Efficient synthesis of 2-unsubstituted 1,3-selenazoles

Article abstract of DOI:10.1055/s-2003-39884

Two new and efficient methods for the synthesis of 2-unsubstituted 1,3-selenazoles, the fragmentation of 2-benzoyl-1,3-selenazoles and the cyclization of α-bromoketones with selenoformamide, are reported.

Full text of DOI:10.1055/s-2003-39884

LETTER
1195
Efficient Synthesis of 2-Unsubstituted 1,3-Selenazoles
Efficient
S
ynthesis
a
of 2-Unsu
r
bstituted
l
1,3-Se
h
lenazoles einz Geisler,* Andreas Künzler, Harald Below, Ehrenfried Bulka, Wolf-Diethard Pfeiffer, Peter Langer*
Institut für Chemie und Biochemie der Ernst-Moritz-Arndt-Universität Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
E-mail: peter.langer@uni-greifswald.de
Received 5 March 2003
Reflux
EtOH
Ph
Abstract: Two new and efficient methods for the synthesis of 2-
unsubstituted 1,3-selenazoles, the fragmentation of 2-benzoyl-1,3-
selenazoles and the cyclization of a-bromoketones with seleno-
formamide, are reported.
O
Ph
H2N
Ph
N
Ph
+
_
H2O
HBr
Se
2a
Se
Br
_
3a (99%)
1a
Key words: cyclization, fragmentation, selenium heterocycles, ox-
idation, 1,3-selenazoles
K2Cr2O7, AcOH
or
SeO2, Dioxane
1,3-Selenazoles are of considerable pharmacological rele-
vance.1–3 The synthesis of 2-unsubstituted 1,3-selenazoles
has been a long-standing problem and only relatively few
derivatives have been prepared to date. Haginiwa et al.
have obtained 4-methylselenazole by reaction of HCN,
H2Se and chloroacetone, however, in only 3% yield.4
Recently, Sonoda et al. have reported the synthesis of 2-
unsubstituted 1,3-selenazoles by reaction of ethyl iso-
cyanoacetate with isoselenocyanates.5 However, this
method is limited to the synthesis of 4,5-disubstituted de-
rivatives. In addition, only arylamino-substituted selen-
azoles could be prepared, due to the nature of the starting
materials employed. Herein, we wish to report a new and
convenient method for the synthesis of 2-unsubstituted
1,3-selenazoles which relies on the fragmentation of novel
2-benzoyl-1,3-selenazoles.6 In addition, a second ap-
proach to 2-unsubstituted 1,3-selenazoles by cyclization
of selenoformamide with a-bromoketones is reported.
Ph
Ph
N
N
NaOH
Ph
Ph
O
Na+
_
O
Se
Se
EtOH
H2O
HO
A
4a (70%)
Ph
Ph
N
O
N
O
_
+
_
Na+
Se
Ph
O
O
Na+
Se
5a (84%)
(0%)
Scheme 1 Synthesis of 2-unsubstituted 1,3-selenazole 5a
The formation of 5a can be explained by addition of a hy-
droxide ion to the carbonyl group to give tetrahedral inter-
mediate A (Scheme 1). Due to steric hindrance of the aryl
groups, a heterolytic fragmentation occurred.10 The for-
mation of 4-phenyl-1,3-selenazole-2-carboxylic acid was
not observed. The regioselectivity of fragmentation can be
explained by stabilization of the negative charge in a 1,3-
selenazolyl carbanion (by interaction of the electrons with
the unoccupied selenium orbitals) and subsequent proto-
nation of the latter by benzoic acid (Figure 1).
The cyclization of a-bromoacetophenone (1a) with sele-
nophenylacetic amide (2a), prepared from phenylacetoni-
trile and P2Se5,3b afforded 2-benzyl-4-phenyl-1,3-
selenazole (3a) in 99% yield (Scheme 1).7 The oxidation
of 3a with K2Cr2O7 in glacial acetic acid gave 2-benzoyl-
4-phenyl-1,3-selenazole (4a). The yield could be im-
proved by the use of SeO2 in 1,4-dioxane.8 After several
trial experimentations we have found that treatment of an
EtOH solution of 4a with NaOH (reflux) afforded the de-
sired 2-unsubstituted 1,3-selenazole 5a in 84% yield (58%
overall yield from 1a). In addition, sodium benzoate was
formed which was isolated in the form of benzoic acid.
During the optimization of the fragmentation reaction, the
base, solvent, concentration and reaction time proved im-
portant parameters.9
R2
R3
R2
R3
R2
R3
R1
N
N
N
R1
Se
Se
Se
O
3a–g
4a–g
5a–e
Figure 1
The preparative scope of our methodology was studied.
