Synthesis of selenophene analogues of the tacrine series: Comparison of classical route and microwave irradiation

Article abstract of DOI:10.1055/s-2008-1067001

New 3-amino-2-selenophenecarbonitriles condensed with cyclanones to afford, in one step, analogues of Tacrine. A comparison between classical heating and microwave irradiation for the Friedlaender condensation is presented. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067001

1600
PAPER
Synthesis of Selenophene Analogues of the Tacrine Series: Comparison of
Classical Route and Microwave Irradiation
S
ynthesis of Selen
a
ophene
A
na
v
logues Usin
i
g Micro
d
wave Irradiation Thomae,a Gilbert Kirsch,*a Pierre Seckb
a
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol, FR CNRS 2843,
1 Boulevard Arago, 57070 Metz, France
Fax +33(3)87315801; E-mail: kirsch@univ-metz.fr
Laboratoire de Chimie, Faculté des Sciences, de la Technologie et de la Communication, Université du Luxembourg,
162a Avenue de la Faïencerie, 1511 Luxembourg, Grand-Duché de Luxembourg
b
Received 28 January 2008
In memory of Ariane Beutler
phenecarbonitriles. In the literature, access to 5-substitut-
ed 3-aminoselenophenes is described starting from ketene
dithioacetals,4 2-cyano-3-phenyl-3-chloroacrylonitrile5 or
3-aryl-3-chloroacrylonitrile6 and these strategies have
been used for the synthesis of 3-amino-2-nitroseleno-
phenes III (Scheme 1). To obtain 2a–f, we applied the
same strategy. Thus, b-chloroacrylonitriles 1a–f were ob-
tained in three steps by a method previously established
by different groups and also used in our laboratory.3,6,7
Freshly prepared sodium selenide, prepared by a known
method,4a,6 was reacted with b-chloroacrylonitriles 1a–f
in N,N-dimethylformamide (DMF) at 60 °C, to form the
intermediate selenolate. After two hours, chloroacetoni-
trile was added dropwise at 60 °C and stirring was con-
tinued for two more hours. Cyclization was performed by
addition of a solution of sodium ethanolate. Pouring the
reaction mixture in to water gave the compounds 2a–f as
solids in good yields (Table 1).
Abstract: New 3-amino-2-selenophenecarbonitriles condensed
with cyclanones to afford, in one step, analogues of Tacrine. A com-
parison between classical heating and microwave irradiation for the
Friedländer condensation is presented.
Key words: Alzheimer disease, Tacrine analogues, Friedländer re-
action, 3-amino-2-cyanoselenophenes, sodium selenide, micro-
wave irradiation
Alzheimer’s disease is a form of dementia of older people
and will be a major problem in the coming decade.1 One
possible treatment is to inhibit acetylcholinesterase,
which plays a role in the formation of the b-amyloïd
plaque. The first acetylcholinesterase inhibitor used was
Tacrine (I) sold under the name COGNEX® (Figure 1).
However, this drug has side effects.2 Our aim was to look
at the effects of structural modifications of Tacrine on its
biological activity. Recently, we described the synthesis
of thiophene analogues of Tacrine,3 based on the
thieno[3,2b]quinoline moiety II (Figure 1). To extend our
library of new analogues of Tacrine, we have developed a
method with which to prepare the selenophenes analogues
3, 4 and 5 (Figure 1).
Se
R1
NO2
iv
R1
Cl
NH2
R1
O
III
i, ii, iii
CN
The precursors of 3, 4 and 5 were the substituted sele-
nophenes 2a–f (Scheme 2) and the first step of the synthesis
was thus to prepare these new 3-amino-2-seleno-
v
Se
R1
1a–f
CN
NH2
NH2
NH2
2a–f
S
Ar
Scheme 1 Reagents and conditions: i) POCl3, DMF, 60 °C, 5 h; ii)
hydroxylamine chloride, EtOH, reflux; iii) Ac2O; iv) Na2Se, DMF,
BrCH2NO2, NaOH; v) Na2Se, DMF, ClCH2CN, NaOEt.
n
N
n = 0, 1, 2
N
I (Tacrine)
R
II
NH2
N
Table 1 Formation of the Selenophenes 2a–f
Se
Entry
1
R1
Yield of 2 (%)a
R1
n
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
64
76
80
77
68
77
3 (n = 0) 4 (n = 1) 5 (n = 2)
4-MeC6H4
4-MeOC6H4
4-ClC6H4
t-Bu
Figure 1 Strucure of Tacrine, thiophene analogues and new seleno-
phene analogues
SYNTHESIS 2008, No. 10, pp 1600–1606
Advanced online publication: 27.03.2008
DOI: 10.1055/s-2008-1067001; Art ID: Z03108SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8
4-O2NC6H4
a Crude product, analytically pure and used without purification.

PAPER
Synthesis of Selenophene Analogues Using Microwave Irradiation
1601
ously described in the litterature.2,8 To aluminium
chloride suspended in anhydrous dichloroethane under an
argon atmosphere, 2d and cyclopentanone were added.
The solution was heated for 12 hours at reflux to give 3d
in 75% yield. In order to improve the reaction, the order
of addition of the reagents was reversed. Thus, when 2
was dissolved in dichloroethane and the cyclanone was
then added followed by aluminium chloride, the reaction
was complete in 1–2 hours, instead of 12 hours, and com-
pounds 3–5 were obtained in good yields (Table 2).
