New ring closing metathesis based methodology for the synthesis of monomeric flavonoids

[摘要] Although the physiological activity of flavonoids stimulated investigations into more efficientsynthetic methods for the preparation of these compounds, many of these routes entailmultiple steps and require the utilization of stoichiometric and often poisonous reagents.Known methodologies are also hampered by difficulties around the isolation of the desiredproduct and often lead to inseparable mixtures, low yields, and tedious synthetic processes.To circumvent these problems and to bring the synthesis of flavonoids in line with modernsynthetic methodologies, it was decided to embark on a process of preparing the differentclasses of flavonoids through the application of a catalytic process, like ring closingmetathesis (RCM), as key step in the methodology. Developing this methodology would havethe added advantage that all the different classes of flavonoids would be reachable fromreadily available starting materials and the application of basically a single catalytic reactionin the final process step.For entry into the first class of flavonoids, i.e. compounds with a 2-phenylchromane skeleton,the preparation of flav-2-enes were investigated as key intermediate. In this regard, allylphenyl ethers, prepared via Williamson etherification [K2CO3 (2.0 e.q), CH3CN, reflux], weresubjected to Claisen rearrangement in a neat microwave assisted process to obtain thesubstituted allyl benzenes, 1-allyl-2-hydroxy-4-methoxybenzene and 1-allyl-2-hydroxy-4,6-dimethoxybenzene, in 44% and 88% yields, respectively. Subsequent esterification of theallyl phenols with substituted benzoyl chlorides [aq. NaOH (2.0 M, 40.0 mL) or 4-dimethylaminopyridine (0.2 eq.), dry pyridine (1.0 eq.), dichloromethane, reflux] afforded aseries of the benzoates, i.e. 2-allylphenyl benzoate, 2-allylphenyl 4-methoxybenzoate, 2-allylphenyl 3,4-dimethoxybenzoate, 2-allylphenyl 3,4,5-trimethoxybenzoate, 2-allyl-5-methoxyphenyl 3,4-dimethoxybenzoate, 2-allyl-5-methoxyphenyl 3,4,5-trimethoxybenzoate,2-allyl-3,5-dimethoxyphenyl 3,4-dimethoxybenzoate and 2-allyl-3,5-dimethoxyphenyl 3,4,5-trimethoxybenzoate in 68 �?98% yield. During methylenation of these esters throughutilisation of the Tebbe reagent, it was found that the reaction is largely dependent on theconcentration of the substrate, as well as reaction time and temperature. High yields (71 �?4%) were obtained with an increase in concentration of the ester and a brief period atelevated temperature (80 �?90°C). While a series of substituted diaryl vinyl ethers could beprepared, methylenation of substrates containing a phloroglucinol-type substitution pattern onwhat was to become the A-ring of the flavonoid failed. Ring closing metathesis of all thevinyl ethers in hand under standard metathesis conditions [Grubbs II, dichloromethane,reflux] led to the formation of flav-2-ene, 4'-methoxyflav-2-ene, 3',4'-dimethoxyflav-2-ene,3',4',5'-trimethoxyflav-2-ene, 3',4',7-trimethoxyflav-2-ene and 3',4',5',7-tetramethoxyflav-2-ene in 41 �?96% yields. Attempts at the epoxidation of flav-2-ene with m-CPBA with andwithout a base (NaHCO3), did not yield any of the desired product.Construction of the isoflavonoid nucleus was first attempted through preparation of theisoflav-2-ene analogue via the deoxybenzoin intermediate, which could be prepared byphenylmagnesium bromide addition to the corresponding phenyl acetate. Although thephenyl acetates (methyl 4-methoxyphenyl acetate, methyl 4-trifluoromethylphenyl acetate,methyl 3-methoxy-4-trifluoromethanesulfonyloxyphenyl acetate and methyl 3,5-dimethoxyphenyl-4-trifluoromethanesulfonyloxyacetate) could be prepared in excellentyields (80 �?99%) via ozonolysis of the substituted allyl benzenes, the transformation of thesecompounds into the required deoxybenzoins was hampered by the inability (even attemperatures as low as -78 °C) to stop the reaction of the Grignard reagent with the substrateat the ketone stage. The methodology for the preparation of isoflavenes was therefore adaptedto the synthesis of the isoflav-3-ene analogues, which could be constructed through a one-potreaction of the substituted benzaldehyde with substituted α-bromoacetophenones followed byWittig reaction with methyltriphenylphosphonium bromide to afford vinyl benzeneintermediates, 4-methoxy-2-[(2-phenylallyl)oxy]-1-vinylbenzene, 1,5-dimethoxy-3-[(2-phenylallyl)oxy]-2-vinylbenzene, 1-{[2-(4-methoxyphenyl)allyl]oxy}-2-vinylbenzene, 4-methoxy-2-{[2-(4-methoxyphenyl)allyl]oxy}-1-vinylbenzene and 1,5-dimethoxy-3-{[2-(4-methoxyphenyl)allyl]oxy}-2-vinylbenzene, in 61 �?89% yield. Subsequent ring closingmetathesis of the 7- and/or 4' substituted vinyl benzenes proceeded smoothly over Grubbs IIcatalyst in refluxing DCM and gave the isoflav-3-enes, (7-methoxyisoflav-3-ene, 4'-methoxyisoflav-3-ene and 4',7-dimethoxyisoflav-3-ene) in 57% to quantitative