Synthesis of 3,5-isoxazolidinediones and 1 H -2,3-benzoxazine-1,4(3 H)-diones from aliphatic oximes and dicarboxylic acid chlorides

Article abstract of DOI:10.1021/jo402708j

The synthesis of the title compounds was carried out by reacting dicarboxylic acid chlorides with oximes in the presence of excess triethylamine. Disubstituted malonyl chlorides gave 2-alkenyl-4,4-dialkyl-3,5- isoxazolidinediones (8a-f) and 2,2′-ethylidene-bis[4,4-dialkyl-3,5- isoxazolidinedione]s (9a-f). Compounds 9 were formed from 8 and its N-unsubstituted 3,5-isoxazolidinedione decomposition product. Phthaloyl chlorides reacted with acetone oxime to yield 3-(1-methylethenyl)-1H-2,3- benzoxazine-1,4(3H)-diones (16a-e). Products 16 spontaneously decomposed to give N-unsubstituted 1H-2,3-benzoxazine-1,4(3H)-diones (17a-e) at rates that were dependent on temperature and solvent. Kinetic studies showed that two of the compounds decomposed by zero-order kinetics under neutral conditions. Butanedioyl chloride did not produce a cyclic product.

Full text of DOI:10.1021/jo402708j

Article
pubs.acs.org/joc
Synthesis of 3,5-Isoxazolidinediones and 1H‑2,3-Benzoxazine-
1,4(3H)‑diones from Aliphatic Oximes and Dicarboxylic Acid
Chlorides
Robert A. Izydore,*,† Joseph T. Jones, Benjamin Mogesa, Ira N. Swain, Ronda G. Davis-Ward,
Dwayne L. Daniels, Felicia Frazier Kpakima, and Sharnelle T. Spaulding-Phifer, II
Department of Chemistry, North Carolina Central University, Durham, North Carolina 27707, United States
S
* Supporting Information
ABSTRACT: The synthesis of the title compounds was carried out by reacting dicarboxylic acid chlorides with oximes in the
presence of excess triethylamine. Disubstituted malonyl chlorides gave 2-alkenyl-4,4-dialkyl-3,5-isoxazolidinediones (8a−f) and
2,2′-ethylidene-bis[4,4-dialkyl-3,5-isoxazolidinedione]s (9a−f). Compounds 9 were formed from 8 and its N-unsubstituted 3,5-
isoxazolidinedione decomposition product. Phthaloyl chlorides reacted with acetone oxime to yield 3-(1-methylethenyl)-1H-2,3-
benzoxazine-1,4(3H)-diones (16a−e). Products 16 spontaneously decomposed to give N-unsubstituted 1H-2,3-benzoxazine-
1,4(3H)-diones (17a−e) at rates that were dependent on temperature and solvent. Kinetic studies showed that two of the
compounds decomposed by zero-order kinetics under neutral conditions. Butanedioyl chloride did not produce a cyclic product.
derivatives of 1, 2, and 3. We reported previously that addition
of dimethyl (6a) and diethylmalonyl chloride (6b) to ether
solutions of acetone oxime (7a) and triethylamine gave 2-(1-
methylethenyl)-3,5-isoxazolidinediones (8a and 8b) and 2,2′-
(1-methylethylidene)bis[4,4-dialkyl-3,5-isoxazolidinedione]s
(9a and 9b). Also formed were small amounts of N-
unsubstituted 3,5-isoxazolidinediones (10a and 10b) and
O,O′-(2,2-dialkyl-1,3-dioxo-1,3-propanediyl)dioxime 2-propa-
nones (11a and 11b) (Scheme 1).49 Products 8a and 8b
represent the only examples of 2-alkenyl-3,5-isoxazolidine-
diones reported to date. Mechanisms for the formation of
products 8 and 9 were proposed. In simple terms products 8
can be considered to arise by the condensation of the oxime
with 6 followed by base-promoted ring closure of the
monooxime ester. Compounds 8b and 9b were subsequently
shown to give moderate lowering of blood serum cholesterol
and serum triglyceride levels in CF1 mice when administered
for 16 days at a dosage of 20 mg/kg/day ip.1,2
INTRODUCTION
■
The 3,5-isoxazolidinediones (1) are an important pharmaco-
logically active class of compounds. We have shown that they
are potent hypolipidemic1−5 and cytotoxic6 agents, specific
inhibitors of the type-2 isoform of IMPDH,7 and inhibitors of
aldose reductase.8,9 They also act as antidiabetic agents.10−15
Six-membered ring analogues of 1 include the 2H-1,2-oxazine-
3,6-diones (2) and the 1H-2,3-benzoxazine-1,4(3H)-diones
(3).16−25 While there has been one report each on the
fungicidal properties23 and the β-Lactamase pro-inhibitory
activity26 of 3, the pharmacological properties of 2 and 3 have
been largely unexplored. In contrast, the corresponding 2H-1,3-
benzoxazine-2,4(3H)-diones (4) have a wide range of
pharmacologic activities including antimycobacterial,27−31
antituberculotic,32−36 analgesic,37,38 cardiovascular,39 antimi-
totic,40 antifungal,41,42 cytotoxic,43 and antifungal,44 and the
2H-1,4-benzoxazine-2,3(4H)diones (5) are active as antimi-
otic,40 antimicrobial,45 antiallergic,46,47 and renin inhibitory48
agents. It appears likely then that 2 and 3 would also have
useful pharmacological activities.
Because only a limited number of derivatives of 8 and 9 were
obtained, we explored in this study additional reactions
between 6 and 7 in order to gain insight into the scope of
the reaction. We also investigated the unreported reactions of
phthaloyl and butanedioyl chlorides, respectively, with oximes
to determine if they would react similarly to 6. Reported herein
are the results of these investigations.
As part of our ongoing investigation into the pharmacological
activities of 3,5-isoxazolidinediones and related ring systems, it
was of interest to investigate the synthesis of N-alkenyl
Received: December 6, 2013
Published: March 12, 2014
© 2014 American Chemical Society
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Scheme 1. Reactions of Substituted Malonyl Chlorides with Oximes
Table 1. Reactions of Dialkylmalonyl Chlorides (6) with Oximes (7)
a
percent yield
acid chloride
oxime
8
9
10
11
13
14
b
,
c
,
d
b
,
c
,
d
b
,
c
b,c
6a
6b
6c
7a
7a
7a
8a (29
)
9a (25
)
10a (2
)
11a (tr )
b
b
b
b
8b (23 )
8c (22)
9b (51 )
9c (28)
10b (tr )
10c (5)
11b (tr )
11c −
e
e
e
8c (28 )
9c (18 )
10c (11 )
6d
7a
8d (tr)
9d (40)
10d (12)
11d −
e
e
e
8d (22 )
9d (30 )
10d (17 )
6b
6c
6b
E-7b
E-7b
12a
8e (45)
8f (18)
9e (16)
9f −
10b −
10c −
11e −
E,E′-11f (40)
f
f
13a (62 )
14a −
g
g
13a (2 )
14a (35 )
14b (16)
6b
12b
13b −
a
Except where noted, the reactions were carried out by adding 6 to an ether solution of 7 and a 50% excess of Et3N at 0 °C and then stirring at rt for
b
c
d
e
20 h. Reference 42. A stoichiometric quantity of Et3N was used. Yield revised from reference 42. 7a was added to an ether solution of 6 and
Et3N. Initial yield by HPLC. Yield by HPLC after 72 h.
f
g
months. Compound 8 (R = H) was too unstable to be isolated.
