Patent Application: US-60649906-A

Abstract:
metal - catalyzed coupling process comprising reacting a compound of general formula 1 with a compound a - x , to obtain a compound of general formula 2 , which may further be converted to a compound of general formula 3

Description:
in fig2 are represented pyridine , pyridazine , pyrimidine and pyrazine n - oxides ( 6 , 6 ′, 50 , 60 , 70 , 80 ) that are used as replacements for organometallic reagents in coupling reactions , in particular in the preparation of biaryl compounds . fig3 to 11 illustrate aspects of the process according to the invention . reaction development was carried out with pyridine n - oxide and 4 - bromotoluene . palladium acetate in combination with tri - tert - butylphosphine ( added to the reaction mixture as the commercially available and air - stable hbf 4 salt ) was used as metal - ligand combination . potassium carbonate was used as base , and toluene was used as solvent . other suitable solvents include dioxane , mesitylene , n , n - dimethylacetamide , tetrahydrofuran , dichloromethane and ether . the reactions were run under quite concentrated conditions ( 0 . 3 m ), with 2 - 4 equiv of pyridine n - oxide . under these conditions ( 4 - bromotoluene , 2 - 4 equiv of pyridine n - oxide , 5 mol % of pd —( oac ) 2 , 15 mol % of pt - bu 3 . hbf 4 , 2 equiv of k 2 co 3 in toluene at 110 ° c . ), 2 - tolylpyridine n - oxide was obtained in 91 % isolated yield exclusively as one regloisomer ( table 1 , entry 1 ). while 4 equiv of the n - oxide are not required , under these conditions , a decrease to 1 equiv leads to diminished yields ( entries 2 - 8 ). when 1 equiv of pyridine n - oxide was used , greater than 95 % of the unreacted n - oxide was recovered by silica gel chromatography , which demonstrates that oxide decomposition does not occur . illustrative examples of the reaction scope are outlined in table 1 . preferably , uncontrolled heating of the reaction media should be avoided , since it is known in the art that pyridine n - oxides exothermically decompose at very high temperature . 17 a wide variety of compounds bearing various substituent types and at various positions can be used in the coupling process according to the invention . both electron - rich ( table 1 , entries 6 - 8 and 11 ) and electron - poor ( table 1 , entries 12 and 13 ) aryl bromides can be used , so as more sterically encumbered ortho - substituted arenes ( table 1 , entries 9 and 10 ). the effect of substitution on the pyridine n - oxide has also been examined . the presence of both electron - donating and - withdrawing groups is tolerated , as exemplified by the successful coupling of both 4 - methoxy and 4 - nitropyridine n - oxide ( table 1 , entries 14 and 15 ). in contrast to reactions performed with many types of organometallics , these reactions are completely insensitive to the presence of water , since 5 equiv of water added at the reaction outset has no deleterious effect on the reaction outcome . the 2 - arylpyridine n - oxide products can easily be converted to the corresponding 2 - aryl pyridines under mild conditions and in high yield via palladium - catalyzed reduction with ammonium formate ( table 2 ). 18a similar yields were obtained using zinc - mediated reduction known in the art . 18b it can be seen that palladium - catalyzed regioselective direct arylation of pyridine n - oxides occurs in high yield with a wide range of aryl bromides . the resulting 2 - arylpyridine n - oxides can be easily reduced to the free pyridine via palladium - catalyzed hydrogenolysis . given the low cost associated with the production of pyridine n - oxides , also given the fact that pyridine n - oxides can be readily available , the coupling process according to the invention should provide a useful alternative to the problematic use of 2 - pyridyl organometallics in the preparation of 2 - arylpyridine n - oxides . recently , the potential of direct arylation as a more efficient alternative to standard cross - couplings has been recognized in the art . 19 direct arylation of n - oxides can be performed thus avoiding the use of unstable / unreactive organometallics in cross - coupling reactions . 20 in the context of this strategy , diazine n - oxides are more challenging than simple pyridine n - oxides since they possess a free nitrogen atom that could bind and poison the catalyst . they are also more n - electron - deficient and less nucleophilic than pyridine n - oxides . according to an aspect of the invention , conditions that enable the use of readily available , bench - stable diazine n - oxides have been established . the diazine n - oxides according to the invention are cost efficient and constitute high yielding reagents in metal - catalyzed coupling reactions . high yielding oxidation of the corresponding free diazine could be achieved by reaction with mcpba . the n - oxides used in this study are bench stable and show no signs of decomposition after storage in vials at room temperature for several months . to overcome catalyst poisoning associated with some n - oxide substrates , a benefical effect of metal salts including copper ( i ) salts was uncovered . the diazine n - oxide functionality can be easily removed after coupling or can be further converted into a wide range of other functional groups . these new reactions can be performed with aryl iodides , bromides and chlorides and include the first examples of n - oxide arylation with equimolar ratios of the two coupling partners that occur in high yield . furthermore , the relative reactivities and regioselectivities point to c — h acidity as a critical factor in reactivity , encouraging consideration of this property in the design of other novel direct arylation processes . initial reaction screens with n - oxides 60 , 70 and 80 under previously described conditions lead to disappointing results , probably due to the fact that the n - oxides were only sparingly soluble in toluene . the reaction conditions were reinvestigated . these efforts lead to the discovery that dioxane provides superior conversions with n - oxides 60 and 80 giving the cross coupled products 81 and 82 in 75 % and 72 % yields respectively ( table 3 , entries 1 and 2 ). these two substrates actually exhibit superior reactivity compared to pyridine n - oxide as demonstrated by a competition experiment between 80 and pyridine n - oxide which results in exclusive arylation of 60 ( table 3 , entry 4 ). in contrast to the excellent results obtained with 60 and 80 , pyrimidine n - oxide 70 reacts in low yield ( table 3 , entry 3 ). conditions : the n - oxide ( 2 equiv . ), aryl halide , pd ( oac ) 2 ( 5 mol %), pt - bu 3 - hbf 4 ( 15 mol %), k 2 co 3 ( 2 equiv .) and the additive ( if indicated , 2 equiv .) were added to a round bottom flask followed by the addition of dioxane and heating to 110 ° c . further investigations revealed that the poor outcomes associated with 70 are not due to low reactivity alone . for example , the addition of pyrimidine n - oxide 70 to a reaction with pyrazine n - oxide 80 results in the exclusive formation of 81 but in a significantly lower yield compared to a reaction performed in the absence of 70 , 9 % vs . 