DCE
NH2
CN
n
O
Se
R1
Se
R1
AlCl3
n
NH2
N
∆ or
MW (100 W)
3a–f (n = 0)
4a–f (n = 1)
5a–f (n = 2)
2a–f
Scheme 2 The Friedländer condensation
Since the pioneering work of Gedye in 1986,9 the use of
microwave irradiation in organic reactions has become
very important.10 Our laboratory has ongoing research in
the microwave field, focussing on improving heterocyclic
synthesis.11 Moreover, some research on the microwave-
assisted synthesis of quinolines have already been pub-
lished.12 After some attempts, we optimised the experi-
The second step of our synthesis was to prepare the sele-
nophene analogues of Tacrine 3a–f, 4a–f and 5a–f
(Scheme 2). As for thieno[3,2b]quinolines,3 the
Friedländer reaction was used. Substituted 3-amino-2-se-
lenophenecarbonitriles reacted with cyclanones in the
presence of aluminium chloride. The first attempt at cy-
clization was realized with 2d under the conditions previ-
Table 2 Yields of the Friedländer Reaction
DCE
NH2
CN
n
O
Se
Se
R1
R1
AlCl3
n
NH2
N
∆ or MW
2a–f
3a–f
4a–f
5a–f
Tacrine analogue
Compound
Classical heating Method A
Microwave irradiation (100 W) Method B
Time (min)
Yield (%)
Time (min)
Yield (%)
NH2
N
n = 0, 3a
n = 1, 4a
n = 2, 5a
120
120
120
65
85
78
2 × 8
2 × 8
2 × 8
70
95
97
Se
n
NH2
n = 0, 3b
n = 1, 4b
n = 2, 5b
60
60
60
83
80
76
1 × 8
1 × 8
1 × 8
93
89
91
Se
n
N
NH2
N
n = 0, 3c
n = 1, 4c
n = 2, 5c
120
60
60
85
73
75
2 × 8
2 × 8
2 × 8
75
84
82
Se
MeO
n
NH2
n = 0, 3d
n = 1, 4d
n = 2, 5d
120
120
120
84
94
90
1 × 10
1 × 10
1 × 10
94
79
88
Se
Cl
n
N
NH2
n = 0, 3e
n = 1, 4e
n = 2, 5e
120
120
120
92
95
91
1 × 8
1 × 8 + 3
1 × 8
93
94
91
Se
t-Bu
n
N
NH2
n = 0, 3f
n = 1, 4f
n = 2, 5f
120
120
120
85
95
85
2 × 8a
2 × 8a
2 × 8a
86
95
88
Se
O2N
n
N
a Reaction performed in THF with AlCl3 (6 equiv).
Synthesis 2008, No. 10, 1600–1606 © Thieme Stuttgart · New York

1602
D. Thomae et al.
PAPER
Preparation of Sodium Selenide
mental conditions through which to prepare 3, 4 and 5
under microwave irradiation. Thus, 2a–f were reacted
with cyclanones in dichloroethane in the presence of alu-
minium chloride in the same proportions used for reflux-
ing. The solution was heated between 8 and 16 minutes at
constant power (100W). 3f, 4f and 5f were not soluble
enough in dichloroethane and the Friedländer reaction did
not go to completion. In this case, when the solvent was
changed to THF, however, 2f rapidly gave the expected
compounds 3f, 4f and 5f in high yields (Table 2). Micro-
wave irradiation helped to reduce the time of reaction and,
in most cases, the yields were better than those obtained
following the classical route (Table 2).
Selenium (0.04 mol) was added to a solution of NaOH (0.224 mol)
and sodium formaldehyde sulfoxylate (0.096 mol) in H2O (40 mL).
After stirring for 1 h at 50 °C, the white precipitate was filtered un-
der an argon atmosphere and rapidly used for the next step.
Synthesis of Substituted 3-Aminoselenophenecarbonitrile (2a–
f); General Procedure
Na2Se (0.04 mol) was suspended in DMF (40 mL) and the corre-
sponding b-chloroacrylonitrile 1a–f (0.04 mol) dissolved in DMF
(15 mL) was added. The mixture was heated at 60 °C for 2 h then
choroacetonitrile (0.04 mol) was added dropwise. After addition,
the mixture was stirred for 2 h at 60 °C then a solution of EtONa
(0.04 mol) in absolute EtOH (25 mL) was added and stirring was
continued for 1 h at the same temperature. The mixture was poured
onto H2O (300 mL) under vigorous stirring and the precipitate was
filtered, washed with H2O (2 × 50 mL), dried at r.t. until constant
weight and recrystallized (EtOH).
Nitro derivatives 3f, 4f and 5f were transformed into the
previously unknown amino compounds 3g, 4g and 5g, re-
spectively, in good yields, using hydrazine hydrate and
palladium on activated carbon (Scheme 3).13
3-Amino-5-phenyl-2-selenophenecarbonitrile (2a)
Yield: 64%; brown solid; mp 110–112 °C (dec).
NH2
IR (neat): 3429 (s), 3332 (s), 3229 (s), 2959 (s), 2197 (s), 1563 (s)
cm–1.
1H NMR (250 MHz, CDCl3): d = 6.58 (s, 2 H, NH2), 7.20 (s, 1 H,
CH), 7.41 (m, 3 H, CH), 7.42 (m, 2 H, 2 × CH).
3f
4f
5f
Se
O2N
n
N
13C NMR (63 MHz, DMSO-d6): d = 72.32, 117.15, 119.31, 125.78,
129.30, 129.41, 134.00, 153.11, 159.48.
i
GC-MS (EI, 70 eV): m/z = 248 [M+], 168, 77.
NH2
Anal. Calcd for C11H8N2Se: C, 56.46; H, 3.26; N, 11.33. Found: C,
56.66; H, 3.23; N, 10.30.
Se
3g (n = 0) 83%
4g (n = 1) 95%
5g (n = 2) 70%
H2N
n
N
3-Amino-5-(4-methylphenyl)-2-selenophenecarbonitrile (2b)
Yield: 76%; brown solid; mp 190–192 °C.
IR (KBr): 3428 (s), 3345 (s), 3242 (s), 2178 (s), 1566 (s) cm–1.
Scheme 3
EtOH, reflux.
Reagents and conditions: i) N2H4·H2O, Pd/C (5%),
1H NMR (250 MHz, DMSO-d6): d = 2.30 (s, 3 H, CH3), 6.54 (s, 2 H,
NH2), 7.15 (s, 1 H, CH), 7.22 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.42 (d,
J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 20.77, 71.67, 117.26, 118.64,
125.68, 129.71, 131.31, 138.34, 153.26, 159.53.
In conclusion, substituted 3-amino-2-cyanoselenophene-
carbonitriles 2a–f were synthesized in four steps with
good yields. Experimental conditions for the Friedländer
reaction under microwave irradiation have been devel-
oped, which allow very rapid access to the target mole-
cules 3–5 in high yields. The expected compounds were
obtained faster and with better yields than those obtained
through classical heating. Biological tests using Ellman’s
test on acetylcholinesterase inhibition procedure14 are un-
derway.
GC-MS (EI, 70 eV): m/z = 262 [M+], 182, 115.
