A Divergent Approach to Indoles and Oxazoles from Enamides by Directing-Group-Controlled Cu-Catalyzed Intramolecular C-H Amination and Alkoxylation

Article abstract of DOI:10.1021/acs.joc.7b01667

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.

Full text of DOI:10.1021/acs.joc.7b01667

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Article
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
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The Journal of Organic Chemistry
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A Divergent Approach to Indoles and Oxazoles from
Enamides by DirectingꢀGroupꢀControlled CuꢀCatalyzed
Intramolecular CꢀH Amination and Alkoxylation
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Chiaki Yamamoto, Kazutaka Takamatsu, Koji Hirano,* and Masahiro Miura*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka
565ꢀ0871, 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)
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
A directingꢀgroupꢀcontrolled, copperꢀcatalyzed divergent approach to indoles and oxazoles from
enamides has been developed. The picolinamideꢀderived 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 arylꢀ or alkylꢀsubstituted enamides
are converted to the 2,4,5ꢀtrisubstituted oxazole frameworks via vinylic C–H alkoxylation under
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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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The Journal of Organic Chemistry
Introduction
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Nitrogenꢀcontaining 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
copperꢀmediated 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
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and isoindolinones.2c
As the next reaction design, we envisioned the C–H amination of
arylꢀsubstituted 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 arylꢀ and alkylꢀsubstituted enamides undergo
the vinylic C–H alkoxylation under identical conditions, delivering the corresponding
2,4,5ꢀtrisubstituted oxazoles selectively (Scheme 1, left).5 Thus, by the judicious choice of directing
group, the single enamide skeleton is divergently converted under the same copperꢀcatalyzed conditions
to indole6 and oxazole7 of great interest in medicinal chemistry. Such a directingꢀgroupꢀcontrolled
regiodivergent C–H activation was observed in some palladiumꢀ or rhodiumꢀbased catalysis8 but still
remains underdeveloped under cooperꢀcatalyzed 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
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On the basis of our previous success of carbazole synthesis,2a optimization studies commenced with
Nꢀpicolinoyl enamide 1a-Py (0.10 mmol; Table 1), which was readily prepared by the CsOHꢀmediated
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 2ꢀphenylindole (2a) in 37% GC yield (entry 1). Same as shown in the
previous work,2a the corresponding Nꢀpicolinoyl indole was not detected at all, and NHꢀindole 2a was
exclusively formed. After the aqueous workup, we successfully detected the picolinic acid in the
aqueous phase by TOFꢀMS. 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 acetateꢀtype 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 <9% GC yield (data not shown).
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Table 1. Optimization for Copper-Catalyzed Intramolecular C–H Amination of Enamide 1a-Py
for Synthesis of Indole 2aa
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entry
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Cu(II)
Cu(OAc)2
Cu(OAc)2
Cu(OPiv)2
Cu(OCOAd)2
Cu(eh)2
additive (equiv)
none
temp (˚C)
yield (%)b
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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)
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Cu(eh)2
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Cu(eh)2
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Cu(eh)2
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Cu(eh)2
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Cu(OPiv)2
Cu(OPiv)2
none
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(91)
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a
Reaction conditions: 1a-Py (0.10 mmol), Cu(II) (0.030 mmol), MnO2 (0.20 mmol), additive, DMF
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(0.60 mL), 1 h, N2, microwave irradiation. b Estimated by GC method. Isolated yield is in parentheses.
Ad = 1ꢀadamanthyl, eh = 2ꢀethylꢀ1ꢀhexanoate, 2ꢀPy = 2ꢀpyridyl.
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Under conditions of entry 11 in Table 1, we performed the aromatic C–H amination of various
enamides. The representative indole products are illustrated in Scheme 2. The copper catalysis was
compatible with electronically diverse functions including methyl, tertꢀbutyl, trifluoromethyl, and
methoxy groups, and the corresponding substituted indoles 2b–d and 2g were obtained in synthetically
useful yields. The aromatic C–Cl and C–Br moieties were also tolerated (2e and 2f), which can
provide a useful synthetic handle for further manipulations based on the palladiumꢀcatalyzed
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crossꢀcoupling chemistry.10 In the cases of metaꢀsubstituted enamides, the more sterically accessible
C–H was preferably aminated (2h and 2i). The same regioselectivity trend was observed in the
reaction of 2ꢀnaphtylꢀsubstituted enamide (2j). On the other hand, thienyl and benzothienyl substrates
were somewhat unstable under the standard conditions with the MnO2 terminal oxidant, but the
corresponding thiopheneꢀfused pyrrole rings 2k and 2l were obtained by using stoichiometric Cu(OPiv)2
and conventional heating method with an oil bath. The stoichiometric conditions also increased the
yield of electronꢀrich 2g. In the stoichiometric reactions of theses electronꢀrich substrates, a small but
significant amount of the corresponding Nꢀpicolinoylindoles was detected by GC and GCMS analysis.
However, upon workup with ethylenediamine, the Nꢀpicolinoyl group was smoothly removed to from
the NH indoles exclusively (see the Experimental Section for details). The copperꢀcatalyzed C–H
amination also accommodated the primary and secondary alkyl substituents to furnish the 2ꢀalkylindoles
in good yields (2m and 2n). The reaction could also be conducted on a preparative scale (1.0 mmol)
(2a). Although similar intramolecular C–H aminations directed toward indole were already reported,4
they still relied on precious Pd catalysts or stoichiometric hypervalent I(III) oxidants. The present
protocol is the first successful example of indole synthesis via copperꢀcatalyzed C–H amination, to the
best of our knowledge.
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Scheme 2. Copper-Catalyzed Intramolecular C–H Amination of Various Enamides 1-Py for
Synthesis of Indoles 2a
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The Journal of Organic Chemistry
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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. b 1.0 mmol scale.
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With 2.0 equiv Cu(OPiv)2 in the absence of MnO2. At 150 ˚C with an oil bath for 4 h.
e
Regioisomeric ratio. The major isomer 2h was isolated in 58% yield.
Combined isolated yield of
regioisomers. Regioisomeric ratio is in parenthesis. f Regioisomeric ratio. The major isomer 2j was
isolated in 40% yield.
