1.2.4- Triazolo heterocycles

The other three chapters in the present volume all deal with bicyclic heterocycles. Dr. H. K. Pujari of Kurukshetra University in India describes condensed 4-thiazolidinones, and Professor M. A. E. Shaban and A. Z. Nasr of Alexandria University in Egypt survey the synthesis of condensed 1,2,4-triazolo heterocycles. Finally, Professor T. A. Crabb of Portsmouth, England has covered saturated bicyclic 6/5 ring-fused systems with a bridgehead nitrogen and a single additional heteroatom. None of these groups of bicyclic heterocycles has been comprehensively reviewed before. 

DAIB-oxidations of the A-arylimines 61, derived from 2-amino-5-formyluracil, lead through N-N bond formation to the pyrazolopyrimidines 62 (Scheme 19) (97SL1409). Oxidative N-N coupling also occurs when the pyridyl- and thiazolyl hydrazones 63 are exposed to DAIB leading, in this case, to the ring-fused 1,2,3-triazolo heterocycles 64 (Scheme 19) (00SC417). 

Unusual heterocyclic systems can be obtained by photodimerizations and for five-membered heterocycles with two or more heteroatoms such dimerizations need be effected on their ring-fused derivatives. Cyclobutanes are usually obtained as in the photodimerization of the s-triazolo[4,3-a]pyridine (540) to the head-to-head dimer (541). These thermally labile photodimers were formed by dimerization of the 5,6-double bond in one molecule with the 7,8-double bond in another (77T1247). Irradiation of the bis( 1,2,4-triazolo[4,3-a]pyridyl)ethane (542) at 300 nm gave the CK0ifused cyclobutane dimer (543). At 254 nm the cage-like structure (544) was formed (77T1253). 

The formal derivation of the analogs, described in the foregoing, represents, from the point of view of systematic organic chemistry, a shift to the derivatives of other heterocyclic systems. In the case of pyrimidine aza analogs we arc dealing with derivatives of symmetrical or asymmetrical triazine in the case of purine aza analogs, the derivatives produced are those of imidazo[4,5]-i -triazine and z -triazolo [4,5-d] pyrimidine. 

Diaminopyrimidines fused to a number of heterocycles (35) were also cyclized with one-carbon inserting agents to the corresponding hetero-cyclo-l,2,4-triazolo[l,5-c]pyrimidines 36 (75M1111 81JHC43 97JIC27). 

Paudler and Helmick515 have measured half-lives for deuteration of some heterocycles by deuterated sulphuric acid at 100 °C. The equivalent first-order rate coefficients (lO ) are as follows imidazo[l, 2-a]pyridine, 427(3-H) imidazo[l,2-a]pyridine-N-methiodide, 62(3-H) imidazo[l,2-a]pyrimidine, 123-(3-H) imidazo[l,2-a]pyrimidine-N-methiodide, < 6.4 (3-H, 5-H) 1,2,4-tri-azolo [1,5-a]pyridimidine, 128(5-H) 1,2,4-triazolo [1,5-a]pyrimidine-N-methiodide, 11.7 (5-H). The lower reactivity in each case of the corresponding methiodides shows that the bases react as such and not as the conjugate acids. 

Kinetic studies of base-catalysed hydrogen exchange of heterocyclic compounds have been carried out. Paudler and Helmick515 measured second-order rate coefficients for deuteration of derivatives of imidazo[l,2-a]pyridine(XXXIII), imidazo[l,2-a]pyrimidine(XXXIV), and 1,2,4-triazolo[1,5-a]pyrimidine(XXXV)... 

The [l,2,3]triazolo[2,l- ]benzotriazole (74 2,3-benzo-l,3a,4,6a-tetraazapentalene) heterocyclic ring system is obtained by an electrophilic attack of singlet nitrene, generated by heating the corresponding nitrophenyl triazole 251 in trialkyl phosphite, on the triazole nitrogen (Equation 39) <1998JOC3352>. 

H(65)1889, 2005EJO3553>. Starting dihydro[l,2,4]triazolo[3, 4-4]benzo[l,2,4]triazines 482 readily react with aromatic aldehydes to yield iminium salts 483. These salts treated with a base (e.g., triethylamine) are deprotonated to reactive 1,3-dipolar azomethine imines 484. In contrast to related five-membered heterocycles, these compounds are relatively unstable on storage in the solid form and particularly in solution. Fortunately, this obstacle can be easily circumvented by their in situ preparation and subsequent 1,3-dipolar cycloaddition. These compounds can participate in 1,3-dipolar cycloadditions with both symmetric and nonsymmetric dipolarophiles to give the expected 1,3-cycloadducts in stereoselective manner. Selected examples are given in Scheme 82. 

