Reaction of Ph3P(SCN)2 with further orthohydroxy carboxylic acid systems, including substituted β-keto acids: Synthesis of novel 2-thio-1,3-oxazines and their subsequent transformation with amines

Article abstract of DOI:10.1080/00397910802267204

We now report the first reaction of Ph3P(SCN)2 with 4,6-dihydroxy-5- methylisophthalic acid to give 10-methyl-2,8-dithio-1,3-oxazino-1,3-benzoxazine- 4,6-dione. Also, the enol tautomer has been utilized in the reaction of β-keto acids with Ph3P(SCN)2 to give novel 2-thio-1,3-oxazines. Subsequent reaction of the 2-thio-1,3-oxazines with benzylamine resulted in opening of the oxazine ring and gave novel dibenzylamino-enamides, which could be cyclized to thiouracils. The reaction of 2-thio-1,3-oxazines with morpholine at low temperature led to the production of unstable 2-Mercapto-2-morpholino-1,3- oxazines. 2-Mercapto-2-morpholin-4-yl-2,3,5,6,7,8-hexahydro-4H-1,3-benzoxazin-4- one was observed to lose H2S at room temperature to give 2-morpholin-4-yl-5,6,7, 8-tetrahydro-4H-1,3-benzoxazin-4-one, which was subsequently tested and found to exhibit some antiplatelet activity. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802267204

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Reaction of Ph3P(SCN)2
with Further Orthohydroxy
Carboxylic Acid Systems,
Including Substituted β-Keto
Acids: Synthesis of Novel 2-
Thio-1,3-oxazines and Their
Subsequent Transformation
with Amines
Kaylene M. Pritchard a & Jasim Al-Rawi a
a School of Pharmacy and Applied Science, La Trobe
University, Bendigo, Australia
Published online: 31 Oct 2008.
To cite this article: Kaylene M. Pritchard & Jasim Al-Rawi (2008): Reaction of
Ph3P(SCN)2 with Further Orthohydroxy Carboxylic Acid Systems, Including Substituted
β-Keto Acids: Synthesis of Novel 2-Thio-1,3-oxazines and Their Subsequent
Transformation with Amines, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:23, 4076-4096
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Synthetic Communications1, 38: 4076–4096, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802267204
Reaction of Ph3P(SCN)2 with Further
Orthohydroxy Carboxylic Acid Systems,
Including Substituted b-Keto Acids: Synthesis of
Novel 2-Thio-1,3-oxazines and Their Subsequent
Transformation with Amines
Kaylene M. Pritchard and Jasim Al-Rawi
School of Pharmacy and Applied Science, La Trobe University, Bendigo,
Australia
Abstract: We now report the first reaction of Ph3P(SCN)2 with 4,6-dihydroxy-5-
methylisophthalic acid to give 10-methyl-2,8-dithio-1,3-oxazino-1,3-benzoxazine-
4,6-dione. Also, the enol tautomer has been utilized in the reaction of b-keto acids
with Ph3P(SCN)2 to give novel 2-thio-1,3-oxazines. Subsequent reaction of the 2-
thio-1,3-oxazines with benzylamine resulted in opening of the oxazine ring and
gave novel dibenzylamino-enamides, which could be cyclized to thiouracils. The
reaction of 2-thio-1,3-oxazines with morpholine at low temperature led to the
production of unstable 2-Mercapto-2-morpholino-1,3-oxazines. 2-Mercapto-2-
morpholin-4-yl-2,3,5,6,7,8-hexahydro-4H-1,3-benzoxazin-4-one was observed to
lose H2S at room temperature to give 2-morpholin-4-yl-5,6,7,8-tetrahydro-4H-
1,3-benzoxazin-4-one, which was subsequently tested and found to exhibit some
antiplatelet activity.
Keywords: Dicarboxylic acid, b-keto acids, 2-morpholino-1,3-oxazines, 2-thio-1,
3-oxazines, thiouracils
Received January 21, 2008.
Address correspondence to Jasim Al-Rawi, School of Pharmacy and Applied
Science, La Trobe University, P.O. Box 199, Bendigo, Australia 3552. E-mail:
j.al-rawi@latrobe.edu.au
4076

Synthesis and Transformation of 2-Thio-1,3-oxazines
INTRODUCTION
4077
The reaction of 2-hydroxy benzoic acids with Ph3P(SCN)2 to give 2-thio-
1,3-benzoxazines has been reported earlier in our work[1] and also by
others.[2] However, the reaction of other orthohydroxy carboxylic acid
systems with Ph3P(SCN)2 is not covered in the literature. The synthesis
of new 2-thio-1,3-oxazine analoges using the aid of Ph2P(SCN)2 is
therefore one area that can be explored further.
Previously reported methods for the synthesis of 2-thio-1,3-oxazines 1
have been limited and have included the reaction of diketen and
ammonia thiocyanate[3] and later the reaction of diketen and N,N-
dimethylthiourea,[4] but the difficulty of producing other diketens[4] meant
that only the 6-methyl-2-thio-1,3-oxazine 1a (Fig. 1) could be easily
prepared in this way.
The subsequent reaction of 1a with amines has also had little cover-
age in the literature. One reaction that has been reported, however, is the
synthesis of 1-substituted-6-methylthiouracils from 1a and primary
amines.[5] Uracil derivatives have immense biological significance[6] and
have been used as precursors for an array of biologically significant
molecules.[7–9] Structurally similar 1,3-oxazine-2,4-diones and their
N-alkyl derivatives have also reportedly been reacted with primary
amines to give uracil derivatives,[4,10–13] with one group suggesting that
the reaction proceeds via a 6-hydroxy intermediate.[11] The reaction of
6-methyl-1,3-oxazine-2,4-dione with aryl amines, however, saw the
isolation of an open-chain urea derivative (with a mixture of imine and
enamine tautomers), which was reported as an intermediate in uracil
synthesis.[13]
Our earlier work has reported an efficient method for the produc-
tion of 2-thio-1,3-benzoxazines using Ph3P(SCN)2.[1] In this article, we
have extended our previously reported method[1] to include the use
of 4,6-dihydroxy-5-methylisophthalic acid 2 for the synthesis of
10-methyl-2,8-dithio-1,3-oxazino-1,3-benzoxazine-4,6-dione 3 and the
use of b-keto acids 4 for the synthesis of new 2-thio-1,3-oxazines 1.
Figure 1. 6-Methyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1a.

