Patent Document

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
     This invention was made with government support under DE-SC0007662 awarded by the Department of Energy. The government has certain rights in this invention. 
    
    
     BACKGROUND OF THE INVENTION 
     Substituted tetracyano-hexaazatricyclics have significant potential use in the electrochemical area. This is due to the high redox capability of the molecules. Potential applications are discussed in further detail in U.S. Pat. No. 8,080,327 (Rasmussen). 
     FIELD OF THE INVENTION 
     The present disclosure relates to chemical processes used to make substituted tetracyano-hexaazatricyclics. More particularly, to processes where the tetracyano-hexaazatricyclics are substituted at the 9 and 10 positions. 
     BRIEF SUMMARY OF THE INVENTION 
     The present disclosure discusses a process to manufacture substituted tetracyano-hexaazatricyclics, with the substitutions occurring at the 9 and 10 hydrogens. The process comprises reacting 2,3-dichloro-5,6-dicyanopyrazine and, in a series of steps, manufacturing the desired tetracyano-hexaazatricyclic embodiment, wherein the embodiment has substitutions occurring at the 9 and 10 hydrogens. 
     The scope of the invention is defined by the claims, which are incorporated into this section by reference. A more complete understanding of embodiments on the present disclosure will be afforded to those skilled in the art, as well as the realization of additional advantages thereof, by consideration of the following detailed description of one or more embodiments. Reference will be made to the appended sheets of drawings that will first be described briefly. 
     The following detailed description of the invention is merely exemplary in nature and is not intended to limit the invention or the application and uses of the invention. Furthermore, there is no intention to be bound by any theory presented in the preceding background of the invention or the following detailed description of the invention. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a depiction of bis(2-methoxyethyl)-2,3,6,7-tetracyano-1,4,5,8,9,10-hexazaanthracene. 
         FIG. 2  is a depiction of bis(2-methoxyethoxyethyl)-2,3,6,7-tetracyano-1,4,5,8,9,10-hexazaanthracene. 
         FIG. 3  is an embodiment of the reaction steps used to make tetracyanohexaazaanthracene. 
         FIG. 4  is an embodiment of the reaction steps used to make substituted tetracyanohexaazaanthracene. 
         FIG. 5  is an embodiment of the traditional reaction steps used to make bis(2-methoxyethyl)-2,3,6,7-tetracyano-1,4,5,8,9,10-hexazaanthracene. 
         FIG. 6  is an embodiment of the traditional reaction steps used to make bis(2-methoxyethoxyethyl)-2,3,6,7-tetracyano-1,4,5,8,9,10-hexazaanthracene. 
         FIG. 7  is an embodiment of the reaction steps used to make bis(2-methoxyethyl)-2,3,6,7-tetracyano-1,4,5,8,9,10-hexazaanthracene. 
         FIG. 8  is an embodiment of the reaction steps used to make hydroxypyrazine. 
         FIG. 9  is an embodiment of a final reaction step used to make bis(2-methoxyethyl)-2,3,6,7-tetracyano-1,4,5,8,9,10-hexazaanthracene. 
         FIG. 10  shows an alternate reaction pathway for the preparation of bis(2-methoxyethoxyethyl)-2,3,6,7-tetracyano-1,4,5,8,9,10-hexazaanthracene. 
         FIG. 11  shows an alternate reaction pathway for the preparation of bis(2-methoxyethyl)-2,3,6,7-tetracyano-1,4,5,8,9,10-hexazaanthracene. 
         FIG. 12  shows a reaction pathway for the preparation of 2,3-Dicyano-1,4-dihydro-5,6-diketopyrazine. 
         FIG. 13  shows a reaction pathway for the preparation of 2,3-Dichloro-5,6-dicyanopyrazine. 
         FIG. 14  shows a reaction pathway for the preparation of 2-(2-Methoxyethylamino)-3-chloro-5,6-dicyanopyrazine. 
         FIG. 15  shows a reaction pathway for the preparation of 5,10-bis(2-methoxyethyl)-5,10-dihydrodipyrazino[2,3-b:2′,3′-e]pyrazine-2,3,7,8-tetracarbonitrile. 
