Solvent-Free Ring Cleavage Hydrazinolysis of Certain Biginelli Pyrimidines

Said, Mohamed A.; Eldehna, Wagdy M.; Ghabbour, Hazem A.; Kabil, Maha M.; Al-shakliah, Nasser S.; Abdel-Aziz, Hatem A.

doi:https://doi.org/10.1155/2018/6354742

Journal of Chemistry

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Abstract Introduction Experimental Results and Discussion Conclusion Conflicts of Interest Acknowledgments Supplementary Materials References Copyright Related Articles

Research Article | Open Access

Volume 2018 | Article ID 6354742 | https://doi.org/10.1155/2018/6354742

Solvent-Free Ring Cleavage Hydrazinolysis of Certain Biginelli Pyrimidines

Mohamed A. Said,¹Wagdy M. Eldehna,²Hazem A. Ghabbour,^3,4Maha M. Kabil,⁵Nasser S. Al-shakliah,^3,6and Hatem A. Abdel-Aziz⁷

Academic Editor: Teodorico C. Ramalho

Received01 Oct 2017

Revised28 Feb 2018

Accepted08 Mar 2018

Published17 Apr 2018

Abstract

Certain Biginelli pyrimidines with ester substitution in C5 were subjected to unexpected ring opening upon solvent-free reaction with hydrazine hydrate to give three products: pyrazole, arylidenehydrazines, and urea/thiourea, respectively. The nonisolable carbohydrazide intermediates are formed firstly followed by the intermolecular nucleophilic attack of terminal amino group of hydrazide function on sp² C6 rather than the sp³ C4 to give the ring adduct which was produced as a final product.

1. Introduction

Pyrimidine derivatives Uracil and Thymine are an integral part of RNA and DNA, respectively. Compounds with pyrimidine scaffolds exhibit wide range of diverse pharmacological actions [1, 2] and biological activities [3] such as anti-HIV agent Stavudine [4], antibiotic Fervennuline [5], antihypertensive drug Minoxidil [6], and antibacterial drug Sulfamethazine [7]. Pyrimidines of Biginelli type (3,4-dihydropyrimidines, DHPMs) showed a broad spectrum of biological activities such as anticancer agent, Monastrol (Figure 1) [8, 9]. The straight forward synthesis of DHPMs resulted in the discovery of many important agents such as calcium channel modulators, adrenergic receptor antagonists, and mitotic kinesin inhibitors, in addition to anticancer, anti-inflammatory, antimicrobial, and antioxidant activities [9–13].

Synthesis of DHPMs (4) is carried out through the reaction of urea/thiourea 1, aldehyde 2, and β-ketone 3 (Figure 1). This reaction was reported by Biginelli and Gazz in 1893 and was then catalyzed by acids [14]. DHPMs can be obtained by few other synthetic protocols [9, 15–17] and several improvements were made to obtain good reaction conditions and better yields [11, 18–27].

DHPMs could be developed with six diversity points (R₁, X, , R₄, R_5, and R₆) [28] (Figure 1). When R₁ = H, DHPMs 4 could be alkylated at [29] whereas the formylation or acylation of of 4 furnishes the -formylated or -acylated derivatives [30]. DHPMs 4 (X = S) could be alkylated in the presence of base [30]. With respect to R₄, the reaction works best with aromatic aldehydes [31]. On the other hand, when R₅ is an ester group, free carboxylic acids can be produced [32–34]. Finally, when R₆ = 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 H₂SO₄, to give hydrazides 5 [37, 38] (Figure 1). The reaction of C5 esters with thiosemicarbazide, in acetone, to afford thiosemicarbazones 6 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.

Interestingly, the reported findings revealed that the hydrazinolysis of pyrimidine-2(1H)-one (7a), 4-methylpyrimidin-2(1H)-one (7b), or 4,6-dimethylpyrimidin-2(1H)-one (7c) resulted in the formation of 1H-pyrazole (8a), 3-methyl-1H-pyrazole (8b) and 3,5-dimethyl-1H-pyrazole (8c), respectively, in addition to urea (1a) in each case (Figure 2) [40]. Furthermore, we found that the reaction of pyrimidines 9a and 9b (R = H, R = Me) with hydrazine hydrate gave pyrazoles 10a and 10b whereas the 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde 9c (R = -CHO) gave pyrazole derivative 10c (Figure 2) [41]. These facts showed the reactivity of sp² C6 of pyrimidines towards hydrazine hydrate and, subsequently, the ring opening of pyrimidine moiety.

Recently, we reported a unique behavior of hydrazine hydrate towards certain benzofurans to produce phenolic-based 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 [44–48], we aim herein to study the solvent-free reaction of hydrazine hydrate on C5 ester Biginelli pyrimidines 4a–4h (Figure 3).

2. Experimental

2.1. General

Melting points were measured with a Stuart melting point apparatus and were uncorrected. ¹H NMR Spectra were recorded on a Varian Mercury NMR spectrometer. ¹H spectrum was run at 400 MHz in deuterated dimethylsulfoxide (DMSO-). Chemical shifts are expressed in values (ppm) using the solvent peak as internal standard. All coupling constant () values are given in hertz. The abbreviations used are as follows: s: singlet; d: doublet; m: multiplet.

