Synthesis and functionalization of 4-halomethyl-1,3-selenazoles

Article abstract of DOI:10.1055/s-2003-39406

Double-functionalized, ionic and multivalent 1,3-selenazoles were prepared by nucleophilic displacement reactions of protected 4-halomethyl-2-amino-1,3-selenazoles.

Full text of DOI:10.1055/s-2003-39406

PAPER
1215
Synthesis and Functionalization of 4-Halomethyl-1,3-selenazoles
S
ynthesis andFun
a
c
tionalizati
r
on of 4-H
l
a
lome
h
thyl-1,3-sele
e
nazoles inz Geisler,* Wolf-Diethard Pfeiffer, Cornelia Müller, Elvira Nobst, Ehrenfried Bulka, Peter Langer*
Institut für Chemie und Biochemie, Ernst-Moritz-Arndt-Universität Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
Fax +49(3834)964346; E-mail: peter.langer@uni-greifswald.de
Received 5 March 2003; revised 31 March 2003
zoles. After much synthetic effort, we have developed
conditions for the efficient synthesis of 3b and 3c. The cy-
clization of , -dichloroacetone (1) with phenylsele-
nourea (2)8 afforded semi-aminal 3a. The isolation of 3a
by precipitation proved essential; however, an attempted
purification resulted in a great loss in yield. Therefore, the
crude material was used for transformation into 3b. Treat-
ment of 3a with acetic anhydride resulted in elimination
of water and protection of the amino group by acetylation
to give, after thorough optimization of the reaction condi-
tions (reaction time, concentration, stoichiometry, solvent
for recrystallization), 4-chloromethyl-1,3-selenazole 3b
in 89% yield (Scheme 1). Treatment of 3b with sodium io-
dide afforded the highly reactive 4-iodomethyl-1,3-sel-
enazole 3c.
Abstract: Double-functionalized, ionic and multivalent 1,3-selena-
zoles were prepared by nucleophilic displacement reactions of pro-
tected 4-halomethyl-2-amino-1,3-selenazoles.
Key words: cyclizations, heterocycles, nucleophilic additions, se-
lenium, halogens
1,3-Selenazoles are of considerable pharmacological rele-
vance.1 Synthetic approaches to these heterocycles mainly
rely on the application of a selena-analogous Hantzsch
procedure.2,3 Double functionalized, multivalent and ionic
1,3-selenazole derivatives are of special pharmacological
importance, due to their water solubility and physical
properties. In addition, they are of interest in the field of
material sciences (e.g. for solvatochromic effects). Inter-
esting syntheses of highly functionalized 1,3-selenazoles
have been reported for example by Banert and Hart-
mann.4,5 Herein, we wish to report the synthesis of a great
variety of double-functionalized and ionic 1,3-selenazoles
by nucleophilic displacement reactions of 4-halomethyl-
1,3-selenazoles.6,7 Based on these results we also report
the synthesis of novel multivalent 1,3-selenazole deriva-
tives.
X
R
N
Se
3b,c (X = Cl, I)
Scheme 2 Nucleophilic displacement reactions of 3b,c
N
4
N(Ac)Ph
N(Ac)Ph
Se
acetone
5a-r
The functionalization of protected 4-halomethyl-2-ami-
no-1,3-selenazoles 3b,c by nucleophilic displacement re-
actions was next studied. During the optimization of the
reaction conditions, important parameters again proved to
be the reaction time, concentration, stoichiometry and the
solvent for recrystallization of the product. The reaction
of 3c with ammonium thiocyanate, potassium selenocyan-
ate, sodium azide and potassium phthalimide afforded the
functionalized 1,3-selenazoles 5a–d in good yields
(Scheme 2, Table 1). The N,N-diethyldithiocarbamate 5e
was prepared from 3c and 4e in good yield. A number of
1,3-selenazoles containing cationic side chains were pre-
pared: selenazoles 5f,g, containing the pharmacologically
relevant isothiouronium and isoselenouronium moieties,
were regioselectively prepared from 3b and the corre-
sponding thio- and selenoureas 4f,g. The reaction of
urotropine with 3c gave the sterically encumbered am-
monium salt 5h. The reaction of tertiary amines 4i–k with
3b,c afforded the ammonium salts 5i–m in quantitative
yield. The reaction of 3c with pyridine, 3-methylpyridine
and phenanthroline gave the pyridinium salts 5n–p. The
reaction of triphenylphosphane (4o) with 3b and 3c af-
forded the phosphonium salts 5q and 5r, respectively, in
quantitative yields. Heterocycles 5a–r show only minor
differences in their 77Se NMR shifts. This can be ex-
plained by the great distance between the selenium atom
O
Cl
reflux
20 min
acetone
OH
N
Cl
Cl
1
.
HCl
_
NH2
H2O
Se
NHPh
NHPh
_
HCl
Se
3a (94%)
2
_
H2O
HCl
+ Ac2O
(excess)
_
I
Cl
N
+ NaI
N
N(Ac)Ph
_
Se
N(Ac)Ph
NaCl
Se
3c (94%)
3b (89%)
Scheme 1 Synthesis of 4-halomethyl-1,3-selenazoles 3b,c
Our starting point was the synthesis of the 4-halomethyl-
2-amino-1,3-selenazoles 3b,c which represent key inter-
mediates for the synthesis of functionalized 1,3-selena-
Synthesis 2003, No. 8, Print: 05 06 2003.
Art Id.1437-210X,E;2003,0,08,1215,1220,ftx,en;T02403SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1216
K. Geisler et al.
PAPER
Table 1 Synthesis of Substituted 2-(N-Acetylanilino)-1,3-selena-
zoles 5a–r
3b
N
N
+
N
N
5
4
3
Reagent (4)
R
Yield Mp
(%)a (°C)
N(Ac)Ph
Se
HN
NH
Ph(Ac)N
Se
6 (32%)
a
b
c
a
b
c
c
c
c
NH4SCN
KSeCN
NaN3
92 154–155
95 162–164
78 104–106
Scheme 3 Synthesis of divalent selenazole 6
SCN
SeCN
N3
cological interest, due to the amplification of the 1,3-sel-
enazole presentation. The reaction of 3b with piperazine
afforded the divalent selenazole 6 (Scheme 3).
