1,2-Diaza-1,3-butadienes: A new approach to the synthesis of selenoheterocycles

Article abstract of DOI:10.1002/1099-0690(200207)2002:14<2323::AID-EJOC2323>3.0.CO;2-F

1,2-Diaza-1,3-butadienes react easily with selenoureas to produce 2-selenazolin-4-one derivatives and with selenobenzamide to afford 2-selenazoline derivatives, the stereochemistries of which were determined. Whereas 2-selenazoline derivatives of 4R*,5R* configuration undergo aromatization under basic conditions, 2-selenazolin-4-ones, under different reaction conditions, appear to be attractive entry compounds to conjugated azoalkenes, 5,5-disubstituted selenazolin-4-ones, and spiro-condensed heterocyclic systems including selenazolinone rings. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200207)2002:14<2323::AID-EJOC2323>3.0.CO;2-F

FULL PAPER
1,2-Diaza-1,3-Butadienes: A New Approach to the Synthesis of
Selenoheterocycles
Orazio A. Attanasi,[a] Paolino Filippone,*[a] Francesca R. Perrulli,[a] and
Stefania Santeusanio*[a]
Keywords: Cyclizations / Heterocycles / Nucleophilic additions / Selenium / Spiro compounds
1,2-Diaza-1,3-butadienes react easily with selenoureas to
produce 2-selenazolin-4-one derivatives and with selenoben-
reaction conditions, appear to be attractive entry compounds
to conjugated azoalkenes, 5,5-disubstituted selenazolin-4-
zamide to afford 2-selenazoline derivatives, the stereochem- ones, and spiro-condensed heterocyclic systems including
istries of which were determined. Whereas 2-selenazoline
derivatives of 4R*,5R* configuration undergo aromatization
under basic conditions, 2-selenazolin-4-ones, under different
selenazolinone rings.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
yield 2-selenazolin-4-one derivatives, mainly in the hy-
drazono forms 4aϪh (Scheme 1 and Table 1).
In recent decades, considerable attention has been de-
voted to the synthesis of selenium-containing heterocyclic
compounds, because of their interesting reactivities[1] and
potential pharmaceutical significance.[2]
The reaction probably proceeds by nucleophilic addition
of the selenium atom of the selenourea derivatives at the
terminal carbon of the heterodiene moiety. Subsequent in-
tramolecular nucleophilic attack by the imidic NH at the
carboxylate group at C-4 of Michael adduct intermediate 3
with the loss of an alcohol molecule should result in the
selenazolinone ring closure, according to our previous find-
ings with analogous materials.[7]
Recent reports demonstrate that many syntheses of five-
or six-membered heterocycles containing both selenium and
nitrogen[3] are based on cycloaddition reactions of selenaaza-
diene systems,[3a] reactions of isoselenocyanates,[3b,3c] or re-
actions between primary selenoamide and α,β-unsaturated
ketones,[3d] bisacyl chlorides,[3e] or α-haloacyl halides.[3f]
In continuation of our investigations designed to develop
the usefulness of conjugated azo-ene systems[4] as building
blocks in heterocyclic compounds,[5] we wish to report here
a new synthetic approach to selenoheterocycles, starting
from 1,2-diaza-1,3-butadienes.
1
In H NMR spectra of 4a؊h, each proton geminal to
the selenium atom appeared as a strong singlet and a weak
doublet centered around the singlet. This doublet, with a
coupling constant of 14Ϫ16 Hz, was attributed to the split-
ting caused by the presence of selenium isotope 77Se, with a
natural abundance of 7.5%. J(13C-77Se) values of 60Ϫ61 Hz
observed for C-5 in compounds 4a؊h were typical of sp3
carbon coupling with selenium.
Pure tautomeric forms 4 or 4Ј were frequently isolable
through fractional crystallization.
Results and Discussion
We next investigated reactions between conjugated
azoalkenes and selenobenzamide, and it was found that the
behavior in the regioselectivity of the closing step was dif-
ferent from that observed for thiobenzamide with the
same reagents.[7]
Since
selenoamides
are
known
to
display
selenoamideϪselenoimidate tautomerism and to possess
two nucleophilic sites, we considered their reactivity to be
of interest in view of the ability of conjugated azoalkenes
to undergo nucleophilic attack.[5a]
We have preliminarily reported the results of reactions
between 1,2-diaza-1,3-butadienes and selenoureas or prim-
ary selenoamide.[6]
1,2-Diaza-1,3-butadienes 1aϪd reacted with selenourea
(2a) or N,N-dimethylselenourea (2b) in MeOH at 0 °C to
In fact, 1aϪd reacted with selenobenzamide (2c) in
MeOH or in CH2Cl2 at 0 °C to afford 2-selenazoline deriv-
atives 5 and 5Ј in different ratios (Scheme 1, Table 1). These
compounds had originated from nucleophilic addition of
the selenium atom at the terminal carbon of the heterodiene
system and subsequent ring closure on the hydrazone func-
tion of 3. The structures of 5 and 5Ј were established by 1H
and 13C NMR spectroscopy. In the 13C NMR, the J (13C-
77Se) values observed for the C-5 resonances (δ ϭ
[a]
`
Istituto di Chimica Organica, Universita di Urbino,
Piazza della Repubblica 13, 61029 Urbino, Italy
Fax: (internat.) ϩ39-0722/2907
E-mail: attanasi@uniurb.it
Eur. J. Org. Chem. 2002, 2323Ϫ2330  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0714Ϫ2323 $ 20.00ϩ.50/0
2323

O. A. Attanasi, P. Filippone, F. R. Perrulli, S. Santeusanio
FULL PAPER
Scheme 1
with 2-selenazoline structures. These compounds, con-
taining two asymmetric centers at C-4 and C-5, consisted
of diastereomers that could often be successfully separated
by chromatography (Scheme 1, Table 1). The stereochem-
istries of the cyclized products 5 and 5Ј were determined by
NOE experiments in [D6]DMSO solutions.
In compound 5d, upon irradiation of the NH signal at
δ ϭ 5.49 ppm, NOE effects were observed for the proton at
δ ϭ 4.91 ppm (8%), for the NH at δ ϭ 8.38 ppm (5%), and
for the CH3 group at δ ϭ 1.47 ppm (4%).
In compound 5Јd, irradiation of the CH3 group at C-4
caused an 8.3% enhancement of the proton at C-5. From
comparison of NOE experiments, 5Јb-d each featured a cis
relationship between the methyl at C-4 and the proton at C-
5. Upon treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) in a THF/MeOH mixture (1:1) at room temperature,
compounds 5Јb؊d afforded methyl 4-methyl-2-phenyl-1,3-
selenazole-5-carboxylate (6, yields from 35 to 58%) whereas
the same treatment of 5a, 5b, and 5d did not reveal any
Table 1. Yields and reaction times required for 2-selenazolin-4-ones
4, 4Ј and 2-selenazolines 5, 5Ј
Reagents
Products
Yield (%)
Reaction time (h)
0.25
1a؉2a
4a
85[a]
5[a]
4Јa
4b؉4Јb
4c
1b؉2a
1c؉2a
84[b]
62[a]
18[a]
71[a]
82[a]
63[a]
21[a]
73[a]
77[a]
68[c]
62[c]
58[c]
36[c]
46[c]
36[c]
1
0.25
4Јc
4d
4e
4f
4Јf
4g
4h
5a
5Јb
5c
5Јc
5d
5Јd
1d؉2a
1a؉2b
1b؉2b
0.25
1.5
0.5
1c؉2b
1d؉2b
1a؉2c
1b؉2c
1c؉2c
0.25
0.25
2
2
1
1d؉2c
0.25
[a]
[b]
Yield of pure isolated product.
Referenced to a crystallized formation of 6, suggesting that the aromatization process
[c]
mixture of 4b and 4Јb. Referenced to pure isolated isomer.
involved an anti elimination of the hydrazine moiety.
In order to verify its synthetic usefulness, different reac-
54.3Ϫ55.9 ppm), the presence of singlets ascribable to C-4 tions were carried out with 2-selenazolin-4-one derivative 4.
at δ ϭ 99.0Ϫ100.5 ppm together with J(1H-77Se) values of Thus, the introduction of a bromine atom at C-5 in com-
14Ϫ16 Hz, and NHϪNH coupling constants of 4.8Ϫ5.0 Hz pound 4d by use of phenyltrimethylammonium tribromide
1
in the H NMR spectra of 5c, 5Јc, and 5Јd were consistent (PTAB) in CH2Cl2 at 0 °C and subsequent treatment with
2324
Eur. J. Org. Chem. 2002, 2323Ϫ2330

A New Approach to the Synthesis of Selenoheterocycles
FULL PAPER
aqueous Na2CO3 provided methyl 2-{1-[2-dimethylamino- derivative 11 as a tautomeric mixture (48.2%). By classic
4-oxo-1,3-selenazol-5(4H)-ylidene]ethyl}diazene-1-carb- derivatization of 11 with PhCOCl, esters 12a (32.0%) and
oxylate (8) in good yield (75%). Owing to the electronic 12b (12.0%) were obtained (Scheme 3).
nature of such a compound, we examined its reactivity to-
Because of the acidity of the protons at C-5, 2-selenazo-
wards a nucleophilic reagent. Base-catalyzed addition of α- lin-4-one derivatives 4 should behave as nucleophiles. In
(acetylphenyl)acetonitrile to 8 in THF afforded the 1,4-con- fact, the base-promoted addition of 4c, 4d, 4g, and 4h to
jugate adduct 9 (58%) in the E configuration[8] and 1-se- 1,2-diaza-1,3-butadienes 1a, 1d, and 1e in THF at room
lena-3,7,8-triazaspiro[4.5]deca-2,6-dien-4-one derivative 10 temperature afforded 5,5-disubstituted 2-selenazolin-4-one
(5%) (Scheme 2).
derivatives 13a؊g as diastereomeric mixtures (Scheme 4,
Table 2).
