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

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Rhodium-catalyzed intermolecular C-H activation of {alpha}, {beta}-unsaturated imines in the presence of alkynes leads to a tandem process in which coupling to the alkyne occurs at the {beta}-C-H bond of the imine, followed by electrocyclization of the resulting azatriene intermediates to give dihydropyridines (eq 1). 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 ... continued below

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2452-2453

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Ellman, Jonathan A.; Yotphan, Sirilata & Bergman, Robert December 10, 2007.

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Rhodium-catalyzed intermolecular C-H activation of {alpha}, {beta}-unsaturated imines in the presence of alkynes leads to a tandem process in which coupling to the alkyne occurs at the {beta}-C-H bond of the imine, followed by electrocyclization of the resulting azatriene intermediates to give dihydropyridines (eq 1). 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. We now wish to report that this intramolecular cyclization occurs smoothly at 100 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. 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. 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{sub 2})PhPEt{sub 2} in 1:1 ratio relative to the metal (entry 6). Other phosphine ligands also provided product 5, but lower yields were observed. Of particular note, the commercially available phosphine, PCy{sub 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. 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. We also investigated the chemistry of 5 due to its novel structure. Upon treatment with Me{sub 2}SO{sub 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). 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 nonplanar (twist). 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.

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2452-2453

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  • Journal Name: Journal of the American Chemical Society

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  • Report No.: LBNL-1484E
  • Grant Number: DE-AC02-05CH11231
  • Office of Scientific & Technical Information Report Number: 948352
  • Archival Resource Key: ark:/67531/metadc895808

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  • December 10, 2007

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  • Sept. 27, 2016, 1:39 a.m.

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  • Oct. 3, 2016, 4:47 p.m.

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Ellman, Jonathan A.; Yotphan, Sirilata & Bergman, Robert. The Stereoselective Formation of Bicyclic Enamines with Bridgehead Unsaturation via Tandem C-H Bond Activation/Alkenylation/Electrocyclization, article, December 10, 2007; Berkeley, California. (digital.library.unt.edu/ark:/67531/metadc895808/: accessed November 18, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.