Anal. Calcd for C12H10N2Se: C, 55.18; H, 3.86; N, 10.73. Found: C,
55.05; H, 4.01; N, 10.78.
3-Amino-5-(4-methoxyphenyl)-2-selenophenecarbonitrile (2c)
Yield: 80%; brown solid; mp 220–222 °C.
IR (KBr): 3458 (s), 3339 (s), 3234 (s), 2182 (s), 1565 (s) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 3.77 (s, 3 H, CH3), 6.52 (s, 2 H,
NH2), 6.96 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.11 (s, 1 H, CH), 7.46 (d,
J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 55.33, 113.47, 114.59, 117.20,
117.94, 126.54, 126.54, 126.97, 157.21, 159.67, 160.20.
Melting points were determined on a Stuart SMP3 apparatus and are
uncorrected. IR spectra were performed using a Perkin–Elmer
Spectrum BxFT-IR spectrophotometer or were recorded neat from
4400 to 600 cm–1 on an Perkin–Elmer FT-IR Baragon 1000PC
equipped with a Graseby–Specac golden gate and treated with the
Spectrum (Perkin–Elmer) software version 5.3.1. 1H and 13C NMR
spectra were recorded on a AC Bruker 250 MHz spectrometer in
CDCl3 or DMSO-d6. MS spectra were recorded on an Agilent Tech-
nologies GC-MS instrument equipped with a 7683 injector, 6890N
gas chromatograph and a 5973 mass-selective detector. The mass
spectrometer was operated in EI mode at 70 eV and MS spectra
were recorded from m/z 50 to 650. Elemental analyses were deter-
mined with a LECO CHNS 932 elemental analyzer. A CEM Dis-
cover oven was used for reactions requiring microwave irradiation.
GC-MS (EI, 70 eV): m/z = 278 [M+], 263, 198.
Anal. Calcd for C12H10N2OSe: C, 52.00; H, 3.64; N, 10.11. Found:
C, 52.16; H, 3.78; N, 10.99.
3-Amino-5-(4-chlorophenyl)-2-selenophenecarbonitrile (2d)
Yield: 77%; green solid; mp 204–206 °C.
IR (KBr): 3429 (s), 3333 (s), 3229 (s), 2198 (s), 1566 (s) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 6.62 (s, 2 H, NH2), 7.25 (s,
1 H, CH), 7.46 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.55 (d, J = 7.5 Hz,
2 H, 2 × CH).
Synthesis 2008, No. 10, 1600–1606 © Thieme Stuttgart · New York

PAPER
Synthesis of Selenophene Analogues Using Microwave Irradiation
1603
13C NMR (63 MHz, DMSO-d6): d = 72.72, 117.07, 120.00, 127.70,
128.73, 132.90, 133.87, 151.39, 159.49.
1H NMR (250 MHz, DMSO-d6): d = 2.10 (m, 2 H, CH2), 2.75 (m,
2 H, CH2), 2.78 (m, 2 H, CH2), 6.23 (s, 2 H, NH2), 7.38 (m, 3 H,
3 × CH), 7.52 (m, 2 H, 2 × CH), 7.52 (s, 1 H, CH).
GC-MS (EI, 70 eV): m/z = 282 [M+], 202.
13C NMR (63 MHz, DMSO-d6): d = 24.65, 27.45, 33.70, 114.54,
117.54, 124.33, 125.91, 127.83, 129.14, 135.50, 146.64, 146.95,
158.78, 163.76.
Anal. Calcd for C11H7ClN2Se: C, 46.92; H, 2.51; N, 9.95. Found: C,
46.81; H, 2.24; N, 9.88.
3-Amino-5-tert-butyl-2-selenophenecarbonitrile (2e)
GC-MS (EI, 70 eV): m/z = 314 [M+], 233.
Yield: 68%; brown solid; mp 122–124 °C.
Anal. Calcd for C16H14N2Se: C, 61.35; H, 4.50; N, 8.94. Found: C,
61.43; H, 4.49; N, 8.89.
IR (KBr): 3414 (s), 3334 (s), 3227 (s), 2959 (s), 2185 (s), 1570 (s)
cm–1.
9-Amino-2-phenyl-5,6,7,8-tetrahydroselenopheno[3,2-b]quino-
line (4a)
Yield: 85% (Method A), 95% (Method B); brown solid; mp 228–
230 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.32 (s, 9 H, 3 × CH3), 4.44 (s,
2 H, NH2), 6.59 (s, 1 H, CH).
13C NMR (63 MHz, DMSO-d6): d = 32.32, 36.94, 79.61, 116.85,
117.68, 156.60, 172.16.
GC-MS (EI, 70 eV): m/z = 228 [M+], 213, 147, 132.
IR (neat): 2926 (m), 164 (s), 1559 (s), 1529 (s), 753 (s), 684 (s)
cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.80 (m, 4 H, 2 × CH2), 2.49
(m, 2 H, CH2), 2.75 (m, 2 H, CH2), 6.09 (s, 2 H, NH2), 7.39 (m, 3 H,
3 × CH), 7.68 (m, 2 H, 2 × CH), 7.80 (s, 1 H, CH).
13C NMR (63 MHz, DMSO-d6): d = 22.38, 22.59, 23.32, 32.52,
110.03, 116.82, 124.30, 125.97, 128.54, 129.14, 135.46, 146.83,
148.70, 154.53, 156.89.
Anal. Calcd for C9H12N2Se: C, 47.58; H, 5.32; N, 12.33. Found: C,
47.84; H, 5.44; N, 12.28.
3-Amino-5-(4-nitrophenyl)-2-selenophenecarbonitrile (2f)
Yield: 77%; orange solid; mp 198–200 °C.
IR (KBr): 3431(s), 3312 (s), 1557 (s) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 6.66 (s, 2 H, NH2), 7.41 (s,
1 H, CH), 7.80 (d, J = 7.5 Hz, 2 H, 2 × CH), 8.23 (d, J = 7.5 Hz,
2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 75.06, 116.74, 122.03, 124.48,
126.62, 140.01, 147.28, 149.92, 159.38.
GC-MS (EI, 70 eV): m/z = 328 [M+], 312, 300.
Anal. Calcd for C17H16N2Se: C, 62.39; H, 4.93; N, 8.56. Found: C,
62.34; H, 4.74; N, 8.65.
10-Amino-2-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]sele-
nopheno[2,3-e]pyridine (5a)
Yield: 78% (Method A), 97% (Method B); brown solid; mp 216–
218 °C.
