A facile synthesis of 2-amino-1,3-selenazole by reaction of N,N-unsubstituted selenourea with ketone

Article abstract of DOI:10.1002/hc.20180

2-Dialkylamino-1,3-selenazoles were yielded by the reaction of N,N-unsubstituted selenoureas with ketones in the presence of ferric chloride.

Full text of DOI:10.1002/hc.20180

Heteroatom Chemistry
Volume 17, Number 2, 2006
A Facile Synthesis of 2-Amino-1,3-selenazole
by Reaction of N,N-Unsubstituted Selenourea
with Ketone
Mamoru Koketsu,1 Koichi Kanoh,2 Hiromune Ando,1
and Hideharu Ishihara2
1Division of Instrumental Analysis, Life Science Research Center, Gifu University,
Gifu 501-1193, Japan
2Department of Chemistry, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan
Received 8 June 2005; revised 7 August 2005
ses of 2-dialkylamino-1,3-selenazoles by the reaction
ABSTRACT: 2-Dialkylamino-1,3-selenazoles were
of selenoureas with ketones. This method would pro-
vide a new route to selenazoles without the use of
lachrymatory halo carbonyl compounds.
yielded by the reaction of N,N-unsubstituted sele-
noureas with ketones in the presence of ferric chlo-
ꢀ
C
ride.
2006 Wiley Periodicals, Inc. Heteroatom Chem
17:88–92, 2006; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20180
RESULTS AND DISCUSSION
Various reactions were investigated to establish
optimal conditions for the synthesis of 4-methyl-
2-piperidino-1,3-selenazoles 3f. The reaction of
1-selenocarbamoylpiperidine 1e with acetone 2b
was carried out under an argon atmosphere. When
reaction was carried out at reflux with acid or base
such as BF3·Et2O, HCl, acetic acid, triethylamine, or
di-isopropylethylamine, unidentifiable mixtures re-
sulted. The reaction with ferric chloride yielded 3f
after a shorter time in higher yield. Next, the opti-
mal solvent was investigated in the presence of ferric
chloride. When ethanol, dichloromethane, and THF
were used as a reaction solvent, the reaction using
ethanol gave 3f exclusively after a shorter time in
high yields.
Using the optimal reaction conditions, several
2-amino-1,3-selenazoles 3a–l were prepared from
the reaction of corresponding N,N-unsubstituted
selenoureas 1 with ketones 2 in the presence of ferric
chloride (Scheme 1). The reaction gave 3 in moder-
ate to high yields in the present study (Table 1). The
reactions using aromatic ketone (3h in 32% yield)
INTRODUCTION
There are many selenium-containing heterocyclic
compounds found in the literature [1]. Of these many
are potential pharmaceutical and dye agents [2]. The
use of selenourea as the precursor is one of the
most efficient methods for the synthesis of hetero-
cyclic compounds containing selenium [3]. Recently,
2-dialkylamino-1,3-selenazole has become of inter-
est as a starting material for preparing dyes. They
are prepared according to the well-known method
[4] from selenoureas and have been converted suc-
cessfully into corresponding azo dye and squarylium
dyes [5]. This result stimulates us to prepare these
compound derivatives. We describe here the synthe-
Correspondence to: Mamoru Koketsu; e-mail: koketsu@cc.gifu-
u.ac.jp.
Contract grant sponsor: Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Contract grant numbers: 15550030 and 17550099.
2006 Wiley Periodicals, Inc.
c
ꢀ
88

A Facile Synthesis of 2-Amino-1,3-selenazole by Reaction of N,N-Unsubstituted Selenourea with Ketone 89
1,3-selenazole was prepared by allowing the ke-
tone to react with iodine (or hypervalent iodine)
and selenourea (H2N C( Se) NH2) [7]. In the
present study, it was confirmed that reacting N,N-
unsubstituted selenourea 1 with ketone 2 in the pres-
ence of ferric chloride gives easily the corresponding
2-dialkylamino-1,3-selenazole 3.