The reaction of a-bromoketones with selenocarboxylic
amides afforded the 1,3-selenazoles 3a–g, containing
benzyl-, p-chlorobenzyl- and p-nitrobenzyl groups at car-
bon C-2, in 60–100% yields (Table 1). The oxidation of
3a–g afforded the 2-benzoyl-1,3-selenazoles 4a–g. In
most cases the yields were significantly higher when SeO2
rather than K2Cr2O7 was used.
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1195,1197,ftx,en;D05403ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1196
K. Geisler et al.
LETTER
Table 1 Synthesis of 1,3-Selenazoles 3a–g and 4a–g
H2N
H2N
O
P2Se5
neat
H
H
3,4 R1
R2
R3
% (3)a % (4)a
Se
ib
iib
6 (34%)
a
b
c
d
e
f
C6H5
C6H5
H
99
77
64 70
EtOH, Pyr
40 °C
R
O
R
N
+
6
C6H5
4-Me(C6H4)
4-Br(C6H4)
4-NO2(C6H4)
C6H5
H
–
74
_
_
H2O
HBr
Se
Br
C6H5
H
100
88
60 80
76 70
5d (79%)
1d
C6H5
H
R = 4-NO2(C6H4)
C6H5
C6H5
H
88
70
–
Scheme 2 Cyclization of selenoformamide with a-bromoketone 1d
4-Cl(C6H4)
4-NO2(C6H4)
C6H5
60
45 84
53 72
g
C6H5
H
78
Acknowledgment
a Isolated yields.
b i: K2Cr2O7, HOAc; ii: SeO2, 1,4-dioxane.
Financial support from the Deutsche Forschungsgemeinschaft
(Heisenberg-scholarship for P. L. and Normalverfahren) is grate-
fully acknowledged.
References
The NaOH/EtOH mediated fragmentation of 2-benzoyl-
1,3-selenazoles 4a–e (R1 = C6H5) afforded the 2-unsubsti-
tuted 1,3-selenazoles 5a–e in 71–90% yields (Table 2).
The effect of R1 on the yield was next studied. The best
yields of 5a (84%) were obtained when 4a or 4g was used
as the starting materials [R1 = C6H5, 4-NO2(C6H4)]. The
use of chloro derivative 4f was less efficient. For protons
2-H, low field resonances in the range of d = 10.13 (5e)
–10.23 (5d) ppm were observed (DMSO-d6).
(1) For the antibiotically active C-glycosyl selenazole
selenazofurin, see: (a) Goldstein, B. M.; Kennedy, S. D.;
Hennen, W. J. J. Am. Chem. Soc. 1990, 112, 8265; and
references cited therein. (b) Shafiee, A.; Khashayarmanesh,
Z.; Kamal, F. J. Sci., Islamic Repub. Iran 1990, 1, 11.
(c) Shafiee, A.; Shafaati, A.; Khamench, B. H. J. Heterocycl.
Chem. 1989, 26, 709. (d) For cancerostatic activity of 1,3-
selenazoles see: Srivastava, P. C.; Robins, R. K. J. Med.
Chem. 1983, 26, 445. (e) Shafiee, A.; Mazloumi, A.; Cohen,
V. J. J. Heterocycl. Chem. 1979, 16, 1563.
(2) (a) Larsen, R. 1,3-Selenazoles, In Comprehensive
Heterocyclic Chemistry II, , Shinkai I., Katritzky A., Rees C.
W., Scriven E. F. V., Vol. 3; Elsevier Science: Oxford, 1996,
Chap. 8. (b) Wirth, T. Organoselenium Chemistry, in
Modern Developments in Organic Synthesis; Springer:
Berlin, 2000.
(3) (a) Koketsu, M.; Nada, F.; Ishihara, H. Synthesis 2002, 195.
(b) Geisler, K.; Jacobs, A.; Künzler, A.; Mattes, M.; Girrleit,
I.; Zimmermann, B.; Bulka, E.; Pfeiffer, W.-D.; Langer, P.
Synlett 2002, 1983. (c) Kaminski, R.; Glass, R. S.;
Skowronska, A. Synthesis 2001, 1308. (d) Ishihara, H.;
Koketsu, M.; Fukuta, Y.; Nada, F. J. Am. Chem. Soc. 2001,
123, 8408. (e) Koketsu, M.; Fukuta, Y.; Ishihara, H.
Tetrahedron Lett. 2001, 42, 6333. (f) Zhang, P.-F.; Chen,
Z.-C. Synthesis 2000, 1219. (g) Maeda, H.; Kambe, N.;
Sonoda, N.; Fujiwara, S.-i.; Sini-ike, T. Tetrahedron 1997,
53, 13667. (h) Lai, L.-L.; Reid, D. H. Synthesis 1993, 870.
(i) Ogawa, A.; Miyaka, J.; Karasaki, Y.; Murai, S.; Sonoda,
N. J. Org. Chem. 1985, 50, 384. (j) Cohen, V. J. Synthesis
1978, 668.