GC-MS (EI, 70 eV): m/z = 293 [M+], 263, 247, 220, 140.
Anal. Calcd for C11H7N3O2Se: C, 45.22; H, 2.42; N, 14.38. Found:
C, 45.84; H, 2.45; N, 14.27.
IR (neat): 2918 (m), 1631 (s), 1558 (s), 1528 (s), 753 (s), 687 (s)
cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.56 (m, 4 H, 2 × CH2), 1.80
(m, 2 H, CH2), 2.73 (m, 2 H, CH2), 2.90 (m, 2 H, CH2), 6.20 (s, 2 H,
NH2), 7.42 (m, 3 H, 3 × CH), 7.68 (m, 2 H, 2 × CH), 7.82 (s, 1 H,
CH).
13C NMR (63 MHz, DMSO-d6): d = 23.63, 24.99, 26.45, 27.29,
31.74, 115.31, 118.87, 124.61, 125.94, 128.47, 129.15, 135.52,
146.79, 147.70, 156.37, 161.72.
Friedländer Reaction (Method A: Refluxing); General Proce-
dure
Cyclanone (1.1 mmol) was added to a solution of selenophene 1 (1
mmol) in CH2Cl2 (25 mL). After stirring 5 min at r.t., aluminium
chloride (1.7 mmol) was added and the mixture was heated at reflux
for 1–2 h. When the reaction was complete (TLC), aq NaOH (10%,
25 mL) was added. After stirring for 30 min, the mixture was ex-
tracted with CH2Cl2 (3 × 10 mL), dried over anhydrous NaSO4, fil-
tered and the solvent was evaporated. The resultant solid was
purified by column chromatography (EtOAc, 100%) or heated in
MeCN (2 mL) and filtered while hot.
GC-MS (EI, 70 eV): m/z = 342 [M+], 327, 313, 288, 77.
Anal. Calcd for C18H18N2Se: C, 63.34; H, 5.32; N, 8.21. Found: C,
63.57; H, 5.13; N, 8.14.
Friedländer Reaction (Method B: Microwave Irradiation);
General Procedure
8-Amino-2-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[b]se-
lenopheno[2,3-e]pyridine (3b)
Yield: 83% (Method A), 93% (Method B); light-brown solid; mp
In a 100 mL round-bottom flask equipped with a condenser, cycla-
none (2.2 mmol) was added to a solution of selenophene 2 (2 mmol)
in CH2Cl2 (34 mL) (or THF when 2f was used). Aluminium chloride
(3.4 mmol or 12 mmol for 2f) was added and the mixture was heated
at reflux for 8–16 min under microwave irradiation (constant power
of 100 W). When the reaction was complete (TLC), aq NaOH (10%,
34 mL) was added and stirring was continued for 30 min. The mix-
ture was extracted with CH2Cl2 (3 × 20 mL), dried over anhydrous
NaSO4, filtered and the solvent was evaporated. The resultant solid
was purified by column chromatography (EtOAc, 100%) or heated
in MeCN (2 mL) and filtered while hot.
264–266 °C.
IR (neat): 2949 (m), 1645 (s), 1561 (s), 1538 (s), 800 (s) cm–1.
1H NMR (250 MHz, CDCl3): d = 2.14 (m, 2 H, CH2), 2.17 (s, 3 H,
CH3), 2.77 (m, 2 H, CH2), 3.00 (m, 2 H, CH2), 4.05 (s, 2 H, NH2),
7.18 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.46 (d, J = 7.5 Hz, 2 H, 2 × CH),
7.57 (s, 1 H, CH).
13C NMR (63 MHz, DMSO-d6): d = 20.76, 22.44, 27.47, 33.81,
114.40, 117.18, 123.89, 125.81, 129.69, 132.84, 138.04, 146.56,
146.76, 159.26, 163.95.
8-Amino-2-phenyl-6,7-dihydro-5H-cyclopenta[b]seleno-
pheno[2,3-e]pyridine (3a)
GC-MS (EI, 70 eV): m/z = 328 [M+], 247, 163, 115, 91.
Yield: 65% (Method A), 70% (Method B); brown solid; mp 234–
236 °C.
Anal. Calcd for C17H16N2Se: C, 62.39; H, 4.93; N, 8.56. Found: C,
62.66; H, 5.14; N, 8.29.
IR (neat): 2949 (m), 1638 (s), 1563 (s), 1540 (s), 753 (s), 680 (s)
cm–1.
Synthesis 2008, No. 10, 1600–1606 © Thieme Stuttgart · New York

1604
D. Thomae et al.
PAPER
GC-MS (EI, 70 eV): m/z = 358 [M+], 343, 330, 315, 219, 207.
9-Amino-2-(4-methylphenyl)-5,6,7,8-tetrahydroselenophe-
no[3,2-b]quinoline (4b)
Yield: 80% (Method A), 89% (Method B); colorless solid; mp 254–
256 °C.
Anal. Calcd for C18H18N2OSe: C, 60.51; H, 5.08; N, 7.84. Found: C,
60.78; H, 5.26; N, 7.94.
IR (neat): 2929 (m), 1646 (s), 1559 (s), 153 (s), 807 (s) cm–1.
10-Amino-2-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-cyclo-
hepta[b]selenopheno[2,3-e]pyridine (5c)
Yield: 75% (Method A), 82% (Method B); colorless solid; mp 240–
242 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.79 (m, 4 H, 2 × CH2), 2.34
(s, 3 H, CH3), 2.50 (m, 2 H, CH2), 2.75 (m, 2 H, CH2), 6.02 (s, 2 H,
NH2), 7.26 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.58 (d, J = 7.5 Hz, 2 H,
2 × CH), 7.76 (s, 1 H, CH).
IR (neat): 2918 (m), 1650 (m), 1533 (s), 1498 (s), 825 (s) cm–1.
13C NMR (63 MHz, DMSO-d6): d = 20.75, 22.43, 22.66, 23.34,
32.67, 109.92, 116.48, 123.82, 125.85, 130.67, 132.80, 138.10,
146.73, 148.50, 154.63, 157.29.
