Synthesis of 5-amino-2-selenoxo-1,3-imidazole-4-carboselenoamides by the reaction of isoselenocyanates with aminoacetonitriles

Article abstract of DOI:10.1016/j.tetlet.2011.06.119

Reaction of isoselenocyanates with aminoacetonitriles afforded 4-amino-2-selenoxo-1,3-imidazole-2-selenones, whereas reaction with aminopropionitriles led to selenoureas. We confirmed that it is easy to distinguish between selenoamides and selenoureas by

Full text of DOI:10.1016/j.tetlet.2011.06.119

Tetrahedron Letters 52 (2011) 4650–4653
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Synthesis of 5-amino-2-selenoxo-1,3-imidazole-4-carboselenoamides
by the reaction of isoselenocyanates with aminoacetonitriles
Nobuhito Tanahashi a, Mamoru Koketsu b,
⇑
a Department of Chemistry, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan
b Department of Materials Science and Technology, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of isoselenocyanates with aminoacetonitriles afforded 4-amino-2-selenoxo-1,3-imidazole-2-
selenones, whereas reaction with aminopropionitriles led to selenoureas. We confirmed that it is easy
to distinguish between selenoamides and selenoureas by comparison of their chemical shift differences
in the 77Se NMR spectra.
Received 31 May 2011
Revised 26 June 2011
Accepted 30 June 2011
Available online 7 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isoselenocyanate
Aminoacetonitrile
Imidazole
Selenium
Isoselenocyanates have emerged as powerful tools for the syn-
thesis of heterocycles, because they are easy to prepare, relatively
nontoxic, and safe to handle and store.1 Isoselenocyanates are used
in the synthesis of versatile selenium-containing compounds such
as 1,3-oxaselenepane,2 3-selena-1-dethiacephem via the corre-
sponding selenourea,3 1,3-selenazole,4 3H-1,2,4-triazole-3-selone,5
1,3-selenazetidine,6 and 1,3-selenazolidine derivatives.7 Recently,
selenium-containing compounds showed significant biological
activities, such as anti-inflammatory, analgesic, and antimicrobial
activities,8 skin melanin biosynthesis inhibitor,9 and antioxidant
activity.10 Therefore, to identify and biologically characterize addi-
tional related active species, new selenium-containing compounds
are required. Herein, we describe the synthesis of novel selenium-
containing compounds by the reaction of isoselenocyanates with
aminoacetonitriles.
Alkyl and aryl isoselenocyanates 1 were prepared by reactions
of N-substituted formamides with an excess of triphosgene, sele-
nium and triethylamine.11 Initially, reaction of p-tolylisoselenocy-
anate (1a) with 2-(phenylamino)acetonitrile (2a, 1 equiv) was
performed in toluene at room temperature and the effects of vari-
ous bases were compared. When triethylamine (Et3N) or pyridine
was used, the reaction gave 5-amino-3-phenyl-2-selenoxo-N,1-
di(4-tolyl)-1,3-imidazole-4-carboselenoamide (3a). Further, in the
presence of K2CO3, DIPEA, or LHMDS, each reaction gave either a
complex mixture or no product. However, when pyridine was used,
the reaction afforded 3a in higher yield as compared to that ob-
tained when Et3N was used. Moreover, in the absence of base, no
product was identified and only staring materials were recovered.
Next, we evaluated the relative stoichiometry of the reagents. The
reaction of 1a (1 equiv) with 2a (1 equiv) in the presence of pyri-
dine at room temperature gave 3a in 19% yield after 4 h. When
the amount of 1a was increased to 2 equiv (2:1 ratio, 1a/2a), the
yield of product 3a was more than doubled (69%). It was subse-
quently confirmed that this reaction consumed 2 equiv of isoselen-
ocyanate 1 for each equivalent of 2 to form product 3. Finally, we
compared the effects of solvents, such as ethanol, chloroform,
dichloromethane, dimethylformamide, THF and toluene, for this
reaction. The reaction using toluene exclusively formed 3a in the
highest yield. These results suggested the following optimized con-
ditions: p-tolylisoselenocyanate (1a, 2 equiv) is reacted with 2-
(phenylamino)acetonitrile (2a, 1 equiv) in the presence of pyridine
at room temperature in toluene for 1 day yielding 5-amino-3-phe-
nyl-2-selenoxo-N,1-di(4-tolyl)-1,3-imidazole-4-carboselenoamide
(3a) in 69% yield (Table 1).
