Synthesis of pyrrolo[2,3-d]pyrimidine-2,4-diones by sunlight photolysis of N-(5-vinyluracil-6-yl)sulfilimines

Article abstract of DOI:10.1016/j.tetlet.2005.06.054

Uracil derivatives having a vinyl group at the C-5 position and a sulfilimine moiety at the C-6 position were prepared and cyclized to 1,3,6-trisubstituted pyrrolo[2,3-d]pyrimidine-2,4-diones by sunlight photolysis in good yields.

Full text of DOI:10.1016/j.tetlet.2005.06.054

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5551–5554
Synthesis of pyrrolo[2,3-d]pyrimidine-2,4-diones by
sunlight photolysis of N-(5-vinyluracil-6-yl)sulfilimines
Nobuaki Matsumoto and Masahiko Takahashi*
Department of Materials Science, Faculty of Engineering, Ibaraki University, Hitachi, Ibaraki 316-8511, Japan
Received 6 May 2005; revised 6 June 2005; accepted 8 June 2005
Available online 1 July 2005
Abstract—Uracil derivatives having a vinyl group at the C-5 position and a sulfilimine moiety at the C-6 position were prepared and
cyclized to 1,3,6-trisubstituted pyrrolo[2,3-d]pyrimidine-2,4-diones by sunlight photolysis in good yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Sulfilimines are known to be useful building blocks for
heterocycles.1 In the course of our studies on the synthe-
sis of heterocycles using N-conjugated sulfilimines, we
previously reported a simple method for the preparation
of 1,2,5-oxadiazolo[3,4-d]-, isoxazolo[3,4-d]-, isothiaz-
olo[3,4-d]-, and 1,2,3-triazolo[4,5-d]pyrimidinediones
from uracils having a nitroso-, a carbonyl-, a carbam-
oyl-, a thiocarbamoyl-,2 or an azo group3 at the C-5
position and a sulfilimine moiety at the C-6 position.
These cyclization reactions proceeded upon thermolysis
or photolysis and resulted in high yields without using oxi-
dizing materials, dehydrating agents, or metal catalysts.
In order to expand the scope of this cyclization reaction,
we tried to synthesize pyrrolo[2,3-d]pyrimidine-2,4-
diones from uracils using a new conjugated system,
N-(5-vinyluracil-6-yl)sulfilimines. Pyrrolo[2,3-d]pyrimi-
dine-2,4-diones have been prepared by Michaeladdition
of 6-aminouracils to acetylenedicarboxyate4 or diacyl-
ethylene5 and by cyclocondensation with glycin deriva-
ity,13 the development of a method for efficient synthesis
of this ring system is desirable. Herein, we report a novel
synthesis of pyrrolo[2,3-d]pyrimidine-2,4-diones by sun-
light photolysis of an N-(5-vinyluracil-6-yl) sulfilimines.
The starting materials, N-(1,3-dialkyluracil-6-yl)-S,S-
diphenylsulfilimines 1 and N-(5-formyl-1,3-dimethylura-
cil-6-yl)-S,S-diphenylsulfilimine (4) were prepared by
the reaction of N-unsubstituted S,S-diphenylsulfilimine
with readily available 1,3-dialkyl-6-chlorouracils and
6-chloro-5-formyl-1,3-dimethyluracil, respectively.2 As
outlined in Scheme 1, uracilderivatives 3a and b having
a 2-(trifluoroacetyl)vinyl group at the C-5 position were
synthesized in 75% and 77% yields, respectively, by the
reaction of 1a and b with 4-ethoxy-1,1,1-trifluorobut-3-
en-2-one (2)14 in dichloromethane at room
temperature.15
On the other hand, the synthetic approach to 3c–e is
based on Wittig reaction of 4 with phosphonium salts
5. A suspension of sulfilimine 4, benzyltriphenylphos-
phonium chloride, and sodium hydride in dry THF
was refluxed to give N-(5-styryluracil-6-yl)sulfilimine
(3c) in 71% yield.16 In a similar manner, 3d and e were
prepared in 64% and 88% yields, respectively. The struc-
tures of the products 3a–e were assigned on the basis of
tives,6 oxalyl dichloride,7 chloroacetaldehyde,8 or
9
diethyloxapl ropionate.
