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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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01667 • Publication Date (Web): 07 Aug 2017 Downloaded from http://pubs.acs.org on August 8, 2017
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The Journal of Organic Chemistry
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 RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)
[email protected];
[email protected] 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 ACS Paragon Plus Environment
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identical conditions.
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The copper catalysis can provide uniquely divergent access to indole and oxazole
heteroaromatic cores of great importance in medicinal and material chemistry.
ACS Paragon Plus Environment
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The Journal of Organic Chemistry
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
copper-mediated 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
aryl-substituted 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, right).3,4 Additionally, we have serendipitously found that similar aryl- and alkyl-substituted enamides undergo the
vinylic
C–H
alkoxylation
under
identical
conditions,
2,4,5-trisubstituted oxazoles selectively (Scheme 1, left).5
delivering
the
corresponding
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-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.
Scheme 1. Directing-Group-Controlled Divergent Approach to Indoles and Oxazoles via Cu-Catalyzed C–H Cleavage
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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 phenylacetylene 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 N-picolinoyl 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 (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
