Purines Traube synthesis

Traube purine synthesis, 423 Triamcinolone, 201 Triamcinolone acetonide, 201 Triamterine, 427 Triazines, synthesis, 280 Triazolam, 368 Trichlomethiazide, 359 Trichomonas, 238 Tricyclic antidepressants, 149 Trifluoperidol, 306 Trifluoromethyl group, potentiation of biologic activity, 380 Triflupromazine, 380, 381 Trihexyphenidil, 47 Triiodothyronine, 95 Trimeprazine, 378 Trimethadione, 232 Trimethobenzamide, 110 Trimethoprim, 262 Trioxsalen, 334 Tripelenamine, 51 Triprolidine, 78 Tropinone, 5 Tropocaine, 7 Truth serum, 274... 

The Traube purine synthesis using 5,6-diaminopyrimidines is well known (1900CB1371, 1900CB3035). According to this method, uric acids are formed from 5,6-diaminouracils and one carbon (Cl) reagents, such as... 

Traube purine synthesis. Preparation of an appropriate 4,5-diaminopyrimidine by introduction of the amino group into the 5 position of 4-amino-6-hydroxy- or 4,6-diaminopyrimidines by nitrosation and ammonium sulfide reduction, followed by ring closure with formic acid or chlorocarbonic ester. 

TRAHANOVSKY Oxidation 386 TRAUBE Purine synthesis 387 TREIBS ARylic oxidation 388 Trochimowski 121 TROST Cyclopentanation 389 Trost 392... 

The chemistry of the Phillips synthesis can be extended to prepare the purine ring system. It is simply necessary to use a diaminopyrimidine in the reaction with a carboxylic acid. This is known as the Traube purine synthesis, and it has been of great significance in purine chemistry. It is illustrated in Scheme 4.25. 

A well-known purine is the central nervous stimulant (CNS) caffeine (9.134), which is found in coffee and chocolate. Its synthesis (Scheme 9.77) illustrates the technique of forming the fused imidazole ring of purines. It was noted in Chapter 4 that diaminobenzenes reacted with carboxylic acids or esters to form benzimidazoles this process is known as the Phillips synthesis. It is this reaction that is used to fuse imidazoles to pyrimidines. Here, the process is known as the Traube purine synthesis. The initially formed purine is tri-methylated with methyl chloride and base to form caffeine (9.134). Note that under these conditions it is the 7-nitrogen that is methylated. 

The purine ring system represents a fusion of the two aromatic heterocycles pyrimidine and imidazole. As a logical consequence, appropriately substituted pyrimidines or imidazoles have been used as precursors followed by a cyclization reaction. The purine heterocycle can also be formed from simple acyclic precursors. The most widely used method to synthesize purine is the addition of an imidazole ring to a functionalized pyrimidine moiety (Traube synthesis). The alternative route for the formation of the purine system by the annulation of the pyrimidine ring to a substituted imidazole relates back to a method of Sarasin and Wegmann, and these synthetic protocols principally follow the biosynthetic pathway of purine synthesis. 

The most versatile method of purine synthesis starts with an appropriately functionalized pyrimidine-4,5-diamine, the second ring is then constructed by a cyclizalion reaction. This reaction protocol is called the Traubc synthesis. The Traube synthesis has the greatest application for the synthesis of purines. In his original work, Traube heated 2,5,6-triaminopyrimidin-4-ol with formic acid to give guanine (1) in the same year, the chemical potential of the method was recognized. 

In the standard method for purine synthesis, 4,5-diaminopyrimidines are subjected to cyclocondensation with formic acid or with formic acid derivatives (Traube synthesis, 1910) ... 

The Traube synthesis represents but one of the many preparations that have been developed for purines. Transesterification of ethyl carboxamidoacetate with methyl urea affords the diamide... 

Similar orf/io-substituted heterocycles react similarly, providing entry into a large number of ring-fused systems, including purines (Traube synthesis). 

The Traube synthesis still remains valuable as a route to the synthesis of specific purines. The method has been used to record the first synthesis of hypoxanthine-/V(7)-oxide (30) by reaction of 6-chloro-5-nitro-4(3H)-pyrimidinone with A-(4-methoxybenzyl)phenacylamine (Scheme 18) <92CPB612>. The same authors also report analogous syntheses of 8-methylguanine-7-oxide and its 9-arylmethyl derivatives, and guanine-7-oxide and some 9-substituted derivatives (92CPB343, 92CPB1315). 