Higher yields of 8b and 9b were obtained when the reactions
were carried out in the presence of a 50% excess of Et3N.49
Accordingly, the reactions in the current study were generally
carried out using this excess.
Dipropylmalonyl chloride (6c) was added to an ether
solution of acetone oxime (7a) in the presence of excess Et3N
at 0 °C, and the mixture was stirred for 20 h at room
RESULTS AND DISCUSSION
■
Reactions of malonyl chlorides with a variety of oximes were
investigated. In our previous study we observed that the
stability of compounds 8 was related to the steric size of the
substituents at position-4 of the ring and followed the order Et
> Me > H. Both 8a and 8b were stable to distillation under
reduced pressure, but when stored at room temperature, 8b was
indefinitely stable, whereas 8a slowly decomposed over several
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temperature to give 8c, 9c, and 10c, respectively (Table 1).
When the reaction was carried out with inverse addition under
the same conditions, i.e., by adding 7a to an ether solution of 6c
and Et3N, the yields of 8c and 10c increased slightly, whereas
that of 9c decreased. In a similar manner dibutylmalonyl
chloride (6d) reacted with 7a to yield 8d, 9d, and 10d. The
yield of 8d was negligible in the standard addition but increased
substantially, along with a decreased yield of 9d and an
increased yield of 10d, in the inverse addition. There was no
evidence of bis-oxime ester formation (11c or 11d) in either of
the two reactions. Compound 8c was stable to heating at 56 °C
for 3.5 h. Both 8c and 8d were indefinitely stable at room
temperature.
Scheme 2. Reaction of Phthaloyl Chlorides with 7a
The reaction of 6b with (E)-acetophenone oxime (7b)
produced both 8e and 9e but no 10b or 11e. Compound 8e
was stable at room temperature but thermally unstable to
vacuum distillation, giving a complex mixture that showed no
1
vinyl hydrogen signals in its H NMR spectrum. The yields of
8e and 9e varied with the amount of base used. When the
reaction was carried out with a stoichiometric quantity of Et3N,
the yields of 8e and 9e were 36% and <1%, respectively.
However, using a 50% excess of Et3N caused the yield of 8e to
increase slightly (39%) and the yield of 9e to increase to 10%,
similar to that observed for 8b and 9b. Compound 9e showed
Table 2. Reaction of Phthaloyl Chlorides (15) with 7a
a
percent yield
acid chloride
oxime
16
17
1
separate H NMR signals for the isoxazolidinyl ethyl groups
15a
15b
15c
15d
7a
7a
7a
7a
16a (74)
17a (11)
due to its asymmetry. Its mass spectrum was typical of
compounds 9 in general in that it did not show a molecular ion
peak but gave instead a peak corresponding to cleavage of one
of the isoxazolidine rings.50 The corresponding reaction of 6c
with E-7b produced a little 8f but no 9f or 10c. Instead E,E′-11f
was obtained as the major product. Apparently the presence of
the larger propyl groups retards ring closure of the initially
formed monooxime ester to 8f and promotes diesterification of
6c. The stereochemistry of 11f has been assigned as E,E′
because it was formed from E-7b and its 13C NMR spectrum
shows the oximyl methyl groups at δ 14.4. The corresponding
methyl groups of the Z,Z′-isomer or one of the methyl groups
of the E,Z-isomer are expected to appear near δ 26.51
16b, 16c (76)
16d, 16e (30)
16f, 16g −
17b, 17c (0)
17d, 17e (<1)
17f, 17g −
a
The reactions were carried out by adding 15 to an ether solution of
7a and a 50% excess of Et3N at 0 °C and then stirring at rt for 24 h.
An attempt to prepare 16a by reacting phthalic anhydride with
7a gave only unreacted starting materials. The reaction between
4-methylphthaloyl chloride (15b) and 7a gave a mixture
containing the 6-methyl- and 7-methyl-3-alkenyl-1H-2,3-
benzoxazine-1,4-diones (16b and 16c). No 17b or 17c was
isolated. The presence of the two isomers was demonstrated in
1
The reaction of 6b with cyclic oximes was studied.
the H NMR spectrum, which showed four vinyl hydrogen
Cyclohexanone oxime (12a) reacted with 6b to yield initially
signals and two methyl singlets (58:42) at δ 2.58 and δ 2.56,
respectively. Attempts to separate the two isomers by column
chromatography or analytical HPLC were unsuccessful. In a
similar manner 4-methoxyphthaloyl chloride (15c) reacted with
7a to produce a nearly equimolar mixture containing the 6-
methoxy- and 7-methoxy-3-alkenyl-1H-2,3-benzoxazine-1.4-di-
ones (16d and 16e). Two methoxy singlets (52:48) appeared
1
13a (62%) and no 14a as shown by H NMR and HPLC
analysis of the isolated product mixture. Compound 13a was
thermally unstable at room temperature and gradually
decomposed over 72 h to give partial conversion to 14a
(35%) and several unidentified decomposition products. Only
2% of 13a remained. It is probable that 10b was an
intermediate in the conversion.49 Intermediate 10b was likely
formed in the same manner as compounds 17 (see discussion
below). The overall process would involve partial decom-
position of 13a to 10b followed by addition of the NH bond of
10b across the alkenyl double bond of 13a. The exact
mechanism for the addition step is not known.
In a similar manner cyclopentanone oxime (12b) reacted
with 6b to produce 14b, but 13b was not obtained. Based on
the behavior observed in the corresponding reaction of 12a, it is
likely that 13b was formed but was not stable enough for
isolation or detection.
1
in the H NMR spectrum at δ 3.89 and 3.87, respectively. 3-
Nitrophthaloyl chloride (15d) reacted with 7a to give a
complex product mixture. The presence of 16f and 16g was not
1
detected in the H NMR spectrum of the mixture, which
showed no vinyl hydrogens, and there was no evidence for the
formation of 17f and 17g. It is possible that the presence of the
strong electron-withdrawing nitro group caused the initially
formed N-alkenyl products 16f and 16g to be too unstable for
isolation.
Compound 16a was found to be thermally unstable. A
sample of pure 16a gradually and completely decomposed in a
sealed glass vial at room temperature over 3 months to yield
17a. Therefore, the decomposition was spontaneous at room
temperature. Similarly, a mixture of 6-methyl- and 7-methyl-
1H-2,3-benzoxazine-1,4-dione 17b and 17c was obtained by
allowing the mixture of 16b and 16c to partially decompose at
room temperature over 2 weeks (33% conversion by HPLC).
