6-Carbohydrazonamidepurines: Convenient Precursors for 4,8-Disubstituted Pyrimido[5,4-d]pyrimidines

Abstract

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 ...

A Tandem Reaction in the Synthesis of New 4,8‐Disubstituted‐pyrimido[5,4‐d]pyrimidine Derivatives

“…Considering that a few number of compounds 3 were generated before from 2 or 4 by reaction with piperidine in ethanol (Scheme 1), [23,24] it was decided to apply these reaction conditions to compound 2 b , hoping to obtain 3 b (Table 1). Compound 2 b was suspended in ethanol, reacting under reflux with piperidine's excess (0.3 mL) (Table 1, entry 1).…”

“…Compounds 3 (R' = NHCOR 2 ) were later obtained from 6amidinopurines 4 in ethanol, in the presence of piperidine, under reflux (Scheme 1). [23] Recently, three new derivatives 3 (R' = NH 2 ) were obtained from the reaction of 2 with piperidine, in ethanol, at 80 °C in variable yields. [24] All the results collected so far from these reactions show that the reaction conditions to convert 2 into 3 are very sensitive and delicate, depending largely on the R' groups.…”

“…The one-pot synthesis was also followed by 1 In this work, we describe an efficient Dimroth rearrangement of compounds 2 (R' = NH 2 ) and 18 in DMSO by the action of piperidine. Previously, Dimroth rearrangement of 2 was performed in ethanol using piperidine (R' = NH 2 ) [24] or hydrochloric acid (R' = OBn), [21] but when these reaction conditions were applied to derivatives 2 (R=NHCOR 2 ) [23] complex mixtures were obtained. Complex mixtures were also obtained when sulfuric acid or aqueous sodium hydroxide were used.…”

“…Compounds 3 (R’=NHCOR 2 ) were later obtained from 6‐amidinopurines 4 in ethanol, in the presence of piperidine, under reflux (Scheme 1). [23] Recently, three new derivatives 3 (R'=NH 2 ) were obtained from the reaction of 2 with piperidine, in ethanol, at 80 °C in variable yields [24] …”