O
O
KN
O
d
e
d
e
c
c
61 181–182
98 101–103
N
O
Se
N(Ac)Ph
NH3
N
3c
S
S
N
N
NaS
S
Ph(Ac)N
N
NEt2
NEt2
NH2
Se
N(Ac)Ph
Se
NH2
NH2
f
f
b
b
54 198–199
47 202–204
S
S
_
_
7a (100%)
+
NH
2 Cl
NHPh
+
NHPh
g
g
Se
Se
Se
N(Ac)Ph
NH
NH2
2 Cl
N
_
+ MeI
N
N
Me
N
N
I
+
N
_
7a
h
h
c
69 158–160
+N
N
N I
N
N
N
N(Ac)Ph
Se
Ph(Ac)N
Se
_
i
i
i
j
j
c
b
c
Me3N
Me3N
Et3N
100 232–234
100 228–230
100 230–232
100 226–228
100 152–153
+
NMe3
I
7b (64%)
_
_
j
k
l
+
Cl
NMe3
Se
N
_
+
Se
I
NEt3
N(Ac)Ph
Ph(Ac)N
+ 3c
b
c
Et3N
+
N
_
Cl
NEt3
N
I
+
N
7a
_
Et2NPh
N
+
m k
N
N(Ac)Ph
I
NEt2Ph
Se
Ph(Ac)N
_
+
N
Se
n
o
l
c
90 223–224
92 214–215
I
7c (77%)
Scheme 4 Synthesis of multivalent selenazoles 7a–c
m c
The reaction of 4-iodomethyl-1,3-selenazole 3c with NH3
resulted in complete alkylation and formation of the tris-
selenazole 7a in quantitative yield (Scheme 4). Alkylation
of 7a with methyl iodide and 3c afforded the interesting
water soluble tris- and tetrakis-1,3-selenazoles 7b and 7c,
respectively.
N
N
+
N
N
_
p
n
c
68 194–196
I
_
+
q
r
o
o
c
PPh3
PPh3
100 204–203
100 244–246
PPh3I
_
+
b
PPh3 Cl
2-(N-Acetylanilino)-4-halomethyl-1,3-selenazoles 3b and 3c
An acetone solution (350 mL) of 1,3-dichloroacetone (14.0 g, 110
mmol) and N-phenylselenourea (11.4 g, 57.0 mmol) was refluxed
for 20 min with exclusion of moisture. A grey solid precipitated. Af-
ter cooling, the solid was filtered off and washed with acetone to
give the salt 3a as a grey solid (mp 130 °C, 17.5 g, 94%). To crude
3a (7.00 g, 21.5 mmol) was added acetic anhydride (200 mL). The
solution was refluxed for 15 min and subsequently concentrated to
80 mL. H2O (20 mL) was added and the solution was cooled to r.t.
with stirring. A yellow oil precipitated which solidified upon stand-
ing. The solid was recrystallized from EtOH to give 3b.
a Yields of isolated products
and the substituent R. Due to the electron withdrawing ef-
fect, a low field shift is observed for 1,3-selenazoles con-
taining a cationic side-chain compared to electroneutral
derivatives.
Multivalent selenazole derivatives are of special pharma-
Synthesis 2003, No. 8, 1215–1220 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
Synthesis and Functionalization of 4-Halomethyl-1,3-selenazoles
1217
Yield: 6.01 g (89%); yellow crystals; mp 132–133 °C.
Anal. Calcd for C13H11N3OSe2 (383.16): C, 40.79; H, 2.93; N,
10.98. Found: C, 40.90; H, 3.20; N, 11.04.
Anal. Calcd for C12H11ClN2OSe (313.7): C, 45.98; H, 3.54; N, 8.93.
Found: C, 45.79; H, 3.55; N, 8.70.
2-(N-Acetylanilino)-4-azidomethyl-1,3-selenazole (5c)
Compound 5c was prepared by reaction of 3c (1.20 g, 3.0 mmol)
and NaN3 (0.20 g, 3.0 mmol) in acetone (20 mL) and H2O (5 mL).
The mixture was refluxed for 30 min. Further purification was car-
ried out as described for 5a.
A mixture of 3b (3.14 g, 10.0 mmol) and NaI (1.90 g, 12.5 mmol)
in dry acetone (50 mL) was refluxed for 5 min. After cooling to r.t.,
a crystalline precipitate formed which was washed with H2O and re-
crystallized (EtOH–H2O) to give 3c.
Yield: 3.82 g (94%); light brown prisms; mp 142 °C.
Yield: 0.75 g (78%); yellow prisms (ligroine); mp 105 °C.
IR (KBr): 698 (s), 764 (m), 844 (w), 949 (w), 990 (w), 1114 (w),
1162 (m), 1282 (s), 1289 (s), 1301 (s), 1331 (m), 1372 (s), 1420 (m),
1490 (s), 1508 (m), 1594 (m), 1669 (s), 3052 (w), 3087 (w) cm–1.
IR (KBr): 759 (w), 992 (w), 1110 (w), 1170 (w), 1237 (m), 1256
(m), 1292 (s), 1333 (m), 1373 (m), 1449 (w), 1488 (s), 1594 (m),
1662 (s), 2093 (s), 2124 (s), 3099 (w) cm–1.
1H NMR (DMSO-d6, 300 MHz): = 1.97 (s, 3 H, CH3), 4.38 (s, 2
H, CH2), 7.43–7.59 (m, 5 H, ArH), 7.79 [s, 1 H, 2J (SeH5) = 42.3 Hz,
H5-selenazole].