Phthaloyl chloride (15a) reacted with 7a in the presence of
triethylamine to yield 3-(1-methylethenyl)-1H-2,3-benzoxazine-
1,4(3H)-dione (16a) and the N-unsubstituted 1H-2,3-benzox-
azine-1,4(3H)-dione (17a)52,53 (Scheme 2). There was no
evidence for the presence of the 2,2-bis(2,3-benzoxazine-1,4-
dione)propane 18 or bis-acetoneoxime phthalate 19 (Table 2).
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Two methyl singlets (52:48) appeared in the 1H NMR
spectrum at δ 2.60 and 2.58, respectively. Compound 16a
decomposed to give 17a (98%) and N-hydroxyphthalimide
(20) (2%) when it was heated under nitrogen at 130 °C for 1 h.
Continued heating for an additional 2 h at 130 °C yielded 20
(99%) and 17a (1%) (Scheme 3). Attempts to purify 16a by
Table 3. Thermal Decomposition of 3-(1-Methylethenyl)-
1H-2,3-benzoxazine-1,4(3H)-diones (16) in Refluxing
a
MeCN/Water Solutions
t1/2 (min) (r2)
concn
neutral
conditions
acidic
conditions
basic
d
a
b
c
compound (M × 103)
conditions
e
f
f
16a
4.9
4.6
4.3
135 (0.993)
38 (0.978)
9 (0.999)
Scheme 3. Thermal Decomposition of 16
e
f
f
16b,c
16d,e
480 (0.984)
50 (0.982)
10 (0.996)
f
f
f
57 (0.998)
40 (0.998)
35 (0.991)
a
The solutions were prepared by dissolving 0.020 g of each compound
b
in 20 mL of the appropriate solvent system. MeCN/water (70:30).
c
d
MeCN/water/chloroacetic acid (68:29:3). MeCN/water/pyridine
e
f
(67:29:4). Zero-order reaction. First-order reaction.
sets of compounds under the different decomposition
conditions. All of the r2 values are high, indicating a high
probability for a linear correlation. Alkaline and acidic
conditions enhanced the rate of decomposition, with basic
conditions having a more pronounced effect. Overall the three
compounds were most stable under neutral conditions and least
stable under alkaline conditions. Under neutral conditions the
order of stability of the three compounds appears to parallel
their expected hydrophilicities. Factors such as polarity,
hydrogen bonding, hydrophilicity, acid−base interactions, and
other factors might make contributions to the observed relative
rates. We will not speculate on the relative importance of these
factors among the three compounds. However, it is important
to emphasize that compounds 16 have N-alkenyl substituents
on a resonance-stabilized amide type of nitrogen, so it is not
surprising that these compounds did not show behavior
consistent with those of enamines. Enamines would be
expected to be more stable under alkaline and neutral
conditions and less stable under acidic conditions.
Reactions exhibiting zero-order kinetics are relatively
uncommon. This order is most often observed in photo-
chemical reactions, heterogeneous reactions, and enzyme-
catalyzed reactions.56 Heterogeneous reactions involving a
solid catalyst and enzyme-catalyzed reactions are found to be
first order with respect to the catalyst or enzyme and zero order
with respect to the substrate. This is because the rate of these
reactions is determined by the concentration of the catalyst or
enzyme, provided that the substrate is in sufficient excess. The
zero-order rates exhibited by 16a and 16b,c are significantly
slower than those of the first-order reactions. These
compounds are less reactive than 16d,e under neutral
conditions, implying different mechanisms. A plausible
explanation for the zero-order reactions is that they occurred
by catalysis on active sites on the surface of their glass reaction
containers, and the number of these active sites was relatively
small compared to the concentration of the compounds. In
contrast, the first-order reactions are spontaneous thermally
induced reactions. They are enhanced under acid or base
catalysis or in the case of 16d,e by the electron-releasing
methoxy group.
recrystallization from hot cyclohexane led to partial conversion
to 17a, and this continued each time the recrystallization was
repeated. The formation of 17 by the thermal decomposition of
16 represents an improved and efficient method for its
formation compared to the previously reported synthetic
route.52,53 It has an advantage in that the loss of the N-alkenyl
substituent of 16 occurs under neutral and relatively mild
thermolytic conditions, so the use of acid, base, or high
temperature is avoided. Thus acetone oxime appears to be a
good reagent for converting phthaloyl chlorides to 17. It should
be noted that compounds 17 cannot be prepared directly from
15 and hydroxylamine; N-hydroxyphthalimide is formed
instead.52−54
Compound 16a was found to be stable in absolute EtOH/
CH2Cl2 (80:20) at room temperature for 30 h. A solution (4.9
× 10−2 M) of 16a in MeCN/water (75:25) at room
temperature showed virtually no decomposition after 1 h and
slight decomposition to 17a (8%) after 10 h as shown by
HPLC analysis. The decompositions were much more rapid
when the solution was heated at reflux, giving 17a (93%) and
20 (7%) after 1 h and 17a (7%) and 20 (89%) after 10 h. The
decomposition behavior observed in the refluxing solvent
system was very similar to that observed from heating 16a at
130 °C under N2. This suggests that the decompositions
occurred by the same mechanism under the two different
conditions.
The relative stabilities of 16a, 16b,c, and 16d,e were
compared in refluxing MeCN/water solutions under neutral
conditions [MeCN/water (70:30)], acidic conditions [MeCN/
water/chloroacetic acid (68:29:3)], and basic conditions
[MeCN/water/pyridine (67:29:4)]. The reactions were moni-
tored by HPLC, and data were taken at 15 min intervals.
Kinetic plots of concn vs time, ln concn vs time, and 1/concn
vs time were made to determine the reaction orders. The
kinetic plots showed that under the neutral conditions 16a and
16b,c decomposed by zero-order kinetics, whereas 16d,e
decomposed by first-order kinetics. All of the compounds
decomposed by first-order kinetics under the acidic and basic
conditions.55 Table 3 shows the decomposition half-lives and
the square of the linear correlation coefficients (r2) for the three
It is likely that either propyne or allene was evolved during
the decompositions. Attempts to form a mercuric derivative of
the evolved gas by the procedure of Johnson and McEwen gave
a solid whose melting point indicated that dipropynyl mercury
might be present.57 When 0.3 mmol of 16b,c was allowed to
stand at 70 °C for 1 h in a sealed IR gas cell, no IR discernible
absorptions were observed. However, when the gas cell was
kept at 70 °C for 24 h, 13% decomposition occurred, and a
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FTIR spectrum identical to that of pure acetone vapor was
obtained. There was no evidence for the presence of either
propyne or allene. In a separate experiment 16a was allowed to
decompose in a sealed flask that was first purged with nitrogen
at room temperature for 1 h and then evacuated to 55 Torr.
