Ring closure reactions of β-nitroso-, β-acyl-, and β-thiocarbamoyl-α,β-unsaturated sulfilimines. Synthesis of [1,2,5]oxadiazolo[3,4-d]-, isoxazolo[3,4-d]-, and isothiazolo[3,4-d]pyrimidine derivatives from uracils

Article abstract of DOI:10.1016/S0040-4020(02)01302-9

1,3-Dialkyl-6-chlorouracils were treated with S,S-diphenylsulfilimine to give N-(1,3-dialkyluracil-6-yl)-S,S-diphenylsulfilimines. The uracilylsulfilimines were nitrosated, acylated, or thiocarbamoylated to give N-(5-nitroso-, 5-acyl-, or 5-thiocarbamoyluracil-6-yl)sulfilimines, respectively. These conjugated sulfilimines were cyclized by thermolysis or photolysis to [1,2,5]oxadiazolo[3,4-d], isoxazolo[3,4-d], or isothiazolo[3,4-d]pyrimidine derivatives.

Full text of DOI:10.1016/S0040-4020(02)01302-9

Tetrahedron 58 (2002) 10073–10079
Ring closure reactions of b-nitroso-, b-acyl-,
and b-thiocarbamoyl-a,b-unsaturated sulfilimines.
Synthesis of [1,2,5]oxadiazolo[3,4-d]-, isoxazolo[3,4-d]-,
and isothiazolo[3,4-d]pyrimidine derivatives from uracils
*
Nobuaki Matsumoto and Masahiko Takahashi
Department of Materials Science, Faculty of Engineering, Ibaraki University, Hitachi, Ibaraki 316-8511, Japan
Received 19 August 2002; accepted 7 October 2002
Abstract—1,3-Dialkyl-6-chlorouracils were treated with S,S-diphenylsulfilimine to give N-(1,3-dialkyluracil-6-yl)-S,S-diphenyl-
sulfilimines. The uracilylsulfilimines were nitrosated, acylated, or thiocarbamoylated to give N-(5-nitroso-, 5-acyl-, or 5-thiocarbamoyl-
uracil-6-yl)sulfilimines, respectively. These conjugated sulfilimines were cyclized by thermolysis or photolysis to [1,2,5]oxadiazolo[3,4-d],
isoxazolo[3,4-d], or isothiazolo[3,4-d]pyrimidine derivatives. q 2002 Published by Elsevier Science Ltd.
1. Introduction
1,2,4-oxadiazoles, condensed imidazolones, isothiazoles,
1,2,4-benzoxadiazines, and oxazolinones. In the course of
our studies on synthesis of heterocycles using sulfilimines,
we have found a one-step method for synthesizing 3-alkyl-
Sulfilimines (R1R2S¼NR3) are a class of sulfur ylides that
occupy an interesting area in sulfur chemistry.1 One
interesting chemical behavior of sulfilimines is based on
the nucleophilic nitrogen atom and a good leaving
sulfonium group. This characteristic reactivity has made
sulfilimines attractive intermediates in the synthesis of
heterocyclic compounds, especially when the ylides are
conjugated with unsaturated bonds. Conjugated sulfilimine
systems such as NvC–NvSR2,2 SvC–NvSR2,3 CvC–
5,6-diphenyluracils
from
N-carbamoylsulfilimines
R–NHCONvSR2 and diphenylcyclopropenone.6 The
preparation of heterocycles using more extended conjugated
sulfilimines has also been reported. In an early study on
sulfilimines, Tamura et al. succeeded in the formation of
isoxazoles (2a) from b-acyl-a, b-unsaturated sulfilimine
(1a) by an intramolecular thermal reaction (Scheme 1).7 The
reaction of the nitrogen analogue (1b) similarly proceeded
to give 1,2,4-oxadiazoles (2b).8 Benzimidazoles (2c) and
4
5
NvSR2 and OvC–NvSR2 have been used for the
synthesis of heterocycles such as 1,2,4-triazole 2-oxides,
Scheme 1.
Keywords: sulfilimine; [1,2,5]oxadiazolo[3,4-d]pyrimidine; isoxazolo[3,4-d]pyrimidine; isothiazolo[3,4-d]pyrimidine; uracil.
*
Corresponding author. Tel.: þ81-294-38-5050; fax: þ81-294-38-5078; e-mail: takamasa@mx.ibaraki.ac.jp
0040–4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)01302-9

10074
N. Matsumoto, M. Takahashi / Tetrahedron 58 (2002) 10073–10079
Scheme 2.
other heterocycles were obtained by thermolysis of N-(N-
arylimidoyl)sulfilimines (1c).9 This nature of sulfilimines
led us to attempt ring closure reactions of other new
conjugated systems of sulfilimines. Use of these conjugated
sulfilimines would provide an excellent method for the
synthesis of heterocycles containing a CvN double bond
without using oxidizing or dehydrating agents for cycliza-
tion. Thus, we have prepared useful conjugated systems,
b-nitroso-a, b-unsaturated sulfilimines (3), b-acyl-a, b-
unsaturated sulfilimines (4), and b-thiocarbamoyl-a,
b-unsaturated sulfilimines (5), using uracils and have
found a facile cyclization to the corresponding fused
[1,2,5]oxadiazoles, isoxazoles, and isothiazoles,
respectively.
nitrite in refluxing toluene for 5 min yielded b-nitroso-a,
b-unsaturated sulfilimines (3), a new conjugated system of
sulfilimine, as blue precipitates in 54–86% yields. The
signals of the olefinic protons observed in the H NMR
spectra of 7a–c disappeared in those of 3a–c, thus
indicating that nitrosation occurred at the C-5 position.