4078
K. M. Pritchard and J. Al-Rawi
Scheme 1. Preparation of dicarboxylic acid 2 from 2-methylresorcinol 8.
It has also been shown in past work that the 2-mercapto tautomer of
2-thio-1,3-benzoxazines can provide a good leaving group for the reac-
tion with morpholine to give antiplatelet 2-morpholino-1,3-benzoxazine
compounds.[14,15] Additionally, the reaction of 2-thio-1,3-benzoxazines
with benzylamine has been found to lead to the opening of the oxazine
ring between position 1 and 2.[14] This work explores the reaction of
2-thio-1,3-oxazines 1 with morpholine to produce 2-morpholino-1,3-
oxazine 5, as well as the reaction of 1 with benzylamine to produce
dibenzylamino-enamides 6 and subsequent thiouracils 7.
RESULTS AND DISCUSSION
In our earlier work, we reported the carboxylation of 2-methylresorcinol
8 to give 2,4-dihydroxy-3-methylbenzoic acid 9 (Scheme 1) which was
then cyclized to the corresponding 2-thio-1,3-benzoxazine.[1] The carbox-
ylation reaction of 2-methylresorcinol 8, however, can also be found to
give 4,6-dihydroxy-5-methylisophthalic acid 2 (Scheme 1) as a minor
product.
The reaction of dicarboxylic acid 2 with Ph3P(SCN)2 was attempted
to see if it would be possible to cyclize both orthohydroxy acid groups to
give the 1,3-oxazine ring structure on either side of the aromatic ring.
Scheme 2. Preparation of dicarboxylic acid 2 from 2-methylresorcinal 9.

Synthesis and Transformation of 2-Thio-1,3-oxazines
4079
Scheme 3. Synthesis of adipic acid 10 from ethyl 2-oxocyclopentanecarboxylate.
A reaction was carried out using the conditions outlined earlier[1] with the
ratio of reagent to acid increased to 2.5:1 to ensure cyclization would
occur on both sides of the molecule (Scheme 2). On completion of the
reaction and subsequent workup, the 10-methyl-2,8-dithio-1,3-oxazino-
1,3-benzoxazine-4,6-dione 3 was isolated.
The synthesis of other 2-thio-1,3-oxazines 1 was also carried out
using b-keto acids 4 as the starting material. In general, the b-keto acids
4 were prepared from their corresponding esters according to two sepa-
rate methods, which were modified from previously reported proce-
dures.[16,17] It is interesting to note, however, that the hydrolysis of
ethyl 2-oxocyclopentane-carboxylate to give the corresponding b-keto
acid 4d required a decreased concentration of NaOH. With increased
NaOH concentration, the formation of adipic acid 10 was favored in a
retro Dieckmann reaction (Scheme 3).
Once isolated, the b-keto acids 4a–h were then allowed to react
with Ph3P(SCN)2 according to our earlier reported method[1] to give
substituted 2-thio-1,3-oxazines 1a–h (Scheme 4).
With the successful synthesis of the 2-thio-1,3-oxazines 1, their
reaction with amines (morpholine and benzylamine) was then explored.
Our results showed that the reaction of 2-thio-1,3-oxazines 1 with
Scheme 4. Compounds 4 and 1; a; R ¼ CH3, R1 ¼ H; b, R ¼ CH2CH3, R1 ¼ H; c,
R ¼ CH2CH2CH3, R1 ¼ H; d, R=R1 ¼ (CH2)3; e, R=R1 ¼ (CH2)4; f, R ¼ CH3,
R1 ¼ CH2 Ph; g, R ¼ CH3, R1 ¼ CH3; h, R ¼ Ph, R1 ¼ H. Note: Numbering is
not according to the IUPAC convention.

4080
K. M. Pritchard and J. Al-Rawi
morpholine requires much milder reaction conditions than those
employed for the synthesis of 2-morpholino-1,3-benzoxazines.[15] The
reaction of 2-thio-1,3-oxazine 1a with morpholine did not give the
expected 2-morpholino product when heated in dioxane and instead gave
the 4-morpholinecarbothioamide 11.
When compounds 1e–g were allowed to react with morpholine while
being cooled in ice, nucleophilic attack of morpholine took place on C-2
without any observed loss of H2S to give the 2 mercapto-2-morpholino-
1,3-oxazine analog 12 (Scheme 5).
After an attempt to recrystallize 12a from toluene, the 4-morpholine-
carbothioamide 11 was again isolated. This suggested that the
2-mercapto intermediate 12 was forming first during the reaction of 1
with morpholine. If the reaction was not kept cool, decomposition
occured, leading to the formation of the unstable keten 13 and the 4-mor-
pholinecarbothioamide 11 (Scheme 5). The keten 13 was not isolated.
The 2-morpholino-1,3-oxazine 5 was isolated after 12a was allowed to stir
in chloroform at room temperature for 48 h (Scheme 6).
1
When observing the H NMR of 12b and 12c, it was possible with
time to see the degradation of the 2-mercapto-2-morpholine oxazines.
However, multiple degradation products were seen for 12b and 12c,
and we were not able to isolate their corresponding 2-morpholino-1,3-
oxazine derivative of 5. It is also interesting to note that it was only pos-
sible to isolate a pure sample of 12 when the starting 2-thio-1,3-oxazine 1
was substituted (other than H) at both C-5 and C-6. When 1b (R1¼H)
was allowed to react with morpholine in a similar manner, a solid was
isolated, but it could not be precisely identified because the 1H and
Scheme 5. Formation of 2-mercapto analog 12 followed by decomposition to give
the keten 13 and 4-morpholinecarbothioamide 11. Compounds 1 and 12; a,
R=R1 ¼ (CH2)4; b, R ¼ CH3, R1 ¼ CH2Ph; c, R ¼ CH3, R1 ¼ CH3.

Synthesis and Transformation of 2-Thio-1,3-oxazines
4081
Scheme 6. Loss of H2S from compound 12a to give 2-morpholino compound 5.
Note: Numbering is not according to the IUPAC convention.
13C NMR showed rapid decomposition at room temperature to multiple
products.
We also wanted to pursue the reaction of 2-thio-1,3-oxazines 1
with benzylamine. Therefore, we attempted the synthesis of 1-benzyl-
thiouracil 7b by heating 1e to reflux with benzylamine in acetic acid
for 4 h according to the earlier method.[13] No product could be isola-
ted from this reaction, and the evolution of H2S could be detected
throughout the reaction. Applying excess benzylamine directly to the
2-thio-1,3-oxazine 1 and leaving it to stand at room temperature for
2 days was also tried, according to our earlier reported method.[15] It
was observed, however, that upon addition of the excess benzylamine
to the 2-thio-1,3-oxazine 1, heat was evolved as the oxazine began to dis-
solve in the amine, and as a result no product was isolated from these
reactions. One exception was noted when 1e was allowed to stand at
room temperature with excess benzylamine: the dibenzylamino 6d was
isolated.
When we cooled the 2-thio-1,3-oxazines 1a–c, e–g before the addition
of benzylamine (2 equivalents) and then stirred it at room temperature in
dichloromethane overnight, the dibenzylamino analogs 6a–f were iso-
lated (Scheme 7). One exception was observed when 6-phenyl oxazine
1h was allowed to react in a similar manner with benzylamine and a
monobenzylamino product was isolated 14 (Scheme 7).
The reaction between 2-thio-1,3-oxazine 1e and benzylamine was
also attempted in an equimolar ratio, but the resulting solid contained
the dibenzylamino product 6d and some unreacted 1e. Furthermore, we
investigated whether the production of H2O, as the dibenzylamino
compound 6 is formed, would have any influence on the reaction yield.
˚
Consequently we performed one reaction with the inclusion of a 4 A
molecular sieve but found that no improvement in yield was achieved,
suggesting that the production of water does not influence the outcome.
The purified dibenzylamino analogs 6a, d–f were heated to reflux in acetic
acid for 2 h and gave the thiouracil 7a–d (Scheme 7). When 14 was heated