We next investigated the effect of substituent on enamide nitrogen and serendipitously found that the
corresponding Nꢀbenzoyl enamide 1a-Ph completely changed the reaction course even under otherwise
identical conditions: the intramolecular vinylic C–H alkoxylation proceeded selectively to afford the
2,4,6ꢀtriphenyloxazole 3a-Ph in 89% isolated yield (Scheme 3). Both an electronꢀdonating methoxy
and an electronꢀwithdrawing trifluoromethyl groups were well tolerated (3a-OMe and 3a-CF3), and
even tertꢀbutylꢀsubstituted enamide was converted to the trisubstituted oxazole in 85% yield (3a-t-Bu).
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Also in this case, the reaction could be easily scaled up to 1.0 mmol (3a-Ph). On the other hand, even
in the absence of Cu(OPiv)2, a small but significant amount of 3a-Ph (24% GC yield) was observed.
Prompted by the above intriguing product selectivity switching, we subsequently implemented the
reaction of various benzoylꢀsubstituted enamides 1-Ph. The corresponding triaryloxazoles were
uniformly formed with good to excellent yields from a wide range of paraꢀ and metaꢀsubstituted
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enamides (3b-Ph–3i-Ph).
The substrates bearing the sterically demanding naphthyl and
heteroaromatic thienyl substituents also underwent the cyclization smoothly (3j-Ph–3l-Ph).
Additionally, the 4ꢀalkyloxazoles were also readily constructed under identical conditions (3m-Ph and
3n-Ph).
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The Journal of Organic Chemistry
Scheme 3. Copper-Catalyzed Intramolecular C–H Alkoxylation of Enamides 1 for Synthesis of
Oxazoles 3a
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a
Reaction conditions: 1 (0.10 mmol), Cu(OPiv) (0.030 mmol), MnO2 (0.20 mmol), PivOH (0.15
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mmol), DMF (0.60 mL), 1 h, N2, microwave irradiation. Isolated yields are given. b 1.0 mmol scale.
c GC yield without Cu(OPiv)2 catalyst.
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The related copperꢀmediated and ꢀcatalyzed cyclization of enamides were already developed by
Stahl5a and Buchwald.5b However, only attempts to construct 2,5ꢀdisubstituted oxazoles were reported.
Thus, we tested the reaction of 1a-Ph under literature conditions (Scheme 4): the trisubstituted oxazole
3a-Ph was formed in 76% GC yield under CuCl2ꢀmediated conditions developed by Stahl whereas
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Buchwald’s procedure using a CuBr2 catalyst gave 3a-Ph in only <2% yield.
Under
microwaveꢀmodified conditions, the CuCl2/NMI system provided 3a-Ph in 90% GC yield, but a
stoichiometric amount of CuCl2 was still necessary. These outcomes demonstrate the synthetic
advantage of our newly developed Cu(OPiv)2/MnO2 catalyst system.
Scheme 4. Attempts to Apply Reported Cu-Promoted Conditions for Synthesis of Oxazole 3a-Ph
To gain some mechanistic insight, several deuteriumꢀlabeling experiments with 1a-Py-d10 and 1a-Ph-d1
were carried out (Scheme 5, see the Supporting Information for more detail). All deuteriumꢀlabeling
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The Journal of Organic Chemistry
experiments were performed under the conventional heating conditions with an oil bath, because under
microwaveꢀassisted conditions the reaction proceeded in the course of the preheating time up to 200 ˚C,
and the conversion at an early stage was difficult to monitor. We initially checked the irreversibility of
C–H cleavage. At an early stage of reaction, no H/D exchange occurred in both indole and oxazole
formations (eqs 1 and 2). Thus, the kinetic isotope effect (KIE) value of each reaction was
investigated: 4.2 and 1.1 were obtained for 1a-Py and 1a-Ph, respectively (eqs 3 and 4).
Scheme 5. Deuterium-Labeling Experiments
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On the basis of the above results and literature information, we are tempted to assume the reaction
mechanism of 1a-Py and 1a-Ph as follows (Scheme 6). For the formation of indole 2a (cycle A), the
starting Cu(OPiv)2 initially undergoes the ligand exchange with 1a-Py generates the N,Nꢀbidentately
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coordinated Cu complex 4.11 Subsequent rateꢀlimiting C–H cleavage12 (4 → 5) is followed by
disproportionation with additional Cu(OPiv)2 to afford a Cu(III) species 6.13 The indole framework 7
is then constructed by reductive elimination from 6. Spontaneous hydrolysis of 7 in situ gives the
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observed NHꢀindole 2a. On the other hand, the formed CuOPiv is reoxidized by MnO2 into
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Cu(OPiv)2 to complete the catalytic cycle A. On the other hand, the oxazole 3a-Ph formation process
(cycle B) includes (1) ligand exchange with 1a-Ph (Cu(OPiv)2 ⟶ 8), (2) disproportionationꢀinduced
oxidation into Cu(III) species 9, and (3) homolysis of the resulting N–Cu(III) bond along with the
regeneration of the staring Cu(OPiv)2.2c,15 The formed amidyl radical 10 undergoes cyclization (10 ⟶
11) followed by the single electron transfer (SET) oxidation (11 ⟶ 12) and deprotonation to furnish the
oxazole 3a-Ph. The minor background reaction observed in Scheme 3 suggests less effective but
significant oxidation aptitude of MnO2 for the generation of radical species 11. However, radical
inhibitors, TEMPO and galvinoxyl, did not completely shut down oxazole formation as well as indole
formation (Scheme 7). Thus, the initial single electron transfer (SET) oxidation, which was originally
proposed by Stahl5a is also plausible, and details still remain to be elucidated.16
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Scheme 6. Plausible Mechanism
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Scheme 7. Effects of Radical Inhibitors
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Conclusion
We have developed a copperꢀcatalyzed oxidative cyclization approach to indoles and oxazoles via C–
H amination and alkoxylation, respectively. The directingꢀgroupꢀcontrolled divergent mechanisms,
namely Cu(I)/(II)/(III) organometallic pathway and amidyl radical pathway, are operated, and indoles
and oxazoles are selectively obtained from enamides of same skeleton.
Such
a
directingꢀgroupꢀcontrollable strategy enables diversityꢀoriented synthesis of Nꢀheterocycles through
multisiteꢀselective C–H functionalization. Further development of related regioselective and/or
ꢀdivergent Cu catalysts is ongoing and will be reported in due course.