1H NMR (250 MHz, DMSO-d6): d = 1.54 (m, 2 H, CH2), 1.56 (m,
2 H, CH2), 1.79 (m, 2 H, CH2), 2.72 (m, 2 H, CH2), 2.88 (m, 2 H,
CH2), 3.79 (s, 3 H, CH3), 5.97 (s, 2 H, NH2), 7.00 (d, J = 7.5 Hz,
2 H, 2 × CH), 7.60 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.67 (s, 1 H, CH).
13C NMR (63 MHz, CDCl3): d = 26.04, 26.64, 27.29, 32.22, 39.05,
55.41, 116.50, 119.92, 123.51, 127.51, 127.76, 128.59, 146.16,
148.08, 157.06, 160.05, 162.65.
GC-MS (EI, 70 eV): m/z = 342 [M+], 326, 314, 163, 115, 91.
Anal. Calcd for C18H18N2Se: C, 63.34; H, 5.32; N, 8.21. Found: C,
63.38; H, 5.33; N, 8.35.
10-Amino-2-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohep-
ta[b]selenopheno[2,3-e]pyridine (5b)
GC-MS (EI, 70 eV): m/z = 372 [M+], 357, 343, 328, 315, 300, 219,
207.
Yield: 76% (Method A), 91% (Method B); light-brown solid; mp
276–278 °C.
IR (neat): 2917 (m), 1648 (s), 1559 (s), 1534 (s), 809 (s) cm–1.
Anal. Calcd for C19H20N2OSe: C, 61.45; H, 5.43; N, 7.54. Found: C,
61.25; H, 5.53; N, 7.72.
8-Amino-2-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]se-
lenopheno[2,3-e]pyridine (3d)
Yield: 84% (Method A), 94% (Method B); brown solid; mp 270–
272 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.55 (m, 4 H, 2 × CH2), 1.58
(m, 2 H, CH2), 2.30 (s, 3 H, CH3), 2.72 (m, 2 H, CH2), 2.89 (m, 2 H,
CH2), 5.99 (s, 2 H, NH2), 7.25 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.56 (d,
J = 7.5 Hz, 2 H, 2 × CH), 7.75 (s, 1 H, CH).
13C NMR (63 MHz, DMSO-d6): d = 20.74, 25.00, 26.47, 27.32,
31.75, 32.07, 115.20, 118.55, 124.01, 125.68, 129.66, 132.83,
138.04, 146.79, 147.58, 156.60, 161.75.
IR (neat): 2952 (m), 1642 (s), 1539 (s), 1562 (s), 814 (s) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 2.04 (m, 2 H, CH2), 2.75 (m
2 H, CH2), 2.83 (m, 2 H, CH2), 6.22 (s, 2 H, NH2), 7.57 (d, J = 7.5
Hz, 2 H, 2 × CH), 7.62 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.71 (s, 1 H,
CH).
13C NMR (63 MHz, DMSO-d6): d = 22.41, 27.47, 33.76, 114.67,
117.80, 125.28, 127.56, 129.08, 132.88, 134.46, 144.87, 146.83,
158.93, 164.10.
GC-MS (EI, 70 eV): m/z = 356 [M+], 341, 327, 163, 115, 91.
Anal. Calcd for C19H20N2Se: C, 64.22; H, 5.67; N, 7.88. Found: C,
64.08; H, 5.57; N, 7.98.
8-Amino-2-(4-methoxyphenyl)-6,7-dihydro-5H-cyclopen-
ta[b]selenopheno [2,3-e]pyridine (3c)
GC-MS (EI, 70 eV): m/z = 348 [M+], 331, 311, 267.
Yield: 83% (Method A), 75% (Method B); light-brown solid; mp
236–238 °C.
IR (neat): 2944 (m), 1647 (m), 1562 (s), 1540 (s), 810 (s) cm–1.
Anal. Calcd for C16H13ClN2Se: C, 55.27; H, 3.77; N, 8.06. Found:
C, 55.54; H, 3.83; N, 8.09.
9-Amino-2-(4-chlorophenyl)-5,6,7,8-tetrahydroselenophe-
no[3,2-b]quinoline (4d)
Yield: 94% (Method A), 79% (Method B); brown solid; mp 258–
1H NMR (250 MHz, CDCl3): d = 2.22 (m, 2 H, CH2), 2.82 (m, 2 H,
CH2), 3.05 (m, 2 H, CH2), 3.87 (s, 3 H, CH3), 4.18 (s, 2 H, NH2),
6.96 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.64 (d, J = 7.5 Hz, 2 H, 2 × CH),
7.71 (s, 1 H, CH).
13C NMR (63 MHz, CDCl3): d = 22.96, 27.27, 34.38, 55.41, 114.36,
115.65, 123.36, 127.86, 128.63, 129.59, 145.00, 147.76, 159.85,
160.04, 165.15.
260 °C.
IR (neat): 2932 (m), 1628 (m), 1557 (s), 1528 (s), 814 (s) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.77 (m, 4 H, 2 × CH2), 2.48
(m, 2 H, CH2), 2.74 (m, 2 H, CH2), 6.08 (s, 2 H, NH2), 7.50 (d,
J = 7.5 Hz, 2 H, 2 × CH), 7.67 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.84 (s,
1 H, CH).
13C NMR (63 MHz, DMSO-d6): d = 22.37, 22.59, 23.35, 32.60,
110.16, 117.05, 125.22, 127.61, 129.09, 132.94, 134.43, 145.07,
148.63, 154.76, 156.95.
GC-MS (EI, 70 eV): m/z = 344 [M+], 329, 300, 219, 207.
Anal. Calcd for C17H16N2OSe: C, 59.48; H, 4.70; N, 8.16. Found: C,
59.61; H, 4.52; N, 8.13.
9-Amino-2-(4-methoxyphenyl)-5,6,7,8-tetrahydroselenophe-
no[3,2-b]quinoline (4c)
GC-MS (EI, 70 eV): m/z = 362 [M+], 346, 334, 281.
Yield: 73% (Method A), 84% (Method B); colorless solid; mp 246–
248 °C.
IR (neat): 2933 (m), 1646 (m), 1532 (s), 1499 (s), 822 (s) cm–1.
Anal. Calcd for C17H15ClN2Se: C, 56.45; H, 4.18; N, 7.74. Found:
C, 56.61; H, 4.16; N, 7.49.
10-Amino-2-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-cyclohep-
ta[b]selenopheno[2,3-e]pyridine (5d)
Yield: 90% (Method A), 88% (Method B); brown solid; mp 274–
276 °C.