4082
K. M. Pritchard and J. Al-Rawi
Scheme 7. Compound 6; a, R ¼ CH3, R1 ¼ H; b, R ¼ CH2CH3, R1 ¼ H;
c, R ¼ CH2CH2CH3, R1 ¼ H; d, R=R1 ¼ (CH2)4; e, R ¼ CH3, R1 ¼ CH2Ph;
f, R ¼ CH3, R1 ¼ CH3. Compound 7: a, R ¼ CH3, R1 ¼ H; b, R=R1 ¼ (CH2)4;
c, R ¼ CH3, R1 ¼ CH2Ph; d, R ¼ CH3, R1 ¼ CH3. Note: Numbering is not
according to the IUPAC convention.
to reflux in acetic acid, however, 80% of the monobenzylamino analog 14
was recovered unchanged.
Given that we were able to isolate the dibenzylamino intermediates 6
prior to the formation of the thiouracil 7, it would appear that the
mechanism for the transformation of 2-thio-1,3-oxazines to thiouracils
most closely resembles the mechanism outlined by Singh and co-
workers[13] in their work with 1,3-oxazine-2,4-diones and aryl amines.
1
The H NMR of 6, however, showed that only the enamine tautomer
was present as none of the imine was detected. The isolation of the
dibenzylamino intermediate 6 is also evidence that the formation of the
thiouracil 7 from the reaction of 2-thio-1,3-oxazines 1 with benzylamine
does not proceed via the 6-hydroxy intermediate as was suggested for
6-methyl-1,3-oxazine-2,4-diones.[11]
It is interesting to note that higher yields were observed for 7b–d in
comparison to 7a, which may suggest that the presence of substituent
groups other than hydrogen at C-5 and C-6 positions in the 2-thio-1,3-
oxazine ring 1 might play some part in the progress of the reaction.
The corresponding 2-thio-1,3-oxazines 1e–g, which contained a substitu-
ent other than hydrogen at the C-5 and C-6 positions, were also found to
give a slightly more stable reaction product 12 from their reaction with

Synthesis and Transformation of 2-Thio-1,3-oxazines
4083
morpholine. In particular, it was noticed that 1e, which most closely
resembles the 2-thio-1,3-benzoxazines, gave the most stable reaction
products with both morpholine and benzylamine.
Overall, it appears to be evident from this work that unlike
2-thio-1,3-benzoxazines, the 2-thio-1,3-oxazine compounds 1 require
much milder temperatures for their reaction with amines. However, it
would appear that it is the 2-thio group that is influencing the stability
of the reaction products because the 2-oxo analog yields 1-substituted
uracils[4,10,12,13,18] when heated with primary amines.
With the exception of the 2-mercapto analogs 12, all newly described
compounds were confirmed using CHN microanalysis and IR, 1H NMR,
and 13C NMR spectroscopy. 2-Mercapto analogs 12 were confirmed
1
using IR, H NMR, and 13C NMR spectroscopy. Assignment of the
carbon-13 chemical shifts for C-2 and C-4 of the oxazine rings were made
using the aid of previously reported oxazine ring chemical shifts.[19]
Recorded carbon-13 chemical shifts for the reaction products of 2-thio-
1,3-benzoxazine with morpholine and benzylamine[19] were also used
where appropriate as well as the 13C NMR spectra of the parent esters.[20]
Experimental data for 4-morpholinecarbothioamide 11 agreed with
previously reported literature values.[21]
The structural similarities between the 2-morpholino-1,3-oxazine 5
and our earlier reported antiplatelet 2-morpholino-1,3-benzoxazines[15]
led us to test 5 to see if it would exhibit antiplatelet properties. There-
fore compound 5 was tested in accordance with our earlier reported
methods[15] against both adenosine triphosphate (ADP)- and collagen-
induced platelet aggregation. Although the results of the antiplatelet tests
showed that 5 did exert some inhibition of platelet aggregation, the IC50
values were much higher than that shown for the 2-morpholino-1,3-ben-
zoxazines.[15] Compound 5 was seen to be most active against ADP-
induced platelet aggregation with an IC50 of 98Æ5.0 mM. The IC50 of 5
against collagen-induced platelet aggregation was found to be more than
130 mM.
CONCLUSION
In conclusion, we have shown that further orthohydroxy carboxylic acid
systems including the enol form of b-keto acids can be successfully uti-
lized in the synthesis of 2-thio-1,3-oxazines 1, extending the use of
Ph3P(SCN)2. Furthermore, we have shown that, in the presence of
amines, the 2-thio-1,3-oxazines 1 require much milder reaction conditions
compared to 2-thio-1,3-benzoxazines. The reaction of 2-thio-1,3-oxazine
1 with morpholine gave the unstable 2-mercapto-2-morpholino analog 12,

4084
K. M. Pritchard and J. Al-Rawi
with the successful elimination of H2S from 12a, giving the 2-morpholino
analog 5. The reaction of 2-thio-1,3-oxazines 1 with benzylamine led to
the synthesis of thiouracil 7 via a dibenzylamino intermediate 6.
EXPERIMENTAL
Infrared spectra were obtained using a Perkin-Elmer FT-IR spectro-
1
meter. H NMR and 13C NMR spectra were obtained at 293 K using a
Bruker AC 200 NMR spectrometer with Techmag upgrade at 200 MHz
and 50 MHz, respectively. All 1H and 13C NMR spectral results are
recorded as chemical shifts (d) with chemical shifts recorded in CDCl3
relative to the internal TMS (0 ppm) and 77.0 ppm respectively. Chemical
shifts recorded in d6-DMSO are relative to 2.5 ppm and 39.5 ppm respec-
tively. Chemical shifts recorded in d6-acetone are relative to 2.05 ppm and
29.8 ppm respectively. Microanalysis was measured by CMAS (Chemical
and Microanalytical Services), Australia. Melting-point determinations
were carried out using a Stuart Scientific (SMP3) melting-point appara-
tus, and all melting points are uncorrected. Aldrich silica gel, 200–400
˚
mesh, 60 A, was used for column chromatography. All esters were
purchased from Aldrich Chemical Company and were used as received
(with the exception of ethyl acetoacetate, which was purchased from
BDH Laboratory Supplies and used as received).
Synthesis of 4,6-Dihydroxy-5-methylisophthalic Acid 2
The carboxylation of 2-methylresorcinol 8 as outlined in the earlier
synthesis of 9[1] gave compound 2 (9%) as a minor product after recrys-
tallization from ethanol=water. Mp 174 ꢀC decomp. (loss of CO2
observed above this temperature). Found: C, 50.89; H, 3.75. C9H8O6
requires C, 50.95; H, 3.80%. IR(KBr) 3280–2380w (OH), 1652 (C¼O)
1
cmꢁ1; H NMR (d6-DMSO) d 12.1 (bs, 2H, COOH), 8.2 (s, 1H, H-2),
5.1 (bs, 2H exchangeable with H2O, 2 ꢂ OH), 2.0 (s, 3H, CH3). 13C
NMR (d6-DMSO) d 171.9 (COOH), 164.4 (C-4=C-6), 131.2 (C-2),
111.1 (C-5), 105.0 (C-1=C-3), 7.4 (CH3).
General Methods for the Synthesis of b-Keto Acids
Method 1
A mixture of the appropriate ester (40 mmol) in 1.5 M aq. NaOH (40 mL)
was stirred at ambient temperature overnight. The reaction mixture was