1
Classically, 1,2,5-oxadiazoles (furazans) and their deriva-
tives have been prepared15 by (i) cyclodehydration of the
corresponding a-dioximes with thionyl chloride, (ii)
oxidation of aromatic nitroso amines with lead tetraacetate,
and (iii) deoxygenation of the corresponding furoxans using
trialkyl phosphate. However, these methods for the
preparation of 1,2,5-oxadiazole require either toxic metals
or corrosive dehydrating agents. A new method for
synthesizing 1,2,5-oxadiazoles is therefore needed. A
mixture of nitroso sulfilimines (3a–c) in toluene was
refluxed for 6 h. The characteristic blue color of the mixture
disappeared as the reaction proceeded. The products
observed on TLC were the corresponding 1,2,5-oxadiazoles
(8a–c) and diphenyl sulfide, giving good isolated yields
(80–98%). The structures of the products 8 were assigned
on the basis of elemental analysis and MS, IR and 1H NMR
spectra. It is noteworthy that the final fused 1,2,5-
oxadiazoles (8a–c) were prepared in one pot in 53–87%
yields from 7a–c without isolation of the nitroso inter-
mediates (3); isopentyl nitrite was first added to a mixture of
7 in toluene and the mixture was refluxed for 1.5–3.5 h. The
blue color of the nitroso derivatives (3) first appeared and
then faded, showing the formation of the product. The
condensed 1,2,5-oxadiazole (8a) was obtained as a by-
product of oxidation of 6-amino-1,3-dimethyl-5-nitro-
souracil by lead tetraacetate,16 by deoxygenation of
N-oxide of 8a,17 by treatment of 6-acetoxyimino-1,3-
dimethyluracil with sodium nitrite,18 and recently by
oxidation of 6-amino-1,3-dimethyl-5-nitrosouracil with a
combination of iodobenzene diacetate and lithium
hydride.19 Thus, we have shown a new route to this
biologically important class of heterocycles.19
2. Results and discussion
2.1. Preparation and cyclization of N-(5-nitrosouracil-6-
yl)sulfilimines (3)
While there are uarcil derivatives that possess ylide
structures, such as dimethylsulfoxonium methylides10 and
iminophosphoranes,11 at the C-6 position, no uracil
derivatives bearing a sulfilimine moiety have been reported.
We used a simple method for the preparation of uracilyl-
sulfilimines, which involves the reaction of 1,3-dialkyl-6-
chlorouracils (6) with S,S-diphenylsulfilimine. This
N-unsubstituted sulfilimine monohydrate can be readily
obtained by acidic hydrolysis of S,S-diphenyl-N-p-tosyl-
sulfilimine.12 As depicted in Scheme 2, the reaction of
6a–c13 with S,S-diphenylsulfilimine monohydrate in the
presence of triethylamine in refluxing methanol gave solid
sulfilimines (7a,b) in 85 and 61% yields, respectively. The
products were easily isolated by addition of water to the
reaction mixture followed by filtration of the resulting
precipitates. The sulfilimines (7a,b) are stable solids and
storable for months. However, 7c (89% crude yield) is an
unstable solid, which was used in the next step without
further purification.
2.2. Preparation and cyclization of N-(5-acyluracil-6-
yl)sulfilimines (4)
6-Aminouracils behave as enamines, and their nitrosation
occurs readily to give 6-amino-5-nitrosouracil derivatives,
which have been used as starting materials for condensed
uracil derivatives.14 Thus, treatment of 7 with isopentyl
In order to extend the utility of sulfilimine (7a) as a building
block for preparation of nitrogen-containing heterocycles,

N. Matsumoto, M. Takahashi / Tetrahedron 58 (2002) 10073–10079
10075
Scheme 3.
we tried to synthesize isoxazolopyrimidines (11a–d), which
are known to be anti-inflammatory and analgesic agents.20
thermolysis of 6-azidouracils in the presence of poly-
phosphoric acid led either to the formation of oxazolo[5,4-
d]pyrimidine-5,7-diones (by reaction with benzoic acid) via
the nitrene/azirine intermediate or to the formation of
isomeric isoxazolo[3,4-d]pyrimidine-4,6-diones (by reac-
tion with aliphatic carboxylic acids) via the nitrene
intermediates. However, the use of our method provided
only isoxazolo[3,4-d]pyrimidine-4,6-diones in good yields.
As outlined in Scheme 3, b-acyl-a, b-unsaturated sulfili-
mines (4c and d) were prepared by the reaction of 7a with
carboxylic acid chloride in dichloromethane in the presence
of triethylamine at room temperature (75–76%), while 7a
was converted to 4b by heating in acetic anhydride (72%).
The formyl derivative (4a) was obtained from 6-chloro-5-
formyluracil (9) and S,S-diphenylsulfilimine in methanol in
the presence of triethylamine without heating (89%).