75 % yield ( table 3 , entry 5 vs . 1 ). why catalyst inhibition occurs with 70 and not with 60 or 80 is a focus of ongoing study . it is noteworthy that resonance contributions for 70 induce different properties compared to those of 60 and 80 . for example , distribution of the positive charge within the ring places a positive charge on the free nitrogen of 60 and 80 but not on 70 . this may result in a diminished capacity to bind to palladium and explain the experimental observations . on the other hand , mesomeric resonance forms where electrons are pushed from the oxyanion into the ring put negative charges on the free nitrogen of 60 and 80 but not on 70 . this should produce a trend opposite to that predicted above and to that obtain experimentally . we note that neither pyridine n - oxide nor pyridine poison the reaction of 80 ( table 3 , entries 4 and 6 ) indicating that these deleterious effects are special to the pyrimidine n - oxide motif . other poisoning studies where the positions adjacent to the n - oxide functional group of pyrimidine n - oxide were blocked with aryl groups also resulted in catalyst inhibition indicating that an interaction with either of these positions may not be responsible for the poor reaction of 70 . to overcome catalyst inhibition , a variety of additives were investigated including phosphines , halides and metals . copper ( i ) salts such as cucl , cubr and cucn were used . for reasons of ease of handling , cucn was selected for further optimization and it was determined that the addition of 10 mol % cucn to the new arylation conditions generates 83 in 61 % isolated yield as one regioisomer . use of cucn may result in the in situ formation of a more nucleophilic heteroarylcopper species or reversibly bind the free nitrogen atom . the scope of these transformations with respect to the aryl halide was evaluated with pyrazine n - oxide 80 ( table 4 ). high yielding arylations can be obtained not only with aryl bromides , but also with aryl iodides ( table 4 , entries 17 and 18 ) even aryl chlorides ( table 4 , entries 13 to 16 ). with aryl iodides , ag 2 co 3 is optionally employed as an additive . a variety of substituents are tolerated on the aryl halide including electron - donating ( table 4 , entries 3 , 6 and 7 ) and electron - withdrawing groups ( table 4 , entries 4 , 8 - 10 and 16 ). more sterically encumbered aryl halides may also be employed ( table 4 , entries 2 , 5 , 9 , 10 , 13 and 14 ). if an excess of aryl halide is used compared to the pyrazine n - oxide , the product of double direct arylation can be obtained in 50 % isolated yield ( table 4 , entry 11 ). the scope of diazine n - oxide substrates was also evaluated ( table 5 ). quinoxaline n - oxide 90 is an excellent substrate in these reactions allowing an equimolar ratio of the n - oxide and aryl halide to be used for the first time ( table 5 , entries 1 to 7 ). more sterically encumbered alkyl substituted pyrazine n - oxides may also be reacted in synthetically useful yields ( table 5 , entries 8 to 11 ). different aryl halides were also examined in reactions with both pyridazine n - oxide 60 ( table 5 , entries 12 to 15 ) and pyridimine n - oxide 70 ( table 5 , entries 16 to 19 ). with 70 , 10 mol % cucn can be added to the reaction to help achieve the cross - coupling . in each case useful yields of the cross - coupled product are obtained . if desired , direct arylation products can be easily deoxygenated ( table 6 ). with pyrazine n - oxides , treatment with ammonium formate and palladium / carbon in methanol at room temperature gives the corresponding free base in excellent yields ( table 6 , method a , entries 1 to 5 ). this protocol may be incompatible with pyridazine n - oxides , however ( table 6 , entry 6 ). an extensive survey of reductive methods for n - oxide lead to the discovery that high yields can be obtained with catalytic pd / c in ammonium hydroxide under a hydrogen atmosphere ( table 6 , method b , entries 7 to 9 ). pyrimidine n - oxide direct arylation products may also be deoxygenated by this second protocol in high yield ( table 6 , entry 10 ). n - oxides are key intermediates in many processes that introduce functionality adjacent to the nitrogen atom as illustrated in fig1 . for example , a new carbon - oxygen bond adjacent to the nitrogen atom may be formed by reaction with acetic anhydride and heating to give 101 . 21 a second direct arylation can also add a second aromatic group as in the formation of 102 . alternatively , the n - oxide may be converted to chloropyrazine 103 by reaction with pocl 3 22 and subsequently used in a wide range of palladium - catalyzed cross - coupling reactions . to illustrate this possibility , a buchwald - hartwig amination was performed , giving 104 in 70 % yield . 23 chloride 103 may also be treated with alkoxides to give compounds such as 105 in good yield . the diazine n - oxide ring may also be reduced to arylpiperazine 106 in 68 % yield by treatment with pto 2 and h 2 . in conclusion , diazine n - oxides are convenient , inexpensive , and readily available replacements for problematic diazine organometallics in palladium - catalyzed coupling reactions . to achieve this reactivity , a variety of metal salts including copper salts may be used and the products can be further converted into a wide range of substituted nitrogen heterocycles by taking advantage of the n - oxide functionality . this chemistry should be of considerable use in the synthesis of these medicinally or industrially important compounds . all experiments were carried out under an atmosphere of nitrogen . 