SCHEME 1
and ketones-bearing bulky groups (in the case of
tertiary butyl group, 5% yield, data not shown) all
gave 3 in low yields. The existence of ferrous chlo-
ride, FeCl2, in the reaction mixture was confirmed
by the addition of potassium ferricyanide. The
1 J (77Se–13C) values (in the case of 3f, J = 93.6 Hz)
at the C5 carbon and the 2 J (77Se–1H) values (in the
case of 3f, J = 52.1 Hz) at the C5 proton of 3 were
clearly observed on the proton-decoupled 13C NMR
and 1H NMR spectra. Although in the case of 3f the
isomeric 5-methyl-1,3-selenazole is a possible prod-
uct, the possibility of its formation was ruled out
by the observation of the 2 J (77Se–1H) values and
1 J(77Se–13C) values at the C5 carbon of 3.
In order to elucidate the reaction mecha-
nism for the formation of compound 3, the re-
action of selenourea, 1-selenocarbamoylpiperidine
1e, with methyl vinyl ketone in methanol was
attempted under similar conditions. This reac-
tion afforded 4-methoxy-4-methyl-5-methylene-2-
piperidino-4,5-dihydro-1,3-selenazole 4 in 79% yield
(Scheme 2). In the case of compound 4, elimina-
tion of alcohol from the selenazole ring could not
proceed due to the lack of a proton at the C5 car-
bon. The formation of 4 was initiated by the nucle-
ophilic addition of the nitrogen atom of selenourea
1 on the carbonyl carbon, affording the 4-methoxy-
4,5-dihydro-1,3-selenazole 4.
EXPERIMENTAL
General
Selenoureas were synthesized according to previ-
ously described procedures [8]. The 77Se chemical
shifts are expressed in ppm deshielded with respect
to near Me2Se in CDCl3. 2 J (77Se–1H) values and
1 J (77Se–13C) values are of the 77Se satellites of the
1H NMR spectra and proton-decoupled 13C NMR
spectra.
General Procedure for Synthesis of 2-Dimethyl-
amino-4,5,6,7-tetrahydrobenzo-1,3-selenazole 3a
Cyclohexanone 2a (0.10 mL, 0.9 mmol) was added
to a stirred solution of N,N-dimethylselenourea 1a
(45 mg, 0.3 mmol) in dry ethanol (3 mL) under an ar-
gon atmosphere. Ferric chloride (0.19 g, 1.2 mmol)
was added into the reaction mixture. The reaction
mixture was refluxed for 2 h. The mixture was ex-
tracted with diethyl ether and washed with H2O.
The organic layer was dried over sodium sulfate
and evaporated to dryness. The residue was pu-
rified by flash chromatography on silica gel with
dichloromethane: n-hexane (2:1) to give 3a (70 mg,
quantitative) as yellow liquid. IR (neat): 2928, 1558
The formation of 3 could be explained by
the following mechanism: the reaction of N,N-
unsubstituted selenourea 1 with ketone 2 is initiated
by the nucleophilic addition of the nitrogen of
the selenourea to the carbonyl carbon, afford-
ing 2-amino-1,3-selenazole 3 (Scheme 3). Previ-
ously, it was reported that the reaction of N,N-
unsubstituted selenoureas with ꢀ-halocarboxylic
acid led to the formation of 2-amino-1,3-selenazol-
4-ones under reflux conditions [6], and 2-amino-
1
cm−1; H NMR (500 MHz, CDCl3) δ 1.75–1.83 (4H,
m, CH2), 2.56–2.59 (2H, m, CH2), 2.67–2.69 (2H, m,
CH2), 3.04 (6H, s, CH3); 13C NMR (125 MHz, CDCl3)
δ 23.1, 23.9, 25.4, 27.9, 41.0, 121.1, 147.1, 170.5; 77Se
NMR (95 MHz, CDCl3) δ 554.2; MS (FAB): m/z = 230
[M+].
