiazolo-quinolines 58 06T3228 . Condensation of anilines 53 with aryl aldehydes 54 followed by endo cyclization results in the formation of thiazoloquinolines 58 under a variety of traditional Pictet-Spengler protocols such as 2% trifluoroacetic acid in dichloromethane. 

A novel series of 5//-thiazolo[3,2-a]pyridine-5-ones 64 is prepared by addition of malonic esters 59 to 2-alkynylthiazoles 60 06H(67)523 . A plausible reaction mechanism involves an intramolecular cyclization of the initial adduct 61 to give the cyclobutenoxide intermediate 62. Ring-opening of this intermediate and subsequent cyclization lead to 5//-thiazolo[3,2-a]pyridine-5-one 64. 

A series of 2-trifluoromethyl and 2-difluoromethyl substituted benzothiazoles 30 has been synthesized by a one-pot reaction of trifluoroacetic acid and difluoroacetic acid, respectively, with 2-aminobenzenethiol 07TL3251 . The reaction pathway presumably involves the imidolyl chloride intermediate 29, which undergoes intramolecular nucleophilic substitution by neighbouring thiol under basic conditions to give benzothiazole 30. 

A convenient synthesis of thiazolo-fused 2-pyridones 41 has been developed 07JOC4917 . Thus, A2-thiazolines 39 undergo acyl ketene imine cyclocondensation with Meldrum s acid derivatives 38 to give the dihydro thiazolo-fused 2-pyridones 40, which transform to 41 via bromination-elimination process. Pyridones 41 are converted to the 2-substituted analogs 43 and the saturated products 42 by Heck coupling and conjugate addition, respectively. 

A one-pot, three-component reaction of isocyanides 45, dialkyl acetylenedicarboxylates 46 and ethyl 2-oxo-2-(l,3-thiazol-2-ylamino)acetates 44 provides easy access to 5H-[1,3]thiazolo[3,2- pyrimidinc derivatives 52 07SL2703 . Presumably, addition of 

A new route to 6-substituted pyrrolo[2,l-b]thiazoles 58 takes advantage of an intramolecular thermal cyclization of acetates 56 07S3037 . These acetates are easily derived from the Morita-Baylis-Hillman adducts of thiazole-2-carboxaldehyde. This strategy has also been extended to the synthesis of the tricyclic analogs 60. 

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As shown in Scheme 8, a common ketone precursor led to the pyrazolo[4,3- ]- and thiazolo[5,4- ]-fused 1,4-benzoxazines (96) and (97) <87JMC580>. For the synthesis of compound (96) the ketone was condensed with HC02Et and subsequently cyclized with hydrazine. For the synthesis of the thiazole (97) a-bromination of the ketone was followed by condensation with thiourea. The linear tricyclic structures (96) and (97) were supported by H and 13C NMR spectroscopic analyses. 

The most commonly used method for the preparation of fused thiazoles involves the reaction of a-mercapto N-heterocyclic compounds of type (138) with an a-halocarbonyl compound or ester to give S-alkylated intermediates (139) which can be dehydrated to (140). When R2 is alkoxy, thiazolones (141) are formed (Hantzsch synthesis). Strong dehydrating agents are necessary to cyclize aldehydes and ketones (139) to fused thiazoles. The method has been used to prepare (dihydro) imidazo[2,l-6]thiazoIes and thiazolo[3,2- ]-s-triazoles (80JHC1321, 78JHC401, 82IJC(B)243). 

Chemistry and heterocyclization of thiosemicarbazones. Synthesis of pyrrohdine, thiazole, thiazoline, thiazohdine, pyrazole, thiadiazole, oxa-(hazole, triazole, pyridazine, thiazine, and triazine derivatives and fused heterocycles 12JHC21. 

In aprotic conditions acetic anhydride sodium acetate induces formation of a fused ring through an intra molecular condensation. It results in a pyrrolo[2,l-fc]thiazole (39), which constitutes an interesting intermediate for the synthesis of dyes (Scheme 18) (40). 

Phenyliodonium ylids of cyclic dicarbonyl compounds (46) react with thiourea to form the thiouronium ylid (47) which on heating is converted into the fused thiazole (48), this method is applicable to subtituted thioureas provided they have at least one free amino group. This reaction can be considered to be a modification of the Hantzsch thiazole synthesis <96JHC575>. 

The synthesis of novel heterocycle-fused troponoids was performed by reaction of the nitrosotropolone acetate 426 in neat thiazole at 70 °C giving the thiazole-condensed heterocycle 427 but in only 13% yield (Equation 196) <2004H(62)535>. 

A regiospecific solid-phase synthesis of 3-methylthiazolo[3,2-c][l,2,3]triazole 105 has been achieved using poly-styrene-sulfonyl hyrazide resin (PS-Ts-NHNH2) 287. The reaction of resin 287 with l-thiazol-2-yl-ethanone in 5% TiCU/MeOH provides hydrazone 288 and subsequent treatment of this latter compound with morpholine at 95 °C gave fused triazole 105 in 60% yield (Scheme 29) <2004TL6129>. 

The synthesis of yet another example begins with the allylation of the enamide (21-2) with methyl iodide. Reaction of this intermediate (23-1) as above with the ami-nopyrrazole (23-2) leads to the formation of the fused pyrimidinopyrrazole (23-3). This last productis is next acylated with thiazole-carboxillic acid (23-4) in the presence of aluminum chloride. There is thus obtained the sleep inducing agent indiplon (23-5) [24]. 

Fused ring systems can be prepared either from an azine precursor or from an oxazole or thiazole precursor. In the sections on the synthesis of these compounds the former method is grouped under Azine approach , the latter under Azole approach . 

The usual precursor to the thiazolo-fused systems is a cyclic thioamide or its tautomeric form . A convenient approach to the synthesis of bicyclic [5-5] systems, e.g., the tricyclic thiazolium salt 46 and 2,3-dihydroimidazo[2,l-A]thiazol-5-one 48, involves the N,S-dialkylation of appropriate precursors 45 and 47 with 1,2-dihaloalkanes (Scheme 31) <1999JMC2828, 2002EJC777>. 

The synthesis of naphthimidazo[2,l-fe]thiazol-3(2//)-ones, in which a 4-thiazolidinone nucleus has fused to both naphth[2,3-d]imidazole and naphth[l,2-c/]imidazole ring systems, has been reported. 

The reaction of 2-aminothiazole and 2-aminobenzothiazole with 2-benzoyl-2-bromoacetate has been employed in the preparation of several fused imidazole systems <89JHC1875>. a-Bromo ketones attack the ring nitrogen of 2-aminothiazoles to give the salts (160). The same type of reaction takes place with ethylbromoacetate (Scheme 39). Basihcation of (160) affords the imines (I6I) which are intermediates in the synthesis of imidazo[2,l-h]thiazoles <89JCS(P1)643>. On the other hand, when an a-bromo aldehyde is made to react with 2-aminothiazoles, the salt (162) is formed directly leading to (163) after basification. 

A review describes the pharmacological properties of l,2-benzisothiazoles. In connection with thiazoles, we find several reviews or papers thiazoles in food aromas patellamides, which are antineoplastic cyclic peptides, from the marine tunicate Lissoclinum patella, which contain an unusual fused oxazoline-thiazole unit and polythiazole-containing peptide antibiotics. An interesting total synthesis of the aglycon of bleomycin A2 should also be mentioned. ... 

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