Efficient Intramolecular Oxidative Amination of Olefins through Direct Dioxygen-Coupled Palladium Catalysis

Abstract

The prominence of five-membered nitrogen-containing heterocycles in natural products and biologically active molecules [1] has prompted considerable efforts toward their synthesis. Intramolecular hydroamination [2, 3] and oxidative amination [4,5] of olefins represent powerful synthetic strategies for heterocycle formation (Scheme 1). [6] The latter isOxH 2 hydroamination oxidative amination Scheme 1. Strategies for the heterocyclization of olefinic amines or amides.particularly attractive in the context of target- [7] and diversityoriented [8] synthesis, because the product retains the olefin functionality. Nevertheless, oxidative methods exhibit added complexity associated with redox catalysis, specifically the need for a stoichiometric oxidant, which is typically an organic or a transition metal reagent such as benzoquinone or CuCl 2 . [9] Furthermore, catalytic rates (< 1 h À1 ) and turnover numbers ( 10 ± 20) are significantly lower than those of hydroamination reactions, for which turnover numbers of ! 300 and frequencies of 50 h À1 are not uncommon. [2] We describe herein the application of a very simple and efficient catalyst system, [Pd(OAc) 2 ]/pyridine (1:2), for the intramolecular oxidative amination of olefins to produce pyrrolidine and pyrroline heterocycles in high yields. These reactions utilize molecular oxygen as the stoichiometric oxidant, require no co-catalyst to facilitate the dioxygen-coupled catalytic turnover, and achieve unprecedented catalytic activity for such reactions.Our recent mechanistic studies of the [Pd(OAc) 2 ]/O 2 / DMSO catalytic oxidation system [9] revealed that oxidation of reduced palladium by molecular oxygen is the turnoverlimiting step of the catalytic cycle. [10] By analogy to recent aerobic oxidation reactions of alcohols, [11±13] we reasoned that pyridine or other imine donor ligands might promote palladium oxidation and thereby increase catalytic efficiency in oxidative amination reactions. Indeed, the oxidative cyclization of (E)-4-hexenyltosylamide (1) worked remarkably well with a catalyst composed of [Pd(OAc) 2 ] (5 mol%) and pyridine (10 mol %) under one atmosphere of molecular oxygen [Eq. (1)]. The pyrrolidine product 2 was obtained in high yield (87 %) within two hours. NHTs Ts N 5 mol% [Pd(OAc) 2 ] toluene, 80 °C (1) 10 mol% pyridine 1 2 + H 2 O + O 2 / 1 2Unlike previous aerobic oxidative amination reactions, this catalyst system operates successfully in a diverse array of solvents (! 80 % yield), ranging from nonpolar (toluene, xylenes, heptane, and diphenyl ether) to polar (dimethoxyethane, acetonitrile, dimethylsulfoxide, and dimethylformamide). The precise role of pyridine in more polar, potentially coordinating solvents remains to be determined.Nonpolar solvents proved to be distinctly superior at lower catalyst loading. The use of [Pd(OAc) 2 ] (0.2 mol %)/pyridine (0.4 mol %) in p-xylene resulted in turnover rates of 70 h À1 during the first two hours of the reaction and overall turnover numbers up to 250 ± 300. [14] These catalyst activities far...

Modular Synthesis of 1,2‐Diamine Derivatives by Palladium‐Catalyzed Aerobic Oxidative Cyclization of Allylic Sulfamides

“…These catalyst systems were only moderately successful (Table 1, entries 1–3; for full screening data, see the Supporting Information). For example, the Pd(OAc) 2 /pyridine catalyst system we originally reported for tosyl‐substituted γ‐aminoalkenes10a afforded the desired cyclic sulfamide 2 in only 39 % yield and generated the imine byproduct 3 in 25 % yield (Table 1, entry 2). In the course of testing other solvents and reaction conditions, we observed that addition of catalytic quantities of dimethyl sulfoxide improved the yield of 2 when Pd(TFA) 2 /pyridine was used as the catalyst in 1,4‐dioxane (Table 1, entries 4 and 5).…”

“…This oxidative cyclization reaction could proceed via two different mechanisms (Scheme ): aminopalladation of the alkene followed by β‐hydride elimination10a or allylic CH activation to form a π‐allyl–palladium(II) intermediate followed by CN coupling 12b,d,e. The chelating sulfoxides 4 and 5 were tested as replacements for dimethyl sulfoxide because these ligands are known to facilitate allylic CH activation;12b,d,e however, only low yields of sulfamide product 2 were obtained in these reactions (Table 1, entries 12 and 13).…”

Gold(I)‐Catalyzed Intramolecular Hydroamination of Alkenyl Carbamates

“…Selective hydroamination of alkenyl carbamates has previously been achieved only through employment of a stoichiometric amount of Hg II followed by reduction 6. 7 Unfortunately, attempted hydroamination of carbamate 4 employing the catalyst system optimized for the hydroamination of 1 required 120 °C and formed protected pyrrolidine 5 in only 50 % yield (determined by 1 H NMR spectroscopic analysis) [Eq. (1)] 8…”

Palladiumoxidasekatalyse: selektive Oxidation durch direkte disauerstoffgekoppelte Umsetzung

“…In Zusammenhang mit der Anwendung dieses Katalysators in anderen Palladiumoxidasereaktionen (siehe Abschnitt 5.3)41 führten wir eine mechanistische Studie zur Pd(OAc) 2 /Pyridin‐katalysierten aeroben Oxidation von Benzylalkohol aus 42. Im Unterschied zur Pd(OAc) 2 /DMSO‐Reaktion – aber übereinstimmend mit anderen Palladium‐Katalysatorsystemen mit Stickstoffliganden (siehe Tabelle 1) – tritt in dieser katalytischen Reaktion ein stationärer Palladium( II )‐Zustand mit einer umsatzbegrenzenden Oxidation des Alkoholsubstrats auf.…”