Although a solution of b-acyl-a, b-unsaturated sulfilimines
(4a–d) in toluene was refluxed for 20 h, they were
recovered unchanged. However, it was found that sulfili-
mines (4a–d) were almost completely converted to the
expected isoxazolopyrimidines (11a–d) by UV irradiation
for 3–4 h in acetonitrle (54–91%). It has been reported that
some conjugated sulfilimines are cyclized to the same
products by thermolysis or photolysis, indicating the
involvement of nitrene intermediates.9 Thus, it seems to
be easier to generate the nitrene intermediate (10) by UV
irradiation than by heating in this case. Thermolysis of
b-azido-a, b-unsaturated ketones and esters is also known
to give isoxazole derivatives via a nitrene or nitrene/azirine
intermediate.21 Stadlbauer et al.22 recently reported that
2.3. Preparation and cyclization of N-(5-thiocarbamoyl-
uracil-6-yl)sulfilimines (5)
The successful cyclization of 4a–d prompted us to use an
analogous conjugated system, b-carbamoyl-a, b-unsatu-
rated sulfilimines (4e), and a new conjugated system,
b-thiocarbamoyl-a, b-unsaturated sulfilimines (5a–e),
which can readily be prepared by reacting the ylide (7a)
with isocyanate or isothiocyanates (Scheme 4). Although N-
[1,3-dimethyl-5-(N-phenylcarbamoyl)-6-uracilyl] sulfili-
mine (4e) was isolated (88%) and cyclized by photolysis
to the corresponding isoxazolo[3,4-d]pyrimidine (11e)
(18%), the corresponding thiocarbamoyl derivatives
(5a–e) were difficult to isolate. Interestingly, however,
the treatment of 7a with a variety of isothiocyanates in
refluxing toluene yielded isothiazolo[3,4-d]pyrimidine-
Scheme 4.

10076
N. Matsumoto, M. Takahashi / Tetrahedron 58 (2002) 10073–10079
4,6(5H,7H)-diones (12a–e) in one step (52–76%) without
isolation of the intermediates (5). This method has an
advantage over the two-step synthesis of isothiazolo[3,4-
d]pyrimidine-4,6-diones by dithiocarboxylation23 or thio-
carbamoylation24 of 6-aminouracils followed by oxidation.
then cooled to room temperature. After the blue precipitate
was separated by filtration, the resultant solid was purified
by recrystallization from chloroform–hexane to give 3a
(633 mg, 86%) as blue needles, mp 181–1828C. IR (KBr):
3055, 1711, 1662, 1580, 1511, 1475, 1443, 1377, 1352,
1231 cm21. 1H NMR (CDCl3): d 3.26 (s, 3H, N–Me), 3.85
(s, 3H, N–Me), 7.47–7.74 (m, 10H, ArH). MS: m/z (%) 186
(Ph2Sþ, 100), 182 (33), 152 (12). Anal. calcd for
C18H16N4O3S (368.41): C, 58.68; H, 4.38; N, 15.21.
Found: C, 58.58; H, 4.46; N, 15.19.
3. Conclusion
In conclusion, we have developed a simple and efficient
method for preparation of [1,2,5]oxadiazolo[3,4-d]-, isoxa-
zolo[3,4-d]-, and isothiazolo[3,4-d]pyrimidine derivatives
using uracil derivatives bearing sulfilimine (7). The methods
are operationally simple and do not require strict conditions
such as the use of anhydrous solvents or the use of oxidizing
or dehydrating agents.
4.1.4. N-(1,3-Diisopropyl-5-nitroso-6-uracilyl)-S,S-
diphenylsulfilimine (3b). Yield 54%, blue plates, mp
150–1518C (chloroform-hexane). IR (KBr): 2973, 1718,
.
1670, 1579, 1509, 1444, 1338, 1220 cm21 1H NMR
(CDCl3): d 1.40 (d, J¼6.8 Hz, 6H, Me), 1.69 (d,
J¼6.8 Hz, 6H, Me), 5.04–5.08 (m, 1H, N–CH), 5.77–
5.81 (m, 1H, N–CH), 7.45–7.70 (m, 10H, ArH). MS: m/z
(%) 238 (Mþ2186, 12), 197 (13), 186 (Ph2Sþ, 100), 181
(18), 155 (19), 138 (8). Anal. calcd for C22H24N4O3S
(424.53): C, 62.24; H, 5.70; N, 13.20. Found: C, 61.79; H,
5.67; N, 13.58.
4. Experimental
4.1. General
All Melting points were determined on a MRK MEL-TEMP
II and are uncorrected. Infrared spectra were recorded on a
JASCO A-102 and JASCO FT/IR-420 spectrophotometers.
1H NMR data were obtained with a JEOL GSX-400
(400 MHz) instrument and chemical shifts are reported in
ppm downfield from TMS. Mass spectral data were
measured on a JEOL JMS DX-300 spectrometer. Elemental
analyses were performed with YANACO CHN-CODER
MT-5.