2-Diethylamino-4,5,6,7-tetrahydrobenzo-1,3-
selenazole 3b
1
Yellow liquid. IR (neat): 2930, 1544 cm−1; H NMR
(500 MHz, CDCl3): δ 1.21 (6H, t, J = 7.2 Hz, CH3),
1.76–1.81 (4H, m, CH2), 2.54–2.57 (2H, m, CH2),
2.65–2.68 (2H, m, CH2), 3.42 (4H, q, J = 7.2 Hz, CH2);
13C NMR (125 MHz, CDCl3): δ 12.7, 23.2, 23.9, 25.4,
27.9, 46.0, 119.7, 146.9, 168.7; 77Se NMR (95 MHz,
CDCl3): δ 550.5; MS (CI): m/z = 259 [M+ + 1].
SCHEME 2

90 Koketsu et al.
TABLE 1 Synthesis of 2-Amino-1,3-selenazoles 3
2-Amino-1,3-selenazole 3
Product
Selenourea 1
Ketone 2
Yield (%)a
1a
2a
3a
Quant.
1b
2a
3b
87
1c
1d
2a
2a
3c
3d
83
Quant.
1e
2a
3e
97
85
1e
1e
2b
2c
3f
3g
73
32
1e
1e
2d
2e
3h
3i
20
3j
52
45
1e
2f
3k
3l
19
aIsolated yield. Reaction conditions: ketone 2 (3 equiv.), selenourea 1 (1 equiv.), dry ethanol, ferric chloride (4 equiv.), reflux, 2 h.

A Facile Synthesis of 2-Amino-1,3-selenazole by Reaction of N,N-Unsubstituted Selenourea with Ketone 91
SCHEME 3
2.21 (3H, s, CH3), 3.40–3.42 (4H, m, CH2), 6.56 (1H,
s, CH) (2 J (77Se–1H) = 52.1 Hz); 13C NMR (125 MHz,
CDCl3): δ 18.7, 24.2, 25.2, 50.7, 103.9, 150.2 (1 J (77Se–
13C) = 93.6 Hz), 173.5; 77Se NMR (95 MHz, CDCl3):
δ 549.4; MS (CI): m/z = 231 [M+ + 1].
2-Morpholino-4,5,6,7-tetrahydrobenzo-1,3-selen-
azole 3c
Pink solid. mp: 52.0–54.0◦C; IR (KBr): 2922, 2857,
1
1547 cm−1; H NMR (500 MHz, CDCl3): δ 1.77–1.83
(4H, m, CH2), 2.55–2.58 (2H, m, CH2), 2.68–2.70 (2H,
m, CH2), 3.38 (4H, t, J = 4.9 Hz, CH2), 3.77 (4H, t,
J = 4.9 Hz, CH2); 13C NMR (125 MHz, CDCl3): δ 23.0,
23.8, 25.4, 27.8, 49.5, 66.2, 122.4, 146.8, 171.5; 77Se
NMR (95 MHz, CDCl3): δ 562.5; MS (CI): m/z = 273
[M+ + 1].
4-Ethyl-5-methyl-2-piperidino-1,3-selenazole 3g
1
Yellow liquid. IR (neat): 2935, 2855, 1540 cm−1; H
NMR (500 MHz, CDCl3): δ 1.16 (3H, t, J = 7.7 Hz,
CH3), 1.59–1.67 (6H, m, CH2), 2.28 (3H, s, CH3), 2.44
(2H, q, J = 7.7 Hz, CH3), 3.32–3.37 (4H, m, CH2); 13
C
2-Pyrrolidino-4,5,6,7-tetrahydrobenzo-1,3-selen-
azole 3d
NMR (125 MHz, CDCl3): δ 12.9, 13.9, 22.6, 24.3, 25.2,
50.5, 117.9, 150.5, 170.2; 77Se NMR (95 MHz, CDCl3):
δ 580.6; MS (CI): m/z = 259 [M+ + 1].
