Migration of an acyl group in the pyrazole system: Synthesis of 1-acyl-3-hydroxy-1H-pyrazoles and related derivatives. A new preparation of N,N′-diacylhydrazines

Article abstract of DOI:10.1039/a803973i

A new general method for the synthesis of 1-acyl-3-hydroxy-1H-pyrazoles 5a-f and related derivatives 5g-i starting from 4-ethoxymethylene-2-phenyloxazol-5(4H)-one (1) and hydrazides, 4-phenylsemicarbazide, 4-phenylthiosemicarbazide and benzyl carbazate in boiling dioxane is described. The method includes a migration of an acyl or related unit. The X-ray study and NMR spectroscopic examination confirmed the structure of the products. A one-pot synthesis of N,N′-diacylhydrazines from hydrazides by the assistance of oxazolone 1 is also presented.

Full text of DOI:10.1039/a803973i

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Migration of an acyl group in the pyrazole system: synthesis
of 1-acyl-3-hydroxy-1H-pyrazoles and related derivatives.
A new preparation of N,NЈ-diacylhydrazines
ˇ
Vladimir Kepe, Franc Pozgan, Amalija Golobicˇ, Slovenko Polanc and
Marijan Kocˇevar*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5,
1000 Ljubljana, Slovenia
A new general method for the synthesis of 1-acyl-3-hydroxy-1H-pyrazoles 5a–f and related derivatives 5g–i
starting from 4-ethoxymethylene-2-phenyloxazol-5(4H)-one (1) and hydrazides, 4-phenylsemicarbazide,
4-phenylthiosemicarbazide and benzyl carbazate in boiling dioxane is described. The method includes a
migration of an acyl or related unit. The X-ray study and NMR spectroscopic examination confirmed the
structure of the products. A one-pot synthesis of N,NЈ-diacylhydrazines from hydrazides by the assistance
of oxazolone 1 is also presented.
Pyrazole derivatives are important as synthons and reagents
H
O
O
in organic synthesis and have found applications as pharma-
ceuticals, agrochemicals, dyestuffs, etc.1 Amongst them, 1-acyl-
3-hydroxy-1H-pyrazoles and related compounds have not been
thoroughly investigated, although several, mostly acetyl deriv-
atives, have been prepared and studied.2 Their potential as
acetylating N-acyl agents has not been described, but it was
found that the 3-acetoxy group of 3-acetoxy-1-acetyl-5-
methylpyrazole has useful acetylating potential.2b,d The reaction
of 3-substituted pyrazol-5(2H)-ones with isocyanates gave 5-
hydroxy-1-carbamoyl derivatives, whereas the O-alkyl analogs
afforded the corresponding 3-alkoxy-1-carbamoyl derivatives.
For the explanation of this phenomenon an intramolecular
hydrogen bond was postulated.2g Treatment of 3-amino-5-
hydroxy-1H-pyrazole with aryl isocyanates resulted in the corre-
sponding 5-amino-1-carbamoyl-3-hydroxypyrazole derivatives,
which were further converted to their 3-amino-5-hydroxy iso-
mers via the migration of substituted carbamoyl groups onto
the nitrogen closer to the hydroxy group.2h
R1XC
O
Ph
O
Ph
R1CXNHNH2 (2)
N
N
N
1,4-Dioxane
2h rt + 2h reflux
NH
CH
EtO CH
1
3
CXR1
R1
R1
C
X
X
C
N
O
NH
N
N
N
119.2-122.8
112.1-115.4
N
PhCONH
4
OH
155.3-158.1
OH
PhCONH
PhCONH
CXR1
5
Yield (%)a
CXR1
Yield (%)a
5
5
69
86
88
79
82
87
82
74
72
a
b
c
d
e
COMe
COPh
f
COCH2NHCOPh
CONHPh
g
h
i
CO-Ph-p-NO2
COTh
CSNHPh
CO2CH2Ph
COPy
Here we present a simple and general synthesis of a series of
1-acyl-3-hydroxy-1H-pyrazoles and related compounds starting
from the oxazolone derivative 13 and hydrazides 2a–f, semi-
carbazide 2g, thiosemicarbazide 2h or benzyl carbazate 2i
(Scheme 1). The method is based on the reactions of hydrazines
with the oxazolone derivative 1 to give the hydrazinomethyl-
eneoxazol-5(4H)-ones and hence the corresponding pyrazolone
derivatives.3,4 To our knowledge, hydrazides and related com-
pounds have never been used in such a transformation. In the
case of hydrazides we expected to obtain the corresponding 1-
acyl-1H-pyrazol-5(2H)-ones 4, since several stable compounds
of this type are known.5 To our surprise, upon stirring the reac-
tion mixture of oxazolone derivative 1 and selected hydrazides 2
in dioxane for 2 h, followed by heating for 2 h, we isolated the
rearranged 1-acyl-3-hydroxy-1H-pyrazoles 5 in high yield. In
the case of compound 5a the structure was confirmed by the
X-ray structure analysis (Fig. 1). It has been shown that such
compounds exist in the 3-OH-tautomeric form, thus supporting
the previously described higher stability of this form of related
1-substituted derivatives in the crystal form and in aprotic sol-
vents,1b,c,2c although in a recent NMR study three examples of
5-methyl-3-oxo-2,3-dihydropyrazole-1-carbothioic acid S-alkyl
esters were described.2i
aIsolated yields of TLC-pure compounds.