Synthesis and Transformation of 2-Thio-1,3-oxazines
4085
extracted with 3 ꢂ 15 mL of ether, and the aqueous layer was cooled in ice
before the addition of sulphuric acid (3.6 mL) diluted in water (10 mL).
The mixture was saturated with NaCl before being extracted with
4 ꢂ 20 mL of ether. The combined organics were dried over Mg2SO4
before the ether was evaporated off in vacuo at ambient temperature.
The residual ether was removed by freeze drying the resulting oil to give
4a–c, e.
Method 2
A mixture of the appropriate ester (40 mmol) in 1.0 M aq. NaOH (80 mL)
was stirred at ambient temperature overnight in the presence of ethanol
(1–2 mL), which promoted the formation of a homogeneous solution.
The reaction mixture was extracted with 3 ꢂ 20 mL of ether, and the aqu-
eous layer was cooled in ice before being strongly acidified with conc.
HCl. The oily acids (4f and 4g) were extracted from the aqueous layer
using 4 ꢂ 20 mL of ether, and the combined organics were washed with
saturated brine (40 ml) before being dried over Mg2SO4. The ether was
evaporated off in vacuo at ambient temperature, and residual ether was
removed by freeze drying. The precipitated acid (4h) was collected by
vacuum filtration using cold water to wash before being freeze dried.
Note: ethyl 2-oxocyclopentanecarboxylate was allowed to react with
NaOH (0.8 M), in the absence of ethanol, for 4 days at ambient tempera-
ture in a modification to method 2 to give 4d.
Experimental data for the prepared b-keto acids 4 agreed with pre-
viously reported literature values[16,17,22,23] where available. Similarly,
the melting point, IR, 1H NMR, and 13C NMR spectroscopic data
obtained for adipic acid 10 agreed with previously reported data.[24,25]
General Method for the Synthesis of 2-Thio-1,3-oxazines
4,6-Dihydroxy-5-methylbenzene-1,3-dicarboxylic acid 2 or b-keto acids
4a–h were allowed to react with Ph3P(SCN)2 according to the general
method (reported earlier[1] in greater detail) to produce 3 and 1a–h.
Triphenylphosphine dibromide (5 mmol) was weighed out under
nitrogen into a three-necked, round-bottomed flask. Dry dichloro-
methane (20 mL) was then added, and the flask was placed into an ice
bath. The reaction vessel was fitted with a nitrogen gas inlet with bub-
bling tube, calcium chloride drying tube, and a dropping funnel. A sus-
pension of lead thiocyanate (6 mmol) in dry dichloromethane (40 mL)
was added slowly with stirring, followed by the addition of acid (4 mmol)

4086
K. M. Pritchard and J. Al-Rawi
in dry dichloromethane (20 mL). The mixture was allowed to warm to
room temperature and then stir for 30 min before being heated at reflux
for 3 h. The reaction mixture was filtered, and the filtrate evaporated off
under reduced pressure. Toluene was used to dissolve any oil, and the
resulting solid was collected by vacuum filtration.
10-Methyl-2,8-dithioxo-2,3,7,8-tetrahydro-4H,6H-[1,3]oxazino[5,6-
g][1,3]benzoxazine-4,6-dione 3
4,6-Dihydroxy-5-methylisophthalic acid 2 (2 mmol) was allowed to react
with Ph3P(SCN)2 according to the conditions outlined previously. On
completion of the reaction, the initial PbBr2 filter cake was collected
and hot filtered using acetone. The acetone filtrate was evaporated to
dryness under reduced pressure, and toluene was used to triturate the
any oil that accompanied the resulting solid. The crude solid was collected
by filtration and recrystallized from 1,4-dioxane to give 3 (39%). Mp
290 ꢀC decomp. Found C, 47.20; H, 3.65; N, 7.24; C11H6N2O4S2 þ 1 mole-
cule of 1,4-dioxane requires C, 47.11; H, 3.69; N, 7.33%. IR(KBr) 3080w
and 2905w (NH), 1737 (C¼O), 1254 (C¼S) cmꢁ1
;
1H NMR (350 K
d6-DMSO) d 8.3 (s, 1H, H-5), 3.4 (bs, 2H, 2 ꢂ NH exchangeable with
H2O), 2.4 (s, 3H, CH3). 13C NMR (350K d6-DMSO) d 180.8 (C-2), 156.9
(C-4), 156.2 (C-10a), 123.2 (C-5), 113.0 (C-10), 112.8 (C-4a), 7.9 (CH3).
6-Methyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1a
3-Oxobutanoic acid 5a was allowed to react with Ph3P(SCN)2 to give 1a
(84%) and recrystallized from toluene. Mp 194 ꢀC decomp. (lit.[26] 201–
203 ꢀC); IR (KBr) 3200w and 3083w (NH), 1722 s and1693s (CO),
1
1247 s (CS) cmꢁ1; H NMR (d6-DMSO) d 13.3 (br s, 1H, NH), 6.1 (s,
1H, H-5), 2.2 (s, 3H, CH3); 13C NMR (d6-DMSO) d 182.8 (C-2), 168.6
(C-4), 158.7 (C-6), 103.4 (C-5), 18.7 (CH3).
6-Ethyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1b
Similarly 3-oxopentanoic acid 5b was allowed to react with Ph3P(SCN)2
to give 1b (83%) and recrystallized from toluene. Mp 148–150 ꢀC; IR
(KBr) 3187w and 3072w (NH), 1684 s (CO), 1293 s (CS) cmꢁ1; 1H NMR
(CDCl3) d 10.6 (br s, 1H, NH), 5.9 (s, 1H, H-5), 2.6 (q, 2H, J¼8.0 Hz,
CH2CH3), 1.3 (t, 3H, J¼8.0 Hz, CH2CH3); 13C NMR (CDCl3)
d 181.7 (C-2), 173.9 (C-4), 159.2 (C-6), 101.6 (C-5), 26.4 (CH2CH3),

