Patent Application: US-13776798-A

Abstract:
robustaflavone , intermediates and analogues thereof and a method for synthesizing the same are provided . the method involves constructing apigenin ethers containing functionalities at the 6 - and 3 ′- positions which could be cross - coupled using transition metal catalysis . the method also involves development of a regioselective iodination of an apigenin derivative at the 6 - position , formation of an apigenin 3 ′- boronate using a palladium - catalyzed exchange of the corresponding 3 ′- iodide with a diboron reagent . finally , suzuki coupling to form the sterically congested 6 - 3 ′″ biaryl bond of robustaflavone provides access to the desired biflavanoid system . robustaflavone intermediates and analogues may be used to prepare analogues of other biflavanoids such as hinokifavone , rhusflavone and succedaneaflavone .

Description:
according to the present invention , the total synthesis of robustaflavone was approached via construction of two apigenin derivatives , one substituted in the 6 - position and one substituted in the 3 ′- position , with groups that could be coupled using transition metal - catalyzed cross coupling methodology . the synthesis of apigenin derivatives substituted in the 3 ′- position is straightforward ( scheme 1 ), involving esterification of phloroacetophenone dimethyl ether ( 1 ) with 3 - substituted p - anisoyl chlorides , such as 3 - iodo - p - anisoyl chloride ( 2a ). rearrangement of the resulting ester ( 3a ) to the β - diketone 4a was achieved by heating in pyridine at 100 ° c . in the presence of powdered koh . cyclization of the diketone 4a under acidic conditions provided 3 ′- iodoapigenin trimethyl ether ( 5a ) 10 , 23 . this route was also utilized to prepare apigenin trimethyl ether ( 5b ), starting with 1 and p - anisoyl chloride . the preparation of apigenin derivatives substituted in the 6 - position presented a more difficult challenge , as direct electrophilic substitution of apigenin ethers occurs preferentially in the 8 - position . an extensive search of the chemical literature yielded only two examples of 6 - halogenated apigenin derivatives ; the first , described in 1939 , reported 6 - bromoapigenin trimethyl ether as an intermediate in a total synthesis of apigenin 11 . however , it was later determined that the position of the ring bromination had been incorrectly assigned in the original report , and that the actual intermediate was 8 - bromoapigenin trimethyl ether 12 . a second route described the iodination of apigenin 7 , 4 ′- dimethyl ether with iodine in an iodic acid solution , which provided a mixture of the 6 - iodo and 8 - iodo derivatives , in a 1 : 4 ratio 13 . the desired 6 - iodinated derivative was reportedly purified by fractional recrystallization , but in very poor yield . the desired 6 - iodinated species was prepared in excellent yield with almost exclusive regioselectivity by exploiting the ortho - directing capabilities of thallium ( i ) salts in the iodination of phenols 14 ( scheme 2 ). selective demethylation of apigenin trimethyl ether ( 5b ) in the 5 - position may be accomplished with boron tribromide in an amount generally ranging between about 0 . 9 equiv and about 3 . 0 equiv , preferably about 1 . 1 equiv boron tribromide , to afford apigenin 7 , 4 ′- dimethyl ether ( 6 ). the reaction is generally carried out a temperature ranging between about − 40 ° c . and about 50 ° c ., preferably about 25 ° c ., for a time period ranging between about 0 . 5 h and about 24 h , preferably about 5 h , in the presence of a suitable solvent such as methylene chloride , chloroform , benzene and toluene , preferably methylene chloride , until a thick precipitate is formed . the precipitate is then collected and recrystallized in a suitable solvent such as ethanol , methanol , ethyl acetate / hexane , preferably ethanol . if desired , other boron compounds such as boron trichloride may be used in place of boron tribromide 29 . thereafter , iodination of 6 is performed with elemental iodine in an amount ranging from about 0 . 8 equiv to about 1 . 5 equiv , preferably about 1 . 0 equiv i 2 , in the presence of a thallium ( i ) salt such as thallium ( i ) acetate , thallium ( i ) chloride and thallium ( i ) bromide , preferably thallium ( i ) acetate , in an amount ranging from about 0 . 8 equiv and about 1 . 5 equiv , preferably about 1 . 2 equiv thallium ( i ) salt , in a suitable solvent , e . g ., ch 2 cl 2 , to provide 6 - iodoapigenin 7 , 4 ′- dimethyl ether ( 7 ), in excellent yields , containing only trace amounts ( less than 1 % determined by 1 h nmr ) of the 8 - iodinated species . methylation of 7 with dimethyl sulfate in an amount ranging between about 1 . 0 equiv and about 10 . 0 equiv , preferably about 2 . 