LETTER
Direct C(sp3)–H Amination Reactions of Isochroman Derivatives
2087
t-BuOOH
NH2
Fe2+
–
OH
+ Fe3+
HN
Fe3+
t-BuO
O+
OH–
O
O
O
Fe2+
H+
B
A
Scheme 2 Probable mechanistic route
With the optimized reaction conditions in hand (Table 1,
entry 12), the generality of the reaction between isochro-
man derivatives and various amines were explored. Some
results are outlined in Scheme 1. Amines with an electron-
donating group worked well under the standard reaction
conditions (Scheme 1, 3f,h). Amines with a weak elec-
tron-withdrawing group also reacted well with isochro-
man (Scheme 1 3b–d). Benzopyran – due to its higher
stability – gave a satisfying isolated yield when used as re-
actant (Scheme 1, 3j–m). 3,4-Dihydro-1H-benzo[h]iso-
chromene also coupled with amines, but the yields were
comparatively low (Scheme 1, 3n–p), maybe because of
the steric hindrance. Anilines with strong electron-with-
drawing groups, such as nitro, difluoro, and dichloro
groups, were also applied in this reaction, but no desired
product was obtained. This can be attributed to the insta-
bility of the isochroman in the weak acidic conditions, that
are present when amines with strong electron-withdraw-
ing groups are used. Applying 4-methoxyaniline also did
not lead to the desired product, because of its sensitivity
to oxidization.
According to the experiments and the literature,1c a plau-
sible mechanism was proposed (Scheme 2). TBHP de-
composed into the tert-butoxyl radical and hydroxyl anion
in the presence of the ferrous catalyst. A hydrogen ab-
straction of the C–H bond adjacent to an oxygen atom af-
forded intermediate A. Then A was oxidized to B by the
ferric ion. Aniline coupled with B and, thereafter, deprot-
onation by the previously released hydroxyl anion gave
the desired product.
Acknowledgment
This work was financially supported by the Natural Science Foun-
dation of China (No. 21272169), the key Innovation Team of Sci-
ence & Technology in Zhejiang Province (No. 2010R50018), and
Taizhou Science & Technology program (No. 08KY10).
Supporting Information for this article is available online at
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Reference and Notes
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In summary, we have successfully realized the direct
C(sp3)–H amination reactions of isochroman derivatives
with arylamines catalyzed by iron under mild reaction
conditions. Further investigations of the application of
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General Procedure
FeCl2·4H2O (0.05 mmol) was placed in a Schlenk tube. Toluene (2
mL), isochroman (1, 0.5 mmol), and t-BuOOH(1.0 mmol) were
then added. The tube was sealed and flushed with nitrogen, and then
the contents were stirred at 75 °C. Arylamine (2, 0.5 mmol) was
slowly added drop-wise into the system through a dropping funnel.
The reaction mixture was stirred for 24 h, then cooled to r.t. and
flushed through a short column of silica gel with EtOAc. The sol-
vent was removed under vacuum. The product was isolated from the
dark purple crude mixture by column chromatography (PE–
EtOAc, 20:1).
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Synlett 2013, 24, 2085–2088