Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold-Catalyzed Oxidative Cyclization/Aldol Addition of Homopropargyl Alcohols with Isatins Ju Cai,†,‡,§ Xin Wang,†,§ Yu Qian,† Lihua Qiu,‡ Wenhao Hu,*,† and Xinfang Xu*,†,‡ †
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
‡
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S Supporting Information *
ABSTRACT: A novel gold-catalyzed oxidative cyclization/aldol addition of homopropargyl alcohols with isatins has been developed that provides an effective access to the 3-hydroxyoxindoles in high yields under mild reaction conditions with high diastereoselectivities. In comparison with disclosed transformations of alkyne oxidations via an α-oxo gold carbene route, this is the first example of an aldol-type interception of an ylide (or its enolate form) intermediate with alkyne as a safe and readily available nondiazo carbene precursor. n recent decades, the α-oxo gold carbene species, which is generated from gold-catalyzed alkyne oxidantion, has shown broad applications in synthetic organic chemistry for the C−C and C−X bond formations.1 For example, these reactive gold carbene intermediates could react with a variety of nucleophilic reagents to form the X−H (X = C, N, and O) insertion products2−5 and others (Scheme 1a).6 In 2010, Zhang’s group reported the first access to α-oxo gold carbene via intermolecular oxidation to the terminal alkyne and then an O−H insertion (Scheme 1b).5 In these studies, the gold
I
carbene forms the gold enolates after addition with the corresponding nucleophiles, followed by protodeauration. Inspired by these advances and as a continuation of our interest in multicomponent reactions (MCRs) via the electrophilic trapping the in situ generated ylide intermediates,7 for example, Aldol-type interception of in situ generated oxonium ylide intermediates with carbonyl compounds (Scheme 1c).8 We envisioned that electrophilic interception of this ylide or its enolate form might be enabled in the presence of reactive electrophilic reagents, such as isatin, instead of direct proton shift.9 Herein, we report a successful implementation of interception the in situ generated oxonium ylide intermediate via aldol-type addition with carbonyl reagents. Notably, this is the first example that the catalytic alkyne oxidation via an α-oxo gold carbene route was introduced as a safe and readily available nondiazo carbene approach in an aldol-type trapping process (Scheme 1d).10 In addition, these 3-hydroxyoxindoles are privileged heterocyclic motifs that existed in a variety of natural products11 and biological active molecules.12 Thus, the development of efficient approaches to the direct construction of polyfunctional oxindole skeletons with readily available materials under mild conditions is of continuing interest in organic synthesis.13 To validate our hypothesis, the readily accessible homopropargylic alcohol 1a and isatin 2a were used as the model substrates (Table 1). To our delight, the expected trapping product 3a was obtained in 58% yield (entry 1) in the presence of gold catalyst with O1 as the oxidant (1.2 equiv) and TFA as additive (2.0 equiv). MsOH was less effective as an acidic additive, and the yield dropped to 46% (entry 2). The investigation of the pyridine-derived oxidants revealed that the less steric hindered oxidant O1 was best (entries 3−5). Further
Scheme 1. Catalytic Interception of Metal Carbene Intermediates
Received: November 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03502 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Condition Optimizationa
Scheme 2. Substrate Scopea
entry
cat (mol %)
oxidant
yieldsb (%)
1 2c 3 4 5 6 7 8 9
JohnphosAu(MeCN)SbF6 (5.0) JohnphosAu(MeCN)SbF6 (5.0) JohnphosAu(MeCN)SbF6 (5.0) JohnphosAu(MeCN)SbF6 (5.0) JohnphosAu(MeCN)SbF6 (5.0) PPh3AuNTf2 (5.0) JohnphosAuCl (5.0)/AgNTf2 (5.0) PPh3AuCl (5.0)/AgSbF6 (5.0) BrettPhosAuNTf2 (5.0)
O1 O1 O2 O3 O4 O1 O1 O1 O1
58 46
