Intramolecular Hydroamination of Aminoalkenes by Calcium and Magnesium Complexes: A Synthetic and Mechanistic Study

Abstract

The beta-diketiminate-stabilized calcium amide complex [{ArNC(Me)CHC(Me)NAr}Ca{N(SiMe(3))(2)}(THF)] (Ar = 2,6-diisopropylphenyl) and magnesium methyl complex [{ArNC(Me)CHC(Me)NAr}Mg(Me)(THF)] are reported as efficient precatalysts for hydroamination/cyclization of aminoalkenes. The reactions proceeded under mild conditions, allowing the synthesis of five-, six-, and seven-membered heterocyclic compounds. Qualitative assessment of these reactions revealed that the ease of catalytic turnover increases (i) for smaller ring sizes (5 > 6 > 7), (ii) substrates that benefit from favorable Thorpe-Ingold effects, and (iii) substrates that do not possess additional substitution on the alkene entity. Prochiral substrates may undergo diastereoselective hydroamination/cyclization depending upon the position of the existing stereocenter. Furthermore, a number of minor byproducts of these reactions, arising from competitive alkene isomerization reactions, were identified. A series of stoichiometric reactions between the precatalysts and primary amines provided an important model for catalyst initiation and suggested that these reactions are facile at room temperature, with the reaction of the calcium precatalyst with benzylamine proceeding with DeltaG(o)(298 K) = -2.7 kcal mol(-1). Both external amine/amide exchange and coordinated amine/amide exchange were observed in model complexes, and the data suggest that these processes occur via low-activation-energy pathways. As a result of the formation of potentially reactive byproducts such as hexamethyldisilazane, calcium-catalyst initiation is reversible, whereas for the magnesium precatalyst, this process is nonreversible. Further stoichiometric reactions of the two precatalysts with 1-amino-2,2-diphenyl-4-pentene demonstrated that the alkene insertion step proceeds via a highly reactive transient alkylmetal intermediate that readily reacts with N-H sigma bonds under catalytically relevant conditions. The results of deuterium-labeling studies are consistent with the formation of a single transient alkyl complex for both the magnesium and calcium precatalysts. Kinetic analysis of the nonreversible magnesium system revealed that the reaction rate depends directly upon catalyst concentration and inversely upon substrate concentration, suggesting that substrate-inhibited alkene insertion is rate-determining.

Iridium-Catalyzed, Intermolecular Hydroetherification of Unactivated Aliphatic Alkenes with Phenols

“…Hill and coworkers examined the intramolecular hydroamination of aminoalkenes catalyzed by calcium amido and magnesium amido complexes ligated by b diketiminates (Scheme 14). [66,67] Kinetic analysis of the reaction catalyzed by the magnesium system revealed a first-order dependence on catalyst concentration and an inverse first-order dependence on the concentration of aminoalkene. Although preliminary, these data are consistent with a mechanism involving turnover-limiting insertion of alkene into the M À N bond, which occurs after dissociation of one substrate from the metal center.…”

Heterofunctionalization catalysis with organometallic complexes of calcium, strontium and barium

“…A number of homoleptic complexes of the form MX 1 2 , however, have also been reported as pre-catalysts for heterofunctionalization of unsaturated substrates. (Crimmin et al 2005(Crimmin et al , 2009). Reactions were shown to proceed in high yield under mild conditions (25-80…”

“…• amide complexes undergo facile external amine/amide exchange along with intramolecular site exchange between amide and amine ligands (Ruspic & Harder 2007;Crimmin et al 2009).…”

Hydroamination reactions by metal triflates: Brønsted acid vs. metal catalysis?

“…4 Certain hydroamination reactions, particularly intramolecular cyclisation of aminoalkenes, can be catalysed by using alkali (earth) metal complexes such as n-BuLi and 40 metal amides. 5,6 As the application of such highly basic entities is not always desirable or practical, much research in the area has been directed towards the development of transition metal catalysts. Two mechanisms are often suggested for these, where C-N formation is triggered by the 45 activation of either the N-H or C=C moiety (Scheme 2).…”