Synthesis of 2‐Arylacrylates from Pyruvate by Tosylhydrazide‐Promoted Pd‐Catalyzed Coupling with Aryl Halides

Abstract

The Pd-catalyzed cross-coupling reaction between tosylhydrazones and aryl halides, recently developed by our group, constitutes a very efficient way to synthesize di-and trisubstituted olefins. [1a] Over the last few years we have shown that this reaction is an excellent way to employ carbonyl compounds as the nucleophilic component of a Pd-catalyzed cross-coupling reaction (Scheme 1). [1, 2] In the context of this study, we turned our attention to hydrazones derived from ethyl pyruvate (1), as a representative of a-oxoesters, in the hope that the coupling reaction would represent a new route to 2-arylacrylates.The importance of this motif as a synthetic intermediate is noteworthy. For instance, 2-arylacrylates provide the main entry into the optically active version of prophens (a-arylpropionic acids), [3] the widely employed nonsteroidal anti-inflammatory agents. Moreover, these structures are activated olefins that are continuously employed as Michael acceptors, [4] dienophiles, [5] dipolarophiles, [6] alkenes for Heck and sequential Pd-catalyzed reactions, [7] intermediates in heterocyclic synthesis, [8] intermediates in the synthesis of cyclopropane carboxylic acids with biological activity, [9] and key fragments to generate diversity in drug discovery programs. [10] While the classical method for the synthesis of 2-arylacrylates is the condensation of the corresponding arylacetate with paraformaldehyde, [11,12] more recently, these systems have been prepared through different Pd-catalyzed crosscoupling reactions: Suzuki cross-couplings with 2-chloracrylates, [13] and alkenyl boronates, [14] Negishi reaction with 2-metallated acrylates, [15] and Pd-catalyzed carbonylation of arylvinyl bromides.[16] In a very recent contribution, Wang et al. reported a new synthesis of 2-arylacrylates by Pd-catalyzed coupling between diazoesters and arylboronic acids.[17]Herein, we present a new Pd-catalyzed cross-coupling approach to these systems that employs the tosylhydrazone of ethyl pyruvate as nucleophilic component, and therefore obviates the need for a stoichiometric organometallic reagent.Our initial experiments showed that the coupling between the tosylhydrazone 2, derived from ethyl pyruvate, and pbromotoluene proceeded in quantitative yield leading to acrylate 3 a by employing the reaction conditions presented in Scheme 2. Notably, the potentially sensitive ester functionality remained unaltered under the relatively harsh basic reaction conditions.To develop a more practical procedure, we studied the reaction starting directly from ethyl pyruvate (1), avoiding the isolation of the tosylhydrazone 2. After some experimentation, a one-pot protocol was optimized. In this process, ethyl pyruvate and tosylhydrazide were stirred for 2 h at 70 8C, then the rest of the reagents were added to the reaction mixture. Following this procedure, similar yields were ob- Scheme 2. Preliminary experiment of the coupling of the hydrazone 2 derived from ethyl pyruvate with an aryl bromide. Xphos: 2-dicyclohexylphosphino-2',4',...

Activation of a C(sp3)H Bond by a Transient σ‐Alkylpalladium(II) Complex: Synthesis of Spirooxindoles Through a Palladium‐Catalyzed Domino Carbopalladation/C(sp3)C(sp3) Bond‐Forming Process

“…The easily accessible N ‐(2‐bromophenyl)‐2‐(2,6‐dimethylphenyl)‐ N ‐methylacrylamide ( 1 a ) was used as a substrate to test the feasibility of our projected domino process (Table 1). 11 Initial efforts employed the catalytic system reported by Guyonnet and Baudoin 4o. Under these conditions, the desired spirooxindole 2 a was indeed obtained,12 albeit accompanied by a significant amount of quinolinone 3 a , which resulted from a 6‐ endo ‐trig cyclization ( 2 a / 3 a =1:2, entry 1, Table 1).…”

Tosylhydrazone – neue Anwendungen klassischer Reagentien in palladiumkatalysierten Kreuzkupplungen und metallfreien Umsetzungen

“…Ethylpyruvat (25) konnte in 2-Arylacrylate 26 umgewandelt werden, die wertvolle Zwischenverbindungen und direkte Vorstufen der entzündungs-hemmenden Prophen-Wirkstoffe sind (Schema 12). [23] Die Esterfunktion wurde durch das stark basische Alkoxid nicht angegriffen. Weiterhin führten Reaktionen mit Hydrazonen 27, die von substituierten 2-Oxoestern abgeleitet wurden, zu den entsprechenden tri-und sogar tetrasubstituierten funktionalisierten Alkenen 28 (Schema 13).…”

“…Das Eintopfverfahren wurde auch für die Synthese von elektrophilen Olefinen genutzt. Ethylpyruvat (25) konnte in 2-Arylacrylate 26 umgewandelt werden, die wertvolle Zwischenverbindungen und direkte Vorstufen der entzündungshemmenden Prophen-Wirkstoffe sind (Schema 12) [23]. Die Esterfunktion wurde durch das stark basische Alkoxid nicht angegriffen.…”

Intermolecular Mizoroki–Heck Reaction of Aliphatic Olefins with High Selectivity for Substitution at the Internal Position

“…[21] Thus, to introduce aryl groups at the a position, cross-couplings of a-halogenated or a-metallated acrylates are often employed. [22] Interestingly, our Heck condition can be applied to perform selective a arylation of acrolein diethyl acetal [Eqs. (5)-(6), Scheme 4].…”