5 equiv , affords the desired 6 - iodoapigenin trimethyl ether ( 8 ). if desired , other suitable methylating agents such as iodomethane may be used in place of dimethyl sulfate . formation of biaryl systems is efficiently achieved via the palladium - catalyzed cross - coupling of aryl halides and aryl boronic acids ( suzuki coupling ) 8 or aryl halides and aryl stannanes ( stille coupling ) 15 , either of which could be applied to the synthesis of robustaflavone from the iodinated species 5a or 8 . conceivably , the iodide of either of these derivatives could be converted to a boronic acid or a stannane , and then cross - coupled with the other iodide to afford robustaflavone hexamethyl ether . in a related example , derivatives of the biflavanoid amentoflavone were synthesized using the palladium - catalyzed cross - coupling of apigenin ethers bearing a boronic acid in the 8 - position with apigenin ethers having an iodide in the 3 ′- position , in very good yields 9 . the apigenin - 8 - boronic acids were synthesized from the 8 - iodinated derivatives via halogen - lithium exchange , followed by quenching with trimethylborate and aqueous workup . attempted conversion of the 3 ′- iodide 5a via halogen - lithium exchange followed by trimethylborate quench were unsuccessful in our hands , as for others 9 . additionally , our attempt to prepare the corresponding apigenin 6 - boronic acid derivative from 8 using this technique were also unsuccessful , in contrast to the reported 9 simple conversion of the 8 - iodinated isomer to its corresponding boronic acid . milder general methods for the preparation of both stannanes 16 and boronic acids 17 have been described , using the palladium - catalyzed exchange of aryl halides with nucleophilic distannane and diboron reagents , respectively . these methods were applied to compound 5a to afford both the corresponding stannane derivative 9a and boronate 9b , illustrated in scheme 3 . treatment of 5a with commercially available hexamethylditin in an amount ranging between about 1 . 0 equiv and about 3 . 0 equiv , preferably about 2 . 0 equiv , in the presence of a palladium ( 0 ) catalyst 30 suitable for cross - coupling reactions such as ( ph 3 p ) 4 pd , pdcl 2 ( dppf ), pdcl 2 and pdcl 2 ( pph 3 ) 2 , preferably ( ph 3 p ) 4 pd , in an amount ranging between about 0 . 05 equiv and about 0 . 2 equiv , preferably about 0 . 1 equiv , in suitable solvent such as toluene , benzene , dioxane and thf , preferably toluene at reflux , affords the trimethylstannane 9a . generally , the reaction temperature ranges between about 65 ° c . and about 120 ° c ., preferably about 110 ° c . if desired , any suitable hexaalkylditin may be used in place of hexamethylditin . similarly , treatment of 5a with bis ( pinacolato ) diboron in an amount ranging between about 1 . 0 equiv and about 3 . 0 equiv , preferably about 1 . 3 equiv , in the presence of catalytic pdcl 2 ( dppf ), pd ( pph 3 ) 4 , pdcl 2 and pdcl 2 ( pph 3 ) 2 , preferably pdcl 2 ( dppf ), in an amount ranging between about 0 . 01 equiv and about 0 . 2 equiv , preferably about 0 . 13 equiv , and excess k 2 co 3 in a suitable solvent such as dmf , dmso , dioxane or thf , preferably dmf , at a temperature ranging between about 25 ° c . and about 100 ° c ., preferably about 85 ° c ., provided boronate ester 9b in 64 % yield . bis ( pinacolato ) diboron was prepared via treatment of tetrakis ( trimethylamino ) diboron 18 with pinacol as previously described 19 , and is commercially available . if desired , pinacolborane 31 or any other suitable nucleophilic source of boron may be used in place of bis ( pinacolato ) diboron . in addition , nahco 3 , khco 3 or naoac may be used in place of k 2 co 3 . attempted stille coupling of 9a with iodide 8 in a variety of solvents ( dmf , toluene , dioxane , thf ) using several palladium catalysts [( ph 3 p ) 4 pd , pd ( oac ) 2 , pdcl 2 , ( ph 3 p ) 2 pdcl 2 ] failed to provide any significant formation of robustaflavone hexamethyl ether ( 10 ). when using toluene as solvent , a very small amount of 10 could be detected by tlc , by comparison with an authentic standard prepared by methylation of natural robustaflavone with dimethylsulfate 7 , but the major product formed in the reaction was apigenin trimethyl ether ( 5b ). it is commonly accepted that transmetallation from tin to palladium represents the rate limiting step in stille couplings 15 . thus , because iodide 8 is particularly reactive toward oxidative addition , accelerated by the presence of the two electron - donating ortho - methoxyl groups , reduction of the aryl iodide apparently occurred much faster than transmetallation . however , it is unclear whether 5b was formed exclusively via reduction of the iodide 8 , or also by proteodesilylation of 9a . following the reaction progress by tlc appeared to indicate that the concentration of 8 decreased over time , while