1 h and 13 c nmr were recorded in cdcl 3 ( with me 4 si as an internal standard ) or ( cd 3 ) 2 co or ( cd 3 ) 2 so solutions using a bruker avance 300 or a bruker avance 400 or a varian 500 spectrometer . high - resolution mass spectra were obtained on a kratos concept iih . infra - red analysis was performed with a bruker equinox 55 . hplc analysis was performed on waters apparatus using photodiode array detector . hplc grade thf , et 2 o , benzene , toluene and ch 2 cl 2 are dried and purified via mbraun sp series solvent purification system . triethylamine was freshly distilled from naoh before every use . dimethyl - acetamide was degassed with n 2 before every use . palladium and copper complexes were stored in a dessicator and were weighed out to air unless otherwise specified . all other reagents and solvents were used without further purification from commercial sources . unless noted below , all other compounds have been reported in the literature or are commercially available . the appropriate diazine ( 1 equiv .) and mcpba ( 1 equiv .) were dissolved in dcm ( 0 . 2 m ). the reaction was allowed to stir for 16 hours . pph 3 ( 0 . 5 equiv .) was then added to reduce any unreacted peracid and the mixture was stirred for an additional 4 h . the volatiles were evaporated under reduce pressure and the residue was purified via silica gel column chromatography . general procedure 2 : palladium - catalyzed direct arylation with aryl chlorides and bromides . to a dried flask was added the diazine n - oxide ( 1 . 0 to 3 . 0 equiv . ), k 2 co 3 ( 2 . 0 equiv . ), pd ( oac ) 2 ( 5 mol %) and hp ( t - bu ) 3 bf 4 ( 15 mol %). if the arylhalide is a solid , it is added at this point ( 1 . 0 equiv .). the flask and its contents were then purged under nitrogen for 10 minutes . if the aryl halide is a liquid , it is added via syringe after purging , followed by the addition of degassed dioxane ( to produce a reaction concentration of 0 . 3 m relative to the halide ). the reaction mixture was then heated at 110 ° c . until the reaction was complete , after which the volatiles were removed under reduced pressure and the residue was purified via silica gel column chromatography . to a dried flask was added the diazine n - oxide ( 1 . 0 to 3 . 0 equiv . ), k 2 co 3 ( 2 . 0 equiv . ), pd ( oac ) 2 ( 5 mol %), hp ( t - bu ) 3 bf 4 ( 15 mol %) and ag 2 co 3 ( 0 . 5 eq .). if the arylhalide is a solid , it is added at this point ( 1 . 0 equiv .). the flask and its contents were then purged under nitrogen for 10 minutes . if the aryl halide is a liquid , it is added via syringe after purging , followed by the addition of degassed dioxane ( to produce a reaction concentration of 0 . 3 m relative to the halide ). the reaction mixture was then heated at 110 ° c . until the reaction was complete , after which the volatiles were removed under reduced pressure and the residue was purified via silica gel column chromatography . to a dried flask was added the diazine n - oxide ( 1 . 0 to 3 . 0 equiv . ), k 2 co 3 ( 2 . 0 equiv . ), pd ( oac ) 2 ( 5 mol %), hp ( t - bu ) 3 bf 4 ( 15 mol %) cucn ( 10 mol %). if the arylhalide is a solid , it is added at this point ( 1 . 0 equiv .). the flask and its contents were then purged under nitrogen for 10 minutes . if the aryl halide is a liquid , it is added via syringe after purging , followed by the addition of degassed dioxane ( to produce a reaction concentration of 0 . 3 m relative to the halide ). the reaction mixture was then heated at 110 ° c . until the reaction was complete , after which the volatiles were removed under reduced pressure and the residue was purified via silica gel column chromatography . ammonium formate (˜ 10 equiv .) or h 2 was added to a stirring methanol ( 0 . 3m ) solution of the n - oxide ( 1 . 0 eq .) and pd / c ( 0 . 1 eq .) in a round bottom flask . when the reaction was deemed complete by tlc analysis , the reaction was filtered through celite and evaporated under reduced pressure . the residue was then purified via silica gel chromatography . a solution of n - oxide ( 1 . 0 eq . ), pd / c ( 0 . 1 eq .) in nh 4 oh ( 0 . 2m ) was reacted under an atmosphere of h 2 in a round bottom flask . when the reaction was deemed complete by tlc analysis , the reaction was filtered through celite and evaporated under reduced pressure . the residue was then purified via silica gel chromatography . synthesized according to general procedure 1 . purification via silica gel column chromatography using 100 % etoac then a mixture of 20 % meoh / etoac gave a white solid ( 88 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 50 ( 2h , d , j = 3 . 9 hz ), 8 . 14 ( 2 h , d , j = 4 . 8 hz ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 147 . 8 , 134 . 0 . hrms calculated for c 4 h 4 n 2 o 1 ( m +) 96 . 0324 ; found : 96 . 0295 . ir ( v max / cm − 1 ): 3120 , 3088 , 1595 , 861 , 847 , 838 . synthesized according to general procedure 1 . purification via silica gel column chromatography using 100 % etoac gave a yellow solid ( 70 %). spectral data is identical to previous reports . 24 synthesized according to general procedure 1 . purification via silica gel column chromatography using 100 % etoac then a mixture of 10 % meoh / etoac gave a white solid ( 88 %). spectral data is identical to previous reports 25 . synthesized according to general procedure 1 . purification via silica gel column chromatography using 100 % etoac then a mixture of 5 % meoh / etoac gave a white solid ( 77 %). 1 h nmr ( 500 mhz , cdcl 3 , 293k , tms ): δ 8 . 26 ( 1h , d , j = 3 . 5 hz ), 8 . 03 ( 1h , d , j = 4 hz ), 2 . 93 ( 4h , dt , j = 6 and 19 hz ), 1 . 93 - 1 . 89 ( 4h , m ). 13 c nmr ( 125 mhz , cdcl 3 , 293k , tms ): 157 . 3 , 143 . 5 , 143 . 2 , 131 . 2 , 31 . 7 , 23 . 5 , 21 . 6 , 21 . 2 . hrms calculated for c 8 h 10 n 2 o 1 ( m +) 150 . 0793 ; found : 150 . 0789 . ir ( v max / cm − 1 ): 3114 , 2939 , 2879 , 1584 , 1453 , 1296 , 975 , 830 . synthesized according to general procedure 1 . purification via silica gel column chromatography using 100 % etoac then a mixture of 20 % meoh / etoac gave a brownish oil ( quant .). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 59 ( 1h , s ), 8 . 33 ( 1h , d , j = 6 . 6 hz ), 7 . 92 - 7 . 87 ( 1h , m ), 7 . 29 ( 1h , dd , j = 5 . 