Triazolo purine

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. 

According to the systematic nomenclature these substances were first named l-f-triazolo[d] pyrimidines in compliance with the general principles of the Ring Index/ More recent papers and Chemical Abstracts indexes use the term i -triazolo[4,5-d]pyrimidine (147) in accord with the lUPAC nomenclature. The numbering of substituents when using the last-mentioned name is different from that of the 8-aza analogs. For the formulas of oxygen and sulfur derivatives names derived from the lactim or thiolactim form are almost exclusively in use (in common with the purine derivatives). These derivatives are thus described as hydroxy and mercapto derivatives, respectively. The name 1,2,3,4,6-pentaazaindene is used only rarely for this system. 

The 8-aza analogs of purine bases were the first to be studied among all the aza analogs of nucleic acid bases (as early as 1945). Before that time the chemistry of these substances had not been treated in detail from any aspect. Thus the entire chemistry of the u-triazolo [4,5-d]pyrimidines was developed only in connection with the study of antimetabolites of nucleic acid components. Therefore all the papers involved are largely of preparative character and only rarely discuss. theoretical points. 

The examples in the fourth column (Table IX) concern the protonation of purine and adenine and their derivatives while those of the last column mainly reflect Kleinpeter s contributions (Table VIII) to the functional tau-tomerism of 7-hydroxy-l,2,4-triazolo[l,5-a]pyrimidines. 

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... 

Oxidation of benzotriazoles and other fused triazoles by potassium permanganate is a well-established route to lif-triazole 4,5-dicarboxylic acid derivatives. Many of the triazolo[d]pyrimidines, synthesized as purine analogs, can be degraded to monocyclic triazoles by acidic or basic hydrolysis (in other triazolopyriraidines, however, the triazole ring is cleaved preferentially ), e.g. Scheme 24. 

Some new bactericidal and fungicidal derivatives of purine and pyrazolo[l,2,4]triazine have been synthesized by the reaction of 4-arylidene-2-phenyl-S-oxazolones with different nucleophilic reagents <99IJC(B)445>. A variety of pyrazolo[3,2-c][l,2,4]-triazin-3-yl 55, 59 and l,2,4-triazolo[33-c][l,2,4]-triazin-3-yl-phosphonic acid dialkyl esters 56, 60 have been synthesized from diazobetaines of pyrazoles 57 and ttiazoles 58 and monocarbanions of certain phosphonates, respectively <99H513>. 

Chlorotheophylline reacted with the nitrilium imides generated in situ from amidrazones treated with triethylamine to give [l,2,4]triazolo[3,4 ]purines as single regioisomers in very high yield (Scheme 1) <2001JOC4055>. The... 

The reaction of 8-chlorotheophyllines with nitrilium imides to give [l,2,4]triazolo[3,4y]purines may be described as a [3+2] cycloaddition process <2001JOC4055> see Section 10.11.5.1. The purine bicycle has been prepared through the Diels-Alder-retro-Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-amino-l-benzylimida-zole <1999JA5833> see Section 10.11.10.3. 

Ultraviolet (UV) spectroscopy does not tend to be the method of choice for structure determination, but a list of UV absorptions was given in the review by Knowles <1996CHEC-II(7)489>. Fluorescence properties and triplet yields of [l,2,3]triazolo[4,5-r/ pyridazines in various solvents have been reported <2002JPH83>. These heterocyclic systems were found to be photochemically very stable. In a recent paper, Wierzchowski et al. studied the fluorescence emission properties of 8-azaxanthine ([l,2,3]triazolo[4,5-r/ pyrimidine-5,7-dione) and its A -alkyl derivatives at various pH s <2006JPH276>. For the 8-azaxanthines, an important characteristic of emission spectra in aqueous solutions was the unusually large Stokes shift. Since 8-azaxanthine is a substrate for purine nucleoside phosphorylase II from Escherichia coli, the reaction is now monitored fluorimetrically. The fluorescence properties of [l,2,3]triazolo[4,5-r/ -pyrimidine ribonucleosides were earlier described by Seela et al. <2005HCA751>. 

For compound 4 there is no recorded spectrum, but compound 5 is reported204 to absorb at 258 nm (e = 4300) in methanol solution. Jain and Anand have reported spectra for the four Af-methyl derivatives 111-114 in acid, neutral, and basic media149 of the two compounds 113 and 114 the spectrum of compound 5 most resembles the former, leading to a 1H-tautomer as the predominant structure. A more recent report205- of the spectrum of compound 111 differs considerably from that given by Jain and Anand. Because of the similarity of systems 4 and 5 to purine (nucleosides from both have been prepared), there has been much interest in the spectra of the amino derivatives and of the triazolopyridinones. For the [1,2,4]triazolo-[4,5-6]pyridines, spectra are reported for the 5-amino derivatives 115,187 116,194 117,153 and 118166 for the 3-amino derivatives 119 and 120181 and for... 