         FIG. 16  shows a reaction pathway for the preparation of 2,3-bis(2-Methoxyethylamino)-5,6-dicyanopyrazine. 
         FIG. 17  shows a reaction pathway for the preparation of 5,10-bis(2-methoxyethyl)-5,10-dihydrodipyrazino[2,3-b:2′,3′-e]pyrazine-2,3,7,8-tetracarbonitrile. 
         FIG. 18  shows a reaction pathway for the preparation of 2-(2-Methoxyethoxy)ethyl ammonium tosylate salt  1001  and 2-(2-Methoxyethoxy)ethyl p-toluenesulfonate. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present disclosure discusses the manufacturing of the molecules shown in  FIG. 1  bis(2-methoxyethyl)-2,3,6,7-tetracyano-1,4,5,8,9,10-hexazaanthracene  101  and  FIG. 2  bis(2-methoxyethoxyethyl)-2,3,6,7-tetracyano-1,4,5,8,9,10-hexazaanthracene  201 . The goal is to manufacture molecules  101  and  201  through practical, direct, and straightforward pathways that could be expanded for multi-gram scale production. Molecules of this type had been previously manufactured but only on small scale with simple alkyl substitution and never with oxygen functionality. 
       FIG. 3  shows how the core structure of the desired tetracyanohexaazaanthracene  307  framework had previously been manufactured. The process begins with 2,3-dichloro-5,6-dicyanopyrazine  301  which is reacted in a ammonia NH3  302  and tetrahydrofuran THF  303  mixture at 15 degrees Celsius; through dimerization of 2-amino-3-chloro-5,6-dicyanopyrazine  304  in refluxing dimethylformamide [DMF]  306  using triethylamine  305  to pick up the eliminated HCl; however the yields were always poor [J. Juang, K. Fukunishi and M. Matsuoka J. Heterocyclic Chem., 34. 653 (1997)]. 
     Following the synthesis of the  307 ,  FIG. 4  shows that substitution of both the 9 &amp; 10 hydrogens with alkyl groups had previously been accomplished using the corresponding alkyl bromide  401  in refluxing DMF  306  solvent—again using triethylamine  305  to absorb HCl, though again in poor yield. Very large molar excesses of the alkyl bromide  401  were also necessary, the temperature was high [DMF reflux; 160° C.] and the reflux period was several days. Substituted root tetracyanohexaazaanthracene  402  is shown with R embodiments represented as CH3  403 , n-butyl  404 , and n-octyl  405 . These characteristics suggested the construction of compounds  101  and  201  would not be simple and application to large scale might be problematic. 
     To explore the synthetic paths to both the bis(2-methoxyethyl) derivative  101  and bis(2-methoxyethoxyethyl) derivative  201 , we accomplished the traditional sequence by first construction of dicyano-dichloropyrazine  304 , converting this to core framework  307  and then using alkylation of  307  with 2-methoxyethyl bromide [CH 3 —O—CH 2 CH 2 —Br]  501  in DMF  306 /TEA  305  giving  101  and 2(2-methoxyethoxy)ethyl bromide [CH 3 —O—CH 2 CH 2 —O—CH 2 CH 2 —Br]  601  in DMF  306 /TEA  305  giving  202 . The synthesis was productive but yields were, as expected, very low. Also, the synthetic process was tedious and expensive because both reagents are expensive and need to be used in 10-20 fold excess to give reasonable reaction rates. Further, even with excess alkylating reagents the sequence required two long heating periods; the first for the conversion of pyrazine  304  to tricyclic  307  and the second alkylation of  307  to give  101  or  201 . Note that the process cannot easily be separated, though there are two sequential steps. Once  307  is produced, its transformation to  101  starts to proceed. 