7 and 6 . 6 hz ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 149 . 8 , 133 . 9 , 133 . 6 , 115 . 9 . hrms calculated for c 4 h 4 n 2 o 1 ( m +) 96 . 0324 ; found : 96 . 0318 . ir ( v max / cm − 1 ): 3109 , 1583 , 1416 , 982 , 847 . synthesized according to general procedure 1 . purification via silica gel column chromatography using 100 % etoac then a mixture of 15 % meoh / etoac gave a white solid ( 92 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 9 . 03 ( 1h , s ), 8 . 47 ( 1h , d , j = 6 . 6 hz ), 8 . 30 ( 1 h , d , j = 4 . 2 hz ), 7 . 39 ( 1h , t , j = 5 . 4 hz ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 149 . 6 , 144 . 1 , 143 . 5 , 121 . 0 . hrms calculated for c 4 h 4 n 2 o 1 ( m +) 96 . 0324 ; found : 96 . 0304 . ir ( v max / cm − 1 ): 3083 , 1653 , 1541 , 1414 , 1251 , 843 . to a dried flask was added the 2 - chloropyrimidine ( 0 . 50 g , 4 . 37 mmol ), phenyl - boronic acid ( 0 . 69 g , 5 . 68 mmol ), na 2 co 3 ( 0 . 92 g , 8 . 70 mmol ), pdcl 2 ( 38 . 7 mg , 0 . 22 mmol ) and dppb ( 92 . 9 mg , 0 . 22 mmol ). the mixture was then purged under nitrogen for 10 minutes , followed by the addition of a degassed mixture of toluene ( 12 ml ), water ( 6 ml ), ethanol ( 2 ml ). the reaction mixture was allowed to stir at 100 ° c . after 20 h , the mixture was filtered on a celite pad , then the volatiles were removed under reduced pressure . purification via silica gel column chromatography using a mixture of 10 % et 2 o / dcm gave a white solid ( 65 %). spectral data is identical to previous reports . 26 synthesized according to general procedure 1 . purification via silica gel column chromatography using 100 % etoac then a mixture of 10 % meoh / etoac gave a beige solide . 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 50 - 8 . 45 ( 3h , m ), 8 . 32 ( 1h , dd , j = 1 . 2 and 3 . 0 hz ), 7 . 51 - 7 . 49 ( 3h , m ), 7 . 18 ( 1h , dd , j = 3 . 0 and 4 . 5 hz ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 156 . 4 , 146 . 6 , 143 . 5 , 131 . 3 , 131 . 1 , 129 . 7 , 127 . 9 , 119 . 2 . hrms calculated for c 10 h 8 n 2 o ( m +) 172 . 0637 ; found : 172 . 0647 . ir ( v max / cm − 1 ): 3097 , 2933 , 1534 , 1400 , 1249 , 722 . synthesized according to general procedure 2 employing the corresponding aryl bromide and chloride or 60 with the corresponding aryl iodide . purification via silica gel column chromatography using 100 % dcm then a mixture of 20 % acetone / dcm gave a white solid , 72 % ( from the bromide ), 75 % ( from the chloride ) and 77 % ( from the iodide ). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 63 ( 1h , s ), 8 . 37 ( 1h , s ), 8 . 20 ( 1h , s ), 7 . 72 ( 2h , d , j = 8 . 1 hz ), 7 . 33 ( 2h , d , j = 7 . 8 hz ), 2 . 43 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 148 . 2 , 145 . 2 , 144 . 6 , 140 . 8 , 134 . 2 , 129 . 8 , 129 . 0 , 125 . 9 , 21 . 5 . hrms calculated for c 11 h 10 n 2 o 1 ( m +) 186 . 0793 ; found : 186 . 0790 . ir ( v max / cm − 1 ): 3110 , 3038 , 2925 , 2850 , 1590 , 1301 , 869 , 821 . synthesized according to general procedure 2 employing the corresponding aryl bromide and chloride . purification via silica gel column chromatography using 100 % dcm then a mixture of 10 % acetone / dcm gave a brown oil , 89 % from the bromide and 60 % from the chloride . 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 61 ( 1h , s ), 8 . 48 ( 1h , d , j = 3 . 9 hz ), 8 . 26 ( 1h , d , j = 4 . 2 hz ), 8 . 00 ( 1h , d , j = 7 . 8 hz ), 7 . 93 - 7 . 87 ( 1h , m ), 7 . 59 - 7 . 37 ( 5h , m ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 150 . 1 , 147 . 1 , 145 . 7 , 134 . 8 , 133 . 9 , 131 . 5 , 131 . 3 , 129 . 2 , 128 . 9 , 127 . 6 , 127 . 0 , 125 . 7 , 125 . 3 . hrms calculated for c 14 h 10 n 2 o 1 ( m +) 222 . 0793 ; found : 222 . 0775 . ir ( v max / cm − 1 ): 3057 , 3010 , 2923 , 2853 , 1578 , 1301 , 873 , 801 , 776 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 15 % acetone / dcm gave a beige solid ( 82 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 62 ( 1h , s ), 8 . 32 ( 1h , s ), 8 . 18 ( 1h , s ), 7 . 82 ( 2h , d , j = 8 . 4 hz ), 7 . 04 ( 2h , d , j = 8 . 7 hz ), 3 . 87 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 161 . 0 , 147 . 9 , 144 . 7 , 144 . 1 , 134 . 3 , 130 . 6 , 120 . 9 , 113 . 9 , 55 . 3 . hrms calculated for c 11 h 10 n 2 o 2 ( m +) 202 . 0742 ; found : 202 . 0755 . ir ( v max / cm − 1 ): 3164 , 3082 , 2965 , 2840 , 1456 , 1294 , 861 , 838 , 820 , 803 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 15 % acetone / dcm gave a white solid ( 53 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 66 ( 1h , s ), 8 . 48 ( 1h , d , j = 3 . 9 hz ), 8 . 24 ( 1h , d , j = 4 . 2 hz ), 7 . 97 ( 2h , d , j = 8 . 1 hz ), 7 . 82 ( 2h , d , j = 8 . 1 hz ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 148 . 1 , 146 . 6 , 142 . 8 , 134 . 5 , 133 . 2 , 132 . 2 , 129 . 8 , 118 . 0 , 113 . 9 . hrms calculated for c 11 h 7 n 3 o 1 ( m +) 197 . 0589 ; found : 197 . 0565 . ir ( v max / cm − 1 ): 3098 , 3067 , 3046 , 2240 , 1589 , 1389 , 870 , 836 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 15 % acetone / dcm gave a beige solid 70 % yield with 2 eq . of the n - oxide and 76 % yield with 3 eq . of the n - oxide . 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 45 ( 1h , d , j = 3 . 9 hz ) 8 . 42 ( 1h , s ), 8 . 26 ( 1h , d , j = 4 . 2 hz ), 7 . 00 ( 2h , s ), 2 . 34 ( 3h , s ), 2 . 07 ( 6h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 149 . 4 , 146 . 2 , 145 . 3 , 140 . 0 , 137 . 2 , 134 . 3 , 128 . 5 , 125 . 7 , 21 . 1 , 19 . 4 . hrms calculated for c 13 h 14 n 2 o 1 ( m +) 214 . 1106 ; found : 214 . 1091 . ir ( v max / cm − 1 ): 3106 , 2971 , 2913 , 2855 , 1582 , 1389 , 1007 , 862 , 843 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 15 % acetone / dcm gave a white solid , 72 % with 2 eq . of the n - oxide and 84 % yield with 3 eq . of the n - oxide ). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 63 ( 1h , s ), 8 . 38 ( 1h , d , j = 3 . 9 hz ), 8 . 20 ( 1h , d , j = 4 . 2 hz ), 7 . 46 - 7 . 29 ( 3h , m ), 7 . 05 ( 1h , dd , j = 1 . 8 and 8 . 4 hz ), 3 . 85 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 159 . 4 , 148 . 3 , 145 . 5 , 144 . 3 , 134 . 4 , 130 . 0 , 129 . 6 , 121 . 3 , 116 . 2 , 114 . 4 , 55 . 3 . hrms calculated for c 11 h 10 n 2 o 2 ( m +) 202 . 0742 ; found : 202 . 