Organic Letters
Letter
C−H amidation at the methoxy-substituted arene (2r: 82%).
In all cases, the dihydroquinolin-2-one formation is charac-
terized by skeletal C−C migration, with the C−N bond being
formed at the position para to the para substituent. Notably,
the Ru-catalyzed cyclization of 3-(4-(benzyloxy)phenethyl)-
1,4,2-dioxazol-5-one (1v) would afford 6-(benzyloxy)-3,4-
dihydroquinolin-2(1H)-one (2v) in 71% yield. According to
literature, 2v exhibits anticonvulsant activities for treating
bipolar disorder and neuropathic pain.11
Table 3. Scope of the Dearomative Spirocyclization
Reaction
For the ortho-substituted substrates (Table 2), the facile
reaction of 3-(2-methylphenethyl)-1,4,2-dioxazol-5-one af-
forded 3a in 60% yield. Again, 3a is characterized by skeletal
C−C migration, with the C−N bond being forged at the
position ortho to the substituent. In this work, the trans-
formation of 3-(2-methoxyphenethyl)-1,4,2-dioxazol-5-one to
3b was less successful. Yet the analogous 2-bromo-substituted
derivative reacted successfully to furnish 3c in 59% yield.
Compared with the current Ru-catalyzed system, the Cp*Ir
catalyst would produce both the C−C migration product and
the direct C−H amidation product in a ratio of 1:1.2.9b−d
For the meta-substituted dioxazolones, the Ru-catalyzed
cyclization of 3-(3-Y-substituted phenethyl)-1,4,2-dioxazol-5-
one (Y = Me, OMe, and Br) furnished the corresponding
dihydroquinoline-2-ones 4a−4c in 39−72% yields. In all cases,
the C−N bond formation occurred at the position para to the
meta substituents. Apparently, skeletal C−C arrangement is
not involved in the dihydroquinolin-2-one formations. The
reaction of the dioxazol-5-one bearing meta- and para-OMe
substituents produced 4d exclusively in 83% yield, presumably
via direct C−H amidation without skeletal rearrangement. Yet
the formation of 4a−4d may also occur via spirocyclization at
the position meta to the substituent, followed by skeletal C−N
rearrangement. The two pathways appear to be difficult to be
differentiated.
Assuming Ru-nitrenoid intermediates, amidation at the
benzylic C(sp3)−H, 20 C(sp3)−H, and 30 C(sp3)−H sites is
likely to be competitive.10 Here the regioselectivity was
assessed by reacting dioxazolones containing benzyl (1s),
ethyl (1t), and isopropyl (1u) side arms under the Ru-
catalyzed conditions. To our delight, the amidation is directed
exclusively to the aryl C(sp2)−H bond, rather than the
benzylic C(sp3)−H (2s), 2 °C(sp3)−H (2t), and 3 °C(sp3)−
H (2u) bonds, and the desired amidation products were
obtained in 78−83% yields.
(6b; 88%; 6c; 83%; 6d: 91%; 6e: 92%). Apparently, the
nitrenoid attack at the position ortho to the hydroxy group
should be facile to furnish 7a in 56% yield. Yet the presence of
a OMe group appears to be critical for an effective reaction
because the production of spirolactam 7b was unsuccessful due
to the lack of a para-methoxy substituent.
The nature of the spirolactamization transition state has
been examined by a Hammett correlation study using a series
of 4-substituted dioxazolones 1-Y (Y = OMe, Me, H, F, and
Cl) as substrates. In this work, dioxazolone 1-Y was subjected
to the standard conditions: 1-Y (0.1 mmol), [Ru1] (10 mol
%), and AgSbF6 (10 mol %) in TFE (1 mL) for 30 min. With
∼10−20% substrate conversion, the yields of the dihydroqui-
nolin-2-ones were determined by 1H NMR spectroscopy. (See
kH (Y = OMe, Me, H, F, and Cl) versus Hammett σpara
constant, a straight line (R2 = 0.98) with slope (ρ) = −0.73.
implies that the Ru-nitrenoid attack on the aryl ring is likely to
be electrophilic in nature.
Scheme 3 depicts the proposed mechanism of the aryl C−H
amidation of the 2- and 4-substituted dioxazolones. Assuming
Scheme 3. Proposed Mechanism
The reactions of the para- and ortho-substituted dioxazo-
lones afforded the dihydroquinoline-2-ones involving skeletal
C−C rearrangement. We postulated that the reactive Ru-
nitrenoid intermediate should initiate the cyclization by
electrophilic amidation at the position para/ortho to the
substituent to form some spirolactam intermediates, and the
subsequent skeletal C−C rearrangement should afford the
observed products. A similar mechanism was reported for the
analogous Cp*Ir(III)-catalyzed intramolecular aryl C−H
amidation.9b−d
To probe the spirolactam formation, 3-(4-hydroxypheneth-
yl)-1,4,2-dioxazol-5-one (5a) was employed as a model
substrate for the Ru-catalyzed amidation, and the desired
azaspiro[4.5]deca-6,9-diene-2,8-dione (6a) was isolated in
95% yield (Table 3). Notably, replacing the 4-OMe substituent
in 1n with a hydroxyl group (5a) led to the successful trapping
of the spirolactam intermediate. Similarly, those phenol-based
dioxazolones bearing OMe and Me groups at the ortho and
meta positions underwent spirolactamization in excellent yield
some Ru-nitrenoid as active intermediates, electrophilic attack
of the nitrenoid moiety at the positions ortho and para to the
substituents should afford the spirolactams. The regioselectiv-
ity of the amidation was probably favored by π-conjugation of
the substituents, resulting in enhanced electron density at the
3312
Org. Lett. 2021, 23, 3310−3314