     The present disclosure explores an alternative, as shown in  FIG. 7 . Rather than prepare the simple dicyano-amino-chloropyrazine  304 , we elected to construct the now substituted 5,6-dicyano-2-methoxyethylamino-3-chloropyrazine  703  using 2-methoxyethylamine  701  in place of ammonia in tetrahydrofuran (THF)  702  at −15. The very high reactivity of the halogens of  301  provided the very nicely crystalline derivative  703  in yields of 80% as a single bright blue fluorescent spot on thin layer chromatography (TLC) or using column chromatography. Upon refluxing derivative  703  in DMF  306 /TEA  305  for 6-8 hours,  101  was afforded in only very modest yield. Never-the-less, the two long heating steps had been converted to one. 
     As we monitored the progress of the conversion of  703  into  101  using TLC or column chromatography, it was noted that a significant new non-fluorescent spot appeared in addition to the bright yellow spot of tricyclic  101 . Isolation of this material and determination of it&#39;s mass spectrum showed the formation of a material eventually identified as hydroxypyrazine  802 , as shown in  FIG. 8 . Also shown is hydroxypyrazine intermediate  801 . Clearly, the DMF  306  solvent had intervened in the reaction and DMF  306  was competing for the reactive halogen of  703  rather than allowing the dimerization of  703  to  101 . This intervention was clearly the reason for the low yields in the conversion of  703  to  101 . 
     Thus, we explored many numerous alternative solvents including other amide solvents such as N-methylpyrrolidone, dimethylacetamide.  FIG. 9  shows the discovered reaction pathway: diglyme [CH 3 —O—CH 2 CH 2 —O—CH 2 CH 2 —OCH 3 ; diethyleneglycol dimethyl ether; bp 160]  901  and diisopropylethylamine [DIPEA]  902  was an excellent medium and solvent to accomplish the transformation of  703  to  101 . Refluxing pyrazine  703  in diglyme  901  with DIPEA  902  afforded good [60-70%] yields of substituted tricyclic  101 . The reaction can be followed easily by TLC or column chromatography and isolation by cooling to room temperature and upon pouring the reaction mix into ice/water, a brownish-yellow-orange solid precipitates almost pure without chromatography. This material has been used extensively in our CV and charge/discharge experiments. 
     Though the construction of bis(2-methoxyethyl) tricyclic  101  was accomplished it remained to be determined if a similar sequence could be established for the synthesis of  201 . 2-Methoxyethylamine is commercially available inexpensively. The required corresponding 2-methoxyethoxyethylamine is not. Several attempts to synthesize this material failed including the Gabriel synthesis using the phthalimide intermediate. The failure in each attempt involved the very high water solubility of the aminodiether.  FIG. 10  shows a new preparation of the required amine  1001  through the construction of the p-toluenesulfonate ester of monoglyme [CH 3 —O—CH 2 CH 2 —O—CH 2 CH 2 —OH]  1002 . Upon treatment of this material with a very large excess of aqueous ammonia at room temperature for several days followed by rotoevaporation of the aqueous solution yields the p-toluenesulfonate salt of 2-methoxyethoxyethylamine  1002 . The salt  1002  is taken up in THF and evaporated to remove traces of water by azeotropic processes. The salt  1002  along with dichloropyrazine  301  was dissolved in THF and treated with DIPEA  902  [2 equivalents] at −15° Celsius gave good yields of the corresponding substituted 2-methoxyethoxyethylamino chloro pyrazine  1003 . Using the same procedure as in the conversion of  703  to  101  (Refluxing  1003  in diglyme  901  with DIPEA  902  to yield  201 ), the more highly oxygenated side-chain aminopyrazine  1003  is converted to  201 . 
     In order to explore routes that would allow the construction of unsymmetrical derivatives of the tetracyano hexaaza tricyclic we have also explored the combination of a disubstituted diaminopyrazine with the dicyanodichloropyrazine  301 , as shown in  FIG. 11 . In the event, dicyanodichloropyrazine  301  was treated with 2 equivalents of 2-methoxyethylamine  701  (in THF  702  at −15 degrees Celsius) and the substitution of both halogens accomplished in a sequential way to give substituted diaminopyrazine  1101  ( 703  is shown as an intermediate in  FIG. 11 ). This was then caused to react with dichloro-dicyanopyrazine  301  to give the exactly the same tricyclic structure  101  as produced by the dimerization of pyrazine  703 . Many other side-chains and derivatives can thus be designed, constructed and explored. 
