научная статья по теме A GREEN SYNTHETIC APPROACH TO THE SYNTHESIS OF SCHIFF BASES FROM 4-AMINO-2-THIOXO-1,3-DIAZASPIRO[5.5]UNDEC-4-ENE-5-CARBONITRILE AS POTENTIAL ANTI-INFLAMMATORY AGENTS Химия

A GREEN SYNTHETIC APPROACH TO THE SYNTHESIS OF SCHIFF BASES FROM 4-AMINO-2-THIOXO-1,3-DIAZASPIRO[5.5]UNDEC-4-ENE-5-CARBONITRILE AS POTENTIAL ANTI-INFLAMMATORY AGENTS

© 2014 Sh. A. Abdel-Mohsen, E. M. Hussein#

Department of Chemistry, Faculty of Science, Assiut University, Assiut, 71516 Egypt Recevied November 27, 2013; in final form, December 24, 2013

A green, novel, rapid, and efficient protocol is developed for the synthesis of various Schiff bases from 4-ami-no-2-thioxo-1,3-diazaspiro[5.5]undec-4-ene-5-carbonitrile using ammonium chloride as a very inexpensive and readily available reagent in refluxing ethanol. High yields, easy work-up, and short reaction times are advantages of this environmentally benign procedure. The prepared compounds were screened for their antiinflammatory activity "at a dose of 10 mg/kg body weight", which revealed promising activities relative to in-domethacin used as a reference standard in this study.

Keywords: green synthesis, Schiff bases, anti-inflammatory, rapid procedure, 4-amino-2-thioxo-1,3-diaza-spiro[5.5]undec-4-ene-5-carbonitrile

DOI: 10.7868/S0132342314030026

INTRODUCTION

3,4-Dihydropyrimidin-2(1#)-ones (DHPM) and their sulfur analogues have been reported to possess remarkable pharmacological properties. Some of the compounds have antiviral, antitumor, antibacterial, anti-inflammatory, and antihypertensive activities [1—5] and, some are calcium channel modulators [6] and a1a adrenoceptor-selective antagonists [7]. Schiff bases are important compounds owing to their wide range of biological activities and industrial applications. They have been found to possess various pharmacological activities such as antitubercular [8], anticancer [9], plant growth inhibiting [10], insecticsidal [11, 12], CNS depressant [13], antibacterial [14, 15], anti-inflammatory and antimicrobial [16]. However, many of procedures to prepare Schiff bases are associated with one or more disadvantages such as the use of toxic, expensive catalysts and hazardous and carcinogenic solvents. The need to reduce the amount of toxic waste and byproducts arising from chemical processes requires increasing emphasis on the use of less toxic and more environmentally compatible materials in the design of new synthetic methods [17]. The development of cost-effective and environmentally benign catalytic systems is one of the main themes of modern organic synthesis. Ammonium chloride (NH4Cl) is a very inexpensive, eco-friendly and easily available catalyst; it has been reported as catalyst for synthesis of various organic compounds. It has effectively promoted Clais-

# Corresponding author (e-mail: essam.hussein78@yahoo.com).

en rearrangement [18], Biginelli synthesis of 3,4-dihy-dropyrimidinones [19], thia-Michael addition reaction [20], the one-pot synthesis of diindolymethanes [21], synthesis of quinoxalines [22], and the synthesis of Schiffbases [23]. In this paper and as a consequence of our previous work on the green synthesis of ^-heterocyclic compounds [24—27], and anti-inflammatory agents [28, 29], we investigated a novel green and efficient protocol that was developed for the synthesis of some Schiff bases (IIIa—f) by the condensation of

4-amino-2-thioxo-1,3-diazaspiro[5.5]undec-4-ene-

5-carbonitrile(I) with aromatic aldehydes (IIa—f) using ammonium chloride (15 mol %) in refluxing ethanol as shown in Scheme 1 and Table 1. The anti-inflammatory properties of the prepared compounds were screened.

RESULTS AND DISCUSSION

4-Amino-2-thioxo-1,3-diazaspiro[5.5]undec-4-ene-5-carbonitrile (I) was prepared via the three-component Biginelli-like condensation of cyclohexanone, malononi-trile, and thiourea as previously reported [27].

To find out the suitable conditions for the reaction, a series of experiments were performed with the standard reaction of 4-amino-2-thioxo-1,3-diazaspiro[5.5]un-dec-4-ene-5-carbonitrile, 4-methoxybenzaldehyde as a model reaction (Table 2).

HN

(I)

CN

nh2

CHO

+

NH4Cl (15 mol %) EtOH/reflux

R

( IIa—f)

HN

„A

(IIIa—f)

(IIIa) R = H (IIIb) R = CH3 (IIIc) R = Cl (IIId) R = Br (IIIe) R = OCH3 (IlIf) R = NO2 Sheme 1. Synthesis of Schiff bases (IIIa—f).

Effect of the Reaction Conditions

In our initial study, we tried to optimize the model procedure mentioned above by detecting the efficiency of different reaction conditions in the absence and presence of catalysts, such as MeOH, EtOH, AcOH, DMF/AcOH, EtOH/AcOH, EtOH/Et3N, dioxane/NH4Cl, DMF/NH4Cl, EtOH/NH4Cl, and H2O/NH4Cl.