Experimental Section
Instrumentation and Chemicals 1H, 13C{1H}, and 19F{1H} NMR spectra were recorded at 400
MHz, 100 MHz, and 376 MHz, respectively, for CDCl3 or DMSOꢀd6 solutions. HRMS data were
obtained by APCI using TOF. GC analysis was carried out using a silicon OVꢀ17 column (2.6 mm i.d.
x 1.5 m) or a CBPꢀ1 capillary column (0.5 mm i.d. x 25 m). TLC analyses were performed on
commercial glass plates bearing a 0.25 mm layer of Merck silica gel 60F254. Silica gel (Wakosil
Cꢀ200) was used for column chromatography. Gel permeation chromatography (GPC) was performed
by LCꢀ6AD (pump, SHIMADZU, 3.5 mL/min CHCl3) and SPDꢀ20A (UV detector, SHIMADZU, 254
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nm) with two inꢀline GPC Hꢀ2001 (20 x 500 mm, particle size: 15 ꢀm) and Hꢀ2002 columns (20 x 500
1
2
mm, particle size: 15 ꢀm) (preparative columns, Shodex, CHCl3 eluent) or by LCꢀ20AR (pump,
SHIMADZU, 7.5 mL/min EtOAc) and SPDꢀ20A (UV detector, SHIMADZU, 254 nm) with two inꢀline
YMCꢀGPC T2000 (20 x 600 mm, particle size: 10 ꢀm) (preparative columns, YMC, EtOAc eluent).
Microwave irradiation was conducted with Initiator+ (Biotage), and the reaction temperature was
measured by an internal probe. Unless otherwise noted, materials obtained from commercial suppliers
were used as received. Cu(OPiv)2 was prepared according to the literature.17 DMF was dried on a
Glass Contour Solvent dispensing system (Nikko Hansen & Co., Ltd.) prior to use. Enamides 1,
except for 1g-Py and 1g-Ph, were synthesized by the CsOHꢀmediated hydroamidation of corresponding
internal alkynes and benzamides.9 Conventional condensation was conducted for the preparation of
1g-Py and 1g-Ph.18 All reactions were carried out under nitrogen atmosphere unless otherwise noted.
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Preparation of 1a-Ph-d1. In a glovebox filled with nitrogen, diphenylacetylene (67 mg, 0.38
mmol), benzamide (45 mg, 0.38 mmol), and CsOH•OH2 (63 mg, 0.38 mmol) were placed in a 2.0 mL
microwave vessel. The vessel was sealed with a cap and then taken out of the glovebox. Dimethyl
sulfoxideꢀd6 (DMSOꢀd6, 1.5 mL) was sequentially injected via a syringe. The mixture was stirred for 24
h at 120 °C. The resulting mixture was then quenched with water. The mixture was extracted with
ethyl acetate three times, and the combined organic layer was dried over anhydrous Na2SO4. After
concentration under reduced pressure, silica gel column purification with hexane/ethyl acetate (3/1, v/v)
afforded (Z)ꢀNꢀ(2ꢀdeuterioꢀ1,2ꢀdiphenylvinyl)benzamide (1a-Ph-d1; 77 mg, 0.26 mmol, 98% D) in 68%
yield.
Typical Procedure for Synthesis of Indoles 2 under Conditions Catalytic in Copper. The
synthesis of 2a is representative (Scheme 2).
Cu(OPiv)2 (8.0 mg, 0.030 mmol),
(Z)ꢀNꢀ(1,2ꢀdiphenylvinyl)picolinamide (1a-Py; 30 mg, 0.10 mmol), pivalic acid (15 mg, 0.15 mmol),
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and MnO2 (17 mg, 0.20 mmol) were placed in a microwave vessel. The vessel was flushed with
nitrogen and then sealed with a cap. DMF (0.60 mL) was sequentially injected via a syringe. The
mixture was irradiated under microwave reactor conditions at 200 °C for 1 h. The resulting mixture
was then quenched with water, and a small amount of ethylenediamine was added to dissolve the
residual copper salts in the aqueous phase. The mixture was extracted with ethyl acetate three times,
and the combined organic layer was dried over anhydrous Na2SO4. After concentration under reduced
pressure, silica gel column purification with hexane/ethyl acetate (10/1, v/v) afforded 2ꢀphenylindole
(2a; 18 mg, 0.091 mmol) in 91% yield.
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2-Phenyl-1H-indole (2a)19 white solid; m.p. 187.6ꢀ189.3 C; 18 mg (91%); H NMR (400 MHz,
CDCl3) δ 6.85 (dd, J = 1.1, 1.9 Hz, 1H), 7.15 (ddd, J = 1.1, 7.0, 8.0 Hz, 1H), 7.22 (ddd, J = 1.1, 7.1, 8.2
13
Hz, 1H), 7.34 (tt, J = 1.1, 7.4 Hz, 1H), 7.40ꢀ7.48 (m, 3H), 7.65ꢀ7.69 (m, 3H), 8.33 (s, 1H); C NMR
(100 MHz, CDCl3) δ 100.0, 110.9, 120.3, 120.7, 122.4, 125.2, 127.7, 129.1, 129.3, 132.4, 136.8, 137.9;
HRMS (APCI) m/z ([M+H]+) calcd for C14H12N: 194.0964, found: 194.0960.
6-Methyl-2-(p-tolyl)-1H-indole (2b) white solid; m.p. 187.6ꢀ189.3 oC; 13 mg (59%); m.p.
