Changing the kinetic order of enantiomer formation and distinguishing between iminium ion and imine as the reactive species in the asymmetric transfer hydrogenation of substituted imines using a cyclopentadienyl iridium (III) complex

Abstract

The iridium (III) complex of pentamethylcyclopentadiene and (S,S) or (R,R)-1,2-diphenyl-N′-tosylethane-1,2-diamine is an effective catalyst for the asymmetric transfer hydrogenation of imines under acidic conditions. However, the enantiomeric excess (ee) of the product amines from the reduction of 1-methyl-3,4-dihydroisoquinolines in either acetonitrile or dichloromethane, decreases exponentially. The dominant cause of the enantioselectivity is the difference in kinetic order of the formation of the two enantiomers with the S-enantiomer being formed in a first-order process whereas that for the R-enantiomer follows zero-order kinetics when (R,R)-TsDPEN is employed, due to different rate-limiting steps for the two processes. A series of 1-fluorinated methyl-3,4-dihydroisoquinolines were synthesised to change the rate-limiting dissociation of the (R) amine product from Ir (III) so that both enantiomers are formed with the same kinetic order. This results in almost complete removal of the enantioselectivity of the reduction. It has been suggested that reduction of imines using transition metal complexes occurs through the neutral imine rather than the more reactive iminium-ion. α-Substituted imines with electron-withdrawing groups make protonation more difficult but enhance the electrophilicity of the imine carbon facilitating nucleophilic attack. The pKa of the iminium ions of 1-fluorinated methyl-3,4-dihydroisoquinolines were determined. Using the relative rates of the cyclopentadienyl iridium (III) complex catalysed reduction of these 1-fluorinated methyl-3,4-dihydroisoquinoline in acetonitrile and, under the acidic conditions of a 5:2 ratio of formic acid:triethylamine, showed that the iminium ion is the reactive species.

Cyclopropenones in the synthesis of indolizidine, pyrrolo[2,1-a]isoquinoline and indolizino[8,7-b]indole alkaloids

“…27 We did not repeat Eicher's work, but extended it by reacting the electron rich dihydroisoquinoline based cyclic ketimines 56a-d (Table 2) with cyclopropenones 38 -40 in acetonitrile or chloroform as solvent and obtained the expected pyrroloisoquinolines 57ai/ii-d (Table 2). The dihydroisoquinoline 56a 37 was prepared by a standard Bischler-Napieralski reaction, whereas the fluorinated analogues 56b and 56c 37 required the use of Movassaghi and Hill's 38 modified procedure using trifluoromethanesulfonic anhydride in the presence of 2chloropyridine. The dihydroisoquinoline 56d was prepared from the reaction of methyl eugenol with acetonitrile, 39 and gave the product 57d as a 2:5 mixture of diastereoisomers.…”

Catalysis, kinetics and mechanisms of organo-iridium enantioselective hydrogenation-reduction

“…The use of iridium in catalysis, both homogeneous and heterogeneous, remains an exciting topic with many new developments, not only for hydrogenation/reduction reactions but for many other reactions. [111][112][113] The observation that enantioselectivity of some reactions can result from enantiomers being formed by different kinetic orders 106,107 highlights the importance and requirement for careful kinetic studies. The field is ripe for the application of physical organic techniques including linear free-energy relationships and kinetic isotope effects.…”

“…Despite a more electrophilic imine carbon the α-trifluoromethyl derivative is completely unreactive towards the cyclopentadienyl IrIJIII) complex catalysed reduction, showing that the iminium ion is the reactive species. 107 It appears in this case that selectivity is almost exclusively due to the different kinetic orders for the rates of formation of the two enantiomers. Changing the ligand to S,S-TsDPEN rather than R,R inverts the kinetic orders of the rates of formation of the two enantiomeric product amines.…”

“…106 Using a series of 1-fluorinated methyl-3,4dihydroisoquinolines as substrates changes the rate-limiting step of dissociation of the (S)-amine product from IrIJIII) k 3 , so that both enantiomers are formed with first-order kinetics. 107 This results in almost complete removal of the enantioselectivity of the reduction.…”

A diversity of recently reported methodology for asymmetric imine reduction

“…A very recent and detailed study of the ATH of CvN bonds in dihydroisoquinolines using chiral Cp*Ir(III) complexes revealed remarkably complex behaviour, including the observation of different kinetic orders of formation for each enantiomeric product. 50 The investigators were also able to conclude, from a very careful series of studies, that the iminium cation was the reduction substrate rather than the free imine. An IrCp* based hybrid catalyst of 33 was prepared using the chiral structure of the antibiotic vancomycin.…”