Synthesis and Transformation of 2-Thio-1,3-oxazines
4087
10.0 (CH2CH3). Anal. calcd for C6 H7 NO2 S: C, 45.85; H, 4.49; N, 8.91.
Found: C, 45.77; H, 4.45; N, 8.86%.
6-Propyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1c
3-Oxohexanoic acid 5c was allowed to react with Ph3P(SCN)2 to give 1c
(57%) and recrystallized from toluene. Mp 123–126 ꢀC; IR (KBr) 3185w
1
and 3094w (NH), 1703 s and 1678 s (CO), 1259 s (CS) cmꢁ1; H NMR
(CDCl3) d 10.4 (br s, 1H, NH), 5.9 (s, 1H, H-5), 2.5 (t, 2H, J¼8.0 Hz,
CH2C-O), 1.7 (sextet, 2H, J¼8.0 Hz, CH2CH3), 1.0 (t, 3H, J¼8.0 Hz,
CH3); 13C NMR (CDCl3) d 181.7 (C-2), 172.7 (C-4), 159.3 (C-6), 102.4
(C-5), 34.9 (CH2 C-O), 19.3 (CH2CH3), 13.3 (CH3). Anal. calcd for
C7H9NO2 S: C, 49.10; H, 5.30; N, 8.18. Found: 49.19; H, 5.24; N, 8.21%.
2-Thioxo-2,3,6,7-tetrahydrocyclopenta[e][1,3]oxazin-4(5H)-one 1d
Similarly, 2-oxocyclopentanecarboxylic acid 5d was allowed to react with
Ph3P(SCN)2 to give 1d (48%) and recrystallized from toluene. Mp 176–
179 ꢀC decomp.; IR (KBr) 3179w and 3070w (NH), 1685 s (CO), 1220 s
1
(CS) cmꢁ1; H NMR (CDCl3) d 10.1 (br s, 1H, NH), 2.9–2.7 (m, 4H,
CH2CH2CH2), 2.2–2.1 (m, 2H, CH2CH2CH2); 13C NMR (CDCl3) d
182.4 (C-2), 171.8 (C-4), 157.6 (C-6), 115.0 (C-5), 31.2 (CH2C-O), 25.2
(CH2C-C¼O), 19.3 (CH2CH2CH2). Anal. calcd. for C7H7NO2S: C,
49.69; H, 4.17; N, 8.28. Found: 49.71; H, 4.15; N, 8.21%.
2-Thioxo-2,3,5,6,7,8-hexahydro-4H-1,3-benzoxazin-4-one 1e
2-Oxocyclohexanecarboxylic acid 5e was allowed to react with
Ph3P(SCN)2 to give 1e (67%) and recrystallized from toluene. Mp 182–
184 ꢀC; IR(KBr) 3179w and 3079w (NH), 1674 s (CO), 1219 s (CS)
1
cmꢁ1; H NMR (CDCl3) d 10.3 (br s, 1H, NH), 2.5–2.4 [br m, 4H,
(CH2)2], 1.9–1.7 [br m, 4H, (CH2)2]; 13C NMR (CDCl3) d 181.6 (C-2),
166.5 (C-4), 159.2 (C-6), 112.2 (C-5), 26.9 (CH2C-O), 21.3=20.8=20.2
[(CH2)3]. Anal. calcd. for C8H9NO2S: C, 52.44; H, 4.95; N, 7.64. Found:
C, 52.31; H, 4.86; N, 7.59%.
5-Benzyl-6-methyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1f
Similarly, 2-benzyl-3-oxobutanoic acid 5f was allowed to react with
Ph3P(SCN)2 (stirred for 7 h at 0 ꢀC and then allowed to warm to rt overnight

4088
K. M. Pritchard and J. Al-Rawi
before being heated). The crude oil was triturated with ether and gave 1f plus
triphenylphosphine oxide. The crude solid was purified by column chroma-
tography on silica using dichloromethane and ethyl acetate (9:1) as eluent,
which gave the oxazine 1f (60%), and recrystallized from toluene. Mp 136–
138 ꢀC; IR (KBr) 3178w and 3085w (NH), 1672 s (CO), 1237 s (CS) cmÀ1
;
1H NMR (CDCl3) d 10.6 (br s, 1H, NH), 7.3–7.1 (m, 5H, Ar), 3.7 (s, 2H,
CH2Ph), 2.3 (s, 3H, CH3); 13C NMR (CDCl3) d 181.1 (C-2), 165.5 (C-4),
159.4 (C-6), 137.4 (C-Ar), 128.7, 128.2 (CH-Ar-o,m), 126.8 (CH-Ar-p),
114.3 (C-5), 29.6 (CH2Ph), 17.5 (CH3). Anal. calcd. for C12H11NO2S:
C, 61.78; H, 4.75; N, 6.00. Found: C, 61.69; H, 4.70; N, 5.94%.
5,6-Dimethyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1g
2-Methyl-3-oxo-butanoic acid 5g was allowed to react with Ph3P(SCN)2
(2 mmol of acid was used and the reaction was stirred for 6 h at 0 ꢀC, then
allowed to warm to rt overnight before being heated) to give 1g (63%); it
was recrystallized from toluene. Mp 192–194 ꢀC; IR (KBr) 3188w and
3089w (NH), 1708s (CO), 1235s (CS) cmÀ1 1H NMR (d6-acetone)
;
d 11.9 (br s, 1H, NH), 2.3 (s, 3H, 6-CH3), 1.9 (s, 3H, 5-CH3);
13C NMR (d6-acetone) d 183.2 (C-2), 164.4 (C-4), 160.0 (C-6), 111.2
(C-5), 17.1 (6-CH3), 9.4 (5-CH3). Anal. calcd. for C6H7NO2S: C, 45.85;
H, 4.49; N, 8.91. Found: C, 45.90; H, 4.52; N, 8.96%.
6-Phenyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1h
3-Oxo-3-phenylpropanoic acid 5h was allowed to react with Ph3P(SCN)2
(2 mmol of acid was used, and the reaction was stirred for 6 h at 0 ꢀC,
then allowed to warm to rt overnight before being heated) to give 1h
(62%); it was recrystallized from toluene, mp 196–199 ꢀC decomp.; IR
(KBr) 3176w and 3062w (NH), 1679 s (CO), 1256 s (CS) cmÀ1 1H
;
NMR (d6-acetone) d 12.1 (br s, 1H, NH), 8.0–7.9 (m, 2H, CH-Ar-o),
7.7–7.6 (m, 3H, CH-Ar-m,p), 6.7 (s, 1H, H-5); 13C NMR (d6-DMSO) d
182.5 (C-2), 164.3 (C-4), 159.3 (C-6), 132.8 (CH-Ar-p), 129.4, 126.4
(CH-Ar-o,m), 128.7 (C-Ar), 100.6 (C-5). Anal. calcd. for C10H7NO2S:
C, 58.52; H, 3.44; N, 6.82. Found: C, 58.57; H, 3.42; N, 6.81%.
General Method for the Synthesis of 2-Mercapto-2-morpholino-
1,3-oxazines
2-Thio-1,3-oxazine 1 (1 mmol) was dissolved in dry dichloromethane
(2 mL) and cooled in an ice=water bath. Morpholine (1 mmol) in dry