IR (neat): 2917 (m), 1648 (m), 1559 (s), 1531 (s), 820 (s) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.57 (m, 4 H, 2 × CH2), 1.79
(m, 2 H, CH2), 2.38 (m, 2 H, CH2), 2.89 (m, 2 H, CH2), 6.06 (s, 2 H,
1H NMR (250 MHz, CDCl3): d = 1.79 (m, 2 H, CH2), 1.81 (m, 2 H,
CH2), 2.47 (m, 2 H, CH2), 2.86 (m, 2 H, CH2), 3.73 (s, 3 H, CH3),
4.13 (s, 2 H, NH2), 6.83 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.49 (d,
J = 7.5 Hz, 2 H, 2 × CH), 7.66 (s, 1 H, CH).
13C NMR (63 MHz, CDCl3): d = 22.71, 22.92, 23.38, 33.04, 55.40,
110.96, 114.35, 123.23, 127.77, 128.55, 129.59, 147.28, 147.91,
155.79, 157.80, 160.07.
Synthesis 2008, No. 10, 1600–1606 © Thieme Stuttgart · New York

PAPER
Synthesis of Selenophene Analogues Using Microwave Irradiation
1605
NH2), 7.55 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.63 (d, J = 7.5 Hz, 2 H,
2 × CH), 7.85 (s, 1 H, CH).
13C NMR (63 MHz, DMSO-d6): d = 23.63, 25.00, 26.45, 27.28,
30.36, 115.46, 119.15, 125.47, 127.59, 129.09, 132.89, 134.48,
145.06, 147.66, 156.36, 161.95.
Hz, 2 H, 2 × CH), 8.11 (s, 1 H, CH), 8.26 (d, J = 7.5 Hz, 2 H,
2 × CH).
13C NMR (63 MHz, CDCl3): d = 22.38, 27.50, 33.71, 115.20,
119.24, 124.39, 126.81, 127.90, 141.82, 143.59, 146.67, 146.98,
158.43, 164.43.
GC-MS (EI, 70 eV): m/z = 376 [M+], 361, 347, 207.
GC-MS (EI, 70 eV): m/z = 248, 168.
Anal. Calcd for C18H17ClN2Se: C, 57.54; H, 4.56; N, 7.46. Found:
C, 57.65; H, 4.50; N, 9.43.
Anal. Calcd for C15H13N3O2Se: C, 53.64; H, 3.66; N, 11.73. Found:
C, 53.46; H, 3.85; N, 11.42.
8-Amino-2-tert-butyl-3-methyl-6,7-dihydro-5H-cyclopen-
ta[b]seleno[2,3-e]pyridine (3e)
Yield: 92% (Method A), 93% (Method B); beige solid; mp 212–
214 °C.
9-Amino-2-(4-nitrophenyl)-5,6,7,8-tetrahydroselenopheno[3,2-
b]quinoline (4f)
Yield: 95% (Method A), 95% (Method B); brown solid; mp 276–
278 °C (MeCN).
IR (neat): 2951 (s), 1646 (s), 1563 (s), 1537 (s) cm–1.
IR (neat): 2932 (m), 1592 (s), 1561 (s), 1511 (s), 1338 (s) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.35 (s, 9 H, 3 × CH3), 2.01
(m, 2 H, CH2), 2.71 (m, 2 H, CH2), 2.79 (m, 2 H, CH2), 5.97 (s, 1 H,
NH2), 7.14 (s, 1 H, CH).
13C NMR (63 MHz, DMSO-d6): d = 22.44, 27.36, 32.13, 32.78,
36.09, 113.58, 116.31, 122.68, 146.70, 158.59, 162.53, 163.25.
1H NMR (250 MHz, CDCl3): d = 1.78 (m, 4 H, 2 × CH2), 2.48 (m,
2 H, CH2), 2.76 (m, 2 H, CH2), 6.17 (s, 2 H, NH2), 7.96 (d, J = 7.5
Hz, 2 H, 2 × CH), 8.10 (s, 1 H, CH), 8.26 (d, J = 7.5 Hz, 2 H,
2 × CH).
13C NMR (63 MHz, CDCl3): d = 22.32, 22.56, 23.19, 32.68, 110.64,
118.39, 124.39, 126.86, 128.11, 141.85, 143.61, 146.70, 148.66,
155.30, 156.73.
GC-MS (EI, 70 eV): m/z = 294 [M+], 279, 263, 251, 237, 199.
Anal. Calcd for C14H18N2Se: C, 57.34; H, 6.19; N, 9.55. Found: C,
57.30; H, 6.11; N, 9.37.
Anal. Calcd for C17H15N3O2Se: C, 54.85; H, 4.06; N, 11.29. Found:
C, 55.12; H, 4.30; N, 11.23.
9-Amino-2-tert-butyl-3-methyl-5,6,7,8-tetrahydroselenophe-
no[3,2-b]quinoline (4e)
Yield: 95% (Method A), 94% (Method B); beige solid; mp 198–
10-Amino-2-(4-nitrophenyl)-6,7,8,9-tetrahydro-5H-cyclohep-
ta[b]selenopheno[2,3-e]pyridine (5f)
Yield: 85% (Method A), 88% (Method B); brown solid; mp 272–
274 °C (MeCN).
IR (neat): 2918 (m), 1591 (s), 1560 (s), 1514 (s), 1338 (s) cm–1.
1H NMR (250 MHz, CDCl3): d = 1.57 (m, 4 H, 2 × CH2), 1.78 (m,
2 H, CH2), 2.76 (m, 2 H, CH2), 2.82 (m, 2 H, CH2), 6.17 (s, 2 H,
NH2), 7.95 (d, J = 7.5 Hz, 2 H, 2 × CH), 8.10 (s, 1 H, CH), 8.26 (d,
J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, CDCl3): d = 25.03, 26.42, 27.22, 29.82, 31.69,
115.94, 120.54, 124.41, 126.83, 128.25, 141.87, 143.67, 146.58,
147.74, 156.07, 162.38.
200 °C.