The flask was submerged in an oil bath maintained at 125 °C
while 16a partially decomposed over 30 min. After cooling, a
volume of the headspace gas was removed and analyzed by
GC−MS. In addition to atmospheric gases only acetone was
observed to be present.
certainty how the acetone was formed, its presence is consistent
with the loss of a three-carbon atom fragment from 16a. In the
catalyzed decomposition reactions carried out in MeCN/water,
the presence of pyridine would serve to enhance the rate of β-
elimination from 21A or 21B by offering a competing pathway
for its occurrence. The presence of chloroacetic acid would
allow for the formation of 16A by β-elimination via 22.
The reaction between 7a and butanedioyl chloride (23) in
the presence of triethylamine was investigated to determine if
the 3-alkenyl-2,3-oxazine-1,4-dione (25) would be produced.
Neither the 3-alkenyl-2,3-oxazine-1,4-dione (25) nor the N-
unsubstituted bis-2,3-2H-1,2-oxazine-3,6-dione (26) was
formed (Scheme 5). The bis-dimethylketoximyl butanedioate
The decomposition of 16a can be depicted as an intra-
molecular β-elimination of either propyne from 21A or allene
from 21B (Scheme 4). In terms of thermodynamic stability
Scheme 4. Decomposition Modes of 3-(1-Methylethenyl)-
Scheme 5. Reaction of Butanedioyl Chloride and 7a
1H-2,3-benzoxazine- 1,4(3H)-diones
(24) was formed instead. Compound 23 apparently reacted in
its preferred anti conformation. The initially formed monoester
did not undergo cyclization but underwent diesterification to
yield 24. Diacid chlorides having carbon chains longer than four
carbons would also be expected to give diesterified products.
Scheme 6 suggests the reaction pathways that are followed in
the reactions that we have investigated involving acetone oxime
with diacid chlorides. Initial reaction between 27 and 7a gives
the monoxime ester 28, which can either lose methyl hydrogen
to triethylamine and undergo ring closure to 30 or react with a
second molecule of 7a to form 29. When X corresponds to one
disubstituted sp3 hybridized carbon atom or ortho-disubstituted
aromatic carbons, 30 is produced. In the former instance the
reactions are sensitive to the size of the substituents both at
position-2 of the malonyl chlorides and on the oxime. When X
corresponds to two (and presumably more than two) sp3
hybridized carbons, dioxime esters 29 are formed. Compounds
30 are thermally unstable and spontaneously decompose at
varying rates with loss of propyne and possibly allene to yield
31. Once formed compounds 31 can add to 30 to produce 32.
This can occur under the reaction conditions or after 30 has
been isolated as shown by the conversion of 13a to 14a.
Compounds 32 are stable. The production of 32 does not
occur in the reactions involving phthaloyl chlorides.
propyne is expected to preferentially form because its
experimental heat of formation is more favorable by 5.5−5.6
kJ/mol than that of allene.58,59 Although difficulties have been
experienced in obtaining accurate C−H bond dissociation
energies of simple alkanes and alkenes, the C−H bond
dissociation energy of ethylene is reported to be 91−116 kJ/
mol greater than that of the allylic C−H bond of propene at
298 K.60,61 No experimental values for bond dissociation
energies for the vinyl C−H bonds of propene have been
published, but ab initio STO-3G calculations have suggested
that the bond dissociation energies of the vinylic CH2 bonds of
propene are within a few percent of the ethylene value.62−64
These bond dissociation energy values argue for the preferred
formation of allene via 21B provided that the decomposition is
governed by kinetic control. It is well established that propyne
and allene exist as an equilibrium mixture. At 298 K the
equilibrium constant (Keq) for the isomerization of allene to
propyne is 24.74.63 This corresponds to a gas phase mixture
containing 96.1% propyne and 3.9% allene. In the decom-
positions carried out in the refluxing solvent systems and at 130
°C equilibrium was probably established fairly rapidly, and if
allene was initially or partially formed, it likely isomerized
quickly to propyne. It is possible that the acetone was formed
by hydration of propyne (or allene) with water that was
adsorbed on the surface of the glass. Glasses are known to
contain dissolved hydroxyl species and water.65−68 Propyne and
other alkynes are known to react with hydroxyl radical at 253−
343 K by an addition mechanism.69,70 Alkenes can also be
hydrated in the gas phase.71−73 Although it is not known with
EXPERIMENTAL SECTION
■
General Procedure for the Reaction of Dialkylmalonyl
Chlorides (6) with Oximes (7). To a solution of 25 mmol of
oxime (7 or 12) and 75 mmol of Et3N in 70 mL of anhydrous Et2O at
0 °C was added dropwise over 15 min 25 mmol of dialkylmalonyl
chloride (6). The reaction mixture was allowed to warm to rt and then
stirred under N2 for 20 h. The white precipitate was filtered, and the
filtrate was washed with HCl (10%, 3 × 25 mL) and then dried
(MgSO4). The Et2O solution was dried (MgSO4) and evaporated
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Scheme 6. Reaction Pathways Followed in the Reaction of Diacid Chlorides with Oximes
under reduced pressure. The residue was purified by column
chromatography over silica gel (230−400 mesh) using hexane/
EtOAc (97:3).
C14H24NO3 254.1757, found 254.1766; HRMS m/z [M + K]+ calcd
for C25H42N2O6K 505.2674, found 505.2676. Reaction of 20 mmol of
diacid chloride using inverse addition gave 1.39 g, 30% of 9d.
4,4-Dibutyl-3,5-isoxazolidinedione (10d). Reaction of 18 mmol
of diacid chloride gave a colorless viscous liquid: yield 0.46 g, 12%;
230−400 mesh silica gel (hexane/EtOAc (80:20)); IR (neat) 1817,
1737 cm−1; 1H NMR (300 MHz; CDC13) δ 10.25 (br s, 1H), 1.84 m,
4H), 1.30 (m, 8H), and 0.89 (t, 6H); 13C NMR (75 MHz; CDCI3) δ
13.6, 22.5, 26.6, 35.1, 51.5, 174.3, 176.0; HRMS m/z [M + Na]+ calcd
for C11H19NO3Na 236.1263, found 236.1248; HRMS m/z [M + K]+
calcd for C11H19NO3K 252.1003, found 252.0985. Reaction of 20
mmol of diacid chloride using inverse addition gave 0.73 g, 17% of
10d.
4,4-Diethyl-2-(1-phenylethenyl)-3,5-isoxazolidinedione (8e).
Reaction of 20 mmol of diacid chloride gave a colorless viscous liquid:
yield 2.32 g, 45%; 60−200 mesh silica gel (CHCl3/hexane (98:2)) or
50 cm ODS-2 HPLC column (MeCN/water (60:40)); IR(neat)
1816(s), and 1721(s) cm−1 (s); 1H NMR (60 MHz; CDC13) δ 7.30 (s
overlapping a small m, 5H), 5.47 (s, 1H), 5.34 (s, 1H), 1.83 (q, 4H),
and 0.91 (t, 6H); MS m/z (rel intensity) 259 (44), 215 (48), 199 (85),
108 (89) and 106 (100); HRMS m/z [M]+ calcd for C15H17NO3
259.1208, found 259.1209. Anal. Calcd for C15H17NO3: C, 69.48; H,
6.61; N, 5.40. Found: C, 69.64; H, 6.91; N, 5.04.
