Solvent-Free Ring Cleavage Hydrazinolysis of Certain Biginelli Pyrimidines

1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, Egypt 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt 3Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia 4Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt 5Department of Infection Control, King Saud University Medical City, Riyadh, Saudi Arabia 6Department of Pharmaceutical Chemistry, College of Pharmacy, Aden University, Aden, Yemen 7Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt

DHPMs could be developed with six diversity points (R 1 , X,  3 , R 4 , R 5, and R 6 ) [28] (Figure 1).When R 1 = H, DHPMs could be alkylated at  1 [29] whereas the formylation or acylation of  3 of furnishes the  3 -formylated or  3acylated derivatives [30].DHPMs (X = S) could be alkylated in the presence of base [30].With respect to R 4 , the reaction works best with aromatic aldehydes [31].On the other hand, when R 5 is an ester group, free carboxylic acids can be produced [32][33][34].Finally, when R 6 = Me, it can be subjected to bromination [35,36].To the best of our knowledge, there are no reports concerned with the accessibility of C6 for the nucleophilic reaction by hydrazine hydrate.However, C5 esters reacted with hydrazine hydrate, in ethyl alcohol and in the presence of H 2 SO 4 , to give hydrazides [37,38] (Figure 1).
(, alkyl, aryl ２ 5 = ？ster, acyl, amide, nitro, nitrile ２ 6 = (, alkyl, aryl ８ = ／, S, NR The reaction of C5 esters with thiosemicarbazide, in acetone, to afford thiosemicarbazones is reported (Figure 1) [39].The latter data stimulate our interest to investigate the reactivity of C5 ester towards hydrazine hydrate under solvent-free conditions which produce three different ring cleavage products.This unexpected result leads us to perform further extensive survey in literature to discover the effect of hydrazine hydrate on pyrimidines other than DHPMs.
Recently, we reported a unique behavior of hydrazine hydrate towards certain benzofurans to produce phenolicbased pyrazoles [42].We also identified malonohydrazide as reaction product besides salicylaldehyde azine upon the reaction of ethyl 2-oxo-2H-chromene-3-carboxylate with hydrazine hydrate [43].In the light of previous data and in continuation of our interest in the chemistry of hydrazine hydrate towards certain heterocycles [44][45][46][47][48], we aim herein to study the solvent-free reaction of hydrazine hydrate on C5 ester Biginelli pyrimidines a-h (Figure 3).The reaction mixture was heated under reflux for 2 h, and the progress of reaction was monitored by TLC.After reaction completion, the reaction mass was cooled and treated with crushed ice.Then the precipitated solid was filtered off, crystallized using methanol/water mixture, and then dried to give DHPMs a-h.

The Reaction of DHPMs Esters 4a-h with Hydrazine
Hydrate in Ethanol.To a solution of DHPMs a-h (0.01 mol) in ethanol (20 mL), hydrazine hydrate (0.03 mol) was added.Then the reaction mixture was heated under reflux for 6 h.The reaction progression was monitored using TLC, which indicated that no reaction occurred [37].

General Procedure for the Neat Reaction of DHPMs Esters 4a-4h with Hydrazine Hydrate.
A mixture of DHPMs a-h (0.01 mol) and excess hydrazine hydrate (5 mL) was heated under reflux for 6 h.The reaction mixture was allowed to cool and poured on crushed ice.The obtained solid product a-d was filtered, crystallized from ethanol, and finally dried.The evaporation of the filtrate gave solid residue which upon fractional crystallization from water gave the pyrazole and urea ( a)/thiourea ( b), respectively.
The reported reactions of hydrazine hydrate with pyrimidines a-7c and a-9c.

Results and Discussion
In a typical experimental procedure a solution of urea (R = H, X = O, a)/thiourea (R = H, X = S, b), aldehydes a-d (R 4 = Ph, 4-MeC 6 H 4 , 4-MeO-C 6 H 4 , 4-Cl-C 6 H 4 ), and ethyl acetoacetate (R 5 = COOEt, R 6 = Me, a) in absolute ethanol was heated under reflux in the presence of catalytic amount of CaCl 2 to give the required DHPM derivatives a-h.Then, we heated DHPM derivatives a-h with hydrazine hydrate in ethanol under reflux (6 h) but we gave no reaction [54].The reaction of DHPM derivatives a-h with excess amount of hydrazine hydrate, in absence of ethanol, under reflux for 6 h showed the disappearance of Biginelli pyrimidines a-h on TLC.The latter reaction gave three products, none of them being the expected hydrazide a-h.
The analyses of the isolated products established their assigned structure as pyrazole , arylidenehydrazines a-d, and urea/thiourea a and b (Figure 3).
The previous conclusions encouraged us to suppose a mechanism for ring opening of DHPMs by hydrazine hydrate (Figure 3).This reaction proceeds through the formation of nonisolable intermediate carbohydrazide a-h at C5 followed by nucleophilic attack of -NH 2 of hydrazide on sp 2 C6 rather than the sp 3 C4 to give the ring opening adducts a-h which produce pyrazole as final product in addition to arylidene of urea/thiourea a-h as nonisolable intermediate.Additional hydrazinolysis of a-h gave arylidenehydrazines a-d and urea/thiourea a and b as end products.

Conclusion
We studied the action of hydrazine hydrate as N-nucleophile on Biginelli pyrimidine esters a-h.They were subjected to unexpected ring cleavage to give pyrazole , arylidenehydrazines a-d, and urea/thiourea a and b where the reaction proceeded through C5 ester and C6.

Figure 3 :
Figure 3: The proposed mechanism for the reaction of DHPM derivatives a-h with hydrazine hydrate.