206.8ꢀ208.2 oC; 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 2.47 (s, 3H), 6.73 (dd, J = 0.8, 2.1 Hz, 1H),
6.94 (dd, J = 0.8, 8.0 Hz, 1H), 7.18 (d, J = 0.6 Hz, 1H), 7.22ꢀ7.25 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H),
13
7.50ꢀ7.55 (m, 2H), 8.17 (s, 1H); C NMR (100 MHz, CDCl3) δ 21.2, 21.8, 99.1, 110.8, 120.1, 122.0,
124.9, 127.1, 129.7, 129.8, 132.0, 137.1, 137.38, 137.40; HRMS (APCI) m/z ([M+H]+) calcd for
C16H16N: 222.1277, found: 222.1278.
o
6-(tert-Butyl)-2-(4-(tert-butyl)phenyl)-1H-indole (2c) white solid; m.p. 142.9ꢀ144.6 C; 22 mg
(71%); 1H NMR (400 MHz, CDCl3) δ 1.36 (s, 9H), 1.39 (s, 9H), 6.74 (t, J = 1.0 Hz, 1H), 7.20 (dd, J =
1.6, 8.4 Hz, 1H), 7.40 (s, 1H), 7.44ꢀ7.47 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.57ꢀ7.59 (m, 2H), 8.23 (s,
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The Journal of Organic Chemistry
1H); 13C NMR (100 MHz, CDCl3) δ 31.3, 31.8, 34.7, 34.8, 99.2, 107.1, 118.5, 120.0, 124.8, 126.0,
127.0, 129.9, 136.9, 137.7, 145.7, 150.6; HRMS (APCI) m/z ([M+H]+) calcd for C22H28N: 306.2216,
found: 306.2218.
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6-(Trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)-1H-indole (2d) white solid; m.p. 115.9ꢀ116.8
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oC; 30 mg (91%); H NMR (400 MHz, CDCl3) δ 6.95 (d, J = 1.4 Hz, 1H), 7.38 (dd, J = 1.0, 8.3 Hz,
1H), 7.69ꢀ7.77 (m, 6H), 8.58 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 101.6, 108.7 (q, J = 4.3 Hz), 117.3
(q, J = 3.7 Hz), 121.4, 124.0 (q, J = 273.8 Hz), 125.0 (q, J = 271.1 Hz), 125.1 (q, J = 31.7 Hz), 125.5,
126.2 (q, J = 3.4 Hz), 130.2 (q, J = 32.7 Hz), 131.3, 134.9, 135.9, 138.8; 19F NMR (376 MHz, CDCl3) δ
ꢀ62.6, ꢀ60.8; HRMS (APCI) m/z ([M+H]+) calcd for C16H10F6N: 330.0712, found: 330.0709.
o
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6-Chloro-2-(4-chlorophenyl)-1H-indole (2e) white solid; m.p. 166.2ꢀ167.2 C; 19 mg (74%); H
NMR (400 MHz, CDCl3) δ 6.77 (dd, J = 0.8, 2.2 Hz, 1H), 7.10 (dd, J = 1.8, 8.4 Hz, 1H), 7.38 (t, J = 0.8
13
Hz, 1H), 7.38ꢀ7.43 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.55ꢀ7.58 (m, 2H), 8.26 (s, 1H); C NMR (100
MHz, CDCl3) δ 100.4, 110.9, 121.3, 121.6, 126.3, 127.7, 128.4, 129.3, 130.4, 133.8, 137.2, 137.4;
HRMS (APCI) m/z ([M+H]+) calcd for C14H10Cl2N: 262.0185, found: 262.0184.
o
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6-Bromo-2-(4-bromophenyl)-1H-indole (2f) white solid; m.p. 187.6ꢀ188.3 C; 18 mg (51%); H
NMR (400 MHz, CDCl3) δ 6.78 (d, J = 1.4 Hz, 1H), 7.23 (dd, J = 1.4, 8.4 Hz, 1H), 7.49 (t, J = 8.7 Hz,
3H), 7.54ꢀ7.58 (m, 3H), 8.27 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 100.5, 113.9, 116.0, 121.9, 123.9,
126.4, 126.6, 128.0, 130.8, 132.3, 137.3, 137.6; HRMS (APCI) m/z ([M+H]+) calcd for C14H10Br2N:
349.9175, found: 349.9179.
2-(4-Methoxyphenyl)-1H-indole (2g) white solid; m.p. 228.5ꢀ229.7 oC; 14 mg (62%); 1H NMR (400
MHz, CDCl3) δ 3.86 (s, 3H), 6.72 (dd, J = 0.8, 2.0 Hz, 1H), 6.96ꢀ7.00 (m, 2H), 7.09ꢀ7.19 (m, 2H),
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13
7.37ꢀ7.39 (m, 1H), 7.58ꢀ7.61 (m, 3H), 8.25 (s, 1H); C NMR (100 MHz, CDCl3) δ 55.4, 98.9, 110.7,
114.5, 120.2, 120.4, 121.9, 125.2, 126.5, 129.4, 136.7, 138.0, 159.4; HRMS (APCI) m/z ([M+H]+) calcd
for C15H14NO: 224.1070, found: 224.1072.
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5-Methyl-2-(m-tolyl)-1H-indole (2h) white solid; m.p. 160.9ꢀ161.6 oC; 19 mg (58%); 1H NMR (400
MHz, CDCl3) δ 2.40 (s, 3H), 2.44 (s, 3H), 6.72 (dd, J = 0.6, 2.0 Hz, 1H), 7.00 (dd, J = 1.3, 8.2 Hz, 1H),
7.11 (d, J = 7.5 Hz, 1H), 7. 24ꢀ7.32 (m, 2H), 7.40 (d, J = 0.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.45 (s,
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1H), 8.20 (s, 1H); C NMR (100 MHz, CDCl3) δ 21.5, 21.6, 99.4, 110.5, 120.3, 122.2, 123.9, 125.8,
128.4, 128.9, 129.4, 129.6, 132.4, 135.1, 138.1, 138.6; HRMS (APCI) m/z ([M+H]+) calcd for C16H16N:
222.1277, found: 222.1275.
