Structure and conformations of monoacyl and diacyl 1,2,4-triazolidine-3,5-diones

Article abstract of DOI:10.1021/jo951965h

A series of monoacyl and diacyl 1,2,4-triazolidine-3,5-diones substituted at position 4 with either a phenyl or a tert-butyl group was prepared. Both acetyl and benzoyl groups were utilized as the acyl substituents. The diacylated compounds containing one or two acetyl groups were somewhat unstable to moisture. The acylated compounds were studied by ¹H, ¹³C and ¹⁵N NMR spectroscopy and X-ray crystallography to determine if they were acylated on nitrogen or ring carbonyl oxygen. The results indicated that the acylations occurred on nitrogen. The NMR spectra and molecular modeling computations were used to assign conformations to several of the diacylated compounds.

Full text of DOI:10.1021/jo951965h

J . Org. Chem. 1996, 61, 3733-3737
3733
Str u ctu r e a n d Con for m a tion s of Mon oa cyl a n d Dia cyl
1,2,4-Tr ia zolid in e-3,5-d ion es
Robert A. Izydore*
Department of Chemistry, North Carolina Central University, Durham, North Carolina 27707
Anthony A. Ribeiro
Duke University NMR Center and Department of Radiology, Duke University Medical Center, Box 3711,
Durham, North Carolina 27710
Iris H. Hall
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, CB# 7360, Beard Hall,
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
Received November 6, 1995X
A series of monoacyl and diacyl 1,2,4-triazolidine-3,5-diones substituted at position 4 with either
a phenyl or a tert-butyl group was prepared. Both acetyl and benzoyl groups were utilized as the
acyl substituents. The diacylated compounds containing one or two acetyl groups were somewhat
unstable to moisture. The acylated compounds were studied by 1H, 13C and 15N NMR spectroscopy
and X-ray crystallography to determine if they were acylated on nitrogen or ring carbonyl oxygen.
The results indicated that the acylations occurred on nitrogen. The NMR spectra and molecular
modeling computations were used to assign conformations to several of the diacylated compounds.
In tr od u ction
O
O
O
O
R2
R3
R2
R3
N
N
N
N
R1
R1
N
Numerous examples of 1,2,4-triazolidine-3,5-diones
substituted at positions 1, 2, and 4 are known. However,
only a few monoacylated and diacylated derivatives have
been reported.1-4 Recently we observed that 4-alkyl- and
4-aryl-substituted monoacylated and diacylated 1,2,4-
triazolidine-3,5-diones are potent hypolipidemic agents
in rodents, both in lowering serum cholesterol and serum
triglycerides.5-7 It is important to know the exact posi-
tion(s) of the acyl substituents on the triazolidinedione
ring. The acyl groups can conceivably be substituted
either on the ring nitrogen atoms (I and II) (N-acylated),
the ring carbonyl oxygen atoms (III and IV) (O-acylated),
or in the case of the diacylated compounds on both
nitrogen and oxygen (V) (N,O-diacylated). This situation
is similar to that which existed with the monoacylated
and diacylated 3,5-pyrazolidinediones and for which we
demonstrated by X-ray analysis and 15N NMR spectros-
copy that the acylations occurred exclusively on the ring
nitrogen atoms.8 In the present study a series of mono-
acylated and diacylated 4-phenyl- and 4-tert-butyl-1,2,4-
triazolidine-3,5-diones were prepared and studied by 1H,
13C, and 15N NMR spectroscopy and molecular modeling
in order to determine the site(s) of acylation and in the
instances of the diacylated compounds the preferred
conformations of their acyl substituents.
N
O
O
O
I
II
O
O
R2
R2
O
O
N
N
N
R1
R1
N
N
N
R3
O
O
R3
III
O
O
O
IV
R2
N
R1
N
N
O
R3
O
V
Resu lts a n d Discu ssion
The mono- and diacylated 1,2,4-triazolidine-3,5-diones
that were studied are shown in Table 1. The monoacy-
lated compounds 29 , 3, and 8 were prepared by reacting
1 or 7 with a 50% excess of the appropriate carboxylic
acid anhydride in methylene chloride at room tempera-
ture for 24-48 h. Compound 9 could not be prepared in
this manner. Reaction of 7 with benzoic anhydride gave
only the dibenzoylated product 11. Reaction of 7 with
benzoyl chloride in the presence of pyridine produced 9
in low yield and 11 as the major product. The diacety-
lated derivatives 49 and 10 were formed by the reactions
of 1 and 7, respectively, with an excess of both acetic
anhydride and lead diacetate trihydrate. The dibenzo-
ylated product 5 was produced in high yield from 1 and
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) Tadakazu, T. Pharm. Bull., 1954, 403, 403.
