Angewandte
Chemie
substituted phenyl boronic acids was comparable, with yields
ranging from 72% to 91%. When heteroaryl boronic acids
such as benzothiophene- and furan-derived coupling reagents
were engaged, the corresponding heteroaryl nitrones 20 and
21 were obtained from 12a in 91% and 79% yields,
respectively, or from 12b in 85% and 82% yields, respec-
tively. In contrast with those gratifying results, ortho-bromo-
phenyl boronic acid proved less effective with yields around
60%. Furthermore, both 4-pyridyl boronic acid and its glycol
ester appeared to be unsuccessful under these cross-coupling
reaction conditions.
Our thioimidate N-oxide substrates were then subjected
to the Stille cross-coupling reaction: the modified conditions
used were the same as above except that CuMeSal was
replaced by CuBr.Me2S (Scheme 6). Similarly, treatment of
Scheme 7. Reactivity of exo-methylene thioimidate N-oxide compounds.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
in THF: the exo-methylene thioimidate N-oxide 26a was
obtained in quantitative yield, and the phenyl analogue 26b in
70% yield. Then our modified Suzuki and Stille reaction
conditions were applied to both 26a and 26b in cross-coupling
reactions. Under Stille conditions, the stannyl thiophene
reagent afforded the exo-methylene thienyl nitrone 25 from
either 26a or 26b (80% and 70% yield, respectively).
Applying Suzuki conditions with para-methoxyphenyl bor-
onic acid more efficiently led to the aryl nitrone 27 from
either 26a or 26b (91% and 88% yield, respectively).
In summary, while exploring the synthesis and properties
of the rarely studied thioimidate N-oxide functional group we
have disclosed an original method to prepare aryl- and vinyl-
substituted cyclic ketonitrones, from d-ribose-derived cyclic
thioimidate N-oxides, a chiral template, by way of the
Liebeskind–Srogl reaction. The scope of this novel synthetic
approach to cyclic ketonitrones appears to be broad and
efficient by using both modified Suzuki and Stille procedures.
The intriguing exo-methylene thioimidate N-oxides 26a and
26b also gave good results in the coupling reactions. Further
exploration on improved methods for the synthesis and
investigation of the reactivity features of the unique thioimi-
date N-oxide functional group are currently being investi-
gated in our laboratory.
Scheme 6. Modified Stille coupling reaction.
tri-n-butylphenyl stannane with both 12a and 12b afforded
the phenyl-substituted nitrone 13, which were isolated in
higher yields (85% and 87% yield, respectively) compared to
when the Suzuki coupling was used. In contrast, 2-(tri-n-
butylstannyl)furan proved less reactive, and the furyl nitrone
19 that was produced from either 12a or 12b was afforded in
approximately 60% yield. The same protocol applied to 2-
(tri-n-butylstannyl)thiophene afforded much better yields of
the thienyl nitrone 22 from either 12a or 12b (95% and 78%
yield, respectively). Finally, two vinyl stannyl reagents were
also tested: in both cases, the coupling reaction smoothly
afforded the corresponding nitrones 23 (ca. 80% yield from
either 12a or 12b) and 24, albeit purification was rather
difficult and only a partially pure compound was obtained.
When we took a closer look at the results obtained for the
coupling reaction with 2-(tri-n-butylstannyl)thiophene, a side
product 25 (Scheme 7) resulting from HBr elimination was
detected and isolated in 5% yield when 12a was used.
Received: September 16, 2009
Published online: December 9, 2009
Keywords: a-substituted nitrones · coupling reactions ·
.
d-ribose · palladium · synthetic methods
[1] R. A. Floyd, R. D. Kopke, C.-H. Choi, S. B. Foster, S. Doblas,
[2] a) Y. Han, B. Tuccio, R. Lauricella, F. A. Villamena, J. Org.
D. F. Ohlweiler, A. A. Carr, T. R. Nieduzak, D. A. Hay, G.
Adams, R. Vaz, R. C. Bernotas, J. Biol. Chem. 1996, 271, 3097 –
3104.
Our interest was spurred by the intriguing structure of 25
and therefore we explored an optimized pathway to prepare
this unique exo-methylene nitrone functional system
(Scheme 7). Deliberate HBr elimination in our thioimidate
N-oxide substrates was more efficiently effected using DBU
Angew. Chem. Int. Ed. 2010, 49, 577 –580
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