Heterocyclic Chemistry, Fifth Edition
Purine Carboxylic Acids
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- 27.11 Synthesis of Purines
27.10
Purine Carboxylic Acids Here again, comparatively little systematic information is available, but in parallel with pyridine α - acids, it can again be implied that purine acids undergo decarboxylation on heating – the 6 - acid at 195 ° C for example. 101 27.11 Synthesis of Purines Because of the ready availability of nucleosides from natural sources, a frequently used route to substituted purines is via the manipulation of one of these. 27.11.1 Ring Synthesis There are two general approaches to the construction of the purine ring system. Additionally, a category which can be defi ned as ‘ one pot ’ methods, are adaptations of the type of process that probably took place in prebiotic times, when simple molecules, such as hydrogen cyanide and ammonia, are believed to have combined to give the fi rst purines. 27.11.1.1 From 4,5 - Diamino - pyrimidines 4,5 - Diamino - pyrimidines react with carboxylic acids, or derivatives, to give purines, the ‘ carboxyl ’ carbon corresponding to C - 8. Purines: Reactions and Synthesis 531 Traube Synthesis 8 - Unsubstituted purines can be prepared simply by heating 4,5 - diaminopyrimidines with formic acid, 102 but formamide 103 (or formamidine 104 ) is better. The reaction proceeds via cyclising dehydration of an inter- mediate formamide; this usually takes place in situ using formamide, but generally requires a second, more forcing step when formic acid is employed initially. Purine itself can be prepared by this route. 105 Aldehydes react with 5,6 - diaminouracils in the presence of bromodimethylsulfonium bromide to give the 8 - substituted xanthines. 106 8 - Substituted purines are comparably prepared using acylating agents corresponding to higher acids; in most cases the amide is isolated and separately cyclised. 107 The diamino - pyrimidines required are usually prepared by the coupling of a 4 - aminopyrimidine with an aryldiazonium ion (or by nitrosation 108 ), then reduction, or by ring synthesis. 109 Precursors to 9 - substituted purines, therefore requiring a substituent on the pyrimidine - 4 - amino group, are available from the reaction of a 4 - chloropyrimidine with a primary amine. When milder conditions are required for the cyclisation, perhaps because of the presence of a sugar residue, an orthoester 110 (often activated 111 with acetic anhydride) or an acetal - ester 112 (illustrated below) can be used. 532 Heterocyclic Chemistry A related reaction is the oxidative cyclisation of anils, originally under vigorous conditions such as heating in nitrobenzene, 113 but now achievable at lower temperatures using diethyl azodicarboxylate. 114 The formation of 8 - oxo - or 8 - thio - purines requires one - carbon components at a higher oxidation level: urea and thiourea are appropriate. The products of chloroformate - initiated fi ve - membered ring cleavage of purines ( 27.1.1.3 ) can be recyclised to produce 8 - oxo - purines. 115 27.11.1.2 From 5 - Aminoimidazole - 4 - Carboxamide or - Nitrile 116 5 - Aminoimidazole - 4 - carboxamides (or - nitriles) interact with components at the carboxylic acid oxidation level giving purines, the ‘ carboxyl ’ carbon becoming C - 2. Biosynthetically, purines are built up via formation of the imidazole ring fi rst, from glycine and formate, and thence to hypoxanthine and then the other natural purines. In the laboratory, most imidazole - based purine syntheses start with 5 - aminoimidazole - 4 - carboxylic acid, particularly its amide (known by the acronym AICA), which as well as its riboside, is commercially available from biological sources. The use of 5 - aminoimidazole - 4 - carbonitrile in this approach results in the formation of 6 - amino - purines, as in a synthesis of adenine itself. 117 Purines: Reactions and Synthesis 533 Conversion into 2 - alkyl - or - aryl - purines requires the insertion of one carbon to create the six - membered ring, and this is usually effected by condensation with esters in the presence of base, 118 although amides 119 are occasionally utilised. The use of an isothiocyanate leads to a 2 - thiopurine. 120 There are a few examples of purine ring syntheses which start from simpler imidazoles, for example a 5 - aminoimidazole, generally prepared and utilised in situ . 121 7 - Substituted purines can be obtained from 4 - aminoimidazole - 5 - carbaldehyde oximes after conversion into imino ethers and reaction with ammonia, as shown below. 122 27.11.1.3 By Cycloadditions Triethyl 1,3,5 - triazine - 2,4,6 - tricarboxylate serves as an azadiene in reaction with 5 - aminopyrazoles to produce purine isosteres, pyrazolo[3,4 - d ]pyrimidines. 123 In order to overcome the relative instability of 5 - aminoimidazoles, required for analogous synthesis of purines, 5 - aminoimidazole - 4 - carboxylic acids can be used, in situ decarboxylation producing the required dienophile. 124 Exactly comparable reaction with 2 - amino - 4 - cyanopyrroles produces pyrrolo[2,3 - d ]pyrimidines. 125 534 Heterocyclic Chemistry 27.11.1.4 ‘ One - step ’ Syntheses It is amazing that relatively complex molecules, such as purines, can be formed by the sequential condensa- tion of very simple molecules, such as ammonia and hydrogen cyanide. That the intrinsic reactivity embod- ied in these simple molecules leads ‘ naturally ’ to purines must surely be relevant to the evolution of a natural system that relies on these ‘ complex ’ molecules. In other words it seems highly likely that purines existed before the evolution of life and were incorporated into its mechanism because they were there and, of course, because they have appropriate chemical properties. Adenine, C 5 H 5 N 5 , is formally a pentamer of hydrogen cyanide and indeed can be produced in the labora- tory by the reaction of ammonia and hydrogen cyanide, although not with great effi ciency. A related and more practical method involves the dehydration of formamide. 126 Purine itself can also be obtained from formamide. 127 Methods derived from this fundamental process involve the condensation of one - , two - and three - carbon units such as amidines, amino - nitriles and carboxamides, which represent intermediate stages of the ammonia/hydrogen cyanide reaction. Pyrimidines or imidazoles are usually intermediates. 128 Download 317.73 Kb. Do'stlaringiz bilan baham: |
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