Synthesis of New Some Imidazole Derivatives Containing β- Lactam Ring

In this work 5-methylene-yl (2-methy –oxazole-4-one) (1H) imidazole (1) were synthesized from the reaction of L-Histidine with acetic anhydride and which converted to the of 5-methylene-yl-(2-methyl 3-amino imidazole-4-one)-1Himidazole (2) by reaction with hydrazine hydrate. Schiff bases (3-6) were synthesized from the reaction of compound (2) with different aromatic aldehyde. Reaction of compounds (3-6) with chloroacetyl chloride gives azetidinone one derivatives (7-10). These compounds were characterized by FT-IR and some of them with 1 H-NMR and 13 C-NMR spectroscopy.


Introduction:
Imidazole is an organic aromatic compound with formula C 3 H 4 N 2 . Many drugs contain an imidazole ring such as antifungal drugs and nitroimidazole [1]. Nitrogen bridge head-fused heterocyclics which contain an imidazole ring are common structural motifs in pharmacologically important molecules, with activities spanning a diverse range of target [2]. The imidazole nucleus appears in a number of naturally occurring product like the amino acid histidine and purines which comprise many of the most important bases in nucleic acid [3]. The most important four-member system is undoubtedly the azetidin-2-one, also called β-lactam. βlactam contaning compounds have a wide spectrum antibiotic which found in natural and synthetic compounds, such as penicillin, cephalosporin, carbaphenems, and monobactams [4,5]. The chemistry of carbonnitrogen double bond plays a vital role in the progresses of chemistry science [6]. Schiff bases can be synthesized by several methods but the most common method is the original reaction of an aromatic amines and carbonyl compounds by nucleophilic reaction with dehydration to generate imine [7,8]. They have been used as analgestic, plan grouth regulator [9,10], antitumor, and other biological activities [11,12]. In this work, we reported synthesis of some new imidazole derivatives containing β-lactam ring starting from amino acid histidine.

Materials and Methods
Melting point was determined in open capillary tubes on Gallenkamp melting point apparatus and wasun corrected. FT-IR spectra were recorded on SHIMADZU FT-IR -8400 Fourier Transform Infrared spectrophotometer as KBR disk. 1 HNMR and 13 CNMR spectra were recorded on Bruker 300MHz, instrument using TMS as internal reference and DMSO-d 6 as a solvent in Jordon.

Synthesis of azetidinone(7-10) [3]
A mixture of Schiff bases (0.00055 mole) and tri ethylamines (0.0011 mole) were dissolved in 1, 4dioxane (10 ml) cooled and stirred. To this well-stirred cooled solution chloroacetyl chloride (0.0022 mole) was added drop wise for period 15 min at zero temperature. The reaction mixture was stirred for addition 3-6 hrs. And left at room temperature for 48 hrs. Table (3) lists physical properties and FT-IR spectral data of compounds (7-10).

Results and Discussion
To obtain our target, the β-lactam cycle containing two imidazole ring, the amino acid L-histidine was chosen as starting material. The multistep synthetic route to these compounds are given in scheme (1).

Scheme (1): Synthetic route for synthesis imidazole derivatives
The first step includes synthesis of compound (1) from the cyclization reaction between L-histidine and acetic anhydride. The mechanism of this reaction was started with nucleophilic attack of amino group on carbonyl carbon according the following mechanism, as shown in scheme (2):

Scheme (2): Mechanism for synthesis of compound (1)
The second step includes synthesis of compound (2) the nucleophilic attack of hydrazine hydrate with compound (1), then compound (2) was introduced in reaction with substituted aromatic aldehyde in the third step to form Schiff's bases (3)(4)(5)(6). The mechanism of Schiff base was started by nucleophilic attack on carbonyl by the lone-pair electron of amine gives a dipolar tetrahedral intermediate. Then a proton transferred from nitrogen to oxygen yielding a carbinolamine, which after protonation and dehydration gives an iminium ion. Losing hydride ion from nitrogen leading to form an imine as shown in scheme (3):

Scheme (3): Mechanism for synthesis Schiff base
The fourth step includes synthesis of compounds (7-10) from the reaction of compounds (3-6) with chloroacetyl chloride through addition cyclization reaction, yielding β-lactam ring according to the short mechanism in scheme (4).

Scheme (4): Mechanism for β-lactam formation
The percentage yield of the prepared Schiff's bases were in the range of {21-54} percent it was noticeable presence of electron with drawing substituent in aromatic ring caused increasing of yield percent of the prepared compounds. The percentage yield of the prepared compounds (7-10) was in the range of {23-96} percent. These compounds were identified by FT-IR and some of them with 1 H-NMRand 13 C-NMR spectroscopy.