IR (neat): 2928 (s), 1641 (s), 1562 (s), 1527 (s) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.35 (s, 9 H, 3 × CH3), 1.74
(m, 4 H, 2 × CH2), 2.48 (m, 2 H, CH2), 2.70 (m, 2 H, CH2), 5.84 (s,
1 H, NH2), 7.11 (s, 1 H, CH).
13C NMR (63 MHz, DMSO-d6): d = 22.49, 22.71, 23.22, 32.10,
32.61, 36.08, 109.17, 115.74, 122.57, 148.48, 153.93, 156.60,
162.80.
GC-MS (EI, 70 eV): m/z = 308 [M+], 293, 277, 265, 213.
Anal. Calcd for C15H20N2Se: C, 58.63; H, 6.56; N, 9.12. Found: C,
58.52; H, 6.40; N, 9.06.
GC-MS (EI, 70 eV): m/z = 357, 342, 328.
Anal. Calcd for C18H17N3O2Se: C, 55.96; H, 4.44; N, 10.88. Found:
C, 55.84; H, 4.59; N, 10.98.
10-Amino-2-tert-butyl-3-methyl-6,7,8,9-tetrahydro-5H-cyclo-
hepta[b]selenopheno[2,3-e]pyridine (5e)
Yield: 91% (Method A), 91% (Method B); beige solid; mp 192–
194 °C.
Reduction of the Nitro Group; General Procedure
In a three-necked round-bottom flask equipped with a magnetic stir-
rer, condenser and stoppers, Pd/C (5%, 60 mg) was added to a solu-
tion of 2f, 3f or 4f (0.5 mmol) in absolute EtOH (10 mL). Hydrazine
hydrate (98%, 1.35 mmol) was added dropwise at r.t. and the mix-
ture was stirred for 30 min. The mixture was then heated at reflux
for 4 h, and every hour, additional hydrazine hydrate (1.35 mmol)
was added. When the reaction was complete, EtOH was evaporated
under vacuum and H2O (30 mL) was added. The precipitate was fil-
tered, washed with H2O (2 × 10 mL), dried at r.t. until constant
weight and recrystallized (EtOH).
IR (neat): 2916 (s), 1680 (s), 1562 (s), 1528 (s) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.35 (s, 9 H, 3 × CH3), 1.52
(m, 4 H, 2 × CH2), 1.74 (m, 2 H, CH2), 2.68 (m, 2 H, CH2), 2.85 (m,
2 H, CH2), 5.85 (s, 1 H, NH2), 7.12 (s, 1 H, CH).
13C NMR (63 MHz, DMSO-d6): d = 24.95, 26.51, 27.40, 31.76,
32.13, 36.07, 38.35, 114.49, 117.72, 122.81, 147.53, 155.87,
161.11, 162.82.
GC-MS (EI, 70 eV): m/z = 322 [M+], 307, 293, 277, 263, 227.
8-Amino-2-(4-aminophenyl)-6,7-dihydro-5H-cyclopenta[b]sele-
nopheno[2,3-e]pyridine (3g)
Yield: 83%; orange solid; mp 210–212 °C.
Anal. Calcd for C17H22N2Se: C, 59.81; H, 6.90; N, 8.72. Found: C,
70.22; H, 6.04; N, 8.87.
8-Amino-2-(4-nitrophenyl)-6,7-dihydro-5H-cyclopenta[b]sele-
nopheno[2,3-e]pyridine (3f)
IR (neat): 3338 (m), 3209 (m), 2949 (m), 1604 (s), 1562 (s), 1502
(s), 821 (s) cm–1.
Yield: 85% (Method A), 86% (Method B); brown solid; mp 286–
288 °C (MeCN).
IR (neat): 2922 (m), 1590 (s), 1562 (s), 1511 (s), 1337 (s) cm–1.
1H NMR (250 MHz, DMSO-d6): d = 2.08 (m, 2 H, CH2), 2.75 (m,
2 H, CH2), 2.85 (m, 2 H, CH2), 6.35 (s, 2 H, NH2), 7.95 (d, J = 7.5
1H NMR (250 MHz, DMSO-d6): d = 2.03 (m, 2 H, CH2), 2.73 (m,
2 H, CH2), 2.81 (m, 2 H, CH2), 5.47 (s, 2 H, NH2), 6.08 (s, 2 H,
NH2), 6.58 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.33 (d, J = 7.5 Hz, 2 H,
2 × CH), 7.48 (s, 1 H, CH).
Synthesis 2008, No. 10, 1600–1606 © Thieme Stuttgart · New York

1606
D. Thomae et al.
PAPER
13C NMR (63 MHz, CDCl3): d = 22.41, 27.42, 33.64, 113.86,
113.92, 115.73, 119.96, 122.91, 126.98, 146.85, 148.50, 149.57,
159.22, 163.04.
(2) Augry, F.; Darch, A.; De Routou, J.; Guelfi, M. C.; Forette,
F. J. Pharm. Clin. 1997, 16, 183.
(3) Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2007, 1027.
(4) (a) Sommen, G.; Comel, A.; Kirsch, G. Synlett 2003, 855.
(b) Sommen, G.; Comel, A.; Kirsch, G. Synthesis 2004, 451.
(5) Gewald, K.; Hain, U. Monatsh. Chem. 1992, 123, 455.
(6) Thomae, D.; Rodriguez Dominguez, J. C.; Kirsch, G.; Seck,
P. Tetrahedron 2008, 64, 3232.
(7) (a) Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2007, 2153.
(b) Migianu, E.; Kirsch, G. Synthesis 2002, 1096. (c) Ren,
W.-Y.; Rao, K.; Kein, R. J. Heterocycl. Chem. 1986, 23,
1757. (d) Vega, S.; Gil, M. S. J. Heterocycl. Chem. 1991, 28,
1757. (e) Hartmann, H.; Liebscher, J. Synthesis 1984, 275.
(f) Hartmann, H.; Liebscher, J. Synthesis 1984, 276.
(g) Liebscher, J.; Neumann, B.; Hartmann, H. J. Prakt.
Chem. 1983, 325, 915. (h) Hartmann, H.; Liebscher, J.
Synthesis 1979, 241.
GC-MS (EI, 70 eV): m/z = 329 [M+], 313, 207.
Anal. Calcd for C16H15N3Se: C, 58.54; H, 4.61; N, 12.80. Found: C,
58.61; H, 4.68; N, 12.79.
9-Amino-2-(4-nitrophenyl)-5,6,7,8-tetrahydroselenopheno[3,2-
b]quinoline (4g)
Yield: 95%; orange solid; mp 208–210 °C.