0770 . ir ( v max / cm − 1 ): 3117 , 3011 , 2976 , 2930 , 2843 , 1591 , 1302 , 886 , 858 , 848 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 10 % acetone / dcm , then a mixture of 15 % acetone / dcm gave a white solid ( 70 %). 1 h nmr ( 400 mhz , cdcl 3 , 293k , tms ): δ 8 . 62 ( 1h , s ), 8 . 39 ( 1h , d , j = 3 . 0 hz ), 8 . 21 ( 1h , d , j = 3 . 0 hz ), 7 . 84 ( 2h , dd , j = 4 . 2 and 6 . 0 hz ), 7 . 22 ( 2h , t , j = 6 . 3 hz ). 13 c nmr ( 100 mhz , cdcl 3 , 293k , tms ): 163 . 7 ( d , j = 250 . 1 hz ), 148 . 1 , 145 . 6 , 143 . 6 , 134 . 4 , 131 . 3 ( d , j = 8 . 6 hz ), 124 . 9 ( d , j = 3 . 5 hz ), 115 . 8 ( d , 21 . 8 hz ). hrms calculated for c 10 h 7 n 2 of ( m +) 190 . 0542 ; found : 190 . 0531 . ir ( v max / cm − 1 ): 3109 , 3073 , 3017 , 1584 , 1458 , 1297 , 832 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 5 % acetone / dcm , then a mixture of 10 % acetone / dcm gave a white solid , 50 % yield with 2 eq . of the n - oxide and 96 % yield with 4 eq . of the n - oxide . 1 h nmr ( 400 mhz , cdcl 3 , 293k , tms ): δ 8 . 49 ( 1h , s ), 8 . 46 ( 1h , d , j = 4 . 0 hz ), 8 . 22 ( 1h , d , j = 4 . 0 hz ), 7 . 27 - 7 . 22 ( 1h , m ), 7 . 08 - 7 . 00 ( 2h , m ), 2 . 23 ( 3h , s ). 13 c nmr ( 100 mhz , cdcl 3 , 293k , tms ): 163 . 7 ( d , j = 248 . 3 hz ), 149 . 0 , 146 . 4 , 145 . 4 , 141 . 5 ( d , j = 8 . 4 hz ), 134 . 1 , 131 . 6 ( d , j = 9 . 0 hz ), 125 . 0 ( d , j = 3 . 2 hz ), 117 . 3 ( d , j = 21 . 6 hz ), 113 . 1 ( d , j = 21 . 8 hz ), 19 . 5 ( d , j = 1 . 4 hz ) hrms calculated for c 11 h 9 n 2 of ( m +) 204 . 0699 ; found : 204 . 0755 . ir ( v max / cm − 1 ): 3083 , 3025 , 2925 , 1582 , 1455 , 1297 , 866 . synthesized according to general procedure 2 and using 0 . 3 eq . of pyrazine n - oxide . purification via silica gel column chromatography using 100 % dcm gave a beige solid ( 50 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 53 ( 2h , s ), 7 . 74 ( 4h , d , j = 8 . 1 hz ), 7 . 32 ( 4h , d , j = 7 . 8 hz ), 2 . 43 ( 6h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 145 . 9 , 144 . 6 , 140 . 4 , 129 . 3 , 129 . 1 , 126 . 5 , 21 . 4 . hrms calculated for c 18 h 16 n 2 o ( m +) 276 . 1263 ; found : 276 . 1279 . ir ( v max / cm − 1 ): 3026 , 2922 , 2862 , 1500 , 1297 , 865 , 826 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm , then a mixture of 10 % acetone / dcm gave a brownish solid , 32 % yield with 2 eq . of the n - oxide and 40 % yield with 3 eq . of the n - oxide ). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 82 ( 1h , s ), 8 . 31 - 8 . 22 ( 1h , m ), 8 . 14 - 8 . 11 ( 1h , m ), 7 . 72 ( 1h , d , j = 16 . 5 hz ), 7 . 62 ( 2h , dd , j = 3 . 0 and 7 . 8 hz ), 7 . 53 ( 1h , d , j = 16 . 5 hz ), 7 . 45 - 7 . 34 ( 3h , m ) 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 145 . 8 , 143 . 9 , 136 . 7 , 135 . 7 , 133 . 9 , 129 . 5 , 128 . 9 , 128 . 4 , 127 . 5 , 115 . 6 . hrms calculated for c 12 h 10 n 2 o ( m +) 198 . 0793 ; found : 198 . 0786 . ir ( v max / cm − 1 ): 3112 , 3061 , 3024 , 1589 , 1410 , 1273 , 981 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 10 % acetone / dcm gave a beige solid ( 82 %). 1 h nmr ( 300 mhz , dmso , 383k ): δ 8 . 77 ( 1h , s ), 8 . 50 ( 1h , d , j = 4 . 2 hz ), 8 . 38 ( 1h , d , j = 4 . 5 hz ), 8 . 08 ( 2h , d , j = 8 . 7 hz ), 8 . 01 ( 2h , d , j = 8 . 7 hz ), 3 . 92 ( 3h , s ). 13 c nmr ( 75 mhz , dmso , 383k ): 165 . 1 , 147 . 5 , 146 . 0 , 142 . 0 , 133 . 9 , 133 . 2 , 130 . 4 , 128 . 8 , 128 . 2 , 51 . 4 . hrms calculated for c 12 h 10 n 2 o 3 ( m +) 230 . 0691 ; found : 230 . 0686 . ir ( v max / cm − 1 ): 3074 , 2917 , 2854 , 1722 , 1384 , 1278 , 856 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 5 % acetone / dcm gave a yellow solid ( 68 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 89 ( 1h , s ), 8 . 69 - 8 . 65 ( 1h , m ), 8 . 13 - 8 . 10 ( 1h , m ), 7 . 91 ( 2h , d , j = 8 . 1 hz ), 7 . 81 - 7 . 73 ( 2h , m ), 7 . 37 ( 2h , d , j = 8 . 1 hz ), 2 . 44 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 147 . 3 , 144 . 2 , 140 . 6 , 139 . 2 , 137 . 3 , 130 . 9 , 130 . 3 , 129 . 8 , 129 . 3 , 129 . 2 , 126 . 9 , 119 . 2 , 21 . 5 . hrms calculated for c 15 h 12 n 2 o 1 ( m +) 236 . 0871 ; found : 236 . 0958 . ir ( v max / cm − 1 ): 3127 , 3034 , 2920 , 2856 , 1578 , 1488 , 1351 , 818 , 763 , 749 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm , then a mixture of 10 % acetone / dcm , then a mixture of 40 % acetone / dcm gave a white solid 50 % with 1 eq . of the n - oxide and 80 % yield with 2 eq . of the n - oxide ). 1 h nmr ( 300 mhz , dmso , 293k ): δ 9 . 18 ( 2h , d , j = 16 . 8 hz ), 8 . 72 ( 1h , s ), 8 . 55 - 8 . 47 ( 2h , m ), 8 . 17 ( 1h , d , j = 7 . 8 hz ), 8 . 00 - 7 . 78 ( 2h , m ), 7 . 62 ( 1h , m ). 13 c nmr ( 75 mhz , dmso , 293k ): 150 . 5 , 149 . 9 , 147 . 6 , 144 . 2 , 137 . 1 , 136 . 4 , 136 . 4 , 131 . 7 , 130 . 7 , 129 . 7 , 126 . 2 , 123 . 2 , 118 . 6 . hrms calculated for c 13 h 9 n 3 o 1 ( m +) 223 . 0746 ; found : 223 . 0726 . ir ( v max / cm − 1 ): 3103 , 3063 , 3025 , 2920 , 1491 , 1327 , 902 , 782 , 770 , 753 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm , then a mixture of 2 . 5 % acetone / dcm , then a mixture of 5 % acetone / dcm gave a beige solid ( 84 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 92 ( 1h , s ), 8 . 68 ( 1h , dd , j = 1 . 5 and 9 hz ), 8 . 23 ( 2h , d , j = 8 . 7 hz ), 8 . 16 ( 1h , d , j = 7 . 8 hz ), 8 . 08 ( 2h , d , j = 8 . 7 hz ), 7 . 82 ( 2 h , m ), 3 . 98 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k ): 166 . 3 , 147 . 0 , 144 . 7 , 138 . 4 , 137 . 4 , 134 . 2 , 131 . 5 , 131 . 4 , 130 . 7 , 130 . 1 , 129 . 7 , 129 . 4 , 119 . 3 , 52 . 4 . hrms calculated for c 16 h 12 n 2 o 3 ( m +) 280 . 0848 ; found : 280 . 0824 . ir ( v max / cm − 1 ): 3116 , 3061 , 2987 , 1715 , 1491 , 1349 , 901 , 766 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm , then a mixture of 2 % acetone / dcm gave a yellow solid ( 57 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 90 ( 1h , s ), 8 . 67 ( 1h , d , j = 7 . 8 hz ), 8 . 12 ( 1h , d , j = 7 . 5 hz ), 7 . 83 - 7 . 74 ( 2h , m ), 7 . 61 ( 1h , s ), 7 . 48 ( 1h , m ), 7 . 07 ( 1h , d , j = 6 . 3 hz ), 3 . 88 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 159 . 4 , 147 . 3 , 144 . 3 , 139 . 0 , 137 . 3 , 131 . 1 , 131 . 0 , 130 . 3 , 129 . 9 , 129 . 6 , 121 . 6 , 119 . 2 , 116 . 3 , 114 . 5 , 55 . 3 . hrms calculated for c 15 h 12 n 2 o 2 ( m +) 252 . 0899 ; found : 252 . 