The structure of 3a was elucidated by IR, NMR (1H, 13C, and
77Se), 2D NMR (COSY, HMQC, and HMBC), MS, and elemental anal-
ysis. Under similar conditions, the reactions of five different alkyl
and aryl isoselenocyanates 1 with 2-(phenylamino)acetonitrile
(2a) or methylaminoacetonitrile (2b) gave the corresponding 5-
amino-2-selenoxo-1,3-imidazole-4-carboselenoamides 3 in mod-
erate to high yields (Table 1). The structures of products 3b–3j
were determined by comparing their spectral data with that of 3a.
To confirm the structure of 3e, we carried out an X-ray analysis
of the crystallized compound.12 The ORTEP drawing depicted in
Figure 1 shows the molecular structure of 3e. The four C–N bond
⇑
Corresponding author. Tel.: +81 58 293 2619; fax: +81 58 293 2794.
E-mail address: koketsu@gifu-u.ac.jp (M. Koketsu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.119

N. Tanahashi, M. Koketsu / Tetrahedron Letters 52 (2011) 4650–4653
4651
Table 1
Synthesis of 5-amino-2-selenoxo-1,3-imidazole-4-carboselenoamides (3) by the reactions of isoselenocya-
nates 1 with aminoacetonitriles 2
Se
R1
R2
H
N
N
N
N
R1
Pyridine
R2
N
C
Se
+
Toluene, rt
H2N
NH
R1
(2 equiv.)
Se
1
2
3
Entry
R1
R2
Time
Yield (%)
1
2
4-CH3C6H41a
C6H51b
4-ClC6H41c
2-CH3C6H41d
Benzyl 1e
4-CH3C6H41a
C6H51b
4-ClC6H41c
2-CH3C6H41d
Benzyl 1e
C6H52a
C6H52a
C6H52a
C6H52a
C6H52a
CH32b
CH32b
CH32b
CH32b
CH32b
1 day
1 day
1 day
1 day
1 day
1 h
1 h
1 h
1 h
1 h
69 (3a)
51 (3b)
93 (3c)
28 (3d)
78 (3e)
80 (3f)
56 (3g)
81 (3h)
72 (3i)
73 (3j)
3
4a
5
6
7
8
9
10
a
Reflux.
The formation of 3 could be explained by the mechanism illus-
trated in Scheme 1. The reaction of 1 with 2 is initiated by the
nucleophilic addition of the nitrogen atom of 2 to the electrophilic
carbon atom of 1 affording the selenourea, which is subsequently
cyclized to give 4-imino-1,3-imidazoline-2-selenone A. Next, the
carbanion of 1,3-imidazolidine ring A attacks the electrophilic car-
bon of another molecule of 1 to form a carboselenoamide, which
subsequently tautomerizes to the more stable amine 3.
In the case of the reaction of an aminoacetonitrile 2 with an iso-
thiocyanate or isocyanate in the absence of base, equimolar quan-
tities of the isothiocyanate or isocyanate were consumed to yield a
cyanomethylthiourea and 4-amino-1,3-imidazolidine-2-thione or
a cyanomethylurea and 4-amino-1,3-imidazolidin-2-one, respec-
tively.14 The present reaction required pyridine and 2 equiv of
isoselenocyanate 1 to obtain 2-selenoxo-1,3-imidazole-5-carbose-
lenoamides 3.
Figure 1. X-ray crystal structure of 5-amino-N,1-dibenzyl-3-phenyl-2-selenoxo-
1,3-imidazole-4-carboselenoamide (3e) (ORTEP drawing).