4.1.5. N-(1,3-Dicyclohexyl-5-nitroso-6-uracilyl)-S,S-
diphenylsulfilimine (3c). Yield 60%, blue powder, mp
178–1798C (chloroform–hexane). IR (KBr): 3062, 2933,
1
2850, 1706, 1662, 1579, 1517, 1473, 1444 cm21. HNMR
(CDCl3): d 1.16–1.98 (m, 16H, –CH2–), 2.28–2.37 (m,
2H, –CH2–), 2.61–2.64 (m, 2H, –CH2–), 4.61–4.67 (m,
1H, N–CH), 5.39 (br s, 1H, N–CH), 7.26–7.72 (m, 10H,
Ar). MS: m/z (%) 237 (Mþ2267, 59), 186 (Ph2Sþ, 100), 155
(82), 83 (27). Anal. calcd for C28H32N4O3S (504.66): C,
66.64; H, 6.39; N, 11.10. Found: C, 66.33; H, 6.34; N, 11.52.
4.1.1. N-(1,3-Dimethyl-6-uracilyl)-S,S-diphenylsulfili-
mine (7a): typical procedure. A mixture of 6-chloro-1,3-
dimethyluracil13 (1.92 g, 11 mmol), S,S-diphenylsulfilimine
monohydrate (4.42 g, 20 mmol) and triethylamine (2.22 g,
22 mmol) in methanol (10 mL) was refluxed for 5 h and
then cooled to room temperature. After water (20 mL) was
added, the white precipitate was separated by filtration. The
resultant solid was purified by recrystallization from
methanol to give 7a (3.17 g, 85%) as colorless plates, mp
232–2338C. IR (KBr): 3049, 1675, 1626, 1560, 1476, 1442,
1286, 1238 cm21. 1H NMR (CDCl3): d 3.30 (s, 3H, N–Me),
3.60 (s, 3H, N–Me), 4.91 (s, 1H, CvCH), 7.52–7.74 (m,
10H, ArH). MS: m/z (%) 339 (Mþ, 7), 186 (Ph2Sþ, 100).
Anal. calcd for C18H17N3O2S (339.41): C, 63.70; H, 5.05;
N, 12.38. Found: C, 63.72; H, 5.12; N, 12.40.
4.1.6. 4,6-Dimethyl[1,2,5]oxadiazolo[3,4-d]pyrimidine-
5,7(4H,6H)-dione (8a): typical procedure. Method A. A
mixture of 3a (368 mg, 1.0 mmol) in toluene (15 mL) was
refluxed for 6 h and then the solvent was removed under
reduced pressure. After the residue was washed with diethyl
ether, the resultant solid was separated by filtration and
recrystallized from methanol to give 8a (166 mg, 91%) as
colorless plates, mp 222–2238C (lit.16 mp 225–2268C).
Method B. A mixture of 7a (339 mg, 1.0 mmol) and
isopentyl nitrite (140 mg, 1.2 mmol) in toluene (10 mL)
was refluxed for 3.5 h and then the solvent was removed
under reduced pressure. After the residue was washed with
diethyl ether, the resultant solid was separated by filtration
and recrystallized from methanol to give 8a (158 mg, 87%).
4.1.2. N-(1,3-Diisopropyl-6-uracilyl)-S,S-diphenylsulfili-
mine (7b). Yield 61%, colorless plates, mp 193–1948C
(MeOH). IR (KBr): 2967, 1685, 1627, 1560, 1475, 1442,
4.1.7. 4,6-Diisopropyl[1,2,5]oxadiazolo[3,4-d]pyrimi-
dine-5,7(4H,6H)-dione (8b). Yield 80% (Method A) or
54% (Method B), colorless plates, mp 82–838C (MeOH). IR
(KBr): 2979, 2940, 2879, 1693, 1617, 1540, 1455, 1375,
1
1272 cm21. H NMR (CDCl3): d 1.43 (d, J¼7.2 Hz, 6H,
Me), 1.56 (d, J¼7.2 Hz, 6H, Me), 4.79 (s, 1H, CvCH),
5.15–5.19 (m, 1H, N–CH), 5.60 (br s, 1H, N–CH), 7.50–
7.70 (m, 10H, ArH). MS: m/z (%) 395 (Mþ, 10), 286 (30),
244 (10), 201 (10), 186 (Ph2Sþ, 100), 152 (8), 109 (9). Anal.
calcd for C22H25N3O2S (395.53): C, 66.81; H, 6.37; N,
10.62. Found: C, 66.69; H, 6.36; N, 10.84.
1351, 1274, 1216 cm21 1H NMR (CDCl3): d 1.52 (d,
.
J¼6.8 Hz, 6H, Me), 1.55 (s, J¼6.8 Hz, 6H, Me), 5.09–5.16
(m, 1H, N–CH), 5.21–5.24 (m, 1H, N–CH). MS: m/z (%)
238 (Mþ, 46), 197 (48), 181 (95), 155 (100), 138 (37). Anal.
calcd for C10H14N4O3 (238.25): C, 50.41; H, 5.92; N, 23.52.
Found: C, 50.16; H, 5.82; N, 23.27.