0911 . ir ( v max / cm − 1 ): 3066 , 3013 , 2970 , 2930 , 1491 , 1354 , 1033 , 760 , 755 . synthesized according to general procedure 3 . purification via silica gel column chromatography using 100 % dcm , then a mixture of 3 % acetone / dcm , then a mixture of 5 % acetone / dcm gave a yellow solid ( 70 %). 1 h nmr ( 300 mhz , dmso , 368 k ): δ 9 . 09 ( 1h , s ), 8 . 58 ( 1h , d , j = 8 . 7 hz ), 8 . 42 - 8 . 28 ( 4h , m ), 8 . 18 ( 1h , d , j = 9 hz ), 8 . 02 - 7 . 84 ( 2h , m ). 13 c nmr ( 75 mhz , dmso , 368k ): 149 . 1 , 148 . 3 , 145 . 5 , 138 . 0 , 137 . 8 , 137 . 2 , 132 . 8 , 131 . 8 , 131 . 6 , 130 . 7 , 124 . 1 , 119 . 7 . hrms calculated for c 14 h 9 n 3 o 3 ( m +) 267 . 0644 ; found : 267 . 0645 . ir ( v max / cm − 1 ): 3108 , 2955 , 2921 , 1519 , 1338 , 842 , 763 . synthesized according to general procedure 3 . purification via silica gel column chromatography using 100 % dcm , then a mixture of 3 % acetone / dcm gave a beige solid ( 84 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 90 ( 1h , s ), 8 . 69 ( 1h , d , j = 7 . 8 hz ), 8 . 13 ( 1h , d , j = 9 . 3 hz ), 7 . 99 ( 2h , d , j = 7 . 8 hz ), 7 . 79 ( 2h , m ), 7 . 62 - 7 . 48 ( 3h , m ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 147 . 4 , 144 . 4 , 139 . 2 , 137 . 3 , 131 . 1 , 130 . 4 , 130 . 2 , 129 . 9 , 129 . 8 , 129 . 3 , 128 . 6 , 119 . 3 . hrms calculated for c 14 h 10 n 2 o ( m +) 222 . 0793 ; found : 222 . 0791 . ir ( v max / cm − 1 ): 3049 , 3006 , 1485 , 1317 , 893 , 766 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 10 % acetone / dcm gave a white solid , 40 % yield with 0 . 5 eq . of the n - oxide , 18 % yield with 1 eq . of the n - oxide , 48 % yield with 2 eq . of the n - oxide and 56 % with 3 eq . of the n - oxide . 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 36 ( 1h , s ), 7 . 67 ( 1h , d , j = 3 . 9 hz ), 7 . 30 ( 1h , d , j = 4 . 2 hz ), 2 . 62 ( 3h , s ), 2 . 54 ( 3h , s ), 2 . 42 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 153 . 5 , 143 . 3 , 142 . 7 , 141 . 8 , 139 . 9 , 129 . 0 , 129 . 0 , 127 . 0 , 22 . 5 , 21 . 4 , 13 . 3 . hrms calculated for c 13 h 14 n 2 o 1 ( m +) 214 . 1106 ; found : 214 . 1117 . ir ( v max / cm − 1 ): 3028 , 2996 , 2918 , 1585 , 1464 , 1300 , 879 , 817 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm , then a mixture of 5 % acetone / dcm gave a white solid , 34 % yield with 1 eq . of the n - oxide , 52 % yield with 2 eq . of the n - oxide and 56 % yield with 3 eq . of the n - oxide . 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 41 ( 1h , s ), 7 . 68 ( 2h , d , j = 8 . 1 hz ), 7 . 30 ( 2h , d , j = 8 . 1 hz ), 3 . 03 - 2 . 90 ( 4 h . m ), 2 . 01 - 1 . 84 ( 4h , m ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 154 . 8 , 143 . 7 , 143 . 4 , 141 . 7 , 139 . 9 , 129 . 1 , 126 . 9 , 31 . 8 , 24 . 1 , 21 . 7 , 21 . 5 , 21 . 4 . hrms calculated for c 15 h 16 n 2 o 1 ( m +) 240 . 1263 ; found : 240 . 9852 . ir ( v max / cm − 1 ): 3031 , 2950 , 2871 , 1584 , 1459 , 1300 , 819 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 10 % acetone / dcm gave a brownish oil ( 72 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 48 ( 1h , d , j = 7 . 2 hz ), 7 . 63 ( 1h , dd , j = 2 . 4 and 6 hz ), 7 . 41 - 7 . 20 ( 4h , m ), 7 . 13 ( 1h , dd , j = 5 . 4 and 6 hz ), 2 . 23 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 149 . 6 , 145 . 7 , 137 . 6 , 135 . 4 , 131 . 6 , 130 . 2 , 129 . 8 , 129 . 1 , 125 . 9 , 115 . 7 , 19 . 2 . hrms calculated for c 11 h 10 n 2 o 1 ( m +) 186 . 0793 ; found : 186 . 0790 . ir ( v max / cm − 1 ): 3058 , 2955 , 2866 , 1539 , 1369 , 768 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 5 % acetone / dcm , then a mixture of 15 % acetone / dcm gave a brownish oil ( 74 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 54 - 8 . 44 ( 1h , m ), 7 . 64 ( 1h , dd , j = 2 . 4 and 9 . 0 hz ), 7 . 23 - 7 . 13 ( 2h , m ), 7 . 04 - 6 . 95 ( 2h , m ), 2 . 23 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 163 . 3 ( d , j = 247 . 7 hz ), 149 . 8 , 144 . 9 , 140 . 6 ( d , j = 8 . 5 hz ), 135 . 5 , 131 . 0 ( d , j = 9 hz ), 127 . 6 ( d , j = 3 . 2 hz ), 117 . 2 ( d , j = 21 . 6 hz ), 115 . 7 , 113 . 0 ( d , 21 . 8 hz ), 19 . 4 . hrms calculated for c 11 h 9 n 2 of ( m +) 204 . 0699 ; found : 204 . 0717 . ir ( v max / cm − 1 ): 3073 , 3033 , 2932 , 1572 , 1449 , 1303 , 871 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 100 % dcm then a mixture of 5 % acetone / dcm gave white solid ( 73 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 40 ( 1h , m ), 7 . 75 ( 1h , dd , j = 2 . 1 and 6 . 0 hz ), 7 . 71 ( 2h , d , j = 8 . 1 hz ), 7 . 28 ( 2h , d , j = 7 . 8 hz ), 7 . 13 ( 1h , dd , j = 5 . 1 and 6 . 0 hz ), 2 . 40 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 148 . 7 , 144 . 3 , 140 . 3 , 134 . 4 , 129 . 0 , 128 . 7 , 128 . 3 , 116 . 3 , 21 . 3 . hrms calculated for c 11 h 10 n 2 o ( m +) 186 . 0793 ; found : 186 . 0768 . ir ( v max / cm − 1 ): 3031 , 2918 , 1451 , 1359 , 1291 , 828 , 783 . synthesized according to general procedure 3 . purification via silica gel column chromatography using 100 % dcm then a mixture of 10 % acetone / dcm gave a white solid ( 91 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 47 - 8 . 38 ( 1h , m ), 7 . 86 - 7 . 74 ( 3h , m ), 7 . 50 - 7 . 43 ( 3h , m ), 7 . 15 ( 1h , dd , j = 5 . 1 and 9 hz ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 149 . 1 , 144 . 3 , 134 . 6 , 131 . 3 , 130 . 0 , 128 . 8 , 128 . 4 , 116 . 3 . hrms calculated for c 10 h 8 n 2 o ( m +) 172 . 0637 ; found : 172 . 0612 . ir ( v max / cm − 1 ): 3078 , 2920 , 1542 , 1375 , 871 , 685 . synthesized according to general procedure 4 . purification via silica gel column chromatography using 100 % dcm then a mixture of 15 % acetone / dcm gave a beige - orange solid ( 61 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 9 . 07 ( 1h , s ), 8 . 21 ( 1h , d , j = 3 hz ), 7 . 91 ( 2h , d , j = 4 . 8 hz ), 7 . 45 ( 1h , d , j = 3 hz ), 7 . 34 ( 2h , d , j = 5 . 1 hz ), 2 . 44 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 153 . 6 , 151 . 2 , 143 . 0 , 141 . 9 , 129 . 3 , 128 . 9 , 126 . 9 , 120 . 8 , 21 . 6 . hrms calculated for c 11 h 10 n 2 o ( m +) 186 . 0793 ; found : 186 . 0780 . ir ( v max / cm − 1 ): 3076 , 3035 , 2922 , 1371 , 1255 , 1038 , 849 , 808 . synthesized according to general procedure 4 . purification via silica gel column chromatography using 100 % dcm then a mixture of 20 % acetone / dcm gave a beige solid ( 50 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 9 . 