1846
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 10, October, 2006
Kislyi et al.
Alkylation of sodium salts of oximes with bromo ketones (synꢀ
thesis of compounds 1a—h, general procedure). A mixture of a
sodium salt of an oxime (5 mmol) and an appropriate bromo
ketone (6 mmol) was stirred in ethanol (or DMF) (5—10 mL) at
~20 °C for 4 h. The precipitate was filtered off (with DMF as
the solvent, the product was precipitated by adding water
(5—10 mL)), washed with a small amount of ether, and dried
in vacuo. The yields, melting points, and 1H NMR spectra of the
products obtained are given in Tables 4 and 5.
since it is commonly believed that the N atom of the
C=N bond is negatively charged and hence addition
should occur at the C atom. However, in the presence of
one or two strong acceptors at the C atom, the electron
density can be substantially redistributed. Actually, AOA
did not form from oxyimino nitrile 1h containing only
one electronꢀwithdrawing group or the yield of product 3
decreased considerably when the starting reagent conꢀ
tained electronꢀreleasing substituents in the carbamoyl
fragment. Thus, the formation of oxaziridine 10 and its
immediate opening into anion 11 become possible only in
the presence of two strong acceptors at the C atom of
Oꢀalkylated oximes 1.
The transformation of anion 11 into AOA 3 can occur
via an attack of the O atom on the C atom of the cyano
group and via a hydride shift giving rise first to anion 12
and then AOA 3. The generated αꢀketo amide anion 12
could be expected to yield carboxylic acids or their esters
of the type 8 through decomposition by strong bases. Howꢀ
ever, only for Ar = 4ꢀNO2C6H4 (see Scheme 4), the corꢀ
responding benzoate was the major reaction product, while
AOA 3d was not detected. Decomposition of other
oxyimino nitriles to carboxylic acids was insignificant unꢀ
less the reaction temperature was raised to 40—60 °C;
however, the ratio of the products under these conditions
was not particularly studied. Such a behavior of some
αꢀketo amides 12 is not in conflict with the literature data
since transformations of aryloxoacetic acid esters with
electronꢀreleasing substituents into the corresponding
benzoic acids are known25,26 to require shortꢀtime heatꢀ
ing (5 min) with NaOH and the presence of a nitro group
in the benzene ring should sharply promote this decomꢀ
position.
Synthesis of 4ꢀaminoisoxazoles 2a—h (general procedure A).
A mixture of compound 1a—h (5 mmol) and LiClO4•3H2O
(1 g) was refluxed in MeCN (10—25 mL) for 5 min to complete
homogenization and left at ~20 °C for ~14 h. The resulting
solution was concentrated and the residue was suspended in
60% ethanol (10—20 mL). Cyclization was carried out by addꢀ
ing dropwise aqueous 5% LiOH with stirring for 20 min
(TLC monitoring until the starting Oꢀalkylated hydroxyimino
nitrile was completely consumed). The precipitate of the prodꢀ
uct was filtered off, washed with 2% HCl and water, and recrysꢀ
1
tallized (see Table 4). The yields, melting points, and H NMR
spectra of the compounds obtained are given in Tables 4 and 5.
Synthesis of 5ꢀaminoꢀ2ꢀbenzoyloxazoleꢀ4ꢀcarboxamides
3a—e (general procedure B). A mixture of Oꢀalkylated oximes
1a—e (5 mmol) and KBr (2 g) in aqueous 60% ethanol (4 mL)
was allowed to stand in an open beaker for ~14 h. The moist
precipitate that formed was suspended in aqueous 60% ethanol
(15—25 mL) and then aqueous 10% KOH (0.6 g) was added
dropwise to the stirred suspension. After 2 h, the precipitate was
filtered off, washed with 2% HCl and water, and dried. The
resulting mixture of 4ꢀaminoisoxazole and 5ꢀaminooxazole was
dissolved in MeCN (25 mL) and concentrated on a rotary evapoꢀ
rator with an equal amount (w/w) of silica gel. The resulting
powder was applied to a column and separated by chromatograꢀ
phy with benzene (for 4ꢀaminoisoxazole) and benzene—AcOEt
(from 10 : 1 to 2 : 1; for 5ꢀaminooxazole) as eluents. The yields,
1
melting points, and H and 13C NMR spectra of the products
obtained are given in Tables 3—5.