     2,3-Dicyano-1,4-dihydro-5,6-diketopyrazine  1204   
       FIG. 12  shows the reaction pathway. A 500 mL Erlenmeyer flask was charged with a magnetic stir bar and to this setup was introduced 375 mL of anhydrous 1,4-dioxane  1201 . The dioxane is cooled in ice/water mixture and after well cooled and with good stirring, 15 mL of oxalyl chloride [171 mmol; d=1.45]  1202  is added slowly. The combination will be exothermic. The mixture is allowed to stand until well chilled and a N 2  sweep is established. To the well stirred mixture is added, in small [˜2 g or smaller] portions over an hour, a total of 15 g [139 mmol] of purified DAMN  1203  in the solid state. After the last portion is added the flask is sealed with parafilm and stirring continued for ˜1 hour followed by then warming in a water bath to 50° C. for some 3-4 hours during which time the solution and thick suspension turned light yellow. The thick suspension is cooled to room temperature and placed in a freezer compartment of a refrigerator [˜−20° C.] for about an hour [not longer or dioxane solvent may freeze]. The solid was filtered by suction on a sintered-glass filter, washed with cold ether and dried. The material can be crystallized from boiling water. Yield ˜85%. 
     2,3-Dichloro-5,6-dicyanopyrazine  301   
       FIG. 13  shows the reaction pathway. This reaction should be carried out in a fume hood. In a 500 mL round-bottomed flask with a 24/40 ground-glass joint attached to an efficient reflux condenser and under a nitrogen atmosphere, a magnetically stirred slurry consisting of 8.10 g (0.050 mol) of 1,4,5,6-tetrahydro-5,6-dioxo-2,3-pyrazinedicarbonitrile, 4.0 mL of dimethylformamide  306  and 160 mL of thionyl chloride  1301  was heated. Gas evolution began at ca. 62° [SO2 &amp; HCl gasses evolved]. After about 3.5 hours, the solid had dissolved and the temperature had risen to 70°. After cooling to room temperature, a Dry Ice/acetone bath was applied until the temperature of the reaction medium was −65°. The crystals which formed were collected by rapid filtration of the cold slurry through a sintered-glass filter under a nitrogen blanket. The solid was washed twice with 150-ml portions of cold diethyl ether and air-dried to give 7 g (70%) of 2,3-dichloro-5,6-dicyanopyrazine  301 , mp 180-182°. Crystallization of the product may be accomplished if dark, from ˜50 mL of chloroform with carbon treatment to give 5.5 g of purified product. 
     2-(2-Methoxyethylamino)-3-chloro-5,6-dicyanopyrazine  1401   
       FIG. 14  shows the reaction pathway. A solution of 5.00 g (25.1 mmoles) of 2,3-dichloro-5,6-dicyanopyrazine  301  in 40 mL of anhydrous tetrahydrofuran was cooled to between −15° and −20° [bath temperature] in a Dry Ice/acetone bath and a solution of 3.95 g (52.6 mmoles) of 2-methoxyethylamine  701  in 30 mL of anhydrous tetrahydrofuran  702  was added drop-wise, with good magnetic stirring over a period of about 30 minutes. After warming to ˜5° for an additional 15 minutes, the still cold reaction mixture was poured, with good agitation, into 400 mL of ice/water mix having ˜5 mL of 10% HCl added, producing an oil which rapidly crystallized to a yellow solid. The solid was filtered, washed well with water and air-dried to give 4.1 g of yellow solid 2-(2-methoxyethylamino)-3-chloro-5,6-dicyanopyrazine  1401 , mp 111°.-113°. The product was purified by crystallization from ethyl acetate/hexane to give the purified product as pale yellow crystals, mp 113°-114°. Exact mass 237.1 [calc 237.04] TLC or column chromatography in ethyl acetate on silica plates shows an intense blue fluorescent spot at Rf ˜0.65; a trace of the double addition 2,3-bis(2-methoxyethylamino)-5,6-dicyanopyrazine can often be seen at Rf ˜0.45. This same process may also be used with 2-(2-methoxyethoxy)ethylamine to afford the more extended derivative. 
