Fleury et al., Tetrahedron Letters. 1974,3967. However, the enamines used in such reactions were prepared from ketones in the presence of ammonia. This preparation lead to synthesis of 6-substituted 2-aminopyrazine compounds.

There still is a need for a process of forming 6-unsubstituted 2-substituted pyrazine heterocycles.

Detailed Description of the Invention The present invention relates to a process of producing 6-unsubstituted 2-substituted pyrazine heterocycles involving the reaction of an oxime with an enamine. The present invention also relates to producing novel intermediates which are useful in producing pyrazine compounds as well as novel substituted pyrazine compounds.

In one embodiment, a pyrazine heterocycle is formed by reacting a secondary amine with an aldehyde to form an enamine. The enamine compound is then reacted with an oxime to produce a novel 2-azadiene compound. Subsequent quenching with ammonia provides a 2-aminopyrazine.

Altenatively, the pyrazine may be formed by reacting the 2-azadiene compound with a thiol bearing compound, such as but not intended to be limited to, thioalkyls, thioalkenyls, thioalkynyls, and thioaryls to produce 2-thioalkyl substituted pyrazines and 2-thioaryl substituted pyrazines.

In a preferred embodiment of the present invention as shown in Scheme 1, pyrrolidine (2) is added to phenylacetaldehyde (1) to form the a novel enamine (3). Malononitrile oximinotosylate (4) is added to the enamine (3) to form a 2-azadiene intermediate (5). The 2-azadiene intermediate (5) is then

subsequently quenched with ammonia to provide a 2-amino-3-cyano- hydridopyrazine (8).

In a preferred embodiment of the present invention as shown in Scheme 1, pyrrolidine (2) is added to phenylacetaldehyde (1) to form the a novel enamine (3). Malononitrile oximinotosylate (4) is added to the enamine (3) to form a 2-azadiene intermediate (5). The 2-azadiene intermediate (5) is then reacted with a thioaryl such as thiophenol (6) to form a novel 3-cyano-5- phenyl-2-phenylthiopyrazine (7).

SCHEME 1

EXAMPLE 1 Malononitrite Oximinotosylate Sodium oximine malononitrile (12.9grams (g), 0.11moles) and 150 milliliters (mL) of acetonitrile were added together and cooled to 0-5°C.

Toluenesulfonyl chloride (19.1g, O. llmoles) was added slowly to keep the temperature below 10°C. The solution was stirred for 10 minutes at 10° C and then 500mL of water was added and the mixture was stirred for 20 minutes. The solids in the mixture were filtered and the solid was washed with 50mL water, followed by 50mL of heptane and dried under vacuum to give a white solid (20g, 78% yield). 1HNMR (300Mhz, CDC13) d 7.80 (d, J=7 Hz), 7.35 (d, J=7 Hz), 2.41 (s, 3H).

EXAMPLE 2 trans-N-('2-pheny!)ethylenepyrrolidinc Pyrrolidine (lOg, 0.14moles) and 5g of sodium sulfate were added to a flask and cooled to <0° C. Phenacetaaldehyde (2.4g., 0.02 moles) was added slowly to the flask to keep the temperature <2° C. The mixture was stirred at 0° C for one hour. The mixture was filtered and the filtered solid was washed with lOmL of heptane and the combined filtrates were then distilled (<40° C) to an oil.

Heptane (30 mL) was added and distilled to an oil.