Scheme 2
From spectroscopic evidence, derivative 10 consisted of a
1
diastereomeric mixture (70:30 ratio by H NMR) and ori-
ginated from intramolecular NH nucleophilic attack on the
acetyl group of the Michael adduct 9 in the Z configura-
tion.
With the goal of obtaining the 5-acetyl-4-hydroxyselena-
zole derivative, tert-butyl 2-[1-(2-amino-4-oxo-4,5-dihydro-
1,3-selenazol-5-yl)ethylidene]hydrazine-1-carboxylate (4c)
was subjected to deprotection with Amberlyst 15 (H) as
catalyst in
a
refluxing (CH3)2CO/H2O mixture
(Scheme 3).[9] This reaction involved the hydrolytic removal
of the NH-BOC-hydrazo protecting group[10] of the car-
bonyl function at C-5 of the selenazolinone ring, to afford
Scheme 4
Table 2. Yields and reaction times required for 5,5-disubstituted 2-
selenazolin-4-one derivatives 13aϪg and 1-selena-3,7-diazaspi-
ro[4.4]nona-2,8-dien-4-one derivatives 14dϪg
Reagents
Products
Yield (%)
dr
Reaction time (h)
4c؉1d
4c؉1a
4d؉1d
4g؉1d
4g؉1a
4h؉1d
4h؉1e
13d
13a
13b
13c
13d
13e
13f
13g
14d
14e
14f
14g
75[a]
69[a]
83[a]
63[a]
74[a]
58[a]
60[a]
44
86:14
83:17
80:20
88:12
76:24
87:13
85:15
24
24
24
24
24
12
30
24
24
24
24
13e
46
48
32
13f
13g
[a]
Scheme 3
Referenced to diastereomeric mixtures.
Eur. J. Org. Chem. 2002, 2323Ϫ2330
2325

O. A. Attanasi, P. Filippone, F. R. Perrulli, S. Santeusanio
FULL PAPER
were generated with ADC/IUPAC Name (Version 3.50, April 5,
1998), Advanced Chemistry Development Inc., Toronto, ON (Can-
ada).
Compounds 13a؊g were then treated with DBU in THF/
MeOH mixtures at room temperature. Although 13a؊c af-
forded intractable crude products under these conditions,
compounds 13d؊g gave rise to 1-selena-3,7-diazaspi-
ro[4.4]nona-2,8-dien-4-one derivatives 14d؊g (Scheme 4,
Table 2) in which both hydrazone side chains had particip-
ated in pyrroline ring closure.[11] Intramolecular nucleo-
philic attack by the hydrazone nitrogen of the first side
chain on the hydrazone carbon at C-5 of the second side
chain produced the new spiro-condensed heterocyclic sys-
tem.
General Procedure for the Synthesis of 2-Selenazolin-4-one Derivati-
ves 4a؊h, 4Јa-c, and 4Јf: The conjugated azoalkene 1a؊d (1 mmol)
was rapidly added at 0 °C to a magnetically stirred solution of
the selenoureas 2a؊b (1 mmol) in MeOH (20 mL). Stirring was
maintained until the disappearance of the reagents (0.25Ϫ1.5 h,
monitored by TLC), and the major products 4a and 4c؊h were
directly filtered off in vacuo or obtained by crystallization from an
appropriate solvent after complete removal of MeOH. Derivatives
4Јa, 4Јc, and 4Јf were obtained after complete evaporation of the
mother liquor and subsequent crystallization from MeOH/Et2O.
The reaction between 2a and 1b produced an inseparable mixture
of 4b and 4Јb (hydrazono form/hydrazino form 46:54%, respect-
Conclusions
1
ively, established by H NMR).
We report here a new route to selenoheterocycles starting
from conjugated azoalkenes. An interesting difference in be-
havior between selenobenzamide and selenoureas in the re-
gioselectivity of the intramolecular closure step of the
Michael adducts was observed. Selenobenzamide preferen-
tially produced 2-selenazolines, in contrast with the results
previously obtained with thiobenzamide and the same sub-
strates,[7] whereas selenoureas afforded 2-selenazolin-4-one
derivatives mainly in their hydrazono forms. These latter
compounds were demonstrated to be susceptible to further
synthetic transformations and so in turn represent useful
starting compounds for spiro-condensed heterocyclic sys-
tems incorporating the 2-selenazolin-4-one nucleus.
2-Amino-[1-(4-oxo-4,5-dihydro-1,3-selenazol-5-yl)ethylidene]-N-
phenylhydrazine-1-carboxamide (4a): Yield: 287 mg (85%), white
1
powder from MeOH, m.p. 143Ϫ144 °C (dec.). H NMR: δ ϭ 1.78
77
(s, 3 H, CH3), 5.48 (s, J1
ϭ 13.9 Hz, 1 H, CH, D2O exch.),
H- Se
6.99 (t, J ϭ 7.6 Hz, 1 H, ArH), 7.28 (t, J ϭ 7.8 Hz, 2 H, ArH),
7.59 (d, J ϭ 7.7 Hz, 2 H, ArH), 8.88 (s, 1 H, NH), 9.04 and 9.42
(2 s, 2 H, NH2), 9.80 (s, 1 H, NH) ppm. 13C NMR: δ ϭ 12.6 (q),
77
61.9 (d, J13
ϭ 60.4 Hz), 119.3 (d), 122.4 (d), 128.6 (d), 139.1
C- Se
(s), 145.0 (s), 153.3 (s), 176.6 (s, J13
ϭ 122.7 Hz), 187.5 (s)
77
C- Se
ppm. IR: ν˜ ϭ 3480, 3374, 3207, 1712, 1662, 1636, 1597, 1542 cmϪ1
.
C12H13N5O2Se (338.2): calcd. C 42.47, H 3.86, N 20.65; found C
42.22, H 3.59, N 20.85.
1-{1-[2-Amino-4-oxo-1,3-selenazol-5(4H)-ylidene]ethyl}-4-phenyl-
semicarbazide (4Јa): Yield: 17 mg (5%), white powder from MeOH/
1
Et2O, m.p. 151Ϫ152 °C (dec.). H NMR: δ ϭ 1.98 (s, 3 H, CH3),
Experimental Section
7.01 (t, J ϭ 7.4 Hz, 1 H, ArH), 7.31 (t, J ϭ 7.6 Hz, 2 H, ArH),
7.50 (d, J ϭ 8.2 Hz, 2 H, ArH), 8.84 (br. s, 4 H, 2 NH and NH2),
12.35 (s, 1 H, NH) ppm. IR: ν˜ ϭ 3455, 3331, 3204, 1715, 1683,
1664, 1644, 1591, 1562 cmϪ1. C12H13N5O2Se (338.2): calcd. C
42.47, H 3.86, N 20.65; found C 42.82, H 3.59, N 20.90.
General: Selenoureas 2a؊b were commercial materials and were
used without further purification. Selenobenzamide (2c) was ob-
tained according to a literature procedure.[12] Solvents were pur-
chased and were used without further purification, with the excep-
tion of THF, which was distilled from sodium hydroxide. ‘‘Light
petroleum ether’’ refers to the fraction of b.p. 40Ϫ60 °C. 1,2-Diaza-
1,3-butadienes 1a؊e were synthesized as standard E/Z isomeric
mixtures according to previously reported procedures.[4a,13] Melting
points were determined in open capillary tubes and are uncorrec-
ted. IR-FT spectra were obtained as Nujol mulls. Mass spectra
2-Amino-5-{1-[2-(4-nitrophenyl)hydrazono]ethyl}-1,3-selenazol-
4(5H)-one (4b) and 2-Amino-5-{1-[2-(4-nitrophenyl)-
hydrazino]ethylidene}-1,3-selenazol-4-one (4Јb): Yield: 286 mg
1
(84%), yellow powder from MeOH. H NMR: δ ϭ 1.88 and 2.01
77
(2 s, 6 H, 2 CH3), 5.43 (s, J1
Se ϭ 13.8 Hz, 1 H, CH, D2O exch.),
H-
7.21 (d, J ϭ 9.1 Hz, 2 H, ArH), 8.11 (d, J ϭ 9.1 Hz, 2 H, ArH),
8.18 (d, J ϭ 9.4 Hz, 2 H, ArH), 8.38 (d, J ϭ 9.4 Hz, 2 H, ArH),
8.57 and 8.80 (2 br s, 4 H, 2 NH and NH2), 9.04 and 9.40 (2 br s,
2 H, NH2), 10.07 (s, 1 H, NH) ppm. IR: ν˜ ϭ 3568, 3388, 3328,
1
were measured at an ionizing voltage of 70 eV. All H NMR and
13C NMR spectra were recorded at 200 or 400 MHz and at 50.32 or
100.56 MHz, respectively, in [D6]DMSO solutions unless specified
otherwise. Chemical shifts (δH) are reported relative to TMS as
internal standard. All coupling constant values (J) are given in Hz.