that of 9a was unchanged , suggesting that reduction of 8 was the likely source of 5b . in contrast to stille coupling , transmetallation from boron to palladium in suzuki couplings is rapid , and oxidative addition is generally the rate - limiting step 8 . we thus turned to coupling of boronate 9b with aryl iodide 8 . using reported conditions described17 for coupling of pinacol boronate esters with aryl halides ( pdcl 2 ( dppf ), dmf , koac , 80 ° c . ), we observed that , again , the major product formed was apigenin trimethyl ether ( 5b ). though we anticipated that coupling between 9b and 8 may be sluggish , due to the steric congestion of the biaryl bond being formed , we were comforted to learn that others 20 had successfully prepared biaryl systems containing similar degrees of steric crowding utilizing suzuki methodology . evaluation of a variety of reaction conditions , conducted by changing the solvent , palladium catalyst , and base , identified coupling conditions that afforded the desired robustaflavone hexamethyl ether ( 10 ) starting from compounds 8 and 9b . in practicing this invention , compounds 8 and 9b are both present in the reaction mixture at a range between about 1 : 1 and about 1 : 3 , preferably about 1 : 2 . conducting the reaction in a suitable solvent such as dmf , dmso , dioxane or thf , preferably dmf , containing between about 3 % ( v / v ) and about 25 % ( v / v ) h 2 o , preferably about 10 % ( v / v ) h 2 o ; between about 1 and about 10 equiv , preferably about 4 . 0 equiv , of base such as naoh , koh , khco 3 , nahco 3 , preferably naoh ; and between about 5 mol % and about 20 mol %, preferably about 10 mol % of a palladium catalyst such as pd ( pph 3 ) 4 , pd ( oac ) 2 , pdcl 2 , pdcl 2 ( pph 3 ) 2 , and pdcl 2 ( dppf ), preferably pd ( pph 3 ) 4 , affords 10 in 30 % yield , with only small amounts of 5b formed as a by - product , and trace amounts of unreacted iodide 8 . it was discovered that utilization of naoh as base resulted in greatly accelerated reaction rates relative to those observed when using k 2 co 3 , and the suzuki coupling was generally complete within one hour . increasing the equivalence of 9b to 1 . 2 increased the yield of 10 to 35 %, and further increasing the stoichiometry of 9b to 2 . 0 equivalents increased the yield of 10 to 50 %. if desired , other solvent systems can be used in place of water - dmf mixtures for the coupling reaction such as dmf alone or dmso , dioxane or thf alone or as a mixture with water . the desired material , robustaflavone hexamethyl ether ( 10 ) was readily purified using silica gel column chromatography and suitable solvent or solvent mixtures such as chloroform / methanol and ethyl acetate / methanol . deprotection of 10 was initially attempted using standard mineral acid conditions , such as hbr and hi . in all cases , the use of mineral acids resulted in wessely - moser rearrangement 21 , and amentoflavone was the major product isolated . similar results were obtained using aqueous ( hbr and hi ) or anhydrous ( hbr in hoac ) conditions . complete demethylation of 10 was achieved by treatment with between about 8 and about 15 equiv bbr 3 , preferably 12 equivalents bbr 3 , in a suitable solvent , e . g ., chcl 3 at reflux , at a temperature ranging between about 25 ° c . and about 80 ° c ., preferably about 60 - 62 ° c . if desired , bcl 3 may be used in place of bbr 3 . attempts to deprotect using amounts of bbr 3 less than 8 equivalents or at temperatures lower than 50 ° c ., did not achieve complete demethylation , and the resulting products contained significant quantities of partially demethylated materials . following demethylation , crude robustaflavone was obtained in 88 . 9 % yield . column chromatography through silica gel ( toluene / pyridine / formic acid , 20 : 10 : 1 ) afforded robustaflavone in 30 % yield . the synthesis of robustaflavone analogues can be approached using the suzuki cross - coupling methodology that was developed during the total synthesis of robustaflavone , or the stille coupling methods . either of the aryl iodides 5b or 8 could be cross - coupled with an aryl - or alkylboronic acid derivative , or with an aryl - or alkylstannane , to afford 3 ′- and 6 - substituted apigenin derivatives , respectively , which effectively represent robustaflavone intermediates or analogues . to serve as an example , 6 -( 2 - methoxyphenyl ) apigenin trimethyl ether 11 was efficiently synthesized via the suzuki coupling of 8 with commercial 2 - methoxyphenylboronic acid as illustrated in scheme 5 and described in example 2 . for the formation of robustaflavone analogues , any number of aryl - or alkyl boronic acids , available either from commercial vendors or prepared from aryl halides using standard halogen - lithium exchange / borate quench , could be cross - coupled with iodides 