4750
J . Org. Chem. 2000, 65, 4750-4752
well as protons c and e, form two separate two-spin pairs,
F or m a tion of
2,6-Bis(4-ch lor op h en yl)-5,6-d ih yd r o-2H-
1,3,4-oxa d ia zin e-4-oxid e by a n
with δd > δe. The HMQC data established the multici-
plicity of all carbons, especially the one-bond connectivity
between carbon A (162.51 ppm) and proton a (8.32 ppm).
In tr a m olecu la r Am in o/Nitr o Deh yd r a tion
The most revealing information comes from an analysis
of the long-range proton-carbon correlation HMBC
spectrum, where all cross-peaks are assigned. The fol-
lowing cross-peaks unequivocally establish certain key
connectivities in the six-membered ring skeleton: carbon
A and proton f, K and a, C and f, as well as E and a.
Finally, a fast 2D NOE experiment3 unveiled the through-
space proximity of protons a and f, supporting the
depicted three-dimensional conformation. The observa-
tion of these cross-peaks implies that the central ring
structure is rigid and provides further spectroscopic
evidence supporting the elucidated structure 3. We are
unaware of any precedent for the unusual downfield
chemical shift for sp3 carbon A (δ 162.5).
It appears that this unusual cyclic structure resulted
through dehydration of a penultimate intermediate 7
formed, in turn, from 6 by intramolecular attack on the
nitro group by the hemiaminal amino group. This latter
intermediate could have arisen either through capture
of the initial aldol product 1 by 4-chlorobenzalimine (5),
formed in situ from 4-chlorobenzaldehyde in the NH4-
OAc/HOAc reaction medium, or by Michael addition of
hemiminal 4 to the nitrostyrene 2. The formation of an
azoxy functionality from an amine and a nitro group has
been observed previously only in rigid systems such as
2-nitrophenylguanidine, 2-nitrophenylhydrazine, or 2-ni-
tro-2′-aminobiphenyl.4 Such a reaction is remarkable in
the present case, however, because the precursor to ring
closure, compound 6, is flexible, and ring closure of 6 to
7 is probably reversible (the 2,6-diaryl substituents in 3
are clearly cis). Furthermore, strong base is not required
for the cyclization/dehydration. It should be noted that
this azoxy synthesis represents an intriguing redox and
regiochemical counterpart to the classical synthesis of
this functionality from nitroso compounds and hydroxy-
lamines, with the added feature that it places oxygen on
the alternate nitrogen atom. This appears to be the first
1,3,4-oxadiazine system to have been prepared with a
nitrogen-nitrogen double bond and one of the very few
examples in which a nitrogen-nitrogen bond is formed
in the cyclization step.5
Edward C. Taylor,* Bin Liu, and Wei Wang1
Department of Chemistry, Princeton University,
Princeton, New J ersey 08544
Etaylor@princeton.edu
Received February 14, 2000
For an ongoing synthetic project, we had need of a
convenient synthesis of â-nitrostyrenes and were at-
tracted to a recent publication describing the condensa-
tion of some electron-rich aldehydes with nitromethane
under ultrasound.2 Electron-neutral aromatic aldehydes
and those containing electron-withdrawing substituents
were reported to give only the intermediate nitro alcohols.
We have confirmed the above results, but in addition
have found that by raising the reaction temperature to
60-65 °C, again under ultrasound conditions, nitrosty-
renes are the major product with both of the above classes
of aldehydes. We report in this paper on a remarkable
compound of unprecedented structural type isolated in
the course of the above synthetic investigation (Scheme
1).
Condensation of 4-chlorobenzaldehyde with nitro-
methane (as solvent) in the presence of 2.2 equiv of
ammonium acetate and 2.6 equiv of acetic acid under
ultrasound irradiation at 60-65 °C for a period of 6 h
gave a reaction mixture that showed by TLC the presence
of a small amount of the intermediate nitro alcohol 1, a
fast-moving spot of the expected nitrostyrene 2, and a
distinct spot of intermediate Rf representing an unknown
reaction product. Separation of the above three com-
pounds was readily achieved by column chromatography,
yielding 4-6% of the nitro alcohol 1 (the only product
formed under ultrasound conditions at room tempera-
ture), 65% of 4-chloro-â-nitrostyrene (2), and an oil
representing the unknown of intermediate Rf (3). Low-
resolution mass spectroscopy revealed that 3 had the
molecular formula C15H12Cl2N2O2. HRMS gave MH+
)
323.0329 (calcd 323.0354), confirmed by microanalysis.
The proton and carbon NMR spectra are also consistent
with the above molecular formula. Repetition of the above
reaction with 2 equiv of 4-chlorobenzaldehyde and only
1 equiv of nitromethane produced an almost identical
reaction mixture. It is remarkable that this byproduct,
clearly formed from two moieties of the aldehyde and one
moiety of nitromethane, is formed even in the presence
of a large excess of nitromethane.
Attempts to extend this curious reaction to other
aldehydes were disappointing. 3-Chlorobenzaldehyde
gave a similar mixture of nitrostyrene, nitro alcohol, and
dihydrooxadiazine-4-oxide, but a variety of other aro-
matic aldehydes (benzaldehyde, 2-chlorobenzaldehyde,
2,4-dimethoxybenzaldehyde, 3,4,5-trimethoxybenzalde-
hyde) gave no detectable amount of dihydrooxadiazine-
4-oxide; the only (major and identified) products appeared
to be the respective nitrostyrenes and nitro alcohols.
A suite of NMR experiments (1D 1H and 13C, 2D COSY,
HMQC, HMBC, and NOESY) were performed, and the
results are summarized in Table 1. The COSY spectrum
showed that protons f, g, and h could be analyzed into
an AMX three-spin system and that protons b and d, as
(3) Wagner, R.; Berger, S. J . Magn. Reson., Ser. A 1996, 123, 119.
(4) (a) For
a discussion and references, see: Katritzky, A. R.;
Lagowski, J . M. Chemistry of the Heterocyclic N-Oxides; Academic
Press: New York, 1971; pp 120-141. (b) Suzuki, H.; Kawakami, T.
Synthesis 1997, 855. (c) Suzuki, H.; Kawakami, T. J . Org. Chem. 1999,
64, 3361.
(5) See: Smalley, R. K. In Comprehensive Heterocyclic Chemistry
II, Vol. 6; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier
Science, Inc.: New York, 1996; pp 737-781.
(1) Present address: Parke-Davis Pharmaceutical Research Divi-
sion, 2800 Plymouth Road, Ann Arbor, MI 48105.
(2) McNulty, J .; Steere, J . A.; Wolf, S. Tetrahedron Lett. 1998, 39,
8013.
10.1021/jo000205q CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/29/2000
Taylor, Edward C.
