Crucial Role of β-Elimination in Determining Regio- and Chemoselectivity of the Rhodium-Catalyzed Hydroformylation of N-Allylpyrroles: A New Approach to 5,6-Dihydroindolizines

Abstract

Rhodium-catalyzed hydroformylation of the chiral (S)-3-alkyl-3-pyrrol-1-ylprop-1-enes at 100 atmospheres total pressure and 25°C led to the preferential formation of the branched 3-alkyl-2-methyl-3-pyrrol-1-ylpropanals. At 30 atmospheres and 125°C, the linear 4-alkyl-4-pyrrol-1-ylbutanals were obtained: these aldehydes are not the final products, but evolve into more stable 5,6-dihydroindolizines, with the same optical purity as the starting olefins, via a domino cyclization-dehydration process. According to the generally accepted mechanism for rhodium-catalyzed hydroformylation, the regioselectivity, and then the final chemoselectivity, can be rationalized by taking into account that while at room temperature no b-elimination occurs, at high temperature the belimination involves the branched rhodium-alkyl intermediate only.According to the generally accepted mechanism for the rhodium-catalyzed hydroformylation of olefins, 1 metal hydride addition to the double bond to give an isomeric metal-alkyl intermediates is a key step. This step can be reversible or nonreversible, depending on the substrate nature and the reaction conditions. Under mild conditions, i.e. at room temperature, the insertion is a nonreversible step; this is very important, because the regioselectivity for the formation of the branched b and the linear l rhodium-alkyl intermediates determines the regioselectivity for the formation of the final aldehydes B and L, respectively (Scheme 1). In contrast, if the alkyl formation is reversible, the selectivity-determining step will occur later, i.e. at the stage of the addition of carbon monoxide to the tricarbonyl species to give the tetracarbonyl species, as demonstrated by theoretical calculations in the case of hydroformylation of 1,1-diphenylethene at 100°C. 2 Both electronic and steric effects determine the regioselectivity of the formation of rhodium-alkyl complexes (Figure 1). Indeed, the hydroformylation under mild conditions of vinylaromatic substrates such as styrene, 3 vinylfurans, 4 vinylthiophenes, 5 vinylpyrroles, 6 and vinylpyridines 7 always provides a large predominance of the branched isomer over the linear one (B/L = 95:5 for styrene). As far as oxygen-containing substrates are concerned, vinyl ethers provide a regioisomeric ratio B/L of ≥ 80:20. 8 Under the same conditions, alkenes with a-hydrogens (i.e., linear alk-1-enes) give the two regioisomers in an almost 1:1 molar ratio. 9 An oxygen in the b-position to the vinyl group favors the formation of the branched isomers, as observed for allyl ethyl ether (B/L = 70:30) and similar substrates. 8 The linear isomers largely predominate over the branched ones in the hydroformylation of 3-alkyl-substituted alk-1-enes (e.g., 3-methylbut-1-ene). 10

Core‐Structure‐Motivated Design of Iminium–Enolate Organocascade Reactions: Enantioselective Syntheses of 5,6‐Dihydroindolizines

“…In addition, 5,6,7,8‐tetra‐ and 5,6‐dihydroindolizine alkaloids are common secondary metabolites in plants, invertebrates, fungi, and bacteria 4. Thus, the design of new synthetic methods to provide molecules in this class of compounds is of interest, and intramolecular cyclization of intermediates using metal‐catalyzed,5c–g radical,5h–i and base‐induced processes have been reported 5…”

Total Synthesis of (−)-Curvulamine

“…To prepare cyanohydrin 11 , a simple three-step sequence was developed (Scheme A). S N 2 reaction of methyl 2-bromopropanoate with the sodium salt of 2-methyl pyrrole (NaH, DMF), followed by methyl ester reduction (DIBAL, PhMe), afforded an intermediate aldehyde that was transformed to cyanohydrin 11 (TMSCN, LiClO 4 , DCM), as an inconsequential mixture of diastereomers (2.4:1). , This process could be conducted on a >100 mmol scale, and 11 was utilized without purification.…”