8 or 5b ( scheme 6 ), using the general conditions described for the synthesis of 11 . following the cross - coupling step , removal of the protective groups , such as described for the conversion of 10 to robustaflavone , will provide the final robustaflavone analogues . the reagents “ r - x ” embody any appropriate reagent which will cross - couple with aryl iodides , including aryl - and alkylboronic acids 26 , aryl - and alkylstannanes 27 , and primary or secondary aliphatic or aromatic amines 28 . suitable , but not limiting , examples of aryl include phenyl and phenyl substituted with one or more alkyl groups , preferably c 1 - c 6 groups , which may be further substituted with one or more halogens , alkoxy groups , and amino groups . suitable , but not limiting , examples of primary or secondary aliphatic or aromatic amines include , without limitation , n - propylamine , pyrrolidine and aniline . alternatively , boronic acid derivative 9b could be cross - coupled with aryl halides , to afford 3 ′- substituted apigenin derivatives , which would effectively represent robustaflavone analogues . this route would offer the advantage that many organic aryl halides representing a wide variety of structural diversity are commercially available . additionally , iodide 8 could be converted to its corresponding 6 - boronic acid derivative ( 12 ) using the same general route illustrated for the synthesis of 9b in scheme 3 . at that point , apigenin derivatives bearing boronic acid moieties in both the 3 ′- and 6 - positions would be available , and allow the rapid construction of analogues via cross - coupling with any variety of organic aryl halide , including but not limited to substituted halogenated benzenes such as iodonitrobenzene and bromoanisole ; halogenated heteroaromatics such as bromopyridine , bromothiophene and bromofuran ; and halogenated polycyclic aromatics such as bromonaphthalene , bromoanthraquinone and bromoanthracene and heteroaromatics such as bromoindole , bromoquinoline and bromobenzofuran ( scheme 7 ), as well as aryl - and vinyltriflates . the generation of robustaflavone derivatives is not restricted to the use of apigenin derivatives protected as methyl ethers . an ordinary skilled artisan would appreciate that the phenol moieties of apigenin could be protected with other alkyl ether groups , including but not limited to isopropyl and benzyl , which could offer simpler deprotection conditions . alternatively , the phenol moieties could be protected as esters of appropriate carboxylic acids such as acetic acid and benzoic acid . the following examples are illustrative of the present invention and do not serve to limit the scope of the invention as claimed . example 1 describes preparation of robustaflavone by the method of the present invention . example 2 describes preparation of 6 -( 2 - methoxyphenyl ) apigenin trimethyl ether , a product produced by the suzuki coupling of 8 with a commercial 2 - methoxyphenylboronic acid . general experimental . 300 mhz 1 h nmr spectra were recorded on a varian gemini 2000 spectrometer . chemical shifts are reported on the δ scale downfield from tetramethylsilane . ei mass spectra were obtained with a finnigan mat 90 mass spectrometer , and apci mass spectra were recorded with a finnigan mat lcq mass spectrometer . infrared spectra were recorded with either a midac m series or a perkin elmer spectra 1000 ftir spectrophotometer . elemental analyses were obtained from midwest microlab , indianapolis , ind . melting points were determined with a mel - temp melting point apparatus and are corrected . column chromatography was conducted with em science silica gel 60 ( 70 - 230 mesh ) with indicated eluents . analytical thin layer chromatography was performed with silica gel 60 f 254 precoated glass - backed plates ( 250 μm ) with indicated eluents . bis ( pinacolato ) diboron was prepared from tetrakis ( dimethylamino ) diboron 18 as previously described 19 . all other reagents and solvents were purchased from commercial sources and used without further purification . 2 , 4 - dimethoxy - 6 - hydroxyacetophenone ( 1 ). to a solution of phloroacetophenone hydrate ( 20 . 5 g , 110 mmol ) and k 2 co 3 ( 22 . 1 g , 160 mmol ) in 150 ml acetone was added dimethylsulfate ( 27 . 7 g , 220 mmol ) slowly over 30 min with mechanical stirring . the solution was heated at reflux overnight , then poured into 500 ml h 2 o , which produced a white solid . the material was collected on a büchner funnel , rinsed with 1 l h 2 o and air dried . recrystallization from 80 ml of 90 % meoh afforded white needles ( 16 . 1 g , 74 . 4 %); mp 79 ° c . ( lit . 10 mp 82 - 83 ° c . ); 1 h nmr ( cdcl 3 ) δ 2 . 61 ( s , 3 h ), 3 . 82 ( s , 3 h ), 3 . 86 ( s , 3 h ), 5 . 92 ( d , 1 h , j = 2 . 4 hz ), 6 . 06 ( d , 1 h , j = 2 . 4 hz ), 7 . 26 ( s , 1 h ), 14 . 03 ( s , 1 h ). 