Th = 2-Thienyl; Py = 4-Pyridyl.
Scheme 1
detailed NMR study including some two-dimensional experi-
ments. Proton 5-H showed in DMSO-d6 a strong singlet
between 8.41 and 8.69 ppm for all compounds with the excep-
tion of compound 5h, where it appeared at 8.95 ppm. The sig-
nals for the hydroxy groups appeared between 11.08 and 11.88
ppm. All 13C signals of the pyrazole skeleton are also in narrow
δ ranges as shown in Scheme 1. Some NMR signals of com-
pound 5a were also determined on the basis of HMBC and
HMQC spectra. We believe that the data we obtained are con-
sistent with the 3-hydroxy tautomeric form of compounds 5.
The proposed tautomeric form may also be supported by the
fact that compound 5a exhibits nearly the same IR spectro-
scopic characteristics in the carbonyl region as a KBr pellet and
in DMSO solution.
Since the migration of the acyl group in our system is in
contradiction with the previous observations in related sys-
tems2d,g,h and since we were not able to isolate the proposed
intermediates 4, we performed some additional experiments in
Since the pyrazole derivatives with this substitution pattern
have not been thoroughly investigated,1,2,6 we performed a
J. Chem. Soc., Perkin Trans. 1, 1998
2813

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disubstituted hydrazines 7a–j. For this purpose, the oxazolone 1
and two equivalents of an appropriate derivative 6 were heated
in dioxane for 0.5–2 h [reaction (1), Table 1].
H
N
1,4-Dioxane
NH
∆, 0.5–2h
1
+
2 R–NHNH2
R–NHNH–R
+
(1)
82–97%
7
O
6
PhCONH
8
Table 1 Synthesis of N,NЈ-diacylhydrazines 7a–j
Fig. 1 ORTEP view of compound 5a: displacement ellipsoids are
shown at 50% probability level. Bond distances are given in Å.
Product 7
R
Yielda (%)
Mp/ЊC
Lit. mp/ЊC
7a
7b
7c
7d
7e
7f
PhCO
97
91
86
89
84
91
90
242–243
301–303
315–317
274–277
230–232
258–260
218–220
267–269
255–257
188–189
237–2389a
297–2989c
315–3169c
2769d
order to find evidence for the transformation of compounds 4
into 5. For this reason, the reaction of the oxazolone derivative
1 with 4-phenylthiosemicarbazide (2h) was performed in the
first step for 24 h at room temperature, thus forming the inter-
mediate 3h. In the second step 2 equivalents of phenyl isocyan-
ate were added and upon heating in 1,4-dioxane for 2 h, the
corresponding phenylcarbamoyl derivative 5g was isolated as
the main product in 29% yield (based on 1), instead of the
phenylthiocarbamoyl derivative 5h. The same product was also
obtained when the pyrazole derivative 5h was refluxed in the
presence of phenyl isocyanate. Since these experiments did
not give any real evidence for the formation of derivative 4h,
the reaction of compound 1 with benzohydrazide (2b) was
performed in the presence of phenyl isocyanate and the prod-
uct 5g was obtained in 16% yield (Scheme 2). An attempt to
prepare compound 5g from 5b and phenyl isocyanate was not
successful.
p-NO2-PhCO
o-HO-PhCO
2-ThienylCO
3-PyridylCO
4-PyridylCO
2-PyrazinylCO
PhCONHCH2CO 88
PhNHCO
PhNHCS
227–2289e
254–2559e
223–2259f
267–2689g
2509h
7g
7h
7i
94
82
7j
1879i
a Isolated yields of TLC-pure compounds.