A
10:1
mixture
of
5-methoxy-2-(3-methoxyphenyl)-1H-indole
(2i)
and
o
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7-methoxy-2-(3-methoxyphenyl)-1H-indole (2i') white solid; m.p. 132.2ꢀ133.9 C; 19 mg (75%); H
NMR (400 MHz, CDCl3) for mixture δ 3.86 (s, 0.91 × 3H for 2i), 3.87 (s, 0.91 × 3H for 2i), 3.88 (s,
0.090 × 3H for 2i'), 3.98 (s, 0.090 × 3H for 2i'), 6.75 (dd, J = 0.7, 2.0 Hz, 0.91 × 1H for 2i), 6.80 (d, J =
2.3 Hz, 0.090 × 1H for 2i'), 6.84ꢀ6.88 (m, 0.91 × 2H for 2i, 0.090 × 2H for 2i'), 7.03 (t, J = 7.9 Hz,
0.090 × 1H for 2i'), 7.07ꢀ7.08 (m, 0.91 × 1H for 2i, 0.090 × 1H for 2i'), 7.17 (t, J = 2.0 Hz, 0.91 × 1H
for 2i), 7.21ꢀ7.24 (m, 0.91 × 1H for 2i, 0.090 × 1H for 2i'), 7.26ꢀ7.28 (m, 0.91 × 1H for 2i, 0.090 × 1H
for 2i'), 7.32ꢀ7.36 (m, 0.91 × 1H for 2i, 0.090 × 1H for 2i'), 8.23 (s, 0.91 × 1H for 2i), 8.54 (s, 0.090 ×
13
1H for 2i'); C NMR (100 MHz, CDCl3) for 2i δ 55.4, 55.8, 100.1, 102.2, 110.9, 111.7, 112.7, 113.0,
117.6, 129.6, 130.1, 132.0, 133.8, 138.5, 154.5, 160.1; HRMS (APCI) m/z ([M+H]+) calcd for
C16H16NO2: 254.1176, found: 254.1174.
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2-(Naphthalen-2-yl)-1H-benzo[f]indole (2j) white solid; m.p. 251.3ꢀ253.0 C; 12 mg (40%); H
NMR (400 MHz, DMSOꢀd6) δ 7.25ꢀ7.35 (m, 3H), 7.54ꢀ7.62 (m, 2H), 7.90ꢀ8.05 (m, 6H), 8.13ꢀ8.15 (m,
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The Journal of Organic Chemistry
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2H), 8.52 (s, 1H), 11.73 (s, 1H); C NMR (100 MHz, DMSOꢀd6) δ 99.2, 106.5, 117.5, 122.7, 123.7,
124.2, 124.5, 126.9, 127.3, 127.7, 128.2, 128.3, 128.5, 128.9, 129.0, 129.7, 130.6, 131.08, 131.14,
133.6, 138.6, 142.3; HRMS (APCI) m/z ([M+H]+) calcd for C22H16N: 294.1277; found: 294.1275.
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2-Butyl-1H-indole (2m) yellow oil; 13 mg (66%); 1H NMR (400 MHz, CDCl3) δ 0.95 (t, J = 7.3 Hz,
3H), 1.41 (sext, J = 7.5 Hz, 2H), 1.66ꢀ1.73 (m, 2H), 2.74 (t, J = 7.6 Hz, 2H), 6.23 (dd, J = 0.9, 2.0 Hz,
1H), 7.04ꢀ7.12 (m, 2H), 7.27ꢀ7.29 (m, 1H), 7.51ꢀ7.53 (m, 1H), 7.82 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.9, 22.4, 28.0, 31.3, 99.5, 110.3, 119.6, 119.7, 120.9, 128.9, 135.8, 140.0; HRMS (APCI)
m/z ([M+H]+) calcd for C12H16N: 174.1277, found: 174.1275.
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2-Cyclohexyl-1H-indole (2n) white solid; m.p. 104.2ꢀ105.6 C; 16 mg (79%); H NMR (400 MHz,
CDCl3) δ 1.23ꢀ1.51 (m, 5H), 1.74ꢀ1.77 (m, 1H), 1.83ꢀ1,87 (m, 2H), 2.07ꢀ2.10 (m, 2H), 2.68ꢀ2.75 (m,
1H), 6.23 (d, J = 1.0 Hz, 1H), 7.04ꢀ7.13 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.90
13
(s, 1H); C NMR (100 MHz, CDCl3) δ 26.1, 26.3, 33.0, 37.3, 97.5, 110.3, 119.6, 119.9, 120.9, 128.6,
135.5, 145.1; HRMS (APCI) m/z ([M+H]+) calcd for C14H18N: 200.1434, found: 200.1434.
Typical Procedure for Synthesis of Indoles 2 under Conditions Stoichiometric in Copper. The
synthesis of 2k is representative (Scheme 2).
Cu(OPiv)2 (53 mg, 0.20 mmol),
(Z)ꢀNꢀ(1,2ꢀdi(thiophenꢀ2ꢀyl)vinyl)picolinamide (1k-Py; 31 mg, 0.10 mmol), and pivalic acid (15 mg,
0.15 mmol) were placed in a 2.0 mL microwave vessel. The vessel was flushed with nitrogen and then
sealed with a cap. DMF (0.60 mL) was sequentially injected via a syringe. The mixture was heated at
150 °C for 4 h with an oil bath. The resulting mixture was then quenched with water, and a small
amount of ethylenediamine was added to dissolve the residual copper salts in the aqueous phase. The
mixture was extracted with ethyl acetate three times, and the combined organic layer was dried over
anhydrous Na2SO4. After concentration under reduced pressure, silica gel column purification with
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hexane/ethyl acetate (10/1, v/v) afforded 5ꢀ(thiophenꢀ2ꢀyl)ꢀ4Hꢀthieno[3,2ꢀb]pyrrole (2k; 8.2 mg, 0.41
1
2
3
mmol) in 41% yield.
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8
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5-(Thiophen-2-yl)-4H-thieno[3,2-b]pyrrole (2k) white solid; m.p. 110.6ꢀ111.9 C; 8.4 mg (41%);
9
1H NMR (400 MHz, CDCl3) δ 6.66 (d, J = 1.8 Hz, 1H), 6.95 (dd, J = 0.6, 5.2 Hz, 1H), 7.05 (dd, J = 3.6,
5.0 Hz, 1H), 7.09 (d, J = 5.2 Hz, 1H), 7.12 (dd, J = 1.1, 3.6 Hz, 1H), 7.20 (dd, J = 1.1, 5.1 Hz, 1H), 8.32
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(s, 1H); C NMR (100 MHz, CDCl3) δ 99.7, 110.9, 121.6, 123.4, 124.2, 125.5, 127.8, 131.6, 136.1,
139.0; HRMS (APCI) m/z ([M+H]+) calcd for C10H8NS2: 206.0093, found: 206.0095.