Synthesis and Transformation of 2-Thio-1,3-oxazines
4089
dichloromethane (1 mL) was added dropwise with stirring. The reaction
was continued at 0–5 ꢀC for 2 h, then the solvent was evaporated off in
vacuo (ice=water bath); ether was added to the resulting oil, and the
mixture was left overnight at 4 ꢀC. The precipitated solid was collected
by vacuum filtration and safely stored at 4 ꢀC for several days.
2-Mercapto-2-morpholin-4-yl-2,3,5,6,7,8-hexahydro-4H-
1,3-benzoxazin-4-one 12a
Compound 1e was allowed to react with morpholine (1.25 mmol) according
to the general method to give 12a (70%); IR (KBr) 2540w (SH), 1661 s (CO)
cmꢁ1; 1H NMR (CDCl3) d 5.1 (br s, 2H, NH & SH), 3.8 (t, 4H, J¼4.6 Hz,
H-30), 3.0 (t, 4H, J¼4.6 Hz, H-20), 2.5–2.3 [m, 4H, (CH2)2], 1.9–1.7 [m, 4H,
(CH2)2]; 13C NMR (CDCl3) d 185.4 (C-2), 165.6=165.3 (C-4=C-6), 112.1
(C-5), 65.0 (C-30), 43.9 (C-20), 26.5 (CH2C-O), 21.3=21.1=20.4 [(CH2)3].
5-Benzyl-2-mercapto-6-methyl-2-morpholin-4-yl-2,3-dihydro-4H-1,3-
oxazin-4-one 12b
Similarly 1f was allowed to react with morpholine according to the gen-
eral method to give 12b (56%), IR (KBr) 2455w (SH), 1654 s (CO) cmꢁ1
;
1H NMR (CDCl3) d 7.3–7.2 (m, 5H, Ar), 6.8 (br s, 2H, NH and SH), 3.8
(t, 4H, J¼4.0 Hz, H-30), 3.7 (s, 2H, CH2 Ph), 3.0 (t, 4H, J¼4.0 Hz, H-20),
2.3 (s, 3H, CH3); 13C NMR (CDCl3) d 185.4 (C-2), 165.4=165.3 (C-4=C-6),
138.4 (C-Ar), 128.6, 127.8 (CH-Ar-o,m), 126.4 (CH-Ar-p), 114.1 (C-5),
65.2 (C-30), 44.1 (C-20), 29.9 (CH2 Ph), 17.3 (CH3).
2-Mercapto-5,6-dimethyl-2-morpholin-4-yl-2,3-dihydro-4H-
1,3-oxazin-4-one 12c
Compound 1g was allowed to react with morpholine according to the
general method to give 12c (29%); IR (KBr) 2628w (SH), 1666 s (CO)
cmꢁ1 1H NMR (CDCl3) d 6.4 (br s, 2H, NH and SH), 3.8 (t, 4H,
;
J¼4.8 Hz, H-30), 3.0 (t, 4H, J¼4.8 Hz, H-20), 2.3 (s, 3H, 6-CH3), 1.9 (s,
3H, 5-CH3); 13C NMR (CDCl3) d 185.2 (C-2), 165.5 (C-4), 163.4 (C-6),
110.7 (C-5), 65.3 (C-30), 44.1 (C-20), 16.9 (6-CH3), 9.6 (5-CH3).
Synthesis of 2-Morpholin-4-yl-5,6,7,8-tetrahydro-4H-1,3-
benzoxazin-4-one 5
Compound 12a (0.18 g, 0.67 mmol) was dissolved in chloroform (4 mL)
and stirred at room temperature for 48 h. On completion of the reaction,

4090
K. M. Pritchard and J. Al-Rawi
the chloroform was evaporated off in vacuo, and cyclohexane (25 mL) was
added. The reaction mixture was heated to boiling, and minimal toluene
was added to aid in dissolving of the oily material. The mixture was hot
filtered to a fresh flask containing cyclohexane, leaving a small amount
of oily material still undissolved. The fresh cyclohexane was then concen-
trated down with heat and allowed to cool. Compound 5 crystallized out
of the cyclohexane (27 mg, 17%) as white crystals; mp 132–135 ꢀC (lit.[27]
129–130 ꢀC); IR (KBr) 1686 m (CO), 1559 s (CN) cmꢁ1; 1H NMR (CDCl3)
d 3.8–3.6 (br m, 8H, H-20 & H-30), 2.5–2.3 [br m, 4H, (CH2)2], 1.9–1.7 [m,
4H, (CH2)2]; 13C NMR (CDCl3) d 169.1 (C-2), 159.3 (C-4), 157.2 (C-8a),
113.7 (C-4a), 66.2 (C-30), 44.1 (C-20), 26.1 (C-8), 21.7, 21.0 [(CH2)3].
General Method for the Reaction of 1,3-Oxazines with Benzylamine
2-Thio-1,3-oxazine 1 (1 mmol) was dissolved in dry dichloromethane
(4 mL) and cooled in an ice=water bath. Benzylamine (2 mmol) in dry
dichloromethane (1 mL) was added dropwise with stirring and the reac-
tion mixture was allowed to return to room temperature and stir at ambi-
ent temperature for 18 h. The dichloromethane was evaporated off in
vacuo, and the reaction mixture was triturated with diethyl ether. The
resulting solid was collected by vacuum filtration.
(2Z)-3-(Benzylamino)-N-[(benzylamino)carbonothioyl]but-2-enamide 6a
6-Methyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1a was allowed to
react with benzylamine according to the general method to give 6a
(51%); and recrystallized from abs. EtOH. Mp 116–117 ꢀC; IR (KBr)
1
3264w (NH), 1623 m (CO), 1173 s (CS) cmꢁ1; H NMR (CDCl3) d 11.0
(br s, 1H, H-12), 9.5 (br s, 1H, H-4), 8.0 (br s, 1H, H-10), 7.4–7.2 (m,
10H, Ar), 4.9 (d, 2H, J¼6.0 Hz, H-13), 4.44 (d, 2H, J¼6.0 Hz, H-5),
4.36 (s, 1H, H-2), 2.0 (s, 3H, CH3); 13C NMR (CDCl3) d 180.9 (C-11),
168.7 (C-1), 164.5 (C-3), 137.7=137.0 (C-6=C-14), 128.9, 128.6, 127.7,
127.6, 127.5, 126.6 (CH-Ar), 84.6 (C-2), 49.3 (C-13), 47.0 (C-5), 19.6
(CH3). Anal. calcd. for C19H21N3OS: C, 67.23; H, 6.24; N, 12.38. Found:
C, 67.21; H, 6.26; N, 12.35%.
(2Z)-3-(Benzylamino)-N-[(benzylamino)carbonothioyl]pent-2-enamide 6b
6-Ethyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1b was allowed to
react with benzylamine according to the general method to give 6b