Cycloadditions are in general an effective way of constructing cyclobutane rings. A wide variety of heterocyclic systems dimerize in this way. 1,3-Diacetylindole, for example, affords the head-to-tail dimer 242 on irradiation in ethanol.185 Ethyl 2-ethoxy-l,2-dihydroquinoline-l-carboxy-late is similarly converted in diethyl ether into the trans head-to-head dimer.186 Notable among many analogous photodimerizations are those reported in 1,4-dihydropyridines,187 in furo[3,2-b]pyridin-2(4//)-ones,188 in 8-methyl-s-triazolo[4,3-a]pyridine,189 and in 2H-2-benzazepine-1,3-diones.190 The [ 2 + 2] dimerization of amidopyrine is the first reported example of a photocycloaddition in a 4-pyrazolin-3-one.191... 

Two types of addition to pyrimidine bases appear to exist. The first, the formation of pyrimidine photohydrates, has been the subject of a detailed review.251 Results suggest that two reactive species may be involved in the photohydration of 1,3-dimethyluracil.252 A recent example of this type of addition is to be found in 6-azacytosine (308) which forms a photohydration product (309) analogous to that found in cytosine.253 The second type of addition proceeds via radical intermediates and is illustrated by the addition of propan-2-ol to the trimethylcytosine 310 to give the alcohol 311 and the dihydro derivative 312.254 The same adduct is formed by a di-tert-butyl peroxide-initiated free radical reaction. Numerous other photoreactions involving the formation by hydrogen abstraction of hydroxyalkyl radicals and their subsequent addition to heterocycles have been reported. Systems studied include 3-aminopyrido[4,3-c]us-triazine,255 02,2 -anhydrouri-dine,256 and sym-triazolo[4,3-fe]pyridazine.257 The photoaddition of alcohols to purines is also a well-documented transformation. The stereospecific addition of methanol to the purine 313, for example, is an important step in the synthesis of coformycin.258 These reactions are frequently more... 

The glutamic moiety of TNP-351, a pyrrolo[2,3-d]pyrimidine glutamic acid derivative, and related compounds have been transformed into their A-co-masked ornithine analogs which show remarkable antifolate activity <00CPB1270>. The reaction of the heterocyclic enamine 77 with tosyl azide leads to the tosylimino derivative of 1,2,4-triazolo[l, 5-a]pyrimidine 79. Extrusion of nitrogen from the primary adduct 78 is followed by a 1,2-shift of a methyl group to yield 79 <00JHC195>. 

The reaction of dimedone with 3-alkyl-5-ercapto-1,2,4-triazoles 315 in the presence of NBS gives intermediates, which after reaction with a solution of aqueous sodium carbonate afford 2-alkyl-5a-hydroxy-6,6-dimethyl-8-oxo-5a, 6,7,8,8a-hexahydro[l,2,4]triazolo[3,2-3]benzothiazoles 49. Finally, reaction with PPA provides the dehydrated heterocyclic derivatives 316 (Scheme 30) <1999IJH127>. 

A series of substituted triazolo[3,4- ][l,3,4]thiadiazoles 455 have been submitted to reaction with different two-carbon activated reagents such as chloranil or 2,3-dichloroquinoxaline, to give the complex linear heterocycles 456... 

The first single-crystal structure was reported for 6-methyl-3-phenyl-.r-triazolo[3,4-3]-l,3,4-thiadiazole in which the nucleus of the triazolothiadiazole system was planar confirming the aromatic character of the lOn-electron system <1974CSC7>. This is generally the case for the entire series of 5,5-fused heterocycles. 

When thioxo (or thiol) derivatives (as part of a thiourea function incorporated into the heterocyclic system) are present, effective. Y-alkylation is observed. Thus, the 3-heteroaryl-substituted [l,2,4]triazolo[3,4-/)][l,3,4]thiadiazole-6(5//)-thiones 37 dissolved in sodium hydroxide solution react with alkyl halides to afford the corresponding 6-alkylthio derivatives 38 (Equation 4) <1992IJB167>. The mesoionic compounds 39, inner salts of anhydro-7-aryl-l-methyl-3-methylthio-6-sulfonyl-[l,2,4]triazolo[4,3-A [l,2,4]triazolium hydroxides, are methylated with methyl iodide to give the corresponding quaternary salts 40 (Equation 5) <1984TL5427, 1986T2121>. 

The reaction of a fourfold excess of aryldiazomethanes 130 with dichlorosulfine leads to 3,5-diaryl[l,2,4]triazolo[5,l+]-[l,3,4]thiadiazole-4-oxides 131. The formation of the fused heterocycles 131 is rationalized on the basis of two consecutive cycloaddition steps, each followed by elimination of hydrogen chloride promoted by the excess of aryldiazomethane (Scheme 9) <1984JCM175>. 

---