13C NMR (DMSO-d6, 75 MHz): = 4.11 (CH2), 23.58 (CH3),
117.77, 128.75, 128.86, 129.63 (CH), 139.90, 147.50 (C), 160.92
(C=O), 170.10 (C-2).
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 682.5.
MS (EI): m/z = 406 (M+, 2), 316 (3), 314 (4), 279 (100), 277 (36),
1H NMR (CDCl3, 300 MHz): = 2.05 (s, 3 H, CH3), 4.10 (s, 2 H,
CH2), 7.25–7.55 (m, 6 H, ArH, H5-selenazole).
13C NMR (CDCl3, 75 MHz): = 23.70 (CH3), 50.96 (CH2), 116.87,
128.47, 128.96, 129.74 (CH), 139.93, 146.08 (C), 161.73 (C=O),
170.10 (C-2).
77Se NMR (CDCl3, 60% Me2Se in CDCl3): = 678.12.
MS (EI): m/z = 321 (M+, 22), 319 (8), 279 (100), 277 (46), 250 (5),
237 (18), 235 (14), 197 (2), 184 (12), 184 (16), 170 (17), 143 (8),
133 (16), 104 (12), 93 (6), 77 (45), 65 (6), 43 (74).
272 (32), 237 (68), 93 (10), 77 (22).
Anal. Calcd for C12H11N2IOSe (405.09): C, 35.58; H, 2.74; N, 6.92.
Found: C, 35.62; H, 2.81; N, 7.13.
Anal. Calcd for C12H11N5OSe (320.2): C, 45.01; H, 3.46; N, 21.87;
Se, 24.66. Found: C, 45.20; H, 3.30; N, 21.98; Se, 24.43.
1,3-Selenazoles 5a–c,e,f; Typical Procedure
N-[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]phthalimide
(5d)
An acetone solution of 3c (2.03 g, 5.0 mmol) and NH4SCN (0.30 g,
5.0 mmol) was refluxed for 20 min. Potassium iodide was filtered
off and the solution was cooled to r.t. A precipitate formed which
was separated and recrystallized (EtOH–H2O) to give 5a.
A DMF solution (20 mL) of phthalimide (2.94 g, 24.0 mmol) was
heated at 80–90 °C. A MeOH solution (6.2 mL) of KOH was added
dropwise with stirring. MeOH was evaporated by distillation to give
a precipitate of potassium phthalimide. A DMF solution (20 mL) of
selenazole 3b (6.27 g, 20.0 mmol) was added dropwise to the mix-
ture at 50 °C and the solution was stirred for 5 h. The mixture was
allowed to stand overnight at 20 °C and poured into ice (50 g). An
aq Na2CO3 solution (50%, 100 mL) of the product mixture was
heated and the precipitated product was filtered off, washed with
H2O, and recrystallized (EtOH–H2O, 1:1) to give 5d.
Yield: 1.56 g (92%); colorless lamella.
2-(N-Acetylanilino)-4-thiocyanatomethyl-1,3-selenazole (5a)
Mp 154–155 °C.
IR (KBr): 965 (m), 998 (m), 1025 (w), 1105 (w), 11.45 (m), 1281
(s), 1290 (s), 1390 (s), 1425 (s), 1498 (s), 1600 (s), 1980 (s), 2155
(m), 2940 (w), 2995 (w), 3100 (w) cm–1.
1H NMR (DMSO-d6, 300 MHz): = 1.85 (s, 3 H, CH3), 4.05 (s, 2
H, CH2), 7.43–751 (m, 5 H, ArH), 7.61 [s, 1 H, 2J (SeH5) = 42 Hz,
H5-selenazole].
Yield: 5.39 g (53%); light brown prisms; mp 181–182 °C.
IR (KBr): 965 (s), 997 (w), 1045 (w), 1085 (m), 1108 (s), 1186 (m),
1198 (m), 1270 (s), 1298 (s), 1320 (s), 1390 (s), 1398 (s), 1426 (s),
1491 (s), 1600 (m), 1672 (s), 1712 (s), 1780 (s), 2930 (w), 3180 (w)
cm–1.
Anal. Calcd for C13H11N3OSSe (338.27): C, 46.30; H, 3.28; N,
12.43. Found: C, 46.10; H, 3.50; N, 12.40.
1H NMR (DMSO-d6, 100 MHz): = 1.95 (s, 3 H, CH3), 4.12 (s, 2
H, CH2), 7.31–7.82 (m, 10 H, ArH, H5-selenazole).
2-(N-Acetylanilino)-4-selenocyanatomethyl-1,3-selenazole (5b)
This compounds was obtained by reaction of 3c (2.03 g, 5.0 mmol)
and KSeCN (0.72 g, 5.0 mmol) in acetone (30 mL) as described for
5a.
Anal. Calcd for C20H15N3O3Se (424.33): C, 56.66; H, 3.56; N, 9.91;
Se, 23.25. Found: C, 57.00, H, 3.10; N, 9.52; Se, 22.73.
[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]-N,N-diethyldi-
thiocarbamate (5e)
A mixture of 3c (0.81 g, 2.0 mmol) and sodium diethyldithiocarb-
amate (2.0 mmol) in acetone (20 mL) was refluxed for 30 min. The
work up was carried out as described for 5a.
Yield 1.82 g (95%); yellow prisms (EtOH–H2O); mp 163 °C.
IR (KBr): 697 (m), 762 (m), 951 (w), 991 (m), 1131 (m), 1205 (m),
1284 (s), 1332 (m), 1375 (s), 1420 (m), 1489 (s), 1594 (s), 1594 (w),
1670 (s), 2146 (m), 3005 (w) cm–1.
1H NMR (DMSO-d6, 300 MHz): = 1.97 (s, 3 H, CH3), 4.16 (s, 2
H, CH2), 7.43–7.54 (m, 5 H, ArH), 7.67 [s, 1 H, 2J (SeH5) = 42.1 Hz,
2J (SeHCH2) = 17.7 Hz), 5-H, selenazole].
