Catalyst Free Synthesis of Pyridine-2 , 6-bis ( 2-bromo-propane-1 , 3-dione ) and Pyrdine-2 , 6-bis ( N-arylthiazoline-2-thiones )

We have described herein a catalyst-free preparation method of pyridine-2,6-bis(N-alkylthiazoline-2-thiones) (4a-i) by the reaction of primary amines, CS2, and pyridine-2,6-bis(2-bromo-1,3dicarbonyl) derivatives (2a-c) in water. Also, we have described a catalyst free, green chemistry protocols to monobromination of pyridine-2,6-bis(2-bromo-1,3-dicarbonyl) derivatives with high yield, using NBS as a brominating agent, that led to eco-friendly isolation and purification procedures. Furthermore, we have studied the reactivity of pyridine-2,6-bis(2-bromo-1-methyl-propane-1,3-dione) (2a) towards thiourea to afford 2,6-bis(5-benzoyl-2-aminothiazol-4-yl)pyridine (9).


Introduction
α-Bromo-1,3-dicarbonyl compounds are highly useful synthetic intermediates in organic synthesis [1] [2]. Many reports researched the bromination of 1,3-diketones and β-keto esters using different reagents such molecular bromine, potassium bromide, sodium hypobromite, and CuBr that are hazardous chemicals and lead to complicated work-up methods [3]- [6]. The other challenge for using these reagents is the selectivity of monobromination toward 1,3 diketones and β-keto esters because these reagents in many cases lead to a mixture of mono and di-brominated products [7] [8]. On the other hand, N-bromosuccinimide is a superior brominating reagent, K. A. Ali et al. 40 inexpensive, easy to handle and can be used in solvent free and eco-friendly organic syntheses [9]. Thus, we have reported herein solvent and catalyst free strategy as an important alternative to the use of organic solvents in selective monobromination of 1,3-diketones and β-keto esters using NBS as brominating agent and comparing with that obtained from monobromination in diethyl ether as a solvent and CH 3 COONH 4 as a catalyst.
Thiazoline-2-thiones derivatives have found a wide range of applications in many fields, such as diffusion transfer colour photographic materials, agriculture, molecular conductors and as powerful ligands [10] [11]. Also, they applied in medicinal chemistry as they have hypoglycemic, anti-inflammatory and antineoplastic activities [12]. There are many recorded protocols for the synthesis of N-substituted thiazoline-2-thiones. For example, they can be prepared by the reaction of α-haloketones with alkyl ammonium dithiocarbamates in the presence of acid [13] or from three component one pot synthesis (carbon disulfide, amines, and ethyl 3-bromo-2-oxopropanoate) in the presence of anhydrous potassium phosphate in DMF [14].
In view of these observations and our interest in the synthesis of biologically target pyridine-2,6-bis(functionalized heterocycles) [15]- [21], we describe herein a catalyst-free, three component one pot synthesis for new class of 2,6-bis(5-substituted-3-aryl-2-thiothiazol-4-yl)pyridine (4a-i) by reaction of primary amines, carbon disulfide, and 2-chloro-1,3-dicarbonyl compounds in water. This protocol and the work-up procedure were facile and we have obtained pure target compounds containing several potential centres for further modification.
A mixture of pyridine-2,6-bis(propane-1,3-dione) derivatives (1a-c) and NBS was triturated in a porcelain mortar at room temperature for 30 min. After grinding in mortar pestle the color of the reaction mixture gradually changed from pale yellow color to deep yellow-brown color. By addition of few amounts of water to the mixture then lifted for 3 h, resulted in formation of yellow paste for each derivative. The past of each product was washed with water many times and the solid products were separated by decantation to afford the corresponding, monobrominated product (2a-c) with good yields, on the basis of the elemental analysis spectral data. The 1 H NMR spectra of the isolated products (2a-c) revealed, in each case a singlet signal at the region of δ 6.00 -6.31 which indicates the presence of the aliphatic CH.

Scheme 1
Treatment of the appropriate freshly prepared pyridine-2,6-bis(2-bromo-1,3-dicarbonyl) compounds (2a-c) with the appropriate primary amines (3a-c) and carbon disulfide in water, under refluxed temperature, afforded the corresponding 2,6-bis(5-substituted-3-aryl-2-thiothiazol-4-yl)pyridine (4a-i) in high yields. The structures of the isolated solid products (4a-i) were confirmed on the bases of elemental analysis and spectral data as presented in the experimental part. The Mass spectra of the synthesized compounds, showed the molecular ion peaks at the appropriate m/z values. Also, IR spectra of each product represent the presence of carbonyl group and are in agreement with the proposed structures. The 1 H NMR spectrum of compound (4c) as an example revealed two singlet signals at 2.13 and 2.28 corresponding to (acetyl and p-toulyl) methyl groups, respectively.

Scheme 3
Also, we have studied The behavior of pyridine-2,6-bis(2-bromo-1-methyl-propane-1,3-dione) (2a) towards thiourea. Thus, treatment of compound 2a with thiourea in refluxing water, in the presence of a catalytic potassium carbonate, afforded 2,6-bis(5-benzoyl-2-aminothiazol-4-yl)pyridine (9) on the basis of its elemental analysis and spectral data. The IR spectrum of the later compound revealed presence of two absorption bands at the region 3309 -3127 corresponding to NH 2 groups in addition to absorption band at 1720 corresponding to carbonyl group. The 1 H NMR of compound 9 revealed broad singlet D 2 O exchangeable singlet signal at δ 4.45 corresponding to amino groups, The mass spectrum of the same product showed a peak at m/z 327 corresponding to its molecular ion (Scheme 4). Scheme 4

Conclusion
We have described herein a convenient route for the synthesis of monobrominated derivatives: pyridine-2,6bis(2-bromo-1,3-dicarbonyl) (2a-c) with high yield using NBS as a brominating agent. Also, we have described a catalyst-free for the preparations of N-arylthiazoline-2-thiones (4a-i) by the reaction of primary amines, CS 2 , and 2-bromo-1,3-dicarbonyl compounds (2a-c) in water. The catalyst-free and green procedure for the preparation of N-arylthiazoline-2-thiones (4a-i) can be considered as an alternative method for the preparation of this type of compounds.