Synthesis of O-unprotected glycosyl selenoureas. A new access to bicyclic sugar isoureas

Article abstract of DOI:10.1016/j.tetlet.2004.03.143

β-D-Gluco and mannopyranosyl selenoureas have been prepared by coupling of the corresponding glycosylamines with phenyl isoselenocyanate in aqueous pyridine. Alkyl and aryl isoselenocyanates, and 1,4-phenylene diisoselenocyanate have been obtained from the corresponding formamides with an excess of triphosgene, black selenium and triethylamine. Treatment of the O-unprotected β-D-glucopyranosyl selenourea with aqueous oxygen peroxide afforded a 1,2-trans-fused bicyclic isourea.

Full text of DOI:10.1016/j.tetlet.2004.03.143

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4081–4084
Synthesis of O-unprotected glycosyl selenoureas. A new
access to bicyclic sugar isoureas
*
ꢀ
Jose G. Fernandez-Bolanos, Oscar Lopez, Vıctor Ulgar, Ines Maya and Jose Fuentes
ꢀ
ꢀ
~
ꢀ
ꢀ
ꢀ
ꢀ
Departamento de Quꢀımica Orgꢀanica, Facultad de Quꢀımica, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
Received 9 March 2004; accepted 24 March 2004
Abstract—b-D-Gluco and mannopyranosyl selenoureas have been prepared by coupling of the corresponding glycosylamines with
phenyl isoselenocyanate in aqueous pyridine. Alkyl and aryl isoselenocyanates, and 1,4-phenylene diisoselenocyanate have been
obtained from the corresponding formamides with an excess of triphosgene, black selenium and triethylamine. Treatment of the
O-unprotected b-D-glucopyranosyl selenourea with aqueous oxygen peroxide afforded a 1,2-trans-fused bicyclic isourea.
Ó 2004 Elsevier Ltd. All rights reserved.
The interest in the chemistry of organoselenium com-
pounds has increased remarkably in the last few decades
due to their synthetic applications1 and biological
activities.2 Selenoureas, useful for the synthesis of sele-
nium-containing heterocycles,3 have been prepared by
different methods: diamino carbenes and selenium,4
carbodiimides and LiAlHSeH,5 cyanamides and H2Se,6
carbon diselenide and amines7 or ureas and bis(tri-
methylsilyl)selenide.8 However, the preparation of sele-
noureas is mainly carried out by reaction of
isoselenocyanates with amines.9;10
Phenyl isoselenocyanate and other alkyl and aryl iso-
selenocyanates were prepared starting from the corre-
sponding formamides15 (Scheme 1), following
a
modification of Barton et al’s procedure.16 We have used
solid triphosgene,17 instead of phosgene, in the one-pot
dehydration of the formamides 1–5 in toluene contain-
ing triethylamine, followed by reaction of the noniso-
lated isocyanides with an excess of selenium black
(Scheme 1, method A). This gave isoselenocyanates 6–10
(Table 1, method A) in 16–75% yields.
The low yield observed for the hitherto unknown 1,4-
phenylene diisoselenocyanate 9 could be explained by
the extensive polymerization18 of the 1,4-phenylene
diisocyanide 4 during the prolonged heating in toluene.
However, the yields were improved considerably (69–
85%, Table 1, method B) when we used refluxing
dichloromethane (Scheme 1, method B) instead of tol-
uene, as the lower temperature reaction could prevent
the 1,4-phenylene diisocyanide polymerization.19 An-
other modification of Barton’s procedure to prepare
isoselenocyanates has recently been reported.20
Much effort has been devoted to the preparation of
sugar ureas11 and thioureas;12 on the contrary, we have
found only one report on the synthesis of sugar sele-
noureas.13 Sensitivity towards oxidation or light of
selenium containing compounds,14 together with the
difficulties in preparing alkyl and aryl isoselenocyanates,
may explain the scarce development of the chemistry of
sugar selenoureas, compared with that of their urea and
thiourea counterparts.
We now report the preparation of b-
selenoureas of gluco and manno configurations 13 and
14 by reaction of the corresponding b- -glycopyrano-
sylamines with phenyl isoselenocyanate in aqueous
pyridine in a 75% and 62% yield, respectively.
D-glycopyranosyl
Compounds 13 and 14 (Scheme 2) are the first examples
D
of O-unprotected b-D
-glycopyranosyl selenoureas21 and
were conventionally acetylated to afford penta-acetyl-
ated derivatives 15 and 16. It is noteworthy that the
acetylation of the selenourea moiety was completely
regioselective, as only the nitrogen bearing the phenyl
group was acylated, despite the conjugation between the
nitrogen lone pair and the aromatic ring. Reaction did
not take place in the nitrogen bound to the sugar ring,
possibly due to steric hindrance.
Keywords: Isoselenocyanates; Selenoureas; Isoureas; Triphosgene;
Selenium; Hydrogen peroxide.
* Corresponding author. Tel.: +34-95-4557151; fax: +34-95-4624960;
e-mail: bolanos@us.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.143

