Article pubs.acs.org/joc
A Divergent Approach to Indoles and Oxazoles from Enamides by Directing-Group-Controlled Cu-Catalyzed Intramolecular C−H Amination and Alkoxylation Chiaki Yamamoto, Kazutaka Takamatsu, Koji Hirano,* and Masahiro Miura* Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan S Supporting Information *
ABSTRACT: A directing-group-controlled, copper-catalyzed divergent approach to indoles and oxazoles from enamides has been developed. The picolinamide-derived enamides undergo the intramolecular aromatic C−H amination in the presence of a Cu(OPiv)2 catalyst and an MnO2 oxidant to form the corresponding indoles in good yields. On the other hand, simpler aryl- or alkyl-substituted enamides are converted to the 2,4,5-trisubstituted oxazole frameworks via vinylic C−H alkoxylation under identical conditions. The copper catalysis can provide uniquely divergent access to indole and oxazole heteroaromatic cores of great importance in medicinal and material chemistry.
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INTRODUCTION Nitrogen-containing heteroaromatic rings are prevalent substructures in bioactive molecules, pharmaceutical targets, and functional materials. Synthetic chemists thus have developed many methodologies for the construction of above heterocycles. Among numerous reported procedures, the coppermediated oxidative cyclization via C−H cleavage now receives significant attention because of its higher synthetic efficiency associated with atom and step economies.1 Our research group also focused on the unique activity of less toxic, stable, and abundant copper salts and developed several Cu(II)-catalyzed intramolecular C−H amination reactions for the synthesis of carbazoles,2a indolines,2b and isoindolinones.2c As the next reaction design, we envisioned the C−H amination of arylsubstituted enamides: the expected Cu(II)-catalyzed aromatic C−H activation occurs with the aid of picolinamide directing group to form the desired indoles in good yields (Scheme 1,
controlled regiodivergent C−H activation was observed in some palladium- or rhodium-based catalysis8 but still remains underdeveloped under cooper-catalyzed conditions.2c The detailed optimization studies and substrate scope are reported herein.
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RESULTS AND DISCUSSION On the basis of our previous success of carbazole synthesis,2a optimization studies commenced with N-picolinoyl enamide 1a-Py (0.10 mmol; Table 1), which was readily prepared by the CsOH-mediated hydroamidation of diphenylacetylene with picolinamide.9 In an initial experiment, heating a DMF suspension of 1a-Py, 30 mol % Cu(OAc)2, and 2.0 equiv of MnO2 under microwave irradiation (180 °C, 1 h) afforded the desired 2-phenylindole (2a) in 37% GC yield (entry 1). Same as shown in the previous work,2a the corresponding Npicolinoyl indole was not detected at all, and NH-indole 2a was exclusively formed. After the aqueous workup, we successfully detected the picolinic acid in the aqueous phase by TOF-MS. Thus, the trace water in DMF solvent can promote the spontaneous hydrolysis in situ (vide infra). The addition of AcOH increased the yield to 63% (entry 2). We then tested several acetate-type Cu(II) salts, and bulkier Cu(OPiv)2, Cu(OCOAd)2, and Cu(eh)2 showed better reactivity (entries 3−5). Subsequent screening of acidic additives with Cu(eh)2 identified PivOH to be optimal (entries 6−8). Additional fine-tuning revealed that a combination of Cu(OPiv)2 and PivOH was best (entries 9 and 10), and finally 91% isolated yield was obtained at slightly higher temperature (entry 11). No reaction occurred in the absence of Cu(OPiv)2, confirming the copper catalysis in the present transformation
Scheme 1. Directing-Group-Controlled Divergent Approach to Indoles and Oxazoles via Cu-Catalyzed C−H Cleavage
right).3,4 Additionally, we have serendipitously found that similar aryl- and alkyl-substituted enamides undergo the vinylic C−H alkoxylation under identical conditions, delivering the corresponding 2,4,5-trisubstituted oxazoles selectively (Scheme 1, left).5 Thus, by the judicious choice of directing group, the single enamide skeleton is divergently converted under the same copper-catalyzed conditions to indole6 and oxazole7 of great interest in medicinal chemistry. Such a directing-group© 2017 American Chemical Society
Received: July 4, 2017 Published: August 7, 2017 9112
DOI: 10.1021/acs.joc.7b01667 J. Org. Chem. 2017, 82, 9112−9118
Article
The Journal of Organic Chemistry Table 1. Optimization for Copper-Catalyzed Intramolecular C−H Amination of Enamide 1a-Py for Synthesis of Indole 2aa
entry
Cu(II)
additive (equiv)
temp (°C)
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12
Cu(OAc)2 Cu(OAc)2 Cu(OPiv)2 Cu(OCOAd)2 Cu(eh)2 Cu(eh)2 Cu(eh)2 Cu(eh)2 Cu(eh)2 Cu(OPiv)2 Cu(OPiv)2 none
none AcOH (1.0) AcOH (1.0) AcOH (1.0) AcOH (1.0) EtCOOH (1.0) PivOH (1.0) AdCOOH (1.0) PivOH (1.5) PivOH (1.5) PivOH (1.5) PivOH (1.5)
180 180 180 180 180 180 180 180 180 180 200 200
37 63 69 72 72 71 77 52 75 84 (84) (91) 0
Scheme 2. Copper-Catalyzed Intramolecular C−H Amination of Various Enamides 1-Py for Synthesis of Indoles 2a
a
Reaction conditions: 1a-Py (0.10 mmol), Cu(II) (0.030 mmol), MnO2 (0.20 mmol), additive, DMF (0.60 mL), 1 h, N2, microwave irradiation. bEstimated by GC method. Isolated yield is in parentheses. Ad = 1-adamanthyl, eh = 2-ethyl-1-hexanoate, 2-Py = 2-pyridyl.
a
Reaction conditions: 1-Py (0.10 mmol), Cu(OPiv) (0.030 mmol), MnO2 (0.20 mmol), PivOH (0.15 mmol), DMF (0.60 mL), 1 h, N2, microwave irradiation. Isolated yields are shown. b1.0 mmol scale. c With 2.0 equiv of Cu(OPiv)2 in the absence of MnO2. At 150 °C with an oil bath for 4 h. dRegioisomeric ratio. The major isomer 2h was isolated in 58% yield. eCombined isolated yield of regioisomers. Regioisomeric ratio is in parentheses. fRegioisomeric ratio. The major isomer 2j was isolated in 40% yield.
(entry 12). Additionally, we also tested other oxidants including AgOAc, K2S2O8, and Mn(OAc)3 under otherwise optimal conditions, but the indole 2a was observed in only