The separation of the products of type 7 from the pyrazolone
by-product 8 was achieved from an alkaline aqueous solution
of the crude material from which the products 7 separated,
whereas pyrazolone derivative 8 was soluble under such
conditions.
In conclusion, we have presented a very convenient synthesis
of various 1-acyl-3-hydroxy-1H-pyrazoles and their structure
determination as well as a method for the synthesis of var-
ious symmetrically N,NЈ-disubstituted hydrazines starting from
easily available, chemically stable and cheap chemicals. The
method also represents a possible route for the activation of
hydrazides, which are known not to be useful donors of acyl
units due to their high resonance stability.10
2 PhNCO
1,4-Dioxane, ∆, 2h
1. 1,4-Dioxane, 24h rt
2. +2 PhNCO, ∆, 2h
1
+
2h
5g
5h
29%
47%
PhNCO
1,4-Dioxane, ∆, 2h
Experimental
1. 1,4-Dioxane, 3h rt
2. +PhNCO, ∆, 2h
1
+
2b
5g
5b
Melting points were determined on a Kofler micro hot stage
and are uncorrected. 1H and 13C NMR spectra were recorded in
DMSO-d6 on a Bruker Avance DPX 300 spectrometer; 1H
NMR spectra were recorded at 300.1 MHz (with TMS as an
internal reference) and 13C NMR spectra at 75.4 MHz using
solvent signal (39.5 ppm) as an internal reference. Coupling
constants J are given in Hz. IR spectra of 5a were taken on a
Perkin-Elmer FTIR 1720 X spectrometer in a KBr pellet and
in DMSO (99.5%, over molecular sieves, with less than 0.01%
of water). Mass spectra were recorded on a VG-Analytical
AutospecQ spectrometer. Elemental analyses (C, H, N) were
performed on a Perkin-Elmer 2400 CHN analyzer. Thin-
layer chromatography was carried out on Fluka silica gel
TLC-cards. Merck silica gel 60 PF254 containing gypsum was
used to prepare chromatotron plates. 4-Ethoxymethylene-
2-phenyloxazol-5(4H)-one (1),3 pyrazine-2-carbohydrazide
(6g)11a and 2-(benzoylamino)acetohydrazide (6h)11b were pre-
pared as described in the literature. 1,4-Dioxane was purified
as described previously.12 All other compounds were used as
received from commercial suppliers (Fluka, Aldrich).
X
16%
Scheme 2
The reaction between compounds 1 and 2b in the presence of
phenyl isocyanate, from which we isolated product 5g (though
in poor yield), could be evidence for the formation of the
intermediate 4b which was trapped by phenyl isocyanate. Of
course, as shown in a separate experiment, product 5g cannot
be formed via compound 5b.
We believe that the transformation of the intermediate 4 to 5
can be explained by the assistance of the nucleophilic oxygen of
1,4-dioxane, or eventually by the intermolecular migration of
acyl groups between two molecules of the pyrazole derivative 4.
In the case of a carbamoyl or thiocarbamoyl group the appear-
ance of an intermediary-formed phenyl isocyanate or phenyl
isothiocyanate also cannot be excluded. The driving force for
the migration might be higher thermodynamic stability of the
products of type 5 in comparison with isomeric compounds 4.
We also investigated the mobility of acyl groups by using the
described compounds as an acylating system.7 In a previous
communication N-acyl pyrazoles were described as relatively
inert acylating agents and that alcoholysis was dramatically
accelerated under the influence of a strong acid or base.8
Instead of starting from compounds 5 and appropriate nucleo-
philes, we carried out such acylation as a one-pot procedure
in which intermediates have not been isolated. This was realized
in the synthesis of previously known9 symmetrically N,NЈ-
General procedure for the preparation of N-(1-acetyl-3-hydroxy-
1H-pyrazol-4-yl)benzamides 5a–i
A mixture of the oxazolone 1 (5 mmol) and a hydrazino deriva-
tive 2 (5 mmol) was stirred in dioxane (10 ml) at room tempera-
ture for 2 h followed by heating under reflux for 2 h. After the
removal of the solvent under reduced pressure, dioxane (2.5 ml)
and ethyl acetate (2.5 ml) were added. Upon cooling, the result-
2814
J. Chem. Soc., Perkin Trans. 1, 1998

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ing solid was filtered off and washed with a small amount of
dioxane. Yields are given in Scheme 1.