4082
J. G. Fernꢀandez-Bola~nos et al. / Tetrahedron Letters 45 (2004) 4081–4084
triphosgene, Et N, Se (powder), toluene
3
R–NHCHO
R–N=C=Se
0 ºC (30 min) ; reflux (18 h)
Method A
Se (powder), CH Cl
triphosgene, Et N, CH Cl
2
2
2
3
2
R–NC
reflux (4-7 h)
reflux (3.5 h)
Method B
Scheme 1.
Table 1. Synthesis of alkyl and aryl isoselenocyanates from N-substituted formamides
R–NHCHO
Compound
R–N@C@Se
Compound
Method A, yield (%)
Method B, yield (%)
NCSe
NHCHO
1
6
67
75
NHCHO
NCSe
2
3
7
8
55
52
88
77
Me
Me
NHCHO
NCSe
OMe
OMe
NHCHO
NCSe
4
5
9
16
75
80
69
NHCHO
NHCHO
NCSe
NCSe
10
1H NMR spectra of compounds 15 and 16 showed sig-
nals corresponding to the NH protons as doublets at
12.49 and 10.68 ppm, respectively. The strong deshiel-
ding of these protons is in agreement with the existence
of the hydrogen bonding NHꢀ ꢀ ꢀO@C–N. The coupling
served. However, in our hands, treatment of
glucopyranosyl selenourea 15 with methanolic sodium
methoxide at 0 °C gave 13 in a 70% yield, without
appreciable decomposition (Scheme 2).
3
constants JH-1;NH (7.7 Hz for 15 and 8.0 Hz for 16)
Compounds 13 and 14 underwent slow decomposition
by sunlight, with precipitation of elemental selenium
and formation of new compounds. In the case of
glucopyranosyl selenourea 13, the formation of bicyclic
isourea 1722 was detected as the only compound formed
and this transformation was accelerated by addition of
hydrogen peroxide (1.1 equiv) and completed in 1 h at
0 °C in an 84% yield (Scheme 3). This reaction can be
considered as a new procedure to prepare cyclic iso-
ureas; other methods for the preparation of cyclic
isoureas involve the cyclodesulfuration of conveniently
hydroxylated thiourea derivatives with Mukaiyama’s
confirm where the N-acetylation took place and suggest
the anti-Z,E conformation shown in Scheme 2.
To our knowledge, the only reported per-O-acetylated
b-D-glycopyranosyl selenoureas were prepared by
Witczak,13 by reaction of fully O-protected glycopyr-
anosyl isoselenocyanates with aniline. He also described
that attempts to prepare free glycosyl selenoureas by
ꢀ
deacetylation under Zemplen conditions using catalytic
sodium methoxide were unsuccessful, and decomposi-
tion with precipitation of elemental selenium was ob-