Chemical shifts (δC) are reported relative to [D6]DMSO as internal
standard, unless otherwise stated, in a broad band decoupled
mode; the multiplicities were obtained by means of 135 and 90°
DEPT experiments to aid in assignment (q ϭ methyl, t ϭ methyl-
ene, d ϭ methyne, s ϭ quaternary). The abbreviations used are as
follows: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet;
br, broad; all the NH, NH2, and OH moieties exchanged with D2O.
Diastereomeric ratios (dr values) of compounds 10 and 13aϪg (un-
assigned configurations) were obtained from 1H NMR spectra; the
NMR spectroscopic data of the major diastereomer are marked*.
Precoated silica gel plates (0.25 mm) were employed for analytical
3265, 3118, 1735, 1719, 1685, 1647, 1601, 1560, 1490, 1336 cmϪ1
.
C11H11N5O3Se (340.2): calcd. C 38.84, H 3.26, N 20.59; found C
39.17, H 3.01, N 20.81.
tert-Butyl 2-[1-(2-Amino-4-oxo-4,5-dihydro-1,3-selenazol-5-yl)ethyl-
idene]hydrazine-1-carboxylate (4c): Yield: 198 mg (62%), white
1
powder from MeOH, m.p. 133Ϫ134 °C (dec.). H NMR: δ ϭ 1.43
77
(s, 9 H, tBu), 1.71 (s, 3 H, CH3), 5.26 (s, J1
ϭ 13.8 Hz, 1 H,
H- Se
CH, D2O exch.), 8.99 and 9.35 (2 br s, 2 H, NH2), 9.70 (s, 1 H,
77
NH) ppm. 13C NMR: δ ϭ 12.8 (q), 28.1 (q), 62.0 (d, J13
ϭ
C- Se
77
61.1 Hz), 79.5 (s), 147.7 (s), 152.9 (s), 176.4 (s, J13
ϭ
C- Se
122.5 Hz), 187.4 (s) ppm. IR: ν˜ ϭ 3217, 3150, 3038, 1728, 1708,
1669, 1538 cmϪ1. C10H16N4O3Se (319.2): calcd. C 37.63, H 5.05, N
17.55; found C 37.91, H 4.78, N 17.75.
˚
thin layer chromatography and silica gel 60 A (35Ϫ70 µ) for column
chromatography. All new compounds showed satisfactory ele-
mental analysis (C Ϯ0.35; H Ϯ0.30, N Ϯ0.30). The chemical names
tert-Butyl 2-{1-[2-Amino-4-oxo-1,3-selenazol-5(4H)-ylidene]-
ethyl}hydrazine-1-carboxylate (4Јc): Yield: 57 mg (18%), light grey
2326
Eur. J. Org. Chem. 2002, 2323Ϫ2330

A New Approach to the Synthesis of Selenoheterocycles
FULL PAPER
ϭ 16.0 Hz, 1 H, CH, D2O exch.), 10.09 (s,
77
powder from MeOH/Et2O, m.p. 149Ϫ150 °C (dec.). 1H NMR: δ ϭ
OCH3), 5.42 (s, J1
H- Se
1.45 (s, 9 H, tBu), 1.88 (s, 3 H, CH3), 8.71 (br. s, 4 H, 2 NH and 1 H, NH) ppm. 13C NMR: δ ϭ 12.9 (q), 40.4 (q), 41.1 (q), 51.9
NH2) ppm. IR: ν˜ ϭ 3339, 3210, 3185, 1724, 1644, 1574 cmϪ1
.
(q), 62.3 (d, J13
Se ϭ 61.4 Hz), 148.1 (s), 154.5 (s), 175.9 (s, J13
77
C
-
C
-
77
C10H16N4O3Se (319.2): calcd. C 37.63, H 5.05, N 17.55; found C
37.39, H 4.77, N 17.82.
ϭ 122.4 Hz), 185.6 (s) ppm. IR: ν˜ ϭ 3212, 3052, 1734, 1717,
Se
1687, 1581 cmϪ1. C9H14N4O3Se (305.2): calcd. C 35.42, H 4.62, N
18.36; found C 35.77, H 4.84, N 18.15.
Methyl 2-[1-(2-Amino-4-oxo-4,5-dihydro-1,3-selenazol-5-yl)ethylide-
Procedure for the Synthesis of 2-Selenazoline Derivatives 5a, 5c, 5Јc,
5d, and 5Јd: Conjugated azoalkene 1 was added portionwise at 0
°C to a magnetically stirred solution of selenobenzamide (2c, 184
mg, 1 mmol) in CH2Cl2 (5 mL, 1aϪb) or in MeOH (5 mL, 1cϪd).
The reaction was complete in 0.25Ϫ2 h (monitored by TLC). The
solvent was then removed under reduced pressure and the crude
product was purified by flash chromatography on silica gel, eluting
with cyclohexane/EtOAc mixtures, or by crystallization with an ap-
propriate solvent.
ne]hydrazine-1-carboxylate (4d): Yield: 197 mg (71%), light orange
1
powder from MeOH, m.p. 125Ϫ126 °C (dec.). H NMR: δ ϭ 1.74
77
(s, 3 H, CH3), 3.66 (s, 3 H, OCH3), 5.30 (s, J1
ϭ 14.0 Hz, 1
H- Se
H, CH, D2O exch.), 9.00 and 9.38 (2 br s, 1 H, NH2), 10.05 (s, 1
77
H, NH) ppm. 13C NMR: δ ϭ 12.7 (q), 51.8 (q), 61.8 (d, J13
Se ϭ
C-
77
60.8 Hz), 148.5 (s), 154.4 (s), 176.3 (s, J13
ϭ 121.6 Hz), 187.2
C- Se
(s) ppm. IR: ν˜ ϭ 3273, 3251, 3029, 1727, 1695, 1637 cmϪ1
.
C7H10N4O3Se (277.1): calcd. C 30.34, H 3.64, N 20.22; found C
30.62, H 3.37, N 20.47.
Methyl
(4S*,5R*)-{4-[2-(Anilinocarbonyl)hydrazino]-4-methyl-2-
1-[(2-Dimethylamino-4-oxo-4,5-dihydro-1,3-selenazol-5-yl)ethyl-
phenyl-4,5-dihydro-1,3-selenazol-5-yl}acetate (5a): Yield: 293 mg
(68%), white powder from CH2Cl2/Et2O, m.p. 115Ϫ117 °C (dec.).
idene]-4-phenylsemicarbazide (4e): Yield: 300 mg (82%), white pow-
der from MeOH, m.p. 170Ϫ175 °C (dec).1H NMR: δ ϭ 1.79 (s, 3
1H NMR: δ ϭ 1.38 (s, 3 H, CH3), 3.75 (s, 3 H, OCH3), 5.04 (s,
77
H, CH3), 3.16 and 3.27 [2 s, 6 H, N(CH3)2], 5.60 (s, J1
ϭ
H- Se
77
J1
ϭ 14.0 Hz, 1 H, CH), 6.29 (br. s, 1 H, NH), 6.95 (t, J ϭ
14.8 Hz, 1 H, CH, D2O exch.), 7.00 (t, J ϭ 7.8 Hz, 1 H, ArH), 7.28
(t, J ϭ 7.8 Hz, 2 H, ArH), 7.60 (d, J ϭ 7.8 Hz, 2 H, ArH), 8.90 (s,
H- Se
7.2 Hz, 1 H), 7.26 (t, J ϭ 7.2 Hz, 2 H, ArH), 7.41Ϫ7.61 (m, 5 H,
1 H, NH), 9.83 (s, 1 H, NH) ppm. 13C NMR: δ ϭ 12.6 (q), 40.4
ArH and NH), 7.72 (d, J ϭ 8.1 Hz, 2 H, ArH), 8.71 (br. s, 1 H,
77
NH) ppm. 13C NMR: δ ϭ 19.0 (q), 52.9 (q), 54.3 (d, J13
ϭ
77
(q), 41.1 (q), 63.3 (d, J13
ϭ 60.1 Hz), 119.2 (d), 122.3 (d),
C- Se
C- Se
128.5 (d), 139.0 (s), 144.2 (s), 153.2 (s), 175.9 (s, J13
ϭ
77
58.4 Hz), 99.3 (s), 118.1 (d), 121.7 (d), 128.3 (d), 128.6 (d), 128.7
(d), 131.8 (d), 134.3 (s), 139.4 (s), 156.5 (s), 161.1 (s) 169.8 (s) ppm.
C- Se
122.2 Hz), 185.6 (s) ppm. IR: ν˜ ϭ 3346, 3187, 1675, 1596,
1578 cmϪ1. C14H17N5O2Se (366.3): calcd. C 45.91, H 4.68, N 19.12;
found C 46.13, H 4.93, N 18.90.
IR: ν˜ ϭ 3340, 3275, 3249, 1722, 1678, 1662, 1620, 1592 cmϪ1
.
C19H20N4O3Se (431.4): calcd. C 52.77, H 4.67, N 12.96; found C
52.60, H 4.67, N 13.09.
