By heterocyclization

Thioethers can be obtained either by heterocyclization (Chapter II) or from the reaction between 2-halothiazoles (102) and the sodium salt of... 

Some 5-thiazolylaryIsulfides have been prepared by heterocyclization... 

Alkoxythiazoles, which are prepared by heterocyclization methods (see Chapter II), are then easily cleaved with acid to give the 5-hydroxy homologs (462. 463),... 

Alkoxythiazoles are prepared by heterocyclization (274, 462). The Williamson method using catalytic amounts of KI and cupric oxide is also possible (278. 288, 306). 5-Acetoxy-4-alkenylthiazoles are obtained by treatment of 242 with acetyl chloride and triethylamine or with acetic anhydride and pyridine (450). Similarly, the reaction of diphenylketene with 242 affords 5-acyloxy-4-alkenylthiazoles (243) (Scheme 120) (450). The readiness of these o-acetylations suggests that 4-alkylidene thiazoline-5-one might be in equilibrium with 4-alkenyl-5-hydroxythiazoles (450). 

Table III-125 Thiazoles substituted by heterocyclic groups nonadjacent to the...

TABLE III-125. THIAZOLES SUBSTITUTED BY HETEROCYCLIC GROUPS NONADJACENT TO THE THIAZOLE RING... 

The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

The 2,4- or 2,5-diacids and 2,4,5-triacids have been prepared in good yields (40 to 50%) by hydrolysis of the esters obtained by heterocyclization (7, 12). 

Chemical studies on nyctinastic leaf movement regulated mainly by heterocycles 99H(51)927. 

Structural basis of protein kinase C activation by heterocyclic tumor promoters 98ACR163. 

Interestingly, replacement of both benzene rings of the prototype molecule (54) by heterocyclic rings is not only consistent with activity, but yields two of the more potent antihistamines. 

The possibility of replacing all three phenyl rings in the triarylmethane lactone structure by heterocycles has also been exploited. The first compound to be described83 was the 3,3-bisindolyl-7-azaphthalide (18). This... 

The hydrohalogenation of phenyl(3-methyl-l,2-butadienyl) phosphinic esters involved protophilic attack of the reagent, followed by heterocyclization of the allenephosphonate system (Scheme 40) [103, 104],... 

Michael addition of (benzotriazol-l-yl)acetonitrile 557 to a,[)-unsatu rated ketones followed by heterocyclization provides new means for preparation of 2,4,5-trisubstituted pyridines. The reaction is catalyzed by bases. In the presence of secondary amines, a nucleophilic attack of amine on the CN group in adduct 556 initiates the cyclization to tetrahydropyridine 558 that subsequently eliminates water and benzotriazole to give pyridine 559. Analogously, in the presence of NaOH, pyridone 560 forms, via intermediate 561 (Scheme 88) <1997JOC6210>. 

Substituted derivatives of l-(tetrahydrobenzo[b]thiophen-2-yl-3-carboxylate)-5-phenyl-6-thio-l,2,4-triazin-4-one have been synthesized by heterocyclization reactions of different hydrazones obtained from 2-amino-tetrahydrobenzo[b]thiophene-3-carboxylate with phenyl isothiocyanate <00PS275>. Reaction of 5-methyl isothiosemicarbazide with a-amino acid vicinal tricarbonyl reactive substrates 1 and 2 yields 1,2,4-triazine substituted a-amino acids, as an equimolar mixture of regioisomers 3a/3b and 4a /4b, respectively <00JCS(P1)299>. 

Over the past few decades, a large variety of ligand systems have been tested with the aim of obtaining novel iron(II) spin crossover systems which could possibly be utilised in electronic devices [1]. In most cases an Fe(II)N6 chro-mophore is required in order to generate the spin crossover phenomenon [2]. A large majority of the ligands used are represented by heterocyclic systems, in which the lone electron pair on the nitrogen atom coordinates to the Fe(II) ion. 

Fused heterocyclic systems derived from 3-mercapto-l,2,4-triazole can be obtained by heterocyclization of 4-allyl-l,2,4-triazole-3-thione derivatives by treatment with halogens or mineral acids <1996T791>. Compounds 342 react with bromine yielding thiazolium halides 28 in good yield (Equation 64) <2000RJOC1033>. 

Instead of replacing phenyl rings by heterocycles in order to get altered electronic properties, perfluorated rings may also be used as building units. One example for a perfluorated dimer is 19 with Tg = 133°C [62, 63],... 