128.5, 132.0, 133.2, 138.3, 156.4, 165.0, 173.4; m/z (FAB-MS)
339 (MHϩ, 37%), 154 (100) (Found: C, 60.1; H, 4.4; N, 16.7.
Calc. for C17H14N4O2S: C, 60.3; H, 4.2; N, 16.6%).
Analytical and spectroscopic data of products 5a–i
N-[3-Hydroxy-1-(benzyloxycarbonyl)-1H-pyrazol-4-yl]benz-
amide 5i. White solid; mp 208–210 ЊC, decomp. (dioxane); δH
5.38 (s, 2H, CH2), 7.40–7.59 (m, 8H, Ph and 3H of COPh), 7.95
(m, 2H, COPh), 8.41 (s, 1H, 5-H), 10.05 (s, 1H, NH), 11.53 (br
s, 1H, OH); δC 68.6, 112.8, 122.1, 127.8, 128.3, 128.4, 128.51,
128.54, 131.8, 133.3, 135.2, 148.8, 157.3, 165.0; m/z (FAB-MS)
338 (MHϩ, 65%), 91 (100) (Found: C, 63.9; H, 4.3; N, 12.5.
Calc. for C18H15N3O4: C, 64.1; H, 4.5; N, 12.5%).
N-(1-Acetyl-3-hydroxy-1H-pyrazol-4-yl)benzamide 5a. White
solid, mp 219–222 ЊC, decomp. (dioxane); δH 2.49 (s, 3H, Me),
7.49–7.62 (m, 3H, Ph), 7.96 (m, 2H, Ph), 8.47 (s, 1H, 5-H),
10.05 (s, 1H, NH), 11.48 (br s, 1H, OH); δC 20.9 (CH3), 114.1
(C-4), 119.2 (C-5), 127.8 (C-2Ј, C-6Ј), 128.4 (C-3Ј, C-5Ј), 131.9
(C-4Ј), 133.4 (C-1Ј), 156.8 (C-3), 165.1 (CONH), 167.9
(COMe); νmax/cmϪ1 (KBr) 1718, 1661, 1635, 1601, 1571, 1513,
1484, 1394; (DMSO, 10% solution) 1711, 1663, 1620, 1602,
1565, 1529; m/z 245 (Mϩ, 18%), 105 (100) (Found: C, 58.8; H,
4.2; N, 17.2. Calc. for C12H11N3O3: C, 58.8; H, 4.5; N, 17.1%).
Reaction of oxazolone 1 with 4-phenylthiosemicarbazide (2h) in
the presence of phenyl isocyanate
A mixture of oxazolone 1 (434 mg, 2 mmol) and 2h (99%, 338
mg, 2 mmol) was stirred in dioxane (4 ml) at room temperature
for 24 h. After evaporation under reduced pressure, EtOAc (1.5
ml) was added to the residue and, upon cooling, 374 mg (55%)
of crude 3h was obtained. The mixture of crude 3h in 1,4-
dioxane (3 ml) and phenyl isocyanate (98%, 255 mg, 2.01 mmol)
was heated under reflux for 2 h. After separation as described in
the general procedure, N-phenylcarbamoyl derivative 5g (188
mg, 29% based on oxazolone 1) was obtained.
N-(1-Benzoyl-3-hydroxy-1H-pyrazol-4-yl)benzamide
5b.
White solid, mp 209–212 ЊC, decomp. (dioxane); δH 7.50–7.67
(m, 6H, two Ph), 7.97 (m, 4H, two Ph), 8.65 (s, 1H, 5-H), 10.15
(s, 1H, NH), 11.67 (br s, 1H, OH); δC 114.4, 120.9, 127.8, 128.0,
128.4, 130.3, 131.9, 132.06, 132.10, 133.3, 157.6, 164.9, 165.2;
m/z 307 (Mϩ, 24%), 105 (100) (Found: C, 66.1; H, 4.1; N, 13.9.
Calc. for C17H13N3O3: C, 66.4; H, 4.3; N, 13.7%).
