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Ruthenium Catalyzed Intramolecular Hydroarylation of Arenes and Mechanistic Study: Synthesis of Dihydrobenzofurans, Indolines, and Chromans Raja K Rit, Koushik Ghosh, Rajib Mandal, and Akhila Kumar Sahoo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01734 • Publication Date (Web): 22 Aug 2016 Downloaded from http://pubs.acs.org on August 26, 2016
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The Journal of Organic Chemistry
Ruthenium Catalyzed Intramolecular Hydroarylation of Arenes and Mechanistic Study: Synthesis of Dihydrobenzofurans, Indolines, and Chromans Raja K. Rit,* Koushik Ghosh, Rajib Mandal, and Akhila K. Sahoo* School of Chemistry, University of Hyderabad, Hyderabad 500046, India
[email protected],
[email protected] RECEIVED DATE (to be automatically inserted)
A ruthenium-catalyzed, amide directed intramolecular hydroarylation of alkene-tethered benzamide derivatives is discussed. This method proficiently constructs dihydrobenzofuran, indoline, and chroman skeletons of biological significance in good to excellent yields; the overall process is atom economical and step-efficient. The reaction exhibits broad scope, tolerating common functional groups, labile protecting units, and heteroaryl motifs. The use of catalytic amount of base suffices the need. Deuterium scrambling and kinetic studies offer valuable facts in understanding the reaction mechanism.
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Introduction
Murai’s discovery of directing group (DG) aided Ru-catalyzed C−C bond formation of aromatic ketones fuelled surge in the development of novel transition-metal catalyzed (TMC) synthetic regimes for the direct functionalization of unactivated C−H bonds, which are ubiquitous.1,2 These elegant manifestations surface in bringing the step- and atom-efficient construction of versatile molecular architectures from simple precursors.3 In particular, the intramolecular functionalization of C−H bonds of the heteroatom bearing scaffolds proficiently manufactures heterocyclic motifs, adequately infusing regio-selectivity in the molecule.4 Therefore, realization of such synthetic manifolds would coherently add value to the rapidly progressing paradigm of C−H activation, which eventually useful for the construction of versatile heterocycle motifs.
Figure 1. Biologically active and drug molecules. Dihydrobenzofuran and indoline skeletons are invariably found in various biologically and pharmaceutically important molecules, such as lithospermic acid, ramelteon, etc (Figure 1).5 Of note, the intramolecular hydroarylation of heteroatom (O/N)-bearing olefin-tethered arenes effectively delivers medium ring-size heterocycles. In this regard, Ellman and Bergman’s group at first demonstrated the Rh-catalyzed aldimine-directed C−H hydroarylation of olefin-tethered arenes to yield various carbo/heterocycles (Figure 2A).6 The Rovis,7 Cramer,8 and Yoshikai9 group have independently developed the Rh- and Co-catalyzed hydroarylation of arenes (Figure 2A). Recently, we have demonstrated an efficient Ru-catalyzed intramolecular hydroarylation of methylphenyl-sulfoximine (MPS, prepared from thioanisole) DG enabled benzoic acid derivatives with olefins for the first time.10 It therefore becomes apparent to survey the identical reaction in a readily accessible common amide ACS Paragon Plus Environment
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The Journal of Organic Chemistry
derivatives, employed for various intermolecular C−H functionalizations,11 under the cost- effective and air-stable Ru-catalysis,12−14 which is so far unprecedented. To broaden the synthetic potential and the utility of the Ru-catalyzed intramolecular hydroarylation of arenes, we herein report N-alkyl amide directed hydroarylation reaction of O/N-tethered olefin bearing arenes for the construction of dihydrobenzofurans, indolines, and chromans. The isotopic labelling and kinetic experiments offer insightful data in deducing the reaction mechanism.
Figure 2. Intramolecular hydroarylation reactions.
Results and Discussion The investigation of amide directed intramolecular hydroarylation was initiated by submitting 1a to [Ru(p-cymene)Cl2]2 (3.0 mol %), AgSbF6 (12 mol %) in ClCH2CH2Cl (1,2-DCE) (Table 1); we were pleased noticing the formation of the expected dihydrobenzofuran 2a even in a trace amount (entry 1). Interestingly, the introduction of Cu(OAc)2 (1.0 equiv) in combination with Ru-catalyst enhanced the reactivity, producing 68% of 2a in 5 h (entry 2), indicating the role of base in this transformation. Other acetate bearing bases were moderate (entries 3−5); in contrast, Zn(OAc)2 and Mn(OAc)2 worked remarkably well, affording 92% and 98% of 2a, respectively (entry 6 and 7). The additives AgBF4, KPF6, or NaPF6 instead of AgSbF6 were found inferior (entries 8−10). The exceptional efficiency of AgSbF6 over AgBF4 is not clear to us; presumably the SbF6− anion in the active catalyst [RuII(pACS Paragon Plus Environment
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cymene)OAc]+[SbF6]− plays vital for the better outcome. The reaction was equally efficient, when catalytic amount of Mn(OAc)2 (50 mol % and 25 mol %) was used; although the reaction took a little longer time for completion (entries 11 and 12). The role of Mn(OAc)2 in this C−H hydroarylation was not known and yet to be established; we believe that Mn(OAc)2 or Zn(OAc)2 presumably facilitates the formation of the active catalyst [Ru(p-cymene)(OAc)]+ in the reaction. Use of Mn(OAc)2 (10 mol %) provided 74% of 2a in 20 h (entry 13). The reaction in the presence of AcOH (1.0 equiv), an acetate as well as proton donor, produced 72% of 2a (entry 14). Thus, the catalytic conditions in entry 12 were reflected optimum for the amide directed intramolecular hydroarylation reaction. Table 1. Optimization of Reaction Parametersa
entry
additive
base
(12 mol %)
(1.0 equiv)
yield (%) 2a
1
AgSbF6
-
