# Solvent-Free Ring Cleavage Hydrazinolysis of Certain Biginelli Pyrimidines

Authors: Mohamed A. Said; Wagdy M. Eldehna; Hazem A. Ghabbour; Maha M. Kabil; Nasser S. Al-shakliah; Hatem A. Abdel-Aziz
Journal: Journal of Chemistry
 (2018)

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## 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 onsp2 C6 rather than thesp3 C4 to give the ring adduct which was produced as a final product.


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## Body

## 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].Figure 1
The structure of 3,4-dihydropyrimidinones (DHPMs)4, anticancer agent Monastrol, hydrazide5, and thiosemicarbazone6.Synthesis of DHPMs(4) is carried out through the reaction of urea/thiourea1, aldehyde2, and β-ketone3 (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, N3, R4, R5, and R6) [28] (Figure 1). When R1 = H, DHPMs4 could be alkylated at N1 [29] whereas the formylation or acylation of N3 of4 furnishes the N3-formylated or N3-acylated derivatives [30]. DHPMs4 (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 hydrazides5 [37, 38] (Figure 1). The reaction of C5 esters with thiosemicarbazide, in acetone, to afford thiosemicarbazones6 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 pyrimidines9a and9b (R = H, R = Me) with hydrazine hydrate gave pyrazoles10a and10b whereas the 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde9c (R = -CHO) gave pyrazole derivative10c (Figure 2) [41]. These facts showed the reactivity ofsp2 C6 of pyrimidines towards hydrazine hydrate and, subsequently, the ring opening of pyrimidine moiety.Figure 2
The reported reactions of hydrazine hydrate with pyrimidines7a–7c and9a–9c.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 pyrimidines4a–4h (Figure 3).Figure 3
The proposed mechanism for the reaction of DHPM derivatives4a–4h with hydrazine hydrate.


## 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-d6). Chemical shifts are expressed in values (ppm) using the solvent peak as internal standard. All coupling constant (J) 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-carboxylates4a–4h

To a solution of urea(1a)/thiourea(1b) (0.050 mol), different aromatic aldehydes2a–2d (0.075 mol), and ethylacetoacetate3a (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 DHPMs4a–h.


### 2.3. The Reaction of DHPMs Esters4a–h with Hydrazine Hydrate in Ethanol

To a solution of DHPMs4a–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 Esters4a–4h with Hydrazine Hydrate

A mixture of DHPMs4a–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 product16a–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 pyrazole13 and urea(1a)/thiourea(1b), respectively.


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

Yield: 42–55% (for4a–4h); m.p. 221–223°C (Lit. [49] m.p. 220–222°C); 1H-NMR (DMSO-d6)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% (for4a) and 67% (for4e); m.p. 89–91°C (Lit. [50] m.p. 90–92°C); 1H-NMR (DMSO-d6)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% (for4b) and 69% (for4f); m.p. 58-59°C (Lit. [51] m.p. 55-56°C); 1H-NMR (DMSO-d6)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% (for4c) and 66% (for4g); m.p. 161-162°C (Lit. [52] m.p. 168°C); 1H-NMR (DMSO-d6)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% (for4d) and 70% (for4h); m.p. 59–61°C (Lit. [53] m.p. 57-58°C); 1H-NMR (DMSO-d6)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).


## 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-d6). Chemical shifts are expressed in values (ppm) using the solvent peak as internal standard. All coupling constant (J) 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-carboxylates4a–4h

To a solution of urea(1a)/thiourea(1b) (0.050 mol), different aromatic aldehydes2a–2d (0.075 mol), and ethylacetoacetate3a (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 DHPMs4a–h.


## 2.3. The Reaction of DHPMs Esters4a–h with Hydrazine Hydrate in Ethanol

To a solution of DHPMs4a–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 Esters4a–4h with Hydrazine Hydrate

A mixture of DHPMs4a–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 product16a–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 pyrazole13 and urea(1a)/thiourea(1b), respectively.


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

Yield: 42–55% (for4a–4h); m.p. 221–223°C (Lit. [49] m.p. 220–222°C); 1H-NMR (DMSO-d6)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% (for4a) and 67% (for4e); m.p. 89–91°C (Lit. [50] m.p. 90–92°C); 1H-NMR (DMSO-d6)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% (for4b) and 69% (for4f); m.p. 58-59°C (Lit. [51] m.p. 55-56°C); 1H-NMR (DMSO-d6)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% (for4c) and 66% (for4g); m.p. 161-162°C (Lit. [52] m.p. 168°C); 1H-NMR (DMSO-d6)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% (for4d) and 70% (for4h); m.p. 59–61°C (Lit. [53] m.p. 57-58°C); 1H-NMR (DMSO-d6)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).


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

Yield: 42–55% (for4a–4h); m.p. 221–223°C (Lit. [49] m.p. 220–222°C); 1H-NMR (DMSO-d6)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% (for4a) and 67% (for4e); m.p. 89–91°C (Lit. [50] m.p. 90–92°C); 1H-NMR (DMSO-d6)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% (for4b) and 69% (for4f); m.p. 58-59°C (Lit. [51] m.p. 55-56°C); 1H-NMR (DMSO-d6)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% (for4c) and 66% (for4g); m.p. 161-162°C (Lit. [52] m.p. 168°C); 1H-NMR (DMSO-d6)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% (for4d) and 70% (for4h); m.p. 59–61°C (Lit. [53] m.p. 57-58°C); 1H-NMR (DMSO-d6)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), aldehydes2a–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 derivatives4a–4h. Then, we heated DHPM derivatives4a–4h with hydrazine hydrate in ethanol under reflux (6 h) but we gave no reaction [54]. The reaction of DHPM derivatives4a–4h with excess amount of hydrazine hydrate, in absence of ethanol, under reflux for 6 h showed the disappearance of Biginelli pyrimidines4a–4h on TLC. The latter reaction gave three products, none of them being the expected hydrazide11a–11h.The analyses of the isolated products established their assigned structure as pyrazole13, arylidenehydrazines16a–16d, and urea/thiourea1a and1b (Figure 3).The previous conclusions encouraged us to suppose a mechanism for ring opening of DHPMs by hydrazine hydrate (Figure3). This reaction proceeds through the formation of nonisolable intermediate carbohydrazide11a–11h at C5 followed by nucleophilic attack of -NH2 of hydrazide onsp2 C6 rather than thesp3 C4 to give the ring opening adducts12a–12h which produce pyrazole13 as final product in addition to arylidene of urea/thiourea14a–14h as nonisolable intermediate. Additional hydrazinolysis of14a–14h gave arylidenehydrazines16a–16d and urea/thiourea1a and1b as end products.


## 4. Conclusion

We studied the action of hydrazine hydrate asN-nucleophile on Biginelli pyrimidine esters4a–4h. They were subjected to unexpected ring cleavage to give pyrazole13, arylidenehydrazines16a–16d, and urea/thiourea1a and1b where the reaction proceeded through C5 ester and C6.



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