Parameters influencing regioselectivity in the palladium catalysed carbonylation of stilbenes and related alkenes

[摘要] English: Flavonoids are polyphenolic naturally occurring compounds with a wide variety of biological and physiological activities, like anti-platelet, anti-inflammatory, antioxidant, antiviral, antiallergenic, and antitumor properties. The potential therapeutic value of these compounds gave impetus to the development of numerous synthetic routes to not only get access to more material than possible through the isolation thereof from natural sources, but also to have access to flavonoids with substitution patterns different to those of naturally occurring analogues. Existing synthetic methodologies, however, involve tedious multistep processes, stoichiometric amounts of sometimes toxic reagents that produce large amounts of waste, harsh reaction conditions and are not always high yielding. With this in mind, it was envisaged that isoflavonoids might be accessible via a catalytic process entailing hydroesterification of 2-hydroxystilbenes. If the desired regio-isomer could be obtained during this reaction, cyclization between the 2-hydroxy group and the introduced ester moiety would give rise to the heterocyclic C-ring of the corresponding isoflavonoid. Although it is known that steric factors play a prominent role in regioselective control during hydroesterification processes, little is known about the role of the electronic environment around the double bond during these reactions. To address this issue and determine the feasibility of hydroesterification methodology for the synthesis of isoflavonoids, various stilbenes with electron-withdrawing and electron-donating groups, respectively on the two aromatic rings were envisaged as substrates to be subjected to palladium catalysed hydroesterification reactions. Since the Wittig reaction is well-known for the formation of alkenes such as the envisaged stilbenes, this approach was followed in order to prepare the required starting materials. Although the phosphonium salts, benzyltriphenylphosphonium bromide and p-methoxybenzyltriphenylphosphonium chloride, required as reactant in the Wittig reaction, could easily be prepared from the benzyl halide and triphenylphosphine (PPh3) in good yields (98 % and 76 %, respectively), preparation of the p-methoxybenzyl bromide/chloride were more challenging and led to an overall yield for the phosphonium salt of only 45 %. Other methodologies towards the synthesis of substituted phosphonium salts, i.e. treatment of p-methoxybenzyl alcohol with PPh3 in trifluoroacetic acid and cleavage of the benzyl methyl ether, p-methoxybenzyl methyl ether, with PPh3 .HBr, were therefore investigated but yields of only 10 and 38 %, respectively, were obtained. With the best methodology for the synthesis of phosphonium salts determined, attention was subsequently turned towards the final step in the preparation of the envisaged starting materials, i.e. synthesis of the oxygenated stilbenes. Methoxystilbene was therefore prepared according to the traditional Wittig reaction between benzyltriphenylphosphonium bromide and p-anisaldehyde, with BuLi as base and the product obtained in only 33 %. In an effort to improve on the yield, the same Wittig reaction was performed utilizing an organic/aqueous (aldehyde and aq. NaOH) biphasic solvent system with NaOH as base, which led to an increase in yield (54 %). Application of the same methodology to the synthesis of 2- methoxystilbene and 4-ethoxymethoxystilbene resulted in the formation of the desired products in 53 and 55 % yields, respectively. The latter compound, 4-ethoxymethoxystilbene, was subsequently subjected to acid catalysed deprotection (quantitative yield) followed by reaction with trifluoromethanesulfonyl chloride and triethylamine to obtain a stilbene, 4-trifluorosulfonyloxystilbene, protected with an electronwithdrawing substituent in 54 % yield. In an effort to improve the yields obtained for the stilbene preparation process to beyond ca. 50 %, a microwave assisted Perkin-type reaction between phydroxybenzaldehyde and phenylacetic acid with a piperidine-imidazole catalyst system and PEG-400 as solvent, was embarked upon and hydroxystilbene obtained in 42 % yield. Although the yield was almost the same as what was found with the Wittig method, this reaction did not require protection of the free phenolic hydroxy group or the time consuming preparation of starting materials and needed reaction times of only 10 minutes, as well as the added advantage of it being an environmentally more favourable procedure compared to the Wittig reaction. Since Pd(OAc)2 together with PPh3 and the Lewis acid activator/co-catalyst Al(OTf)3 have been reported as one of the best catalyst systems for the methoxycarbonylation of many different