Cascade Synthesis of Thieno [ 2 , 3-b ] pyridines by Using Intramolecular Cyclization Reactions of 3-Cyano-2-( organylmethylthio ) pyridines

*e-mail: hsheibani@mail.uk.ac.ir Cascade Synthesis of Thieno[2,3-b]pyridines by Using Intramolecular Cyclization Reactions of 3-Cyano-2-(organylmethylthio)pyridines Fatemeh Alinaghizadeh,a Mahboobeh Zahedifar,b Mohammad Seifia and Hassan Sheibani*,a Department of Chemistry, Shahid Bahonar University of Kerman, 76169 Kerman, Iran Department of Chemistry, Faculty of Science, University of Jiroft, 364 Jiroft, Iran


Introduction
In organic chemistry, derivatives of pyridine fused to thiophene systems are one important class of heterocyclic compounds and they attract considerable interest because of their great practical usefulness, primarily due to their various biological activities. 1 The synthesis of thienopyridines has been the subject of several reviews which demonstrate the high importance of this class of compounds. 2Six isomeric thienopyridine structures characterized by different annelation modes are known: thieno [2,3-b]pyridine, thieno [3,2-b]pyridine, thieno [2,3-c]  pyridine, thieno [3,2-c]pyridine, thieno [3,4-b]pyridine and thieno [3,4-c]pyridine.The first four thienopyridines were studied in detail in the literature. 3Data on the "isostructural" isomers thieno [3,4-b]pyridine and thieno [3,4-c]pyridine are scarce and disembodied and they are beyond the scope.Our main focus is on synthesis of some new thieno [2,3-b]pyridine derivatives.These compounds have been investigated in relation with their biological and pharmacological activities.Some of them have proved to possess antibacterial, 4,5 antiviral, 6 antihypertensive 7 and antimicrobial 8 activities.So the certain thieno [2,3-b]  pyridine derivatives were prepared as anti-inflammatory agents, particularly for treating arthritis and bone resorption inhibiting agents. 9These potential therapeutic applications made these compounds as a privileged scaffold.1][12] Thieno[2,3-b]pyridine derivatives have been previously prepared in a multistep procedure from either a thiophene or a pyridine ring and further ring closure leading to the other heterocyclic fused system.4][15][16] Therefore, reinvestigation of the classical conditions seemed warranted for developing conditions for suitable library synthesis.In view of all these benefits and as a continuation of our interest in the field of heterocyclic compounds, [17][18][19][20] we undertook the synthesis of new thieno [2,3-b]pyridine derivatives by the reaction of 2-amino-4-aryl-6-mercaptopyridine-3,5-dicarbonitriles with halogen compounds in the presence of sodium alkoxide at room temperature.
(IR) spectra were measured on a Mattson 1000 Fourier transform IR (FTIR) spectrometer.The proton and carbon nuclear magnetic resonance (NMR) spectra were recorded with a Bruker DRX-400 AVANCE spectrometer at 400 and 100 MHz, respectively.Mass spectra (MS) were recorded on a Shimadzu MS-QP2000A mass spectrometer operating at an electrospray ionization (ESI) potential of 70 eV.Elemental analyses were performed using a Heracus CHN-O-Rapid analyzer.2,2-Dicyanooxiranes 1a-d were prepared according to a literature procedure. 19

Preparation of high surface area MgO
The catalysts used in this study were obtained by calcinations of rehydrated Mg(OH) 2 .The experimental results showed that an optimal calcination temperature in the range 400-500 o C gives poorly crystalline, high surface area (HSA) MgO that can be regenerated by washing, and then reused.After separation of the product by filtration, the recovered solvent containing MgO was reused twice without loss of activity of the catalyst. 21,22eparation of nanosized MgO The MgO nanoparticles were synthesized by precipitation of the magnesium hydroxide gels in aqueous solution using Mg(NO 3 ) 2 as salt and liquid ammonia as the precipitating agent.Initially, the pH of 200 mL of distilled water was adjusted to 10.5 by addition of liquid ammonia.To this solution, 0.1 mol L -1 magnesium nitrate solution (0.0148 g mL -1 ) was added dropwise with continuous stirring.The rate of addition of the salt solution was kept at 20 mL h -1 .During the addition, the pH of the mixture decreased due to hydrolysis of the salt.The pH was maintained at 10.5 by controlled addition of liquid ammonia solution.After completion of the precipitation procedure, the mixture was stirred at ambient temperature for 12 h, filtered, repeatedly washed with distilled water, dried at 120 o C, and calcined at 500 o C for 2 h. 23epwise one-pot general procedure for the preparation of 2-amino-4-aryl-3,5-dicarbonitrile-6-(phenylthio)pyridines in the presence of base catalysts (4a-d)