13C NMR (DMSO-d6, 75 MHz): = 23.66 (CH3), 29.71 (CH2),
104.73 (C), 118.64, 128.91, 128.98, 129.78 (CH), 140.14, 146.08
(C), 161.53 (C=O), 170.18 (C-2).
Yield: 98%; colorless lamella (ligroine); mp 102 °C.
IR (KBr): 700 (s), 768 (m), 826 (w), 915 (w), 986 (m), 1010 (m),
1142 (m), 1205 (s), 1273 (s), 1301 (s), 1331 (m), 1355 (m), 1370
(m), 1415 (m), 1452 (w), 1486 (s), 1596 (m), 1667 (s), 2977 (m)
cm–1.
1H NMR (300 MHz, DMSO-d6): = 1.14 (s, 6 H, CH3), 1.96 (s, 3,
CH3), 3.63–3.70 (q, 2 H, CH2), 3.88–3.95 (q, 2 H, CH2), 4.27 (s, 2
H, SCH2), 7.42–7.58 (m, 5 H, ArH), 7.64 [s, 1 H, 2J (SeH5), 42.5
Hz, H5-selenazole].
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 681.19 (Se1),
281.51 (SeSeCN).
MS (EI): m/z = 385, 383 (M+, 4), 345 (6), 343 (20), 341 (19), 339
(12), 237 (100), 235 (60), 93 (16), 77 (38).
13C NMR (75 MHz, DMSO-d6): = 11.25, 12.24 (CH2CH3), 23.57
(CH3), 38.23 (CH2), 46.36, 48.86 (CH2CH3), 117.43, 128.78,
Synthesis 2003, No. 8, 1215–1220 ISSN 1234-567-89 © Thieme Stuttgart · New York

1218
K. Geisler et al.
PAPER
128.85, 129.63 (CH), 140.05, 144.85 (C), 161.10 (C=O), 169.89 (C-
2), 193.13 (C=S).
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 678.66.
MS (EI): m/z = 427 (M+, 20), 313 (22), 311 (100), 269 (38), 237
(22), 197 (3), 176 (4).
2980 (w) cm–1.
1H NMR (DMSO-d6, 300 MHz): = 2.00 (s, 3 H, CH3), 3.89 (s, 2
H, NCH2), 4.42 (d, 3 H, NCH2), 4.56 (d, 3 H, NCH2), 4.93 (s, 6 H,
NCH2), 7.48 (m, 5 H, ArH), 8.01 [s, 1 H, 2J (SeH5) = 40.64 Hz, H5-
selenazole].
13C NMR (DMSO-d6, 50 MHz): = 23.56 (CH3), 55.34, 69.74,
77.88 (CH2), 125.14, 128.73, 129.11, 129.67 (CH), 136.66, 140.09
(C), 162.90 (C=O), 170.15 (C-2).
Anal. Calcd for C17H21N3OS2Se (426.5): C, 47.88; H, 4.96; N, 9.85.
Found: C, 47.90; H, 5.00; N, 9.76.
S-[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]isothiuronium
Chloride (5f)
A mixture of 3b (3.14 g, 10.0 mmol) and thiourea (0.76 g, 10.0
mmol) in acetone (65 mL) was refluxed for 35 min. The work up
was carried out as described for 5a.
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 692.12.
MS (EI): m/z = 417/420 (M+, 100/18), 415 (20), 306 (25), 280 (20),
238 (28), 184 (28), 140 (6), 119 (4), 91 (12), 77 (30), 58 (76), 43
(90).
Anal. Calcd for C18H23N6IOSe (545.26): C, 39.65; H, 4.25; N,
15.42. Found: C, 39.80; H, 4.40; N, 15.45.
Yield 2.10 g (54%); colorless prisms (EtOH–H2O); mp 198–
199 °C.
IR (KBr): 703 (m), 721 (w), 741 (w), 993 (w), 1164 (w), 1299 (s),
1335 (m), 1363 (m), 1435 (m), 1454 (m), 1477 (s), 1489 (s), 1523
(w), 1649 (s), 1677 (s), 2742 (m), 2958 (m), 3010 (m), 3077 (m),
3192 (m), 3261 (m), 3287 (m) cm–1.
1H NMR (300 MHz, DMSO-d6): = 2.01 (s, 3 H, CH3), 4.30 (s, 2
H, CH2), 7.21–7.64 (m, 5 H, ArH), 7.75 [s, 1 H, 2J (SeH5) = 41.6 Hz,
H5-selenazole], 9.15 (s, 4 H, H2N, H2N+).
13C NMR (CDCl3, 50 MHz): = 23.63 (CH3), 31.59 (CH2), 118.63,
128.61, 129.64, 130.12 (CH), 139.67, 144.39 (C), 163.08 (C=O),
170.12, 170.74 (C-2, C=NH2).
[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]trimethylammo-
nium Iodide (5i)
Compound 1c (4.05 g, 10.0 mmol) was dissolved in C6H6 (35 mL)
and Me3N (2 mL) was added dropwise. The mixture was gently
heated and subsequently allowed to stand at 20 °C for 2 h to give a
crystalline precipitate which was filtered off.
Yield: 4.64 g (100%); colorless prisms (DMF–Et2O); mp 232–
234 °C.
IR (KBr): 698 (m), 759 (w), 806 (w), 892 (m), 954 (m), 989 (m),
1139 (m), 1286 (s), 1304 (s), 1320 (m), 1382 (m), 1429 (w), 1453
(w), 1489 (s), 1596 (m), 1667 (s) cm–1.
1H NMR (CDCl3, 100 MHz): = 1.96 (s, 3 H, CH3), 3.13 (s, 9 H,
Me), 4.58 (s, 2 H, CH2), 7.17–7.52 (m, 5 H, ArH), 8.37 (s, 1 H, H5-
selenazole).
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 681.99.
