A series of 4-arylamino-8-(alkyl or aryl)hydrazidepyrimido [5,4-d]pyrimidines was obtained efficiently from 6-carbohydrazonamidepurines by reaction with piperidine. The 6-carbohydrazonamidepurines were generated selectively by the reaction of 6-imidatopurine with hydrazides under acidic conditions. Tuberculosis affects much of the world population and it is estimated that 9.2 million new cases appear each year, from which many lead to death. 1 The emergence of multidrug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) has added urgency to the search for new antitubercular agents 2 and, since the last decade of the 20 th century, the scientific community has undertaken intensive research in this area. 3 Recently, in our research group, the pyrimido[5,4-d]pyrimidines ( Figure 1) were identified as a promising new class of antitubercular agents. 4 The new compounds showed high potency that depends on the substituents R 1 and R 2 . Furthermore, the new compounds have no structural similarity to any other compounds active against Mycobacterium tuberculosis and may have a different mechanism of action in relation to drugs currently on the market. Therefore a research program was started in order to develop new methods for the efficient synthesis of new pyrimido [5,4-d]pyrimidines derivatives 3 (Scheme 1) for structureactivity relationship studies. Figure 1 A new class of antitubercular agentsIn the literature, the pyrimido[5,4-d]pyrimidine core structure has been prepared from a substituted pyrimidine, upon reaction with an appropriate electrophile or nucleophile. 5 Amino substituents are usually incorporated into the heteroaromatic ring by nucleophilic substitution of chlorine atoms by amines. 6 The 6-cyanopurines have also been used as precursors of substituted pyrimido [5,4-d]pyrimidines, as the reaction with amines leads to the desired structure by an ANRORC-type mechanism. 7 This approach has been used in our group for the efficient synthesis of compounds 2 (Scheme 1). 4,8-10 According to the literature, structure 2 can be used to generate the aromatic analogue 3 by Dimroth rearrangement, in the presence of acid or base catalysis. 11 Furthermore, our studies on the reactivity of the pyrimidopyrimidine derivatives 2 (R 2 = OBn) have proved that the conversion of 2 (R 2 = OBn) into 3 (R 2 = OBn) occurs efficiently under acid conditions although other products may also be formed (Scheme 1). 10 In the present work, compounds 2 were considered to be convenient precursors of the aromatic pyrimido[5,4-d]pyrimidines 3 (R 2 = NHCOR 3 ).Scheme 1 Synthesis of 2, its conversion into 3 (R 2 = OBn) and attempts to generate new derivatives 3 (R 1 = 4-NCC 6 H 4 , R 2 = NHCOR 3 ).Herein we report our attempts to convert pyrimido[5,4-d]pyrimidine 2 (R 2 = NHCOR 3 ) into 3 (R 2 = NHCOR 3 ) and the new synthetic strategy designed to generate derivatives 3 starting from 6-carbohydrazonamidepurines 4 that have proved to be valuable precursors for the target compounds 3. Compound 2 (R 1 = 4-NCC 6 H ...
2-(Nitrophenyl)adenine derivatives were isolated from the reaction of 5-amino-4-amidino-imidazoles with nitrobenzaldehydes. The conversion of the nitro derivatives to 2-(aminophenyl)adenine derivatives was performed using iron/acetic acid as reducing agent, in 70% aqueous ethanol. The products were isolated in good yield and the isolation protocol involves simple filtration and extraction procedures. This methodology is compatible with the presence of functional groups such as amines, ethers, halofluorides, and halochlorides.
A simple and general 'one-pot' procedure for the synthesis of 2,9-diarylpurines with one or multiple hydroxyl groups in the 2-aryl unit is described, from the reaction of 5-amino-4-amidinoimidazoles with phenolic aldehydes.Purines have attracted attention of the scientific community mainly due to their biological activity. 1 During the last decade, purine derivatives were identified as a promising new class of antitubercular agents. The research was focused on the synthesis of nucleoside analogues as siderophore biosynthesis inhibitors 2 and on non-nucleosides. 3 In the non-nucleoside series, purines having an aryl, a small alkyl, or a proton on N-9 were essentially inactive, whereas 9-benzyl-6-(2-furyl)purines, 3b,h,j 9-sulfonyl-6-mercaptopurines, or 6-alkylthiopurines 3e,k were highly potent. In addition, we recently described the first example of 2,9-diarylpurines ( Figure 1) active against Mycobacterium tuberculosis. 4 The results from biological evaluation showed that the potency of the compounds depends on the substituents in N-9, C-2, and C-6 of the purine core. The presence of a 4-tolyl group in N-9 and a 3-hydroxyphenyl or a 4-hydroxyphenyl substituent in C-2 combined with a secondary amine in C-6 proved to be important features for activity ( Figure 1) but a clear structure-activity correlation pattern could not be identified. 4 Figure 1 Hit compounds active on Mycobacterium tuberculosisA number of synthetic methods were developed to incorporate functional groups in the purine core, but costly reagents are usually required. 5a,b In our research group purine derivatives have been obtained by a simple and inexpensive synthetic approach that uses the versatile reactivity of a substituted imidazole. 4,5c-l The 6-amino-2,9-diarylpurines ( Figure 1) are a new promising scaffold active against Mycobacterium tuberculosis and the presence of hydroxyl groups in the aryl subunit in C-2 was considered an important feature for activity. The microorganism needs iron for the biochemical processes, and multiple hydroxyl groups in the phenolic subunit could enhance the complexation with the metal. This perception prompted us to develop a new synthetic approach that would allow the efficient synthesis of purines 6 (Table 1) having a phenolic subunit in C-2 with two and three hydroxyl substituents. The previous method only allowed the introduction of phenolic units with one hydroxyl group as the reaction with polyphenolic aldehydes, performed in basic medium, was very slow (8-54 d) and extensive degradation occurred. 4 Herein we describe a new and general synthetic approach for 6-amino-9-aryl-2-hydroxy or 2-(polyhydroxyphenyl)purines 6 using imidazole 1, phenolic aldehydes 2, and a cascade of acid and base catalysis. When compound 1a (Scheme 1) was combined with 3,4,5-trihydroxybenzaldehyde (2a) in ethanol at 0°C, using trifluoroacetic acid as catalyst, the starting materials were dissolved and a new white solid precipitated after five minutes. This compound was identified as the trifluoroacetate salt of starting materi...
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