4.1.3. N-(1,3-Dimethyl-5-nitroso-6-uracilyl)-S,S-di-
phenylsulfilimine (3a): typical procedure. A mixture of
7a (678 mg, 2.0 mmol) and isopentyl nitrite (281 mg,
2.4 mmol) in toluene (10 mL) was refluxed for 5 min and
4.1.8. 4,6-Dicyclohexyl[1,2,5]oxadiazolo[3,4-d]pyrimi-
dine-5,7(4H,6H)-dione (8c). Yield 98% (Method A) or

N. Matsumoto, M. Takahashi / Tetrahedron 58 (2002) 10073–10079
10077
53% (Method B), white plates, mp 153–1548C (MeOH). IR
(KBr): 2940, 2863, 1729, 1683, 1614, 1538, 1452, 1272,
1187, 1135 cm21. 1H NMR (CDCl3): d 1.23–1.94 (m, 16H,
–CH2–), 2.23–2.43 (m, 4H, –CH2–), 4.67–4.73 (m, 1H,
N–CH), 4.78–4.84 (m, 1H, N–CH). MS: m/z (%) 318 (Mþ,
1), 237 (36), 155 (59), 55 (100). Anal. calcd for C16H22N4O3
(318.38): C, 60.36; H, 6.97; N, 17.60. Found: C, 60.36; H,
6.91; N, 17.39.
(407.49): C, 64.85; H, 5.19; N, 10.31. Found: C, 64.69; H,
5.23; N, 10.34.
4.1.13. N-[1,3-Dimethyl-5-(N-phenylcarbamoyl)-6-ura-
cilyl]-S,S-diphenylsulfilimine (4e). A mixture of 7a
(339 mg, 1.0 mmol) and phenyl isocyanate (413 mg,
3.4 mmol) in toluene (5 mL) was refluxed for 20 h and
then the solvent was removed under reduced pressure. After
the residue was washed with diethyl ether, the resultant solid
was separated by filtration and recrystallized from methanol
to give 4e (403 mg, 88% yield) as white needles, mp 180–
1818C. IR (KBr): 3056, 1693, 1648, 1585, 1538, 1442,
4.1.9. N-(5-Formyl-1,3-dimethyl-6-uracilyl)-S,S-di-
A
mixture of 925 (1.01 g,
phenylsulfilimine (4a).
5.0 mmol), S,S-diphenylsulfilimine monohydrate (1.31 g,
6.0 mmol), and triethylamine (1.01 g, 10.0 mmol) in
methanol (10 mL) was stirred for 1 h and then the
precipitate was separated by filtration. The precipitates
were purified by recrystallization from methanol to give 4a
(1.63 g, 89%) as colorless plates, mp 202–2038C. IR (KBr):
3056, 1702, 1623, 1492, 1440, 1367, 1301, 1213,
1
1359, 1213, 1166 cm21. H NMR (CDCl3): d 3.36 (s, 3H,
N–Me), 3.65 (s, 3H, N–Me), 6.98–7.75 (m, 15H, ArH),
11.57 (s, 1H, NH). MS: m/z (%) 458 (Mþ, 1), 366 (13), 339
(9), 186 (Ph2Sþ, 100), 119 (24). Anal. calcd for
C25H22N4O3S (458.53): C, 65.48; H, 4.84; N, 12.22.
Found: C, 65.19; H, 4.95; N, 12.05.
1070 cm21 1H NMR (CDCl3): d 3.33 (s, 3H, N–Me),
.
3.56 (s, 3H, N–Me), 7.49–7.74 (m, 15H, ArH), 9.71 (s, 1H,
CHO). MS: m/z (%) 367 (Mþ, 1), 258 (12), 186 (Ph2Sþ,
100). Anal. calcd for C19H17N3O3S (367.42): C, 62.11; H,
4.66; N, 11.44. Found: C, 62.11; H, 4.75; N, 11.35.
4.1.14. 5,7-Dimethylisoxazolo[3,4-d]pyrimidine-
4,6(5H,7H)-dione (11a): typical procedure. A solution
of 4a (367 mg, 1.0 mmol) in acetonitrile (60 mL) was
irradiated for 3 h using a high-pressure mercury lamp under
nitrogen atmosphere and then the solvent was removed
under reduced pressure. The resultant residue was chro-
matographed (silica gel, CHCl3–AcOEt¼1:1 as eluent) to
give 11a (165 mg, 91%) as white plates, mp 167–1688C
(MeOH). IR (KBr): 3079, 1679, 1552, 1465, 1428, 1367,
4.1.10. N-(5-Acetyl-1,3-dimethyl-6-uracilyl)-S,S-di-
phenylsulfilimine (4b).
A mixture of 7a (678 mg,
2.0 mmol) and acetic anhydride (10 mL) was refluxed for
1 h and then the solvent was removed under reduced
pressure. After the residue was washed with methanol, the
resultant solid was separated by filtration and recrystallized
from methanol to give 4b (547 mg, 72%) as colorless plates,
mp 189–1908C. IR (KBr): 3054, 2944, 1693, 1633, 1596,
1
1284, 1126, 1060 cm21. H NMR (CDCl3): d 3.39 (s, 3H,
N–Me), 3.54 (s, 3H, N–Me), 8.98 (s, 1H, –CvCH–O–).
MS: m/z (%) 181 (Mþ, 85), 124 (66), 96 (100). Anal. calcd
for C7H7N3O3 (181.15): C, 46.41; H, 3.89; N, 23.20. Found:
C, 46.23; H, 3.91; N, 23.14.
1
1430, 1224, 1160 cm21. H NMR (CDCl3): d 2.40 (s, 3H,
–CO–Me), 3.32 (s, 3H, N–Me), 3.58 (s, 3H, N–Me),
7.38–7.71 (m, 10H, ArH). MS: m/z (%) 381 (Mþ, 1), 339
(6), 195 (19), 186 (Ph2Sþ, 100). Anal. calcd for
C20H19N3O3S (381.45): C, 62.97; H, 5.02; N, 11.02.