aliphatic alkenes, this catalyst system was utilized in the methoxycarbonylation (35 bar CO pressure, 95 °C) of model substrates like hex-1-ene, styrene and allylbenzene and obtained conversions to the corresponding methyl ester products of 70, 99 and 57 %, respectively. When trans-stilbene was, however subjected to the same reaction conditions and catalyst system, virtually no product was formed, so it was decided to use the model substrate, trans-β-methylstyrene, for determining the best catalyst system and reaction conditions for the methoxycarbonylation of substrates that has the double bond in conjugation with an aromatic ring. While it was found during this investigation that the reaction conditions of 35 bar and 95 °C was indeed the optimum for trans-β-methylstyrene, PdCl2 proved to be more reactive than Pd(OAc)2 when applied to the methoxycarbonylation of substrates with conjugated double bonds, with a 90 % conversion to the products, methyl 4-phenylbutanoate, methyl 2-methyl-3-phenylpropanoate and methyl 2-phenylbutanoate, in a 6:2:1 ratio. Due to the insolubility of trans-stilbene in pure methanol, a solvent study was embarked upon and MeOH:THF (1:1) was found to be the best alternative to pure methanol (conversion of 61 vs. 90 % in pure MeOH). With the optimum reaction conditions determined, the influence of a higher degree of substitution around the double bond as well as position of substituents attached to the double bond were investigated, it was also decided to evaluate the effect of the electron-donating and electron-withdrawing substituents attached to the aromatic ring, on the outcome of the reaction. Subjecting α-methylstyrene and 2-methyl-1- phenylprop-1-ene to the reaction conditions, led to the conversion (38 and 22 %, respectively) and isolation of the expected products, methyl 3-phenylbutanoate and methyl 3-methyl-4-phenylbutanoate, indicating that the steric environment around the double bond indeed has a significant influence on the reaction. The electronic effects were studied through the methoxycarbonylation of trans-anethole (the p-methoxy equivalent of trans-β-methylstyrene) and 1-(4'-trifluoromethanesulfonyloxyphenyl)prop-1-ene and, while the three expected products were obtained, it was found that an aromatic methoxy substitutent has an inhibiting effect on the reaction (21 % vs. 90 % conversion of trans-β-methylstyrene), while the substrate with the deactivating group showed a much improved conversion (31 %) compared to the p-methoxy analogue. Performing the methoxycarbonylation of trans-β-methylstyrene (in MeOH) in the presence of anisole (1:1) proved that aromatic methyl ethers indeed have a detrimental effect on the reaction, since only trace amounts of the products could be detected in this instance. Since chiral induction during the enantioselective synthesis of isoflavonoids has been achieved through utilization of amide chiral auxiliaries, like 2-imidazolidinones, it was decided to investigate the possibility of transforming an alkene into an amide in a one-step reaction and therefore circumvent the need for a second reaction to obtain the desired amide. Trans-β-methylstyrene was therefore subjected to the methoxycarbonylation conditions developed before [PdCl2/Al(OTf)3/PPh3, 35 bar CO, 95 °C], but in an inert solvent (THF) containing aniline as nucleophile and 53 % conversion to N,2-diphenylbutanamide and 2-methyl-N,3-diphenylpropanamide in a 6:1 ratio was obtained. Encouraged by the success of the first ever palladium catalysed aminocarbonylation reaction, the scope of the reaction was extended to include substrates like benzamide, n-butylamine and piperidine, but these nucleophiles were found to be unreactive, so more work is clearly needed to determine the conditions necessary for the successful utilization of these compounds in aminocarbonylation reactions. Finally, attention was turned to the methoxycarbonylation of the stilbenes, therefore trans- and cis-stilbene as well as trans-2-methoxystilbene were subjected to the palladium catalysed reaction, but only very low conversions (trace amounts up to 4 %) were found. Since everything pointed towards the electronic effect of conjugation, which deactivates the double bond to such an extent that the reaction with the palladium catalyst is supressed, being the cause of the failure of stilbenes to undergo methoxycarbonylation, 1,3- diphenylprop-1-ene, a substrate with the double bond not in conjugation with the two aromatic rings, were therefore subjected to the reaction and a conversion of 27 % to the product, methyl 2,4-diphenylbutanoate, was obtained. This result clearly demonstrates that the failure of stilbenes to undergo hydroesterification reactions originates in the fact that the double bond is in conjugation with two aromatic rings.

[发布机构] University of the Free State