2.2. General Procedure for the Synthesis of Ethyl 6-Methyl-4-(substituted)phenyl-2-(oxo/thioxo)-1,2,3,4-tetrahydropyrimidine-5-carboxylates 4a–4h

To a solution of urea (1a)/thiourea (1b) (0.050 mol), different aromatic aldehydes 2a–2d (0.075 mol), and ethylacetoacetate 3a (0.075 mol) in ethanol (35 mL), a catalytic amount of CaCl₂ (0.020 mol) was added. 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 4a–h.

2.3. The Reaction of DHPMs Esters 4a–h with Hydrazine Hydrate in Ethanol

To a solution of DHPMs 4a–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].

2.4. General Procedure for the Neat Reaction of DHPMs Esters 4a–4h with Hydrazine Hydrate

A mixture of DHPMs 4a–4h (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 16a–16d 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 13 and urea (1a)/thiourea (1b), respectively.

2.4.1. 3-Methyl-1H-pyrazol-5-ol (13)

Yield: 42–55% (for 4a–4h); m.p. 221–223°C (Lit. [49] m.p. 220–222°C); ¹H-NMR (DMSO-) δ (ppm): 2.47 (s, 3H, -CH3), 6.83 (s, 1H, Ar-H), 10.07 (s, 1H, OH), 12.10 (s, 1H, NH).

2.4.2. Benzylidenehydrazine (16a)

Yield: 62% (for 4a) and 67% (for 4e); m.p. 89–91°C (Lit. [50] m.p. 90–92°C); ¹H-NMR (DMSO-) δ (ppm): 5.37 (s, 2H, NH₂, D₂O-exchangeable), 7.38–7.41 (m, 3H, Ar-H), 7.64 (d, J = 8.0 Hz, 2H, Ar-H,), 7.71 (s, 1H, CH=N).

2.4.3. 4-Methylbenzylidenehydrazine (16b)

Yield: 58% (for 4b) and 69% (for 4f); m.p. 58-59°C (Lit. [51] m.p. 55-56°C); ¹H-NMR (DMSO-) δ (ppm): 2.21 (s, 3H, CH₃), 5.31 (s, 2H, NH₂, D₂O-exchangeable), 6.96 (d, J = 8.0 Hz, 2H, Ar-H), 7.56 (d, J = 8.4 Hz, 2H, Ar-H), 7.70 (s, 1H, CH=N).

2.4.4. 4-Methoxybenzylidenehydrazine (16c)

Yield: 60% (for 4c) and 66% (for 4g); m.p. 161-162°C (Lit. [52] m.p. 168°C); ¹H-NMR (DMSO-) δ (ppm): 3.82 (s, 3H, OCH₃), 5.36 (s, 2H, NH₂, D₂O-exchangeable), 6.92 (d, J = 8.4 Hz, 2H, Ar-H), 7.54 (d, J = 8.4 Hz, 2H, Ar-H), 7.75 (s, 1H, -CH=N).

2.4.5. 4-Chlorobenzylidenehydrazine (16d)

Yield: 62% (for 4d) and 70% (for 4h); m.p. 59–61°C (Lit. [53] m.p. 57-58°C); ¹H-NMR (DMSO-) δ (ppm): 5.38 (s, 2H, NH₂, D₂O-exchangeable), 7.31 (d, J = 8.4 Hz, 2H, Ar-H), 7.70 (d, J = 8.4 Hz, 2H, Ar-H), 7.77 (s, 1H, -CH=N).

3. Results and Discussion

In a typical experimental procedure a solution of urea (R = H, X = O, 1a)/thiourea (R = H, X = S, 1b), aldehydes 2a–2d (R₄ = Ph, 4-MeC₆H₄, 4-MeO-C₆H₄, 4-Cl-C₆H₄), and ethyl acetoacetate (R₅ = COOEt, R₆ = Me, 3a) in absolute ethanol was heated under reflux in the presence of catalytic amount of CaCl₂ to give the required DHPM derivatives 4a–4h. Then, we heated DHPM derivatives 4a–4h with hydrazine hydrate in ethanol under reflux (6 h) but we gave no reaction [54]. The reaction of DHPM derivatives 4a–4h with excess amount of hydrazine hydrate, in absence of ethanol, under reflux for 6 h showed the disappearance of Biginelli pyrimidines 4a–4h on TLC. The latter reaction gave three products, none of them being the expected hydrazide 11a–11h.

The analyses of the isolated products established their assigned structure as pyrazole 13, arylidenehydrazines 16a–16d, and urea/thiourea 1a and 1b (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 11a–11h at C5 followed by nucleophilic attack of -NH₂ of hydrazide on sp² C6 rather than the sp³ C4 to give the ring opening adducts 12a–12h which produce pyrazole 13 as final product in addition to arylidene of urea/thiourea 14a–14h as nonisolable intermediate. Additional hydrazinolysis of 14a–14h gave arylidenehydrazines 16a–16d and urea/thiourea 1a and 1b as end products.

4. Conclusion

We studied the action of hydrazine hydrate as N-nucleophile on Biginelli pyrimidine esters 4a–4h. They were subjected to unexpected ring cleavage to give pyrazole 13, arylidenehydrazines 16a–16d, and urea/thiourea 1a and 1b where the reaction proceeded through C5 ester and C6.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group, Project no. RGP-1436-038.

Supplementary Materials

Graphical abstract figure shows the ring opening of certain Biginelli pyrimidines using hydrazine. (Supplementary Materials)

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