2-(Dimethylamino)-5-{1-[2-(4-nitrophenyl)hydrazono]ethyl}-1,3-
Methyl
(4R*,5R*)-{4-Methyl-4-[2-(4-nitrophenyl)hydrazino]-2-
selenazol-4(5H)-one (4f): Yield: 232 mg (63%), yellow powder from
MeOH, m.p. 139Ϫ142 °C (dec.). 1H NMR: δ ϭ 1.89 (s, 3 H, CH3),
phenyl-4,5-dihydro-1,3-selenazol-5-yl}acetate (5Јb): Yield: 269 mg
77
3.14 and 3.26 [2 s, 6 H, N(CH3)2], 5.54 (s, J1
ϭ 15.2 Hz, 1 H,
(62%), light yellow powder from Et2O-light petroleum ether, m.p.
H- Se
1
95Ϫ98 °C (dec.). H NMR: δ ϭ 1.55 (s, 3 H, CH3), 3.65 (s, 3 H,
CH, D2O exch.), 7.21 (d, J ϭ 9.1 Hz, 2 H, ArH), 8.10 (d, J ϭ
77
OCH3), 4.98 (s, J1
ϭ 16.0 Hz, 1 H, CH), 5.72 (br. s, 1 H,
9.1 Hz, 2 H, ArH), 10.06 (s, 1 H, NH) ppm. 13C NMR: δ ϭ 13.2
H- Se
77
(q), 40.4 (q), 41.0 (q), 63.7 (d, J13
Se ϭ 61.0 Hz), 111.8 (d), 125.8
NH), 6.93 (d, J ϭ 9.2 Hz, 2 H, ArH), 7.44Ϫ7.60 (m, 3 H, ArH),
7.74 (d, J ϭ 8.0 Hz, 2 H, ArH), 8.00 (d, J ϭ 9.2 Hz, 2 H, ArH),
C-
(d), 138.6 (s), 145.5 (s), 151.0 (s), 175.9 (s, J13
ϭ 121.5 Hz),
77
C- Se
8.33 (br. s, 1 H, NH) ppm. 13C NMR: δ ϭ 22.8 (q), 52.6 (q), 55.9
185.6 (s) ppm. IR: ν˜ ϭ 3266, 1682, 1593, 1573, 1489, 1324 cmϪ1
.
77
(d, J13
ϭ 59.8 Hz), 99.1 (s), 110.2 (d), 125.6 (d), 128.3 (d),
C- Se
C13H15N5O3Se (368.3): calcd. C 42.40, H 4.11, N 19.02; found C
42.64, H 3.89, N 19.27.
128.6 (d), 131.7 (d), 134.0 (s), 136.2 (s), 156.5 (s), 160.4 (s) 169.8 (s)
ppm. IR: ν˜ ϭ 3329, 3265, 3214, 1714, 1621, 1603, 1505, 1345 cmϪ1
.
2-(Dimethylamino)-5-{1-[2-(4-nitrophenyl)hydrazino]ethylidene}-1,3-
selenazol-4-one (4Јf): Yield: 77 mg (21%), red orange powder from
MeOH, m.p. 130Ϫ132 °C (dec.). 1H NMR: δ ϭ 2.02 (s, 3 H, CH3),
3.21 and 3.29 [2 s, 6 H, N(CH3)2], 7.61 (br. s, 1 H, NH), 8.19 (d,
J ϭ 9.2 Hz, 2 H, ArH), 8.37 (d, J ϭ 9.2 Hz, 2 H, ArH), 9.10 (br.
s, 1 H, NH) ppm. IR: ν˜ ϭ 3575, 3297, 1646, 1615, 1593, 1582,
1489, 1333 cmϪ1. C13H15N5O3Se (368.3): calcd. C 42.40, H 4.11, N
19.02; found C 42.63, H 4.32, N 18.77.
C18H18N4O4Se (433.3): calcd. C 49.89, H 4.19, N 12.93; found C
50.20, H 4.08, N 13.21.
tert-Butyl (4S*,5R*)-2-[5-(Methoxycarbonyl)-4-methyl-2-phenyl-
4,5-dihydro-1,3-selenazol-4-yl]hydrazine-1-carboxylate (5c): Yield:
239 mg (58%), yellow crystals from Et2O-light petroleum ether,
1
m.p. 121Ϫ122 °C (dec.). H NMR: δ ϭ 1.31 (s, 9 H, tBu), 1.47 (s,
77
3 H, CH3), 3.66 (s, 3 H, OCH3), 4.90 (s, 1 H, J1
ϭ 16.0 Hz,
H- Se
CH), 5.32 (d, J
ϭ 4.8 Hz, 1 H, NH), 7.40Ϫ7.57 (m, 3 H,
NHNH
tert-Butyl 2-[1-(2-Dimethylamino-4-oxo-4,5-dihydro-1,3-selenazol-5-
yl)ethylidene]hydrazine-1-carboxylate (4g): Yield: 253 mg (73%),
white powder from MeOH, m.p. 112Ϫ115 °C (dec.). 1H NMR: δ ϭ
ArH), 7.69 (d, J ϭ 6.5 Hz, 2 H, ArH), 8.19 (br. s, 1 H, NH) ppm.
77
13C NMR: δ ϭ 20.6 (q), 28.1 (q), 52.3 (q), 54.4 (d, J13
ϭ
C- Se
59.9 Hz), 78.4 (s), 100.6 (s), 128.6 (2d), 131.7 (d), 134.3 (s), 156.2
(s), 161.1 (s) 170.9 (s) ppm. IR: ν˜ ϭ 3280, 3173, 1733, 1619, 1608,
1581 cmϪ1. C17H23N3O4Se (412.3): calcd. C 49.52, H 5.62, N 10.19;
found C 49.60, H 5.44, N 10.29.
1.45 (s, 9 H, tBu), 1.73 (s, 3 H, CH3), 3.14 and 3.25 [2 s, 6 H,
77
N(CH3)2], 5.38 (s, J1
ϭ 14.0 Hz, 1 H, CH, D2O exch.), 9.75
H- Se
(s, 1 H, NH) ppm. 13C NMR: δ ϭ 12.8 (q), 28.0 (q), 40.3 (q), 41.0
77
(q), 63.4 (d, J13
Se ϭ 54.8 Hz), 79.5 (s), 147.1 (s), 152.8 (s), 175.9
C-
tert-Butyl (4R*,5R*)-2-[5-(Methoxycarbonyl)-4-methyl-2-phenyl-
4,5-dihydro-1,3-selenazol-4-yl]hydrazine-1-carboxylate (5Јc): Yield:
77
(s, J13
ϭ 121.7 Hz), 185.6 (s) ppm. IR: ν˜ ϭ 3206, 1715, 1699,
C- Se
1680, 1570 cmϪ1. C12H20N4O3Se (347.3): calcd. C 41.50, H 5.80, N
148 mg (36%), colorless glass. 1H NMR: δ ϭ 1.34 (s, 9 H, tBu),
16.13; found C 41.72, H 6.05, N 15.85.
77
1.53 (s, 3 H, CH3), 3.68 (s, 3 H, OCH3), 4.87 (s, 1 H, J1
ϭ
H- Se
Methyl 2-[1-(2-Dimethylamino-4-oxo-4,5-dihydro-1,3-selenazol-5- 16.0 Hz, CH), 5.31 (d, JNHNH ϭ 5.0 Hz, 1 H, NH), 7.42Ϫ7.57 (m,
yl)ethylidene]hydrazine-1-carboxylate (4h): Yield: 235 mg (77%),
white powder from EtOAc, m.p. 142Ϫ143 °C. H NMR: δ ϭ 1.74
3 H, ArH), 7.68 (d, J ϭ 6.7 Hz, 2 H, ArH), 7.98 (br. s, 1 H, NH)
ppm. 13C NMR: δ ϭ 23.0 (q), 28.1 (q), 52.5 (q), 55.8 (d, J13
Se ϭ
1
77
C-
(s, 3 H, CH3), 3.14 and 3.25 [2 s, 6 H, N(CH3)2], 3.67 (s, 3 H, 60.0 Hz), 78.5 (s), 99.0 (s), 128.4 (d), 128.5 (d), 131.6 (d), 134.1 (s),
Eur. J. Org. Chem. 2002, 2323Ϫ2330 2327

O. A. Attanasi, P. Filippone, F. R. Perrulli, S. Santeusanio
FULL PAPER
155.7 (s), 159.4 (s), 170.1 (s) ppm. IR: ν˜ ϭ 3425, 3302, 1738, 1720, amount of sodium methoxide was added to a magnetically stirred
1618, 1581 cmϪ1. C17H23N3O4Se (412.3): calcd. C 49.52, H 5.62, N
10.19; found C 49.44, H 5.73, N 10.21.
solution of α-acetylphenylacetonitrile (159 mg, 1 mmol) in THF
(10 mL); after 5 min the conjugated azoalkene 8 (303 mg, 1 mmol)
was added portionwise. Stirring was maintained at room temper-
ature until the disappearance of the reagents (36 h, monitored by
TLC). The solvent was removed under reduced pressure and the
crude product was purified by flash chromatography on a silica gel
column, eluting with cyclohexane/EtOAc mixtures, to obtain pure
derivatives 9 and 10.