Yellow solid. mp 75.0–78.5◦C; IR (KBr): 2924,
1
1540 cm−1; H NMR (500 MHz, CDCl3): δ 1.76–1.83
(4H, m, CH2), 1.98–2.03 (4H, m, CH2), 2.58–2.60
(2H, m, CH2), 2.67–2.70 (2H, m, CH2), 3.38–3.41
(4H, m, CH2); 13C NMR (125 MHz, CDCl3): δ 23.1,
23.9, 25.46, 25.51, 27.9, 50.1, 120.1, 147.0, 166.7; 77Se
NMR (95 MHz, CDCl3): δ 551.1; MS (CI): m/z = 257
[M+ + 1].
4-Phenyl-2-piperidino-1,3-selenazole 3h [4]
Yellow liquid. IR (neat): 2935, 2847, 1543 cm−1;
1H NMR (500 MHz, CDCl3): δ 1.63–1.71 (6H, m,
CH2), 3.51 (4H, t, J = 5.2 Hz, CH2), 7.25 (1H, t,
J = 7.5 Hz, CH), 7.28 (1H, s, CH), 7.34 (2H, dd,
J = 7.5, 8.3 Hz, CH), 7.85 (2H, d, J = 8.3 Hz, CH);
13C NMR (125 MHz, CDCl3): δ 24.3, 25.3, 50.8, 104.9
(1 J (77Se–13C) = 97.2 Hz), 126.3, 127.2, 128.4, 136.1,
152.8, 172.8; 77Se NMR (95 MHz, CDCl3): δ 575.9; MS
(CI): m/z = 293 [M+ + 1].
2-Piperidino-4,5,6,7-tetrahydrobenzo-1,3-selena-
zole 3e
1
Yellow liquid. IR (neat): 2931, 2939, 1535 cm−1; H
NMR (500 MHz, CDCl3): δ 1.63–1.66 (6H, m, CH2),
1.75–1.82 (4H, m, CH2), 2.53–2.57 (2H, m, CH2),
4-Butyl-2-piperidino-1,3-selenazole 3i
Orange liquid. IR (neat): 2934, 2856, 1534 cm−1; H
2.66–2.68 (2H, m, CH2), 3.34–3.39 (4H, m, CH2); 13
C
1
NMR (125 MHz, CDCl3): δ 23.1, 23.8, 24.2, 25.1, 25.4,
27.8, 50.5, 120.9, 146.6, 171.1; 77Se NMR (95 MHz,
CDCl3): δ 556.7; MS (CI): m/z = 271 [M+ + 1].
NMR (500 MHz, CDCl3): δ 0.92 (3H, t, J = 7.5 Hz,
CH3), 1.33–1.39 (2H, m, CH2), 1.59–1.66 (10H, m,
CH2), 2.52 (2H, t, J = 7.5 Hz, CH2), 3.40–3.43 (4H, m,
CH2), 6.57 (1H, s, CH) (2 J (77Se–1H) = 52.1 Hz); 13C
NMR (125 MHz, CDCl3): δ 14.0, 22.5, 24.3, 25.3, 30.8,
32.9, 50.7, 103.1, 155.4, 173.5; 77Se NMR (95 MHz,
CDCl3): δ 544.4; MS (CI): m/z = 273 [M+ + 1].
4-Methyl-2-piperidino-1,3-selenazole 3f [4]
1
Yellow liquid. IR (neat): 2936, 2853, 1534 cm−1; H
NMR (500 MHz, CDCl3): δ 1.64–1.68 (6H, m, CH2),

92 Koketsu et al.
REFERENCES
4-Methyl-2-piperidino-5-propyl-1,3-selenazole 3j
1
Orange liquid. IR (neat): 2933, 2855, 1535 cm−1; H
[1] (a) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.