N-[3-Hydroxy-1-(4-nitrobenzoyl)-1H-pyrazol-4-yl]benzamide
5c. White solid, mp 294–296 ЊC, decomp. (dioxane); δH 7.51–
7.64 (m, 3H, Ph), 7.98 (m, 2H, Ph), 8.16 (d, 2H, J 8.9, p-NO2-
Ph), 8.37 (d, 2H, J 8.9, p-NO2-Ph), 8.67 (s, 1H, 5-H), 10.19 (s,
1H, NH), 11.85 (br s, 1H, OH); δC 115.2, 120.4, 123.0, 127.9,
128.4, 131.4, 132.0, 133.2, 138.2, 149.1, 158.0, 163.5, 165.3; m/z
352 (Mϩ, 22%), 105 (100) (Found: C, 57.8; H, 3.2; N, 16.05.
Calc. for C17H12N4O5: C, 58.0; H, 3.4; N, 15.9%).
Reaction of N-[3-hydroxy-1-(N-phenylthiocarbamoyl)-1H-
pyrazol-4-yl]benzamide (5h) with phenyl isocyanate
A mixture of 5h (200 mg, 0.591 mmol) and phenyl isocyanate
(144 mg, 1.185 mmol) in 1,4-dioxane (2 ml) was heated under
reflux for 2 h. After separation as described in the general pro-
cedure, N-phenylcarbamoyl derivative 5g (89 mg, 47%) was
obtained.
N-[3-Hydroxy-1-(2-thienylcarbonyl)-1H-pyrazol-4-yl]-
benzamide 5d. White solid, mp 235–238 ЊC, decomp. (dioxane);
δH 7.30 (dd, 1H, J1 4.9, J2 4.0, 4Ј-H), 7.53–7.65 (m, 3H, Ph), 8.01
(m, 2H, Ph), 8.12 (dd, 1H, J1 4.9, J2 1.2, 5Ј-H), 8.35 (dd, 1H, J1
4.0, J2 1.2, 3Ј-H), 8.69 (s, 1H, 5-H), 10.17 (s, 1H, NH), 11.70 (br
s, 1H, OH); δC 114.6, 120.4, 127.6, 127.8, 128.4, 132.0, 132.4,
133.3, 137.30, 137.33, 157.18, 157.24, 165.2; m/z 313 (Mϩ, 45%),
105 (100) (Found: C, 57.4; H, 3.7; N, 13.6. Calc. for
C15H11N3O3S: C, 57.5; H, 3.5; N, 13.4%).
N-[3-Hydroxy-1-(pyridin-4-ylcarbonyl)-1H-pyrazol-4-yl]-
benzamide 5e. Yellowish solid, 265–267 ЊC, decomp. (dioxane);
δH 7.50–7.63 (m, 3H, Ph), 7.82 (d, 2H, J 5.9, Py), 7.98 (m, 2H,
Ph), 8.65 (s, 1H, 5-H), 8.78 (deg d, 2H, Py), 10.19 (s, 1H, NH),
11.88 (br s, 1H, OH); δC 115.4, 120.2, 123.5, 127.9, 128.4, 132.0,
133.2, 139.8, 149.7, 158.1, 163.6, 165.3; m/z 308 (Mϩ, 34%), 105
(100) (Found: C, 62.0; H, 3.9; N, 18.1. Calc. for C16H12N4O3: C,
62.3; H, 3.9; N, 18.2%).
Reaction of oxazolone 1 with benzohydrazide (2b) in the presence
of phenyl isocyanate
A mixture of oxazolone 1 (326 mg, 1.50 mmol) and 2b (98%,
205 mg, 1.51 mmol) in dioxane (3 ml) was stirred at room tem-
perature for 3 h. Upon cooling and filtering off, 382 mg (83%)
of crude 3b was obtained. To the boiling mixture of crude 3b in
1,4-dioxane (4 ml), phenyl isocyanate (170 mg, 1.40 mmol) was
added and heated under reflux for 2 h. After separation follow-
ing the general procedure, a crude mixture of products in which
1
approximately 61 mg (based on H NMR analysis, 16% based
on 1) of compound 5g was obtained. The pure 5g can be
obtained by purification on a chromatotron by using first a
mixture CHCl3–EtOAc (10:1), then CHCl3–EtOAc (1:1), and
finally EtOAc as eluents.
N-{3-Hydroxy-1-[2-(benzoylamino)acetyl]-1H-pyrazol-4-yl}-
benzamide 5f. White solid, mp 269–272 ЊC, decomp. (diox-
ane); δH 4.68 (d, 2H, J 5.7, NHCH2), 7.48–7.62 (m, 6H, two Ph),
7.90–7.98 (m, 4H, two Ph), 8.48 (s, 1H, 5-H), 8.95 (t, 1H, J 5.7,
NHCH2), 10.11 (s, 1H, 4-NH), 11.72 (br s, 1H, OH); δC 41.3,
114.3, 119.5, 127.3, 127.8, 128.4 (two signals), 131.6, 131.9,
133.3, 133.7, 157.3, 165.2, 166.6, 166.8; m/z (FAB-MS) 365
(MHϩ, 8%), 154 (100) (Found: C, 62.4; H, 4.3; N, 15.2. Calc. for
C19H16N4O4: C, 62.6; H, 4.4; N, 15.4%).