Methyl (4S*,5R*)-2-[5-(Methoxycarbonyl)-4-methyl-2-phenyl-4,5-
dihydro-1,3-selenazol-4-yl]hydrazine-1-carboxylate (5d): Yield:
170 mg (46%), yellow foam. 1H NMR: δ ϭ 1.47 (s, 3 H, CH3), 3.51
77
(s, 3 H, OCH3), 3.66 (s, 3 H, OCH3), 4.91 (s, J1
ϭ 14.0 Hz, 1
H- Se
H, CH), 5.49 (br. s, 1 H, NH), 7.42Ϫ7.59 (m, 3 H, ArH), 7.70 (d,
J ϭ 7.9 Hz, 2 H, ArH), 8.38 (br. s, 1 H, NH) ppm. 13C NMR: δ ϭ
77
20.5 (q), 51.5 (q), 52.3 (q), 54.4 (d, J13
ϭ 58.6 Hz), 100.5 (s),
Compound 9: Yield: 268 mg (58%), white powder from Et2O, m.p.
C- Se
1
188Ϫ190 °C (dec.). H NMR: δ ϭ 1.78 (s, 3 H, CH3), 2.59 (s, 3 H,
128.7 (2d), 133.7 (d), 134.2 (s), 157.5 (s), 163.3 (s), 170.8 (s) ppm.
IR: ν˜ ϭ 3301, 3173, 1737, 1674, 1615, 1578 cmϪ1. C14H17N3O4Se
(370.3): calcd. C 45.41, H 4.63, N 11.35; found C 45.71, H 4.61,
N 11.11.
COCH3), 2.96 and 2.98 [2 s, 6 H, N(CH3)2], 3.71 (s, 3 H, OCH3),
7.30Ϫ7.32 (m, 2 H ArH), 7.39Ϫ7.41 (m, 3 H, ArH), 10.38 (br. s, 1
H, NH) ppm. 13C NMR: δ ϭ 13.8 (q), 27.9 (q), 40.0 (q), 40.8 (q),
52.2 (q), 61.3 (s), 80.2 (s), 119.0 (s), 128.0 (s), 128.4 (d), 129.2 (d),
129.4 (d), 146.1 (s), 154.4 (s), 177.3 (s), 183.4 (s), 198.4 (s) ppm.
IR: ν˜ ϭ 3230, 3169, 2238, 1716, 1677, 1566 cmϪ1. C19H21N5O4Se
(462.4): calcd. C 49.36, H 4.58, N 15.15; found C 49.37, H 4.57,
N 15.24.
Methyl (4R*,5R*)-2-[5-(Methoxycarbonyl)-4-methyl-2-phenyl-4,5-
dihydro-1,3-selenazol-4-yl]hydrazine-1-carboxylate (5Јd): Yield:
133 mg (36%), light pink powder from Et2O/light petroleum ether,
1
m.p. 108Ϫ111 °C (dec.). H NMR: δ ϭ 1.51 (s, 3 H, CH3), 3.54 (s,
77
3 H, OCH3), 3.66 (s, 3 H, OCH3), 4.87 (s, J1
ϭ 16.0 Hz, 1 H,
H- Se
Compound 10: Yield: 23 mg (5%), white powder from Et2O; dr
70:30. 1H NMR: δ ϭ 1.59* and 1.74 (2 s, 3 H, CH3), 1.98* and
2.15 (2 s, 3 H, COCH3), 3.06, 3.16*, and 3.24* [3 s, 6 H, N(CH3)2],
3.69* and 3.75 (2 s, 3 H, OCH3). 7.05Ϫ7.74 (2 m, 5 H ArH), 8.44*
and 8.47 (s and br s, 1 H, OH) ppm. 13C NMR: δ ϭ 21.1 and 21.9
(2 q), 25.9 and 30.6 (2 q), 40.8, 41.4, and 41.5 (3 q), 53.9 and 54.6
(2 q), 62.0 and 66.4 (2 s), 82.6 and 82.7 (2 s), 99.0 and 99.2 (2 s),
118.9 and 120.2 (2 s), 127.2 and 127.6 (2 d), 128.4 and 128.6 (2 d),
129.1 and 129.5 (2 d), 130.3 and 132.4 (2 s), 142.3 and 145.1 (2 s),
151.5 and 154.4 (2 s), 172.6 and 177.0 (2 s), 181.9 (s) ppm. IR: ν˜ ϭ
CH), 5.38 (d, J
ϭ 5.0 Hz, 1 H, NH), 7.42Ϫ7.58 (m, 3 H,
NHNH
ArH), 7.69 (d, J ϭ 6.5 Hz, 2 H, ArH), 8.32 (br. s, 1 H, NH) ppm.
13C NMR: δ ϭ 22.6 (q), 51.6 (q), 52.5 (q), 55.4 (d, J
ϭ
13 77
C- Se
58.4 Hz), 99.1 (s), 128.5 (d), 128.8 (d), 131.8 (d), 134.2 (s), 157.3
(s), 159.6 (s), 170.5 (s) ppm. IR: ν˜ ϭ 3340, 3284, 1725, 1709, 1614,
1581 cmϪ1. C14H17N3O4Se (370.3): calcd. C 45.41, H 4.63, N 11.35;
found C 45.24, H 4.92, N 11.34.
Methyl 4-Methyl-2-phenyl-1,3-selenazole-5-carboxylate (6): DBU
(152 mg, 1 mmol) in a THF/MeOH mixture (1:1, 5 mL) was added
dropwise to a magnetically stirred solution of 5Јb؊d (1 mmol) in
the same solvent mixture (10 mL). The light pink solution was left
to stand at room temperature until the complete disappearance of
the reagent (36Ϫ48 h, monitored by TLC). The solvent was
evaporated under reduced pressure and the crude product was puri-
fied by flash chromatography on a silica gel column, eluting with
3060, 3034, 2774, 2241, 1733, 1660, 1619, 1571 cmϪ1
.
C19H21N5O4Se (462.4): calcd. C 49.36, H 4.58, N 15.15; found C
49.39, H 4.58, N 15.11.
Procedure for the Synthesis of 1-[2-(Dimethylamino)-4-hydroxy-1,3-
selenazol-5-yl]ethan-1-one (11): Compound 4g (347 mg, 1 mmol)
was heated under reflux in a Me2CO/H2O mixture (10:1, 10 mL)
in the presence of Amberlyst 15 (H) (500 mg) for 10 h. The resin
was filtered off and, after evaporation of the solvent under reduced
pressure, the residue was crystallized with EtOAc/Et2O to obtain
derivative 11. Yield: 112 mg (48%), light yellow powder from
EtOAc/Et2O, m.p. 85Ϫ87 °C. 1H NMR (CDCl3): δ ϭ 2.11 and 2.42
cyclohexane/EtOAc mixtures, to obtain pure derivative
6 in
35Ϫ58% yield. White powder from light petroleum ether, m.p.
72Ϫ74 °C. 1H NMR: δ ϭ 2.88 (s, 3 H, CH3), 3.79 (s, 3 H, OCH3),
7.45Ϫ7.57 (m, 3 H, ArH), 7.91Ϫ7.97 (m, 2 H, ArH) ppm. 13C
NMR: δ ϭ 23.1 (q), 57.6 (q), 132.1 (d), 134.3 (s), 134.5 (d), 136.8
(d), 140.1 (s), 165.9 (s), 168.6 (s), 181.3 (s) ppm. IR: ν˜ ϭ 1716,
1523 cmϪ1. MS: m/z (%) ϭ 281 [Mϩ ϩ 1] (100). C12H11NO2Se
(280.2): calcd. C 51.44, H 3.96, N 5.00; found C 51.22, H 4.17,
N 5.18.
(2 s, 3 H, COCH3), 3.09, 3.17, 3.34, and 3.37 [4 s, 6 H, N(CH3)2],
77
5.31 and 14.03 (s and br s, J1
ϭ 16.0 Hz, 1 H, CH and OH)
H- Se
ppm. 13C NMR (CDCl3): δ ϭ 24.6 (q), 27.3 (q), 40.0 (q), 40.1 (q),
77
41.3 (q), 41.4 (q), 65.9 (d, J13
ϭ 61.0 Hz), 103.1 (s), 171.4 (s),
C- Se
172.8 (s), 176.6 (s), 183.4 (s), 184.6 (s) 198.8 (s) ppm. IR: ν˜ ϭ 3241,
2725, 1637, 1615 cmϪ1. MS: m/z (%) ϭ 234 [Mϩ 1] (15), 192 (7),
71 (100). C7H10N2O2Se (233.1): calcd. C 36.06, H 4.32, N 12.02;
found C 36.10, H 4.27, N 12.21.
Procedure for the Synthesis of Methyl 2-{1-[2-Dimethylamino-4-oxo-
1,3-selenazol-5(4H)-ylidene]ethyl}diazene-1-carboxylate (8): PTAB
(mg 413.5, 1.1 mmol) was added portionwise to a stirred solution
of compound 4h (mg 305, 1 mmol) in CH2Cl2 (20 mL), maintained
at 0° C. Stirring was continued for 5 h, and the formed yellow sus-
pension was then transferred into a separating funnel and washed
with water (1ϫ) and with satd. Na2CO3 (4ϫ). The red organic layer
was dried with Na2SO4 and filtered, and the solvent was evaporated
under reduced pressure to obtain a residue that, on treatment with
Et2O, furnished pure derivative 8. Yield: 227 mg (75%), dark or-
ange powder from Et2O, m.p. 140 °C (dec.). 1H NMR (CDCl3):
δ ϭ 2.61 (s, 3 H, CH3), 3.21 and 3.43 [2 s, 6 H, N(CH3)2], 4.06 (s,
3 H, OCH3) ppm. 13C NMR (CDCl3): δ ϭ 13.2 (q), 40.4 (q), 40.9
(q), 54.9 (q), 148.2 (s), 153.4 (s), 161.8 (s), 174.4 (s), 181.2 (s) ppm.