(4) Haginiwa, J. Yakugaku Zasshi 1948, 68, 191.
(5) Maeda, H.; Kambe, N.; Sonoda, N.; Fujiwara, S.-i.; Sini-ike,
T. Tetrahedron 1997, 53, 13667; and references cited
therein.
(6) For 2-benzoyl-1,3-benzoselenazole, see: Mbuyi, M.; Evers,
M.; Tihange, G.; Luxen, A.; Christiaens, L. Tetrahedron
Lett. 1983, 5873.
(7) Synthesis of 2-Benzyl-4-phenyl-1,3-selenazole(3a).
Typical Procedure. An EtOH solution (20 mL) of a-
bromoacetophenone (0.20 g, 1.0 mmol) and phenylseleno-
acetic amide (0.20 g, 1.0 mmol) was refluxed for 5 min.
After cooling to 20 °C the precipitate was filtered off and
recrystallized from EtOH to give 3a as colourless needles
Some years ago some of us reported the synthesis of sele-
noformamide (6) by reaction of neat formamide with
P2Se5.11a,12 Herein, we wish to report the application of
this interesting small molecule to the synthesis of 1,3-sel-
enazoles.11b The cyclization of a-bromoketones with 6
provided an independent and useful approach to 2-unsub-
stituted 1,3-selenazoles: The reaction of 1d with 6 afford-
ed 1,3-selenazole 5d in 79% yield (Scheme 2).13 The
advantage of this methodology lies in the fact that only
two rather than four synthetic steps are required.
Table 2 Synthesis of 2-Unsubstituted 1,3-Selenazoles 5a–e
a
Educt 5
R2
R3
H
%
2-Hb
5-Hb
4a
4f
a
a
a
b
c
C6H5
84
60
84
90
83
71
77
10.16 8.69
10.16 8.69
10.16 8.69
10.15 8.60
10.15 8.76
10.23 9.06
C6H5
H
4g
4b
4c
4d
4e
C6H5
H
4-Me(C6H4)
4-Br(C6H4)
4-NO2(C6H4)
C6H5
H
H
d
e
H
C6H5
10.13c
–
a Isolated yields.
b 1H NMR (DMSO-d6) [ppm].
c CDCl3: 9.86 ppm.
Synlett 2003, No. 8, 1195–1197 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
(0.29 g, 99%), mp 99.5–100 °C. 1H NMR (300 MHz,
Efficient Synthesis of 2-Unsubstituted 1,3-Selenazoles
1197
129.35, 129.84, 133.96. 77Se NMR (CDCl3, 60% Me2Se in
CDCl3): d = 806.24, 135.25,149.18, 150.85, 156.78. IR
(KBr): 875 (m), 1080 (w), 1190 (w), 1270 (w), 1445 (s),
1495 (m), 1502 (m), 1605 (m), 3080 (m)cm–1. MS (70 eV):
m/z (%) = 285 (60) [M+], 257 (13), 204 (15) , 178 (100).
Anal. Calcd for C15H11NSe (284.22): C, 63.39; H, 3.90; N,
4.93. Found: C, 63.21; H, 3.94; N, 4.93.
CDCl3): d = 4.34 (s, 2 H, CH2), 7.31–7.90 (m, 10 H, Ar),
7.96 [s, 1 H, 2J (SeH) = 51.3 Hz, 5-H, selenazole]. 13C NMR
(75 MHz, CDCl3): d = 43.28, 118.86 [C-5, 1J (C5Se) = 106.6
Hz], 126.62, 127.33, 127.75, 128.70, 128.87, 129.27,
135.51, 138.34, 155.78, 177.95. 77Se NMR (CDCl3, 60%
Me2Se in CDCl3): d = 738.79. IR (KBr): 1042 (s), 1125 (s),
1320 (w), 1420 (m), 1465 (m), 1520 (s), 3050 (w), 3080 (w)
cm–1. MS (70 eV): m/z (%) = 298 (68) [M+], 182 (100), 102
(93). Anal. Calcd for C16H13NSe (298.25): C, 64.44; H, 4.39;
N, 4.70. Found: C, 6.40; H, 4.20; N, 4.79. All products gave
correct spectroscopic data and correct elemental analyses
and/or high resolution mass data.
(10) 2-Unsubstituted 1,3-thiazoles have been prepared by
decarboxylation of 1,3-thiazolyl-2-carboxylic acids; see for
example: (a) Sarodnick, G.; Kempter, G. Pharmazie 1983,
38, 829. (b) Pirotte, B.; Delarge, J. J. Chem. Res., Miniprint
1990, 7, 1634. (c) Strehlke, P. Chem. Ber. 1973, 106, 721.
