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Efficient and Selective Synthesis of (E)-Enamides via Ru(II)-Catalyzed Hydroamidation of Internal Alkynes Changsheng Kuai, Lianhui Wang, Haoyi Cui, Jinhai Shen, Yadong Feng, and Xiuling Cui ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b01791 • Publication Date (Web): 30 Nov 2015 Downloaded from http://pubs.acs.org on December 2, 2015
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ACS Catalysis
Efficient and Selective Synthesis of (E)-Enamides via Ru(II)Catalyzed Hydroamidation of Internal Alkynes Changsheng Kuai, Lianhui Wang, Haoyi Cui, Jinhai Shen, Yadong Feng, Xiuling Cui* Engineering Research Center of Molecular Medicine, Ministry of Education, Key Laboratory of Xiamen Marine and Gene Drugs, Institute of Molecular Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, 361021, China ABSTRACT: An efficient hydroamidation of benzylamides with internal alkynes catalyzed by Ru(II) has been developed. Various (E)-enamides were afforded in up to 95 % yield for 28 examples. The protocol features excellent regio- and stereoselectivity, widely functional group tolerance, and easily accessible starting materials.
KEYWORDS: Hydroamidation, Enamides, Interanl alkynes, Ruthenium, C-N Formation
The enamide moiety is a key functionality in numerous natural products1 and pharmaceuticals with antibiotic2, antitumor3, cytotoxic4, anthelmintic5 and antifungal6 activities (Chart 1). They also serves as important intermediates in organic reactions, such as [4+2]-cycloaddition7, cross-coupling reaction8, enantioselective addition9 or asymmetric hydrogenation10. Accordingly, much effort has been paid toward the development of new synthetic methods to build such a structure11. Considering the relatively harsh conditions, poor selectivity12, or the limited substrate scope13 with the conventional procedures, the hydroamidation of alkynes has appeared as a promising method due to its mild reaction conditions and 100% atom economy in recent years14. However, to the best of our knowledge, almost all protocols presented so far are restricted to terminal alkynes15. Only one example is applicable to internal alkynes with amide reported by Kozmin and Sun16, in which, silver-catalyzed hydroamidation of siloxy alkynes was successfully achieved (Scheme 1). However, this method is limited to electron-rich alkyne. Therefore, it is still highly desirable to discover new pathway to construct enamide that displays the broad scope of internal alkynes, high regioselectivity and efficiency. Herein, we present a novel hydroamidation of benzylamides with various alkynes catalyzed by Ru(II), affording the corresponding (E)-enamides in moderate to excellent yields, which featured excellent regio- and stereoselectivity, widely functional group tolerance, and easily accessible starting materials. To the best of our knowledge, this is the first example for the hydroamidation of electron-deficient internal alkynes (Scheme 1). In our initial studies, the reaction of benzylamides 1a with tolane 2a was chosen as a model reaction to optimize various reaction parameters (Table 1). The product of oxidative annulation of benzylamines with alkynes was not detected. However, the unexpected product 3aa was obtained in 81% yield with [Ru(p-cymene)Cl2]2 (5 mol%) and AgSbF6 (20 mol%) as a co-catalyst (entry 1). The structure of the product 3aa was confirmed by single crystal X-ray diffraction (Chart 2). The desired product 3aa could not be detected in the absence of [Ru(p-cymene)Cl2]2, AgSbF6 or Cu(OAc)2 (entries 2-4). With such an exciting preliminary result in hand, a
systematic screening of reaction solvents was carried out (entries 5-9). Among the solvents examined, 1,2-DCE was proved to be the best choice. Moreover, we were pleased to find that decreasing the loading of Cu(OAc) 2 from stoichiometry to catalytic amounts (10 mol%) led to increasing
Chart 1. Biologically active natural products containing enamide motif
Scheme 1. Catalytic Hydroamidation of alkynes
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the yield from 81% to 93% (entries 10-11). Besides, various additives, such as KOAc, NaOAc, HOAc and PivOH, were screened. Lower yields were obtained in all cases (entries 1215). Notably, reducing the catalyst loading to 3 mol% and 4 mol% significantly influence this reaction (entry 11). Table 1. Optimization of the reaction conditionsa
entry
solvent
additive (equiv)
3aa (%)b
1
1,2-DCE
Cu(OAc)2 (2)
81
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3). Likewise, electron-withdrawing groups, such as X- (Cl-, F), NO2- and CF3-substituted benzylamides 1e-h also reacted efficiently with 2a, giving trisubstituted alkenes 3ea-ha in 88%, 95%, 91% and 86% yields, respectively (entries 4-7). Ortho-Me, -F and -CF3 benzylamines 1i, 1j and 1k was less effectively, probably due to the steric effect, giving the target, Table 2. Scope of benzylamidesa
entry
substrate 1
product 3
yield (%)b