2-(Benzo[b]thiophen-2-yl)-1H-benzo[4,5]thieno[3,2-b]pyrrole (2l) brown solid; m.p. 196.2ꢀ197.5
oC; 5.8 mg (19%); 1H NMR (400 MHz, CDCl3) δ 6.84 (d, J = 1.9 Hz, 1H), 7.26ꢀ7.40 (m, 5H), 7.74ꢀ7.82
13
(m, 4H), 8.84 (s, 1H); C NMR (100 MHz, CDCl3) δ 102.1, 117.4, 118.4, 122.2, 123.3, 123.4, 124.2,
124.30, 124.33, 124.6, 124.8, 126.4, 131.5, 133.6, 135.4, 138.5, 140.4, 142.3; HRMS (APCI) m/z
([M+H]+) calcd for C18H12NS2: 306.0406, found: 306.0394.
Typical Procedure for Synthesis of Oxazoles 3. The synthesis of 3a-Ph is representative (Scheme
3). Cu(OPiv)2 (8.0 mg, 0.030 mmol), (Z)ꢀNꢀ(1,2ꢀdiphenylvinyl)benzamide (1a-Ph; 30 mg, 0.10
mmol), pivalic acid (15 mg, 0.15 mmol), and MnO2 (17 mg, 0.2 mmol) were placed in a microwave
vessel. The vessel was flushed with nitrogen and then sealed with a cap. DMF (0.60 mL) was
sequentially injected via a syringe. The mixture was irradiated under microwave reactor conditions at
200 °C for 1 h. The resulting mixture was then quenched with water, and a small amount of
ethylenediamine was added to dissolve the residual copper salts in the aqueous phase. The mixture
was extracted with ethyl acetate three times, and the combined organic layer was dried over anhydrous
Na2SO4. After concentration under reduced pressure, silica gel column purification with hexane/ethyl
acetate (20/1, v/v) afforded 2,4,5ꢀtriphenyloxazole (3a-Ph; 27 mg, 0.089 mmol) in 89% yield.
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The Journal of Organic Chemistry
1
2
3
o
2,4,5-Triphenyloxazole (3a-Ph)20 white solid; m.p. 112.9ꢀ113.5 C; 260 mg (86%); 27 mg (89%) on
4
5
6
1
a 0.10 mmol scale; H NMR (400 MHz, CDCl3) δ 7.32ꢀ7.42 (m, 6H), 7.45ꢀ7.51 (m, 3H), 7.66ꢀ7.69 (m,
7
8
13
2H), 7.71ꢀ7.74 (m, 2H), 8.15ꢀ8.17 (m, 2H); C NMR (100 MHz, CDCl3) δ 126.5, 126.6, 127.4, 128.2,
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128.3, 128.57, 128.65, 128.7, 128.8, 129.0, 130.4, 132.6, 136.8, 145.6, 160.2; HRMS (APCI) m/z
([M+H]+) calcd for C21H16NO: 298.1226, found: 298.1228.
o
2-(4-Methoxyphenyl)-4,5-diphenyloxazole (3a-OMe) white solid; m.p. 110.9ꢀ111.9 C; 29 mg
(87%); 1H NMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 6.98ꢀ7.00 (m, 2H), 7.32ꢀ7.42 (m, 6H), 7.65ꢀ7.67 (m,
13
2H), 7.71ꢀ7.73 (m, 2H), 8.07ꢀ8.10 (m, 2H); C NMR (100 MHz, CDCl3) δ 55.4, 114.2, 120.2, 126.5,
128.1, 128.17, 128.19, 128.4, 128.6, 128.7, 129.2, 132.7, 136.6, 145.0, 160.3, 161.4; HRMS (APCI) m/z
([M+H]+) calcd for C22H18NO2: 328.1332, found: 328.1331.
o
4,5-Diphenyl-2-(4-(trifluoromethyl)phenyl)oxazole (3a-CF3) white solid; m.p. 137.8ꢀ139.9 C; 33
1
mg (89%); H NMR (400 MHz, CDCl3) δ 7.35ꢀ7.44 (m, 6H), 7.66ꢀ7.75 (m, 6H), 8.30 (d, J = 8.1 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 123.9 (q, J = 272.4 Hz), 125.8 (q, J = 3.9 Hz), 126.6, 126.7, 128.1,
19
128.5, 128.6, 128.7, 128.8, 128.9, 130.5, 131.9 (q, J = 32.7 Hz), 132.2, 137.2, 146.4, 158.7; F NMR
(376 MHz, CDCl3) δ ꢀ62.8; HRMS (APCI) m/z ([M+H]+) calcd for C22H15F3NO: 366.1100, found:
366.1104.
o
2-(tert-Butyl)-4,5-diphenyloxazole (3a-t-Bu) white solid; m.p. 58.9ꢀ60.3 C; 24 mg (85%); 1H NMR
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(400 MHz, CDCl3) δ 1.48 (s, 9H), 7.27ꢀ7.38 (m, 6H), 7.56ꢀ7.59 (m, 2H), 7.63ꢀ7.66 (m, 2H); C NMR
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(100 MHz, CDCl3) δ 28.7, 33.8, 126.3, 127.9, 128.1, 128.2, 128.55, 128.59, 129.4, 132.9, 134.9, 144.7,
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169.9; HRMS (APCI) m/z ([M+H]+) calcd for C19H20NO: 278.1539, found: 278.1537.
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2-Phenyl-4,5-di-p-tolyloxazole (3b-Ph) white solid; m.p. 131.3ꢀ132.0 C; 30 mg (93%); H NMR
(400 MHz, CDCl3) δ 2.39 (s, 3H), 2.39 (s, 3H), 7.18ꢀ7.22 (m, 4H), 7.44ꢀ7.50 (m, 3H), 7.57 (d, J = 8.2
Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 8.13ꢀ8.16 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.38, 21.42,
126.3, 126.4, 126.5, 127.5, 128.0, 128.7, 129.3, 129.4, 129.8, 130.2, 136.3, 137.9, 138.5, 145.5, 159.8;
HRMS (APCI) m/z ([M+H]+) calcd for C23H20NO: 326.1539, found: 326.1538.
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4,5-Bis(4-(tert-butyl)phenyl)-2-phenyloxazole (3c-Ph) white solid; m.p. 154.2ꢀ155.6 C; 37 mg
(89%); 1H NMR (400 MHz, CDCl3) δ 1.35 (s, 9H), 1.36 (s, 9H), 7.41ꢀ7.49 (m, 7H), 7.65ꢀ7.70 (m, 4H),
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8.13ꢀ8.16 (m, 2H); C NMR (100 MHz, CDCl3) δ 31.25, 31.34, 34.7, 34.8, 125.5, 125.6, 126.2, 126.3,
126.4, 127.6, 127.7, 128.7, 129.8, 130.2, 136.3, 145.4, 151.1, 151.6, 159.8; HRMS (APCI) m/z
([M+H]+) calcd for C29H32NO: 410.2478, found: 410.2474.