Synthesis and Transformation of 2-Thio-1,3-oxazines
4091
(73%) and recrystallized from abs. EtOH. Mp 128–130 ꢀC; IR (KBr)
1
3216w (NH), 1627 m (CO), 1182 s (CS) cmꢁ1; H NMR (CDCl3) d 11.0
(br s, 1H, H-12), 9.5 (t, 1H, J¼6.4 Hz, H-4), 8.2 (br s, 1H, H-10), 7.4–
7.2 (m, 10H, Ar), 4.9 (d, 2H, J¼5.4 Hz, H-13), 4.5 (d, 2H, J¼6.4 Hz,
H-5), 4.4 (s, 1H, H-2), 2.3 (q, 2H, J¼7.5 Hz, CH2 CH3), 1.1 (t, 3H,
J¼7.5 Hz, CH2CH3); 13C NMR (CDCl3) d 181.0 (C-11), 169.5=169.0
(C-1=C-3), 137.8=137.1 (C-6=C-14), 128.9, 128.7, 127.7, 127.6, 127.5,
126.6 (CH-Ar), 82.7 (C-2), 49.3 (C-13), 46.5 (C-5), 25.4 (CH2CH3),
12.1 (CH2CH3). Anal. calcd. for C20H23N3OS: C, 67.96; H, 6.56;
N, 11.89. Found: C, 68.05; H, 6.60; N, 11.91%.
(2Z)-3-(Benzylamino)-N-[(benzylamino)carbonothioyl]hex-2-enamide 6c
6-Propyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1c was allowed to react
with benzylamine according to the general method to give 6c (48%) and
recrystallized from abs. EtOH. Mp 105–106ꢀC; IR (KBr) 3214w (NH),
1
1628 m (CO), 1172 s (CS) cmꢁ1; H NMR (CDCl3) d 11.0 (br s, 1H,
H-12), 9.5 (br s, 1H, H-4), 8.0 (br s, 1H, H-10), 7.3–7.2 (m, 10H, Ar), 4.9
(d, 2H, J¼5.5 Hz, H-13), 4.44 (d, 2H, J¼6.4 Hz, H-5), 4.37 (s, 1H, H-2),
2.2 (t, 2H, J¼7.7 Hz, CH2CH2CH3), 1.6–1.5 (m, 2H, CH2CH2CH3), 1.0
(t, 3H, J¼7.3Hz, CH3); 13C NMR (CDCl3) d 181.0 (C-11), 168.9=
168.2 (C-1=C-3), 137.9=137.1 (C-6=C-14), 128.8, 128.6, 127.7, 127.6, 127.5,
126.7 (CH-Ar), 83.7 (C-2), 49.3 (C-13), 46.6 (C-5), 34.3 (CH2CH2CH3),
21.2 (CH2CH2CH3), 13.8 (CH3). Anal. Calcd for C21H25N3OS: C, 68.63;
H, 6.86; N, 11.43. Found: C, 68.63; H, 6.96; N, 11.37%.
N-[(Benzylamino)carbonothioyl]-2-(benzylamino)cyclohex-1-ene-1-
carboxamide 6d
2-Thioxo-2,3,5,6,7,8-hexahydro-4H-1,3-benzoxazin-4-one 1e was allowed
to react with benzylamine according to the general method to give 6d
(53%) and recrystallized from abs. EtOH. Mp 115–116 ꢀC; IR (KBr)
1
3442w and 3181w (NH), 1619 m (CO), 1169 m (CS) cmꢁ1; H NMR
(CDCl3) d 11.3 (br s, 1H, H-12), 10.2 (t, 1H, J¼6.1 Hz, H-4), 8.2 (br s,
1H, H-10), 7.3–7.2 (m, 10H, Ar), 4.9 (d, 2H, J¼5.4 Hz, H-13), 4.4 (d,
2H, J¼6.1 Hz, H-5), 2.4–2.2 (bm, 4H, (CH2)2), 1.7–1.5 (bm, 4H,
(CH2)2); 13C NMR (CDCl3) d 181.0 (C-11), 169.3 (C-1), 163.3 (C-3),
138.3=137.0 (C-6=C-14) 128.8, 128.6, 127.7, 127.5, 127.4, 126.6 (CH-
Ar), 88.9 (C-2), 49.4 (C-13), 46.2 (C-5), 26.7 (CH2C-N), 23.9, 22.3, 21.5
[(CH2)3]. Anal. calcd. for C22H25N3OS: C, 69.62; H, 6.64; N, 11.07.
Found: C, 69.56; H, 6.61; N, 11.12%.

4092
K. M. Pritchard and J. Al-Rawi
(2Z)-3-(Benzylamino)-2-benzyl-N-[(benzylamino)carbonothioyl]but-2-
enamide 6e
5-Benzyl-6-methyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1f was allowed
to react with benzylamine according to the general method to give 6e
(70%) and recrystallized from abs. EtOH. Mp 141–143 ꢀC; IR (KBr)
;
3425w and 3170 (NH), 1618 m (CO), 1167 s (CS) cmꢁ1 1H NMR
(CDCl3) d 11.2 (br s, 1H, H-12), 10.7 (br s, 1H, H-4), 8.1 (br s, 1H, H-
10), 7.3–7.2 (m, 15H, Ar), 4.8 (d, 2H, J¼5.3 Hz, H-13), 4.5 (d, 2H,
J¼6.0 Hz, H-5), 3.6 (s, 2H, CCH2Ph), 2.0 (s, 3H, CH3); 13C NMR
(CDCl3) d 181.0 (C-11), 169.5 (C-1), 164.6 (C-3), 138.8=138.0=137.0 (C-
6=C-14=C-Ar), 129.0, 128.9, 128.6, 127.8, 127.6, 127.5, 127.4, 126.9,
126.6 (CH-Ar), 90.5 (C-2), 49.4 (C-13), 47.5 (C-5), 33.0 (CCH2Ph), 16.0
(CH3). Anal. calcd. for C26H27N3OS: C, 72.69; H, 6.34; N, 9.78. Found:
72.70; H, 6.44; N, 9.83%.
(2Z)-3-(Benzylamino)-N-[(benzylamino)carbonothioyl]-2-methylbut-2-
enamide 6f
5,6-Dimethyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1g was allowed
to react with benzylamine according to the general method to give 6f
(69%) and recrystallized from abs. EtOH. Mp 137–138 ꢀC; IR (KBr)
;
3449w and 3178 (NH), 1621 m (CO), 1170 s (CS) cmꢁ1 1H NMR
(CDCl3) d 11.3 (br s, 1H, H-12), 10.5 (br s, 1H, H-4), 8.2 (br s, 1H, H-
10), 7.4–7.2 (m, 10H, Ar), 4.9 (d, 2H, J¼5.5 Hz, H-13), 4.5 (d, 2H,
J¼6.2 Hz, H-5), 2.0 (s, 3H, 3-CH3), 1.9 (s, 3H, 2-CH3); 13C NMR
(CDCl3) d 181.0 (C-11), 169.2 (C-1), 163.1 (C-3), 138.2=136.9 (C-6=
C-14), 128.7, 128.6, 127.6, 127.4, 127.3, 126.5 (CH-Ar), 86.5 (C-2), 49.3
(C-13), 47.2 (C-5), 16.0 (3-CH3), 13.0 (2-CH3). Anal. calcd. for
C20H23N3OS: 67.96; H, 6.56; N, 11.89. Found: C, 68.05; H, 6.63; N,
11.82%.
N-[(benzylamino)carbonothioyl]-3-oxo-3-phenylpropanamide 14
6-Phenyl-2-thioxo-2,3-dihydro-4H-1,3-oxazin-4-one 1h was allowed to
react with benzylamine according to the general method to give 14
(53%) and recrystallized from abs. EtOH. Mp 171–173 ꢀC; IR (KBr)
;
3189w (NH), 1705s (CO), 1677s (CO), 1166s (CS) cmꢁ1 1H NMR
(d6-DMSO) d 11.5 (br s, 0.8H, H-8 keto), 11.3 (br s, 0.2H, H-8 enol),
10.9 (t, 0.8H, J¼5.3 Hz, H-10 keto), 10.8 (br s, 0.2H, H-10 enol), 8.0–
7.3 (m, 10H, Ar), 6.2 (s, 0.2H, H-2 enol), 4.8 (d, 2H, J¼5.3 Hz, H-11),