     5,10-bis(2-methoxyethyl)-5,10-dihydrodipyrazino[2,3-b:2′,3′-e]pyrazine-2,3,7,8-tetracarbonitrile  101  (also known as bis(2-methoxyethyl)-2,3,6,7-tetracyano-1,4,5,8,9,10-hexazaanthracene) 
       FIG. 15  shows the reaction pathway. In a 100 mL round-bottom flask with 14/20 glass joint and attached to an air-condenser having a magnetic stir-bar was add 4.8 g [0.02 mole] of 2(2-methoxyethylamino)-3-chloro-5,6-dicyanopyrazine  1401  and 25 mL of diglyme  901  [diethyleneglycol dimethylether]. The reaction was stirred for about an hour until all the solid had dissolved. To this solution was added 6.2 g of diisopropylethylamine  902  drop-wise with stirring. The reaction was then brought to reflux using a sand-bath at ˜180° Celsius. All under a nitrogen sweep. The solution acquired an orange yellow color as heating took place. Reaction was monitored by TLC or column chromatography [silica plates] using ethyl acetate; the bright blue fluorescent starting material spot at Rf: 0.65 slowly faded and was converted to a bright yellow spot at Rf: 0.98. After 5 hours the starting material spot had disappeared and the new yellow spot at solvent front in TLC or column chromatography predominated. Solution cooled to rt and poured, with good stirring into 400 mL of water/ice mixture having ˜5 mL of 10% HCl. Brown-yellow mixture was allowed to stand ˜24 hrs and filtered by suction and washed with water. Material was dried in vac. drying oven at 70°. There was obtained 4.1 g of yellow brown powder. Exact mass 402.2 [calc 402.13]. 
     2,3-bis(2-Methoxyethylamino)-5,6-dicyanopyrazine  1101   
       FIG. 16  shows the reaction pathway. A solution of 5.00 g (25.1 mmoles) of 2,3-dichloro-5,6-dicyanopyrazine  301  in 40 mL of anhydrous tetrahydrofuran  702  was cooled to between −15° and −20° [bath temperature] in a Dry Ice/acetone bath and a solution of 8 g (104 mmoles) of 2-methoxyethylamine  701  in 30 mL of anhydrous tetrahydrofuran  702  was added drop-wise, with good magnetic stirring over a period of about 30 minutes. After warming to ˜5° for an additional 15 minutes, the still cold reaction mixture was poured, with good agitation, into 500 mL of ice/water mix having ˜5 mL of 10% HCl added, producing an oil which rapidly crystallized to a yellow solid. The solid was filtered, washed well with water and air-dried to give 4.7 g of pale yellow solid 2,3-bis(2-methoxyethylamino)-5,6-dicyanopyrazine  1101 . Rf: 0.45 in ethyl acetate on silica plates. 
     The amount of primary amine can be reduced by half by substituting another amine such as diisopropylethylamine to react with the HCl generated during the reaction. Thus, instead of 8 g of 2-methoxyethylamine  701 , one can use 4 g of 2-methoxyethylamine  701  and 5 g diisopropylethylamine mixture in 30 mL THF  702 . 
     5,10-bis(2-methoxyethyl)-5,10-dihydrodipyrazino[2,3-b:2′,3′-e]pyrazine-2,3,7,8-tetracarbonitrile  101   
       FIG. 17  shows the reaction pathway. In a 100 mL round-bottom flask having a magnetic stir-bar and with 14/20 glass joint attached to an air-condenser was add 0.48 g [0.002 mole] of 2,3-bis(2-methoxyethylamino)-5,6-dicyanopyrazine  1101 , 2,3-dichloro-5,6-dicyanopyrazine  301  and 5 mL of diglyme  901  [diethyleneglycoldimethylether]. The reaction was stirred for about an hour until all the solids had dissolved. To this solution was added 0.6 g of diisopropylethylamine  902  drop-wise with stirring. The reaction was then brought to reflux using a sand-bath at ˜180°. All under a nitrogen sweep. The solution acquired a dark gray orange color as heating took place. Reaction was monitored by TLC or column chromatography [silica plates] using ethyl acetate; the bright blue fluorescent starting material spot at Rf: 0.45 slowly faded and was converted to a bright yellow spot at Rf: 0.98 identical to the material formed from dimerization. After 5 hours the starting material spot remained though the yellow spot corresponding to the expected product at solvent front in TLC or column chromatography was present. Solution cooled to rt and poured, with good stirring into 40 mL of water/ice mixture having ˜0.5 mL of 10% HCl. Dark mixture was allowed to stand ˜24 hrs and filtered by suction and washed with water. Material was dried in vac. drying oven at 70°. There was obtained 0.6 g of yellow brown powder having both starting material and desired tetracyanodipyrazinepyrazine. Exact mass 402.2 [calc 402.13]. 