With very few exceptions, by far the most important synthetic routes to the purine ring system remain the Traube synthesis from pyrimidines and the synthesis achieved by cyclization of an appropriate aminoimidazole. One of the more active areas of synthesis since the mid-1980s has been the acyclonucleosides, i.e. purines, especially guanine, with a 9-substituent which possesses some of... 

Almost all recorded purine syntheses from imidazoles involve the cyclization of 5(4)-aminoimidazole-4(5)-carboxylic acid derivatives especially the carboxamides, thiocar-boxamides, carboxamidines, carboxamidoximes, nitriles and esters. The intermediates used for completion of the purine ring are much the same as have been used for Traube cyclization of diaminopyrimidines (Section 4.09.7.3), especially formic and carbonic acid derivatives, and cyclization generally occurs-under much milder conditions. This feature has been of special value in the synthesis of purine nucleosides from imidazole nucleoside precursors. The resultant purine will have variable substituents at C-2 and C-6 and it is convenient to discuss and classify the various preparations largely in terms of the introduced 2-substituents. The C-6 substituents largely reflect the type of carboxylic acid moiety used and do not vary very much between amino, oxo and thioxo. 

Purines have also been obtained by transformations of appropriate pteridines (75CPB2678,73CB3203). Also the 6-azapteridine (363) on reduction produced 8-substituted theophylline (Scheme 154) (69MI40900). Similarly the 7-azapteridine (364) with hot formamide afforded 8-phenyltheophylline (Scheme 154) (76H(4)749), and the diazepinone (365) with alkoxide also produced the 9-(2-propenyl)purine (366) by what is ultimately a Traube synthesis (Scheme 155) (70JHC1029). 

Aminopurines have usually been prepared from 8-chloropurines as in the amination of 8-chlorocaffeine to 8-aminocaffeine (1882LA(2 15)265), or alternatively from 8-methyl-thiopurine as in the synthesis of 8-amino-, 8-methylamino- or 8-dimethylamino-purine from 8-methylthiopurine with ammonia, methylamine or dimethylamine, respectively (54JCS2060). A good yield of 8-amino-6-oxo-l,6-dihydropurine was obtained in a Traube synthesis from 4,5-diamino-6-oxo-l,6-dihydropyrimidine and guanidine at 200 °C (58JA6671). 

The availability of functionalized pyrimidines (cf. also Section 6.2.1.) gives the Traube synthesis great flexibility. The probability of ring closure during the Traube synthesis depends on the substituents of the pyrimidine-4,5-diamines, the condensation reagent and the reaction conditions. Problems are encountered with the ring closure of pyrimidine-6-thiols which can form thiazolo[5,4- f]pyrimidines 2. However, the 5-formamido derivative of 4,5-diaminopyrim-idine-6-thiol under alkaline conditions gives purine-6(li/)-thione 3. ... 

Purine (6) itself is a colorless crystalline weak base which was first prepared by Fischer " the first synthesis using the Traubc condensation was reported by Isay. The Traube protocol is probably the best method to prepare purine, using pyrimidine-4,5-diamine as precursor and formic acid in an atmosphere of carbon dioxide or diethoxymethyl acetate as cyclizing reagents. 

Halopurines are valuable intermediates for conversion to other purines. The halogen substituents show selectivity for positions 2, 6 and 8. The chloropurines are usually obtained by displacement reactions on hydroxy- or sulfanylpurines (see Sections 7.1.1.3.4.5.2. and 7.1.1.3.4.5.3.). However, they are also accessible by Traube synthesis care must be taken that the reactive halogen substituents are not displaced during the condensation reaction. 2-Chloro-purine (la), 6-chloropurine (lb), and 2,6-dichloropurine (Ic) are obtained from appropriately halogenated pyrimidine-4,5-diamines and ethyl orthoformate. ... 

The methods described in this section have been found to be of limited use in the synthesis of purines. However, they are useful for the rearrangement of the wrong reaction products of the Traube synthesis into the final purines. 

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