The chemistry of l,2,4-triazolo[4,3-a]pyrimidines is covered in the first installment of a general treatment of 1,2,4-triazolopyrimidines (isostears of purines) by Professor M. A. E. Shaban and Dr. A. E. A. Morgaan (Alexandria University, Egypt). The final installment of Dr. I. Hermecz s (CHINOIN Ltd., Hungary) five-part-series on pyrido-oxazines, -diazines, and -thiazines comprises Chapter 4 of the present volume and covers ben-zologs of pyrido[l,2,-a]pyrimidines. Parts I through IV appeared in Volumes 69-72 of our series. 

Okamura et al. (2002, 2004a) recently reported the study of a new series of l,2,4-triazolo[5,l-i]purines. This research group highlighted the structural similarity between the new class of compounds and the triazoloquinazoline derivatives and consequently evaluated the corresponding A3 adenosine receptor affinities. These investigations led to potent and selective hA3 ligands, the most potent of which are reported in Fig. 7.12 (19, 20), in particular 5-n-butyl-8-(4-n-propoxyphenyl)-3H- 1,2,4 triazolo 5,1 -ilpurinc 20 exhibited the best selectivity profile of this series... 

Aryl-7,8-diamino-1,2,4-triazololl, 5-c]pyrimidines (97 R= H) selectively acylate on the 8-amino group to give the amides (97 R= R CO) which cyclise on heating with PPA to yield 2-aryl-8-fIuorobenzyl-l,2,4-triazolo[5,l-/]purines (98) [94JHC1171],... 

Pyrimidines have attracted the attention of organic chemists and biochemists because of their role in biological systems, particularly in nucleic acids, which contain pyrimidines and purines as the main nucleobases. Consequently, the aza analogs of purines, mainly the triazolo and tetrazolo[.r,y-zjpyrimidines, also are important. 

In many cases, the literature since CHEC-I of those systems in class (i) has been extensive, mainly because most are related to the purine nucleus by the inclusion of a further heteroatom for example azapurine derivatives which have shown pharmaceutical or physiological action. The methods of synthesis, except in a few cases, have not changed since the publication of CHEC-I and thus more emphasis has been placed on the physical properties, reactivity, and reactivity of substituents of compounds within these systems. In contrast, in most cases very little literature is available for systems of class (ii) and synthesis has assumed paramount importance. Only two reviews since the early 1980s are applicable to this chapter the conversion of [l,2,5]oxadiazolo[3,4- f]pyrimidines (9) to pteridines <82MI 713-01) and the chemistry and physical properties of 1,2,3-triazolo[4,5-djpyrimidines (7) <86AHC(39)l 17>. The incidence of publications relating to the use of Structures (1)-(50) in such applications as pharmaceuticals, agrochemicals, and even explosives has increased since the publication of CHEC-I and these are discussed in Section 7.13.10. 

In the systems in this chapter, research has concentrated on the synthesis of the fully conjugated derivatives, most of which tend to be stable and crystalline. Only l,2,3-triazolo[4,5-heterocyclic systems using a theoretical aromaticity index <87T4275> and was shown to be comparable to purine. With so many diverse structures, it is considered impossible to make useful comments about melting points, solubilities, etc. No record of any work on tautomerism has been found. The measurement of pKa has been confined to a comprehensive list of derivatives of l,2,3-triazolo[4,5- ]pyrimidine (7) <86AHC(39)ii7>. 

The interest in the sugar derivatives of some of these systems as isosteres of purine nucleosides has led to considerable research into their direct electrophilic coupling reactions with halo-sugars or other activated sugars. Generally however, electrophilic attack occurs at several positions as is evident with 7-amino-1,2,3-triazolo[4,5-t/]pyrimidine (54a), the so-called 8-azaadenine , giving rise... 

Pyrazolo[4,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine sulfonamides have been synthesized as selective calcitonin inducers <02JMC2342>. A series of para-substituted 3-arylpyrazolo[3,4-d]pyrimidines have been synthesized and evaluated as inhibitors of lck kinase <02BMCL1687). The synthesis of 3-aryl-pyrazolo[4,3- f]pyrimidines as potential corticotropin-releasing factor (CRF-1) antagonists has been described <02BMCL2133>. Cyclization of 4-chloro-5-heteroimine-l,2,3-thiadiazoles furnished pyrazolo[3,4-d]pyrimidines, triazolo[4,5-d]pyrimidines and purines <02BMC449>. 

Dealkylation, of azolium quaternary salts and betaines, 60, 244 Deazaflavines, bent, 55, 192 5-Deazalumazines, see Pyrido[2,3-(/]pyrimidine-2,4-diones Deaza-purines, -flavines, etc., see the systematically-named ring systems 4-Deazatoxoflavins, syntheses, 55, 182 Dechlorination, catalytic, of chloro-[ 1,2.4]triazolo[ 1,5-a]pyrimidines, 57, 125... 

JCS(P1)2585], j-Triazolo[4,3-a]purines are synthesized by condensation of ortho esters and 2-hydrazinopurine, which is readily available from 5,6-diamino-2-thiouracil (85CPB3113) (Scheme 125). 

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