3 - iodo - p - anisic acid . to a mechanically stirred suspension of p - anisic acid ( 59 . 90 g , 394 mmol ) and iodine ( 100 . 0 g , 394 mmol ) in a mixture of 325 ml glacial acetic acid and 60 g conc h 2 so 4 , heated to 45 ° c . with a water bath , was added dropwise a solution of 40 g conc hno 3 in 60 ml hoac at such a rate that the temperature was maintained between 40 - 50 ° c . ( ca . 90 min ). after addition , the mixture was stirred for 30 min at 50 ° c ., then diluted with 400 ml h 2 o , which produced a pink solid . the material was collected on a büchner funnel , rinsed with 1 l 10 % na 2 s 2 o 4 and 1 l h 2 o , then air dried . recrystallization from 700 ml pyridine / meoh ( 1 : 1 ) provided colorless plates . the crystals were collected on a büchner funnel , rinsed with 500 ml meoh , then allowed to air dry . after drying under high vacuum overnight , 71 . 4 g ( 65 . 2 %) of the desired product was obtained ; mp 243 - 244 ° c . ( lit . 10 mp 238 ° c . ); 1 h nmr ( dmso - d 6 ) δ 3 . 91 ( s , 3 h ), 7 . 00 ( d , 1 h , j = 8 . 7 hz ), 7 . 95 ( dd , 1 h , j = 8 . 7 , 1 . 8 hz ), 8 . 27 ( d , 1 h , j = 1 . 8 hz ), 12 . 89 ( br s , 1 h ). 3 - iodo - p - anisoyl chloride ( 2a ). to a suspension of pcl 5 ( 33 . 0 g , 158 mmol ) in 30 ml chcl 3 was added , with magnetic stirring , 3 - iodo - p - anisic acid ( 40 . 0 g , 144 mmol ) in small portions . the solution was heated at reflux for b 1 h under a gentle nitrogen sweep , during which time the solution became homogenous . the solvent was evaporated under reduced pressure , then the residue was distilled under high vacuum . the fraction distilling at 152 - 156 ° c . ( 5 mm hg ; lit . 10 bp 183 - 185 ° c ., 12 - 13 mm hg ) was collected , which rapidly solidified as a pink solid . recrystallization from 200 ml hexane / ch 2 cl 2 afforded the desired product as white needles ( 36 . 4 g , 85 . 5 %); mp 58 ° c . ; 1 h nmr ( cdcl 3 ) δ 3 . 99 ( s , 3 h ), 6 . 88 ( d , 1 h , j = 8 . 7 hz ), 8 . 13 ( dd , 1 h , j = 8 . 7 , 2 . 4 hz ), 8 . 52 ( d , 1 h , j = 2 . 4 hz ); ei - ms m / z 296 ( m + , 42 ), 261 ( 100 ). 4 , 6 - dimethoxy - 2 -( 3 ′- iodo - 4 ′- methoxybenzoyloxy ) acetophenone ( 3a ). to a solution of 1 ( 5 . 00 g , 25 . 5 mmol ) in 15 ml pyridine was added 2a ( 9 . 08 g , 30 . 6 mmol ), and the solution heated to 100 ° c . in an oil bath with magnetic stirring for 10 min . the solution was cooled to room temperature , then diluted with 20 ml meoh . the solution was cooled in an ice bath and , following scratching with a glass rod , colorless needles formed . the crystals were collected on a büchner funnel , rinsed with cold mcoh and air dried to provide 10 . 1 g ( 86 . 4 %) of the desired product ; mp 146 ° c . ( lit . 10 mp 158 ° c . ; 1 h nmr ( cdcl 3 ) δ 2 . 47 ( s , 3 h ), 3 . 83 ( s , 3 h ), 3 . 87 ( s , 3 h ), 3 . 96 ( s , 3 h ), 6 . 34 ( d , 1 h , j = 2 . 1 hz ), 6 . 41 ( d , 1 h , j = 2 . 1 hz ), 6 . 87 ( d , 1h , j = 8 . 7 hz ), 8 . 12 ( dd , 1h , j = 8 . 7 , 2 . 1 hz ), 8 . 55 ( d , 1 h , j = 2 . 1 hz ); ei - ms m / z 456 ( m + , 41 ), 261 ( 100 ). 1 -( 3 ′- iodo - 4 ′- methoxyphenyl )- 3 -( 2 ″- hydroxy - 3 ″, 6 ″- dimethoxyphenyl )- 1 , 3 - propanedione ( 4a ). to a suspension of 3a ( 9 . 12 g , 20 . 0 mmol ) in 20 ml pyridine was added 2 . 80 g ( 50 mmol ) powdered koh , and the solution heated to 100 ° c . with magnetic stirring in an oil bath for 10 min . the solution was cooled to room temperature and treated with 10 ml hoac , which produced a yellow paste . addition of 20 ml meoh and cooling in an ice bath afforded a yellow powder , which was collected on a büchner funnel , rinsed with 100 ml meoh and air dried to provide 5 . 68 g ( 62 . 3 %) of the desired product ; mp 170 - 171 ° c . ( lit . 10 mp 168 ° c . ); 1 h nmr ( cdc 3 ) δ 3 . 51 ( s , 3 h ), 3 . 82 ( s , 3 h ), 3 . 97 ( s , 3 h ), 4 . 48 ( s , 2 h ), 5 . 85 ( d , 1 h , j = 2 . 1 hz ), 6 . 09 ( d , 1 h , j = 2 . 1 hz ), 6 . 89 ( d , 1 h , j = 8 . 7 hz ), 7 . 96 ( dd , 1 h , j = 8 . 7 , 2 . 1 hz ), 8 . 40 ( d , 1 h , j = 2 . 1 hz ), 13 . 68 ( s , 1h ); ei - ms m / z 456 ( m + , 70 ), 181 ( 100 ). 3 ′- iodo - 5 , 7 , 4 ′- trimethoxyflavone ( 5a ). to a magnetically stirred solution of 4a ( 5 . 00 g , 11 . 0 mmol ) in 60 ml hoac at 100 ° c . ( water bath ) was added 10 ml of 20 % h 2 so 4 / hoac . after stirring at 100 ° c . for 10 min , the solution was poured into 250 ml h 2 o , which produced a white precipitate . the solid was collected on a büchner funnel , rinsed with 500 ml h 2 o and air dried . recrystallization from 150 ml dioxane produced white needles ( 2 . 83 g , 58 . 9 %). evaporation of the mother liquor and recrystallization afforded an additional 1 . 35 g ( total yield 4 . 18 g , 87 . 0 %); mp 209 - 210 ° c . ( lit . 10 mp 223 ° c . ); 1 h nmr ( dmso - d 6 ) δ 3 . 83 ( s , 3 h ), 3 . 91 ( s , 3 h ), 3 . 92 ( s , 3 h ), 6 . 50 ( d , 1 h , j = 2 . 