Synthesis and Transformation of 2-Thio-1,3-oxazines
4093
4.3 (s, 1.8H, H-2 keto); 13C NMR (d6-DMSO) d 194.1 (C-3), 180.2 (C-9),
169.2 (C-1), 137.4=136.0 (C-4=C-12), 134.0 (C-7), 129.0=128.6=128.4=
127.7 (C-5=C-6=C-13=C-14), 127.5 (C-15), 48.0 (C-2 & C-11) [171.3
(C-3 enol) 129.1, 128.4, 127.1, 125.9 (Ar-enol), 89.1 (C-2 enol)]. Anal.
calcd. for C17H16N2O2S: C, 65.36; H, 5.16; N, 8.97. Found: C, 65.28;
H, 5.20; N, 9.03%.
General Method for the Synthesis of Thiouracils
Dibenzylamino compound 6 (0.2 g) was heated to reflux in acetic acid
(3 mL) for 2 h before being cooled, and the acetic acid evaporated off
in vacuo. The oily reaction mixture was triturated with diethyl ether,
and the resulting solid was collected by vacuum filtration and recrystal-
lized from the appropriate solvent.
1-Benzyl-6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one 7a
A suspension of 6a was heated to reflux in acetic acid according to the
general method to give 7a (28%) and recrystallized from abs. EtOH.
Mp 211–212 ꢀC; IR (KBr) 3178w and 3081w (NH), 1654 s (CO),
1
1192 m (CS) cmꢁ1; H NMR (CDCl3) d 9.9 (br s, 1H, NH), 7.4–7.2
(m, 5H, Ar), 5.9 (s, 1H, H-5), 5.7 (s, 2H, H-7), 2.2 (s, 3H, CH3); 13C
NMR (CDCl3) d 178.4 (C-2), 159.4 (C-4), 154.9 (C-6), 134.6 (C-8),
129.1=125.8 (C-9=C-10), 127.9 (C-11), 107.6 (C-5), 53.3 (C-7), 21.3
(CH3). Anal. calcd. for C12H12N2OS: C, 62.04; H, 5.21; N, 12.06. Found:
61.96; H, 5.33; N, 12.15%.
1-Benzyl-2-thioxo-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one 7b
A suspension of 6d was heated to reflux in acetic acid according to the
general method to give 7b (67%) and recrystallized from abs. EtOH.
Mp 241–242 ꢀC; IR (KBr) 3163w and 3059w (NH), 1663 s (CO),
1
1172 s (CS) cmꢁ1; H NMR (CDCl3) d 9.8 (br s, 1H, NH), 7.4–7.2
(m, 5H, Ar), 5.8 (br s, 2H, H-7), 2.6–2.3 [br m, 4H, (CH2)2], 1.8–1.5
[br m, 4H, (CH2)2]; 13C NMR (CDCl3) d 176.7 (C-2), 159.5 (C-4),
151.1 (C-6), 135.0 (C-8), 129.0=125.6 (C-9=C-10), 127.7 (C-11), 116.3
(C-5), 52.6 (C-7), 27.2 (CH2C-N), 22.1, 21.8, 20.2 [(CH2)3]. Anal. calcd.
for C15 H16 N2 OS: C, 66.15; H, 5.92; N, 10.29. Found: C, 66.23; H,
6.07; N, 10.24%.

4094
K. M. Pritchard and J. Al-Rawi
1,5-Dibenzyl-6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one 7c
A suspension of 6e was heated to reflux in acetic acid according to the
general method to give 7c (52%) and recrystallized from methanol. Mp
164–165 ꢀC; IR (KBr) 3160w and 3060w (NH), 1663 s (CO), 1218 m (CS)
1
cmꢁ1; H NMR (CDCl3) d 10.1 (br s, 1H, NH), 7.4–7.2 (m, 10H, Ar), 5.8
(br s, 2H, H-7), 3.8 (s, 2H, CCH2 Ph), 2.2 (s, 3H, CH3); 13C NMR (CDCl3)
d 177.0 (C-2), 159.6 (C-4), 151.6 (C-6), 138.4=134.8 (C-8=C-Ar), 129.1=
128.6=128.0=125.7 (C-9=C-10=CH-Ar-o,m), 127.8=126.5 (C-11=CH-Ar-p),
118.0 (C-5), 54.1 (C-7), 31.1 (CCH2Ph), 17.7 (CH3). Anal. calcd. for
C19H18N2OS: C, 70.78; H, 5.63; N, 8.69. Found: 70.71; H, 5.65; N, 8.75%.
1-Benzyl-5,6-dimethyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one 7d
A suspension of 6f was heated to reflux in acetic acid according to the
general method to give 7d (63%) and recrystallized from methanol. Mp
221–223 ꢀC; IR (KBr) 3161w and 3052w (NH), 1656 s (CO), 1235 m
1
(CS) cmꢁ1; H NMR (CDCl3) d 10.1 (br s, 1H, NH), 7.4–7.2 (m, 5H,
Ar), 5.8 (br s, 2H, H-7), 2.2 (s, 3H, 6-CH3), 2.0 (s, 3H, 5-CH3); 13C
NMR (CDCl3) d 176.7 (C-2), 159.7 (C-4), 149.9 (C-6), 134.9 (C-8),
129.1=125.8 (C-9=C-10), 127.8 (C-11), 114.7 (C-5), 54.2 (C-7), 17.5 (6-
CH3), 11.5 (5-CH3). Anal. calcd. for C13H14N2OS: C, 63.39; H, 5.73;
N, 11.37. Found: C, 63.22; H, 5.74; N, 11.21%.
Platelet Aggregometry
The test compound was dissolved in ethanol, and antiplatelet evaluation
was carried out according to our earlier reported procedure.[15] Platelet
aggregation was determined by the optical method in a two-channel platelet
aggregometer (Chrono-Log). The agonists used were ADP (final concentra-
tion 10 mM) and collagen (final concentration 4mg=mL). The concentration
of the compound at which the aggregation was inhibited by 50% (IC50) was
determined as the average of multiple determinations (three or more) where
platelet aggregation was reduced by 50%. La Trobe University Human
Ethics Committee approval was obtained (HREC Number 06–16).
ACKNOWLEDGMENTS
The authors gratefully acknowledge the financial support of the
Australian Research Council (Australian Postgraduate Award) and La

Synthesis and Transformation of 2-Thio-1,3-oxazines
4095
Trobe University. They also acknowledge the preliminary work carried
out by Jacob Nankervis.
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