     2-(2-Methoxyethoxy)ethyl ammonium tosylate salt  1001  and 2-(2-Methoxyethoxy)ethyl p-toluenesulfonate  1002   
       FIG. 18  shows the reaction pathway. In a 500 mL Erlenmeyer flask 38 g of p-toluenesulfonyl chloride  1801  was dissolved in 90 mL of dichloromethane  1802  with stirring using a magnetic stirrer. To this solution was added 24 g of 2-(2-methoxyethoxy)ethanol  1803 . The solution was cooled in an ice/water mixture and to this clear, cold, slightly yellow solution was added, with good stirring 20.4 g of triethylamine  1804 , drop-wise by pipette. The amine  1804  was added over ˜20 min. At the end of the addition, crystals of triethylamine hydrochloride had started to deposit from the solution. Reaction was allowed to stir over night. The reaction solution was then poured into ˜200 mL of ice/water containing 10 mL of concentrated hydrochloric acid. The mixtures was stirred well, and the organic layer removed by separatory funnel. The aqueous layer was extracted with another 40 mL of dichloromethane  1802  and added to the previous. The combined organic layers were washed with saturated salt solution and dried over anhydrous sodium sulfate. After decanting from Na 2 SO 4  and roto-evaporation, there was obtained 50.4 g of pale, tan oil. Upon several cooling, warming sequences in a dry-ice/acetone bath while under vacuum, the oil crystallized. The tosylate is a solid at 0° but melts to a syrup at room-temperature. Yield 50.4 g [theory 54 g]. 
     2-(2-Methoxyethoxy)ethyl ammonium tosylate salt 
     The whole of the 2-(2-methoxyethoxy)ethyl tosylate  1805  [50 g] was dissolved in 100 mL of methanol  1806  and this solution was added with good stirring to 300 mL of concentrated aqueous ammonia  1807  in a 500 mL Erlenmeyer flask. After about ⅔ of the addition, incremental amounts of methanol were required to maintain a clear solution as the methanol/tosylate solution was added. Total volume at the end of the addition was ˜500 mL. The reaction flask was covered and allowed to stir for ˜4 days. From the beginning of the addition of the tosylate to the ammonia solution, a distinct yellow hue was observed. As the reaction proceeded, this color faded. At the end of the reaction period the clear solution was transferred to a beaker and allowed to stand in the hood to allow ammonia and methanol to evaporate for ˜24 hrs. The remaining water/methanol/ammonia was then removed through roto-evaporation and the residual syrup taken up in tetrahydrofuran and the THF/water azeotrope removed successively. Finally the syrup was taken up in THF and filtered from the crystalline residual ammonium tosylate salt [˜5 g]. Evaporation of the THF on roto-evaporator yielded 48 g of light tan syrup: 2-(2-methoxyethoxy)ethyl ammonium tosylate salt. Mass Spectral data for both negative  1002  and positive ions  1001  were observed at 171 and 131 respectively. 
     All patents and publications mentioned in the prior art are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference, to the extent that they do not conflict with this disclosure. 
     While the present invention has been described with reference to exemplary embodiments, it will be readily apparent to those skilled in the art that the invention is not limited to the disclosed or illustrated embodiments but, on the contrary, is intended to cover numerous other modifications, substitutions, variations, and broad equivalent arrangements. o-3-chloropyrazine used in the next step.

Technology Category: c