MS (EI): m/z = 354 (M+, 2), 314 (6), 312 (34), 310 (14), 272 (12),
270 (58), 268 (27), 237 (56), 235 (28), 197 (2), 189 (12), 166 (4),
156 (11), 118 (18), 93 (13), 77 (42), 71 (10), 51 (19), 43 (100).
13C NMR (DMSO-d6):
= 23.59 (CH3), 52.02, 63.89 [CH2,
Anal. Calcd for C13H15N4ClOSSe (389.77): C, 40.06; H, 3.88; N,
14.37; Cl, 9.09. Found: C, 39.70; H, 3.90; N, 14.38; Cl, 9.04.
N(CH3)], 126.40, 128.70, 129.02, 129.66 (CH), 139.17, 139.98 (C),
162.43 (C=O), 170.22 (C-2).
Se-[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]-N-phenyliso-
selenouronium Chloride (5g)
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 696.98.
MS (EI): m/z = 336/338/339 (M+, 50/100/60), 279 (12).
A mixture of 3b (0.95 g, 3.0 mmol) and N-phenylselenourea (0.60
g, 3.0 mmol) in PrOH (20 mL) was refluxed for 1 h. PrOH was dis-
tilled in vacuo. After cooling and addition of Et2O, a crystalline pre-
cipitate formed which was recrystallized (EtOH–Et2O, 1:1) to give
5g.
Anal. Calcd for C15H20N3IOSe (464.21). C, 38.81; H, 4.34; N, 9.05.
Found: C, 39.10; H, 4.10; N, 8.97.
[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyltrimethyl]ammo-
nium Chloride (5j)
The product was obtained by reaction of 3b (3.14 g, 10.0 mmol) and
Me3N (2 mL) in C6H5 (5 mL) as described for the preparation of 5i.
Yield: 0.72 g (47%); slight brown prisms; mp 202–203 °C.
IR (KBr): 996 (w), 1080 (w), 1150 (w), 1180 (w), 1220 (w), 1285
(s), 1345 (m), 1380 (s), 1450 (s), 1480 (s), 1498 (s), 1585 (s), 1598
(s), 1645 (s), 1690 (s), 2930 (m), 3055 (w) cm–1.
1H NMR (DMSO-d6, 100 MHz): = 2.11 (s, 3 H, CH3), 4.32 (s, 2
H CH2), 7.02–7.72 (m, 9 H, ArH, H5-selenazole), 9.30 (s, 3 H, NH,
H2N+).
Yield: 3.71 g (100%); colorless prisms (DMF–Et2O); mp 228–
230 °C.
Anal. Calcd for C15H20N2ClOSe (372.7): C, 48.34, H, 5.41; N,
11.27; Se, 21.18. Found: C, 48.40; H, 5.40; N, 10.86; Se, 21.07.
Anal. Calcd for C19H19N4ClOSe2 (512.77): C, 44.51; H, 3.73; N,
10.92; Cl, 6.91. Found: C, 44.52; H, 3.78; N, 10.50; Cl, 6.83.
[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]triethylammon-
ium Iodide (5k)
The product was obtained by reaction of 1c (4.05 g, 10.0 mmol) and
Et3N (2 mL) in C6H6 (50 mL). The mixture was allowed to stand at
20 °C for 2 d to give a precipitate, which was filtered off.
[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]hexamethylene-
tetrammonium Iodide (5h)
An EtOH solution (50 mL) of NaI (1.00 g, 5.0 mmol) was added to
a mechanically stirred solution of urotropine (1.00 g, 7.5 mmol). An
EtOH solution (15 mL) of 3c (1.57 g, 5.0 mmol) was poured into the
mixture. The solution was allowed to stand at 20 °C for 2 d. The pre-
cipitated product was collected by filtration and recrystallized
(EtOH) to give 5h.
Yield: 5.06 g (100%); colorless prisms (DMF–Et2O); mp 230–
232 °C.
IR (KBr): 705 (m), 730 (w), 760 (m), 770 (s), 800 (m), 840 (w), 900
(w), 940 (w), 960 (w), 995 (m), 1015 (w), 1030 (w), 1080 (w), 1115
(w), 1130 (w), 1160 (w), 1180 (w), 1270 (m), 1300 (s), 1375 (s),
1455 (s), 1500 (s), 1525 (m), 1600 (s), 1670 (s), 3010 (w), 3050 (w)
cm–1.
Yield: 1.87 g (69%); colorless prisms; mp 158–160 °C.
IR (KBr): 702 (m), 783 (m), 807 (w), 826 (m), 934 (m), 1006 (s),
1042 (m), 1121 (m), 1121 (m), 1225 (w), 1268 (s), 1296 (s), 1311
(m), 1374 (m), 1455 (m), 1484 (s), 1493 (s), 1659 (m), 1675 (m),
1H NMR (CDCl3, 100 MHz): = 1.05 (t, 9 H, CH3), 1.97 (s, 3 H,
Me), 3.16 (q, 6 H, CH2), 4.30 (s, 2 H, CH2), 7.20–7.52 (m, 5 H,
ArH), 8.28 (s, 1 H, H5-selenazole).
Synthesis 2003, No. 8, 1215–1220 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
Synthesis and Functionalization of 4-Halomethyl-1,3-selenazoles
1219
Anal. Calcd for C18H26NIOSe (506.3): C, 42.70; H, 5.18; N, 8.30.
Found: C, 42.50; H, 5.10; N, 8.34.
13C NMR (DMSO-d6, 50 MHz): = 17.88 (CH3 to pyridine), 23.55
(CH3), 59.90 (CH2), 120.18, 127.04, 128.54, 128.87, 129.81 (CH),
138.05, 139.62 (C), 141.79 (CH), 142.35 (C), 144.22, 146.05 (CH),
162.55 (C=O), 169.98 (C-2).
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 699.86.
MS (EI): m/z = 368/369/370/372/374 (M+, 19/20/58/100/20), 279
[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]triethylammoni-
um Chloride (5l)
The product was obtained by reaction of 3b (3.14 g, 10.0 mmol) and
Et3N (2 mL) in C6H6 (50 mL). The mixture was allowed to stand at
20 °C for 1 month.
