Traube pyrimidine synthesis

JHC1149) for example, see 4 in Scheme 2. They are analogs of the enamide intermediates suggested by Katritzky et al. (87T5171) in certain types of Traube s pyrimidine synthesis. 

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. 

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... 

Pteridine syntheses from pyrimidine intermediates Traube synthesis and can be condensed with 1,2-dicarbonyl compounds and ketones and aldehydes, respectively, in a very effective manner. There is also a series of regioselective approaches leading towards 6- and 7-substituted pteridine derivatives carrying a broad variety of substituents in these positions. 

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. 

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. 

Aminohydroxypurines are prepared analogously to hydroxypurines by the cyclization of 2- and/or 6-substituted pyrimidine-4,5-diamines with the appropriate condensation agent. Guanine (1) is obtained by Traube synthesis using 2,5,6-triaminopurin-4-ol and formic acid as the Cj unit. ... 

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. ... 

Usually, the pyrimidine ring used in the Traube synthesis carries two amino groups in the 4-and 5-position. I lowevcr, the condensation reaction can also be performed with other precursor molecules. The most common ones are 5-nitropyrimidin-4-amines and 5-nitrosopyrimidin-4-amines, as well as 5-azopyrimidin-4-amines. 

The application of pyrimidine-4,5-diols in Traube synthesis is less common. Isodialuric acid and urea can be condensed in sulfuric acid to form uric acid... 

The Traube synthesis has proved to be compatible with many kinds of groups in the starting pyrimidine (R and R in 60), even with the thioxo (mercapto) and primary amino groups. Pyrimidine iV-oxides are also acceptable.Moreover, 8-azapurines with substitutents in the usually difficult 1 and 3 positions have been formed by Traube reactions (refs. 150 and 151, respectively). 2-Pyrimidyl-8-azapurines have also been produced in this way. The Traube reaction permitted amino-acid substituents (as R in 60) to retain full optical purity. Radioactive labeling survived well when a diaminopyrimidine, made in five steps from diethyl malonate-7- C, was cyclized. ... 

For performing a Traube synthesis, two methods have been found best. In the first, the selected pyrimidine (60) was dissolved in water as its hydrochloride (or in dilute hydrochloric or acetic acid) and stirred with sodium nitrite at 0 ° C, after which it was often (but not necessarily) heated at 60 -100° ... 

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