Catalytic Synthesis of Nonracemic Azaproline Derivatives by Cyclization of β‐Alkynyl Hydrazines under Kinetic Resolution Conditions

Abstract

Heteroatom addition reactions to unactivated alkynes are thought to be best mediated by transition-metal catalysts such as palladium [1] and gold. [2] Recent studies by Hammond and co-workers [3] and others [4] demonstrate that cyclizations of alkynes with nitrogen-and oxygen-containing nucleophiles are possible using stoichiometric amounts of tetra-n-butylammonium fluoride. However, these examples appear to be limited to aryl or a,a-difluoro alkynes. As described herein, we have discovered by serendipity a nonmetal catalyzed addition of amine to unactivated alkynes to yield azaproline derivatives (Scheme 1). Although the nature of this catalysis reaction is not clear, these reactions proceed in excellent yields and lead to enantioenriched azaprolines under kinetic resolution conditions using ammonium phase-transfer catalysts.We decided to further investigate this cyclization reaction partly out of mechanistic curiosity but also mindful that azaprolines have taken on an increasingly important role in bioorganic [5] and medicinal chemistry. [6] Indeed, there has been a great deal of interest in the synthesis of azaproline derivatives over the last decade. The earliest approach pioneered by Carreira and co-workers involved diastereoselective [3+2] additions of diazoalkanes with a,b-unsaturated chiral esters. [7] More recently this method has been expanded to include other dipolar diazo reactions [8] including those catalyzed by chiral magnesium bisoxazole [9] as well as titanium BINOL-ate. [10] The pyrazolidine ring of azaprolines has also been prepared by palladium-catalyzed cyclizations of optically active allenylic hydrazines [11] or hydrazine adducts produced from racemic allenyl phosphine oxides. [12] However, herein we report related cyclization reactions catalyzed by nonmetal cations, which have allowed for an exciting class of chiral ammonium phase-transfer catalysts to be brought to bear to produce nonracemic azaproline derivatives (Scheme 1).Based on our previous experience with g-silyl allenyl esters, [13] we hypothesized that base-catalyzed addition of dinitrogen-containing electrophiles such as azidodicarboxylates should lead to b-alkynyl hydrazine intermediates. Indeed, with substrates 1 and 2 (EWG = CO 2 tBu and CO 2 Et) DBU catalyzed this transformation but the reactions were sluggish especially with larger a-substituents (Table 1). By applying a procedure similar to one we had previously reported, [14] g-silyl allenyl and propargyl thioesters (EWG = COStBu) were prepared and, as expected, these substrates underwent rapid addition to azidodicarboxylates with DBU even at À20 8C. Less basic amines failed to give hydrazine products even with these thio-Scheme 1. Catalytic generation of azaprolines by cyclization of b-alkynyl hydrazine compounds. EWG = electron-withdrawing group. Table 1: Additions of allenyl esters to azidodicarboxylates catalyzed by DBU. Entry EWG R 1 SiR 3 R 2 T [8C] t [h] Yield [%] [a]