New ring closing metathesis based methodology for the synthesis of monomeric flavonoids
Loading...
Date
2017-02
Authors
Pieterse, Tanya
Journal Title
Journal ISSN
Volume Title
Publisher
University of the Free State
Abstract
Although the physiological activity of flavonoids stimulated investigations into more efficient
synthetic methods for the preparation of these compounds, many of these routes entail
multiple steps and require the utilization of stoichiometric and often poisonous reagents.
Known methodologies are also hampered by difficulties around the isolation of the desired
product 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 modern
synthetic methodologies, it was decided to embark on a process of preparing the different
classes of flavonoids through the application of a catalytic process, like ring closing
metathesis (RCM), as key step in the methodology. Developing this methodology would have
the added advantage that all the different classes of flavonoids would be reachable from
readily available starting materials and the application of basically a single catalytic reaction
in 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, allyl
phenyl ethers, prepared via Williamson etherification [K2CO3 (2.0 e.q), CH3CN, reflux], were
subjected to Claisen rearrangement in a neat microwave assisted process to obtain the
substituted 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 the
allyl 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 a
series 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 through
utilisation of the Tebbe reagent, it was found that the reaction is largely dependent on the
concentration of the substrate, as well as reaction time and temperature. High yields (71 –
94%) were obtained with an increase in concentration of the ester and a brief period at
elevated temperature (80 – 90°C). While a series of substituted diaryl vinyl ethers could be
prepared, methylenation of substrates containing a phloroglucinol-type substitution pattern on
what was to become the A-ring of the flavonoid failed. Ring closing metathesis of all the
vinyl 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 and
without a base (NaHCO3), did not yield any of the desired product.
Construction of the isoflavonoid nucleus was first attempted through preparation of the
isoflav-2-ene analogue via the deoxybenzoin intermediate, which could be prepared by
phenylmagnesium bromide addition to the corresponding phenyl acetate. Although the
phenyl 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 excellent
yields (80 – 99%) via ozonolysis of the substituted allyl benzenes, the transformation of these
compounds into the required deoxybenzoins was hampered by the inability (even at
temperatures as low as -78 °C) to stop the reaction of the Grignard reagent with the substrate
at the ketone stage. The methodology for the preparation of isoflavenes was therefore adapted
to the synthesis of the isoflav-3-ene analogues, which could be constructed through a one-pot
reaction of the substituted benzaldehyde with substituted α-bromoacetophenones followed by
Wittig reaction with methyltriphenylphosphonium bromide to afford vinyl benzene
intermediates, 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 closing
metathesis of the 7- and/or 4' substituted vinyl benzenes proceeded smoothly over Grubbs II
catalyst 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. RCM
of the vinyl benzenes with a phloroglucinol-type substitution pattern, however, required
elevated temperatures (refluxing toluene) and/or the addition of 1,4-benzoquinone in order to
form the isoflav-3-enes, 5,7-dimethoxyisoflav-3-ene and 4',5,7-trimethoxyisoflav-3-ene, in
decent yields (67 and 65%, respectively). Subsequent epoxidation of 7-methoxyisoflav-3-ene
with m-CPBA and NaHCO3 in dichloromethane again failed to give any of the desired
isoflavene epoxide.
Although the neoflavonoid nucleus could be reached through Claisen rearrangement of 1-
cinnamyloxybenzenes followed by vinylation of the phenolic hydroxy entity or Wittig
mediated methylenation of 2-allyloxybenzophenones, followed by ring closing metathesis,
this methodology was not viewed as being appropriate for application to oxygenated
substrates as a number of process steps would be required to obtain oxygenated starting
materials. It was therefore decided to follow a process where the appropriate acetophenones
would be converted into the substituted styrenes by a Grignard reaction-dehydration process.
Since electron-rich acetophenones are notorious for being lousy substrates in Grignard
reactions the addition of aluminium triflate to the reaction mixture to enhance the reactivity
of the reactant was investigated and it was found that the addition of Al(OTf)3 to the reaction
mixture had a significant effect on the reaction of 4-methoxyphenylmagnesium bromide and
2-allyloxy-4-methoxyacetophenone. Not only did the presence of the Lewis acid increase the
reaction 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 the
substituted 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 analogous
alcohols were obtained in 50% and 4% yields, respectively. When employing standard
Grignard conditions (THF, -60 °C) i.e. without Al(OTf)3 activation, the tertiary alcohol
products could be obtained 60% and 80% yields, respectively. Subsequent CuSO4-mediated
dehydration of the alcohols yielded the desired styrenes (75% and 65%, respectively). Ring
closing metathesis of all the styrene intermediates in hand proceeded smoothly and yielded
the 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 of
Grignard reagents to the acetophenones required for the synthesis of neoflavenes and that the
styrenes could be obtained in a one-step process, it was decided to explore the scope of this
novel process towards other ketones. During this investigation it was determined that the
addition of Grignard reagents like phenylmagnesium bromide, benzylmagnesium bromide
and ethylmagnesium bromide, to electron-rich ketones, i.e. 4-methoxyacetophenone, 2,4-
dimethoxyacetophenone, 2,4-dimethoxypropiophenone and 4-chromanone, led to the
formation 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 furthermore
observed that for the reaction of 4-methoxyacetophenone with ethyl - and benzylmagnesium
bromide only the E-isomers of the product was formed, while only the Z-isomer was obtained
during the addition of ethylmagnesium bromide to 2,4-dimethoxyacetophenone. The reaction
of 2,4-dimethoxypropiophenone with phenylmagnesium bromide, on the other hand, yielded
both 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 is
probably explicable in terms of an E2 elimination process involving the preferred sterically
less hindered gauche conformation of the transition state. Extending the reaction to the
addition of phenylmagnesium bromide to α,β -unsaturated systems, like chalcone, indicated
Al(OTf)3 to also have an activating effect in this regard, albeit to a marginal extent, since
only 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 this
reaction when p-methoxy-1-phenylstyrene could be prepared in 82% yield by utilising
Al(OTf)3 in 10 mol%; thus rendering the new methodology the first Grignard based Lewis
acid catalysed process for the direct synthesis of alkenes.
Description
Keywords
Ring closing metathesis, Flavonoid, Claisen rearrangement, Tebbe, Grubbs II, Isoflavonoid, Wittig, Neoflavonoid, Aluminium triflate, Elimination, Thesis (Ph.D. (Chemistry)--University of the Free State, 2017