1 hz ), 6 . 73 ( s , 1 h ), 6 . 91 ( d , 1 h , j = 2 . 1 hz ), 7 . 14 ( d , 1 h , j = 8 . 7 hz ), 8 . 06 ( dd , 1 h , j = 8 . 7 , 2 . 4 hz ), 8 . 41 ( d , 1 h , j = 2 . 4 hz ); ei - ms m / z 438 ( m + , 100 ). 4 , 6 - dimethoxy - 2 -( 4 ′- methoxybenzoyloxy ) acetophenone ( 3b ). to a solution of 1 ( 20 . 0 g , 102 mmol ) in 60 ml pyridine was added 20 . 9 g ( 122 mmol ) p - anisoyl chloride ( 2b ), and the solution heated at 100 ° c . for 10 min with magnetic stirring in an oil bath . the solution was cooled to room temperature , then diluted first with 50 ml etoh followed by 50 ml h 2 o . the mixture was cooled to 0 ° c . in an ice bath which , after scratching with a glass rod , produced shiny white plates . the crystals were collected on a büchner funnel , rinsed with cold 50 % etoh and air dried to afford 27 . 4 g ( 81 . 4 %) of desired product ; mp 97 - 98 ° c . ( lit . 23 mp 115 - 116 ° c . ); 1 h nmr ( cdcl 3 ) δ 2 . 46 ( s , 3 h ), 3 . 82 ( s , 3 h ), 3 . 86 ( s , 3 h ), 3 . 88 ( s , 3 h ), 6 . 37 ( d , 1 h , j ab = 2 . 1 hz ), 6 . 39 ( d , 1 h , j ab = 2 . 1 hz ), 6 . 96 ( d , 2 h , j = 8 . 9 hz ), 8 . 09 ( d , 2 h , j = 8 . 9 hz ); ei - ms m / z 330 ( m + , 23 ), 135 ( 100 ). anal . calcd for c 18 h 18 , o 6 : c , 65 . 45 ; h , 5 . 49 . found : c , 65 . 55 ; h , 5 . 57 . 1 -( 4 ′- methoxyphenyl )- 3 -( 2 ″- hydroxy - 3 ″, 6 ″- dimethoxyphenyl )- 1 , 3 - propanedione ( 4b ). to a solution of 3b ( 30 . 0 g , 90 . 8 mmol ) in 120 ml pyridine was added 12 . 7 g ( 153 mmol ) powdered koh , and the solution heated to 100 ° c . in an oil bath with magnetic stirring for 10 min . the mixture was cooled to room temperature , then treated with 50 ml glacial acetic acid , which produced a thick yellow paste . the mixture was diluted with 100 ml etoh , which afforded a homogenous solution , followed by 100 ml h 2 o . upon cooling to 0 ° c ., the product crystallized as yellow prisms . the crystals were collected on a büchner funnel , rinsed with cold 50 % etoh and air dried to provide 20 . 72 g ( 69 . 1 %) of desired product ; mp 132 - 133 ° c . ( lit . 23 mp 147 - 149 ° c . ); 1 h nmr ( cdcl 3 ) δ 3 . 48 ( s , 3 h ), 3 . 81 ( s , 3 h ), 3 . 89 ( s , 3 h ), 4 . 51 ( s , 2 h ), 5 . 83 ( d , 1 h , j = 2 . 4 hz ), 6 . 09 ( s , 1 h , j = 2 . 4 hz ), 6 . 97 ( d , 2 h , j = 9 . 1 hz ), 7 . 94 ( d , 2 h , j = 9 . 1 hz ), 13 . 74 ( s , 1 h ); ftir ( kbr ) 3071 , 1724 , 1584 , 1182 , 1138 cm − 1 ; ei - ms m / z 330 ( m + , 46 ), 135 ( 100 ). anal . calcd for c 18 h 18 o 6 : c , 65 . 45 ; h , 5 . 49 . found : c , 65 . 38 ; h , 5 . 54 . the 1 h nmr spectra also indicated the presence of enol tautomers . 5 , 7 , 4 ′- trimethoxyflavone ( apigenin trimethyl ether , 5b ). a suspension of 4b ( 18 . 6 g , 56 . 4 mmol ) in 200 ml glacial acetic acid was heated to 100 ° c . with magnetic stirring in an oil bath . to this suspension was added 40 ml of 20 % h 2 so 4 in acetic acid , and the mixture stirred at 100 ° c . for 10 min . the mixture was poured into 1 l h 2 o , which produced a pale - yellow gelatinous solid . the solid was collected on a büchner funnel , allowed to partially dry by drawing air through the funnel , and then partitioned between 600 ml each of chcl 3 and h 2 o . the organic layer was separated and washed with 600 ml each of 5 % nahco 3 and saturated brine , dried over magnesium sulfate , filtered and evaporated to afford a light yellow solid . recrystallization from 300 ml acetone provided white needles ( 12 . 45 g , 70 . 8 %); mp 159 ° c . ( lit . 24 mp 156 ° c . ); 1 h nmr ( dmso - d 6 ) δ 3 . 83 ( s , 3 h ), 3 . 85 ( s , 3 h ), 3 . 90 ( s , 3 h ), 6 . 50 ( d , 1 h , j = 2 . 1 hz ), 6 . 67 ( s , 1 h ), 6 . 84 ( d , 1 h , j = 2 . 1 hz ), 7 . 09 ( d , 2 h , j = 8 . 9 hz ), 7 . 99 ( d , 2 h , j = 8 . 9 hz ; ftir ( kbr ) 1644 , 1348 , 1256 , 1121 , 831 cm − 1 ; ei - ms m / z 312 ( m + , 100 ). anal . calcd for c 18 h 16 o 5 : c , 69 . 22 ; h , 5 . 16 . found : c , 69 . 35 ; h , 5 . 32 . 7 , 4 ′- dimethoxy - 5 - hydroxyflavone ( 6 ). to a solution of 5b ( 10 . 0 g , 32 . 1 mmol ) in 200 ml anhydrous ch 2 cl 2 was added dropwise a 1 m solution of bbr 3 ( 35 . 3 ml , 35 . 3 mmol ) over 15 min at room temperature with magnetic stirring . a thick yellow precipitate formed rapidly during the addition . after stirring 5 h , the reaction was quenched by adding 200 ml etoh , and the solvent was then evaporated in vacuo . the yellow residue was triturated with 300 ml boiling 50 % etoh . after cooling to room temperature , the yellow solid was collected on a büchner funnel , rinsed with 500 ml 50 % etoh and air dried . recrystallization from 1 . 5 l etoh provided 8 . 16 g ( 85 . 4 %) of the title product as fine , pale - yellow needles ; mp 176 - 177 ° c . ( lit . 25 mp 174 - 175 ° c . ); 1 h nmr ( cdcl 3 ) δ 3 . 88 ( s , 3 h ), 3 . 89 ( s , 3 h ), 6 . 36 ( d , 1 h , j = 2 . 1 hz ), 6 . 