(2) Milton, K. M. U.S. Patent 3,295,981, 1967. Chem. Abstr. 1967,
66, 120803y.
(3) Zinner, G.; Boese, D. Arch. Pharm. 1970, 303, 222.
(4) Shigematsu, T.; Tonita, M.; Shibahara, T.; Nakazawa, M. J apan
Kokai 1977, 83,562; Chem. Abstr. 1977, 88, P6891e.
(5) Izydore, R. A.; Hall, I. H. U.S. Patent 5,192,761, 1993.
(6) Simlot, R.; Izydore, R. A.; Wong, O. T.; Hall, I. H. J . Pharm. Sci.
1993, 82, 408.
(7) Simlot, R.; Izydore, R. A.; Wong, O. T.; Hall, I. H. J . Pharm. Sci.
1994, 83, 367.
(8) Izydore, R. A.; Bernal-Ramirez, J . A.; Singh, P. J . Org. Chem.
1990, 55, 3761.
(9) Izydore, R. A.; J ohnson, H. E.; Horton, R. T. J . Org. Chem. 1985,
50, 4589.
S0022-3263(95)01965-7 CCC: $12.00 © 1996 American Chemical Society

3734 J . Org. Chem., Vol. 61, No. 11, 1996
Izydore et al.
Ta ble 1. Mon oa cyl a n d Dia cyl
1,2,4-Tr ia zolid in e-3,5-d ion es Stu d ied
for compounds 5 and 11 where they absorbed at δ -225.5
and δ -229.2, respectively. In all instances the nonpro-
tonated nitrogens at ring positions 1 or 1 and 2 of the
acylated compounds absorbed at δ -174.2 to δ -186.1.
The latter absorptions are in the same chemical shift
region as the other nitrogen atoms in the ring. These
nitrogens have chemical shifts that are consistent with
“pyrrole-like” nitrogens.10 If the substitutions had oc-
curred on the carbonyl oxygen atoms, the nitrogens would
be “pyridine-like” and would appear 50-200 ppm farther
downfield than was observed. Therefore, the 15N NMR
data indicate that the acylations gave the N-acylated
1,2,4-triazolidine-3,5-diones I and II and not the O-
acylated products III and IV.11
compound
R1
R2
R3
1
2
3
4
5
6
7
8
9
Ph
H
H
H
H
Me
Ph
Me
H
H
H
Ph
Ph
Ph
Ph
Me
Ph
Me
Ph
Ph
H
Me
Ph
Me
Ph
Ph
Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
10
11
12
Me
Ph
Me
The diacetylated derivative 4 was analyzed by X-ray
crystallography.12 The analysis showed that the com-
pound was acylated on the nitrogen atoms at positions 1
and 2 (i.e. II; R1 ) Ph, R2 ) R3 ) Me). Thus the X-ray
results confirm the conclusion drawn from the 15N NMR
data. There are three limiting N,N-diacetylated confor-
mations for the acetyl groups of compound 4. They are
the endo,endo; endo,exo; and exo,exo N,N-diacetylated
conformations. The acetyl groups were in the endo,endo
conformation. The carbonyl groups were twisted conro-
tatory out of planarity with the triazolidine ring by an
average of 33°. This is comparable to the average
conrotatory twisting of 31° that was previously observed
for the two acetyl groups in endo,endo-1,2-diacetyl-4,4-
diethyl-3,5-pyrazolidinedione.8 The phenyl group at posi-
tion 4 was twisted out of coplanarity by approximately
80°.
a 50% excess of benzoic anhydride in the presence of a
stoichiometric quantity of sodium benzoate and as the
minor product when the reaction was carried out in the
absence of sodium benzoate. In the former instance the
sodium benzoate apparently functioned as a base to
catalyze the addition of the second benzoyl group. How-
ever, the reaction of 1 and 7, respectively, with excess
benzoic anhydride in the presence of excess lead diacetate
trihydrate gave only the mixed diacylated products 6 and
12. In these instances the acetate anion apparently
functioned in a dual capacity, i.e. as a base to catalyze
diacylation and as a nucleophile in its reaction with
benzoic anhydride to produce the mixed anhydride which
added the acetyl substituent to the triazolidine ring.