Sulfisoxazole Sulfisoxazole, ATi-(3,4-dimethyl-5-isoxazolyl)sulfanilamide (33.1.19), is synthesized by reacting 4-acetylaminobenzenesulfonyl chloride with 5-amino-3, 4-dimethylisoxazol (33.1.17), which is in turn synthesized by heterocyclization of 2-methy-lacetylacetonitrile with hydroxylamine, and subsequent acidic hydrolysis (hydrochloric add) of the protective acetyl group in the resulting product (33.1.18) [18,19]. 

Azirine derivatives 318 were shown in the same article to be precursors of triazines 324 (30-35% yield) and pyrimidines 326 (30% yield) upon treatment in DMSO with guanidine and formamidine, respectively (Scheme 71). A similar pathway to that outlined above is also invoked to explain these results thus, intermediate 323 would yield 324 by electro-cyclic ring closure, whereas 326 would be formed by heterocyclization of 325 and loss of ammonia (91JOC7). 

Benzene rings often serve in drugs simply as flat, relatively electron-rich moieties. Many examples have been noted thus far where such rings can be replaced by heterocycles that have some degree of aromatic character. 

Poly(arylene ether triazole)s have also been prepared by heterocyclic-activated displacement polymerization [36], The 1,2,4-triazole unit sufficiently activated, albeit weakly, aryl fluorides for nucleophilic displacement. Several 3,5-bis(4-fluorophenyl)-4-aryl-l,2,4-triazoles were polymerized with various bis-phenols to yield polymers with Tgs from 185 to 230 °C [36]. The 1,2,4-triazole unit appears to be one of the more weakly activating heterocycles towards nucleophilic substitution polymerization. 

Reactions Catalyzed by Heterocyclic Compounds E. Imoto, Kagaku no Ryoiki, Zokan, 1969,87,51-98. 

Compounds with heterocyclic rings are inextricably woven into the most basic biochemical processes of life. If one were to choose a step in a biochemical pathway at random, there would be a very good chance that one of the reactants or products would be a heterocyclic compound. Even if this was not true, participation of heterocyclics in the reaction in question would almost be certain as all biochemical transformations are catalyzed by enzymes, and three of the twenty amino acids found in enzymes contain heterocyclic rings. Of these, the imidazole ring of histidine in particular would be likely to be involved histidine is present at the active sites of many enzymes and usually functions as a general acid-base or as a metal ion ligand. Furthermore, many enzymes function only in the presence of certain small non-amino acid molecules called coenzymes (or cofactors) which more often than not are heterocyclic compounds. But even if the enzyme in question contained none of these coenzymes or the three amino acids referred to above, an essential role would still be played by heterocycles as all enzymes are synthesized according to the code in DNA, which of course is defined by the sequence of the heterocyclic bases found in DNA. 

Other 7- substituents that have been introduced include the dialkylamino, acetamido, hydroxy, alkoxy and alkylthio groups (B-71MI11209). Acylation of the 7-amino group by heterocycles such as cyanuric chloride and its derivatives was inevitable, as was incorporation of a 7-triazole substitution pattern by diazotization of the 7-amino group and o-coupling with 2-naphthylamine followed by triazolization (94). 

One or both of the carbocyclic aromatic rings in stilbenes or azobenzenes can be replaced by heterocycles. Examples include 2-styrylpyridine methiodide (138) and 4,4 -azopyridine (139) (53JCS1281). 

The synthesis of 2-arylbenzofurans 226 by heterocyclic ring closure of acetylenic compounds 225 with pyridine hydrochloride is a variation487 of the general method of heterocyclic ring closure of acetylenic compounds 221. 

The carbocyclic azo dye class provides dyes having high cost-effectiveness combined with good all-around fastness properties. However, they lack brightness, and consequently, they cannot compete with anthraquinone dyes lor brightness. This shortcoming of carbocyclic azo dyes is overcome by heterocyclic azo dyes. 

Synthesis of the dibenzofuran (27) by irradiation of grisa-3, 5 -diene-2, 3 -dione (28) is believed to involve electrocyclic ring opening followed by intramolecular cycloaddition to the ketene and elimination of carbon dioxide, as shown in Scheme 2.24 Analogous photocyclizations are responsible for the photochromism exhibited by heterocyclic fulgides such as ( )-a-3-furyl-ethy idene(isopropylidene)succinic anhydride (29), which on irradiation... 

---