J. G. Fernꢀandez-Bola~nos et al. / Tetrahedron Letters 45 (2004) 4081–4084
OH
4083
OH
2
2
R
R
NCSe
H
N
H
N
O
O
HO
HO
HO
HO
NH
2
1:1 H O–Py
2
1
1
R
R
Ar, rt, 5h
Se
1
2
1
2
11 R = OH, R = H
13 R = OH, R = H (75%)
1
2
1
2
12 R = H, R = OH
14 R = H, R = OH (62%)
Ac O–Py
2
0 ºC, 20 h
OH
OAc
O
H
Me
2
R
H
N
H
N
O
O
NaOMe, MeOH
0 ºC, 2.5 h
HO
HO
N
AcO
AcO
N
1
OH
R
Se
Se
1
2
15 R = OAc, R = H (72%)
13 (70%)
1
2
16 R = H, R = OAc (69%)
Scheme 2.
OH
O
OH
H
N
H
N
O
OH
N
H
H O (1.1 equiv.)
H O, 0 ºC, 1h
2
HO
HO
2
2
HO
HO
N
O
Se0 + H O
Se
2
13
17 (84%)
Scheme 3.
reagent,23 p-toluenesulfonyl chloride/NaOH24 or MeI/
lutidine.25 Our results contrast with those reported by
Treppendahl,26 who described the oxidation of N,N0-
isoureas. Furthermore, we have proved that the prepa-
ration of alkyl and aryl isoselenocyanates, and
1,4-phenylene diisoselenocyanate following Barton’s
procedure is improved by using triphosgene instead of
phosgene and dichloromethane instead of the less polar
toluene.
diphenylselenourea with H2O2 to give
a benzo-
selenazoylguanidine (a selenoanalogue to Hugershoff’s
base) and a cyclic dimer of the corresponding carbo-
diimide. Oxidation of selenoureas with NaIO4 in re-
fluxing DMF to give carbodiimides has recently been
reported.9
References and notes
The structure of 17 was confirmed by comparison of its
1H and 13C NMR data with those of other bicyclic
isoureas previously prepared by us from O-unprotected
1. (a) Organoselenium Chemistry: Modern Developments in
Organic Synthesis; Wirth, T., Ed.; Springer: Berlin, 2000;
(b) Nicolaou, K. C.; Fylaktakidou, K. C.; Mitchell, H. J.;
b-D-glucopyranosyl thioureas by treatment with yellow
HgO.27 Treatment of the mannopyranosyl selenourea 14
with hydrogen peroxide under the above described
conditions led to a nonresolved mixture of unidentified
compounds, maybe due to the less stability of five-
membered–six-membered cis-fused bicyclic isoureas.28
The mild oxidation of glycopyranosyl selenoureas with
hydrogen peroxide suggests that they may be used as
antioxidant agents.29
ꢀ
Van Delft, F. L.; Rodrıguez, R. M.; Conley, S. R.; Jin, Z.
Chem. Eur. J. 2000, 6, 3166–3185; (c) Petragnani, N.;
Stefani, A.; Valduga, C. J. Tetrahedron 2001, 57, 1411–
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2. (a) Koketsu, M.; Yang, H. O.; Kim, Y. M.; Ichihashi, M.;
Ishihara, H. Org. Lett. 2001, 3, 1705–1707; (b) Birringer,
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In conclusion, we have developed a practical procedure
for the preparation of unprotected glycopyranosyl sele-
noureas and their mild transformation into bicyclic