4,4-Dipropyl-2-(1-methylethenyl)-3,5-isoxazolidinedione
(8c). Reaction of 27 mmol of diacid chloride gave a colorless oil: yield
1
1.35 g, 22%, IR (neat) 1821, 1726, 1641 cm−1; H NMR (300 MHz;
CDC13) δ 5.02 (s, 1H), 4.60 (s, 1H), 2.21 (s, 3H), 1.82 (m, 4H), 1.31
(m, 4H) and 0.92 (t, 6H); 13C NMR (75 MHz; CDCI3) δ 13.8, 18.0,
19.6, 37.9, 53.1, 100.3, 136.4, 167.7, 172.2; HRMS m/z [M + H]+
calcd for C12H20NO3 226.1444, found 226.1446; HRMS m/z [M +
Na]+ calcd for C12H19NO3Na 248.126, found 248.126. Reaction of 25
mmol of diacid chloride using inverse addition gave 1.56 g, 28% of 8c.
2,2′-(1-Methylethylidene)bis[4,4-dipropyl-3,5-isoxazolidine-
dione] (9c). Reaction of 27 mmol of diacid chloride using inverse
addition gave a colorless viscous liquid which solidified on standing:
yield 1.54 g, 28%; mp 74−76 °C (LB pet ether); IR (neat) 1817 (s),
1738 cm−1 (s); 1H NMR (300 MHz; CDC13) δ 2.09 (s, 6H), 1.74 (m,
8H), 1.31 (m, 8H), and 0.92 (t, 12H); 13C NMR (75 MHz; CDCI3) δ
13.9, 17.9, 25.7, 37.7, 53.2, 78.8, 170.5, 171.9; HRMS m/z [M + K]+
calcd for C21H34N2O6K 449.2055, found 449.2037. Anal. Calcd for
C21H34N2O6: C, 61.44; H, 8.35; N, 6.82. Found: C, 61.37; H, 8.24; N,
6.71. Reaction of 25 mmol of diacid chloride using inverse addition
gave 0.90 g, 18% of 9c.
4,4-Dipropyl-3,5-isoxazolidinedione (10c). Reaction of 27
mmol of diacid chloride gave a colorless viscous liquid: yield 0.25 g,
5%; IR (neat) 1817, 1738 cm−1; 1H NMR (300 MHz; CDC13) δ 8.54
(br s, 1H), 1.80 (m, 4H), 1.31 (m, 4H), and 0.92 (t, 6H); 13C NMR
(75 MHz; CDCI3) δ 13.8, 17.9, 37.4, 51.6, 174.6, 175.7; HRMS m/z
[M + Na]+ calcd for C9H15NO3Na 208.0950, found 208.0948.
Reaction of 25 mmol of diacid chloride using inverse addition gave
0.50 g, 11% of 10c.
2,2′-(1-Phenylethylidene)bis[4,4-diethyl-3,5-Isoxazolidine-
dione] (9e). Reaction of 20 mmol of diacid chloride gave white
crystals that precipitated from the crude product mixture: yield 0.66 g,
16%; mp 143−145 °C (LB pet ether); IR (Nujol) 1760(s) and
1
1672(s) cm−1; H NMR (60 MHz, CDC13) δ 7.43 (m, 5H), 3.75 (s,
3H), 2.03 (q, 4H), 1.63 (q, 4H), 1.06 (t, 6H), and 0.47 (t, 6H); MS
m/z (rel intensity) 260 (3) (M − C7H17NO3), 247 (45), 246 (100),
219 (52), and 105 (99); HPLC purity (254 nm, Partisil 10, hexane/
EtOAc (80:20): 99.6%.; HRMS m/z [M − C7H17NO3]+ calcd for
C15H18NO3 260.1286, found 260.1286.
4,4-Dibutyl-2-(1-methylethenyl)-3,5-isoxazolidinedione
(8d). Reaction of 20 mmol of diacid chloride using inverse addition
gave a colorless viscous liquid: yield 1.12 g, 22%; IR (neat) 1820, 1728,
1
1642 cm−1; H NMR (300 MHz; CDC13) δ 5.04 (s, 1H), 4.60 (s,
4,4-Dipropyl-2-(1-phenylethenyl)-3,5-isoxazolidinedione
1H), 2.22 (s, 3H), 1.83 (m, 4H), 1.28 (m, 8H) and 0.90 (t, 6H); 13C
NMR (75 MHz; CDCI3) δ 13.7, 19.6, 22.5, 26.6, 35.7, 53.0, 100.3,
136.5, 167.8, 172.2; HRMS m/z [M + H]+ calcd for C14H24NO3
254.1751, found 254.1755; HRMS m/z [M + Na]+ calcd for
C14H23NO3Na 276.156, found 276.158.
(8f). Reaction of 22 mmol of diacid chloride gave a colorless viscous
1
liquid: yield 1.14 g, 18%; IR (neat) 1817, 1737 cm−1 (s); H NMR
(300 MHz; CDC13) δ 7.39 (s overlapping a small m, 5H), 5.56 (s,
1H), 5.44 (s, 1H), 1.87 (m, 4H), 1.40 (m, 4H), and 0.96 (t, 6H); 13C
NMR (75 MHz; CDCI3) δ 13.9, 18.3, 38.1, 53.0, 109.1, 126.7, 128.5,
129.4, 133.1, 139.7, 169.0, 172.5; HRMS m/z [M + H]+ calcd for
C17H21NO3H 288.1601, found 288.1617; HRMS m/z [M + Na]+
calcd for C17H21NO3Na 310.1420, found 310.1498.
O,O′-(2,2-Dipropyl-1,3-dioxo-1,3-propanediyl)-E,E′-dioxime
1-Phenylethanone (11f). Reaction of 22 mmol of diacid chloride
gave a white solid: yield 1.87 g, 40%; mp 104−105 °C (absolute
EtOH); IR (Nujol) 1778, 1755 cm−1 (s); 1H NMR (300 MHz;
CDC13) δ 7.75 (m, 4H), 7.43 (m, 6H), 2.34 (s, 6H), 2.09 (m, 4H),
2,2′-(1-Methylethylidene)bis[4,4-dibutyl-3,5-isoxazolidine-
dione] (9d). Reaction of 18 mmol of diacid chloride gave a colorless
viscous liquid that solidified on standing: yield 1.70 g, 40%; mp 67−68
1
°C (LB pet ether); IR (neat) 1822, 1735 cm−1 (s); H NMR (300
MHz; CDC13) δ 2.10 (s, 6H), 1.79 m, 8H), 1.30 (m, 16H), and 0.89
(t, 12H); 13C NMR (75 MHz; CDCI3) δ 13.6, 22.6, 25.7, 26.5, 35.4,
53.0, 78.8, 170.5, 171.8; HRMS m/z [M + H]+ calcd for C25H43N2O6
467.3116, found 467.3105; HRMS m/z [M − C11H18NO3]+ calcd for
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1.40 (m, 4H), and 0.99 (t, 6H); 13C NMR (75 MHz; CDCI3) δ 14.4,
14.5, 17.5, 35.1, 57.2, 127.1, 128.6, 130.8, 134.5, 163.8, 168.5. Anal.
