Merging rhodium-catalysed C–H activation and hydroamination in a highly selective [4+2] imine/alkyne annulation

Catalytic C–H activation and hydroamination represent two important strategies for eco-friendly chemical synthesis with high atom efficiency and reduced waste production. Combining both C–H activation and hydroamination in a cascade process, preferably with a single catalyst, would allow rapid access to valuable nitrogen-containing molecules from readily available building blocks. Here we report a single metal catalyst-based approach for N-heterocycle construction by tandem C–H functionalization and alkene hydroamination. A simple catalyst system of cationic rhodium(I) precursor and phosphine ligand promotes redox-neutral [4+2] annulation between N–H aromatic ketimines and internal alkynes to form multi-substituted 3,4-dihydroisoquinolines (DHIQs) in high chemoselectivity over competing annulation processes, exclusive cis-diastereoselectivity, and distinct regioselectivity for alkyne addition. This study demonstrates the potential of tandem C–H activation and alkene hydrofunctionalization as a general strategy for modular and atom-efficient assembly of six-membered heterocycles with multiple chirality centres.

(not detected during our catalysis development).

Supplementary Discussion: Result Analysis of the Deuterium Labeling Experiments
The experiments followed the general procedure for Rh(I)-catalyzed redox-neutral [4+2] annulation as described above. All reactions were carried out using diphenylacetylene (2a) as the alkyne substrate. No additional deuterium or proton sources were added when using partially deuterated benzophenone imine (d 1 -1a or d 5 -1a) 1   The partial D incorporation at C4 suggested that the protonation of Rh-alkyl linkage following the intramolecular alkene hydroamination/N-heterocyclization process may involve intramolecular proton transfer from the iminium proton (as the major pathway) or iminium deuterium (minor pathway), or intermolecular deuterium transfer from MeOD as an external Brønsted acid (minor pathway).

General Experimental Procedures and Reagent Availability
Unless otherwise noted, all manipulations were carried out under a N 2 atmosphere using standard Schlenk-line or glovebox techniques. All glassware was oven-dried for at least 1 h prior to use. THF, toluene, and hexane were degassed by purging with N 2 for 45 min and dried with a followed an analogous procedure reported by Bergman and Ellman. 4 Rh(III)-catalyzed C-H functionalization of 9a to form products 12 and 13 followed an analogous procedure reported by Li 5 and Glorius 6 respectively.
Single crystal X-ray diffraction data of 5aa, 5an, 5na, 9a and 11 were collected on a Bruker Apex Duo diffractometer with a Apex 2 CCD area detector at T = 100K. Cu radiation was used. All structures were processed with Apex 2 v2010.9-1 software package (SAINT v. 7.68A, XSHELL v. 6.3.1). Direct method was used to solve the structures after multi-scan absorption corrections. Details of data collection and refinement are given in Table S2.

General Procedure for Rh(I)-Catalyzed Redox-Neutral [4+2] Annulation
Method A: For internal alkyne substrate scope. Into a 4 mL scintillation vial equipped with a magnetic stir bar was placed [Rh(cod) 2 ]BF 4 (6, 5.6 mg, 0.014 mmol, 0.050 equiv), DPEphos were removed under reduced pressure to afford a darkred-colored powder that contains the mixture of complex 11 and remaining reactants. Further crystallization was carried out in a mixed solvent system of chloroform and layered with pentane to produce a small amount of single crystals suitable for X-ray diffraction analysis.     cis-3,4-Bis(4-methoxyphenyl)-1-phenyl-3,4-dihydro-isoquinoline (5ad)
This product was contaminated with ~10% of the corresponding isoquinoline byproduct (generated by product decomposition during separation and purification), and the yield for 5ao was estimated to be 75% by 1 H NMR analysis (see Figure 33). 1