(30), 237 (18), 176 (4).
Anal. Calcd for C18H18N3IOSe (498.2): C, 43.39; H, 3.64; N, 8.43.
Found: C, 43.40; H, 3.70; N, 8.61.
Yield: 4.15 g (100%); colorless prisms (DMF–Et2O); mp 226–
228 °C.
Anal. Calcd for C18H26N3ClOSe (414.84): C, 52.12; H, 6.32; N,
10.13; Se, 19.03. Found: C, 52.26; H, 6.45; N, 10.35; Se, 19.33.
[2-(N-Acetylanilino)selenazol-4-ylmethyl]-1,10-phenanthrolin-
ium Iodide (5p)
A mixture of 3c (4.05 g, 10.0 mmol) and 1,10-phenanthroline (1.8
g, 10 mmol) in DMF (10 mL) was heated for 1 min at 40 °C. After
cooling and addition of Et2O, a crystalline precipitate was formed.
The product was collected by filtration.
[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]-N,N-diethyl-
anilinium Iodide (5m)
Compound 1c (4.05 g, 10.0 mmol) was added portionwise to a DMF
solution (10 mL) of PhNEt2 (1 mL) with stirring. After stirring for
2 h, the mixture was treated with Et2O and the precipitated product
was separated by filtration.
Yield: 4.00 g (68%); yellow prisms (DMF–Et2O); mp 194–196 °C.
IR (KBr): 698 (w), 727 (w), 758 (w), 852 (w), 991 (m), 1155 (w),
1241 (w), 1284 (s), 1371 (m), 1486 (s), 1527 (m), 1591 (w), 1668
(s), 2991 (w), 3050 (w) cm–1.
1H NMR (DMSO-d6, 300 MHz): = 1.80 (s, 3 H, CH3), 6.94 (s, 2
H, NCH2), 7.31–9.40 (m, 13 H, ArH, phenanthroline), 7.82 [s, 1 H,
2J (SeH5) = 41.91 Hz, H5-selenazole].
Yield: 5.54 g (100%); colorless lamella (EtOH); mp 151–153 °C.
IR (KBr): 700 (w), 800 (m), 835 (w), 850 (w), 980 (w), 940 (w), 960
(w), 1000 (w), 1090 (w), 1075 (w), 1115 (w), 1205 (m), 1260 (m),
1300 (s), 1380 (m), 1460 (m), 1495 (s), 1600 (m), 1675 (s), 3035
(w) cm–1.
13C NMR (DMSO-d6, 50 MHz): = 23.44 (CH3), 62.78 (CH2),
117.50, 124.06, 125.24, 126.78, 128.15, 128.69, 129.30, 130.51
(CH), 131.38, 132.11, 136.47 (C), 137.68 (CH), 139.45, 139.51,
144.10 (C), 147.45, 149.36, 151.52 (CH), 161.42 (C=O), 169.74 (C-
2).
1H NMR (CDCl3, 100 MHz): = 0.77 (t, 6 H, CH3) 1.96 (s, 3 H,
CH3), 3.77 (m, 4 H, CH2), 4.85 (s, 2 H, CH2) 7.19–7.97 (m, 10 H,
ArH, H5-selenazole).
Anal. Calcd for C22H26N3IOSe (554.3): C, 47.67; H, 4.73; N, 7.58.
Found: C, 47.60; H, 4.60; N, 7.56.
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 696.14.
[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]pyridinium
Iodide (5n)
Anal. Calcd for C24H19N4IOSe (585.3): C, 49.25; H, 3.27; N, 9.57.
Found: C, 49.30; H, 3.10; N, 9.60.
A mixture of 3c (4.05 g, 10.0 mmol), pyridine (1 mL) and DMF (10
mL) was stirred at 20 °C for 3 h. The solution was treated with Et2O
and the precipitated product was separated by filtration.
[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]triphenylphos-
phonium Iodide (5q)
A CDCl3 solution (5 mL) of 1c (0.40 g, 1.0 mmol) and Ph3P (0.26
g, 1.0 mmol) was stirred for 1 h at 20 °C. The mixture was allowed
to stand for 3 d to give a crystalline precipitate.
Yield: 4.45 g (90%); colorless prisms (EtOH); mp 223–224 °C.
IR (KBr): 705 (s), 742 (m), 774 (m), 991 (m), 1041 (w), 1169 (m),
1287 (s), 1313 (m), 1328 (m), 1340 (m), 1372 (s), 1444 (w), 1484
(s), 1596 (m), 1630 (m), 1666 (s), 3045 (m) cm–1.
1H NMR (DMSO-d6, 300 MHz): = 2.05 (s, 3 H, CH3), 5.64 (s, 2
Yield: 0.67 g, (100%); colorless prisms (EtOH–H2O); mp 204–
205 °C.
IR (KBr): 635 (w), 694 (m), 751 (m), 846 (w), 993 (w), 1110 (m),
1156 (w), 1296 (s), 1330 (w), 1372 (m), 1483 (m), 1519 (w), 1591
(w), 1670 (s), 2847 (w), 3053 (w) cm–1.
1H NMR (CDCl3, 300 MHz): = 1.95 (s, 3 H, CH3), 5.23–5.27 (d,
2 H, J = 13.8 Hz), 6.95–8.17 (m, 20 H, ArH), 8.17–8.18 (d, J = 3.37
Hz, 1 H), 2J (SeH5) = 43.34 Hz, H5-selenazole.
H, CH2), 7.32–8.78 (m, 11 H, ArH, H5-selenazole and pyridine).
13C NMR (DMSO-d6): = 23.56 (CH3), 60.19 (CH2), 120.23,
127.73, 128.58, 128.91, 129.55 (CH), 139.61, 142.54 (C), 144.67,
145.87 (CH), 162.63 (C=O), 170.06 (C-2).