Calcd for C25H30N2O4: C, 71.07; H, 7.14; N, 6.63. Found: C, 70.98;
H, 7.14; N, 6.51.
6- and 7-Methyl-1H-2,3-benzoxazine-1,4(3H)-dione (17b)
and (17c). A mixture (52:48) of 16b and 16c weighing 1.91 g (8.8
mmol) was exposed to the atmosphere at rt for 2 weeks. Analysis of
the solid by HPLC showed 33% decomposition of the alkene mixture,
The solid was stirred in 20 mL of cold CHCl3 for 15 min and filtered
to yield a mixture of 17b and 17c as a white solid: yield 0.48 g, 31%;
mp 188−194 °C dec (CHCl3); IR (Nujol) 1759 (s), 1659 (s) cm−1;
1H NMR (300 MHz; acetone-d6) δ 7.78−8.08 (m, 6H), 2.60 (d, 3H)
2-(1-Cyclohexenyl)-4,4-diethyl-3,5-isoxazolidinedione (13a).
Reaction of 20 mmol of diacid chloride gave 3.4 g of an unstable
brown oil; yield 62%, initial yield gradually decomposed to 2% after 72
h by HPLC; ODS-2 using H2O/MeCN (40:60) at 254 nm; IR(neat)
1
1817 (s), 1728 (s) cm−1; H NMR (60 MHz, CDC13) δ 5.96 (m, br,
and 2.58 (s, 3H); 13C NMR (75 MHz; DMSO-d6) δ 17.1, 17.4, 116.7,
119.1, 120.3, 121.4, 121.5, 122.8, 124.3, 124.6, 130.9, 132.5, 140.9,
142.9, 154.5, 154.6, 157.5, and 157.8. The peak integration ratio of the
1H)), 2.6 (m, 4H), 2.1−1.4 (m, 8H), and 0.90 (t, 6H).
1,l-Bis(2-(4,4-Diethyl-3,5-isoxazolidinedione)cyclohexane
(14a). Reaction of 20 mmol of diacid chloride gave a white crystalline
solid that precipitated over 72 h from the product mixture: yield 1.38
g, 35%; mp 102−103 °C (HB pet ether); IR (Nujol) 1810(s) and
1715 cm −1 (s); 1H NMR (300 MHz; CDC13) δ 2.60 (br t, 4H), 1.86
(m, 8H), 1.69 (m, 4H), 1.57 (m, 2H), and 0.95 (t, 12H); 13C NMR
(75 MHz; CDCl3) δ 9.1, 22.3, 24.4, 28.7, 33.6, 54.5, 82.5, 70.2, 171.9;
MS m/z (rel intensity) 238 (66%) (M − C7H10NO3), 193 (10%), 164
(11%), 98 (26%), 97 (57%), 95 (100%). HRMS m/z [M −
C7H10NO3]+ calcd for C13H20NO3 238.1443, found 238.1444. Anal.
Calcd for C20H30N2O6: C, 60.89; H, 7.67. Found: C, 60.91; H, 7.62.
1,l-Bis(2-(4,4-Diethylisoxazolidine-3,5-dione)cyclopentane
(14b). Reaction of 20 mmol of diacid chloride gave a white crystalline
solid precipitated over 24 h from the crude product mixture: yield 0.62
g, 16%; mp 100−101 °C (LB pet ether); IR (Nujol) 1810 (s) and
1
two H NMR methyl singlets at δ 2.60 and 2.58, respectively, was
52:48. Anal. Calcd for C9H7NO3: C, 61.01; H, 3.99; N, 7.91. Found:
C, 60.74; H, 3.73; N, 7.68.
6- and 7-Methoxy-3-(1-methylethenyl)-1H-2,3-benzoxazine-
1,4(3H)-dione (16d) and (16e). Reaction of 11 mmol of diacid
chloride gave a white crystalline solid: yield 0.77 g, 30%; 100−200
mesh silica gel (CH2Cl2); mp 93−105 °C; IR (Nujol) 1747, 1656
1
cm−1; H NMR (300 MHz; CDCI3) δ 7.20−8.13 (m, 6H), 5.39 (s, 1
H), 5.37 (s, 1 H), 5.13 (s, 1 H), 5.11 (s, 1 H), 3.89 (s, 3H), 3.87 (s,
3H), 2.12 (s, 6H); 13C NMR (75 MHz; CDCl3) δ 18.8, 18.9, 55.1,
55.2, 109.1, 110.2, 111.1, 111.4, 111.5, 114.9, 120.9, 122.0, 122.6,
124.3, 129.1, 130.7, 131.5, 138.8, 154.7, 154.9, 158.5, 158.9, 162.9,
1
164.6; MS m/z (rel intensity) 233 (0.3), 189 (39), 55 (100). The H
NMR peak integration ratio of the two methoxy singlets at δ 3.89 and
3.87, respectively, was 52:48. Anal. Calcd for C12H11NO4: C, 61.60; H,
4.76; N, 6.01. Found: C, 61.56; H, 4.63; N, 5.64.
−1
1
1715 cm (s); H NMR (300 MHz; CDC13) δ 2.63 (m, 4H), 2.2−
1.5 (m, 12H), and 0.95 (t, 12H). Anal. Calcd for C19H28N2O6: C,
59.98; H, 7.42; N, 7.37. Found: C, 59.75; H, 7.35; N, 7.29.
General Procedure for the Preparation of the 3-(1-
Methylethenyl)-1H-2,3-benzoxazine-1,4(3H)-diones (16). In a
three-neck flask fitted with an addition funnel and a condenser was
prepared a solution containing acetone oxime (7a) (20 mmol) and
Et3N (60 mmol) in 70 mL of anhydrous Et2O. The flask was swept
with N2, and the solution was chilled in an ice−water bath to 0 °C with
stirring. To the cold solution was added dropwise over a 15 min period
20 mmol of the phthaloyl chloride (15) in 50 mL of anhydrous Et2O.
The solution was stirred at rt under N2 for 24 h. The white precipitate
was filtered, and the filtrate was washed with HCl (10%, 3 × 50 mL)
and then dried (MgSO4). The filtrate was concentrated to give crude
16. Purification by column chromatography over silica gel gave pure
16.