IR: ν˜ ϭ 1756, 1683, 1600, 1591 cmϪ1. C9H12N4O3Se (303.2): calcd.
C 35.66, H 3.99, N 18.48; found C 35.80, H 3.99, N 18.57.
Procedure for the Synthesis of Benzoyl Derivatives of 11 (12a؊b):
Pyridine (158 mg, 2 mmol) and benzoyl chloride (281 mg, 2 mmol)
in THF (5 mL) were added to a magnetically stirred suspension
of 11 (233 mg, 1 mmol) in THF (5 mL), maintained at 0° C. The
temperature was allowed to rise to room temperature and the stir-
ring was maintained for 24 h. The solvent was removed under re-
duced pressure, and the residue was dissolved in CH2Cl2 and
washed in a separating funnel with satd. NaHCO3 and with brine.
The organic layer was dried with Na2SO4 and filtered, and the solv-
ent was evaporated under reduced pressure to furnish a red oil that
was purified by flash chromatography on a silica gel column (eluent
cyclohexane/EtOAc mixtures) to afford pure compounds 12a؊b.
Procedure for the Synthesis of Michael Adduct 9 and 1-Selena-3,7,8-
1-[2-(Dimethylamino)-4-oxo-1,3-selenazol-5(4H)-ylidene]ethyl
triazaspiro[4.5]deca-2,6-dien-4-one Derivative 10:
A
catalytic Benzoate (12a): Yield: 103 mg (32%), white powder from light pet-
2328
Eur. J. Org. Chem. 2002, 2323Ϫ2330

A New Approach to the Synthesis of Selenoheterocycles
FULL PAPER
1522 cmϪ1. C14H20N6O7Se (463.3): calcd. C 36.29, H 4.35, N 18.14;
1
roleum ether, m.p. 155Ϫ158 °C. H NMR (CDCl3): δ ϭ 2.70 (s, 3
H, CH3), 3.07 and 3.35 [2 s, 6 H, N(CH3)2], 7.50 (t, J ϭ 7.6 Hz, 2 found C 36.59, H 4.13, N 18.00.
H, ArH), 7.65 (t, J ϭ 7.6 Hz, 1 H, ArH), 8.08 (d, J ϭ 7.6 Hz, 2
Compound 13d: Yield: 336 mg (63%), beige powder from EtOAc/
light petroleum ether; dr 88:12. H NMR: δ ϭ 1.36 and 1.44* (2 s,
H, ArH) ppm. 13C NMR: δ ϭ 18.4 (q), 40.0 (q), 40.9 (q), 123.2
(s), 128.5 (d), 128.7 (d), 130.0 (d), 134.0 (s), 156.4 (s), 162.8 (s),
170.7 (s), 179.9 (s) ppm. IR: ν˜ ϭ 2740, 1682, 1640, 1566 cmϪ1. MS:
m/z (%) ϭ 338 [Mϩ ϩ 1] (100). C14H14N2O2Se (321.2): calcd. C
49.86, H 4.18, N 8.31; found C 49.61, H 4.36, N 8.31.
1
9 H, tBu), 1.67* and 1.71 (2 s, 3 H, CH3), 1.81 and 2.16* (2 s, 3
H, CH3), 3.14*, 3.20, and 3.24* [3 s, 6 H, N(CH3)2], 3.54 (s, 3 H,
OCH3), 3.62 (s, 3 H, OCH3), 4.28 and 4.36* (2 s, 1 H, CH), 9.52*
and 9.61 (2 br s, 1 H, NH), 9.86 and 9.99* (2 br s, 1 H, NH) ppm.
13C NMR: δ ϭ 13.1 (q), 19.1 (q), 28.1 (q), 39.7 and 40.7 (2 q), 51.7
(q), 51.8 (d), 51.9 (q), 55.7 (d), 75.3 (s), 79.5 (s), 147.6 (s), 149.7
(s), 152.8 (s), 154.2 (s), 169.0 (s), 181.3 (s), 188.7 (s) ppm. IR: ν˜ ϭ
3250, 3155, 1752, 1693, 1671, 1575 cmϪ1. C19H30N6O7Se (533.4):
calcd. C 42.78, H 5.67, N 15.75; found C 42.93, H 5.80, N 15.94.
5-Acetyl-2-(dimethylamino)-1,3-selenazol-4-yl
Benzoate
(12b):
Yield: 38 mg (12%), light yellow powder from Et2O/light petroleum
ether, m.p. 129Ϫ130 °C. 1H NMR (CDCl3): δ ϭ 2.34 (s, 3 H, CH3),
3.12 and 3.13 [2 s, 6 H, N(CH3)2], 7.52 (t, J ϭ 8.0 Hz, 2 H, ArH),
7.65 (t, J ϭ 8.0 Hz, 1 H, ArH), 8.20 (d, J ϭ 8.0 Hz, 2 H, ArH)
ppm. 13C NMR: δ ϭ 27.4 (q), 40.0 (q), 40.7 (q), 118.3 (s), 128.2
(d), 128.7 (d), 130.3 (d), 134.2 (s), 154.6 (s), 163.6 (s), 170.5 (s),
189.0 (s) ppm. IR: ν˜ ϭ 2734, 1628, 1599, 1572 cmϪ1. MS: m/z
(%) ϭ 338 [Mϩ ϩ 1] (100). C14H14N2O2Se (321.2): calcd. C 49.86,
H 4.18, N 8.31; found C 49.84, H 4.45, N 8.22.
Compound 13e: Yield: 440 mg (74%), white powder from EtOAc/
Et2O; dr 76:24. 1H NMR: δ ϭ 1.44 *and 1.45 (2 s, 9 H, tBu), 1.73*
and 1.75 (2 s, 3 H, CH3), 1.86 and 2.19* (2 s, 3 H, CH3), 3.06, 3.07,
3.18*, and 3.26* [4 s, 6 H, N(CH3)2], 3.58* and 3.70 (2 s, 3 H,
OCH3), 4.34 and 4.49* (2 s, 1 H, CH), 6.96Ϫ7.02 (m, 1 H, ArH),
7.24Ϫ7.34 (m, 2 H, ArH), 7.46 and 7.55 (2 d, 2 H, J ϭ 8.0 Hz,
ArH), 8.21 and 8.31* (2 s, 1 H, NH), 9.57*, 9.59*, 9.70, and 9.86
(4 s, 2 H, 2 NH) ppm. 13C NMR: δ ϭ 13.3 and 13.5 (2 q), 16.6
and 19.1 (2 q), 28.1 (q), 39.9, 40.8, and 41.2 (3 q), 52.1 and 52.3 (2
q), 55.5 e 56.1 (2 d), 75.3 and 77.5 (2 s), 79.4 and 79.6 (2 s), 118.1
and 118.6 (2 d), 122.2 and 122.5 (2 d), 128.7 and 128.9 (2 d), 138.7
and 138.9 (2 s), 147.6 (s), 148.2 (s), 152.3 (s), 152.8 and 153.1 (2 s),
169.1 and 171.4 (2 s), 179.0 (s), 186.3 (s) ppm. IR: ν˜ ϭ 3366, 3343,
3306, 3223, 1742, 1719, 1690, 1677, 1579 cmϪ1. C24H33N7O6Se
(594.5): calcd. C 48.49, H 5.59, N 16.49; found C 48.38, H 5.63,
N 16.72.
General Procedure for the Synthesis of 5,5-Disubstituted 2-Selenazo-
lin-4-one Derivatives 13a؊g: A catalytic amount of sodium methox-
ide was added to a magnetically stirred suspension of selenazoli-
none 4c؊d or solution of selenazolinone 4g؊h (1 mmol) in THF
(20 mL), followed by the conjugated azoalkene 1a, 1d, or 1e. The
reaction mixture was maintained at room temperature until the
complete disappearance of the reagents (12Ϫ30 h, monitored by
TLC). The solvent was removed under reduced pressure, and the
oily residue was crystallized from the appropriate solvents to give
compounds 13a؊g as diastereomeric mixtures.
Compound 13a: Yield: 379 mg (75%), light yellow powder from
EtOAc/light petroleum ether; dr 86:14. 1H NMR: δ ϭ 1.38 and
1.44* (2 s, 9 H, tBu), 1.68* and 1.76 (2 s, 3 H, CH3), 1.95 and
2.15* (2 s, 3 H, CH3), 3.54 (s, 3 H, OCH3), 3.62 (s, 3 H, OCH3),
4.25 and 4.34* (2 s, 1 H, CH), 8.32 and 9.03 (2 br s, 2 H, NH2),
9.52 (br. s, 1 H, NH), 9.95 (br. s, 1 H, NH) ppm. 13C NMR: δ ϭ
13.2 and 14.0 (2 q), 19.2 and 20.7 (2 q), 28.10 (q), 51.6 (q), 51.9
(q), 55.8 (d), 73.7 (s), 79.5 (s), 148.2 (s), 149.7 (s), 152.8 (s), 154.2
(s), 169.2 (s), 182.3 (s), 188.4 (s) ppm. IR: ν˜ ϭ 3389, 3217, 1729,
1662, 1647, 1634 cmϪ1. C17H26N6O7Se (505.4): calcd. C 40.40, H
5.19, N 16.63; found C 40.28, H 5.29, N 16.61.