The monoacylated compounds 2, 3, 8, and 9 and the
dibenzoylated compounds 5 and 11 were stable to mois-
ture. The diacylated compounds 4, 6, 10, and 12 were
unstable to moisture. These compounds decomposed
slowly on storage and more rapidly when directly exposed
to water in solution as shown by HPLC analysis. This
behavior is analogous to that displayed by 1,2-diacyl-3,5-
pyrazolidinediones and 2-benzoyl-3,5-isoxazolidinediones
which decompose by hydrolysis of their N-acyl ring
substituents in the presence of atmospheric moisture.8,9
Me
Me
O
O
O
O
O
N
N
N
N
N
N
Ph
Ph
Ph
Me
O
O
Me
O
endo, exo
endo, endo
O
O
The 1H and 13C NMR spectral data of compounds 1-12
in DMSO-d6 are given in Tables 2 and 3. The spectra of
the diacylated compounds 4, 6, 10, and 12 which contain
at least one acetyl group contained weak signals that
could be attributed to the presence of hydrolysis products
of the compounds.
Me
Me
N
N
N
O
O
exo, exo
When the NMR solutions were allowed to stand for ten
weeks, the extent of hydrolysis gradually increased as
the compounds reacted with the small amount of water
that had been absorbed by the solutions. Thus compound
4 had undergone 6% hydrolysis after ten weeks and
contained both the monoacylated derivative 2 and acetic
acid. Compound 6 was 7% hydrolyzed and contained 2,
3 (trace), and benzoic acid. In a similar manner the
solution of compound 10 contained 42% of 8 plus acetic
acid, and the solution of compound 12 contained 41% of
8, 1% of 9, benzoic acid, and acetic acid (trace). When
the NMR solutions of the compounds were heated to 140
°C for 30 min, the hydrolyses were 70-96% complete.
The 15N NMR spectra (Table 4) of compounds 1 and 7
in DMSO-d6 showed their protonated nitrogens at δ
-232.8 and δ -235.4, respectively, and their nonproto-
nated nitrogens at δ -204.7 and δ -205.5, respectively,
relative to external nitric acid. The nitrogens at ring
position 2 (NH) of the four monoacylated derivatives
appeared at δ -222.2 to δ -230.4. The ring nitrogens
at position 4 of all of the acylated compounds appeared
as weak-intensity peaks at δ -200.7 to δ -208.8 except
The Tripos Associates SYBYL (version 6.1a) molecular
modeling software was used to model the three limiting
conformations of 4. The conformations were built and
minimized in vacuo to a gradient of 0.005 kcal/(mol*A)
using the Tripos force field and Gasteiger-Marsili charges.
The endo,endo conformation was predicted to be 1.104
kcal/mol more stable than the endo,exo conformation and
8.382 kcal/mol more stable than the exo,exo conformation.
This prediction is in agreement with the X-ray crystal-
lographic analysis results. The acetyl groups of the exo,-
exo conformation were twisted conrotatory approximately
12° above and below the triazolidine ring to relieve the
steric interaction between the two acetyl methyl groups,
and the ring itself was twisted out of planarity, showing
a ring CNNC torsion angle of -7.6°. The acetyl groups
(10) Levy, G. C.; and Lichter, R. L. Nitrogen-15 Nuclear Magnetic
Resonance Spectroscopy; J ohn Wiley and Sons: New York, 1979;
Chapter 3.
(11) Compounds 10 and 12 showed several weak-intensity reso-
nances which were in agreement with the partial hydrolysis of these
compounds that was exhibited in their 1H and 13C NMR spectra.
(12) Izydore, R. A.; Singh, P. Acta Crystallogr., in press.