Reaction of 1,4-Butanedioyl Chloride (23) with Acetone
Oxime (7a). A solution of 1.83 g (25 mmol of acetone oxime (7a) in
50 mL of anhydrous Et2O was cooled to 0 °C with stirring. To the
solution was added 5.1 g (50 mmol) of Et3N in 40 mL of dry ether. A
solution of 3.9 g (25 mmol) of 1,4-butanedioyl chloride (23) was
added dropwise over 15 min with stirring. The mixture was stirred at rt
for 24 h. The mixture was filtered, dried (MgSO4), and concentrated
under reduced pressure to give a tan solid. Chromatography over silica
gel (60−200 mesh) with EtOAc (100%) yielded O,O′-(1,4-dioxo-1,4-
butanediyl)dioxime 2-propanone (24) as a pale yellow oil that
solidified on standing: yield 1.05 g (37%); mp 60−63 °C (CCl4/HB
1
petroleum ether (2:1)); IR (Nujol) 1765 (s) cm−1 (s); H NMR (60
MHz, CDC13) δ 2.8 0 (s, 4H), 2.08 (s, 6H), 2.03 (s, 6H); HRMS m/z
[M − C3H6NO]+ calcd for C7H10NO3 156.0060, found 156.0060.
Anal. Calcd for C10H16N2O4: C, 52.62; H, 7.07; N, 12.28. Found: C,
52.37; H, 7.35; N, 12.05.
Stability of 3-(1-Methylethenyl)-1H-2,3-benzoxazine-1,4-
(3H)dione (16a). Thermal Stability. A 0.50 g portion of 15a was
heated under N2 for 1 h at 130 °C to yield a mixture of 17a (98%) and
N-hydroxyphthalimide (20) (2%): mp 231−232 °C. Heating 15a for 3
h at 130 °C yielded a mixture of 20 (99%) and 17a (1%): mp 233−
234 °C (dec). (lit. mp 232−133 °C74)
In Absolute EtOH for 30 h. A solution of 0.20 g of 16a in 15 mL of
absolute EtOH/CH2Cl2 (80:20) was allowed to stand at rt for 30 h.
The solution was concentrated to give unchanged 16a.
3-(1-Methylethenyl)-1H-2,3-benzoxazine-1,4(3H)-dione
(16a). Reaction of 20 mmol of diacid chloride gave a white crystalline
solid: yield 3.02 g, 74%; 60−200 mesh silica gel (CHCl3); mp 102−
103 °C; IR (Nujol) 1748, 1667 cm−1; 1H NMR (300 MHz; CDCI3) δ
7.8−8.4 (m, 4H), 5.40 (s, 1 H), 5.18 (s, 1 H), 2.2 (s, 3H); HRMS m/z
[M]+ calcd for C11H9NO3 203.0582, found 203.0585. Anal. Calcd for
C11H9NO3: C, 65.02; H, 4.46; N, 6.89. Found: C, 64.80; H, 4.62; N,
6.82. Compound 16a gradually decomposed to 17a over several
months when stored in a capped vial at room temperature.
1H-2,3-Benzoxazine-1,4-dione (17a). Recrystallization of crude
11a (see above) from cyclohexane and then CHCl3 gave 17a as a
white crystalline solid: yield 0.37 g, 11%; mp 231−232 °C (lit. mp 226
°C52); IR (Nujol) 1760(s), 1685(m) cm−1; 1H NMR (300 MHz;
CDCI3) δ 7.95 (m); HRMS m/z [M]+ calcd for C8H5NO3 163.0269,
found 163.0266. Anal. Calcd for C8H5NO3: C, 58.89; H, 3.09; N, 8.59.
Found: C, 58.89; H, 3.19; N, 8.45.
In MeCN/Water (75:25) at rt. A 4.9 × 10−2 M solution containing
0.50 g of 16a in 50 mL of MeCN/water (75:25) was stirred at rt for 1
h. The MeCN was removed under reduced pressure, and the aqueous
solution was extracted with CHCl3 (2 × 50 mL). The CHCl3 washings
were dried (MgSO4) and concentrated to give unchanged 16a. A
separate reaction was carried out for 10 h under the same conditions
to give a white fluffy solid: mp 101−105 °C. Analysis by HPLC
showed 8% decomposition.
6- and 7-Methyl-3-(1-methylethenyl)-1H-2,3-benzoxazine-
1,4(3H)-dione (16b) and (16c). Reaction of 20 mmol of diacid
chloride gave a white crystalline solid: yield 3.78 g, 76%; 230−400
mesh silica gel (EtOAc/LB petroleum ether (5:95)); mp 70−110 °C;
In Refluxing MeCN/Water (75:25). A 4.9 × 10−2 M solution
containing 0.50 g of 16a in 50 mL of MeCN/water (75:25) was heated
at reflux for 1 h with stirring. Upon cooling to rt the MeCN was
removed under reduced pressure, and the remaining aqueous solution
was extracted with CHCl3 (2 × 25 mL). The CHCl3 washings were
dried (MgSO4) and concentrated to give a mixture containing 17a
(93%) and 20 (7%) as shown by HPLC analysis. A separate reaction
was carried out under the same conditions for 10 h to give a mixture
containing 17a (7%) and 20 (89%).
1
IR (Nujol) 1747, 1664 cm−1; H NMR (300 MHz; CDCI3) δ 7.64−
8.21 (m, 6H), 5.49 (s, 1 H), 5.48 (s, 1 H), 5.24 (s, 1 H), 5.23 (s, 1 H),
2.58 (s, 3H), 2.56 (s, 3H), 2.21 (s, 6H); 13C NMR (75 MHz; CDCI3)
δ 19.8, 19.9, 22.1, 22.2, 112.4, 112.9, 121.1, 122.0, 128.2, 128.8, 129.6,
130.0, 130.2, 130.3, 135.0, 135.3, 140.0, 140.2, 147.5, 147.8, 156.2,
156.6, 159.9, 160.4; MS m/z (rel intensity) 217 (0.1), 173 (33), 55
(100). Anal. Calcd for C12H11NO3: C, 66.35; H, 5.11; N, 6.45. Found:
C, 66.13; H, 5.23; N, 6.33. The 1H NMR peak integration ratio of the
two methyl singlets at δ 2.58 and 2.56, respectively, was 58:42.
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Stability of 3-(1-Methylethenyl)-1H-2,3-benzoxazine-
1,4(3H)-diones (16a) in Refluxing MeCN/Water (70:30). General
Procedure for the Determination of the Relative Stabilities of
16a and mixtures of 16b and 16c and 16d and 16e. A solution
of 0.020 g (0.10 mmol) of 3-(1-methylethenyl)-2,3-benzoxazine-l,4-
dione (16a) in 20 mL of MeCN/water (70:30) was heated under
reflux for 90 m. A small aliquot was removed every 15 min and
analyzed by reverse phase HPLC using a solvent system of MeCN/
water (70:30), a flow rate of 2.0 mL/min, and a detector wavelength of
280 nm. The peak areas were corrected for the weight response factors
of the components. In a similar manner the decomposition of 16a in
refluxing MeCN/water/chloroacetic acid (68:29:3) and in refluxing
MeCN/water/pyridine (67:29:4) were carried out. Also studied in
each of the three refluxing solvent systems were a mixture of 16b and
16c (58:42) and a mixture of 16d and 16e (52:48).