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2-Phenyl-4,5-bis(4-(trifluoromethyl)phenyl)oxazole (3d-Ph) white solid; m.p. 165.3ꢀ166.0 C; 40
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mg (92%); H NMR (400 MHz, CDCl3) δ 7.50ꢀ7.53 (m, 3H), 7.66ꢀ7.70 (m, 4H), 7.77 (d, J = 8.0 Hz,
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2H), 7.84 (d, J = 8.0 Hz, 2H), 8.13ꢀ8.18 (m, 2H); C NMR (100 MHz, CDCl3) δ 123.8 (q, J = 270.5
Hz), 124.0 (q, J = 270.5 Hz), 125.8 (q, J = 3.6 Hz), 125.9 (q, J = 3.9 Hz), 126.66, 126.74, 128.4, 128.9,
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130.0, 130.6 (q, J = 33.0 Hz), 130.7 (q, J = 32.3 Hz), 131.87, 131.89, 135.7, 137.0, 144.9, 161.2; F
NMR (376 MHz, CDCl3) δ −62.8, −62.7; HRMS (APCI) m/z ([M+H]+) calcd for C23H14F6NO:
434.0974, found: 434.0976.
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4,5-Bis(4-chlorophenyl)-2-phenyloxazole (3e-Ph) white solid; m.p. 145.9ꢀ147.0 C; 29 mg (78%);
1H NMR (400 MHz, CDCl3) δ 7.36ꢀ7.40 (m, 4H), 7.47ꢀ7.50 (m, 3H), 7.57ꢀ7.59 (m, 2H), 7.63ꢀ7.66 (m,
2H), 8.11ꢀ8.14 (m, 2H); 13C NMR (100 MHz; CDCl3) δ 126.5, 127.0, 127.2, 127.8, 128.9, 129.0, 129.1,
129.4, 130.7, 130.8, 134.3, 134.7, 136.1, 144.7, 160.5; HRMS (APCI) m/z ([M+H]+) calcd for
C21H14Cl2NO: 366.0447, found: 366.0446.
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4,5-Bis(4-bromophenyl)-2-phenyloxazole (3f-Ph) white solid; m.p. 165.9ꢀ167.9 C; 17 mg (53%);
1H NMR (400 MHz, CDCl3) δ 7.48ꢀ7.60 (m, 11H), 8.12ꢀ8.14 (m, 2H); 13C NMR (100 MHz, CDCl3) ) δ
122.5, 122.9, 126.5, 127.0, 127.6, 128.0, 128.9, 129.6, 130.70, 130.71, 131.2, 132.0, 132.1, 136.2,
160.6; HRMS (APCI) m/z ([M+H]+) calcd for C21H14Br2NO: 453.9437, found: 453.9423.
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4-(4-Methoxyphenyl)-2,5-diphenyloxazole (3g-Ph) white solid; m.p. 127.2ꢀ127.9 C; 31 mg (93%);
1H NMR (400 MHz, CDCl3) δ 3.85 (s, 3H), 6.93ꢀ6.96 (m, 2H), 7.30ꢀ7.41 (m, 3H), 7.45ꢀ7.51 (m, 3H),
7.63ꢀ7.69 (m, 4H), 8.13ꢀ8.16 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 55.3, 114.1, 125.0, 126.39,
126.44, 127.5, 128.4, 128.7, 128.8, 129.2, 129.5, 130.3, 136.6, 144.9, 159.6, 160.0; HRMS (APCI) m/z
([M+H]+) calcd for C22H18NO2: 328.1132, found: 328.1131.
2-Phenyl-4,5-di-m-tolyloxazole (3h-Ph) colorless liquid; 29 mg (90%); 1H NMR (400 MHz, CDCl3)
δ 2.36 (s, 3H), 2.38 (s, 3H), 7.14ꢀ7.18 (m, 2H), 7.23ꢀ7.29 (m, 2H), 7.45ꢀ7.50 (m, 5H), 7.53 (s, 1H), 7.60
(s, 1H), 8.14ꢀ8.17 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.47, 21.49, 123.8, 125.2, 126.5, 127.1,
127.5, 128.4, 128.6, 128.77, 128.82, 129.96, 129.99, 129.3, 130.3, 132.5, 136.8, 138.3, 138.4, 145.7,
160.0; HRMS (APCI) m/z ([M+H]+) calcd for C23H20NO; 326.1539, found: 326.1537.
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4,5-Bis(3-methoxyphenyl)-2-phenyloxazole (3i-Ph) white solid; m.p. 73.9ꢀ75.2 C; 34 mg (96%);
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1H NMR (400 MHz, CDCl3) δ 3.78 (s, 3H), 3.82 (s, 3H), 6.88ꢀ6.93 (m, 2H), 7.23ꢀ7.24 (m, 1H),
7.27ꢀ7.33 (m, 5H), 7.46ꢀ7.51 (m, 3H), 8.15ꢀ8.17 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 55.29, 55.33,
111.8, 113.3, 114.6, 119.1, 120.7, 126.5, 127.3, 128.8, 129.6, 129.8, 130.1, 130.41, 130.43, 133.8,
136.9, 145.5, 159.7, 159.8, 160.0; HRMS (APCI) m/z ([M+H]+) calcd for C23H20NO3: 358.1438, found:
358.1436.
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4,5-Di(naphthalen-2-yl)-2-phenyloxazole (3j-Ph) white solid; m.p. 180.3ꢀ181.3 C; 37 mg (94%);
1H NMR (400 MHz, CDCl3) δ 7.48ꢀ7.55 (m, 7H), 7.75 (dd, J = 1.7, 8.6 Hz, 1H), 7.80ꢀ7.88 (m, 7H),
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8.23ꢀ8.26 (m, 3H), 8.33 (s, 1H); C NMR (100 MHz, CDCl3) δ 124.2, 125.89, 125.92, 126.31, 126.34,
126.4, 126.6, 126.68, 126.74, 127.4, 127.7, 127.8, 128.2, 128.36, 128.38, 128.39, 128.85, 128.88, 130.0,
130.5, 133.17, 133.21, 133.3, 133.5, 137.2, 146.0, 160.5; HRMS (APCI) m/z ([M+H]+) calcd for
C29H20NO: 398.1539, found: 398.1537.