Monoacyl and Diacyl 1,2,4-Triazolidine-3,5-diones
J . Org. Chem., Vol. 61, No. 11, 1996 3735
Ta ble 2. 1H NMR Sp ectr a l Da ta for Com p ou n d s 1-12a
H type
1
2
3
4
5
6
7
8
9
10
11
12
1.57
2.51
t-Bu
CH3CO
Ph
1.47 1.57 1.53
2.43
1.56 1.51
2.42
2.49
7.73-7.47 7.43-7.56 7.40-7.84 7.47-7.56 7.43-7.98 7.45-7.97
10.5 10.5
2.48
2.57
7.47-7.73
7.44-7.96 7.46-7.99
NH
-
9.6 11.6 11.5
a
1H NMR chemical shifts are at 28 °C in DMSO-d6 relative to internal TMS.
Ta ble 3. 13C NMR Sp ectr a l Da ta for Com p ou n d s 1-12a ,b
C type
t-Bu CH3
t-Bu quaternary
CH3
CO (Me)
CO (Ph)
1
2
3
4
5
6
7
8
9
10
11
12
28.11
56.13
27.96
57.47
23.21
27.89
57.49
27.91
58.99
23.66
27.91
57.54
27.69
59.00
23.60
22.74
163.12
23.44
164.92
23.39
164.52
164.12
163.13
165.02
164.48
163.11
163.01
167.40
163.15
163.19 164.95
167.40
ring CO (1)
147.33 147.38 148.63 147.32
150.21
147.61
148.36
148.36 148.08 149.09 148.11 148.89
151.71
148.38
ring CO (2)
ring CO (NH)
Ph
153.98 149.48 150.29
126.46 126.53 126.90 127.37 126.90-
128.06 128.24 127.82 129.06 133.8
129.22 128.74 128.50 129.16 (12 peaks) 128.92
132.27 130.80 128.95 130.42
155.91 151.19 151.69
127.31
128.23
127.72
129.22
132.17
132.95
127.76 128.29
128.59 130.74
129.25 132.06
129.31 134.00
130.86
129.13
130.28
130.57
131.77
133.96
129.50
131.10
132.53
132.56
132.21
132.87
132.99
a
b
13C NMR chemical shifts are at 28 °C in DMSO-d6 relative to internal TMS. Data for 5 and 11 are for the endo,exo conformations.
Ta ble 4. 15N NMR Sp ectr a l Da ta for Com p ou n d s 1-12a
that the fast minimizations in vacuo give reasonably good
approximations of the geometries of the three limiting
conformations of the molecule.
compound
15N chemical shift, δ
1
2
3
4
5
6
7
8
9
-232.8, -204.7
In order to compare the relative stabilities of the three
limiting conformations in DMSO solution, each limiting
conformation was solvated with one layer of DMSO
molecules and minimized as above to a gradient of 0.05
kcal/(mol*A). Under these conditions the relative stabili-
ties of the solvated systems were endo,exo (250 solvent
molecules) > endo,endo (249 solvent molecules) > exo,-
exo (235 solvent molecules). The endo,exo system was
37 kcal/mol more stable than the endo,endo system and
216 kcal/mol more stable than the exo,exo system. In
each solvated conformation the acetyl groups were twisted
slightly out of planarity with the triazolidine ring. Care
must be taken in interpreting the calculated results. It
is obvious that the number of solvent molecules involved
in each system contributes greatly to its minimized
energy, and other factors are undoubtedly operative.
Therefore, the calculated order of stability for the sol-
vated conformations is not conclusive, and the ranking
of the endo,endo and endo,exo conformations is in doubt.
In any event the barriers to rotation among the three
conformations are expected to be low, and all three
conformations are expected to contribute to the equilib-
rium mixture in solution. The NMR spectrum of the
molecule would not be effected by the equilibrium com-
position.
The 13C NMR spectra of the dibenzoylated derivatives
5 and 11 showed six carbonyl carbons for each compound.
