Two new classes of highly active yet air- and moisture-stable π-R-allylpalladium complexes containing bulky biaryl- and bipyrazolylphosphines with extremely broad ligand scope have been developed. Neutral π-allylpalladium complexes incorporated a range of biaryl/bipyrazolylphosphine ligands, while extremely bulky ligands were accommodated by a cationic scaffold. These complexes are easily activated under mild conditions and are efficient for a wide array of challenging C-C and C-X (X = heteroatom) cross-coupling reactions. Their high activity is correlated to their facile activation to a 12-electron-based "L-Pd(0)" catalyst under commonly employed conditions for cross-coupling reactions, noninhibitory byproduct release upon activation, and suppression of the off-cycle pathway to form dinuclear (μ-allyl)(μ-Cl)Pd2(L)2 species, supported by structural (single crystal X-ray) and kinetic studies. A broad scope of C-C and C-X coupling reactions with low catalyst loadings and short reaction times highlight the versatility and practicality of these catalysts in organic synthesis.
Herein, we provide crystallographic and computational evidence that Hashimoto’s Rh2(S-PTTL)4 catalyst adopts a “chiral crown” conformation with a reactive chiral face and an unreactive achiral face. In Rh2(S-PTTL)4, all four t-butyl groups are aligned on the same face of the catalyst, and each C-(t-Bu) bond is roughly parallel to the central Rh-Rh bond. This orients the four phthalimido groups on the opposite face of the catalyst. Also described is an enantioselective and diastereoselective protocol for intermolecular Rh2(S-PTTL)4 catalyzed cyclopropanation using α-alkyl-α-diazoesters. Intermolecular cyclopropanation is selective over two competing intramolecular pathways: C–H insertion and β–hydride elimination. Based on DFT calculations and the Davies-Singleton model for cyclopropanation, a model for asymmetric induction is proposed.
A catalytic, enantioselective method for the C-H functionalization of indoles by diazo compounds has been achieved. With catalytic amounts of Rh 2 (S-NTTL) 4 , the putative Rh-carbene intermediates from α-alkyl-α-diazoesters react with indoles at C(3) to provide α-alkyl-α-indolylacetates in high yield and enantioselectivity. From DFT calculations, a mechanism is proposed that involves a Rh-ylide intermediate with oxocarbenium character.Indoles are important structural motifs in a myriad of biologically interesting natural products and pharmaceutical targets. 1 Accordingly, several methods have been developed for the generation of highly functionalized indoles. 2 Among these strategies is the selective functionalization by metal carbenes derived from α-diazocarbonyl compounds, 3 a reactivity pattern that has been utilized in various total syntheses 4 as well as selective tryptophan modification in peptides and proteins. 5 However, the only catalytic enantioselective reaction of indoles and transient metal carbenes is Davies' [3+2] annulation of indoles with styryldiazoacetates (eq. 1). 6 While indol-3-yl acetate derivatives with stereogenic centers positioned α-to C-3 have high medicinal value, 1e,f only one example of an enantioselective C-H functionalization reaction of an indole has been reported, and the ee was < 5%. 6 Described herein is a general Rh-catalyzed method for enantioselective C-H functionalization of indoles by carbenoids derived from α-alkyl-α-diazoesters (eq. 2).(1) (2) jmfox@udel.edu . Supporting Information Available: Full experimental details, 1 H and 13 C-NMR spectra, stereochemical assignments, computational details and crystallographic (CIF) data are provided. This material is available free of charge via the Internet at http://pubs.acs.org. 4 ]. 10,11 Models for asymmetric induction based on chiral crown conformations have been proposed 7a,9 and debated, 12 and factors that create bias for the chiral crown configuration over competing conformations have been discussed. 7a,9,10 With this foundation, we hypothesized that enantioselective reactions between indoles and α-alkyl-α-diazoesters could be catalyzed by Rh-complexes proposed to adopt chiral crown conformations. NIH Public AccessWe began our investigation with the reaction of 1,2-dimethylindole with a 2-fold excess of ethyl 2-diazohexanoate (Table 1). A variety of Rh-complexes derived from t-leucine were screened, as were Rh 2 (S-DOSP) 4 and Rh 2 (S-PTAD) 4 . While many of the catalysts screened gave 1 with good enantioselectivity, it was found that Rh 2 (S-NTTL) 4 in toluene at −78 °C was optimal both in terms of yield and enantioselectivity, as 1 was formed in 95% yield and 95% ee. In line with our previous observations, 7 the use of low temperature was critical to the success of the reaction: the analogous reaction at higher temperature (0 °C) gave 1 in only 36% yield and 85% ee (entry 7).With the optimized reaction conditions in hand, the scope of this transformation was then explored, and the results are summarized in T...
CONSPECTUS Rh-carbenes derived from α-diazocarbonyl compounds have found broad utility across a remarkable range of reactivity, including cyclopropanation, cyclopropenation, C–H insertions, heteroatom–H insertions, and ylide forming reactions. However, in contrast to α-aryl or α-vinyl-α-diazocarbonyl compounds, the utility of α-alkyl-α-diazocarbonyl compounds had been moderated by the propensity of such compounds to undergo intramolecular β-hydride migration to give alkene products. Especially challenging had been intermolecular reactions involving α-alkyl-α-diazocarbonyl compounds.
Bimetallic paddlewheel complexes derived from imides of (S)-t-leucine adopt ‘chiral crown’ configurations in which the four imide groups are projected in a chiral arrangement on one face, and the four t-butyl groups are projected on the opposite face. In this contribution, the generality of the chiral crown conformation is examined through crystallographic studies where the metal and the nature of the chiral ligands are altered. Based upon these observations, a model is proposed to explain the factors which create bias for the chiral crown configuration.
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