4084
J. G. Fernꢀandez-Bola~nos et al. / Tetrahedron Letters 45 (2004) 4081–4084
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Nardelli, A.; Sunji, V. Synthesis 1996, 553–576.
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21. For the preparation of 13: To a solution of phenyl
isoselenocyanate (244 mg, 1.34 mmol) in pyridine (2 mL),
at rt under argon, was added a solution of b-D-glucopyr-
9. Koketsu, M.; Suzuki, N.; Ishihara, H. J. Org. Chem. 1999,
64, 6473–6475.
anosylamine 11 (200 mg, 1.12 mmol) in water (2 mL).
The reaction was kept in the darkness at rt for 5 h,
concentrated to dryness and purified by column chromato-
10. Fujiwara, S.-I.; Kambe, N.; Sonoda, N. In Organosele-
nium Chemistry: A Practical Approach; Back, T. G., Ed.;
Oxford University Press, 1999; pp 223–240.
11. (a) Ichikawa, Y.; Nishiyama, T.; Isobe, M. J. Org. Chem.
2001, 66, 4200–4205; (b) Nishiyama, T.; Ichikawa, Y.;
graphy to afford 13 (302 mg, 75%). Selected data for
26
D
13: ½aꢁ ꢂ19° (c 1.4, CH3OH); IR mmax 3317, 1545 cmꢂ1
;
1H NMR (300 MHz, CD3OD) d 5.61 (br s, 1H, H-1); 13C
NMR (75.5 MHz, CD3OD) d 182.8 (C@Se), 88.2 (C-1);
HRFABMS calcd for C13H18N2NaO580Se [M þ Na]þ
385.0279, found 385.0267.
ꢀ
Isobe, M. Synlett 2003, 47–50; (c) Maya, I.; Lopez, O.;
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22. For the preparation of 17: To a solution of N-(b-
13 (26 mg,
D-
glucopyranosyl)-N0-phenylselenourea
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0.07 mmol) in water (0.5 mL) at 0 °C was added 3.3%
w/v hydrogen peroxide (0.076 mL, 0.07 mmol). The
reaction was kept at that temperature for 1 h and then it
was diluted with EtOH and filtered over Celite. The filtrate
was concentrated to dryness and purified by column
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chromatography to give pure isourea 17 (17 mg, 84%).
21
D
Selected data for 17: ½aꢁ þ85° (c 1.3, DMSO); IR mmax
1
15. General procedure for the preparation of isoselenocya-
nates. Method A: to a mixture of formamides 1–5
(1.5 mmol), selenium powder (3.0 mmol) and triethylamine
(6.0 mmol) in toluene (15 mL), at 0 °C under argon, was
dropwise added a solution of triphosgene (1.0 mmol) in
toluene (10 mL) for a period of 30 min. After the addition,
the resulting mixture was refluxed for 16 h in the darkness
and then it was filtered over Celite and the filtrate was
purified by column chromatography (hexane–EtOAc gra-
dient) to afford isoselenocyanates 6–10. Method B: to a
refluxing mixture of the formamides 1–5 (1.5 mmol),
3341, 1647 cmꢂ1; H NMR (500 MHz, CD3OD) d 4.85 (d,
1H, J1;2 ¼ 9:6 Hz, H-1); 13C NMR (125.7 MHz, CD3OD) d
159.8 (C@N), 95.1 (C-1); HRFABMS calcd for
C13H16N2NaO5 [M þ Na]þ 303.0957, found 303.0963.
23. (a) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1979, 18,
707–721; (b) Takeda, T.; Mukaiyama, T. Chem. Lett.
1980, 163–166.
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25. Almaraz, M.; Raposo, C.; Martin, M.; Caballero, M. C.;
Moran, J. R. J. Am. Chem. Soc. 1998, 120, 3516–
3517.
ꢁ
triethylamine (6.4 mmol) in CH2Cl2 (5 mL) and 4 A
molecular sieves was dropwise added a solution of
triphosgene (0.8 mmol) in CH2Cl2 (2 mL) for a period of
1 h. After the addition, it was refluxed for 2.5 h and then,
selenium powder (3.0 mmol) was added. The resulting
mixture was refluxed for other 4–7 h; conventional work-
up and column chromatography afforded isoselenocya-
nates 6–10.
26. Treppendahl, S. Acta Chem. Scand. 1975, B29, 385–388.
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