Recently, we have reported interesting spectral features of 77Se
NMR spectra and selenium coupling in 1H NMR. The difference in
the chemical shift between diacyl selenides (R–CO–Se–CO–R) and
diacyl diselenides (R–CO–Se–Se–CO–R) can facilitate their detec-
lengths of C1–N2 (1.346(5) Å), C1–N1 (1.369(4) Å), N1–C2
(1.363(5) Å), and C2–N3 (1.436(4) Å) in the imidazole ring of 3e
are shorter than the typical single-bond length of 1.47 Å.13 Atoms
Se1, C1, N1, C2, C3, N2, C11, Se2, and N3 atoms are all coplanar.
Se
Se
C
R1
R2
R1
R2
H
N
N
N
H
N
R1
N
N
C
N
C
Se
Se
R2
HN
A
N
2
1
1
Se
Se
Se
R1
R2
R1
R2
R1
R2
R1
N
N
N
N
N
N
N
C
H
HN
H2N
NH
R1
HN
NH
R1
Se
Se
A
3
Scheme 1. Mechanism of reaction of isoselenocyanates with aminoacetonitriles.

4652
N. Tanahashi, M. Koketsu / Tetrahedron Letters 52 (2011) 4650–4653
Table 2
Chemical shifts of selenocarbonyl group in selenoureas and selenoamides
Selenoureas
Se(1)
Se
Se
Se
Se
Se
NH
Se(1)
Se
R3
R
R2
R
R3
R
R2
R
R1
Ph
Ph
N
N
N
N
H
N
H
N
H
N
NH2
N
N
N
N
HN
N
R1 R2
R1
R1
O
H2N
R
Se(2)3
R
R1 NH
A
B
C
D
E
F
R2 = Ph
R2 = CH3
Sea
336.2 20.3c
193.4 3.1c
177.7 7.7c
180.2 0.6c
194.7 53.0d
177.3 1.6d
225.7 13.3e
176.4 1.7e
267.8 16.1f
183.6 0.8f
88.7 1.1g
137.9 24.3
161.8 0.3
94.5 19.3
158.6 0.9
C@Seb
158.5 1.4g
Selenoamides
Se(2)
Se
R2
Se
Se
Se Se
Se(1)
R2
NC
R
NH2
R1
N
R
N
R
NH2
H2N
R
NH2
N
R1
G
H
I
J
H2N
Se(2)3
R1 NH
R2 = Ph
R2 = CH3
Sea
701.5 41.7h
203.3 1.8h
629.3 53.7i
212.4 6.7j
614.9 83.7k
210.6 4.4k
543.6 62.7k
208.4 3.7k
491.3 72.6
174.9 0.7
544.3 19.2
179.4 0.1
C@Seb
a
b
c
d
e
f
Average chemical shift of selenium in 77Se NMR spectra.
Average chemical shift of selenocarbonyl carbon in 13C NMR spectra.
Ref. 17, J. Org. Chem., 2002, 67, 1008–1011.
Ref. 18, Synth. Commun., 2002, 32, 3075–3079.
Ref. 19, Tetrahedron Lett., 2001, 42, 6333–6335.
Ref. 20, J. Heterocycl. Chem., 2007, 44, 79–81.
Ref. 21, Heterocycles, 2006, 68, 1191–1200.
Ref. 22, Heteroat. Chem., 2002, 13, 195–198.
Ref. 23, Molecules, 2009, 14, 884–892.
g
h
i
j
Ref. 24, Chem. Lett., 1998, 1287–1288.
Ref. 25, Heteroat. Chem., 2003, 14, 106–110.