Thus, although Oꢀalkylated oximes 1 predominantly
exist in the Zꢀform stabilized by intramolecular hydrogen
bonding,11 we failed to select conditions for the synthesis
of AOA 3 as sole products. Apparently, this is due to slow
rearrangement of anion 9 into anion 11, which allows a
considerable part of Oꢀalkylated oxime to convert into the
Eꢀform and then into AIA. Aminooxazoles with two elecꢀ
tronꢀwithdrawing substituents can be synthesized in less
ambiguous and preparatively more suitable ways.27,28
NꢀPhenylꢀ4ꢀaminoꢀ5ꢀbenzoylisoxazoleꢀ3ꢀcarboxamide (2a)
and Nꢀphenylꢀ5ꢀaminoꢀ2ꢀbenzoyloxazoleꢀ4ꢀcarboxamide (3a)
were obtained in the ratio 72 : 28 from Nꢀphenylꢀ2ꢀ(benzoylꢀ
methoxyimino)cyanoacetamide (1a) (2 g, 6.5 mmol) and KBr
(2.5 g) according to general procedure B. The total yield of their
mixture was 918 mg. Separation by column chromatography
gave compounds 2a (597 mg) and 3a (218 mg).
1
Compound 2a. For m.p. and H NMR data, see Tables 4
and 5, respectively. MS, m/z: 307 (18), 202 (14), 188 (24), 119
(18), 105 (100), 93 (44), 77 (81). IR, ν/cm–1: 3472, 3392, 3352,
1688, 1648, 1600, 1540, 1504.
1
Experimental
Compound 3a. For m.p. and H NMR data, see Tables 4
and 5, respectively. MS, m/z: 307 (20), 202 (2), 149 (4), 119 (7),
105 (100), 93 (25), 77 (51). IR, ν/cm–1: 3440, 3400, 3264, 1664,
1632, 1600, 1548, 1516.
1
H and 13C NMR spectra were recorded on Bruker DRXꢀ500
and Bruker AMꢀ300 instruments (500.13 and 75.47 MHz, reꢀ
spectively) in DMSOꢀd6. IR spectra were recorded on a Specord
Mꢀ80 instrument (in KBr pellets). Mass spectra were recorded
on a FinniganꢀMAT instrument (EI, 70 eV). Sodium salts of
oximes were prepared according to a known procedure.11
αꢀBromoacetophenone, αꢀbromoꢀ4ꢀmethoxyacetophenone, and
α,4ꢀdibromoacetophenone were synthesized by bromination in
methanol according to a published procedure;29 αꢀbromoꢀ4ꢀ
nitroacetophenone was prepared by bromination in dioxane as
described earlier.30
Xꢀray diffraction analysis of compound 3a. Light yellow
needleꢀlike crystals are orthorhombic, C17H13N3O3
(M = 307.30); at 120 K, a = 12.090(4) Å, b = 32.174(11) Å,
c = 7.424(3) Å, α = 90.00°, β = 90.00°, γ = 90.00°, V =
2887.8(18) Å3, space group Pca21, Z = 8, dcalc = 1.414 g cm–3
.
An experimental array of 25 443 reflections was collected from a
single crystal (0.7×0.02×0.01 mm) on a Bruker SMART 1000
CCD diffractometer at 120 K (MoꢀKα radiation, λ = 0.71073 Å,
2θ
= 54°). After the averaging of equivalent reflections,
max
Kislyi