Three were assignable to ring carbonyl carbons, and three
were assignable to benzoyl carbonyl carbons. Compound
11 showed two sets of tert-butyl group signals in a
relative ratio of 83:17 and 12 aromatic carbons. Com-
pound 5 showed 20 aromatic carbons. After the solutions
had been stored for ten weeks at room temperature, the
minor-intensity set of tert-butyl signals and two of the
carbonyl signals, one each in the ring carbonyl and
-222.2, -200.7, -175.8
-222.9, -205.0, -181.2
-202.7, -174.2
-225.5, -181.6
-203.6, -179.8, -174.2
-235.4, -205.5
-230.1, -206.7, -183.2
-230.4, -208.8, -186.1
-208.1, -181.3
-229.2, -185.0
-225.7, -185.0, -180.9
10
11
12
15N NMR chemical shifts are at 28 °C in DMSO-d6 relative to
external nitric acid.
a
of the endo,endo and endo,exo conformations were copla-
nar with the triazolidine ring. The phenyl groups of all
three conformations were twisted by approximately 42°
relative to the triazolidine ring. The endo,endo confor-
mation was solvated with two layers of DMSO molecules
(249 solvent molecules) with the SYBYL Molecular
Silverware algorithm in a periodic box using periodic
boundary conditions. The solvated molecule was mini-
mized as described above and using minimum periodic
boundary conditions. A total of 95500 iterations were
required. The minimized system showed the two acetyl
carbonyl groups twisted conrotatory 2.7° and 2.4° above
and below the ring, respectively. The phenyl group was
twisted by 38° relative to the triazolidine ring, and the
triazolidine ring itself was twisted out of planarity by 1°.
The results indicate that solvation with DMSO leads to
a slight twisting of the acetyl groups out of the plane of
the triazolidine ring, but the twisting is much less than
that which occurs in the crystalline state. The solvation
has only a small effect on the twisting of the phenyl
group. The slight changes in the torsion angles of the
acetyl groups would not be expected to have a significant
effect on the NMR spectra of the molecule. It appears

3736 J . Org. Chem., Vol. 61, No. 11, 1996
Izydore et al.
benzoyl carbonyl regions, of 11 had disappeared, and four
of the aromatic signals had virtually disappeared. Two
of the carbonyl signals and eight of the aromatic signals
of 5 were weaker in intensity.
the plane of the triazolidine ring. The planes of the
benzene rings were rotated approximately 58° relative
to the triazolidine ring.
The exo,exo and the more stable of the endo,exo and
endo,endo conformations of 11 were solvated in SYBYL
with one layer of DMSO molecules and minimized to a
gradient of 0.05 kcal/(mol*A) as described above. The
relative energies of the minimized solvated systems were
endo,exo (187 solvent molecules) > exo,exo (188 solvent
molecules) > endo,endo (183 solvent molecules). The
endo,exo system was 11 kcal/mol more stable than the
exo,exo system and 72 kcal/mol more stable than the
endo,endo system. The torsion angles between the acetyl
carbonyl groups and the triazolidine ring for the confor-
mations were comparable to those calculated for the
nonsolvated conformations. In 11 the calculated relative
order of stability of the solvated conformations is more
likely to be accurate than those of 4 in that the confor-
mation predicted to be most stable had one fewer
molecule of solvation than did the second most stable
conformation.
Both 5 and 11 were studied by variable temperature
1H and 13C NMR spectroscopy. Spectra were recorded
at 28 °C, 56 °C, 84 °C, 112 °C, 140 °C, and after the
samples were cooled back to 28 °C. Compound 11 was
stable over the entire temperature range. However,
there were significant changes in the appearance of its
phenyl hydrogen multiplets in its 1H NMR spectrum
beginning at 84 °C and becoming more pronounced at
112 °C. At 28 °C the aromatic region of 11 showed four
multiplets at δ 7.96 (d, J ) 7.0 Hz), 7.70 (d, J ) 7.0 Hz),
7.59 (multiplet, J ) 7.0-8.5 Hz), and 7.47 (sextet, 2
overlapping t, J ) 8.0 Hz) having relative intensities of
1:1:1:2. At 112 °C the two downfield doublets were
slightly broadened, and the peaks at δ 7.59 and δ 7.47
were broad distorted multiplets. The 13C NMR spectra
remained relatively unchanged to 84 °C. At 112 °C one
ring carbonyl, one benzoyl carbonyl, and the minor
intensity set of tert-butyl group signals were missing. In
the aromatic region four of the signals were considerably
weaker. At 140 °C the four weak aromatic signals were
virtually gone, and the remaining eight signals were very
near their original positions. On cooling the sample back
to 28 °C the spectrum was virtually unchanged from that
at 140 °C. Compound 5 exhibited similar behavior. At
112 °C its 13C NMR spectrum showed only four carbonyl
carbons and 12 primary aromatic carbons. At 140 °C and
after cooling the sample back to 28 °C all the weak
intensity aromatic resonances had disappeared.
