Catalytic, Transition-Metal-Free Semireduction of Propiolamide Derivatives: Scope and Mechanistic Investigation

Abstract

We report a transition-metal-free trans-selective semireduction of alkynes with pinacolborane and catalytic potassium tertbutoxide. A variety of 3-substituted primary and secondary propiolamides, including an analog of FK866, a potent nicotinamide mononucleotide adenyltransferase (NMNAT) inhibitor, are reduced to the corresponding (E)-3-substituted acrylamide derivatives in up to 99% yield with >99:1 E/Z selectivity. Mechanistic studies suggest that an activated Lewis acid−base complex transfers a hydride to the αcarbon followed by rapid protonation in a trans fashion.T he semireduction of an alkyne to a (Z)-or (E)-alkene is fundamental in organic synthesis. Methods toward the (Z)-selective semireduction of alkynes are well established, 1 with the most popular being semihydrogenation mediated by Lindlar's catalyst (Pd/CaCO 3 /Pb/quinoline). 2 The complementary reduction methods affording (E)-alkenes are limited. Early work involved treating alkynes with dissolved metals, 3 low-valent chromium salts, 4 or metal hydrides; 5 however, these methods are harsh and highly substrate-dependent. Trost and coworkers later developed a general method for the (E)selective semireduction of alkynes via a ruthenium-mediated hydrosilylation, which is subsequently protodesilylated with TBAF, affording (E)-alkenes in high yield with excellent stereoselectivity. 6 Similarly, Furstner developed a one-step, stereoselective semireduction of alkynes using a similar ruthenium catalyst. 7 Beyond these two examples, various transition-metal-catalyzed methods toward the (E)-selective semireduction of alkynes have been developed, such as Pd, 1i,n,8 Rh, 9 Ru, 1q,10 In, 11 Ir, 1ab,12 Co, 1ac,13 Ni, 1ad,14 and Fe 15 (Scheme 1A).The transition-metal-free semireduction of alkynes to (E)alkenes is limited to a few examples. Koide treated γ-hydroxyα,β-alkynoic esters with Red-Al or NaBH 4 and obtained alkenoic esters in good yield with good stereoselectivity, although the substrate scope is limited by the necessity of the directing ability of the γ-hydroxyl moiety (Scheme 1B). 16 Chen and Liu employed sodium sulfide nonahydrate as a reducing reagent to facilitate the stereoselective semihydrogenation of diarylalkynes to (E)-alkenes (Scheme 1C). This method successfully reduced a broad scope of diarylalkynes in good to excellent yield with high stereoselectivity (98:2 E/Z). 17 Similarly, Zhou and Liu demonstrated the semireduction of diarylalkynes utilizing H 2 Se, which was generated in situ from Se/DMF/H 2 O (Scheme 1C), to obtain alkenes in good yield with high stereoselectivity (>95:5 E/Z). 18 However, both aforementioned methods were limited to diarylalkynes, and the reaction conditions were fairly harsh. Recently, our group

Roles of Alkali Metals tert‐Butoxide as Catalysts and Activators in Organic Transformations

“…The semi-reduction of alkynes into (E)-selective alkenes under transition metal-free conditions with pinacolborane and catalytic potassium tertiary butoxide were demonstrated by Grams and co-workers. [34] This protocol involves the reaction of primary and secondary propiolamide to provide the (E) isomer selectively and a broad range of substrate scope has been developed under the optimized reaction conditions. Instead of stoichiometric amounts, a catalytic amount of KO t Bu produces the required molecules efficiently and in good yields.…”

In Situ Formation of an Efficient Catalyst for the Semihydrogenation of Alkynes from Imidazolone and BH3

“…Furthermore, the last decade has witnessed a proliferation of reports on first-row transition-metal complexes that effectively catalyze this synthetically relevant transformation . Other established methods for the semireduction of alkynes make use of stoichiometric amounts of boranes . Motivated by the seminal finding from Stephan and co-workers that certain combinations of sterically encumbered Lewis bases and highly Lewis acidic boranes, referred to as frustrated Lewis pairs (FLP), are able to activate dihydrogen, Repo et al devised a protocol for an FLP-catalyzed semihydrogenation of alkynes (Scheme ).…”

Organocatalytic Trans Semireduction of Primary and Secondary Propiolamides: Substrate Scope and Mechanistic Studies

“…We recently reported the stereoselective semireduction of primary and secondary propiolamides using stoichioimetric pinacolborane and catalytic potassium tertbutoxide that produced cinnamamides in high yield and > 99:1 E:Z stereoselectivity. [22] While the reaction conditions was tolerant of various functional groups, a significant limitation is the presence of ketone in substrates where a competing 1,2-reduction of the carbonyl group occurs (Scheme 1F). To circumvent these issues, we investigated the ability of Lewis basic phosphines to catalyze the semireduction of propiolamides.…”