Analysis of the Gas Evolved during Thermal Decomposition
of 3-(1-MethyletHenyl)-1H-2,3-benzoxazine-l,4(3H)-dione
(16a). Preparation of Mercuric Derivative. A procedure similar to
that of Johnson and McEwen was used.57 An ethanolic solution of the
gas evolved in the thermal decomposition of 16a at 130 °C was treated
with aqueous alkaline mercuric iodide with stirring for 10 m. The
precipitate was removed by suction filtration to yield a yellow-green
powder: mp 190−210 °C partial melting. Johnson and McEwen
reported that dipropynyl mercury melted at 203−204 °C.57
(4) Izydore, R. A.; Hall, I. H.; Woodard, T.; Daniels, D. L.; Debnath,
M. L.; Simlot, R.; Wong, O. T.; Elsourady, H. Pharm. Res. 1995, 21, 24.
(5) Hall, I. H.; Izydore, R. A.; Barnes, B. J.; Wang, F.; Warren, A. E.;
Barnes, C. R.; Coleman, D. E.; White, C.; Frazier, F. E. Recent Res. Dev.
Lipids Res. 1997, 1, 297.
(6) Hall, I. H.; Izydore, R. A.; Zhou, X.; Daniels, D. L.; Woodard, T.;
Debnath, M. L.; Tse, E.; Muhammad, R. A. Arch. Pharm. 1997, 330,
67.
(7) Hall, I. H.; Barnes, B. J.; Ward, E. S.; Wheaton, J. R.; Warren, A.
E.; Izydore, R. A. Arch. Pharm. Med. Chem. 2001, 334, 109.
(8) Hall, I. H.; Izydore, R. A.; Simlot, R.; Wong, O. T. Experimentia
1992, 48, 383.
(9) Richon, A. B.; Maragoudakis, M. E.; Wasvary, J. S. J. Med. Chem.
1982, 25, 745.
(10) Druzgala, P.; Milner, P. G. PCT Int. Appl. 2002, WO
2002024689 A1 20020328 CAN 136:257265 AN 2002: 240766.
(11) Shibata, T.; Matsui, K.; Yonemori, F.; Wakitani, K. Eur. J.
Pharmacol. 1999, 373, 85.
(12) Shibata, T.; Matsui, K.; Nagao, K.; Shinkai, H.; Yonemori, F.;
Wakitani, K. Eur. J. Pharmacol. 1999, 364, 211.
(13) Shibata, T.; Matsui, K.; Yonemori, F.; Wakitani, K. Br. J.
Pharmacol. 1998, 125, 1744.
(14) Shinkai, H.; Onogi, S.; Tanaka, M.; Shibata, T.; Iwao, M.;
Wakitani, K.; Uchida, I. J. Med. Chem. 1998, 41, 1927.
(15) Jadhav, R.; Gupta-Rajoria, R.; Pal, T.; Subramanian, R. C. Med.
Chem. 2013, 9, 104.
FTIR Analysis of the Gas Evolved during Thermal Decomposition.
The gas evolved during the thermal decomposition of 16a at 130 °C
was collected in an IR gas cell and sealed: FTIR 2932 (w), 1737 (m),
1441(w), and 1365 (w) cm−1. The FTIR spectrum was identical with
that obtained with vaporized acetone.
(16) Procter, G.; Nally, J.; Ordsmith, N. H. R. Tetrahedron 1995, 51,
12837.
GC−MS Headspace Analysis of the Gas Evolved during Thermal
Decomposition. A 250 mL three-neck round-bottom flask was
charged with 0.30 g (1.5 mmol) of 16a. The flask was purged with
N2 for 1 h. The pressure was reduced to 55 Torr, and the sealed flask
was submerged in an oil bath heated to 125 °C. Gas was evolved over
30 min. The flask was allowed to cool, and a sample of the headspace
gas was analyzed by GC−MS. The gas was found to contain 5%
acetone plus atmospheric components.
(17) Nally, J.; Ordsmith, N. H. R.; Procter, G. Tetrahedron Lett. 1985,
26, 4107.
(18) Silvestri, L. G.; Hill, L. R. J. Bacteriol. 1965, 90, 136.
(19) Keller-Schierlein, W.; Mertens, P.; Prelog, V.; Walser, A. Helv.
Chim. Acta 1965, 48, 710.
(20) Hurd, C. D.; Buess, C. M.; Bauer, L. J. Org. Chem. 1954, 19,
1140.
(21) Zinner, G.; Ruthe, V.; Hitze, M.; Vollrath, R. Synthesis 1971, 3,
148.
ASSOCIATED CONTENT
(22) Zinner, G.; Ruthe, V. Justus Liebigs Ann. Chem. 1975, 11, 2006.
(23) Krenzer, J. Substituted phenyl benzoxazine dione compounds.
U.S. Patent 3,541,092, November 17, 1970.
■
S
* Supporting Information
NMR spectra and kinetic plots. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rizydore@durhameagle.com.
(28) Waisser, K.; Perina, M.; Kunes, J.; Klimesova, V.; Kaustova. J.
Farmaco 2003, 58, 1137.
Present Address
(29) Waisser, K.; Hladuvkova, J.; Gregor, J.; Rada, T.; Kubicova, L.;
Klimesova, V.; Kaustova, J. Arch. Pharmazie 1998, 331, 3.
(30) Petrlikova, E.; Waisser, K.; Divisova, H. P.; Vrabcova, P.; Kunes,
J.; Karel, K.; Stolarikova, J. Biorg. Med. Chem. 2010, 18, 8178.
(31) Waisser, K.; Matyk, J.; Kunes, J.; Skaba, P.; Kaustova, J. Folia
Pharm. Univ. Carol. 2010, 38, 31.
†Durham Eagle LLC, 2602 Oberlin Dr., Durham, NC 27705
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(32) Waisser, K.; Matyk, J.; Kunes, J.; Dolezal, R.; Kaustova, J.;
Dahse, H.-M. Arch. Pharm. 2008, 341, 800.
■
The authors thank the National Institutes of Health, National
Institute for General Medical Sciences Minority Biomedical
Research Support Program (NIH-NIGMS-MBRS) for support
of this investigation.
(33) Waisser, K.; Matyk, J.; Divisova, H.; Husakova, P.; Kunes, J.;
Klimesova, V.; Palat, K.; Kaustova, J. Arch. Pharm. 2007, 340, 264.
(34) Waisser, K.; Perina, M.; Kaustova. Folia Pharm. Univ. Carol.
2003, 29−30, 35.
(35) Waisser, K.; Holy, P.; Bures, O.; Kunes, J.; Kaustova, J. Ceska
Slov. Farm. 2003, 52, 42.
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