N-[3-Hydroxy-1-(N-phenylcarbamoyl)-1H-pyrazol-4-yl]-
benzamide 5g. White solid, mp 230–233 ЊC, decomp. (dioxane);
δH 7.12 (t, 1H, J 7.4, NH-Ph), 7.36 (deg dd, 2H, NH-Ph), 7.53–
7.65 (m, 3H, COPh), 7.72 (d, 2H, J 7.8, NH-Ph), 7.98 (m, 2H,
COPh), 8.48 (s, 1H, 5-H), 9.85 (s, 1H, NH), 10.09 (s, 1H, NH),
11.08 (br s, 1H, OH); δC 112.1, 120.4, 120.8, 123.8, 127.7, 128.5,
128.7, 132.0, 133.3, 137.7, 147.5, 155.3, 165.1; m/z (FAB-MS)
323 (MHϩ, 20%), 154 (100) (Found: C, 63.05; H, 4.5; N, 17.2.
Calc. for C17H14N4O3: C, 63.35; H, 4.4; N, 17.4%).
Reaction of N-[1-benzoyl-3-hydroxy-1H-pyrazol-4-yl]benzamide
(5b) with phenyl isocyanate
A mixture of 5b (100 mg, 0.325 mmol) and phenyl isocyanate
(43 mg, 0.354 mmol) in 1,4-dioxane (2 ml) was heated under
reflux for 2 h. After separation following the general procedure,
the starting material 5b (70 mg, 70%) was recovered and no
formation of 5g was confirmed by TLC.
General procedure for the preparation of symmetrically
disubstituted N,NЈ-diacylhydrazines (7)
A mixture of a hydrazine derivative 6 (10 mmol) and oxazolone
1 (5 mmol) in 1,4-dioxane (10 ml) was heated under reflux for
0.5 h (compounds 7b, 7i and 7j) or for 2 h (all other com-
pounds). Water (5 ml) was added to the cooled mixture and the
pH value was adjusted to 10 with 1 M NaOH in order to dis-
solve pyrazolone 8. The product was filtered off and thoroughly
washed with dioxane. Yields of products 7 are given in Table 1.
N-(2,3-Dihydro-3-oxo-1H-pyrazol-4-yl)benzamide 8. This
compound can be isolated from the water layer by acidification
to pH 5 with acetic acid and filtration of the resulting solid, mp
205–206 ЊC (lit.,3 204–205 ЊC).
N-[3-Hydroxy-1-(N-phenylthiocarbamoyl)-1H-pyrazol-4-yl]-
benzamide 5h. White solid, mp 164–166 ЊC, decomp. (dioxane);
δH 7.27 (t, 1H, J 7.4, NH-Ph), 7.42 (deg dd, 2H, NH-Ph), 7.52–
7.66 (m, 5H, 3H of COPh and 2H of NH-Ph), 7.99 (m, 2H,
COPh), 8.95 (s, 1H, 5-H), 10.14 (s, 1H, NH), 11.08 (s, 1H, NH),
11.48 (br s, 1H, OH); δC 113.7, 122.8, 125.3, 126.2, 127.7, 128.4,
X-Ray crystallography
Crystal data. C12H11N3O3, M = 245.2, monoclinic, a =
J. Chem. Soc., Perkin Trans. 1, 1998
2815

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Pharm. Bull., 1974, 22, 207; (d) K. Arakawa, T. Miyasaka and H.
11.443(1), b = 5.035(1), c = 19.676(2) Å, β = 99.39(1)Њ, V =
1118.5(3) Å3 (by least-squares refinement on diffractometer
angles for 50 automatically centred reflections with 8.20Њ р
θ р 13.38Њ), T = 293 K, λ = 0.71069 Å, space group P21/c (No.