(d) Sarodnick, G.; Kempter, G. Z. Chem. 1979, 19, 21.
(11) (a) Geisler, K.; Below, H.; Möller, A.; Bulka, E. Z. Chem.
1984, 24, 99. (b) For the synthesis of an 1,3-oxaseleno
derivative, see: Weber, M.; Hartmann, H. Z. Chem. 1987, 27,
95.
(8) Synthesis of 2-Benzoyl-4-phenyl-1,3-selenazole (4a).
Typical Procedure. To a dioxane solution (20 mL) of 3a
(1.49 g, 5.0 mmol) was added SeO2 (0.55 g, 5.0 mmol) with
stirring. The mixture was heated in a water bath at 40 °C for
3 h. The hot solution was subsequently filtered, cooled, and
poured into ice water (50 mL). The crystalline precipitate
was filtered off, washed (H2O), dried in vacuo and
(12) Synthesis of Selenoformamide.11a To freshly prepared
P2Se5 (114.18 g, 250 mmol, see ref.3b) was added destilled
formamide (37.16 g, 825 mmol). The reaction mixture was
stirred at 60 °C for 5 h and was subsequently extracted with
dry Et2O for 8 h using a Soxhlet apparatus. The Et2O solution
of the extract was collected and the precipitated oil was
separated, filtered (to remove precipitated selenium) and
dried in vacuo. The oil solidified upon standing in the
refrigerator. The solid was recrystallized from Et2O to give
6 as yellow needles, mp 35–37 °C. IR (KBr): 980 (m), 1095
(m), 1170 (m), 1305 (s), 1375 (s), 1415 (s), 1610 (s), 1680
(s), 2330 (w), 2780 (w), 3300 (s, br) cm–1. Anal. Calcd for
CH3NSe: C, 11.11; H, 2.80; N, 13.02. Found: C, 11.40; H,
3.10; N, 13.11. The solidification of 6 can be achieved only
for crude products of good purity. Decomposition of
selenoformamide (6) occurred upon standing at 20 °C.
However, it can be stored at –20 °C for several days. Freshly
prepared material should be used for reactions.
(13) Cyclization of 6 with 1d. To an EtOH solution of 6 (1.1 g,
10 mmol) was added 1d (2.4 g, 10 mmol) and pyridine (0.79
g, 10 mmol). The solution was gently warmed, the
precipitate formed was filtered off and the filtrate was
concentrated. The product precipitated upon standing of the
solution at 0 °C and was recrystallized from dry i-PrOH or
EtOH to give 5d as slight yellow needles (2.00 g, 79%), mp
160–162 °C.
recrystallized (EtOH) to give 4a as yellow needles (1.09 g,
70%), mp 76–77 °C. 1H NMR (300 MHz, CDCl3): d = 7.38–
8.62 (m, 10 H, ArH), 8.54 [s, 1 H, 2J (SeH) = 50 Hz, 5-H,
selenazole]. 13C NMR (75 MHz, CDCl3): d = 126.71,
126.77, 128.43, 128.93, 131.45, 133.63, 134.53, 134.92,
158.70, 175.08, 184.67. 77Se NMR (CDCl3, 60% Me2Se in
CDCl3): d = 807.31. IR (KBr): 840 (m), 901 (m), 1025 (w),
1050 (w), 1075 (w), 1110 (w), 1190 (m), 1270 (s), 1298 (s),
1430 (s), 1465 (s), 1505 (s) cm–1. MS (70 eV): m/z (%) = 312
(24) [M+], 299 (3), 285 (2), 182 (10), 105 (100), 102 (17), 77
(63), 51 (16), 28 (14). Anal. Calcd for C16H11NOSe (312.22):
C, 61.55; H, 3.55; N, 4.49. Found: C, 61.80; H, 3.90; N, 4.29.
(9) Synthesis of 4,5-Diphenyl-1,3-selenazole (5e). Typical
Procedure. An EtOH solution (30 mL) of 2-benzoyl-4,5-
diphenyl-1,3-selenazole (4e) (1.65 g, 5 mmol) and NaOH
(0.40 g, 10 mmol) was refluxed for 1 h. After cooling, the
sodium benzoate formed was filtered off and the solution
was poured into ice water. The product was filtered off, dried
in vacuo (P4O10) and recrystallized from petroleum ether to
give 5e as beige needles (0.93 g, 77%), mp 73–74 °C. 1H
NMR (200 MHz, CDCl3): d = 7.30–7.56 (m, 10 H, ArH),
9.86 [s, 1 H, 2J (SeH) = 57.26 Hz, 2-H, selenazole]. 13
NMR (50 MHz, CDCl3): d = 127.59, 128.0, 128.34, 128.66,
C
Synlett 2003, No. 8, 1195–1197 ISSN 1234-567-89 © Thieme Stuttgart · New York