Intermolecular 2+2 imine-olefin photocycloadditions enabled by Cu(I)-alkene MLCT

Abstract

2 + 2 Photocycloadditions are idealized, convergent construction approaches of 4-membered heterocyclic rings, including azetidines. However, methods of direct excitation are limited by the unfavorable photophysical properties of imines and electronically unbiased alkenes. Here, we report copper-catalyzed photocycloadditions of non-conjugated imines and alkenes to produce a variety of substituted azetidines. Design principles allow this base metal-catalyzed method to achieve 2 + 2 imine-olefin photocycloaddition via selective alkene activation through a coordination-MLCT pathway supported by combined experimental and computational mechanistic studies.

Fig. 1. Previous strategies of azetidine forming 2 + 2 photocycloadditions and this approach.

a Use of substrate π-stacking pre-organization. b Activation via cyclic glyoxylate imine sensitization. c Xanthone sensitization. d Activation via Ir-mediated sensitization. e Alkene activation via Cu-coordination and excitation. Tp = hydrotris(pyrazolyl)borate.

Fig. 2. 2 + 2 Imine-olefin photocycloaddition reaction scope.

Summary of imine and alkene substrate variation. All reactions carried out with 1 equiv alkene, 1.1 equiv imine, 20 mol % TpCu, in diethyl ether (0.15 M) and irradiated with a 100 W Hg lamp in borosilicate tubes; all yields are of isolated material following purification via basic alumina chromatography and diastereomeric ratios were determined via gas chromatography of crude reaction mixtures; all products detected as >95:5 exo:endo diastereomers. Yield in parentheses obtained in the absence of TpCu. ^a3 equiv of imine used.

Fig. 3. Spectroscopic investigations of 2 + 2 IOPC reaction intermediates.

a Synthesis of hydrotris(pyrazolyl)borate copper olefin compounds. b X-ray structures of the norbornene and maleic anhydride complexes TpCu-NB and TpCu-MA. c Electronic absorption spectra of reaction components (TpCu, MA = maleic anhydride, imine = 1) and transmission spectrum of reaction vessels used. Pink line = stoichiometric mixture of TpCu and maleic anhydride; orange line = stoichiometric mixture of TpCu, maleic anhydride, and 1; gold line = stoichiometric mixture of TpCu and 1; green line = TpCu; light blue line = maleic anhydride; dark blue line = 1. Gray shaded area indicates transmission spectrum of the borosilicate glass reaction vessels used. A.U. = arbitrary units.

Fig. 4. Mechanistic proposal of the title reaction.

The proposed 2 + 2 IOPC mechanism commences with olefin substrate coordination to TpCu. Ligand exchange experiments indicate that imine substrates undergo rapid and reversible coordination to TpCu. The active TpCu-olefin chromophore then undergoes a MLCT from computationally visualized TpCu-NB HOMO-1 which is primarily Cu-based to TpCu-NB LUMO which is olefin(π*)-based. Capture by the imine C = N double bond leads to azetidine formation and release of TpCu.