Compound 13f: Yield: 285 mg (58%), white powder from Et2O; dr
87:13. 1H NMR: δ ϭ 1.68* and 1.74 (2 s, 3 H, CH3), 1.98 and
2.14* (2 s, 3 H, CH3), 3.07, 3.11, 3.15*, and 3.24* [4 s, 6 H,
N(CH3)2], 3.55 (s, 3 H, OCH3), 3.62 (s, 3 H, OCH3), 3.65 (s, 3 H,
OCH3), 4.27 and 4.35* (2 s, 1 H, CH), 9.95 and 10.00 (2 br s, 2 H,
2 NH) ppm. 13C NMR: δ ϭ 13.2 (q), 19.0 (q), 39.9 and 40.7 (2 q),
51.9 (q), 52.0 (q), 52.1 (q), 55.8 (d), 75.1 (s), 148.5 (s), 149.9 (s),
154.3 (s), 154.5 (s), 169.1 (s), 181.3 (s), 186.8 (s) ppm. IR: ν˜ ϭ 3242,
3152, 3089, 1741, 1716, 1669, 1574 cmϪ1. C16H24N6O7Se (491.4):
calcd. C 39.11, H 4.92, N 17.10; found C 39.44, H 4.90, N 17.07.
Compound 13g: Yield: 340 mg (60%), white powder from Et2O; dr
85:15. 1H NMR: δ ϭ 1.67* and 1.74 (2 s, 3 H, CH3), 1.98 and
2.15* (2 s, 3 H, CH3), 3.10, 3.13, 3.22*, and 3.24* [4 s, 6 H,
N(CH3)2], 3.54 (s, 3 H, OCH3), 3.65 (s, 3 H, OCH3), 4.28 and 4.35*
(2 s, 1 H, CH), 5.05Ϫ5.13 (m, 2 H, OCH2Ph), 7.24Ϫ7.42 (m, 5 H,
ArH), 9.89* and 9.95 (2 s, 1 H, NH), 10.04 (br. s, 1 H, NH) ppm.
13C NMR: δ ϭ 13.2 (q), 19.0 (q), 39.9 and 40.7 (2 q), 52.0 (q), 52.2
(q), 55.8 (d), 66.0 (t), 75.0 (s), 128.1 (d), 128.3 (d), 128.4 (d), 136.5
(s), 147.8 (s), 148.4 (s), 154.3 (s), 154.5 (s), 169.1 (s), 181.3 (s), 186.8
Compound 13b: Yield: 398 mg (69%), light yellow powder from
EtOAc/Et2O; dr 83:17. 1H NMR: δ ϭ 1.38 and 1.42* (2 s, 9 H,
tBu), 1.73* and 1.78 (2 s, 3 H, CH3), 2.05 and 2.17* (2 s, 3 H,
CH3), 3.56 (s, 3 H, OCH3), 4.32 and 4.47* (2 s, 1 H, CH), 6.99 (t,
J ϭ 7.3 Hz, 1 H, ArH), 7.28 (t, J ϭ 7.3 Hz, 2 H, ArH), 7.94 (d,
J ϭ 7.3 Hz, 2 H, ArH), 8.09 (br. s, 1 H, NH), 8.97 and 9.20 (2 br
s, 2 H, NH2), 9.55 (br. s, 1 H, NH), 9.59 (s, 1 H, NH) ppm. 13C
NMR: δ ϭ 13.4 and 14.1 (2 q), 19.4 and 20.9 (2 q), 27.9 and 28.10
(2 q), 52.2 (q), 56.3 (d), 74.0 (s), 79.6 (s), 118.3 (d), 122.4 (d), 128.9
(d), 138.9 (s), 148.1 (s), 148.4 (s), 152.4 (s), 154.9 (s), 169.3 (s),
179.6 (s), 188.0 (s) ppm. IR: ν˜ ϭ 3388, 3318, 3262, 3179, 1756,
1741, 1715, 1687, 1637, 1606, 1595 cmϪ1. C22H29N7O6Se (566.5):
calcd. C 46.65, H 5.16, N 17.31; found C 46.90, H 5.02, N 17.48.
(s) ppm. IR: ν˜ ϭ 3243, 1751, 1735, 1700, 1685, 1676, 1565 cmϪ1
.
C22H28N6O7Se (567.5): calcd. C 46.57, H 4.97, N 14.81; found C
46.81, H 5.01, N 15.08.
General Procedure for the Synthesis of 1-Selena-3,7-diazaspi-
ro[4.4]nona-2,8-dien-4-one Derivatives 14d؊g: DBU (1 mmol) in a
THF/MeOH mixture (1:1, 5 mL) was added dropwise to a magnet-
ically stirred solution of 13d؊g (1 mmol) in the same solvent mix-
ture (10 mL). The light yellow solution, maintained at room tem-
perature, darkened, and the reaction was complete in 24 h (mon-
Compound 13c: Yield: 384 mg (83%), light orange powder from
1
EtOAc; dr 80:20. H NMR: δ ϭ 1.69* and 1.87 (2 s, 3 H, CH3),
1.98 and 2.12 (2 s, 3 H, CH3), 3.53 (s, 3 H, OCH3), 3.60 (s, 3 H,
OCH3), 3.64 (s, 3 H, OCH3), 4.27 and 4.32* (2 s, 1 H, CH), 8.82
and 9.04 (2 br s, 2 H, NH2), 9.91 (s, 2 H, 2 NH) ppm. 13C NMR: itored by TLC). The solvent was removed under reduced pressure
δ ϭ 13.1 and 14.0 (2 q), 18.9 and 19.1 (2 q), 51.7 (q), 51.8 (q), 51.9
and the dark residue was purified by flash chromatography on a
(q), 56.0 (d), 73.6 (s), 148.8 (s), 149.7 (s), 154.2 (s), 154.5 (s), 169.2 silica gel column, eluting with EtOAc or EtOAc/MeOH mixtures,
(s), 182.3 (s), 188.4 (s) ppm. IR: ν˜ ϭ 3268, 3192, 1737, 1715, 1637,
Eur. J. Org. Chem. 2002, 2323Ϫ2330
to give pure derivatives 14d؊g.
2329

O. A. Attanasi, P. Filippone, F. R. Perrulli, S. Santeusanio
FULL PAPER
Compound 14d: Yield: 235 mg (44%), white powder from Et2O, m.p.
135 °C (dec.). 1H NMR: δ ϭ 1.37 (s, 9 H, tBu), 1.41 (s, 3 H, CH3),
2.03 (s, 3 H, CH3), 3.10 and 3.32 [2 s, 6 H, N(CH3)2], 3.55 (s, 3 H,
OCH3), 3.67 (s, 3 H, OCH3), 5.82 (s, 1 H, NH), 7.89 (s, 1 H, NH),
8.85 (s, 1 H, NH) ppm. 13C NMR: δ ϭ 11.8 (q), 21.7 (q), 28.0 (q),
39.5 (q), 41.2 (q), 50.5 (q), 52.4 (q), 78.7 (s), 81.5 (s), 89.5 (s), 100.4
(s), 155.6 (s), 156.3 (s), 162.7 (s), 163.1 (s), 174.3 (s), 186.7 (s) ppm.
[1]
[1a] A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Comprehensive
Heterocyclic Chemistry II.
A Review of the Literature
1982Ϫ1995, Elsevier Science, Oxford, 1996, vol. 1Ϫ11.
[1b]
T. Wirth, Organoselenium Chemistry: Modern Development
in Organic Synthesis, Springer, Berlin, 2000.
[2] [2a]
P. C. Srivastava, R. K. Robin, J. Med. Chem. 1983, 26,
[2b]
445Ϫ448.
Y. Kumar, R. Green, K. Z. Borysko, D. S. Wise,
IR: ν˜ ϭ 3326, 3277, 3253, 1754, 1737, 1699, 1613, 1573 cmϪ1
.
L. Wotring, L. B. Townsend, J. Med. Chem. 1993, 36,
[2c]
C19H30N6O7Se (533.4): calcd. C 42.78, H 5.67, N 15.75; found C
42.68, H 5.76, N 15.81.
3843Ϫ3848.
Comm. Mol. Pathol. Pharmacol. 1998, 101, 179Ϫ186.
Koketsu, H. Hishihara, W. Wu, K. Murakami, I. Saiki, Eur. J.
M. Koketsu, H. Hishihara, M. Hatsu, Res.
[2d]
M.
[2e]
Compound 14e: Yield: 273 mg (46%), beige powder from Et2O, m.p.
