Isomerisation versus carbonylative pathways in the hydroxy-carbonylation, methoxy-carbonylation, and amino-carbonylation of N-tosyl-3-pyrroline

Abstract

Abstract:The reactivity of N-tosyl-3-pyrroline is significantly lower than that of mono-substituted alkenes in Pd catalysed methoxycarbonylation reactions. For example, most bulky diphosphine/ Pd catalysts, including the well-known Pd catalyst derived from 1,2-bis(Di-TertButylPhosphinoXylene (DTBPX), were found to give no product at all in the methoxycarbonylation of N-tosyl-3-pyrroline. The competing pathways in methoxycarbonylation of N-methane-sulfonyl-3-pyrroline using Pd/ DTBPX were studied using DFT calculations; these show that the coordination of the alkene is unfavourable, and once coordinated, isomerisation is a lower energy pathway that ultimately leads to an alternative product. Experimentally a side product resulting from alkene isomerisation and addition of methanol is formed slowly (if CO is present), and rapidly if CO is not. A less bulky derivative of DTBPX forms the required alkene complex with much lower barriers. A study has been made of the enantioselective carbonylation of N-tosyl-3-pyrroline using water, methanol or aniline as nucleophile. This revealed that there is a range of possible products with most of these initiated by a Pd-catalysed isomerisation of the alkene. Using less bulky members of the Pd/Phanephos family of catalysts, it is possible to produce the methoxycarbonylation product from this poorly reactive alkene with reasonably good chemoselectivity and around 80% e.e. at higher pressures of CO. IntroductionPalladium catalysed alkene carbonylation is a very important reaction in industrial synthesis, since it uses very cheap reagents in a very atom efficient manner. [1][2][3][4][5][6] Applications that have been practiced at commercial scale include: polymer synthesis by co-polymerisation, methyl propionate synthesis by ethylene methoxycarbonylation and formation of racemic fine chemicals by hydroxycarbonylation of vinyl arenes (sometimes generated in situ from alcohols).1,2 A stand-out catalyst is the Pd complex formed from 1,2-bis(Di-Tert-ButylPhosphinoXylene (DTBPX from this point forward), which gives very high rates in ethylene methoxycarbonylation, 1b, 1l, 1o and has also been used for some other applications. 5 The potential for enantioselective hydroxycarbonylation and alkoxycarbonylation to be a useful method for large scale asymmetric synthesis has been appreciated for a long time.2-4 However, this is a challenging reaction and despite many important contributions, high enantioselectivity is rare especially for the intermolecular reaction; further research is needed. Catalysts which do give good enantioselectivity, combined with high regioselectivity in the methoxycarbonylation of styrene are Pd catalysts derived from the bulkier members of the Phanephos ligand family (shown in Scheme 1), 3,4 providing impetus to seek to evaluate and increase substrate scope for alkene carbonylation. In the literature, there are very sparse examples, even using achiral catalysts. Most examples of methoxycarbonylation of internal alkenes have led to tandem isomerisation-linear select...

Structural and theoretical studies of the methoxycarbonylation of higher olefins catalysed by (Pyrazolyl‐ethyl)pyridine palladium (II) complexes

“…Consistent with previous findings, changing from PPh 3 to P (OMe) 3 was followed by a drastic shift in the composition of the branched esters from 41% to 82% (Table , entries 1 and 9). This trend has been associated with minimal steric hindrance to give the bulkier branched esters …”

“…In terms of regioselectivity, we observed the formation of more branched esters (40%) at higher catalyst loadings of 1 mol% compared to 18% of the branched esters reported at 0.25 mol% (Table , entries 5 and 6). This could be attributed to enhanced isomerization reactions at higher catalyst loadings …”

Kinetic Modeling of the Palladium‐Catalyzed Isomerizing Methoxycarbonylation of 1‐Decene

“…The inhibiting effect of CO on the isomerization as well as the inhibiting effect of 1-decene on both reactions could be confirmed by the fitting results. Fuentes et al [20] observed the same negative effect of CO on the isomerization of N-toysl-pyrroline experimentally and theoretically. In the latter, DFT calculations revealed evidence for a catalyst preequilibrium with CO where the Pd-catalyst is kept in a stable resting state with CO.…”

Norhygrine Alkaloid and Its Derivatives: Synthetic Approaches and Applications to the Natural Products Synthesis

“…An attempt of hydroxycarbonylation of 1-tosyl-2,5dihydro-1H-pyrrole (89) in the presence of a palladium catalyst in acetone unexpectedly resulted in ketone 91 as the main product, [81] 1-tosylpyrrolidine-3-carboxylic acid 90 is formed in trace amounts (Scheme 18).…”