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Table 1. Ruthenium-catalyzed hydrogen peroxide oxidation of hydroxamic acids
Entry
Hydroxamic acids
Catalyst
Oxidant
H2O2
Solvent
Cycloadduct
Yield (%)a
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
–
CH2Cl2
CH2Cl2
2a
2a
2a
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
0
33
39
90
90
91
92
74
76
81
84
99
99
TPAPb
O2
c
TPAPb
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
CH2Cl2
Ru(II)(pybox-dh)(pydic)
Ru(II)(pybox-dh)(pydic)
Ru(II)(pybox-dh)(pydic)
Ru(II)(pybox-dh)(pydic)
Ru(II)(pybox-dh)(pydic)
Ru(II)(pybox-dh)(pydic)
Ru(II)(pybox-dh)(pydic)
Ru(II)(pybox-dh)(pydic)
Ru(II)(pybox-dh)(pydic)
Ru(II)(pybox-dh)(pydic)
CH3OH–H2Od
THF
CH3OH–H2Od
THF
CH3OH–H2Od
THF
9
10
11
12
13
CH3OH–H2Od
THF
CH3OH–H2Od
THF
a Isolated yield.
b Tetrapropylammoniumperruthenate.
c 1 atm.
d 1/1 v/v.
Typical experimental procedure: To a solution of
hydroxamic acid 1a (24.1 mg, 0.176 mmol) in THF (2.0
mL) was added a solid ruthenium(II)(pybox-dh)(pydic)
(10.0 mg, 0.0194 mmol) at 0°C followed by addition of
30% H2O2 (0.077 mL, 0.70 mmol) and freshly distilled
cyclopentadiene (0.072 mL, 0.88 mmol) in one portion.
The resulting dark blue mixture was stirred at room
temperature. After 2 h, TLC showed no starting mate-
rial was present. The product was extracted with ether,
dried over Na2SO4 and purified by flash column chro-
matography on silica gel (hexane:EtOAc=1:3 v/v) to
give the cycloadduct 2a (31.8 mg) in 90% isolated
yield.10
ene. The transient nitroso intermediate was subse-
quently trapped with the diene to give the correspond-
ing 1,2-oxazine
TPAP–H2O2 system also gave the same level of the
2 in 33% yield (entry 2). The
yield (entry 3).
On the other hand, acyl nitroso intermediates can be
efficiently generated by the mild oxidation of hydrox-
amic acid with Ru(pybox-dh)(pydic) (11 mol%) and
hydrogen peroxide (4 equiv.) in both CH3OH–H2O and
THF (entries 4 and 5). The ruthenium catalyst was
synthesized from the same procedure as we reported
before.9 The optimized condition on solvent system and
reaction temperature were briefly surveyed and polar
solvent at 0°C to room temperature was the best for
this reaction because of the solubility of hydroxamic
acids and stability of cyclopentadiene. The nitroso
intermediate, formed by the ruthenium catalyst with
hydrogen peroxide, smoothly reacted with the diene to
produce the corresponding cycloadducts 1,2-oxazines 2
in high yields (entries 6–11). Even in 1 mol% catalyst
loading, the reaction efficiently proceeded in high yield
(91%). Especially, t-butoxycarbonyl hydroxamic acid 1e
gave the corresponding cycloadduct in a quantitative
yield (entries 12 and 13). THF, THF–H2O or CH3OH–
H2O proved to be relatively good solvents system for
the preparation of nitroso intermediate as well as for
the hetero Diels–Alder reactions. To best of our knowl-
edge, this ruthenium(II) (pybox)(pydic) system of the
pre-catalyst works much better than any other oxida-
tion method reported in previous literature. Further-
more, the double bond of the cycloadducts and
hydroxyl group of the solvent system have no effect
during the reaction time. The mechanism for the
present oxidation of hydroxamic acids is still unclear.
However, this ruthenium catalyzed hydrogen peroxide
oxidation condition can be used for the synthesis of
highly functionalized molecules since the hydrogen per-
oxide is low cost and safety oxidant. We are also
applying this method for intramolecular nitroso hetero
Diels–Alder reactions.
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