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The Journal of Organic Chemistry
Note
functionalization process. Various aminooxylated oxindoles
were produced by using the present strategy. The benzylic
and α-methylene C−H bonds could also couple with NHPI in
the current oxidative system to generate the corresponding
aminooxylated coupling products in good to high yields.
Further experimental studies to elucidate the mechanistic
details and further investigation of relevant reactions based on
this K2S2O8/tetrabutyl quaternary ammonium salts combined
strategy are currently underway, and these studies will be
reported in due course.
Scheme 4. Radical Verification Experiments
EXPERIMENTAL SECTION
■
General Information. All reagents used were obtained
commercially and used without further purification unless indicated
otherwise. Solvents were dried and distilled prior to use according to
the standard protocols. Column chromatography was carried out on
1
silica gel (300−400 grading). H NMR and 13C NMR were recorded
in CDCl3 and DMSO-d6 at room temperature on the Bruker
1
spectrometer (400 MHz H). The chemical-shifts scale is based on
Scheme 5. Proposed Mechanism for the K2S2O8/TBAI-
Triggered Reaction
internal TMS. Multiplicities are indicated as s (singlet), d (doublet),
t (triplet), q (quintet), and m (multiplet), and coupling constants (J)
are reported in hertz. HRMS was measured on an electrospray
ionization (ESI) apparatus using time-of-flight (TOF) mass
spectrometry. Melting points were determined using XT-4 apparatus
and are uncorrected.
Preparation of N-Arylacrylamides. N-Arylacrylamide substrates
1a−n were prepared according to the literature.20
A Typical Procedure for the Direct Annulations Toward
Aminooxylated Oxindoles. N-Arylacrylamide 1 (52.5 mg, 0.3
mmol), N-hydroxyphthalimide (NHPI: 34 mg, 0.2 mmol), K2S2O8
(65.5 mg, 0.24 mmol), TBAI (15 mg, 20 mol %), and anhydrous
1,2-dichloroethane (DCE: 1.0 mL) were added to a 25 mL Schlenk
flask equipped with a high-vacuum PTFE valve-to-glass seal. Then
the flask was evacuated and backfilled with nitrogen for three times.
After that, the mixture was stirred at 90 °C under a nitrogen
atmosphere for 24 h. Upon completion, the reaction mixture was
extracted with dichloromethane (3 × 10 mL). The combined organic
layers were washed with brine (20 mL), dried over Na2SO4, filtered,
and concentrated in vacuum. The resulting residue was purified by
silica gel column chromatography (petroleum ether/ethyl acetate) to
afford the desired products 2.
On the basis of these preliminary evidence as well as
previous literature, a plausible mechanistic pathway for this
reaction is depicted in Scheme 5. Similar to a TEAB-catalyzed
dehydrogenative arylation of aldehydes, TBAI might act as an
initiator for producing the active sulfate radical anions in our
reaction system.16 Being different from that of the radical
cyclization between homopropargylic alcohols and sulfonyl
hydrazides triggered by K2S2O8/TBAI, the phthalimide N-oxyl
radical (PINO) is generated from NHPI by sulfate radical
anions.17 Further evidence was provided by two control
experiments.18 The addition of phthalimide N-oxyl radical to
the carbon−carbon double bond of N-arylacrylamide 1a
would produce an oxygenated alkyl radical A. The resulting
alkyl radical would then readily aromatize to give the aryl
radical B.10b,c Single electron oxidation of B by sulfate radical
anions gives rise to a carbocation C, which is deprotonated by
the generated sulfate dianion to yield the desired oxygenated
product 2a.16 On the other hand, alkyl radicals likely
produced upon the H abstraction from sp3-hydrocarbons by
PINO radical19 and the resulting NHPI molecules were
reoxidized by sulfate radical anions to produce the PINO
radical via a similar H abstraction process again. Obviously,
the cross-coupling products (i.e., 3, 4, and 5) were produced
from the coupling of two radicals (i.e., alkyl radical and PINO
radical).
2-((1,3-Dimethyl-2-oxoindolin-3-yl)methoxy)isoindoline-1,3-
dione (2a). By following the typical procedure, the product was
isolated as a white solid, 54.5 mg (81% yield), flash chromatography
(petroleum ether/ethyl acetate, 4/1); mp: 155−157 °C; 1H NMR
(400 MHz, CDCl3) δ 7.77−7.68 (m, 4H), 7.41 (d, J = 7.2 Hz, 1H),
7.29−7.25 (m, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz,
1H), 4.59 (d, J = 9.2 Hz, 1H), 4.44 (d, J = 9.2 Hz, 1H), 3.26 (s,
3H), 1.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.5, 162.8,
143.5, 134.4, 130.9, 128.7, 128.4, 123.5, 123.4, 122.6, 108.3, 80.7,
+
48.6, 26.4, 20.2; HRMS m/z (ESI) calcd for C19H16N2O4 [M+]:
336.1110; found 336.1093.
2-((5-Fluoro-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)-
isoindoline-1,3-dione (2b). By following the typical procedure, the
product was isolated as a white solid, 40.4 mg (57% yield), flash
chromatography (petroleum ether/ethyl acetate, 4/1); mp: 160−161
1
°C; H NMR (400 MHz, CDCl3) δ 7.78−7.71 (m, 4H), 7.19 (d, J =
8.0 Hz, 1H), 7.02−6.96 (m, 1H), 6.80−6.77 (m, 1H), 4.55 (d, J =
9.6 Hz, 1H), 4.43 (d, J = 9.6 Hz, 1H), 3.24 (s, 3H), 1.47 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 177.1, 162.8, 139.4, 134.5, 132.6,
132.5, 128.7, 123.4, 114.7, 114.5, 112.1, 111.8, 108.8, 108.7, 80.5,
+
49.0, 26.6, 20.1; HRMS m/z (ESI) calcd for C19H15FN2O4 [M+]:
354.1016; found 354.1011.
2-((5-Chloro-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)-
isoindoline-1,3-dione (2c). By following the typical procedure, the
product was isolated as a white solid, 46 mg (62% yield), flash
chromatography (petroleum ether/ethyl acetate, 4/1); mp: 162−163
In summary, we have developed an efficient amino-
oxyarylation of N-arylacrylamides with NHPI. This reaction
preceded in the presence of K2S2O8/TBAI via a radical C−H
1
°C; H NMR (400 MHz, CDCl3) δ 7.77−7.70 (m, 4H), 7.38 (d, J =
2.0 Hz, 1H), 7.23 (dd, J = 8.4, 2.4 Hz, 1H), 6.78 (d, J = 8.4 Hz,
D
DOI: 10.1021/acs.joc.7b02740
J. Org. Chem. XXXX, XXX, XXX−XXX