48 ( d , 1 h , j = 2 . 1 hz ), 6 . 57 ( s , 1 h ), 7 . 01 ( d , 2 h , j ab = 9 . 0 hz ), 7 . 84 ( d , 2 h , j ab = 9 . 0 hz ), 12 . 81 ( s , 1 h ); ei - ms m / z 298 ( m + , 100 ). anal . calcd for c 17 h 14 o 5 : c , 68 . 45 ; h , 4 . 73 . found : c , 68 . 25 ; h , 4 . 77 . 7 , 4 ′- dimethoxy - 5 - hydroxy - 6 - iodoflavone ( 7 ). to a solution of 6 ( 2 . 98 g , 10 . 0 mmol ) in 300 ml ch 2 cl 2 was added thallium ( i ) acetate ( 3 . 16 g , 10 . 2 mmol ). with magnetic stirring , a solution of iodine ( 2 . 54 g , 10 . 0 mmol ) in 200 ml ch 2 cl 2 was added dropwise over 1 h . during the addition , a fine suspension of thallium salts precipitated . the solution was stirred at room temperature overnight , then filtered through a bed of celite to remove the precipitated salts . the filtrate was extracted sequentially with 500 ml each of 5 % nahco 3 , 10 % na 2 s 2 o 4 , and saturated brine , then dried over magnesium sulfate and filtered . evaporation in vacuo provided an orange solid . recrystallization from 300 ml chcl 3 / etoh ( 1 : 2 ) afforded fine yellow needles ( 3 . 10 g , 73 . 1 %); mp 227 - 228 ° c . ( lit . 13 mp 205 - 207 ° c . ); 1 h nmr ( cdcl 3 ) δ 3 . 90 ( s , 3 h ), 4 . 00 ( s , 3 h ), 6 . 54 ( s , 1 h ), 6 . 64 ( s , 1 h ), 7 . 02 ( d , 2 h , j = 9 . 0 hz ), 7 . 85 ( d , 2 h , j = 9 . 0 hz ), 13 . 84 ( s , 1 h ); 13 c nmr ( 75 mhz , cdcl 3 ) δ 181 . 7 , 164 . 4 , 163 . 5 , 162 . 9 , 161 . 3 , 158 . 3 , 128 . 2 , 123 . 3 , 114 . 6 , 104 . 4 , 104 . 3 , 90 . 5 , 90 . 4 , 56 . 8 , 55 . 5 ; ei - ms m / z 424 ( m + , 100 ). anal . calcd for c 17 h 13 io 5 : c , 48 . 14 ; h , 3 . 09 . found : c , 48 . 30 ; h , 3 . 11 . 6 - iodo - 5 , 7 , 4 ′- trimethoxyflavone ( 8 ). to a solution of 7 ( 3 . 00 g , 7 . 08 mmol ) and k 2 co 3 ( 1 . 47 g , 10 . 6 mmol ) in 150 ml thf was added dimethylsulfate ( 1 . 07 g , 8 . 49 mmol ) and the solution heated at reflux overnight . the solvent was evaporated and the residue partitioned between 50 ml each of chcl 3 and h 2 o . the organic phase was separated and washed with saturated brine , dried over magnesium sulfate , filtered and evaporated to provide a yellow solid . recrystallization from chcl 3 / etoh ( 1 : 2 , 150 ml ) afforded pale - yellow needles . column chromatography of the evaporated mother liquor ( 100 g silica gel , 2 % meoh / ch 2 cl 2 ) afforded an additional 720 mg of desired product ( total yield 2 . 21 g , 71 . 3 %); mp 204 ° c . ( lit . 13 mp 191 - 194 ° c . ); 1 h nmr ( cdcl 3 ) δ 3 . 89 ( s , 3 h ), 3 . 94 ( s , 3 h ), 4 . 01 ( s , 3 h ), 6 . 62 ( s , 1 h ), 6 . 78 ( s , 1 h ), 7 . 01 ( d , 2 h , j = 9 . 1 hz ), 7 . 83 ( d , 2 h , j = 9 . 1 hz ); ei - ms in / z 438 ( m + , 65 ), 311 ( 100 ). anal . calcd for c 18 h 15 io 5 : c , 49 . 34 ; h , 3 . 45 . found : c , 48 . 58 ; h , 3 . 21 . 5 , 7 - 4 ′- trimethoxy - 3 ′-( trimethylstannyl ) flavone ( 9a ). to a solution of 5a ( 438 mg , 1 . 00 mmol ) in 30 ml toluene was added pd ( ph 3 p ) 4 ( 150 mg , 0 . 13 mmol ) and hexamethylditin ( 655 mg , 2 . 00 mmol ), and the solution heated to reflux under n 2 for 16 h . the solution was filtered and the solvent evaporated in vacuo . the residue was dissolved in 75 ml chcl 3 , washed with 75 ml saturated brine , dried over magnesium sulfate , filtered and evaporated to provide a white crystalline solid . the solid was triturated with 10 ml etoh , collected on a buchner funnel , rinsed with fresh etoh and air dried ( 270 mg , 56 . 8 %). an analytical sample was obtained via recrystallization from etoh , which produced fine colorless needles ; mp 154 ° c . ; 1 h nmr ( dmso - d 6 ) δ 0 . 31 ( s , 9 h ), 3 . 83 ( s , 3 h ), 3 . 85 ( s , 3 h ), 3 . 91 ( s , 3 h ), 6 . 51 ( d , 1 h , j = 2 . 4 hz ), 6 . 65 ( s , 1 h ), 6 . 82 ( d , 1 h , j = 2 . 4 hz ), 7 . 08 ( d , 1 h , j = 8 . 7 hz ), 7 . 86 ( d , 1 h , j = 2 . 4 hz ), 8 . 01 ( dd , 1 h , j = 8 . 7 , 2 . 4 hz ); 13 c nmr ( 75 mhz , cdcl 3 ) δ 177 . 9 , 166 . 5 , 164 . 0 , 161 . 4 , 161 . 0 , 160 . 1 , 134 . 3 , 131 . 7 , 128 . 6 , 124 . 1 , 109 . 1 , 107 . 7 , 96 . 0 , 92 . 9 , 56 . 4 , 55 . 7 , 55 . 5 ; ei - ms m / z 476 ( m + , 64 ), 461 ( 100 ). anal . calcd for c 21 h 24 o 5 sn : c , 53 . 09 ; h , 5 . 09 . found : c , 52 . 74 ; h , 5 . 01 . pinacol 5 , 7 - 4 ′- trimethoxyflavone - 3 ′- boronate ( 9b ). a solution of 5a ( 2 . 00 g , 4 . 56 mmol ), bis ( pinacolato ) diboron ( 1 . 50 g , 5 . 93 mmol ), koac ( 1 . 79 g , 18 . 24 mmol ) and pdcl 2 ( dppf ) ( 372 mg , 0 . 456 mmol ) in 60 ml dmf was stirred at 80 ° c . overnight . the reaction mixture was filtered , diluted with 200 ml etoac , then washed with h 2 o ( 3 ×) and brine . after drying over sodium sulfate , the solvent was evaporated . the product was chromatographed over silica gel ( etoac / meoh , 96 : 4 ) to afford 1 . 21 g ( 60 . 5 %) of the desired product as a gray solid . the material could be recrystallized from ch 2 cl 2 / etoac , as pale gray needles ; mp 218 - 220 ° c . ; 1 h nmr ( cdcl 3 ) δ 1 . 