Palladium catalysed hydroesterification and aminocarbonylation of substituted alkenes and alkynes

[摘要] Since the aim of this study was to investigate the influence of the electronic environmentaround the double bond of alkenes on the reactivity and regioselectivity of themethoxycarbonylation reaction for developing new methodology towards the synthesis ofisoflavonoids, several aryl substituted alkenes were subjected to methoxycarbonylationutilizing the Pd(OAc)2/Al(OTf)3/PPh3 catalyst system in MeOH under the optimumconditions of 35 bar of CO pressure and 95 °C. In order to be able to compare current resultswith literature values, 1-octene, 2-octene and styrene, were the first substrates to bemethoxycarbonylated and gave anticipated high conversions (100%, 83% and 91%,respectively) to the expected linear (l) and branched (b) methyl esters, methyl nonanoate andmethyl 2-methylnonanoate as well as methyl 3-phenylpropanoate and methyl 2-phenylpropanoate, respectively in a l:b ratio of ca. 3:1. A set of trans-β-methylstyreneanalogues, i.e. trans-β-methylstyrene, trans-p-methoxy-β-methylstyrene and trans-omethoxy-β-methylstyrene as well as a set of allylbenzene analogues, i.e. allylbenzene, pmethoxyallylbenzene,p-trifluoromethylallylbenzene, o-methoxyallylbenzene and otrifluoromethanesulfonyloxyallylbenzenewere subjected to the methoxycarbonylationreaction conditions and the products obtained in high conversions (88-96%) except for thealkenes with methoxy substituents in the para-position, i.e. p-methoxy-β-methylstyrene andp-methoxyallylbenzene (49% and 66%, respectively). During these investigationsisomerization of the double bond in the β-methylstyrenes to the terminal position, formingallylbenzene analogues proved to be a feasible side-reaction, so the same products, i.e. linear(l), branched (b) and benzylic (bn) carboxylated products were formed from the β-methylstyrenes and corresponding allylbenzenes. During the investigation it was also foundthat a p-methoxy substituent on the β-methylstyrene or allylbenzene resulted in a decrease inreaction rate, while an o-methoxy substituent increases the reaction rate substantially incomparison to the p-methoxy analogues. Ortho-substituents (methoxy or triflate group) alsoresulted in a drastic increase in the formation of the linear products for both the β-methylstyrene and allylbenzene substrates, i.e. 3:2:1 vs. 10:4:1 and 8:2:1 vs. 15:5:1 vs. 5:1:0,respectively. It was also determined that a more electron-rich aromatic ring has an enhancingeffect on the formation of the benzylic products as was determined by the methoxycarbonylationof 1,3-diphenylpropene, which gave methyl 2,4-diphenylbutanoate in 64%yield and 95% regioselectivity. Sterically more demanding disubstituted and trisubstituteddouble bonds, like in α-methylstyrene and 2-methyl-1-phenylprop-1-ene, were also subjectedto the methoxycarbonylation reaction and resulted in the formation of methyl 3-phenylbutanoate in 63% and methyl 3-methyl-4-phenylbutanonate in 26% yield, respectively,albeit after extended reaction periods (4-6 h).Since the availability of CO and thus the CO concentration in solution should have asignificant influence on the rate of the reactions unless CO is not involved in the rate limitingstep of the process, the effect of mass transfer limitations on the reaction rate of the substratesmentioned above were also studied and it was found that an 8-18% increase in reaction rateswere observed for conditions of proper mass transfer for styrene, allylbenzene, and p- and omethoxyallylbenzeneswhere isomerization of the double bond is insignificant.Since hydroesterification under microwave radiation conditions has not been reported to date,the effect, if any, of microwave radiation vs. thermal heating conditions were alsoinvestigated. Owing to the pressure limit (12 bar) of the glass reaction vessel in themicrowave reactor all reactions were executed at 12 bar in order to allow direct comparison ofthe results and a definite increase in reaction rate (99% conversion after only 10 min. vs. 99%after 30 min. at 35 bar) was observed for the microwave hydroesterification reactions of 1-octene and styrene. Although a general increase in reaction rate was not found for theallylbenzene substrate, a ca. 15% increase in yield was observed for p-methoxyallylbenzene(20% vs. 37%), o-methoxyallylbenzene (73% vs. 89%) and β-methylstyrene (66% vs. 88%)as substrates when the microwave reactions were compared to those performed underconventional heating under the same pressure.When the nucleophile in the carbonylation reactions was changed from oxygen (methanol) tonitrogen (aniline) and the ligand to BINAP in the same catalyst system, the