11 ( 1h , s ), 8 . 28 ( 1h , d , j = 5 . 1 hz ), 8 . 19 ( 2h , d , j = 8 . 4 hz ), 8 . 06 ( 2h , d , j = 8 . 1 hz ), 7 . 49 ( 1h , d , j = 4 . 8 hz ), 3 . 97 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 151 . 2 , 143 . 3 , 133 . 9 , 132 . 3 , 129 . 9 , 129 . 7 , 129 . 1 , 121 . 2 , 99 . 4 , 52 . 5 . hrms calculated for c 12 h 10 n 2 o 3 ( m +) 230 . 2194 ; found : 230 . 0671 . ir ( v max / cm − 1 ): 3029 , 2920 , 2857 , 1733 , 1652 , 1254 , 739 . synthesized according to general procedure 4 . purification via silica gel column chromatography using 100 % dcm then a mixture of 20 % acetone / dcm gave an orange oil ( 62 %). 1 h nmr ( 400 mhz , cdcl 3 , 293k , tms ): δ 9 . 08 ( 1h , s ), 8 . 23 ( 1h , d , j = 4 . 8 hz ), 7 . 61 ( 1h , m ), 7 . 46 - 7 . 41 ( 3h , m ), 7 . 08 ( 1h , dt , j = 2 . 4 and 9 . 6 hz ), 3 . 86 ( 3h , s ). 13 c nmr ( 100 mhz , cdcl 3 , 293k , tms ): 159 . 4 , 153 . 4 , 151 . 1 , 143 . 3 , 130 . 9 , 129 . 6 , 121 . 2 , 121 . 2 , 117 . 2 , 114 . 2 , 55 . 4 . hrms calculated for c 11 h 10 n 2 o 2 ( m +) 202 . 0742 ; found : 202 . 0762 . ir ( v max / cm − 1 ): 3080 , 2962 , 2837 , 1696 , 1585 , 1477 , 1258 , 1028 . synthesized according to general procedure 4 . purification via silica gel column chromatography using 100 % dcm then a mixture of 15 % acetone / dcm gave a orange oil ( 55 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 9 . 08 ( 1h , s ), 8 . 22 ( 1h , d , j = 4 . 8 hz ), 7 . 55 ( 2h , s ), 7 . 42 ( 1h , d , j = 5 . 1 hz ), 7 . 17 ( 1h , s ), 2 . 39 ( 6h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 151 . 0 , 143 . 2 , 138 . 2 , 132 . 9 , 129 . 6 , 126 . 6 , 121 . 2 , 21 . 3 . 2 peaks are overlaping . hrms calculated for c 11 h 12 n 2 o ( m +) 200 . 0950 ; found : 200 . 0970 . ir ( v max / cm − 1 ): 3090 , 2920 , 2860 , 1698 , 1579 , 1373 , 1254 , 834 . synthesized according to general procedure 5 . purification via silica gel column chromatography using 100 % dcm then a mixture of 2 . 5 % acetone / dcm gave a white solid ( 86 %). synthesized according to general procedure 5 . purification via silica gel column chromatography using 100 % dcm then a mixture of 5 % acetone / dcm gave a white solid ( 82 %). synthesized according to general procedure 5 . purification via silica gel column chromatography using 100 % dcm then a mixture of 10 % acetone / dcm gave a yellow solid ( 98 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 9 . 35 ( 1h , s ), 8 . 29 - 8 . 11 ( 6h , m ), 7 . 84 - 7 . 72 ( 2h , m ), 3 . 97 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 166 . 5 , 150 . 5 , 143 . 1 , 142 . 1 , 141 . 7 , 140 . 7 , 131 . 3 , 130 . 5 , 130 . 2 , 130 . 0 , 129 . 7 , 129 . 1 , 127 . 4 , 52 . 3 . hrms calculated for c 16 h 12 n 2 o 2 ( m +) 264 . 0899 ; found : 264 . 0883 . ir ( v max / cm − 1 ): 2952 , 2924 , 2853 , 1733 , 1605 , 1285 , 772 , 755 . synthesized according to general procedure 5 . purification via silica gel column chromatography using 100 % dcm then a mixture of 3 % acetone / dcm gave a white solid ( 84 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 71 ( 1h , s ), 7 . 87 ( 2h , d , j = 8 . 1 hz ), 7 . 29 ( 2h , d , j = 8 . 1 hz ), 3 . 06 - 2 . 93 ( 4h , m ), 2 . 41 ( 3h , s ), 2 . 00 - 1 . 90 ( 4h , m ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 152 . 1 , 150 . 7 , 149 . 7 , 139 . 2 , 138 . 6 , 134 . 1 , 129 . 6 , 126 . 6 , 32 . 2 , 31 . 7 , 22 . 7 , 21 . 3 . 2 peaks are overlaping . hrms calculated for c 15 h 16 n 2 ( m +) 224 . 1313 ; found : 224 . 1326 . ir ( v max / cm − 1 ): 3067 , 3017 , 2943 , 2862 , 1451 , 1143 , 826 . synthesized according to general procedure 5 . purification via silica gel column chromatography using 100 % dcm gave a white solid ( 76 %). synthesized according to general procedure 6 . purification via silica gel column chromatography using a mixture of 5 % acetone / dcm gave a beige solid ( 81 %). synthesized according to general procedure 6 . the product was obtained pure without purification ( 87 %). synthesized according to general procedure 6 . purification via silica gel column chromatography using a mixture of 30 % etoac / benzene , then a mixture of 45 % etoac / benzene gave brown oil ( 70 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 9 . 20 ( 1h , dd , j = 1 . 8 and 6 . 0 hz ), 7 . 61 - 7 . 53 ( 2h , m ), 7 . 46 - 7 . 31 ( 4h , m ), 2 . 40 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 162 . 2 , 149 . 6 , 137 . 2 , 136 . 1 , 130 . 9 , 129 . 8 , 129 . 2 , 127 . 2 , 126 . 1 , 126 . 1 , 20 . 3 . hrms calculated for c 11 h 10 n 2 ( m +) 170 . 0844 ; found : 170 . 0838 . ir ( v max / cm − 1 ): 3065 , 2963 , 2928 , 1580 , 1435 , 765 . synthesized according to general procedure 6 . purification via silica gel column chromatography using a mixture of 35 % etoac / benzene , then a mixture of 50 % etoac / benzene gave brown oil ( 70 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 9 . 10 ( 1h , d , j = 4 . 5 hz ), 8 . 06 ( 2h , d , j = 9 . 0 hz ), 7 . 80 ( 1h , d , j = 9 . 6 hz ), 7 . 49 ( 1h , dd , j = 4 . 8 and 9 . 0 hz ), 7 . 05 ( 2h , d , j = 8 . 7 hz ), 3 . 88 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 161 . 3 , 158 . 9 , 149 . 4 , 128 . 7 , 128 . 4 , 126 . 6 , 123 . 1 , 114 . 4 , 55 . 3 . hrms calculated for c 11 h 10 n 2 o ( m +) 186 . 0793 ; found : 186 . 0794 . ir ( v max / cm − 1 ): 3054 , 2929 , 2847 , 1612 , 1436 , 1249 , 1025 , 811 . synthesized according to general procedure 2 . purification via silica gel column chromatography using 15 % acetone / dcm then a mixture of 25 % acetone / dcm gave a beige solid ( 74 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 58 ( 2h , d , j = 10 . 8 hz ), 8 . 18 ( 2h , d , j = 8 . 4 hz ), 7 . 93 ( 2h , d , j = 8 . 4 hz ), 7 . 74 ( 2h , d , j = 8 . 1 hz ), 7 . 33 ( 2h , d , j = 8 . 1 hz ), 3 . 96 ( 3h , s ), 2 . 43 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 166 . 3 , 146 . 9 , 146 . 0 , 144 . 8 , 143 . 7 , 140 . 7 , 133 . 9 , 131 . 4 , 129 . 5 , 129 . 4 , 129 . 2 , 129 . 2 , 126 . 2 , 52 . 3 , 21 . 5 . hrms calculated for c 19 h 16 n 2 o 3 ( m +) 320 . 1161 ; found : 320 . 1141 . ir ( v max / cm − 1 ): 2964 , 2921 , 2854 , 1727 , 1612 , 1291 , 1105 , 815 . to a solution of toluene ( 1 . 0 ml ) and dmf ( 1 . 0 ml ) was added pocl 3 ( 0 . 049 ml , 0 . 