14), Z = 4, Dx = 1.456 g cmϪ3, colorless plate: 0.65 × 0.16 × 0.05
Ochi, Chem. Pharm. Bull., 1974, 22, 214; (e) H. Ochi, T. Miyasaka
and K. Arakawa, Bull. Chem. Soc. Jpn., 1977, 50, 2991; ( f ) A. Hadi,
N. Martin, C. Seoane and J. L. Soto, J. Chem. Soc., Perkin Trans. 1,
1993, 1045; (g) K. Mitsuhashi, H. Takayanagi, S. Matsuno and K.
Tanaka, J. Heterocycl. Chem., 1982, 19, 1389; (h) J. T. Drummond
and G. Johnson, J. Heterocycl. Chem., 1988, 25, 1123; (i) Ú. Í.
Jónsson, H. Kristinsson, H. Nussbaumer, V. Skúlason and T.
Winkler, Synthesis, 1995, 805.
3 J. W. Cornforth, The Chemistry of Penicillin, ed. H. T. Clarke, J. R.
Johnson and R. Robinson, Princeton University Press, Princeton,
1949, p. 730.
4 (a) Y. S. Rao and R. Filler, in The Chemistry of Heterocyclic
Compounds: Oxazoles, ed. A. Weissberger and E. C. Taylor,
Interscience, New York, 1986, p. 361; (b) F. W. Hartner, Jr., in ref. 1c,
vol. 3, p. 261; (c) S.-S. Homami and A. K. Mukerjee, Indian J.
Chem., Sect. B, 1992, 31, 411.
5 O. A. Attanasi, L. De Crescentini, P. Filippone, E. Foresti, R.
Galeazzi, I. Ghiviriga and A. R. Katritzky, Tetrahedron, 1997, 53,
5617, and references cited therein.
6 M. Begtrup, G. Boyer, P. Cabildo, C. Cativiela, R. M. Claramunt,
J. Elguero, J. I. García, C. Toiron and P. Vedso, Magn. Reson.
Chem., 1993, 31, 107.
7 (a) T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, Wiley, New York, 1991; (b) P. J. Kocieñski, Protecting
Groups, Georg Thieme Verlag, Stuttgart, 1994.
8 C. Kashima, H. Harada, I. Kita, I. Fukuchi and A. Hosomo,
Synthesis, 1994, 61.
9 (a) C. M. Anderson and E. C. Gilbert, J. Am. Chem. Soc., 1942, 64,
2369; (b) H. Zhao, N. Neamati, S. Sunder, H. Hong, S. Wang, G. W.
A. Milne, Y. Pommier and T. R. Burke, Jr., J. Med. Chem., 1997, 40,
937; (c) H. Zhao and T. R. Burke, Jr., Tetrahedron, 1997, 53, 4219;
(d) G. Kossmehl and G. Manecke, Makromol. Chem., 1969, 123, 233
(Chem. Abstr., 1969, 71, 3748b); (e) R. Graf, J. Prakt. Chem., 1933,
138, 289 (Chem. Abstr., 1934, 28, 7697); ( f ) O. Dalmer, C. Diehl
and E. Walter, USP 2 176 063, 1940 (Chem. Abstr., 1940, 34, 18202);
(g) S. Grudzin´ski, Roczniki Chem., 1959, 33, 655 (Chem. Abstr.,
1960, 54, 2184c); (h) R. E. Rosenkranz, K. Allner, R. Good, W. v.
Philipsborn and C. H. Eugster, Helv. Chim. Acta, 1963, 46, 1259;
(i) M. Freund and S. Wischewiansky, Chem. Ber., 1893, 26, 2877;
(j) O. Prakash, V. Sharma and A. Sadana, Synth. Commun., 1997,
27, 3371.
10 H. Paulsen and D. Stoye, The Chemistry of Amides, Interscience,
London, 1970, p. 515; (b) P. D. Bailey, I. D. Collier and K. H.
Morgan, in Comprehensive Organic Functional Group Trans-
formations, ed. A. R. Katritzky, O. Meth-Cohn and C. W. Rees,
Pergamon Press, Oxford, 1995, vol. 5, p. 257; (c) R. D. Connell, in
ref. 10b, p. 309.
11 (a) G. Carrara, F. M. Chiancone, V. D’Amato, E. Ginoulhiac, C.
Martinuzzi, U. M. Teotino and N. Visconti, Gazz. Chim. Ital., 1952,
82, 652 (Chem. Abstr., 1954, 48, 6423d); (b) Th. Curtius, Chem. Ber.,
1890, 23, 3023.