IR (neat): 3338 (m), 3208 (m), 2924 (m), 2856 (m), 1603 (s),
1531(s), 1500 (s) cm–1.
1H NMR (250 MHz, CDCl3): d = 1.76 (m, 4 H, 2 × CH2), 2.48 (m,
2 H, CH2), 2.71 (m, 2 H, CH2), 5.48 (s, 2 H, NH2), 5.96 (s, 2 H,
NH2), 6.58 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.33 (d, J = 7.5 Hz, 2 H,
2 × CH), 7.45 (s, 1 H, CH).
(8) (a) Marco-Contelles, J.; Leon, R.; De los Rios, C.; Garcia,
A. G.; Lopez, M. G.; Villarroya, M. Bioorg. Med. Chem.
2006, 14, 8176. (b) Marco-Contelles, J.; Leon, R.;
De los Rios, C.; Garcia, A. G.; Lopez, M. G.; Villarroya, M.
Eur. J. Med. Chem. 2006, 41, 1464. (c) Leon, R.; Marco-
Contelles, J.; Garcia, A. G.; Villarroya, M. Bioorg. Med.
Chem. 2005, 13, 1167. (d) Marco, J. L.; De Los Rios, C.;
Garcia, A.; Villarroya, M.; Carreiras, C.; Martins, C.;
Eleutério, A.; Morreale, A.; Orozco, M.; Luque, F. J. Bioorg.
Med. Chem. 2004, 12, 2199. (e) De Los Rios, C.; Marco, J.
L.; Carreiras, M. D. C.; Chinchon, P. M.; Garcia, A.;
Villarroya, M. Bioorg. Med. Chem. 2002, 10, 2077.
(f) Marco, J. L.; De Los Rios, C.; Carreiras, C.; Baños, J. E.;
Badia, A.; Vivas, N. M. Bioorg. Med. Chem. 2001, 9, 727.
(g) Grau, A. M.; Marco, J. L. Bioorg. Med. Chem. 1997, 24,
3165.
13C NMR (63 MHz, CDCl3): d = 22.41, 22.60, 23.23, 32.35, 109.42,
113.85, 115.14, 119.83, 122.86, 127.04, 148.56, 148.65, 149.62,
153.83, 157.32.
Anal. Calcd for C17H17N3Se: C, 59.65; H, 5.01; N, 12.28. Found: C,
59.74; H, 5.32; N, 12.39.
10-Amino-2-(4-nitrophenyl)-6,7,8,9-tetrahydro-5H-cyclohep-
ta[b]selenopheno[2,3-e]pyridine (5g)
Yield: 70%; orange solid; mp 212–214 °C.
IR (neat): 3341 (m), 3193 (m), 2916 (m), 2847 (m), 1601 (s), 1529
(s), 1500 (s), 816 (s) cm–1.
1H NMR (250 MHz, CDCl3): d = 1.48 (m, 4 H, 2 × CH2), 1.78 (m,
2 H, CH2), 2.71 (m, 2 H, CH2), 2.86 (m, 2 H, CH2), 5.47 (s, 2 H,
NH2), 5.91 (s, 2 H, NH2), 6.58 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.33 (d,
J = 7.5 Hz, 2 H, 2 × CH), 7.45 (s, 1 H, CH).
13C NMR (63 MHz, CDCl3): d = 18.51, 24.95, 26.41, 27.29, 31.74,
113.75, 114.72, 117.12, 119.92, 123.66, 126.97, 147.77, 149.60,
150.42, 154.84, 160.86.
(9) Gedye, R. N.; Smith, F.; Westaway, K.; Ali, H.; Baldisera,
L.; Laberge, L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279.
(10) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199.
(11) (a) Hesse, S.; Perspicaco, E.; Kirsch, G. Tetrahedron Lett.
2007, 48, 5261. (b) Begouin, A.; Hesse, S.; Kirsch, G.
ARKIVOC 2008, (vii), 84.
GC-MS (EI, 70 eV): m/z = 220.
(12) (a) Song, S. J.; Cho, S. J.; Park, D. K.; Kwon, T. W.;
Jenekhe, S. A. Tetrahedron Lett. 2003, 44, 255. (b) Muscia,
G. C.; Bollini, M.; Carnevale, J. P.; Bruno, A. M.; Asis, S. E.
Tetrahedron Lett. 2006, 44, 8811. (c) Jia, C. S.; Zhang, Z.;
Tu, S. J.; Wang, G. W. Org. Biomol. Chem. 2006, 4, 104.
(d) Frideling, A.; Faure, R.; Galy, J. P.; Kenz, A.; Alkorta, I.;
Elguero, J. Eur. J. Med. Chem. 2004, 39, 37.
(13) (a) Yun, Y. K.; Porco, J. A. Jr.; Labadie, J. Synlett 2002,
742. (b) Borza, I.; Bozo, E.; Barta-Szalaï, G.; Kiss, C.;
Tarkani, G.; Demeter, A.; Gati, T.; Hada, V.; Kolok, S.;
Gere, A.; Fodor, L.; Nagy, J.; Gagoczy, K.; Magdo, I.; Bela,
A.; Fetter, J.; Bertha, F.; Kerserü, G. M.; Horvath, C.;
Farkas, S.; Greiner, I.; Domany, G. J. Med. Chem. 2007, 50,
901.
Anal. Calcd for C18H19N3Se: C, 60.67; H, 5.37; N, 11.79. Found: C,
60.62; H, 5.27; N, 1.84.
Acknowledgment
We thank to the Ministère de l’Education Nationale, de l’Enseigne-
ment Supérieur et de la Recherche for a PhD grant to D.T. We thank
also the Université du Luxembourg for financial support to P.S. We
are grateful to Ms. Veronique Poddig for recording NMR spectra
and Dr Serge Schneider and Dr Marc Schuman from the Laboratoire
de Toxicologie at the Laboratoire National de Santé (Luxembourg)
for recording the IR and MS spectra.
(14) Ellman, G. L.; Courtney, K. D.; Andres, V.; Feather-Stone,
R. M. Biochem. Pharmacol. 1961, 7, 88.
References
(1) Francotte, P.; Grandorge, E.; Boverie, S.; De Tullio, P.;
Pirotte, B. Curr. Med. Chem. 2004, 11, 1757.
Synthesis 2008, No. 10, 1600–1606 © Thieme Stuttgart · New York