Compound 11 was subjected to both the Systematic
Search and Simulated Annealing routines in SYBYL in
order to determine its limiting conformations. Only
conformations involving the orientations of the benzoyl
groups were considered. Conformations involving mirror
images or orientations of the tert-butyl group were
ignored. The Simulated Annealing routine utilized the
Tripos force field and Gasteiger-Marsili charges. The
SYBYL default settings were used. The resulting con-
formations were minimized in vacuo as described above.
One exo,exo conformation, two endo,exo conformations,
and two endo,endo conformations were found. The exo,-
exo conformation was lowest in energy being 2.678 and
3.739 kcal/mol, respectively, lower in energy than the
endo,exo conformations and 3.169 and 3.411 kcal/mol,
respectively, lower in energy than the endo,endo confor-
mations. The two OCNN torsion angles between the
benzoyl carbonyls and the triazolidine ring of the exo,-
exo conformation were twisted conrotatory 13° above and
below the plane of the ring, respectively. The planes of
the two benzene rings were both twisted conrotatory
42.4° relative to the triazolidine ring such that the two
benzene rings were situated one on top of the other and
nearly parallel to each other. The benzene rings were
2.870 Å apart at their ipso carbons and 3.600 Å apart at
their para carbons. The benzoyl carbonyls of the more
stable of the two endo,exo conformations were both
rotated conrotatory 12° relative to the plane of the
triazolidine ring, and the planes of the aromatic rings
were twisted such that the angle between them was 70°,
i.e. they were nearly perpendicular to each other, and
their angles relative to the plane of the triazolidine ring
were 130° (exo) and 119° (endo), respectively. In the more
stable of the two endo,endo conformations the carbonyl
groups were rotated conrotatory by 8° above and below
The NMR data of 11 are in agreement with both the
calculated order of stability of its solvated conformations
and the molecular modeling geometries obtained for it.
The 13C NMR carbonyl region of the endo,exo conforma-
tion would be expected to show two triazolidine ring and
two benzoyl group carbonyl peaks, and the aromatic
region would show eight aromatic resonances. The exo,-
exo and endo,endo conformtions would be expected to
show two peaks each in the carbonyl region because of
the symmetry that is present in them. Additionally the
exo,exo conformation would show six and the endo,endo
conformation would show four aromatic carbons assum-
ing rapid rotation about the phenyl to carbonyl bonds in
the latter conformation.13 The data does not support the
presence of the exo,exo conformation. Initially both the
endo,exo and the endo,endo conformations were present
with the former conformation being the major component.
On standing at room temperature for ten weeks or upon
heating to 112 °C, all of the endo,endo conformation
converted to the endo,exo conformation. The barrier to
rotation back to the endo,endo conformation was appar-
ently sufficiently high that this rotation did not occur.
The torsional barrier into and out of the exo,exo confor-
mation is likely prohibitively high because of steric
factors, and this conformation is not observed. Separate
signals for the two aromatic rings are clearly visible in
1
the H NMR spectrum of the endo,exo conformation at
28 °C. The two doublets at δ 7.96 and δ 7.70 represent
the ortho hydrogens, the multiplet at δ 7.59 corresponds
to the para hydrogens, and the overlapping triplets at δ
7.47 correspond to the meta hydrogens of the respective
rings. The cause of the changes in the 1H NMR spectrum
at the higher temperatures is not readily clear. One
possibility is that an interconversion between the endo,-
exo conformation and its equivalent exo,endo conforma-
tion is taking place.
The variable temperature NMR spectra of 5 were
similar to those of 11. These results are consistent with
(13) It has been suggested that simultaneous “rocking” of the amide
carbonyl bonds of the exo,exo conformation would lead to four rather
than six aromatic carbons in its 13C NMR spectrum. While this is a
possibility, the close proximity of the “stacked” benzene rings in this
conformation would be expected to lead to an observable anisotropic
(ring-current) effect in its 1H NMR spectrum. Since the aromatic
chemical shift range observed in 12, which would not show this
anisotropic effect, is virtually identical to that of 11, it can be concluded
that the endo,endo conformation of 11 is not present in DMSO solution.