Palladium (II)-catalyzed cycli-
zation10 of 5-allyl-6-aminouracils or 6-(N-allyl)amino-
uracils, photolysis of 6-(10-triazolyl)uracil,11 and
intramolecular insertion reaction of carbene generated
from 6-(N-allyl-N-methylamino)-5-tosylhydrazonoura-
cil12 are unique methods for the synthesis of this con-
densed ring. Since some pyrrolo[2,3-d]pyrimidine-2,4-
diones show antibacterial, anticancer, or antiviral activ-
1
elemental analysis, MS, IR, and H NMR spectra. The
resulting sulfilimines 3a–e are stable yellow solids and
unchanged in a solution in the dark.
Cyclization reactions of 3a–e to pyrrolo[2,3-d]pyrimi-
dine-2,4-diones 6a–e were undertaken under various
conditions. Thermolysis of 3a in refluxing toluene for
30 h was unsuccessful. However, sulfilimine 3a was
Keywords: Sulfilimines; Uracils; Sunlight; Photolysis; Pyrrolo[2,3-d]-
pyrimidine-2,4-diones.
*
Corresponding author. Tel.: +81 294 38 5050; fax: +81 294 38
5078; e-mail: takamasa@mx.ibaraki.ac.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.054

5552
N. Matsumoto, M. Takahashi / Tetrahedron Letters 46(2005) 5551–5554
CF3
EtO
O
O
O
R1
O
R1
O
COCF3
SPh2
N
2
N
N
SPh2
N
N
CH2Cl2
r.t.
N
R1
R1
1a: R1=Me b: R1=iso-Pr
3a: R1=Me
b: R1=iso-Pr
R2CH2P Ph3Cl
O
O
Me
O
CHO
SPh2
Me
N
R2
5
N
SPh2
N
N
Me
N
NaH/THF
reflux
O
N
Me
4
3c: R2=Ph d: R2=p-Tolyl
e: R2=p-Chlorophenyl
Scheme 1. Preparation of N-(5-vinyluracil-1-yl) sulfilimines 3.
Table 1. Preparation of 6a–e upon sunlight photolysis of 3a–e
almost completely converted to the corresponding 6a by
UV irradiation using a high-pressure mercury lamp un-
der a nitrogen atmosphere for 10 min in acetonitrile
(Scheme 2).
Product
Photolysis time
Yield (%)
6a
6b
6c
6d
6e
5.0 h
3.5 h
88
96
91
89
84
40 min
40 min
40 min
Encouraged by the success of this ring closure reaction,
we then applied it to the synthesis of 6c. However, sim-
ilar irradiation of 3c in acetonitrile resulted in decompo-
sition of the starting materialwith no significant amount
of 6c. Severalreaction conditions were examined in
order to realize the cyclization to 6c. As a result, almost
quantitative yield of 6c was obtained, essentially by sim-
ple stirring of a solution of 3c in ethanolfor 40 min on
exposure to sunlight under aerial atmosphere. The pro-
gress of the reaction was easily monitored by color
change of the solution from yellow to pink and the prod-
ucts were isolated by a simple procedure. Thus, all the
samples 3a–e were subjected to irradiation of sunlight
under aerialatmosphere, and they were converted in
excellent yields to 6a–e (Table 1).17 The reaction would
proceed through the generation of nitrene intermediates
followed by 6p electrocyclization.1h,18 In the synthetic
photochemistry of uracils and related compounds,19
reactions involving sunlight are scarcely known: autore-
cycling oxidation of cyclopentanol to cyclopentanone
under an oxygen atmosphere using Ôdoubled 5-deazaf-
lavinsÕ and Ômixed flavinsÕ as catalysts was greatly accel-
erated by sunlight.20 It is noteworthy that sunlight was
effectively used in our preparation of uracil derivatives.
