Palladium catalysed hydroesterification and aminocarbonylation of substituted alkenes and alkynes
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Date
2018-04
Authors
Du Plessis, Maretha
Journal Title
Journal ISSN
Volume Title
Publisher
University of the Free State
Abstract
Since the aim of this study was to investigate the influence of the electronic environment
around the double bond of alkenes on the reactivity and regioselectivity of the
methoxycarbonylation reaction for developing new methodology towards the synthesis of
isoflavonoids, several aryl substituted alkenes were subjected to methoxycarbonylation
utilizing the Pd(OAc)2/Al(OTf)3/PPh3 catalyst system in MeOH under the optimum
conditions of 35 bar of CO pressure and 95 °C. In order to be able to compare current results
with literature values, 1-octene, 2-octene and styrene, were the first substrates to be
methoxycarbonylated and gave anticipated high conversions (100%, 83% and 91%,
respectively) to the expected linear (l) and branched (b) methyl esters, methyl nonanoate and
methyl 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-methylstyrene
analogues, 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 otrifluoromethanesulfonyloxyallylbenzene
were subjected to the methoxycarbonylation
reaction conditions and the products obtained in high conversions (88-96%) except for the
alkenes with methoxy substituents in the para-position, i.e. p-methoxy-β-methylstyrene and
p-methoxyallylbenzene (49% and 66%, respectively). During these investigations
isomerization of the double bond in the β-methylstyrenes to the terminal position, forming
allylbenzene 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 found
that a p-methoxy substituent on the β-methylstyrene or allylbenzene resulted in a decrease in
reaction rate, while an o-methoxy substituent increases the reaction rate substantially in
comparison to the p-methoxy analogues. Ortho-substituents (methoxy or triflate group) also
resulted 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 enhancing
effect on the formation of the benzylic products as was determined by the methoxycarbonylation
of 1,3-diphenylpropene, which gave methyl 2,4-diphenylbutanoate in 64%
yield and 95% regioselectivity. Sterically more demanding disubstituted and trisubstituted
double bonds, like in α-methylstyrene and 2-methyl-1-phenylprop-1-ene, were also subjected
to 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 a
significant influence on the rate of the reactions unless CO is not involved in the rate limiting
step of the process, the effect of mass transfer limitations on the reaction rate of the substrates
mentioned above were also studied and it was found that an 8-18% increase in reaction rates
were observed for conditions of proper mass transfer for styrene, allylbenzene, and p- and omethoxyallylbenzenes
where 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 also
investigated. Owing to the pressure limit (12 bar) of the glass reaction vessel in the
microwave reactor all reactions were executed at 12 bar in order to allow direct comparison of
the 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 the
allylbenzene 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 under
conventional heating under the same pressure.
When the nucleophile in the carbonylation reactions was changed from oxygen (methanol) to
nitrogen (aniline) and the ligand to BINAP in the same catalyst system, the first
aminocarbonylation reaction was observed. Reaction of the o- and p-methoxy substituted
allylbenzenes with aniline, anisidine and 4-chloroaniline resulted in the successful formation
of the linear and branched amides (anilides) in 87-97% yield. Extending the methodology to
trans-β-methylstyrene and α-methylstyrene with aniline, however, gave the amides in only
18% and 16% yield, respectively. When the aminocarbonylation of allylbenzene was
investigated with strongly deactivated anilines (2,4-dichloro- and 4-nitroaniline), primary
amines (butylamine and benzylamine) and amides (acetamide) no product formation could be
detected, so it was suspected that the reaction may be dependent on the pKa of the amine, with
pKa-values below 3 being too acidic and pKa-values above 9 basic enough to be deactivated
by complexation to the Lewis acid [Al(OTf)3] in the catalyst system. Although the successful
hydroamidation (25% conversion) of 4-chlorobenzylamine (pKa = 9.17) gave some credence
to this hypothesis, this aspect of the investigation still needs more attention in a follow-up
investigation.
Subsequently, attention was turned towards the original aim of this project, i.e.
methoxycarbonylation of stilbene analogues. Unsubstituted stilbene, 4-methoxystilbene and
2-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 distal
isomer, i.e. methyl 3-(2-methoxyphenyl)-2-phenylpropanoate, was observed.
Since the alkoxycarbonylation of alkynes is a well-documented reaction and these substrates
could also function as starting material for the synthesis of isoflavonoids, albeit with an
additional reduction step, the investigation was changed to the methoxycarbonylation of
substituted diphenylacetylenes. In order to evaluate the influence of electron-donating and
electron-withdrawing substituents on the rings of the phenylphenylacetylenes on the
regioselectivity of the reactions, 4-methoxyphenyl- and (2-methoxyphenyl)phenylacetylene
were prepared both in 69% yield by utilizing the Sonogashira coupling under conventional
heating conditions (CuI/DABCO/K2CO3/DMF). (2,4-Dimethoxyphenyl)phenylacetylene was
prepared in 91% yield by utilizing the Pd(PPh3)2Cl2/CuI/Et2NH/DMF reagent system under
microwave irradiation (200 W). The electron-deficient diphenylacetylenes, (4-
trifluoromethanesulfonyloxyphenyl)phenylacetylene, 4-methoxyphenyl-4'-trifluoromethanesulfonyloxyphenylacetylene
and 4-methoxyphenyl-2',4'-bis(trifluoromethanesulfonyloxy)-
phenylacetylene, were prepared in overall 81%, 87% and 19% yields via Sonogashira
coupling 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 methoxycarbonylation
reaction 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 addition
to the triple bond and subsequent demethylation, (2,4-dimethoxyphenyl)phenylacetylene gave
only 35% of the desired product, which was accompanied by 46% of the corresponding
deoxybenzoin. While some selectivity towards the proximal isomer of the esters were found
for the two monomethoxy substituted diphenylacetylenes (2:1, proximal:distal), the methoxy
carbonylation of (4-trifluoromethanesulfonyloxyphenyl)phenylacetylene gave the two esters
in a ratio of 1:1. Methoxycarbonylation of the 4-methoxyphenyl-4'-trifluoromethanesulfonyloxyphenylacetylene
and 4-methoxyphenyl-2',4'-bis(trifluoromethanesulfonyloxy)-
phenylacetylene led to the two ester products in 71 and 72% yields, respectively with the
proximal isomer (carboxylate function next to the methoxy carrying ring) obtained in a 3:1
and excellent 18:1 ratio, respectively.
It was thus amply demonstrated that substituted diphenylacetylenes can be methoxycarbonylated
successfully and that high selectivity towards the isomer that would allow
cyclization to the 6-membered heterocyclic ring of the isoflavonoid nucleus is possible.
Method development for the preparation of diphenylacetylenes with substitution patterns
resembling those found in naturally occurring isoflavonoids and the synthesis of those
isoflavonoids could therefore be embarked upon with confidence. Complete development of
this new methodology towards the synthesis of isoflavonoids and the preparation of these
compounds in enantiomerically pure form through stereoselective reduction of the remaining
double bond in the methoxycarbonylated diphenylacetylenes, will receive further attention in
a follow-up investigation.
Description
Keywords
Thesis (Ph.D. (Chemistry)--University of the Free State, 2018, Alkenes, Alkynes, Palladium catalysed hydroesterification, Isoflavonoids, Methoxycarbonylation, Reactivity, Regioselectivity