k
tion in the 77Se NMR spectra. While the difference between the
chemical shift of the carbonyl C-atoms of a diacyl selenide and that
of a diacyl diselenide in 13C NMR spectra is not significant, the cor-
responding difference in the chemical shift of selenium in 77Se
NMR spectra between the two species is substantial.15 Addition-
ally, selenium shows strong coupling with the trans proton with re-
spect to selenium atom at an exocyclic double bond, whereas
similar coupling with the cis proton is not observed.3,16 Further-
more, structural confirmation studies can take advantage of the
significant differences in the chemical shift between selenazeti-
dines and selenoureas, including cyclic selenoureas, in 77Se NMR
spectra.6a Thus, 77Se NMR spectra give important information for
structural analysis and confirmation. In this study, we isolated 2-
selenoxo-1,3-imidazole-4-carboselenoamides 3, incorporate a cyc-
lic selenourea and a selenoamide group in the structure. Reported
chemical shifts of selenocarbonyl groups in selenoureas and sele-
noamides are summarized in Table 2. In 13C NMR spectra, most
chemical shifts for carbonyl carbons of selenocarbonyl groups in
selenoureas are observed at higher fields than those of selenoa-
mides; however, the difference is minimal. In contrast, the chemi-
cal shift of the C-atom of the selenocarbonyl group in selenoureas
A (193.4 3.1 ppm), B (180.2 0.6 ppm), C (177.3 1.6 ppm), and
E (183.6 0.8 ppm) is observed at lower fields than the chemical
shift (174.9 0.7 ppm or 179.4 0.1 ppm) of Se2 of the selenoa-
mide group in compound 3. Similar to the above-reported finding
comparing diacyl selenides and diacyl diselenides, the difference in
the chemical shift of Se between selenoureas and selenoamides in
the 77Se NMR spectra is greater than that of C in the corresponding
13C NMR spectra, and therefore, the two species can be distin-
guished easily. Values for the chemical shift of Se in selenoureas
and selenoamides do not reverse in the 77Se NMR spectra. In the
case of selenoureas including compounds 3, signals for Se-atoms
are observed in the range of 88–336 ppm. The chemical shift values
for selenium in selenoamides fall in the range of 491–702 ppm,
which is obviously lower than those for selenoureas. The average
chemical shift (94.5 19.3 ppm) of Se1 (urea) for compound 3
(R2 = methyl) is at a higher field than that of 3 (R2 = phenyl,
137.9 24.3 ppm). The average chemical shift (544.3 19.2 ppm)
of Se2 (amide) for compound 3 (R2 = methyl) is also at lower field
than that of 3 (R2 = phenyl, 491.3 72.6 ppm). This clearly reflects
the variable pattern of electron density provided by the alkyl and
aryl substituents around the selenium atom in 3. Furthermore,
Se
N
H
N
Pyridine / 1 day / rt
Toluene
+
N
H
N
R
R
N
N
C
Se
4
5
1a
R = Ph (5a: 99%)
CH3 (5b: 99%)
Scheme 2. Reaction of p-tolylisoselenocyanate (1a) with 3-aminopropionitrile (4).

N. Tanahashi, M. Koketsu / Tetrahedron Letters 52 (2011) 4650–4653
4653
6. (a) Koketsu, M.; Otsuka, T.; Ishihara, H. Heterocycles 2006, 68, 2107–2112; (b)
Koketsu, M.; Yamamura, Y.; Ando, H.; Ishihara, H. Heterocycles 2006, 68, 1267–
1273; (c) Sommen, G. L.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2005, 88,
766–773.
we can distinguish between the selenoamide and selenourea frag-
ments by their significant differences in their chemical shifts in the
77Se NMR spectra.
7. (a) Koketsu, M.; Yamamura, Y.; Ishihara, H. Synthesis 2006, 2738–2742; (b)
Koketsu, M.; Kiyokuni, T.; Sakai, T.; Ando, H.; Ishihara, H. Chem. Lett. 2006, 35,
626–627; (c) Sommen, G. L.; Linden, A.; Heimgartner, H. Tetrahedron 2006, 62,
3344–3354; (d) Sommen, G. L.; Linden, A.; Heimgartner, H. Eur. J. Org. Chem.
2005, 3128–3137.
8. (a) Nam, K.-N.; Koketsu, M.; Lee, E. H. Eur. J. Pharmacol. 2008, 589, 53–57; (b)
Abdel-Hafez, S. H. Eur. J. Med. Chem. 2008, 43, 1971–1977; (c) Kloc, K.;
Maliszewska, I.; Mlochowski, J. Synth. Commun. 2003, 33, 3805–3815.
9. Lee, E. H.; Lim, Y.-J.; Ha, S. K.; Kang, T. H.; Koketsu, M.; Kang, C.; Kim, S. Y.; Park,
J.-H. J. Pharm. Pharmacol. 2010, 62, 352–359.