39 ( s , 12 h ), 3 . 91 ( s , 3 h ), 3 . 92 ( s , 3 h ), 3 . 96 ( s , 3 h ), 6 . 38 ( d , 1 h , j = 2 . 2 hz ), 6 . 60 ( d , 1 h , j = 2 . 2 hz ), 6 . 66 ( s , 1 h ), 6 . 96 ( d , 1 h , j = 8 . 9 hz ), 7 . 96 ( dd , 1 h , j = 8 . 9 , 2 . 4 hz ), 8 . 18 ( d , 1 h , j = 2 . 4 hz ); 13 c nmr ( cdcl 3 ) δ 177 . 9 , 166 . 6 , 164 . 0 , 161 . 0 , 160 . 9 , 160 . 0 , 134 . 9 , 130 . 4 , 123 . 3 , 114 . 4 , 110 . 6 , 109 . 3 , 107 . 8 , 96 . 0 , 93 . 0 , 83 . 9 , 56 . 4 , 55 . 9 , 55 . 7 , 24 . 7 ; ftir ( kbr ) 1645 , 1602 , 1330 , 1148 cm − 1 ; apci - ms m / z 439 ( mh + , 100 ). anal . calcd for c 24 h 27 bo 7 . ½ h 2 o : c , 64 . 45 ; h , 6 . 31 . found : c , 64 . 17 ; h , 6 . 05 . robustaflavone hexamethyl ether ( 10 ). to a solution of 8 ( 25 . 0 mg , 0 . 057 mmol ) and 9a ( 50 . 0 mg , 0 . 114 mmol ) in dmf / h 2 o ( 9 : 1 ) which had been deoxygenated for 15 min by bubbling n 2 , was added naoh ( 9 . 1 mg , 0 . 23 mmol ) and pd ( pph 3 ) 4 ( 6 . 6 mg , 0 . 0057 mmol ), and the reaction stirred at 80 ° c . for 2 h . the solution was diluted with ch 2 cl 2 , then extracted with h 2 o and saturated brine . the organic layer was dried over magnesium sulfate , filtered and evaporated in vacuo . column chromatography ( silica gel , ch 2 cl 2 / meoh , 96 : 4 ) afforded the desired product 10 ( 17 . 7 mg , 50 %), identical with an authentic sample prepared via methylation of robustaflavone 7 : mp 296 - 297 ° c . ( lit . 7 mp 303 - 305 ° c .) 1 h nmr ( cdcl 3 ) δ 3 . 62 ( s , 3 h ), 3 . 85 ( s , 3 h ), 3 . 87 ( s , 3 h ), 3 . 91 ( s , 6 h ), 3 . 96 ( s , 3 h ), 6 . 37 ( d , 1 h , j = 2 . 1 hz ), 6 . 60 ( d , 1 h , j = 2 . 4 hz ), 6 . 69 ( s , 1 h ), 6 . 74 ( s , 1 h ), 6 . 89 ( s , 1 h ), 7 . 04 ( d , 2 h , j = 9 . 0 hz ), 7 . 10 ( d , 1 h , j = 8 . 7 hz ), 7 . 81 ( d , 1 h , j = 2 . 4 hz ), 7 . 89 ( d , 2 h , j = 9 . 0 hz ), 7 . 89 ( dt , 1 h , j = 2 . 1 , 8 . 7 hz ). anal . calcd for c 36 h 30 o 10 . ½ h 2 o : c , 68 . 46 ; h , 4 . 91 . found : c , 68 . 28 ; h , 5 . 19 . robustaflavone . to a solution of 10 ( 75 . 0 mg , 0 . 12 mmol ) in 10 ml dry chc 3 was added bbr 3 ( 1 . 0 m in ch 2 cl 2 , 1 . 45 ml , 1 . 45 mmol ), and the resulting yellow slurry was stirred at reflux overnight . the reaction mixture was cooled to room temperature , quenched by the careful addition of meoh , and evaporated in vacuo . the resulting orange solid was triturated with meoh , the solvent again evaporated in vacuo , and the solid was partitioned between etoac and 1 m naoh . the organic layer was discarded , and the aqueous layer was extracted with etoac . after cooling to 0 ° c ., the aqueous layer was carefully acidified to ph 3 . 0 by the dropwise addition of 3 m hcl . the resulting yellow precipitate was collected by vacuum filtration , rinsed with water and air dried ( 38 . 7 mg ). the crude material was chromatographed through silica gel , eluting with a mixture of toluene / pyridine / formic acid ( 20 : 10 : 1 ). appropriate fractions were combined and evaporated to afford 19 . 4 mg ( 30 . 0 %) robustaflavone . an analytical sample was obtained via recrystallization from pyridine / h 2 o ( 1 : 1 ); mp 370 - 372 ° c ., dec . ( lit . 1 mp 350 - 352 ° c .). spectral data of synthetic robustaflavone was identical to that recently reported 1 for the natural product isolated from rhus succedanea . anal . calcd for c 30 h 18 o 10 . 1 . 25 h 2 o : c , 64 . 23 ; h , 3 . 68 . found : c , 64 . 17 ; h , 3 . 68 . to a solution of 8 ( 25 mg , 0 . 057 mmol ) and 2 - methoxyphyenylboronic acid ( 13 mg , 0 . 086 mmol ) in a mixture of dmf / h 2 o ( 9 : 1 ) containing 9 . 1 mg ( 0 . 228 ) naoh was added pd ( pph 3 ) 4 ( 6 . 6mg , 0 . 0057 mmol ). the solution was magnetically stirred for 90 minutes at 80 ° c . then cooled to room temperature . after diluting with etoac , the solution was washed with h 2 o and saturated brine , then dried over magnesium sulfate , filtered and concentrated in vacuo . the residue was purified using silica gel column chromatography ( etoac / hexane , 1 : 1 ) to afford 15 . 8 mg ( 66 . 2 %) of the anticipated product ; 1 h nmr ( cdcl 3 ) 3 . 60 s , 3 h ), 3 . 76 ( s , 3h ), 3 . 84 ( s , 3h ), 3 . 90 ( s , 3 h ), 6 . 62 ( s , 1 h ), 6 . 85 ( s , 1 h ), 7 . 03 ( m , 4h ), 7 . 20 ( dd , 1 h , j = 8 . 0 , 1 . 5 hz ), 7 . 39 ( dt , 1 h , j = 7 . 9 , 1 . 5 hz ), 7 . 86 ( m , 2h ); apci - ms m / z 419 ( mh 4 , 100 ), 405 . while the fundamental novel features of the invention have been described , it will be understood that various omissions , substitutions and changes in the form and details illustrated may be made by those skilled in the art without departing from the spirit of the invention . it is the intention , therefore , to be limited only as indicated by the scope of the claims . 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