Comprehensive Heterocyclic Chemistry II; Pergamon
Press: New York, 1996; Vols. 1–11; (b) Back, T. G.
Organoselenium Chemistry: A Practical Approach;
Oxford University Press: New York, 1999; (c) Wirth, T.
Organoselenium Chemistry. Modern Developments
in Organic Synthesis; Springer: New York, 2000; (d)
Murai, T.; Kato, S. Top Curr Chem 2000, 208, 177; (e)
Ishihara, H.; Koketsu, M.; Fukuta, Y.; Nada, F. J Am
Chem Soc 2001, 123, 8408.
NMR (500 MHz, CDCl3): δ 0.95 (3H, t, J = 7.5 Hz,
CH3), 1.54–1.68 (8H, m, CH2), 2.10 (3H, s, CH3), 2.59
(2H, t, J = 7.5 Hz, CH2), 3.34–3.36 (4H, m, CH2); 13
C
NMR (125 MHz, CDCl3): δ 13.5, 15.5, 24.2, 25.2, 26.0,
30.4, 50.4, 125.3 (1 J (77Se–13C) = 92.4 Hz), 143.9,
170.2; 77Se NMR (95 MHz, CDCl3): δ 561.5; MS (CI):
m/z = 273 [M+ + 1].
[2] (a) Koketsu, M.; Ishihara, H.; Wu, W.; Murakami, K.;
Saiki, I. Eur J Pharm Sci 1999, 9, 157; (b) Wu, W.;
Murakami, K.; Koketsu, M.; Yamada, Y.; Saiki, I. Anti-
cancer Res 1999, 19, 5375; (c) Cho, S. I.; Koketsu, M.;
Ishihara, H.; Matsushita, M.; Nairn, A. C.; Fukazawa,
H.; Uehara, Y. Biochim Biophys Acta 2000, 1475, 207;
(d) Koketsu, M.; Yang, H. O.; Kim, Y. M.; Ichihashi,
M.; Ishihara, H. Org Lett 2001, 3, 1705; (e) Koketsu,
M.; Choi, S. Y.; Ishihara, H.; Lim, B. O.; Kim, H.; Kim,
S. Y. Chem Pharm Bull 2002, 50, 1594; (f) Gutzkow,
K. B.; La˚hne, H. U.; Naderi, S.; Torgersen, K. M.;
Ska˚lhegg, B.; Koketsu, M.; Uehara, Y.; Blomhoff,
H. K. Cell Signal 2003, 15, 871; (g) Park, Y.-J.;
Koketsu, M.; Kim, J. M.; Yeo, J.-H.; Ishihara, H.; Lee,
K.-G.; Kim, S. Y.; Kim, C.-K. Biol Pharm Bull 2003,
26, 1657.
4-(2-Methylpropyl)-2-piperidino-1,3-selenazole
3k
1
Orange liquid. IR (neat): 2937, 2864, 1534 cm−1; H
NMR (500 MHz, CDCl3): δ 0.91 (6H, d, J = 6.9 Hz,
CH3), 1.62–1.67 (6H, m, CH2), 1.96–2.07 (1H, m, CH),
2.36 (2H, d, J = 7.5 Hz, CH2), 3.39–3.41 (4H, m, CH2),
6.56 (1H, s, CH) (2 J (77Se–1H) = 52.1 Hz); 13C NMR
(125 MHz, CDCl3): δ 22.5, 24.3, 25.2, 27.7, 42.5, 50.7,
104.3 (1 J (77Se–13C) = 93.6 Hz), 154.3, 173.4; 77Se
NMR (95 MHz, CDCl3): δ 542.6; MS (CI): m/z = 273
[M+ + 1].
