The Stereoselective Formation of Bicyclic Enamines with Bridgehead Unsaturation via Tandem C-H Bond Activation/Alkenylation/Electrocyclization Sirilata Yotphan, Robert G. Bergman,* Jonathan A. Ellman* Department of Chemistry, University of California, and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720 RECEIVED DATE (automatically inserted by publisher); E-mail: bergman@cchem.berkeley.edu; jellman@uclink.berkeley.edu Rhodium-catalyzed intermolecular C-H activation of α, β- unsaturated imines in the presence of alkynes leads to a tandem process in which coupling to the alkyne occurs at the β-C-H bond of the imine, followed by electrocyclization of the resulting aza- triene intermediates to give dihydropyridines (eq 1). 1,2 N Bn + Et Et 2.5 mol% [RhCl(coe) 2 ] 2 10 mol% FcPCy 2 toluene, 50 o C Et N Bn Et Et N Bn Et Table 1. Optimization of Reaction Conditions 5 mol% catalyst N toluene 100 o C N Entry a Catalyst Ru(H 2 )CO(PPh 3 ) 3 Rh(PPh 3 ) 3 Cl [Rh(coe) 2 Cl] 2 [Rh(coe) 2 Cl] 2 [Rh(coe) 2 Cl] 2 [Rh(coe) 2 Cl] 2 [Rh(coe) 2 Cl] 2 Added Ligand a PPh 3 PCy 3 FcPCy 2 (p-NMe 2 )PhPEt 2 (p-NMe 2 )PhPCy 2 time (h) b % Yield b 75 (54) c Consideration of the intramolecular version of this overall transformation (Scheme 1) raises interesting regiochemical issues. For example in a compound such as 1, where the nitrogen and alkyne are connected by a 4-carbon tether, the presumed first- formed hydrido(vinyl)rhodium function can add to the triple bond in a 1,2-fashion, producing complex 2 with a new endocyclic double bond. Alternatively, addition might occur in a 2,1- fashion, leading to product 4 with an exocyclic double bond. cat [R h I ] H N H [R h] -[R h] N [R h] N -[R h] N N N 5 mol % ligand (1:1 ratio to the catalyst) was added. All yields were determined by NMR integration relative to 2,6-dimethoxytoluene as an internal standard. c Isolated yield. N migration N H [R h] migration N [R h] H Scheme 1. Proposed Mechanism for the Formation of 5. We now wish to report that this intramolecular cyclization occurs smoothly at 100 o C, and the exocyclic double bond route is exclusively followed. Remarkably, products such as 4 do not resist further cyclization. Even though both the transition state for this process and the resulting product are presumably strained, the overall transformation leads to good yields of unusual bridgehead doubly-bonded enamines such as 5. 3 The unique chemistry of conjugated enamine 5 is consistent with the increased strain of this molecule as well as with inhibited conjugation between the nitrogen lone pair and the adjacent double bond (vida infra). We began our investigation into the C-H activation/cyclization of alkyne-tethered imine 1 by extensive screening of transition metal catalysts for this process. 4 Rhodium-based catalysts were found to be the most efficient (Table 1), leading exclusively to the bridgehead dienamine; none of the catalysts that were employed in the screening led to quinolizidine 3 or to the product of intramolecular Diels-Alder reaction. The optimized reaction conditions employ the electron-rich monophosphine ligand (p-NMe 2 )PhPEt 2 in 1:1 ratio relative to the metal (entry 6). 1b Other phosphine ligands also provided product 5, but lower yields were observed. Of particular note, the commercially available phosphine, PCy 3 , gave yields that were nearly identical to those obtained using the optimized conditions (entry 4). Monitoring the progress of the reaction by NMR showed that the nine-membered ring aza-triene intermediate 4 was observed to form initially, as is proposed in Scheme 1. This intermediate undergoes spontaneous electrocyclization to form 5. 5 In the Rh-H addition step, the geometry of the alkyne-tethered imine substrate presumably guides H-transfer to the less hindered site of the tethered alkyne. MeSO 4 N Me 2 SO 4 , THF N We also investigated the chemistry of 5 due to its novel structure. Upon treatment with Me 2 SO 4 , 5 was converted exclusively to N-methylated product 6, a regioselectivity that is opposite to that observed with acyclic and monocyclic enamines, which usually give C-alkylation (eq 2). 6,7 Crystals of 6 suitable for X-ray analysis were obtained, and the resulting crystal structure (Figure 1) confirmed the structure for 5 proposed above. The bridgehead double bond of 6 is found to be significantly non- planar (twist). 8 The deviation from the optimal planar geometry caused by the bicyclic structure in 5 presumably also results in poor delocalization of the nitrogen lone pair electrons into the adjacent diene orbitals, which would account for the observation of N-alkylation. 9

The Stereoselective Formation of Bicyclic Enamines with Bridgehead Unsaturation via Tandem C-H Bond Activation/Alkenylation/Electrocyclization

Synthetic Applications of Cyclopropene and Cyclopropenone: Recent Progress and Developments

Rh(III)-Catalyzed [5 + 1] Annulation of Indole-enaminones with Diazo Compounds To Form Highly Functionalized Carbazoles.

Rhodium(III)-Catalyzed [4 + 2] Annulation of N-Arylbenzamidines with Propargyl Alcohols: Highly Regioselective Synthesis of 1-Aminoisoquinolines Controlled by Noncovalent Interaction.

Rhodium-Catalyzed Annulation of Phenacyl Ammonium Salts with Propargylic Alcohols via a Sequential Dual C-H and a C-C Bond Activation: Modular Entry to Diverse Isochromenones.

A traceless approach to quinolin-4(1H)-one scaffolds through Rh(III)-catalyzed redox-neutral [3+3] cyclization of N-nitrosoanilines with cyclopropenones has been achieved. This protocol features short reaction time and atom-economical combination without extra additives, which can be further applied in the construction of privileged heterocyclic compounds in pharmaceutical chemistry.

https://www.mdpi.com/1420-3049/25/2/268/pdf

Rhodium(III)-Catalyzed Redox-Neutral [3+3] Annulation of N-nitrosoanilines with Cyclopropenones: A Traceless Approach to Quinolin-4(1H)-One Scaffolds.

Rhodium-Catalyzed C−H Activation/Annulation Cascade of Aryl Oximes and Propargyl Alcohols to Isoquinoline N-Oxides

A Rh(III)-catalyzed C–H activation and regiospecific annulation cascade of benzoic acid with propargyl acetate was developed to produce an unreported 3-alkylidene-isochromanone scaffold. The biggest merit of this reaction is achieving the regioselective control in the alkyne insertion and the precise removal of the acetyl group to eventually form 3-alkylidene-isochromanone scaffolds possessing an unusual exocyclic double bond with moderate to excellent yields (up to 93%) under mild temperature along with broad generality and versatility.

Jiyuan Li

Papers

Rhodium(III)-Catalyzed Redox-Neutral [3+3] Annulation of N-nitrosoanilines with Cyclopropenones: A Traceless Approach to Quinolin-4(1H)-One Scaffolds.

Rhodium-Catalyzed C−H Activation/Annulation Cascade of Aryl Oximes and Propargyl Alcohols to Isoquinoline N-Oxides

A Rh(III)-catalyzed C–H activation/regiospecific annulation cascade of benzoic acids with propargyl acetates to unusual 3-alkylidene-isochromanones

Rh(III)-Catalyzed C-H Activation and [4+1+1] Sequential Cyclization Cascade to Give Highly Fused Indano[1,2-b]azirines.