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 691.99.
Anal. Calcd for C17H16N3IOSe (484.2): C, 41.91; H, 3.30; N, 8.62.
Found: C, 41.82; H, 3.34; N, 8.67.
13C NMR (75 MHz, DMSO-d6): = 23.42 (CH3), 27.02 (d, CH2),
118.34, 119.48 (Ar), 120.99 (d, Ph to P), 128.34, 129.0 (Ar), 129.66
(d, Ph to P), 133.52 (d, Ph to P), 134.34 (Ar), 137.65 (d, Ph to P),
139.56 (Ar), 162.03 (C=O), 170.01 (C-2).
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 683.99.
MS: m/z = 539/540/541/542/543 (M+, 13/65/100/32/20).
[2-(N-Acetylanilino)-1,3-selenazol-4-ylmethyl]-3-methylpyri-
dinium Iodide (5o)
The compound was obtained from 3c (4.05 g, 10.0 mmol) and 3-me-
thylpyridine (1 mL) in DMF (10 mL) as described for the prepara-
tion of 5n.
Anal. Calcd for C30H26N2IOPSe (667.4): C, 53.99; H, 3.93; N, 4.20.
Found: C, 53.70; H, 4.00; N, 4.45.
Yield: 4.60 g (92%); colorless rods (EtOH); mp 214–215 °C.
IR (KBr): 707 (m), 758 (m), 992 (w), 1024 (w), 1155 (m), 1170 (m),
1247 (m), 1282 (s), 1303 (s), 1337 (m), 1375 (s), 1487 (s), 1505 (s),
1595 (m), 1633 (w), 1667 (s), 2981 (m), 3001 (m), 3035 (m), 3048
(m) cm–1.
1H NMR (DMSO-d6, 300 MHz): = 1.99 (s, 3 H, CH3), 2.46 (s, 3
H, CH3), 5.63 (s, 2 H, CH2), 7.31–8.71 (m, 10 H, ArH, H5-selena-
zole, pyridine).
[2-(N-Acetylanilino)selenazol-4-ylmethyl]triphenylphosphoni-
um Chloride (5r)
Compound 3b (0.31 g, 1.0 mmol) and Ph3P (0.26 g, 1.0 mmol) in
CDCl3 (5 mL) was allowed to stand at 20 °C for 6 d. The precipitat-
ed product was collected by filtration.
Yield: 0.50 g (100%); colorless prisms (EtOH–Et2O); mp 244–
246 °C.
Synthesis 2003, No. 8, 1215–1220 ISSN 1234-567-89 © Thieme Stuttgart · New York

1220
K. Geisler et al.
PAPER
IR (KBr): 1110 (m), 1250 (m), 1308 (s), 1430 (m),1480 (s), 1560
(s), 2961 (s) cm–1.
1H NMR (DMSO-d6, 300 MHz): = 1.89 (s, 3 H, CH3), 5.10–5.15
(d, CH2, J = 13.8 Hz), 7.13–7.89 (m, 21 H, ArH, H5-selenazole).
IR (KBr): 701 (s), 724 (w), 741 (w), 760 (m), 825 (w), 843 (w), 953
(w), 990 (m), 1102 (w), 1175 (w), 1296 (s), 1428 (m), 1437 (m),
1452 (m), 1490 (m), 1494 (m), 1673 (s), 3006 (w), 3099 (w) cm–1.
1H NMR (CDCl3, 300 MHz): = 2.06 (s, 12 H, CH3), 3.92, (s, 8 H,
CH2), 6.80 [s, 1 H, 2J (SeH5) = 42.73 Hz, H5-selenazole], 7.39–8.02
(m, 24 H, ArH, H5-selenazole).
13C NMR (50 MHz, DMSO-d6): = 23.71 (CH3), 57.84 (CH2),
127.83, 128.93, 129.63, 130.61 (CH), 138.10, 140.38 (C), 162.06
(C=O), 170.15 (C-2).
Anal. Calcd for C30H26N2ClOPSe (575.94): C, 62.56; H, 4.55; N,
4.86. Found: C, 62.61; H, 4.65; N, 4.69.
1,4-[Bis-2-(N-acetylanilino)-1,3-selenazol-4-ylmethyl]pipera-
zine (6)
Compound 3b (6.30 g, 20.0 mmol) and piperazine hexahydrate
(2.80 g, 20.0 mmol) were dissolved in acetone (20 mL). The mix-
ture was allowed to stand for 2 d. During this time a crystalline pre-
cipitate formed which was filtered off.
77Se NMR (CDCl3, 60% Me2Se in CDCl3): = 681.99.
Anal. Calcd for C48H44N9IO4Se4 (1253.4): C, 45.99; H, 3.54; N,
10.05; I, 10.12. Found: C, 45.60; H, 3.80; N, 10.11; I, 9.93.
Yield: 0.70 g (32%); colorless lamella (PrOH); mp 211 °C.
1H NMR (DMSO-d6, 100 MHz): = 1.97 (s, 6 H, CH3), 4.07–4.12
Acknowledgment
(t, 8 H, NCH2), 7.43–8.01 (m, 12 H, ArH, H5-selenazole).
Financial support from the Deutsche Forschungsgemeinschaft (Hei-
senberg-scholarship for P. L. and Normalverfahren) is gratefully
acknowledged.
Anal. Calcd for C28H30N6O2Se2 (640.5): C, 52.51; H, 4.72; N, 13.12.
Found: C, 52.48; H, 4.70; N, 12.92.
Tris[2-(N-acetylanilino)-1,3-selenazol-4-ylmethyl]amine (7a)
To a DMF solution (50 mL) of 3c was added NH3 for 15 min with
stirring. The precipitated product was collected by filtration.
References
(1) For the antibiotically active C-glycosyl selenazole
selenazofurin, see: Goldstein, B. M.; Kennedy, S. D.;
Hennen, W. J. J. Am. Chem. Soc. 1990, 112, 8265; and
references cited therein.
