Organic Letters
Letter
have long recognized TBN as a potent electrophilic nitrosyl
transfer reagent19 and consequently have believed that TBN
alone, at room temperature without the use of a catalyst or an
additive, could undergo nitrosyl transfer to diazo compounds,
resulting in the formation of nitrile oxides (Scheme 1d).
To test this hypothesis, commercially available ethyl
diazoacetate (EDA, 1a) was treated with excess TBN (90%
Scheme 2. Direct TBN Reactions with Diazoacetates,
Diazoacetamides, and Terminal Diazoketones: Synthesis of
a
Furoxan Dimers
t
TBN in BuOH, 2.5 equiv) all at once. As result, without
solvent, the reaction was immediate and exothermic, and the
reaction mixture changed in color from orange, the typical
color of 1a, to light-green, forming furoxan dimer 2a, which
t
after removal of BuOH and excess TBN was isolated in 85%
yield. The exothermic reaction was moderated by performing
the addition of TBN to EDA in a solvent, and as a
consequence, the reaction time increased but with no loss in
product yield (see Table S1). The reaction rate correlated with
the number of equivalents of TBN, and 2.5 equiv was judged
to be optimal for a reaction time of 2−3 h. DCM was found to
be the most suitable solvent. Notably, no reduction in yield
was observed in a gram-scale reaction (eq 1).
Considering the balance between the number of TBN
equivalents and the reaction time, representative terminal
diazocarbonyl compounds, including diazoacetates, diazoace-
tamides, and diazoketones, were treated under the optimum
reaction conditions. Good to excellent yields of their
corresponding furoxan compounds 2 were found, suggesting
the broad scope of this direct uncatalyzed nitrile oxide
generation (Scheme 2). α-Diazocarbonyl compounds 1a−n
bearing alkoxy, amide, and aryl groups reacted with TBN at
room temperature in an air atmosphere within a reaction time
of 2 h. These reactions occurred without interference from
ether, ester, halide, ketal, or ketone functional groups, and the
dimer furoxan structure was further confirmed by X-ray
crystallography of the product from the reaction of
androsterone diazoacetate with TBN (2f).
Although diazoacetamides are ordinarily much less reactive
toward electrophiles than diazoacetates or diazoketones,20
diazoacetamide 1g was more reactive toward TBN than
diazoester 1a. The competitive reaction with equivalent
amounts of 1a and 1g gave a 40% yield of 2g and an 8%
yield of 2ag, and 2a was not observed (eq 2).
a
Reaction conditions: TBN (2.5 equiv) was added all at once to 1
(0.4 mmol) in 3.0 mL of DCM, and the reaction was terminated at 2
h. 10% of 1d was recovered. 6 h. 18 h.
b
c
d
temperature using 2.5 equiv of TBN, which gave isoxazole
5a in 94% yield in just 2 h (Table S2). When non-halogenated
solvents were used, the reaction proceeded at a lower rate. The
substrate scope for the synthesis of isoxazole and isoxazoline
compounds was investigated under the optimized conditions
using three representative diazo compounds; acetate 1a, amide
1g, and ketone 1n (Scheme 3). Heterocycles 5 and 6 were
obtained via [3 + 2] cycloaddition at room temperature in
about 2 h in moderate to excellent yields, and the slow
addition of TBN prevented formation of the furoxan dimer 2
with only the exception of alkyne 3d. This method delivered
isoxazoles and isoxazolines from a variety of alkenes and
alkynes (5a−c, 5g−l, 6a−c, and 6g−l). Notably, unprotected
alcohols did not undergo competitive nitrosyl exchange with
TBN19 and provided the corresponding heterocycle-carbinol
products in good to excellent yields without a decrease in
reaction efficiency (5d−f and 6d−f). As expected from the
electrophilic nitrosyl exchange, the [3 + 2] cycloaddition with
secondary amine 3e and TBN furnished N-nitroso isoxazole
5m.
To further demonstrate the synthetic applications of the
generation of nitrile oxide with 1a and TBN, we turned our
attention to the gram-scale synthesis of biologically active
isoxazole 8, which was shown to have antituberculosis
activities,21 and the precursor of SS-208, which is an effective
antitumor agent (Scheme 4).22 Cycloaddition of alkyne 7 with
EDA/TBN afforded 8 in 78% isolated yield with a total
amount of 2.2 equiv of 1a (1.2 equiv at the beginning and
another 1.0 equiv after 12 h) and TBN at room temperature
(Scheme 4a). Isoxazole 10, the precursor of the biologically
Nitrile oxides undergo [3 + 2] cycloaddition with alkenes
and alkynes, and these reactions occur in competition with
nitrile oxide dimerization. To determine whether cycloaddition
was competitive, 1a and TBN as precursors of the nitrile oxide
dipole and ethyl propiolate (3a) as a representative
dipolarophile were chosen. In order to avoid the formation
of dimer 2a, TBN was introduced over a period of 1 h using a
syringe pump. The reaction of 1a (0.2 mmol), TBN (1.5
equiv), and 3a (1.2 equiv) furnished isoxazole 5a in 84% yield
after 4 h at room temperature. Optimal conditions were found
to be chloroform as the solvent for reactions at room
926
Org. Lett. 2021, 23, 925−929