In conclusion, we have established a new photochemical
method for the preparation of 1,3,6-trisubstituted pyr-
rolo[2,3-d]pyrimidine-2,4-diones 6a–e from uracils 3a–e
having a vinylgroup at the C-5 position and a sufilil-
mine moiety at the C-6 position.
Acknowledgment
The authors would like to thank Atsushi Kawamata, an
undergraduate student, for his technicalassistance.
O
O
R1
O
R1
O
R2
sunlight
N
N
EtOH
r.t.
N
N
H
R2
SPh2
N
N
R1
R1
References and notes
6a-e
3a-e
1. (a) Wang, Q.; Nara, S.; Padwa, A. Org. Lett. 2005, 7, 839–
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3403; (d) Ikeda, K.; Honda, H.; Matsuo, T.; Yamamoto,
T. Org. Prep. Proced. Int. 1995, 27, 103–106; (e) Rossi, E.;
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(f) Abou-Gharbia, M.; Ketcha, D. M.; Zacharias, D. E.;
Swern, D. J. Org. Chem. 1985, 50, 2224–2228; (g)
3, 6a: R1=Me R2=COCF3
b: R1=iso-Pr R2=COCF3
d: R1=Me R2=p-Tolyl
c: R1=Me R2=Ph
e: R1=Me R2=p-Chlrorophenyl
Scheme 2. Sunlight photolysis of 3 to 6.

N. Matsumoto, M. Takahashi / Tetrahedron Letters 46(2005) 5551–5554
5553
Tomimatsu, Y.; Satoh, K.; Sakamoto, M. Heterocycles
1977, 8, 109–114; (h) Fuchigami, T.; Odo, K. Bull. Chem.
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ride (778 mg, 2.0 mmol), and sodium hydride (60% in oil,
120 mg, 3.0 mmol) in dry THF (10 mL) was refluxed for
20 h. The resulting mixture was dissolved in water
(100 mL) and then extracted with CH2Cl2 (3 · 100 mL).
The combined organic layer was dried over MgSO4,
filtered, and concentrated under reduced pressure. The
crude materialwas purified by coulmn chromatography
on silica gel using AcOEt/CH2Cl2 (1/1) as eluent to give N-
(1,3-dimethyl-5-styryluracil-6-yl)-S,S-diphenylsulfilimine
(3c) (157 mg, 71%), as light-yellow needles, mp 154–155 ꢁC
(MeOH); IR (KBr) 1684, 1635, 1537, 1442, 1419 cmꢀ1; 1H
NMR (CDCl3) d 3.38 (s, 3H), 3.56 (s, 3H), 6.50 (d,
J = 16.0 Hz, 1H), 6.81–6.83 (m, 2H), 7.04–7.06 (m, 3H),
7.26 (d, J = 16.0 Hz, 1H), 7.46–7.55 (m, 6H), 7.69–7.72 (m,
4H); MS m/z (%) 255 (M+ꢀ186, 10), 186 (100), 92 (10), 77
(25); UV (MeOH) kmax (loge) 206 (4.7), 232 (4.5), 307
(4.3). Anal. Calcd for C26H23N3O2S: C, 70.72; H, 5.25; N,
9.52. Found: C, 70.43; H, 5.27; N, 9.53. Compound 3d:
64%, mp 171–172 ꢁC (MeOH); IR (KBr) 1683, 1633, 1612,
1545, 1444 cmꢀ1; 1H NMR (CDCl3) d 2.27 (s, 3H), 3.38 (s,
3H), 3.56 (s, 3H), 6.45 (d, J = 16.0 Hz, 1H), 6.73 (d,
J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 7.22 (d,
J = 16 Hz, 1H), 7.47–7.71 (m, 10H); MS m/z (%) 269
(M+ꢀ186, 17), 212 (15), 186 (100). Compound 3e: 88%,
mp 177–178 ꢁC (MeOH); IR (KBr) 1684, 1633, 1529,
1444 cmꢀ1; 1H NMR (CDCl3) d 3.38 (s, 3H), 3.55 (s, 3H),
6.45 (d, J = 16.0 Hz, 1H), 6.67–6.70 (m, 2H), 6.98–7.00 (m,
2H), 7.26 (d, J = 16.0 Hz, 1H), 7.48–7.73 (m, 10H); MS m/
z (%) 289 (M+ꢀ186, 26), 232 (22), 186 (100), 175 (21), 109
(19).