Monoacyl and Diacyl 1,2,4-Triazolidine-3,5-diones
J . Org. Chem., Vol. 61, No. 11, 1996 3737
acetone (50:50) gave 1.3 g (16%) of pure 5: mp 272-273 °C;
IR (Nujol), 1797 (m), 1754 (s), 1724 (s), 1704 cm-1 (s). Anal.
Calcd for C22H15N3O4: C 68.56, H 3.92, N 10.90. Found: C
68.52, H 3.80, N 10.90. Compound 5 was alternately prepared
in higher yield (44%) by reacting 1 (5.30 g, 30 mmol) and
benzoic anhydride (20.3 g, 90 mmol) in the presence of sodium
benzoate (8.64 g, 60 mmol) in CH2Cl2 (150 mL) at rt for 20 h.
2-Acet yl-1-b en zoyl-4-p h en yl-1,2,4-t r ia zolid in e-3,5-d i-
on e (6). To a mixture of 1 (5.30 g, 30 mmol) and powdered
Pb(OAc)2‚3H2O (22.8 g, 60 mmol) in CH2Cl2 (200 mL) was
added benzoic anhydride (33.9 g, 150 mmol). The mixture was
allowed to stir at rt for 48 h and filtered, and to the filtrate
was added concd HCl (5 mL). The filtrate was washed with
water (3 × 100 mL) and 10% Na2CO3 (3 × 75 mL), dried
(MgSO4), and evaporated under reduced pressure to give a
viscous light-tan oil. The oil was stirred with absolute EtOH
(60 mL) to precipitate a white solid that was filtered to yield
3.65 g (38%) of 6 as a white solid. Recrystallization of the solid
from absolute EtOH gave 3.3 g (39%) of pure 6: mp 145.5-
146 °C; IR (Nujol) 1814 (m), 1753 (s), 1715 cm-1 (s). Anal.
Calcd for C17H13N3O4: C 63.15, H 4.05, N 13.00. Found: C
62.95, H 3.96, N 12.95.
1-Ben zoyl-4-ter t-b u t yl-1,2,4-t r ia zolid in e-3,5-d ion e (9)
a n d 1,2-Diben zoyl-4-ter t-bu tyl-1,2,4-tr ia zolid in e-3,5-d i-
on e (11). To a mixture of 4-tert-butyl-1,2,4-triazolidine-3,5-
dione (7) (2.00 g, 12.7 mmol) and pyridine (1.50 g, 19 mmol)
in CH2Cl2 (70 mL) was added benzoyl chloride (1.79 g, 12.7
mmol). The mixture was stirred at rt for 20 h. The resulting
solution was washed with 10% HCl (2 × 30 mL) and 10% Na2-
CO3 (3 × 30 mL). The carbonate washings were acidified (HCl)
to produce a white precipitate that was removed by filtration
to yield 0.17 g (5%) of 9. Recrystallization from cyclohexane
gave pure 9: mp 131-133 °C (lit.6 mp 96-98 °C); IR (Nujol),
3144 (m), 1791 (m), 1722 (s), 1682 cm-1(s). Anal. Calcd for
C13H15N3O3: C 59.76, H 5.79, N 16.08. Found: C 59.68, H
5.83, N 16.03.
the presence of a mixture of endo,exo and endo,endo
conformations in the original sample. At approximately
112 °C or on standing at room temperature the endo,-
endo comformation converted to the more stable endo,-
exo conformation.
Con clu sion
The acylations of 4-substituted 1,2,4-triazolidine-3,5-
diones occur exclusively on the ring nitrogen atoms.
There is no evidence that either O-acyl, O,O-diacyl, or
N,O-diacyl groups were present in any of the compounds.
The diacylated structures containing one or two acetyl
groups were somewhat unstable to hydrolysis, and the
hydrolyses were largely complete on heating to 140 °C.
The diacetylated derivative 4 exists in the endo,endo
conformation in the solid state, but the identity of the
preferred conformation in DMSO solution is uncertain.
The dibenzoylated derivatives 5 and 11 exist primarily
in the endo,exo conformation in DMSO solution at 28 °C.