Found: C, 62.81; H, 5.08; N, 11.01.
4.1.15. 3,5,7-Trimethylisoxazolo[3,4-d]pyrimidine-
4,6(5H,7H)-dione (11b). Yield 88%, white needles, mp
200–2018C (MeOH) (lit.22 mp 200–2028C). IR (KBr):
2956, 1725, 1679, 1650, 1560, 1508, 1427, 1361, 1297,
1272, 1234 cm21. 1H NMR (CDCl3): d 2.75 (s, 3H, C–Me),
3.36 (s, 3H, N–Me), 3.48 (s, 3H, N–Me). 13C NMR
(CDCl3): d 13.2, 28.0, 30.3, 99.8, 151.0, 157.5, 157.9, 174.6.
4.1.11. N-(5-Benzoyl-1,3-dimethyl-6-uracilyl)-S,S-di-
A mixture of 7a (678 mg,
phenylsulfilimine (4d).
2.0 mmol), benzoyl chloride (322 mg, 2.3 mmol), and
triethylamine (303 mg, 3.0 mmol) in dichloromethane
(10 mL) was stirred for 20 h and then the solvent was
removed under reduced pressure. The resultant residue was
chromatographed (silica gel, CHCl3 as eluent) to give 4d
(665 mg, 75%), white needles, mp 126–1278C (MeOH). IR
(KBr): 3052, 1687, 1623, 1573, 1502, 1430, 1386 cm21. 1H
NMR (CDCl3): d 3.25 (s, 3H, N–Me), 3.71 (s, 3H, N–Me),
7.22–7.59 (m, 15H, ArH). MS: m/z (%) 443 (Mþ, 5), 257
(8), 186 (Ph2Sþ, 65), 105 (100). Anal. calcd for C25H21N3-
O3S·1/2H2O (452.53): C, 66.35; H, 4.90; N, 9.33. Found: C,
66.80; H, 4.98; N, 9.28.
4.1.16. 3-Cyclopropyl -5,7-dimethylisoxazolo[3,4-d]pyri-
midine-4,6(5H,7H)-dione (11c). Yield 54%, white needles,
mp120–1218C (MeOH). IR (KBr): 1727, 1691, 1639, 1519,
1427, 1280, 1020 cm21. 1H NMR (CDCl3): d 1.29–1.33 (m,
2H, CH2), 1.42–1.45 (m, 2H, CH2), 2.67–2.71 (m, 1H,
C–CH–C), 3.36 (s, 3H, N–Me), 3.46 (s, 3H, N–Me). MS:
m/z (%) 221 (Mþ, 70), 164 (14), 136 (8), 107 (8), 69 (100).
Anal. calcd for C10H11N3O3 (221.21): C, 54.29; H, 5.01; N,
19.00. Found: C, 54.17; H, 4.98; N, 18.95.
4.1.17. 5,7-Dimethyl-3-phenylisoxazolo[3,4-d]pyrimi-
dine-4,6(5H,7H)-dione (11d). Yield 78%, yellow needles,
mp 197–1988C (MeOH) (lit.22 mp 197–1988C). IR (KBr):
3062, 1716, 1671, 1616, 1475, 1425, 1371, 1056 cm21. 1H
NMR (CDCl3): d 3.43 (s, 3H, N–Me), 3.55 (s, 3H, N–Me),
7.53–7.59 (m, 3H, ArH), 8.49–8.51 (m, 2H, ArH). 13C
NMR (CDCl3): d 28.6, 30.5, 98.2, 125.5, 128.5, 128.6,
128.9, 132.8, 150.7, 157.2, 158.7, 172.4.
4.1.12. N-(5-Cyclopropyl-1,3-dimethyl-6-uracilyl)-S,S-
diphenylsulfilimine (4c). This compound was prepared in
the similar manner as 4d. Yield 76%, white plates, mp 163–
1648C (MeOH). IR (KBr): 3000, 1691, 1639, 1596, 1479,
1
1430, 1390, 1278, 1209 cm21. H NMR (CDCl3): d 0.73–
0.77 (m, 2H, CH2), 0.87–0.91 (m, 2H, CH2), 3.07–3.11 (m,
1H, C–CH–C), 3.34 (s, 3H, N–Me), 3.59 (s, 3H, N–Me),
7.37–7.67 (m, 10H, ArH). MS: m/z (%) 407 (Mþ, 2), 339
(18), 186 (Ph2Sþ, 100). Anal. calcd for C22H21N3O3S
4.1.18. 5,7-Dimethyl-3-(phenylamino)isoxazolo[3,4-
d]pyrimidine-4,6(5H,7H)-dione (11e). Yield. 18%, yellow

10078
N. Matsumoto, M. Takahashi / Tetrahedron 58 (2002) 10073–10079
powder, mp 235–2368C (MeOH). IR (KBr): 3355, 2927,
1714, 1644, 1596, 1548, 1486, 1446, 1361, 1290 cm21. 1H
NMR (CDCl3): d 3.34 (s, 3H, N–Me), 3.43 (s, 3H, N–Me),
7.20–7.42 (m, 5H, ArH), 8.19 (s, 1H, NH) MS: m/z (%) 272
(Mþ, 100), 243 (6), 215 (18). Anal. calcd for C13H12N4O3
(272.26): C, 57.35; H, 4.44; N, 20.58. Found: C, 57.15; H,
4.53; N, 20.15.