54 mmol ). the mixture was stirred for 10 minutes at 0 ° c ., then 2 - p - tolylpyrazine n - oxide ( 50 mg , 0 . 27 mmol ) in dmf ( 0 . 5 ml ) was added . after 10 minutes , the reaction mixture was allowed to warm to room temperature and stirred over night . the solvent was then evaporated via kugelrohr distillation . the residue was cooled in a ice bath and a saturated solution of nahco 3 was added . the aqueous layer was extracted 3 times with dcm . the combined organic phases was dried over mgso 4 , filtered and concentrated under vacuum to give a pure pale yellow solid ( 54 mg , 98 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 89 ( 1h , s ), 8 . 47 ( 1h , s ), 7 . 92 ( 2h , d , j = 7 . 8 hz ), 7 . 31 ( 2h , d , j = 7 . 8 hz ), 2 . 42 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 152 . 5 , 148 . 8 , 141 . 9 , 140 . 9 , 139 . 1 , 131 . 9 , 129 . 8 , 126 . 9 , 21 . 4 . hrms calculated for c 11 h 9 n 2 cl ( m +) 204 . 0454 ; found : 204 . 0447 . ir ( v max / cm − 1 ): 3029 , 2919 , 2855 , 1507 , 1158 , 1005 , 821 . to a solution of toluene ( 1 . 0 ml ) and dmf ( 1 . 0 ml ) was added pocl 3 ( 0 . 045 ml , 0 . 49 mmol ). the mixture was stirred for 10 minutes at 0 ° c ., then 2 -( 4 - methoxyphenyl ) pyrazine n - oxide ( 50 mg , 0 . 25 mmol ) in dmf ( 0 . 5 ml ) was added . after 10 minutes , the reaction mixture was allowed to warm to room temperature and stirred over night . the solvent was then evaporated via kugelrohr distillation . the residue was cooled in a ice bath and a saturated solution of nahco 3 was added . the aqueous layer was extracted 3 times with dcm . the combined organic phases was dried over mgso 4 , filtered and concentrated under vacuum to give a pure pale yellow solid ( 47 . 3 mg , 87 %). exhibited identical spectral data according to previous reports 31 . to a round bottom flask was added pt 2 o ( 8 mg , 0 . 03 mmol ) and 2 - p - tolyl - pyrazine n - oxide ( 50 mg , 0 . 27 mmol ). the mixture was then purged under nitrogen for 10 minutes . addition of the acetic acid ( 3 ml ) was followed by the addition of hydrogen via a balloon . when complete , the reaction mixture was filtered trought a pad of celite , and the solvent was evaporated via kugelrohr distillation . a 10 % solution of naoh was added and the aqueous layer was extracted 3 times with dcm . the combined organic phases was dried over mgso 4 , filtered and concentrated under vacuum to give a pure beige solid ( 32 mg , 68 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 7 . 27 ( 2h , d , j = 7 . 8 hz ), 7 . 13 ( 2h , j = 7 . 8 hz ), 3 . 71 ( 1h , dd , j = 2 . 4 and 9 hz ), 3 . 13 - 2 . 82 ( 5h , m ), 2 . 70 ( 1h , dd , j = 10 . 2 and 12 hz ), 2 . 33 ( 3h , s ), 1 . 84 ( 2h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 139 . 7 , 137 . 0 , 129 . 0 , 126 . 7 , 61 . 7 , 54 . 3 , 47 . 8 , 46 . 0 , 21 . 0 . hrms calculated for c 11 h 6 n 2 ( m +) 176 . 1313 ; found : 176 . 1319 . ir ( v max / cm − 1 ): 3274 , 3018 , 2940 , 2826 , 1514 , 813 . to a dry schlenck tube was added 2 - chloro - 6 - p - tolylpyrazine ( 60 mg , 0 . 29 mmol ), sodium tert - butoxide ( 40 mg , 0 . 41 mmol ), pd ( oac ) 2 ( 2 mg , 0 . 01 mmol ) and 2 -( dicyclohexylphosphino ) biphenyl ( 6 mg , 0 . 02 ). the mixture was then purged under nitrogen for 10 minutes . addition of morpholine ( 0 . 031 ml , 0 . 35 mmol ) was followed by the addition of degassed toluene ( 1 . 0 ml ). the reaction mixture was heated at 100 ° c . over night . the reaction was filtered trought a pad of celite , and the solvent was evaporated under reduce pressure . purification of the residue via silica gel column chromatography using 100 % dcm , then a mixture of 5 % acetone / dcm gave a pale yellow solid ( 70 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 37 ( 1h , s ), 8 . 03 ( 1h , s ), 7 . 90 ( 2h , d , j = 8 . 1 hz ), 7 . 27 ( 2h , d , j = 8 . 1 hz ), 3 . 86 ( 4h , t , j = 4 . 5 hz ), 3 . 65 ( 4h , t , j = 5 . 1 hz ), 2 . 40 ( 3h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 154 . 1 , 149 . 3 , 139 . 5 , 134 . 1 , 130 . 2 , 129 . 4 , 128 . 3 , 126 . 6 , 66 . 6 , 44 . 7 , 21 . 3 . hrms calculated for c 15 h 17 n 3 o ( m +) 255 . 1372 ; found : 255 . 1362 . ir ( v max / cm − 1 ): 3058 , 2963 , 2854 , 1525 , 1253 , 820 . to a round bottom flask was added 2 - chloro - 6 - p - tolylpyrazine ( 60 mg , 0 . 29 mmol ), sodium ethoxide ( 60 mg , 0 . 88 mmol ) and etoh ( 3 ml ). the reaction mixture was heated at 90 ° c . for 2 days . the solvent was evaporated under reduce pressure and the residue was extracted 3 times using water / brine and dcm . the combined organic phases was dried over mgso 4 , filtered and concentrated under vacuum . purification of the residue via silica gel column chromatography using 100 % dcm , then a mixture of 2 % acetone / dcm gave a pale yellow solid ( 85 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 55 ( 1h , s ), 8 . 10 ( 1h , s ), 7 . 92 ( 2h , d , j = 7 . 8 hz ), 7 . 28 ( 2h , d , j = 7 . 8 hz ), 4 . 50 ( 2h , q , j = 6 . 9 hz ), 2 . 41 ( 3h , s ), 1 . 45 ( 3h , t , j = 6 . 9 hz ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 159 . 4 , 148 . 9 , 139 . 7 , 133 . 5 , 133 . 2 , 132 . 6 , 129 . 5 , 126 . 6 , 61 . 9 , 21 . 3 , 14 . 4 . hrms calculated for c 13 h 14 n 2 o ( m +) 214 . 1106 ; found : 214 . 1115 . ir ( v max / cm − 1 ): 3070 , 2981 , 2920 , 1538 , 1424 , 826 . to a round bottom flask was added 2 - p - tolylpyrazine n - oxide and acetic anhydride ( 0 . 65 ml ). the solvent was evaporated via kugelrohr distillation and the residue was stirred over night at 50 ° c . in a acetone / silica gel mixture . the solvent was removed under vacum purified via silica gel column chromatography using a mixture of 20 % acetone / dcm . a yellow oil was obtained ( 71 %). 1 h nmr ( 300 mhz , cdcl 3 , 293k , tms ): δ 8 . 92 ( 1h , s ), 8 . 39 ( 1h , s ), 7 . 90 ( 2h , d , j = 8 . 1 hz ), 7 . 30 ( 2h , d , j = 8 . 1 hz ), 2 . 41 ( 6h , s ). 13 c nmr ( 75 mhz , cdcl 3 , 293k , tms ): 168 . 5 , 153 . 8 , 151 . 4 , 140 . 6 , 139 . 0 , 136 . 2 , 132 . 2 , 129 . 8 , 127 . 0 , 21 . 4 , 21 . 1 . hrms calculated for c 13 h 12 n 2 o 2 ( m +) 228 . 0899 ; found : 228 . 0880 . ir ( v max / cm − 1 ): 3062 , 2924 , 2855 , 1773 , 1531 , 1185 , 822 . 1 ( a ) metal - catalyzed cross - coupling reactions ; diederich , f ., stang , p . j ., eds . ; wiley - vch : new york , 1998 . 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