In each case, the reactants (10 mmol) were allowed together in 10 mL solvent at reflux temperature. In the absence of catalyst, the reaction proceeded with longer reaction time and comparatively lower reaction yield (Table 2, entries 1-3). DMF/AcOH, EtOH/AcOH, and EtOH/Et3N can push the reaction towards the formation of product in yields of 54, 60, and 51%, respectively (Table 2, entries 4-6). In the presence of ammonium chloride (NH4Cl) the reaction was possible and the product (IIIe) was obtained in good yields. Ammonium chloride was used in different reaction media such as dioxane, DMF, ethanol and water (Table 2, entries 7-10). The best results were obtained when NH4Cl was used as catalyst in ethanol as reaction medium, which provided a yield of 91%. To determine

the appropriate concentration of the catalyst used, we investigated the model reaction at different concentrations of NH4Cl (5, 10, 15, 20, and 25 mol %). The product was formed in 65, 80, 91, 91, and 90% yield, respectively (Table 3). This indicates that 15 mol % NH4Cl is sufficient to carry out the reaction smoothly.

The structures of the isolated new products (IIIa—f) were deduced by analyzing their physical and spectro-scopic data, such as the data obtained using IR, 1H NMR, and 13C NMR spectroscopy. Taking (IIIe) as an example, sharp absorption bands at 3310 and 3200 cm-1 for two NH groups and 2220 cm-1, for CN group were observed in the IR spectrum. The 1H NMR spectrum showed the presence of a multiplet signal at 5 = 1.25-1.40 ppm for the cyclohexyl protons and four singlet signals at 4.15, 8.27, 9.75, and 10.15 ppm for methyl, methine, and two NH protons, as well as, two doublet signals at 7.00 and 7.40 ppm for the aromatic protons. In the 13C NMR spectrum, the quaternary spiro carbon typically appeared at 5 = 43.4 ppm. The nitrile and thiocarbonyl carbons resonated at 122.6 and 173.5 ppm, respectively.

Table 1. Synthesis of Schiff bases (IIIa-f) using NH4Cl (15 mol %)

Entry Producta R Time, min Yield, %b

1 (IIIa) H 35 80

2 (IIIb) CH3 35 75

3 (IIIc) Cl 40 84

4 (IIId) Br 50 79

5 (IIIe) OCH3 15 91

6 (IIIf) NO2 60 81

a Reaction conditions: 4-amino-2-thioxo-1,3-diazaspiro[5.5]undec-4-ene-5-carbonitrile (I) (10 mmol), aromatic aldehydes (IIa—f)

(10 mmol), and NH4Cl (15 mol %) in 10 mL ethanol at refluxing temperature. b Isolated yields.

Reaction Mechanism tives (Illa—f). Ammonium chloride may activate the

Scheme 2, briefly shows the catalytic behavior of carbonyl compounds by hydrogen bonding to promote

ammonium chloride through predicted mechanistic the reaction via the nucleophilic attack of amines [30]

pathway for the synthesis of 4-arylideneamino deriva- (Scheme 2).

(Ila—f) O Ar y H

»«■H-NH

3

NC NH2

Änh

N-BN-i

S (I)

NH4C1 c2hoh Nh4 +eci

ho.

Ar

'^f-H e NC ®NH2 C1

/ \/ \ —NH4C1

N-/HN—(

Ar HO-^

NC NH

NH HN-(

I

-H2O

Ar

NC N

HN ^

NH

S

(IIIa—f)

Scheme 2. Mechanistic pathway for the synthesis of Schiffbases (IIIa—f).

Anti-Inflammatory Activity

Anti-inflammatory activity of the target compounds (I) and (IIIa—f) (at a dose of 10 mg/kg body weight) was determined in vivo by the acute carra-geenan-induced paw oedema standard [31].

The anti-inflammatory properties were recorded at successive time intervals 0.5, 1, 2, 3, 4, and 5 h and compared with that of indomethacin (at a dose of 10 mg/kg body weight) which was used as a reference standard.

From the obtained results (Table 4) it has been noticed after 5 h, that the parent compound (I) has relatively poor anti-inflammatory activity with potency (percentage oedema inhibition of the tested compounds relative to percentage oedema inhibition of indomethacin) of 0.42. However, all of the tested Schiff bases (IIIa—f) exhibit remarkable anti-inflammatory activities, specially, compounds (IIIb), (IIId), (IIIe), and (IIIf) which reveal remarkable activities with potency of 0.71, 0.90, 0.76, and 0.90, respectively. However, compounds (IIIa) and (IIIc) have moderate activities with potency 0.66 and 0.62, respectively.

Structure—activity relationships based on the obtained results indicated that the type of substituent (R) attached to C-4 in the phenyl group is the controlling

factor in developing the total pharmacological properties of the tested Schiff bases (IIIa—f). The best antiinflammatory properties were exhibited by compounds (IIId) and (IlIf) in which the phenyl group is attached to bromo or nitro group, respectively. However, substituting the phenyl ring with methyl or meth-oxy groups results in moderate anti-inflammatory as shown in (IIIb) and (IIIe). When phenyl group is attached to chloro group, as well as in the case of unsub-stituted phenyl ring, the anti-inflammatory activity decreased as shown in compounds (IIIa) and (IIIc).

Acute toxicity; the median lethal doses (LD50) of the most active compounds (IIId) and (IIIf) were determined in mice according to reported procedures [32]. The results showed that the (LD50) of the most active compounds (IIId) and (IIIf) were non-toxic at doses up to 160 mg/kg.

CONCLUSIONS

The authors have developed a novel green, rapid and efficient protocol for the synthesis of various Schiff bases from 4-amino-2-thioxo-1,3-diazaspiro[5.5]un-dec-4-ene-5-carbonitrile using ammonium chloride in refluxing ethanol. The results clearly demonstrate that

Table 2. The effect of reaction condition on the synthesis of (IIIe)a

Entry Solventb Catalystc Time, min Yield, %d

1 AcOH - 300 46

2 MeOH - 300 42

3 EtOH - 30

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