(8), 111 (11). Anal. calcd for C13H11ClN4O2S (322.77):
C, 48.37; H, 3.44; N, 17.36. Found: C, 48.30; H, 3.66; N,
17.48.
References
4.1.19. 5,7-Dimethyl-3-(methylamino)isothiazolo[3,4-
d]pyrimidine-4,6(5H,7H)-dione (12a): typical procedure.
A mixture of 7a (339 mg, 1.0 mmol) and methyl isothio-
cyanate (220 mg, 3.0 mmol) in toluene (3 mL) was refluxed
for 14 h and then the solvent was removed under reduced
pressure. The resultant residue was chromatographed (silica
gel, CHCl3–AcOEt¼1:1 as eluent) to give 12a (133 mg,
59%), mp 196–1978C (MeOH). IR (KBr): 3342, 2950,
1702, 1646, 1592, 1544, 1508, 1452, 1417, 1268 cm21. 1H
NMR (CDCl3): d 3.06 (d, J¼5.2 Hz, 3H, NH–Me), 3.34 (s,
3H, N–Me), 3.52 (s, 3H, N–Me), 7.40 (br s, 1H, NH) MS:
m/z (%) 226 (Mþ,100), 198 (24), 169 (8), 141 (16), 112 (18).
Anal. calcd for C8H10N4O2S (226.26): C, 42.47; H, 4.45; N,
24.76. Found: C, 42.27; H, 4.39; N, 24.89.
1. Reviews: (a) Gilchrist, T. L.; Moody, C. J. Chem. Rev. 1977,
77, 409–435. (b) Koval, I. V. Sulfur Rep. 1993, 14, 149–221.
(c) Taylor, P. C. Sulfur Rep. 1999, 21, 241–280. (d) Lakeev,
S. N.; Maydanova, I. O.; Galin, F. Z.; Tolstikov, G. A. Russ.
Chem. Rev. 2001, 70, 655–672.
2. (a) Gilchrist, T. L.; Harris, C. J.; Hawkins, D. G.; Moody, C. J.;
Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1976, 2166–2170.
(b) Fuchigami, T.; Odo, K. Bull. Chem. Soc. Jpn 1977, 50,
1793–1796. (c) Tomimatsu, Y.; Satoh, K.; Sakamoto, M.
Heterocycles 1977, 8, 109–114.
3. Yoshida, H.; Taketani, H.; Ogata, T.; Inokawa, S. Bull. Chem.
Soc. Jpn 1976, 49, 3124–3127.
4. Gilchrist, T. L.; Harris, C. J.; King, F. D.; Peek, M. E.; Rees,
C. W. J. Chem. Soc., Perkin Trans. 1 1976, 2161–2165.
5. Ketcha, D. M.; Abou-Gharbia, M.; Smith, F. X.; Swern, D.
Tetrahedron Lett. 1983, 24, 2811–2814.
4.1.20. 3-Benzylamino-5,7-dimethylisothiazolo[3,4-
d]pyrimidine-4,6(5H,7H)-dione (12b). Yield 52%, white
needles, mp 170–1718C (MeOH). IR (KBr): 3338, 1695,
1643, 1592, 1542, 1509, 1446, 1243, 1105, 1066 cm21. 1H
NMR (CDCl3): d 3.33 (s, 3H, N–Me), 3.50 (s, 3H, N–Me),
4.43 (d, J¼5.6 Hz, 2H, N–CH2–), 7.26–7.48 (m, 5H,
ArH), 7.89 (br s, 1H, N–H). MS: m/z (%) 302 (Mþ, 23),
224 (4), 91 (100). Anal. calcd for C14H14N4O2S (302.35):
C, 55.61; H, 4.67; N, 18.53. Found: C, 55.71; H, 4.65; N,
18.60.
6. Takahashi, M.; Kadowaki, Y.; Uno, Y.; Nakano, Y. Hetero-
cycles 1999, 51, 2035–2039.
7. Tamura, Y.; Sumoto, K.; Matsushima, H.; Taniguchi, H.;
Ikeda, M. J. Org. Chem. 1973, 38, 4324–4328.
8. Fuchigami, T.; Odo, K. Chem. Lett. 1974, 247–250.
9. Gilchrist, T. L.; Moody, C. J.; Rees, C. W. J Chem. Soc.,
Perkin Trans. 1 1975, 1964–1969.
10. Norris, P.; Shechter, H. J. Org. Chem. 1999, 64,
7290–7298.
11. (a) Molina, P.; Vilaplana, M. J. Synthesis 1990, 474–475.
(b) Wamhoff, H.; Schmidt, A. J. Org. Chem. 1993, 58,
6976–6984. (c) Hamed, A.; Al-Talib, M. Org. Prep. Proced.
Int. 1996, 28, 694–699. (d) Nitta, M.; Kanda, H. Heterocycles
2002, 56, 491–499, and references cited therein.