12 B. S. Furniss, A. J. Hannaford, P. W. G. Smith and A. R. Tatchell,
Vogel’s Textbook of Practical Organic Chemistry, Longman
(co-published with Wiley), New York, 1989, 5th edn., p. 407.
13 A. Altomare, M. C. Burla, M. Camalli, G. Cascarano, C.
Giacovazzo, A. Guagliardi and G. Polidori, J. Appl. Crystallogr.,
1994, 27, 435.
mm, µ(Mo-Kα) = 0.101 mmϪ1
.
Data collection and processing. Enraf–Nonius CAD4 dif-
fractometer, graphite-monochromated Mo-Kα radiation, ω–2θ
scans with ω scan width (0.85 ϩ 0.30 tan θ)Њ; 10822 reflections
measured (θmax = 28Њ, Ϫ15 < h < 15, Ϫ6 < k < 6, Ϫ25 < l < 25),
2694 unique (merging R = 0.0315), giving 1247 with I > 2.5σ(I).
No corrections for absorption were required. Intensity
decay = 0.22% (correction was applied).†
Structure solution and refinement. The structure was solved
(all non-H atoms) by direct methods (SIR92).13 Full-matrix
least-squares refinement on F with all non-H atoms anisotropic;
hydrogen atoms were located from a ∆F synthesis and were
not refined. The weighting scheme w = 6.0 × Wf × Ws where
Wf(|Fo| < 6.75) = (|Fo|/6.75)1.2, Wf(|Fo| > 24.0) = (24.0/|Fo|), Wf -
(6.75 р |Fo| р 24.0) = 1.0 and Ws(sin θ < 0.37) = (sin θ/0.37)
and Ws(0.37 р sin θ) = 1.0. The correction for the secondary
extinction14 was applied with g = 0.19(6) × 104. In the final
least-square cycle there were 2087 contributing reflections
(included were those unobserved reflections for which Fc was
greater than Fo) and 164 parameters. The final R and Rw values
were 0.052 and 0.055, respectively. The final maximum shift/esd
was 0.0001. The maximal residual density in the final difference
map was 0.439 e ÅϪ3 and the minimal was Ϫ0.389 e ÅϪ3. The
XTAL3.415 system of crystallographic programs was used for
the correlation and reduction of data, structure refinement and
interpretation. ORTEPII16 was used to produce molecular
graphics.
Acknowledgements
We thank the Ministry of Science and Technology for financial
ˇ
support. Dr B. Kralj and Dr D. Zigon (Center for Mass
Spectroscopy, “Jozef Stefan” Institute, Ljubljana, Slovenia) are
ˇ
gratefully acknowledged for mass measurements.
† Full crystallographic details, excluding structure factor tables, have
been deposited at the Cambridge Crystallographic Data Centre
(CCDC). For details of the deposition scheme, see ‘Instructions for
Authors’, J. Chem. Soc., Perkin Trans. 1, available via the RSC Web
page (http://www.rsc.org/authors). Any request to the CCDC for this
material should quote the full literature citation and the reference
number 207/243.
References
1 (a) R. Fusco, in The Chemistry of Heterocyclic Compounds:
Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles and Condensed
Rings, ed. R. H. Wiley, Interscience, New York, 1967, p. 3; (b)
J. Elguero, in Comprehensive Heterocyclic Chemistry, ed. A. R.
Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984, vol. 5,
p. 167; (c) J. Elguero, in Comprehensive Heterocyclic Chemistry II,
ed. A. R. Katritzky, C. W. Rees and E. F. C. Scriven, Pergamon
Press, Oxford, 1996, vol. 3, p. 1.
14 A. C. Larson, Crystallographic Computing, ed. F. R. Ahmed, S. R.
Hall and C. P. Huber, Munksgaard, Copenhagen, 1970, p. 291.
15 S. R. Hall, G. S. D. King and J. M. Stewart, The Xtal3.4 User’s
Manual, University of Western Australia, Lamb, Perth, 1995.
16 C. K. Johnson, ORTEPII, Report ORNL-5138, Oak Ridge
National Laboratory, Tennessee, USA, 1976.
Paper 8/03973I
Received 27th May 1998
Accepted 8th July 1998
2 (a) A. Weissberger and H. D. Porter, J. Am. Chem. Soc., 1943, 65,
1495; (b) M. Irie, T. Miyasaka and K. Arakawa, J. Biochem. (Tokyo),
1972, 72, 65; (c) K. Arakawa, T. Miyasaka and H. Ochi, Chem.
2816
J. Chem. Soc., Perkin Trans. 1, 1998