[3] (a) Takahashi, M.; Watanabe, S.; Kasai, T. Heterocy-
cles 1980, 14, 1921; (b) Kristian, P.; Koscik, D.; Gonda,
J. Collect Czech Chem Commun 1983, 48, 3567; (c)
Maslankiewicz, A.; Skrzypek, L.; Niedbala, A. Pol J
Chem 1996, 70, 54; (d) Keil, D.; Hartmann, H. Phos-
phorus Sulfur Silicon Relat Elem 1999, 152, 169; (e)
Shafiee, A.; Ebrahimzadeh, M. A.; Maleki, A. J Hete-
rocycl Chem 1999, 36, 901; (f) Koketsu, M.; Suzuki,
N.; Ishihara, H. J Org Chem 1999, 64, 6473; (g) Zhou,
Y.; Linden, A.; Heimgartner, H. Helv Chim Acta 2000,
83, 1576; (h) Attanasi, O. A.; Filippone, P.; Guidi, B.;
Perrulli, F. R.; Santeusanio, S. Synlett 2001, 144.
[4] Keil, D.; Hartmann, H. Phosphorus Sulfur Silicon
Relat Elem 1999, 152, 169.
4-Methyl-5-(2-methylethyl)-2-piperidino-1,3-
selenazole 3l
Yellow solid. mp: 38.0–40.0◦C; IR (KBr): 2934, 2853,
1541 cm−1; 1H NMR (500 MHz, CDCl3): δ 1.20 (6H, d,
J = 6.9 Hz, CH3), 1.59–1.67 (6H, m, CH2), 2.12 (3H, s,
CH3), 3.00–3.07 (1H, m, J = 6.9 Hz, CH), 3.37 (4H, t,
J = 5.2 Hz CH2); 13C NMR (125 MHz, CDCl3): δ 15.7,
24.3, 25.3, 26.1, 29.2, 50.4, 134.3, 142.0, 170.0; 77Se
NMR (95 MHz, CDCl3): δ 528.9; MS (CI): m/z = 273
[M+ + 1].
[5] (a) Keil, D.; Hartmann. H. Dyes and Pigments 2000,
44, 149; (b) Keil, D.; Hartmann. H.; Zug, I.; Schroder,
A. J Prakt Chem 2000, 42, 169.
[6] (a) Geisler, K.; Ku¨ nzler, A.; Below, H.; Bulka, E.;
Pfeiffer, W.-D.; Langer, P. Synthesis 2004, 97;
(b) Geisler, K.; Pfeiffer, W.-D.; Ku¨ nzler, A.; Below, H.;
Bulka, E.; Langer, P. Synthesis 2004, 875.
[7] (a) King, L. C.; Hlavacek, R. J. J Am Chem Soc 1951,
73, 1864; (b) Moriarty, R. M.; Vaid, B. K.; Duncan,
M. P.; Levy, S. G.; Prakash, O.; Goyal, S. Synthesis
1992, 845; (c) Zhang, P.-F.; Chen, Z.-C. Synthesis 2000,
1219.
4-Methoxy-4-methyl-5-methylene-2-piperidino-
4,5-dihydro-1,3-selenazole 4
1H NMR (500 MHz, CDCl3): δ 1.60–1.68 (6H, m,
CH2), 2.17 (3H, s, CH3), 3.33 (3H, s, CH3), 3.38–3.43
(4H, m, CH2), 3.00–3.07 (1H, m, J = 6.9 Hz, CH),
4.46 (2H, S, CH2); 13C NMR (125 MHz, CDCl3): δ
15.7, 24.1, 25.1, 50.4, 56.9, 67.9, 120.22 (1 J (77Se–
13C) = 91.2 Hz), 147.6, 171.9; 77Se NMR (95 MHz,
CDCl3): δ 564.5; MS (CI): m/z = 274 [M+ + 1].
[8] (a) Koketsu, M.; Fukuta, Y.; Ishihara, H.; Tetrahedron
Lett 2001, 42, 6333; (b) Koketsu, M.; Takakura, N.;
Ishihara, H. Synth Commun 2002, 32, 3075.