Enantioselective copper catalysed intramolecular C–H insertion reactions of α-diazo-β-keto sulfones, α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones; the influence of the carbene substituent

Abstract

Enantioselective C–H insertion reactions are described.

Substrate and Catalyst Effects in the Enantioselective Copper‐Catalysed C–H Insertion Reactions of α‐Diazo‐β‐oxo Sulfones

“…It is clear from Table the (4 R )‐Ph and the (4 R ,5 S )‐diPh ligands yielded the highest enantioselectivities, with α‐diazo‐β‐oxo sulfone 1a , of 98 % ee and 95 % ee respectively, while the (4 R )‐Bn, (4 S )‐ t Bu and (3 S ,8 R )‐Ind ligands led to lower levels of enantiocontrol. This result is in contrast with that observed in the C–H insertion reactions of α‐diazo‐β‐keto sulfones yielding cyclopentanones, where the (3 S ,8 R )‐Ind ligand leads to the highest levels of asymmetric induction of up to 91 % ee . Interestingly, a modest ligand effect on product distribution was observed.…”

“…For the enantioselective copper‐catalysed C–H insertion reactions a copper source (5 mol‐%), bis(oxazoline) ligand (6 mol‐%) and additive NaBARF (6 mol‐%) were added to the reaction flask at the same time as the α‐diazo‐β‐oxo sulfone 1 and the resulting reaction mixture was then heated under reflux with the insertion appearing to proceed under homogeneous conditions. While pre‐mixing has been shown to be critical in carrying out the C–H insertion leading to the cyclopentanone, in general with the insertions to form the thiopyrans (typically slower reactions) there was very little impact on efficiency or enantioselectivity through pre‐mixing the catalyst ,. [14b] Accordingly, the experiments reported herein have been carried out without pre‐mixing.…”

“…The first copper‐catalysed asymmetric C–H insertion reaction was carried out by Sulikowski using bis(oxazoline) ligands in 1995 with enantioselectivities of up to 20 % ee obtained . In recent years within the Maguire group we have demonstrated that excellent enantiocontrol can be achieved using a copper catalyst system in the intramolecular asymmetric C–H insertion reactions of α‐diazo‐β‐oxo sulfones, α‐diazo‐β‐keto sulfones, and α‐diazoacetamides with thiopyrans, cyclopentanones and γ‐lactams generated in enantioselectivities of up to 98 % ee , 91 % ee , and 82 % ee , respectively. The copper catalyst system is comprised of copper‐bis(oxazoline) ligand‐NaBARF, with the inclusion of NaBARF essential to achieving high levels of asymmetric induction, through alteration of the catalyst geometry via abstraction of the chloride by the sodium cation of NaBARF as we have discussed previously …”

Exploiting the Continuous in situ Generation of Mesyl Azide for Use in a Telescoped Process

“…All commercial reagents were used without further purification unless otherwise stated. 1‐Phenylsulfonyl‐5‐phenylpentan‐2‐one ( 4g ) was prepared according to literature methods . 1 H (400 MHz) and 13 C (100.6 MHz) NMR spectra were recorded on a Bruker Avance 400 MHz NMR spectrometer.…”

Exploiting Continuous Processing for Challenging Diazo Transfer and Telescoped Copper-Catalyzed Asymmetric Transformations

“…1−5 In particular, enantioselective rhodiumand copper-catalyzed processes have attracted significant attention, facilitating the efficient formation of new C−C bonds, among other transformations, in a highly diastereoselective and enantioselective fashion, including C−H insertion, 4,5 aromatic addition reaction, 1 and cyclopropanation. 6−8 Within our research team, highly enantioselective coppercatalyzed C−H insertions, employing bis(oxazoline) ligands, have been reported across a range of substrates leading to thiopyran S,S-dioxides (up to 98% ee), 9 sulfolanes (up to 80% ee), 10 cyclopentanones (up to 82% ee), 11 and βand γ-lactams (up to 82% ee), 12 with particular success using sulfonylsubstituted α-diazoketones and α-diazoesters. Extension of this work to copper-mediated desymmetrization proved highly effective, resulting in formation of the desymmetrized thiopyran S,S-dioxide in up to 98% ee.…”