yields. RCMof the vinyl benzenes with a phloroglucinol-type substitution pattern, however, requiredelevated temperatures (refluxing toluene) and/or the addition of 1,4-benzoquinone in order toform the isoflav-3-enes, 5,7-dimethoxyisoflav-3-ene and 4',5,7-trimethoxyisoflav-3-ene, indecent yields (67 and 65%, respectively). Subsequent epoxidation of 7-methoxyisoflav-3-enewith m-CPBA and NaHCO3 in dichloromethane again failed to give any of the desiredisoflavene epoxide.Although the neoflavonoid nucleus could be reached through Claisen rearrangement of 1-cinnamyloxybenzenes followed by vinylation of the phenolic hydroxy entity or Wittigmediated methylenation of 2-allyloxybenzophenones, followed by ring closing metathesis,this methodology was not viewed as being appropriate for application to oxygenatedsubstrates as a number of process steps would be required to obtain oxygenated startingmaterials. It was therefore decided to follow a process where the appropriate acetophenoneswould be converted into the substituted styrenes by a Grignard reaction-dehydration process.Since electron-rich acetophenones are notorious for being lousy substrates in Grignardreactions the addition of aluminium triflate to the reaction mixture to enhance the reactivityof the reactant was investigated and it was found that the addition of Al(OTf)3 to the reactionmixture had a significant effect on the reaction of 4-methoxyphenylmagnesium bromide and2-allyloxy-4-methoxyacetophenone. Not only did the presence of the Lewis acid increase thereaction rate, but it also led to the direct formation of the substituted styrene in 66% yield.Extending this reaction to the addition of phenylmagnesium bromide to 2-allyloxy-4,6-dimethoxyacetophenone and the addition of 4-methoxyphenylmagnesium bromide to 2-allyloxy-4,6-dimethoxyacetophenone and 2-allyloxy-4,5-dimethoxyacetophenone gave thesubstituted styrene products in moderate to high yields (52 �?94%). When 3,4-dimethoxyphenylmagnesium bromide was utilised in reactions with 2-allyloxy-4-methoxyacetophenone and 2-allyloxy-4,5-dimethoxyacetophenone, however, the analogousalcohols were obtained in 50% and 4% yields, respectively. When employing standardGrignard conditions (THF, -60 °C) i.e. without Al(OTf)3 activation, the tertiary alcoholproducts could be obtained 60% and 80% yields, respectively. Subsequent CuSO4-mediateddehydration of the alcohols yielded the desired styrenes (75% and 65%, respectively). Ringclosing metathesis of all the styrene intermediates in hand proceeded smoothly and yieldedthe series of neoflav-3-enes, (4',7-dimethoxyneoflav-3-ene, 5,7-dimethoxyneoflav-3-ene,4',5,7-trimethoxyneoflav-3-ene, 4',6,7-trimethoxyneoflav-3-ene, 3',4',7-trimethoxyneoflav-3-ene and 3',4',6,7-tetramethoxyneoflav-3-ene) in excellent yields (67% �?quant.).Since it was shown that aluminium triflate had an enhancing effect on the addition ofGrignard reagents to the acetophenones required for the synthesis of neoflavenes and that thestyrenes could be obtained in a one-step process, it was decided to explore the scope of thisnovel process towards other ketones. During this investigation it was determined that theaddition of Grignard reagents like phenylmagnesium bromide, benzylmagnesium bromideand ethylmagnesium bromide, to electron-rich ketones, i.e. 4-methoxyacetophenone, 2,4-dimethoxyacetophenone, 2,4-dimethoxypropiophenone and 4-chromanone, led to theformation of respective alkenes in 46 �?97% yields, while no product formation was observed for the less activated substrates like 4-chloroacetophenone and α-tetralone. It was furthermoreobserved that for the reaction of 4-methoxyacetophenone with ethyl - and benzylmagnesiumbromide only the E-isomers of the product was formed, while only the Z-isomer was obtainedduring the addition of ethylmagnesium bromide to 2,4-dimethoxyacetophenone. The reactionof 2,4-dimethoxypropiophenone with phenylmagnesium bromide, on the other hand, yieldedboth geometric isomers in a 1:1 ratio. The stereoselectivity found during the reactions of 4-methoxy- and 2,4-dimethoxyacetophenone with ethyl - and benzylmagnesium bromide isprobably explicable in terms of an E2 elimination process involving the preferred stericallyless hindered gauche conformation of the transition state. Extending the reaction to theaddition of phenylmagnesium bromide to α,β -unsaturated systems, like chalcone, indicatedAl(OTf)3 to also have an activating effect in this regard, albeit to a marginal extent, sinceonly an 8% increase in the yield of the 1,4-addition product was observed. Finally,indications were also found that Al(OTf)3 may also be utilized in catalytic quantities for thisreaction when p-methoxy-1-phenylstyrene could be prepared in 82% yield by utilisingAl(OTf)3 in 10 mol%; thus rendering the new methodology the first Grignard based Lewisacid catalysed process for the direct synthesis of alkenes.

[发布机构] University of the Free State