10. Bhabak, K. P.; Mugesh, G. Chem. Eur. J. 2007, 13, 4594–4601; Tsukagoshi, H.;
Koketsu, M.; Kato, M.; Kurabayashi, M.; Nishina, A.; Kimura, H. FEBS J. 2007,
274, 6046–6054; (c) Takahashi, H.; Nishina, A.; Fukumoto, R.; Kimura, H.;
Koketsu, M.; Ishihara, H. Eur. J. Pharm. Sci. 2005, 24, 291–295; (d) Sekiguchi, A.;
Nishina, A.; Kimura, H.; Fukumoto, R.; Kanoh, K.; Ishihara, H.; Koketsu, M.
Chem. Pharm. Bull. 2005, 53, 1439–1442.
Next, we evaluated the reaction of p-tolylisoselenocyanate (1a)
with a homolog of 2, 3-aminopropionitrile (4) using the same reac-
tion conditions. We expected the generation of a six-membered
pyrimidine derivative. However, reactions of 1a with two examples
of 4 afforded the corresponding acyclic selenourea derivatives 5 in
quantitative yields (Scheme 2).
We have demonstrated the one-pot synthesis of 5-amino-2-sel-
enoxo-1,3-imidazole-4-carboselenoamides 3 generated by react-
ing isoselenocyanates 1 with 2-aminoacetonitriles 2. The reaction
of 1 with 3-aminopropionitrile 4 gave the corresponding selenou-
reas 5 in quantitative yield. In conclusion, we confirmed that it is
easy to distinguish between selenoamides and selenoureas by
comparison of their chemical shift differences in the 77Se NMR
spectra.
11. Fernández-Bolaños, J. G.; López, Ó.; Ulgar, V.; Maya, I.; Fuentes, J. Tetrahedron
Lett. 2004, 45, 4081.
12. CCDC 768825 for 3e contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
13. (a) Li, G. M.; Zingaro, R. A.; Segi, M.; Reibenspies, J. H.; Nakajima, T.
Organometallics 1997, 16, 756–762; Tables of Interatomic Distances and
Configuration in Molecules and Ions; The Chemical Society: London, 1958.;
Tables of Interatomic Distances and Configuration in Molecules and Ions; The
Chemical Society: London, 1965.
Acknowledgments
This work was supported by a Grant-in-Aid for Science Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology of Japan (Nos. 17550099 and 23590005) to which we are
grateful.
14. Historically, the reaction between isothiocyanates and aminoacetonitrile was
reported to give 5-amino-1,3-thiazole. (Cook, A. H.; Downer, J. D.; Heilbron, Sir,
I. J. Chem. Soc., 1948, 1262–1267.) However, on reinvestigation, subsequent
Supplementary data
reports corrected the product structures to
a cyanomethylthiourea or an
imidazole-2-thione. (a) Kinoshita, T.; Watanabe, H.; Sato, S.; Tamura, C. Bull.
Chem. Soc. Jpn. 1980, 53, 442–445; (b) Balquist, J. M.; Goetz, F. J. J. Heterocycl.
Chem. 1972, 9, 937–938.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.119.
15. Koketsu, M.; Nada, F.; Hiramatsu, S.; Ishihara, H. J. Chem. Soc., Perkin Trans.1
2002, 737–740.
16. (a) Garud, D. R.; Makimura, M.; Ando, H.; Ishihara, H.; Koketsu, M. Tetrahedron
Lett. 2007, 48, 7764–7768; (b) Koketsu, M.; Sakai, T.; Kiyokuni, T.; Garud, D. R.;
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17. Koketsu, M.; Fukuta, Y.; Ishihara, H. J. Org. Chem. 2002, 67, 1008–1011.
18. Koketsu, M.; Takakura, N.; Ishihara, H. Synth. Commun. 2002, 32, 3075–
3079.
19. Koketsu, M.; Fukuta, Y.; Ishihara, H. Tetrahedron Lett. 2001, 42, 6333–6335.
20. Koketsu, M.; Takahashi, A.; Ishihara, H. J. Heterocycl. Chem. 2007, 44, 79–81.
21. Koketsu, M.; Yamamura, Y.; Ishihara, H. Heterocycles 2006, 68, 1191–1200.
22. Koketsu, M.; Okayama, Y.; Ishihara, H. Heteroat. Chem. 2002, 13, 195–198.
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