Organic Letters
Letter
1,2,3-Triazine 1-oxide 2a, whose structure was confirmed by X-
ray crystallography, was prepared in 83% isolated yield in a
gram-scale reaction. This method also demonstrates high
functional group tolerance with vinyldiazo reactants having
phenylalkyl, tert-butyldimethylsilyl ether (OTBS), azide, and 4-
alkyl-3-aryl substituents that produced triazine 1-oxides 2h−2k
in good to excellent yield. For the synthesis of bicyclic triazine
N-oxides, four, five, and six membered vinyl groups linked to
diazoacetates (1l−q) were suitable substrates to furnish the
desired products. To further demonstrate the generality of this
method, 1,2,3-triazine N-oxides bearing one substituent in the
4-position (2r), two substituents in the 4,5- or 4,6-positions
(2s and 2t), or fully substituted in the 4,5,6-positions (2u)
were selectively prepared in excellent yield, suggesting the
opportunity provided by this methodology for the placement
of substituents at the 5- and 6-positions, in addition to the
carboxylate group at the 4-position. Surprisingly, the reaction
of styryl diazoacetate with TBN produced a complex mixture
of byproducts that were not further analyzed. Potential late-
stage functionalization was examined with this method using
vinyldiazo compounds 1v and 1w derived from epiandroster-
one and estrone, respectively. They were converted to the
corresponding 1,2,3-triazine 1-oxides 2v and 2w in 87% and
91% isolated yield, respectively, by simple evaporation of the
solvent without chromatography (eqs 1 and 2).
Scheme 4. Synthesis of Isoxazoles by Thermal
Decomposition of 1,2,3-Triazine 1-Oxides
a
a
Reaction conditions: a solution of 2 (0.2 mmol, 0.1 M in PhCl) was
b
c
d
e
reflux for 6 h. 24 h. 72 h. 48 h. NMR yield.
was transformed to isoxazole 3v in 93% yield, demonstrating
the effectiveness of this transformation in a late-stage
functionalization process.
A probable mechanism for the synthesis of the triazine N-
oxide 2 through formal intramolecular [5 + 1] cycloaddition is
proposed in Scheme 5. Consistent with previous findings on
Scheme 5. Proposed Mechanism for the Formation of 1,2,3-
Triazine 1-Oxide
Isoxazoles represent another important class of heterocycles
due to their biological activities and therapeutic applications.17
Their most direct synthesis is the [3 + 2]-cycloaddition of
nitrile oxides and alkynes.10,19 We recognized that 1,2,3-
triazine 1-oxides 2 bearing an EWG at 4-position might
undergo thermal decomposition with loss of dinitrogen to
furnish isoxazole 3. Indeed, in refluxing chlorobenzene, 5-
phenyl-1,2,3-triazine 1-oxide 2a was thermally converted to 4-
phenyl isoxazole 3a in 98% isolated yield in 6 h (Scheme 4).
Notably, no loss of yield was observed when 3a was prepared
in a gram-scale reaction.
A representative array of isoxazoles 3 was prepared in
excellent yields suggesting the broad application of this
method. However, a limitation in this methodology appears
in the attempted failed conversion of 2l to the corresponding
strained isoxazole. However, this method favors the synthesis
of fully substituted isoxazoles such as 3u since the alternative
1,3-dipolar cycloaddition approach of nitrile oxides with
asymmetric alkynes suffers from low regioselectivity and
often gives mixtures of regioisomers.20 The preparation of
polycyclic isoxazoles proposed by previously reported methods
is also challenging;21 polycyclic isoxazoles 3n, 3p, and 3q were
obtained from the thermal decomposition of triazine N-oxide
2n, 2p, and 2q in excellent yield. The more complex triazine
N-oxide 2v derived from the natural product epiandrosterone
the nucleophilicity of the terminal carbon of vinyldiazo
esters,12,22 1 selectively undergoes nitrosyl exchange with
TBN to generate the nitroso-vinyl diazonium intermediate A
and tert-butoxide, or either its azo-tert-butoxide or tert-butyl
alcohol from proton exchange with HFIP. Then intramolecular
nucleophilic association of the nitrosyl nitrogen with the
terminal nitrogen of the diazonium ion occurs followed by the
deprotonation to furnish the 1,2,3-triazine 1-oxide 2. The role
of HFIP is inexorably linked with stabilization of tert-butoxide
in its role as the nitrosyl donor and proton removal.
In summary, we have disclosed a novel and practical method
for the synthesis of 1,2,3-triazine 1-oxides under mild
conditions in high yields from vinyl diazoacetates and TBN.
High selectivity of the N-oxide position, excellent functional
group tolerance, and potential late-stage functionalization have
been achieved. Isoxazoles are formed from 1,2,3-triazine 1-
oxides by their thermal dinitrogen extrusion in excellent yield.
ASSOCIATED CONTENT
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6544
Org. Lett. 2021, 23, 6542−6546