Method A (triethylamine as base catalyst)
To a stirred solution of aldehyde (1 mmol) in ethanol (10 mL) was added a solution of malononitrile (1 mmol in 2.0 mL of ethanol) and 3 drops of triethylamine.The pale yellow solution was then refluxed for 60 min.To this was then added thiophenol (1 mmol), and the mixture was refluxed for a further 45 min.Another 1 mmol of malononitrile in 2.0 mL of ethanol was added, and the reaction mixture was refluxed for a further 60 min.The reaction mixture was then exposed to air overnight.The yellow crystalline precipitate formed was collected by suction filtration, washed with n-hexane/ethanol (9:1), followed by n-hexane.To a stirred solution of aldehyde (1 mmol) and malononitrile (1 mmol) in 10 mL ethanol were added 50 mg MgO (high surface area or nanosized) at ambient temperature.The resulting mixture was heated to 50 o C, the thiophenol (1 mmol) was added and the reaction mixture was refluxed for 45 min.Another 1 mmol of malononitrile in 2.0 mL of ethanol was added, and the reaction mixture was refluxed for a further 60 min.The reaction mixture was then exposed to air overnight.The mixture was centrifuged to separate the catalyst and the catalyst was washed with ethyl acetate (3 × 5 mL).The solvent was evaporated under reduced pressure and the crude product obtained was purified by recrystallization from ethanol.General procedure for the preparation of 2-amino-4-aryl-6mercaptopyridine-3,5-dicarbonitriles (5)   The compound 4 (2-amino-4-aryl-3,5-dicarbonitrile-6-(phenylthio)pyridine) (3 mmol) was dissolved in N,N-dimethylformamide (DMF) (10 mL) and to this was added sodium sulfide (0.78 g, 10 mmol) and the mixture stirred at 80 o C for 2 h.Upon cooling at ambient temperature, 1 mol L -1 HCl (20 mL) was added, resulting in the formation of a yellow precipitate.The crude product was collected by filtration.Compounds 5a-d have been reported previously. 25eparation of 2-amino-6-(2-oxo-2-phenyl-ethylsulfanyl)-4phenyl-pyridine-3,5-dicarbonitrile (I) A mixture of 2-amino-4-phenyl-6-(phenylthio)pyridine-3,5-dicarbonitrile 5a (2 mmol), 2-bromoacetophenone (2 mmol) and Et 3 N (0.1 mL) in ethanol (20 mL) was stirred at ambient temperature.After  General procedure for the preparation of 3,6-diamino-2benzoyl-4-aryl-thieno[2,3-b]pyridine-5-carbonitrile (6a-f) A mixture of 2-amino-4-aryl-6-mercaptopyridine-3,5-dicarbonitriles 5a-d (2 mmol), 2-bromoacetophenone (2 mmol) and NaOEt in absolute ethanol (20 mL) was stirred at ambient temperature for 10 min.After this time a yellow solid appeared which was collected by filtration.The crude product was purified by ethanol.

Results and Discussion
In our preliminary studies, the 2-amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitrile derivatives 4a-d have been prepared by an efficient stepwise onepot three multicomponent reaction of aldehydes 1a-d, malononitrile 2, and benzenethiol 3 in the presence of base catalysts such as triethylamine, HSA-MgO or nanocrystalline magnesium oxide in moderate to good yields.Pyridine formation occurred according to a preparation by Kambe et al. 26 to give the phenyl protected sulfides 4 in the 6-position of the ring.To obtain the free thiol in the 6-position of the pyridine ring 5, the 2-amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitriles 4 along with 3.3 eq of sodium sulfide in DMF were heated at 80 o C for 2-3 h which resulted in quantitative yields of 2-amino-4-aryl-6-mercaptopyridine-3,5-dicarbonitriles 5.The final step was the reaction of the free thiol 5 with α-halogen compounds in the presence of base catalyst such as sodium alkoxide at room temperature which led to preparation of thieno [2,3-b]pyridine derivatives (6a-f) (Scheme 1).Reaction time for the synthesis of compounds 6 from compounds 5 is very short at room temperature, about 5-10 min.
A few multicomponent reactions (MCRs) are also reported for synthesis of diverse substituted 2-amino-3,5dicarbonitrile-6-thiopyridines, such as three-component condensations of aldehyde, malononitrile and thiol using various base catalysts. 24,27When the one-pot procedures such as using high surface area MgO or nanocrystalline magnesium oxide were applied to preparation of 2-amino-3,5-dicarbonitrile-6-thiopyridines as starting materials, the yields were significantly lower than 60% (Table 1).
For this reason, a simple variation on these one-pot procedures was employed for the improvement of the reaction conditions.These reactions were carried out by a stepwise addition of reagents which were followed by preparation of products 6 with improvement of the reaction yields up to 75%.The reported mechanism of pyridine dicarbonitrile formation involves the attack of a malononitrile anion upon the aromatic aldehyde which was activated by MgO followed by elimination of water to form aryllidenemalononitriles. Subsequent addition of a second malononitrile anion along with addition of thiol to nitrile group of malononitrile provides penultimate intermediate II, which is followed by loss of molecular hydrogen to furnish the product (Scheme 2).

Conclusions
In summary, we have developed a simple and efficient method for the synthesis of thieno [2,3-b]pyridines via reaction of α-halogen compounds with 2-amino-4-aryl-Scheme 1. Synthetic route to the synthesis of compounds 6. 6-mercaptopyridine-3,5-dicarbonitriles which were prepared from 2-amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitrile derivatives.These compounds as starting materials have been prepared on stepwise one-pot three component reaction of malononitrile, aldehydes and thiophenol by using high surface area MgO or nanocrystalline magnesium oxide as base catalysts.The advantage of these procedures reported here are: short reaction times, high purity of products and easy workup.
Methods B and C (high surface area and nanosized MgO as base catalysts)

Scheme 3 .
Scheme 3.Putative mechanism for the formation of compounds 6.

Table 1 .
Synthesis of compounds 4a-d in the presence of base catalysts a High surface area MgO.Scheme 2. Synthesis of compound 4 in the presence of MgO as catalyst.