Traube synthesis

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... 

Pteridine syntheses from pyrimidine intermediates 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. 

A minor extension of the Traube synthesis involves the reduction of a 4,5-diaminopyrimidine precursor in the presence of an acylating agent such as formic acid. 

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 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. ... 

Triazine has been u.sed for the introduction of a C, unit during Traube synthesis. Theophylline (8) can be prepared by this route. 

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. ... 

The Traube synthesis is also useful for the preparation of 8-arylpurines, for example, formation of 8-phenylpurine-2,6-diamine (4) by cyclization of 5-benzamidopyrimidin-4-amines with phos-phoryl chlorideT ... 

The preparation of N-alkylpurines and derivatives encounters problems. When electrophilic alkylation reactions are employed, e.g. methylation, regioisomers are formed. However, in several cases, the Traube synthesis offers a regiospecific or a regioselective route for the synthesis of N-alkylpurines and of related natural products, such as nucleosides. 

All of the N-monomethyl derivatives of adenine, hypoxanthine, guanine, xanthine and uric acid have been synthesized. Several A -methylpurine derivatives were prepared by Traube himself, e.g. 1-methylguanine (1), or by the protocol of the Traube synthesis. ... 

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 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. 

The original Traube synthesis, conveniently generalized as 60 — 61, has proved suitable for preparing many 8-azapurines. The R group may be... 

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° ... 

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 formamides 16 are intermediates. Formamide (Bredereck variant of the Traube synthesis [149]), formamidine, orthoformic ester, diethoxymethyl acetate, Vilsmeier reagent (fi om DMF and POCI3) and dithioformic acid are used as formic acid derivatives. 4,5-Diaminopyrimidines can be obtained from 4-aminopyrimidines 17 by nitrosation with HNO2 followed by reduction of the nitroso compounds 18 ... 

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