(2) (a) Larsen, R. 1,3-Selenazoles, In Comprehensive
Heterocyclic Chemistry II, Vol. 3; Shinkai, I.; Katritzky, A.;
Rees, C. W.; Scriven, E. F. V., Eds.; Elsevier Science:
Oxford, 1996, Chapt. 8:. (b) Wirth, T. Organoselenium
Chemistry. 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) Lai, L.-L.; Reid, D. H. Synthesis
1993, 870. (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, 9, 1219.
(g) Maeda, H.; Kambe, N.; Sonoda, N.; Fujiwara, S.-I.; Sini-
ike, T. Tetrahedron 1997, 53, 13667. (h) Ogawa, A.;
Miyaka, J.; Karasaki, Y.; Murai, S.; Sonoda, N. J. Org.
Chem. 1985, 50, 384. (i) Kaminski, R.; Glass, R. S.;
Skowronska, A. Synthesis 2001, 1308. (j) Cohen, V. J.
Synthesis 1978, 668.
Yield: 2.83 g (100%); colorless prisms (DMF); mp 244–246 °C.
IR (KBr): 705 (w), 745 (w), 765 (w), 835 (m), 950 (m), 995 (m),
1040 (m), 1060 (m), 1080 (m), 11.30 (m), 1165 (m), 1180 (m), 1240
(m), 1292 (s), 1320 (m), 1375 (s), 1430 (m), 1460 (m), 1490 (s),
1530 (m), 1600 (m), 1675 (s), 28.30 (w), 3080 (w) cm–1.
1H NMR (CDCl3, 100 MHz): = 1.89 (s, 9 H, CH3), 3.29 (s, 6 H,
CH2), 7.10–7.54 (m, 18 H, ArH, H5-selenazole).
13C NMR (50 MHz, DMSO-d6): = 23.56 (CH3), 58.89 (CH2),
127.24, 128.82, 129.25, 129.98 (CH), 138.27, 140.19 (C), 162.08
(C=O), 170.16 (C-2).
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 692.79.
Anal. Calcd for C26H33N7O3Se3 (848.6): C, 50.95; H, 3.92; N,
11.35; Se, 27.91. Found: C, 50.80; H, 4.10; N, 11.51; Se, 28.33.
Tris[2-(N-acetylanilino)selenazol-4-ylmethyl]methylammon-
ium Iodide (7b)
To a stirred DMF solution (70 mL) of 7a (2.55 g, 3.0 mmol) MeI
(1.14 g, 8.0 mmol) was added dropwise at 60 °C. After cooling,
Et2O was added to give a colorless precipitate.
Yield: 1.90 g (64%); colorless prisms (DMF–Et2O); mp 184–
186 °C.
(4) Banert, K.; Toth, C. Angew. Chem. Int. Ed. Engl. 1995, 34,
1627; Angew. Chem. 1995, 107, 1776, and references cited
therein.
(5) (a) Hartmann, H.; Eckert, K.; Schröder, A. Angew. Chem.
Int. Ed. 2000, 39, 556; Angew. Chem. 2000, 112, 567, and
references cited therein. (b) Keil, D.; Hartmann, H.; Zug, I.;
Schröder, A. J. Prakt. Chem. 2000, 342, 169.
IR (KBr): 700 (m), 759 (w), 994 (w), 1117 (w), 1164 (w), 1291 (s),
1373 (m), 1429 (w), 1455 (w), 1488 (s), 1599 (w), 1672 (s), 3012
(w), 3058 (w), 3093 (w) cm–1.
1H NMR (CDCl3, 100 MHz): = 2.11 (s, 9 H, CH3), 2.55 (s, 3 H,
CH3), 4.21 (s, 6 H, CH2), 7.59–7.75 (m, 18 H, ArH, H5-selenazole).
77Se NMR (DMSO-d6, 60% Me2Se in CDCl3): = 692.79.
MS (EI): m/z = 860/862/864/866 (M+, 46, 38, 69, 78, 62), 602 (96),
(6) For 4-halomethyl-1,3-thiazoles, see: Simiti I., Farkas M.,
Silberg S.; Chem. Ber.; 1962, 95: 2672.
468 (10), 406 (40), 379 (95), 278 (100), 236 (29), 207 (18).
(7) (a) For a preliminary communication, see: Geisler, K.;
Meinke, H.-J.; Müller, C.; Nobst, E.; Bulka, E. Wiss. Z.
Univ. Greifswald 1988, 37, 1. (b) for reactions of 4-
chloromethyl-1,3-selenazoles, see: Kumar, Y.; Green, R.;
Borysko, K. Z.; Wise, ; Wotring, L. L.; Townsend, L. B. J.
Med. Chem. 1993, 36 , 3843. (c) Hanson, R. N.; Davis, A.
M. J. Heterocycl. Chem. 1981, 18, 205. (d) Shafiee, A.;
Kiaeay, G.; Vosooghi, M. J. Heterocycl. Chem. 1981, 18,
789.
Anal. Calcd for C37H36N7IO3Se3 (990.5): C, 44.86; H, 3.66; N, 9.90;
I, 12.65. Found: C, 45.10; H, 3.90; N, 10.03; I, 12.65.
Tetrakis[2-(N-acetylanilino)-1,3-selenazol-4-ylmethyl]ammoni-
um Iodide (7c)
A DMF solution (70 mL) of 7a (2.55 g, 3.0 mmol) and 3c (1.20 g,
3.0 mmol) was heated at 100 °C. Further preparation was carried
out as described for 7a.
(8) For the synthesis of 2, see: Bulka, E.; Ahlers, K.-D.; Tucek,
E. Chem. Ber. 1967, 10, 1367.
Yield: 2.90 g (77%); yellow prisms (DMF–Et2O); mp 185–187 °C.
Synthesis 2003, No. 8, 1215–1220 ISSN 1234-567-89 © Thieme Stuttgart · New York