EXAMPLE 3 3-aza-2-cyano-4-phenvl-5-N-pent-2 4-dienitrile Pyrrolidine (7.1g, 0.10mole) and sodium sulfate (5g) was added to a flask and cooled to <0°C. Phenylacetaldehyde (2.4g, 0.02mole) was added slowly to the flask to keep temperature <2°C. The mixture was stirred at 0°C for 1 hour. Then it was filtered and the solid was washed with lOmL heptane and the combined filtrate was distilled (<40°C) under vacuum to an oil. Heptane (30ml) was added and then distilled to oil. The final oil was mixed with dimethyformamide (DMF) (7ml) and triethylamine (3.03g, 0.03moles). The mixture was then slowly added into a flask containing malononitrile oximinotosylate (4.98g, 0.02moles) in DMF

(20mL) at 0°C+5°C. This reaction mixture was stirred at 0°C for 5 minutes and then 100 ml of water was added 10°C and this was stirred for 15 minutes at room temperature. The solid was filtered washed with 30ml of water and then stirred with 60 ml methanol for 15 minutes. The solid was the filtered and washed with 10ml methanol and dried to give orange solid (3.3g, 66% yield). 1HNMR (300 Mhz, CDC13) d 7.71 (s, 1H), 7.5-7.47 (m, 6H), 7.22-7.15 (m, 4H), 6.96 (s, 1H), 4.09 (m, 1H), 3.80-3.68 (m, 4H), 2.70 (t, J=7H2,3H), 2.2-2.05 (m, 2H), 2.07-1.93 (m, 2H), 1.93- 1.8 (m, 4H).

EXAMPLE 4 2-Amino 3-Cyano-5-Phenyl-pvrazine Pyrrolidine (lOg, 0.14mole) and sodium sulfate (5g) were added to a flask and cooled to <0°C. Phenylacetaldehyde (2.4g, 0.02mole) was added slowly to the flask to keep temperature <2°C. The mixture was stirred at 0°C for 1 hour. Then it was filtered and the solid was washed with 10ml heptane and the combined filtrate was distilled (<40°C) under vacuum to an oil. Heptane (30ml) was added then distilled to oil. The final oil was mixed with dimethyformamide (DMF) (6ml) and triethylamine (2.02g, 0.02moles). The mixture was then slowly added into a flask containing malononitrile oximinotosylate (4.98g, 0.02moles) in DMF (20moi) at 0°C+3°C. This reaction mixture was stirred at 0°C for 15 minutes and then aqueous ammonium hydroxide (llml, 28-33% w/w) in methanol (lOml) was added. This mixture was stirred for 20 minutes at 15°C. 100 ml of 3% HCI was added at 10°C and this was stirred for 15 minutes at room temperature. The solid was filtered and mixed with 40ml methanol and stirred for 20 minutes at 10°C and filtered. The solid was washed with 10ml of cold methanol and dried to give a yellow solid (2.5g, 64%). 1HNMR (300 Mhz) d 8.93 (s, 1H, 7.97-7.7.95 (m, 2H), 7.52-7.38 (m, 5H).

EXAMPLE 5 <BR> <BR> <BR> 3-Cvano-5-phenyl-2-nhenylthionyrazine<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> Pyrrolidine (10g, 0.14mole) and sodium sulfate (5g) was added to a flask and cooled to <0°C. Phenylacetaldehyde (2.4g, 0.02mole) was added slowly to the flask to keep temperature <2°C. The mixture was stirred at 0°C for 1 hour. Then it was filtered and the solid was washed with 10ml heptane and combined filtrate was distilled (<40°C) under vacuum to an oil. Heptane (30ml) was added

and then distilled to oil. The final oil was mixed with dimethyformamide (DMF) (6ml) and triethylamine (6.06g, 0.06moles). The mixture was then slowly added into a flask containing malononitrile oximinotosylate (4.98g, 0.02moles) in DMF (20ml) at 0°C+3°C. This reaction mixture was stirred at 0°C for 30 minutes and then thiophenol (2.4g, 0.022moles) was added. This mixture was stirred 3 hours at ambient temperature. 100 ml of water was added at 10°C and this was stirred for 20 minutes at room temperature. The solid was filtered and mixed with 50ml methanol and stirred for 20 minutes and filtered. The solid was washed with 10ml of methanol and dried to give grayish solid (2.98g, 51%). 1HNMR (300 Mhz, CDC13) d 8.9 (s, 1H), 8.0-7.9 (m, 2H), 7.7-7.6 (m, 2H), 7.6-7.45 (m, 6H)