firstaminocarbonylation reaction was observed. Reaction of the o- and p-methoxy substitutedallylbenzenes with aniline, anisidine and 4-chloroaniline resulted in the successful formationof the linear and branched amides (anilides) in 87-97% yield. Extending the methodology totrans-β-methylstyrene and α-methylstyrene with aniline, however, gave the amides in only18% and 16% yield, respectively. When the aminocarbonylation of allylbenzene wasinvestigated with strongly deactivated anilines (2,4-dichloro- and 4-nitroaniline), primaryamines (butylamine and benzylamine) and amides (acetamide) no product formation could bedetected, so it was suspected that the reaction may be dependent on the pKa of the amine, withpKa-values below 3 being too acidic and pKa-values above 9 basic enough to be deactivatedby complexation to the Lewis acid [Al(OTf)3] in the catalyst system. Although the successfulhydroamidation (25% conversion) of 4-chlorobenzylamine (pKa = 9.17) gave some credenceto this hypothesis, this aspect of the investigation still needs more attention in a follow-upinvestigation.Subsequently, attention was turned towards the original aim of this project, i.e.methoxycarbonylation of stilbene analogues. Unsubstituted stilbene, 4-methoxystilbene and2-methoxystilbene, however, gave poor results (conversions = 16-19% and yields = 2-6%),although some selectivity (4:1 for 2-methoxystilbene) towards the formation of the distalisomer, i.e. methyl 3-(2-methoxyphenyl)-2-phenylpropanoate, was observed.Since the alkoxycarbonylation of alkynes is a well-documented reaction and these substratescould also function as starting material for the synthesis of isoflavonoids, albeit with anadditional reduction step, the investigation was changed to the methoxycarbonylation ofsubstituted diphenylacetylenes. In order to evaluate the influence of electron-donating andelectron-withdrawing substituents on the rings of the phenylphenylacetylenes on theregioselectivity of the reactions, 4-methoxyphenyl- and (2-methoxyphenyl)phenylacetylenewere prepared both in 69% yield by utilizing the Sonogashira coupling under conventionalheating conditions (CuI/DABCO/K2CO3/DMF). (2,4-Dimethoxyphenyl)phenylacetylene wasprepared in 91% yield by utilizing the Pd(PPh3)2Cl2/CuI/Et2NH/DMF reagent system undermicrowave irradiation (200 W). The electron-deficient diphenylacetylenes, (4-trifluoromethanesulfonyloxyphenyl)phenylacetylene, 4-methoxyphenyl-4'-trifluoromethanesulfonyloxyphenylacetyleneand 4-methoxyphenyl-2',4'-bis(trifluoromethanesulfonyloxy)-phenylacetylene, were prepared in overall 81%, 87% and 19% yields via Sonogashiracoupling and formation of the triflate from the free phenolic analogues.The 2-, 4-methoxy and 4-triflate substituted diphenylacetylenes, with the exception of (2,4-dimethoxyphenyl)phenylacetylene, were excellent substrates for the methoxycarbonylationreaction catalysed by Pd(OAc)2/Al(OTf)3/BINAP and gave good to excellent conversions(>97%) and yields (89%, 89% and 71%). Owing to Lewis acid catalysed methanol additionto the triple bond and subsequent demethylation, (2,4-dimethoxyphenyl)phenylacetylene gaveonly 35% of the desired product, which was accompanied by 46% of the correspondingdeoxybenzoin. While some selectivity towards the proximal isomer of the esters were foundfor the two monomethoxy substituted diphenylacetylenes (2:1, proximal:distal), the methoxycarbonylation of (4-trifluoromethanesulfonyloxyphenyl)phenylacetylene gave the two estersin a ratio of 1:1. Methoxycarbonylation of the 4-methoxyphenyl-4'-trifluoromethanesulfonyloxyphenylacetyleneand 4-methoxyphenyl-2',4'-bis(trifluoromethanesulfonyloxy)-phenylacetylene led to the two ester products in 71 and 72% yields, respectively with theproximal isomer (carboxylate function next to the methoxy carrying ring) obtained in a 3:1and excellent 18:1 ratio, respectively.It was thus amply demonstrated that substituted diphenylacetylenes can be methoxycarbonylatedsuccessfully and that high selectivity towards the isomer that would allowcyclization to the 6-membered heterocyclic ring of the isoflavonoid nucleus is possible.Method development for the preparation of diphenylacetylenes with substitution patternsresembling those found in naturally occurring isoflavonoids and the synthesis of thoseisoflavonoids could therefore be embarked upon with confidence. Complete development ofthis new methodology towards the synthesis of isoflavonoids and the preparation of thesecompounds in enantiomerically pure form through stereoselective reduction of the remainingdouble bond in the methoxycarbonylated diphenylacetylenes, will receive further attention ina follow-up investigation.

[发布机构] University of the Free State