146 °C (dec.). 1H NMR: δ ϭ 1.15 (s, 3 H, CH3), 1.36 (s, 9 H, tBu),
2.16 (s, 3 H, CH3), 3.19 and 3.25 [2 s, 6 H, N(CH3)2], 3.50 (s, 3 H,
OCH3), 5.83 (d, JNHNH ϭ 4.0 Hz, 1 H, NH), 6.99 (t, J ϭ 7.4 Hz,
1 H, ArH), 7.28 (t, J ϭ 7.4 Hz, 2 H, ArH), 7.60 (d, J ϭ 7.4 Hz, 2
H, ArH), 8.12 (br. s, 1 H, NH), 8.36 (s, 1 H, NH), 8.85 (s, 1 H,
NH) ppm. 13C NMR: δ ϭ 11.6 (q), 14.8 (q), 28.0 (q), 39.6 (q), 40.8
(q), 50.0 (q), 79.0 (s), 82.0 (s), 86.6 (s), 100.3 (s), 118.3 (d), 122.5
(d), 128.7 (d), 138.9 (s), 155.5 (s), 156.2 (s), 160.4 (s), 163.8 (s),
180.2 (s), 189.3 (s) ppm. IR: ν˜ ϭ 3304, 3285, 3256, 1688, 1673,
1597, 1568 cmϪ1. C24H33N7O6Se (594.5): calcd. C 48.49, H 5.59, N
16.49; found C 48.70, H 5.42, N 16.61.
Pharm. Sci. 1999, 9, 156Ϫ161.
Koketsu, Y. Yamada, I. Saiki, Anticancer Res. 1999, 19,
W. Wu, K. Murakami, M.
5375Ϫ5381.
[3] [3a]
`
F. Purseigle, D. Dubreuil, A. Marchand, J. P. Pradere, M.
Goli, L. Toupet, Tetrahedron 1998, 54, 2545Ϫ2562.
Maeda, N. Kambe, N. Sonoda, S. Fujiwara, T. Shin-ike, Tetra-
[3b]
H.
[3c]
hedron 1997, 53, 13667Ϫ13680.
Y. Zhou, A. Linden, H.
Heimgartner, Helv. Chim. Acta 2000, 1576Ϫ1592. [3d] M. Kok-
etsu, T. Senda, K. Yoshimura, H. Ishihara, J. Chem. Soc., Per-
[3e]
kin Trans. 1 1999, 453Ϫ456.
M. Koketsu, S. Hiramatsu,
[3f]
H. Ishihara, Chem. Lett. 1999, 485Ϫ486.
M. Koketsu, Y.
Takenaka, H. Ishihara, Synthesis 2001, 731Ϫ734.
[4] [4a]
O. A. Attanasi, L. Caglioti, Org. Prep. Proced. Int. 1986,
[4b]
18, 299Ϫ327.
J. G. Schantl, in: 1-Azo-1-Alkene (Houben-
Weyl) (Eds.: H. Kropf, E. Schaumann), Thieme, Stuttgart
1990, Vol. E15, 909Ϫ1100. [4c] K. Banert, in: Targets in Hetero-
cyclic Systems Ϫ Chemistry and Properties (Eds.: O. A. Attan-
Compound 14f: Yield: 236 mg (48%), beige powder from Et2O, m.p.
141 °C (dec.). 1H NMR: δ ϭ 1.41 (s, 3 H, CH3), 1.99 (s, 3 H, CH3),
3.10 and 3.25 [2 s, 6 H, N(CH3)2], 3.54 (s, 3 H, OCH3), 3.56 (s, 3
H, OCH3), 3.66 (s, 3 H, OCH3), 6.01 (br. s, 1 H, NH), 8.18 (s, 1
H, NH), 8.71 (s, 1 H, NH) ppm. 13C NMR: δ ϭ 11.8 (q), 21.8 (q),
39.7 (q), 41.3 (q), 50.7 (q), 52.4 (q), 52.5 (q), 81.3 (s), 89.5 (s), 100.4
(s), 156.3 (s), 156.8 (s), 163.0 (s), 163.2 (s), 174.4 (s), 187.0 (s) ppm.
IR: ν˜ ϭ 3310, 3270, 3233, 3198, 1750, 1713, 1697, 1657, 1622,
1568 cmϪ1. C16H24N6O7Se (491.4): calcd. C 39.11, H 4.92, N 17.10;
found C 39.10, H 5.10, N 16.92.
`
asi, D. Spinelli), Societa Chimica Italiana, Rome, 2000, Vol.
[4d]
3, 1Ϫ32.
S. Polanc, in: Targets in Heterocyclic Systems Ϫ
Chemistry and Properties (Eds.: O. A. Attanasi, D. Spinelli),
`
Societa Chimica Italiana, Rome, 2000, Vol. 3, 33Ϫ91.
[5] [5a]
[5b]
O. A. Attanasi, P. Filippone, Synlett 1997, 1128Ϫ1140.
O. A. Attanasi, P. Filippone, C. Fiorucci, E. Foresti, F. Man-
tellini, J. Org. Chem. 1998, 63, 9880Ϫ9887.
L. De Crescentini, P. Filippone, F. R. Perrulli, S. Santeusanio,
[5c]
O. A. Attanasi,
[5d]
Synlett 1999, 339Ϫ341.
O. A. Attanasi, P. Filippone, F. R.
[5e]
Compound 14g: Yield: 182 mg (32%), light pink powder from Et2O,
Perrulli, S. Santeusanio, Tetrahedron 2001, 57, 1387Ϫ1394.
G. Abbiati, A. Arcadi, O. A. Attanasi, L. De Crescentini, E.
Rossi, Tetrahedron 2001, 57, 2031Ϫ2038. [5f] O. A. Attanasi, L.
De Crescentini, P. Filippone, F. Fringuelli, F. Mantellini, M.
1
m.p. 138 °C (dec.). H NMR: δ ϭ 1.41 (s, 3 H, CH3), 2.01 (s, 3 H,
CH3), 3.11 and 3.26 [2 s, 6 H, N(CH3)2], 3.55 (s, 3 H, OCH3), 3.56
(s, 3 H, OCH3), 5.12 (d, J ϭ 12.0 Hz, 1 H, OCH2CHaCHbPh), 5.15
(d, J ϭ 12.0 Hz, 1 H, OCH2CHaCHbPh), 5.98 (s, 1 H, NH), 7.39
(br. s, 5 H ArH), 8.18 (s, 1 H, NH), 8.78 (s, 1 H, NH) ppm. 13C
NMR: δ ϭ 11.8 (q), 21.8 (q), 39.9 (q), 41.3 (q), 50.8 (q), 52.5 (q),
66.8 (t), 81.4 (s), 89.6 (s), 100.5 (s), 128.1 (d), 128.4 (d), 128.7 (d),
136.3 (s), 156.0 (s), 156.9 (s), 162.9 (s), 163.3 (s), 174.5 (s), 187.1 (s)
Matteucci, O. Piermatti, F. Pizzo, Helv. Chim. Acta 2001, 84,
[5g]
513Ϫ525.
O. A. Attanasi, L. De Crescentini, P. Filippone,
[5h]
F. Mantellini, Synlett 2001, 557Ϫ559.
De Crescentini, P. Filippone, F. Mantellini, S. Santeusanio,
Helv. Chim. Acta 2001, 84, 2379Ϫ2386.
O. A. Attanasi, L.
[5i]
O. A. Attanasi, P.
Filippone, S. Santeusanio, Acc. Chem. Res. in press.
O. A. Attanasi, P. Filippone, B. Guidi, F. R. Perrulli, S. Santeu-
sanio, Synlett 2001, 144Ϫ146.
O. A. Attanasi, L. De Crescentini, E. Foresti, R. Galarini, S.
Santeusanio, F. Serra-Zanetti, Synthesis 1995, 1397Ϫ1400.
O. A. Attanasi, P. Filippone, B. Guidi, F. R. Perrulli, S. Santeu-
sanio, Heterocycles 1999, 51, 2423Ϫ2430.
R. Ballini, J. Chem. Soc., Perkin Trans. 1 1991, 1419Ϫ1421.
A. Arcadi, O. A. Attanasi, L. De Crescentini, B. Guidi, S. San-
teusanio, Gazz. Chim. Ital. 1997, 127, 609Ϫ612.
O. A. Attanasi, P. Filippone, E. Foresti, B. Guidi, S. Santeus-
anio, Tetrahedron 1999, 55, 13423Ϫ13444.
L.-L. Lai, D. H. Reid, Synthesis 1993, 870Ϫ872.
S. Sommer, Tetrahedron Lett. 1977, 18, 117Ϫ120.
Received February 1, 2002
ppm. IR: ν˜ ϭ 3318, 3251, 3211, 1752, 1723, 1686, 1606, 1568 cmϪ1
.
[6]
[7]
[8]
C22H28N6O7Se (567.5): calcd. C 46.57, H 4.97, N 14.81; found C
46.88, H 4.90, N 14.66.
[9]
[10]
Acknowledgments
This work was supported by financial assistance from the Ministero
[11]
`
dell’Universita
e
della Ricerca Scientifica
e
Tecnologica
(M.U.R.S.T.-Roma), Progetto 40%, the Consiglio Nazionale delle
[12]
[13]
`
Ricerche (C. N. R.-Roma), and the Universita degli Studi di Ur-
bino. The authors are very grateful to Dr. Gianfranco Favi for help
with NMR experiments.
[O02056]
2330
Eur. J. Org. Chem. 2002, 2323Ϫ2330