4.1.21. 5,7-Dimethyl-3-(phenylamino)isothiazolo[3,4-
d]pyrimidine-4,6(5H,7H)-dione (12c). Yield 76%, white
needles, mp 180–1818C (MeOH). IR (KBr): 3280, 1698,
1643, 1571, 1519, 1461, 1442, 1349, 1276 cm21. 1H NMR
(CDCl3): d 3.39 (s, 3H, N–Me), 3.56 (s, 3H, N–Me), 7.13–
7.46 (m, 5H, ArH), 9.90 (s, 1H, N–H). MS: m/z (%) 288
(Mþ, 100), 230 (34), 202 (9), 174 (8), 144 (20). Anal. calcd
for C13H12N4O2S (288.33): C, 54.15; H, 4.19; N, 19.43.
Found: C, 54.31; H, 4.21; N, 19.53.
12. Yoshimura, T.; Omata, T.; Furukawa, N.; Oae, S. J. Org.
Chem. 1976, 41, 1728–1733.
13. (a) Pfleiderer, W.; Schu¨ndehu¨tte, K. Ann. Chem. 1958, 612,
158–163. (b) Fuchs, H.; Gottlieb, M.; Pfleiderer, W. Chem.
Ber. 1978, 111, 982–995.
14. For example: (a) Marchal, A.; Melguizo, M.; Nogueras, M.;
´
Sanchez, A.; Low, J. N. Synlett 2002, 255–258. (b) Giori, P.;
4.1.22. 5,7-Dimethyl-3-(p-tolylamino)isothiazolo[3,4-
d]pyrimidine-4,6(5H,7H)-dione (12d). Yield 70%, white
powder, mp 192–1938C (MeOH). IR (KBr): 3264, 2921,
1700, 1650, 1600, 1577, 1513, 1459, 1344, 1276 cm21. 1H
NMR (CDCl3): d 2.36 (s, 3H, Me), 3.39 (s, 3H, N–Me),
3.55 (s, 3H, N–Me), 7.05 (d, J¼8.8 Hz, 2H, ArH), 7.24 (d,
J¼8.8 Hz, 2H, ArH), 9.78 (s, 1H, NH). MS: m/z (%) 302
(Mþ, 100), 274 (4), 244 (18), 216 (12), 91 (24). Anal. calcd
for C14H14N4O2S (302.35): C, 55.61; H, 4.67; N, 18.53.
Found: C, 55.69; H, 4.87; N, 18.66.
Poli, T.; Veronese, A. V.; Vicentini, C. B.; Manfrini, M.;
Guarneri, M. J. Heterocycl. Chem. 1986, 23, 1661–1665.
(c) Yoneda, F.; Koga, R.; Nishigaki, S.; Fukazawa, S.
J. Heterocycl. Chem. 1982, 19, 949–951. (d) Zvilichovsky,
G.; Garbi, H.; Nemes, E. J. Heterocycl. Chem. 1982, 19,
205–209.
15. For example: (a) Pollet, P.; Gelin, S. Synthesis 1979, 977–979.
(b) Baraldi, P. G.; de las Infantas, M. J. P.; Manfredini, S.;
Romagnoli, R. Synthesis 2000, 72–74. (c) Ackrell, J.;
Boulton, A. J. J. Chem. Soc., Perkin Trans. 1 1973,
351–355.
4.1.23. 3-(p-Chlorophenyl)amino-5,7-dimethylisothia-
zolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (12e). Yield
73%, white powder, mp 251–2528C (MeOH). IR (KBr):
3261, 1706, 1656, 1600, 1577, 1515, 1455, 1272,
16. Taylor, E. C.; Maki, Y.; McKillop, A. J. Org. Chem. 1972, 37,
1601–1605.
1
1099 cm21. H NMR (DMSO-d6): d 3.23 (s, 3H, N–Me),
17. Yoneda, F.; Sakuma, Y. J. Heterocycl. Chem. 1973, 10,
993–996.
3.39 (s, 3H, N–Me), 7.41 (d, J¼9.2 Hz, 2H, ArH), 7.52 (d,
J¼9.2 Hz, 2H, ArH), 10.19 (s, 1H, NH). MS: m/z (%) 324
(Mþþ2, 36), 322 (Mþ, 100), 264 (17), 236 (6), 208 (6), 178
18. Nutiu, R.; Boulton, A. J. J. Chem. Soc., Perkin Trans. 1 1976,
1327–1331.

N. Matsumoto, M. Takahashi / Tetrahedron 58 (2002) 10073–10079
10079
19. Sako, M.; Oda, S.; Hirota, K.; Beardsley, G. P. Synthesis 1997,
1255–1257.
23. Okuda, H.; Tominaga, Y.; Matsuda, Y.; Kobayashi, G.
Heterocycles 1979, 12, 485–488.
20. Marumoto, R.; Furukawa, S.; Kawai, K. German Offen.
2714253, 1976.
24. (a) Niss, R.; Eilingsfeld, H. Ann. Chem. 1974, 2019–2029.
(b) Furukawa, Y.; Shima, S. Chem. Pharm. Bull. 1976, 24,
979–986.
21. Pinho e Melo, T. M. V. D.; Lopes, C. S. J.; Gonsalves, A. M.
d’A. R.; Storr, R. C. Synthesis 2002, 605–608, and references
cited therein.
25. Senda, S.; Hirota, K.; Yang, G.-N.; Shirahashi, M. Yakugaku
Zasshi 1971, 91, 1372–1376.
22. Tinh, D. V.; Stadlbauer, W. J. Heterocycl. Chem. 1996, 33,
1025–1030.