2. Matsumoto, N.; Takahashi, M. Tetrahedron 2002, 58,
10073–10079.
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2677–2684.
4. (a) Bhuyan, P. J.; Lekhok, K. C.; Sandhu, J. S. J. Chem.
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Pharm. Bull. 1976, 24, 1160–1164.
6. (a) Edstrom, E. D.; Wei, Y. J. Org. Chem. 1995, 60, 5069–
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7. Bernier, J.-L.; HeÕnichart, J.-P. J. Heterocycl. Chem. 1979,
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9. Yamasaki, T.; Nishida, K.; Okamoto, Y.; Okawara, T.;
Furukawa, M. Heterocycles 1998, 47, 315–327.
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12. Noguchi, M.; Fujimoto, N.; Nagashima, M.; Kajigaeshi,
S. Heterocycles 1989, 29, 1993–1996.
13. For recent reports, see: (a) Bio, M. M.; Xu, F.; Waters,
M.; Williams, J. M.; Savary, K. A.; Cowden, C. J.; Yang,
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17. A typicalexperimentalprocedure. Method A. A soul tion
of 3a (231 mg, 0.50 mmol) in acetonitrile (50 mL) was
irradiated for 10 min using a high-pressure mercury lamp
under a nitrogen atmosphere. The resulting solution was
concentrated under reduced pressure. After the residue had
been washed with diethyl ether, the resultant solid was
separated by filtration, and recrystallized from methanol to
give 6-trifluoroacetyl-1,3-dimethyl-1,2,3,4-tetrahydro-7H-
pyrrolo[2,3-d]pyrimidine-2,4-dione (6a) (124 mg, 90%) as
white powder, mp 292–293 ꢁC (lit.,21 mp 281 ꢁC); IR (KBr)
1
3188, 3113, 1730, 1678, 1645, 1606, 1570, 1421 cmꢀ1; H
NMR (CDCl3) d 3.22 (s, 3H), 3.50 (s, 3H), 7.51 (q,
J = 2.0 Hz, 1H); MS m/z (%) 275 (M+, 65), 218 (35), 206
(24), 149 (97), 66 (100). Anal. Calcd for C10H8F3N3O3: C,
43.65; H, 2.93; N, 15.27. Found: C, 43.59; H, 3.00; N,
15.34. Method B. A solution of 3a (231 mg, 0.50 mmol) in
ethanol(30 mL) was irradiated for 5.0 h using sunilght
under aerial atmosphere. The resulting solution was
concentrated under reduced pressure. After the residue
had been washed with diethyl ether, the resultant solid was
separated by filtration, and recrystallized from methanol to
give 6a (121 mg, 88%). Compound 6b: mp 214–215 ꢁC
(MeOH); IR (KBr) 3352, 1722, 1678, 1649, 1597, 1566,
1246, 1153 cmꢀ1; 1H NMR (CDCl3) d 1.50 (d, J = 6.8 Hz,
6H), 1.62 (d, J = 6.8 Hz, 6H), 4.90 (qq, J = 6.8 and 6.8 Hz,
1H), 5.26 (qq, J = 6.8 and 6.8 Hz, 1H), 7.72 (q, J = 2.0 Hz,
1H), 10.20 (br s, 1H); MS m/z (%) 331 (M+, 54), 247 (100),
231 (64), 294 (57), 174 (64), 161 (72), 135 (65). Compound
6c: mp 287–289 ꢁC (MeOH); IR (KBr) 3188, 1687, 1637,
1568 cmꢀ1; 1H NMR (CDCl3) d 3.23 (s, 3H), 3.54 (s, 3H),
6.84 (s, 1H), 7.23–7.77 (m, 5H), 11.58 (br s, 1H); MS m/z
(%) 255 (M+, 100), 198 (65), 183 (15), 170 (32), 155 (15), 104
(15). Compound 6d: mp 330–332 ꢁC (MeOH); IR (KBr)
14. Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo,
S. Chem. Lett. 1976, 499–502.
15. A typicalexperimentalprocedure. A mixture of
1a2
(339 mg, 1.0 mmol) and 214 (504 mg, 3.0 mmol) in CH2Cl2
(3 mL) was stirred for 5 days at room temperature. The
resulting mixture was concentrated under reduced pres-
sure. The crude materialwas purified by coul mn chroma-
tography on silica gel using CH2Cl2 as eluent to give N-[5-
(4,4,4-trifluoro-3-oxo-1-butenyl)-1,3-dimethyluracil-6-yl]-
S,S-diphenylsulfilimine (3a) (346 mg, 75%), as light-yellow
needles, mp 207–208 ꢁC (MeOH); IR (KBr) 1695, 1641,
1
1537, 1495, 1439 cmꢀ1; H NMR (CDCl3) d 3.36 (s, 3H),
3.65 (s, 3H), 7.53–7.84 (m, 12H); MS m/z (%) 275
(M+ꢀ186, 16), 259 (16), 186 (100), 147 (24); UV (MeOH)
kmax (loge) 206 (4.7), 339 (4.1), 407 (4.3) nm. Anal. Calcd
for C22H18F3N3O3S: C, 57.26; H, 3.93; N, 9.11. Found: C,
57.29; H, 3.98; N, 9.13. Compound 3b: 77%, mp 152–
153 ꢁC (MeOH); IR (KBr) 1687, 1637, 1547, 1475, 1441,
1
1
1254 cmꢀ1; H NMR (CDCl3) d 1.45 (d, J = 6.8 Hz, 6H),
3273, 1698, 1684, 1641, 1568 cmꢀ1; H NMR (CDCl3) d
1.46 (d, J = 6.8 Hz, 6H), 5.20 (qq, J = 6.8 and 6.8 Hz, 1H),
5.63 (qq, J = 6.8 and 6.8 Hz, 1H), 7.26–7.78 (m, 12H); MS
m/z (%) 517 (M+, 6), 331 (8), 289 (13), 247 (14), 186 (100).
2.31 (s, 3H), 3.23 (s, 3H), 3.53 (s, 3H), 6.77 (s, 1H), 7.21 (d,
J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 11.53 (br s, 1H);
MS m/z (%) 269 (100), 212 (76), 185 (73), 169 (32).
Compound 6e: mp 340–342 ꢁC (MeOH); IR (KBr) 3300,
16. A typicalexperimentalprocedure. A mixture of
(183 mg, 0.50 mmol), benzyltriphenylphosphonium chlo-
42
1688, 1633, 1566 cmꢀ1 1H NMR (DMSO-d6) d 3.23 (s,
;

5554
N. Matsumoto, M. Takahashi / Tetrahedron Letters 46(2005) 5551–5554
3H), 3.53 (s, 3H), 6.91 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.79
(d, J = 8.4 Hz, 2H), 11.62 (br s, 1H); MS m/z (%) 291/289
Tetrahedron Lett. 2002, 43, 3113–3115;; (c) Skalski, B.;
Rapp, M.; Suchowiak, M.; Golankiewicz, K. Tetrahedron
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¨
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