H. Below, W.-D. Pfeiffer, K. Geisler, M. Lalk, P. Langer
SHORT COMMUNICATION
solution of the ketone was portionwise added crude seleno-
formamide until the reaction was complete (monitoring of
the reaction by HPLC). The cyclizations were carried out
in the presence of either pyridine or the acidic ion exchange
resin Amberlite IR-120; the absence of base or the use of
sodium acetate resulted in formation of considerable
amounts of diphenacyl selenides (ArCOCH2)2Se. The latter
were formed as side-products, even under optimized condi-
tions, and had to be separated by precipitation. The 1,3-
selenazoles were finally isolated by crystallization or by pre-
parative HPLC.
Scheme 2. Synthesis of parent 1,3-selenazole.
Experimental Section
Synthesis of 1,3-Selenazole (5): 1-Bromo-2,2-diethoxyethane
(2.92 g, 14.8 mmol) was hydrolyzed by stirring with concentrated
hydrochloric acid (2.9 mL) at 50–60 °C for 30 min. The mixture
was cooled to 10 °C and MeOH (10 mL) was added. To the solu-
tion was portionwise added pyridine (0.82 mL); subsequently, an
MeOH solution (10 mL) of selenoformamide (1) was portionwise
added at 35 °C. The progress of the reaction was monitored by
HPLC. After stirring at 35 °C for 12 h, the mixture was poured
into H2O and an aqueous solution of NaOH (10 ) was added
until the solution was adjusted to pH = 3.6. The solution was ex-
tracted with diethyl ether (4×50 mL) and the combined organic
layers were extracted with hydrochloric acid (3.5%, 50 mL). To the
aqueous layer was added an aqueous solution of NaOH (10 ) un-
til the solution was adjusted to pH = 3.6; subsequently, the solution
was extracted again with diethyl ether. This procedure was repeated
until pyridine could not be detected anymore by HPLC. The com-
bined organic layers were dried (Na2SO4), filtered and most of the
solvent was removed by distillation in vacuo to give a brownish oil
(0.050 g, 3%), b.p. 128.5 °C (determined by gas chromatography).
All attempts to remove a rest of solvent resulted in decomposition
(product/solvent = 2:1). A small amount of an unknown impurity
Scheme 1. Cyclization of selenoformamide with α-bromo ketones.
Table 1. Products and yields.
3
R
Yield [%] 3[a]
Method[b]
a
a
b
c
d
e
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
4-(MeO)C6H4
4-(O2N)C6H4
13
22
9
20
6
A
B
A
B
B
A
could not be removed. IR (KBr): ν = 728 (m), 789 (s), 844 (w), 1020
˜
(m), 1396 (s), 1438 (m), 1489 (s), 1651(m), 2926 (w), 3074 cm–1. 1H
2
NMR (300 MHz, CDCl3): δ = 8.01 (d, J4,5 = 3.7, JSeH = 50.23, 1
3
H, 5-H), 8.06 (q, JSeH = 65.9 Hz, 1 H, 4-H), 9.92 (d, J2,5 = 0.8,
28
2JSeH = 60.29, 1 H, 2-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
124.61 (C-5), 143.90 (C-4), 159.28 (C-2) ppm. 77Se NMR (CDCl3,
60% Me2Se in CDCl3): δ = 728.9 ppm. MS (EI, 70 eV): m/z (%) =
128/129 (18/15), 130/132 (48/100), 134 (15) [M+], 108 (9), 106 (50),
104 (24), 103 (8), 102 (9), 82 (3), 80 (18), 78 (7), 77 (3), 76 (3), 51
(2). HR-FTICR-MS: calcd. for C3H4NSe [M + H]+: 133.95089;
found: 133.95017 (∆m = 5.4 ppm).
[a] Isolated yields. [b] A: Amberlite IR-120, B: pyridine.
The synthesis of parent 1,3-selenazole by our methodol-
ogy proved to be difficult, due to its unstable nature and
volatility. Eventually, 1,3-selenazole (5) was successfully
prepared by pyridine-mediated cyclization of selenoform-
amide with bromoacetaldehyde (4) which was generated
by treatment of 1-bromo-2,2-diethoxyethane with HCl
(Scheme 2). 1,3-Selenazole was obtained in 3% yield as a
brownish, unstable oil; all attempts to remove a rest of sol-
vent resulted in decomposition. A small amount of an un-
known impurity could not be removed, due to decomposi-
tion. The boiling point was estimated by gas chromatog-
raphy (128.5 °C) and the structure was confirmed by spec-
troscopic methods. In the 1H NMR spectrum (CDCl3),
three signals are observed at δ = 8.01 (5-H), 8.06 (4-H) and
Acknowledgments
We are grateful to Prof. Dr. med. Axel Kramer (Institute of Hy-
giene and Environmental Medicine, University of Greifswald) for
his generous support of this work and Mrs. Rita Schroeder for
experimental contributions. Financial support by the state of
Mecklenburg-Vorpommern (Landesforschungsschwerpunkt “Neue
Wirkstoffe und Screeningverfahren”) is gratefully acknowledged.
9.92 (2-H) ppm exhibiting the expected coupling constants [1] a) R. Larsen, 1,3-Selenazoles, in: Comprehensive Heterocyclic
Chemistry II (Eds.: I. Shinkai, A. R. Katritzky, C. W. Rees,
JHH and JSeH. A low-field shift is observed for 2-H and 5-
E. F. V. Scriven), Elsevier Science: Oxford, 1996, vol. 3, pp.
H relative to the respective signals of thiazole [CDCl3; δ =
493–510; b) W. D. Pfeiffer, 1,3-Selenazoles, in: Science of Syn-
thesis (Ed.: E. Schaumann), Thieme Verlag: Stuttgart, New
7.41 (5-H), 7.98 (4-H) and 8.88 (2-H)]. The 13C NMR spec-
trum of 1,3-selenazole shows three signals at δ = 124.61 (C-
5), 143.90 (C-4) and 159.28 (C-2) ppm. As expected, a sin-
gle signal is observed by 77Se NMR (δ = 728.9 ppm). The
mass spectrum (EI) exhibits the characteristic pattern for
the presence of a selenium atom; the exact mass for
C3H4NSe was confirmed by HR-FTICR.
York, 2002, vol. 11, pp. 941–989; c) I. Lalezari, M. Shafiee, 1,3-
Selenazoles, in: Comprehensive Heterocyclic Chemistry (Eds.:
A. R. Katritzky, C. W. Rees, K. T. Potts), Elsevier Science, Ox-
ford, 1984, vol. 6, pp. 333–363; d) T. Wirth, Organoselenium
Chemistry, in: Modern Developments in Organic Synthesis,
Springer, Berlin, 2000; e) M. Koketsu, H. Ishihara, Curr. Org.
Chem. 2003, 7, 175.
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Eur. J. Org. Chem. 2005, 3637–3639