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2-Phenyl-4,5-di(thiophen-2-yl)oxazole (3k-Ph) white solid; m.p. 102.9ꢀ104.2 C; 28 mg (89%); H
NMR (400 MHz, CDCl3) δ 7.10 (dd, J = 3.6, 5.2 Hz, 1H), 7.13 (dd, J = 3.6, 5.1 H, 1H), 7.39 (dd, J =
1.0, 5.1 Hz, 1H), 7.42 (dd, J = 1.0, 5.1 Hz, 1H), 7.47ꢀ7.52 (m, 3H), 7.55ꢀ7.56 (m, 2H), 8.11ꢀ8.16 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 126.26, 126.31, 126.6, 126.76, 126.83, 126.9, 127.5, 127.6, 128.8,
129.7, 130.7, 131.4, 134.0, 140.4, 159.9; HRMS (APCI) m/z ([M+H]+) calcd for C17H12NOS2:
310.0355, found: 310.0356.
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4,5-Bis(benzo[b]thiophen-2-yl)-2-phenyloxazole (3l-Ph) white solid; m.p. 236.9ꢀ238.6 C; 39 mg
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(96%); H NMR (400 MHz, CDCl3) δ 7.35ꢀ7.54 (m, 4H), 7.50ꢀ7.54 (m, 3H), 7.82ꢀ7.91 (m, 6H),
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8.18ꢀ8.20 (m, 2H); C NMR (100 MHz, CDCl3) δ 122.26, 122.29, 123.4, 123.6, 123.9, 124.1, 124.6,
124.86, 124.92, 125.4, 126.6, 126.8, 128.9, 129.3, 131.0, 132.8, 133.9, 139.4, 139.8, 140.0, 140.2,
141.4, 160.6; HRMS (APCI) m/z ([M+H]+) calcd for C25H16NOS2: 410.0668, found: 410.0677.
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4-Butyl-2,5-diphenyloxazole (3m-Ph) colorless liquid; 14 mg (49%); 1H NMR (400 MHz, CDCl3) δ
0.97 (t, J = 7.3 Hz, 3H), 1.47 (sext, J = 7.5 Hz, 2H), 1.74ꢀ1.82 (m, 2H), 2.82 (t, J = 7.9 Hz, 2H), 7.34 (t,
J = 7.4 Hz, 1H), 7.42ꢀ7.49 (m, 5H), 7.67ꢀ7.69 (m, 2H), 8.08ꢀ8.10 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 14.0, 22.7, 27.1, 31.1, 125.5, 126.3, 127.6, 127.7, 128.7, 128.8, 129.3, 130.1, 138.2, 145.2, 159.5;
HRMS (APCI) m/z ([M+H]+) calcd for C19H20NO: 278.1539, found: 278.1540.
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4-Cyclohexyl-2,5-diphenyloxazole (3n-Ph) white solid; m.p. 133.6ꢀ134.0 C; 24 mg (80%); H
NMR (400 MHz, CDCl3) δ 1.38ꢀ1.42 (m, 3H), 1.75ꢀ1.89 (m, 7H), 2.86ꢀ2.93 (m, 1H), 7.34 (tt, J = 1.2,
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7.4 Hz, 1H), 7.42ꢀ7.49 (m, 5H), 7.63ꢀ7.66 (m, 2H), 8.07ꢀ8.10 (m, 2H); C NMR (100 MHz, CDCl3) δ
25.9, 26.5, 31.0, 36.0, 126.0, 126.4, 127.7, 127.8, 128.7, 128.8, 129.4, 129.9, 142.8, 144.3, 159.7;
HRMS (APCI) m/z ([M+H]+) calcd for C21H22NO: 304.1696, found: 304.1697.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publication website at DOI:
10.1021/acs.joc.7b00682.
1H, 13C{1H}, and 19F{1H} NMR spectra for products and kinetic profiles (PDF)
AUTHOR INFORMATION
Corresponding Authors
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*Eꢀmail: k_hirano@chem.eng.osakaꢀu.ac.jp.
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*Eꢀmail: miura@chem.eng.osakaꢀu.ac.jp.
ORCID
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Koji Hirano: 0000ꢀ0001ꢀ9752ꢀ1985
Masahiro Miura: 0000ꢀ0001ꢀ8288ꢀ6439
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Nos. JP 17J00349 (GrantꢀinꢀAid for JSPS Research
Fellow) to K.T., JP 15K13696 (GrantꢀinꢀAid for Exploratory Research) and JP 15H05485 (GrantꢀinꢀAid
for Young Scientists (A)) to K.H., and JP 17H01202 (GrantꢀinꢀAid for Scientific Research (A)) and JP
17H06092 (GrantꢀinꢀAid for Specially Promoted Research) to M.M.
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(12) Although the detailed mechanism of C–H cleavage is not clear at present, the observed positive
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Troitskaya, L. L.; Reutov, O. A. J. Organomet. Chem. 1979, 182, 537. (b) Ryabov, A. D.;
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(15) Pan, F.; Shi, Z.ꢀJ. Chem.–Eur. J. 2016, 22, 6487.
(16) Actually, in the synthesis of electronꢀrich 2g and 2l in Scheme 2, a small but significant amount of
the corresponding oxazoles was detected by GC and GCMS analysis (ca. 10%). The MnO2ꢀinduned
background reaction can also occur through a similar SET process.
(17) Xie, L.ꢀH.; Suh, M. P. Chem.–Eur. J. 2011, 17, 13653.
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(18) Chen, J.; Zhang, W.; Geng, H.; Li, W.; Hou, G.; Lei, A.; Zhang, X. Angew. Chem., Int. Ed. 2009,
48, 800.
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(19) Commercially available: SigmaꢀAldrich P26600 (CAS: 948ꢀ65ꢀ2).
(20) Chatterjee, T.; Cho, J. Y.; Cho, E. J. J. Org. Chem. 2016, 81, 6995.
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