It does not appear that the endo,exo conformation con-
verts to the endo,endo and/or exo,exo conformations on
heating.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. HPLC analyses
were carried out on a Whatman ODS-2 reverse-phase HPLC
column. Elemental analyses were performed by Desert Ana-
lytics, Tucson, AZ. NMR spectra were obtained in DMSO-d6
1
1
at 28 °C. The H NMR spectra were recorded with a 5 mm H
probe operating at 499.843 MHz. The proton 90° pulse was
10.0 µs. The spectral width was 8000.0 Hz, the relaxation
delay was 1.000 s, and the acquisition time was 1.892 s. The
13C NMR spectra were recorded with a 5 mm probe operating
at 125.697 MHz. The carbon 90° pulse was 8.0 µs. The
spectral width was 25000.0 Hz, the relaxation delay was 0.200
s, and acquisition time was 1.300 sec. TMS was the internal
reference standard for both the 1H and 13C NMR spectra. The
15N NMR spectra were recorded with a 10 mm probe operating
at 50.653 MHz. The spectral width was 23242.3 Hz, the
relaxation delay was 6.900 s, and the acquisition time was
0.705 s. External nitric acid was the reference standard.
The 1,2-unsubstituted urazoles 1 and 7 were purchased from
the Aldrich Chemical Co. and Lancaster Synthesis, Inc.,
respectively. Compounds 2, 4, 8 (mp 103-104.5 °C, lit. mp
117-119 °C6), and 10 were prepared as previously reported.6,7
1-Ben zoyl-4-p h en yl-1,2,4-tr ia zolid in e-3,5-d ion e (3) a n d
1,2-Diben zoyl-4-p h en yl-1,2,4-tr ia zolid in e-3,5-d ion e (5). To
a solution of benzoic anhydride (10.2 g, 45 mmol) in CH2Cl2
(150 mL) was added 4-phenyl-1,2,4-triazolidine-3,5-dione (1)
(5.30 g, 30 mmol). The mixture was allowed to stir at rt for
48 h. The mixture was filtered to give a white solid. Recrys-
tallization of the solid from absolute EtOH gave 3.3 g (39%)
of pure 3: mp 211-213 °C; IR (Nujol) 1784 (m), 1714 (s), 1682
cm-1 (s). Anal. Calcd for C15H11N3O3, C 64.05, H 3.94, N
14.94. Found: C 63.81, H 3.76, N 14.81.
The CH2Cl2 solution was dried (MgSO4) and evaporated
under reduced pressure to yield 1.30 g (56%) of 11. Recrys-
tallization from EtOH/acetone (70:30) gave pure 11: mp
244.5-245 °C; IR (Nujol), 1796 (m), 1738 (s), 1728 (s), 1698
cm-1 (s). Anal. Calcd for C20H19N3O4: C 65.74, H 5.24, N
11.50. Found: C 65.77, H 5.02, N, 11.28. When the reaction
was carried out with a 50% molar excess of benzoyl chloride,
the yield of 11 was increased to 82%.
2-Acet yl-1-b en zoyl-4-ter t-b u t yl-1,2,4-t r ia zolid in e-3,5-
d ion e (12). To a mixture of 7 (1.00 g, 6.37 mmol) and
powdered Pb(OAc)2‚3H2O (4.83 g, 12.7 mmol) in CH2Cl2 (100
mL) was added benzoic anhydride (4.32 g, 19.1 mmol). The
mixture was allowed to stir at rt for 42 h, filtered, washed
with water (3 × 50 mL) and 10% Na2CO3 (3 × 50 mL), dried
(MgSO4), and evaporated under reduced pressure to yield 1.35
g (70%) of 12 as a white solid. Recrystallization of the solid
from absolute EtOH gave pure 12: mp 164-166 °C; IR (Nujol)
1806 (m), 1742 (s), 1711 cm-1 (s). Anal. Calcd for C15H17
-
N3O4: C 59.39, H 5.65, N 13.85. Found: C 59.59, H 5.61, N
13.66.
Ack n ow led gm en t. The authors wish to thank the
National Institutes of Health Minority Biomedical
Research Support Program (MBRS) for partial support
of this study.
The CH2Cl2 solution was washed with 10% Na2CO3 (3 × 50
mL), dried (MgSO4), and evaporated under reduced pressure
to yield a white solid. Recrystallization of the solid from EtOH/
J O951965H