Synthesis of selenium-substituted pyrroles and pyrazol-3-ones

Article abstract of DOI:10.1055/s-0029-1216630

An approach to the synthesis of 4-(phenylseleno)pyrroles, 4-(phenylseleno)pyrazol-3-ones, and 4-(1,3-benzoselenazol-2-ylthio)pyrazol-3- ones is described. Their formation passes through hydrazonic intermediates obtained by the reaction between 1,2-diaza-1

Full text of DOI:10.1055/s-0029-1216630

1118
LETTER
Synthesis of Selenium-Substituted Pyrroles and Pyrazol-3-ones
S
ynthesis of Selen
r
ium-Sub
a
stituted Pyr
z
roles io A. Attanasi,*a Lucia De Crescentini,*a Fabio Mantellini,a Francesca Marini,b Simona Nicolini,a
Silvia Sternativo,b Marcello Tiecco*b
a
Istituto di Chimica Organica, Università degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti, 24, 61029 Urbino (PU), Italy
Fax +39(0722)303441; E-mail: orazio.attanasi@uniurb.it; E-mail: lucia.decrescentini@uniurb.it
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Università di Perugia, 06123 Perugia, Italy
b
Received 20 November 2008
reagents to effect nonconventional conversions of func-
Abstract: An approach to the synthesis of 4-(phenylseleno)pyr-
tional groups under mild reaction conditions.8f–i
roles, 4-(phenylseleno)pyrazol-3-ones, and 4-(1,3-benzoselenazol-
2-ylthio)pyrazol-3-ones is described. Their formation passes
through hydrazonic intermediates obtained by the reaction between
1,2-diaza-1,3-butadienes and 1-(phenylseleno)ketones, phenylsele-
nol, or 2-mercaptobenzoselenazole, respectively.
Considering the actual growing interest on the biochemi-
cal and pharmacological properties of organoselenium
compounds and their potential use as therapeutic and
chemopreventive agents9 we have designed a procedure to
prepare Se-substituted pyrroles and pyrazol-3-ones,10,11
starting from 1,2-diaza-1,3-butadienes and Se-containing
nucleophiles.
Key words: 1,2-diaza-1,3-butadienes, Michael additions, seleni-
um, pyrroles, pyrazoles
The first experiments were carried out with 1,2-diaza-1,3-
butadiene 1a and 1-(phenylseleno)acetone12 (2a) or 1-
phenyl-2-(phenylseleno)ethanone12 (2b) in the molar ratio
of 1:1, in tetrahydrofuran at room temperature, with a cat-
alytic amount of sodium hydride. The b-(phenylsele-
no)hydrazones 3a,b were thus obtained (path a,
Scheme 1, Table 1).13 Under the same experimental con-
ditions, compounds 1b,c with 2a,b gave complicated mix-
tures.
Pyrroles are ubiquitous heterocycles as they occur in
many naturally and biologically active compounds, such
as porphyrins, phthalocyanines, alkaloids, and vitamin
B12.1 Furthermore, a variety of synthetic pyrrolo deriva-
tives are of pharmaceutical or phytopharmaceutical rele-
vance.1 Among these, heterosubstituted pyrroles represent
an important subclass, both as synthons2 and themselves
as functionalized heterocycles. On the other hand, pyra-
zoles often recur in organic, biological, and medicinal
chemistry, and they have been applied also in the analyti-
cal and agricultural fields.3,4
The same reaction between 1,2-diaza-1,3-butadienes 1a,b
and 1-(phenylseleno)ketones 2a,b in the molar ratio of
2:1, with a stoichiometric amount of sodium hydride, di-
rectly produced 4-(phenylseleno)pyrroles 4a–c in good
yields.14 Under these conditions, the concomitant forma-
tion of the 2-oxohydrazonic byproducts 5a,b also oc-
curred (path b, Scheme 1, Table 1).14,15 All attempts to
obtain pyrazoles 4 from hydrazones 3a,b failed, probably
because of the poor stability of compounds 3.
In recent years, Attanasi and co-workers have addressed
their interest in developing new synthetic strategies to
reach polyfunctionalized pyrroles5,6 and pyrazoles,5,7
starting from 1,2-diaza-1,3-butadienes and various nu-
cleophiles.
At the same time, Tiecco and collaborators have turned
their attention to the chemistry of organoselenium com-
pounds.8a–e These compounds are useful and powerful
In agreement with our previous findings,5,6 the formation
of hydrazones 3 is due to the preliminary 1,4-addition
Table 1 b-(Phenylseleno)hydrazones 3a,b, 4-(Phenylseleno)pyrroles 4a–c, and 2-Oxohydrazones 5a,b
1
R1
Et
R2
R3
2
R4
3a
Yield (%)b Time (h)c 4e
Yield (%)b Time (h)c
5
Yield (%)b
1a
1b
1a
Me
Et
NH2
NH2
NH2
2a
2a
2b
Me
Me
Ph
3a
74
1.0
4a
4b
4c
70
71
59
8.0
6.0
8.0
5a
5b
5a
22
23
21
d
Me
Et
Me
3b
68
1.5
a Products obtained starting from 1a–c/2a–c (2:1), THF, NaH (cat.), r.t. (path a, Scheme 1).
b Yield of pure isolated products based on starting 2.
c Time of disappearance of the starting 2.
d The reaction gave a complicated mixture.
e Products obtained from 1a–c/2a–c (2:1), THF, NaH (1 equiv), r.t. (path b, Scheme 1).
SYNLETT 2009, No. 7, pp 1118–1122
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x.
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Advanced online publication: 02.04.2009
DOI: 10.1055/s-0029-1216630; Art ID: D39108ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Selenium-Substituted Pyrroles
1119
O
R2
O
R2
H
N
R1
O
N
R3
path a, i
R1
R3
N
O
N
Se
X
+
R4
O
O
1a–c
2a–c
O
Se
O
H C
2
R4
2a,b
X =
X = H
2c
3a,b
path b, ii
Se
R2
O
R2
H
N
O
from 6a,b
R1
O
R3
R1
Se
N
N
H
O
R2
iii
O
O
N
H
Se
O
+
R1
N
R3
R4
R2
R3
O
N
from 6c
N
N
iii
7a,b
O
O
6a–c
H
Se
O
R2
5a,b
O
4a–c
N
H
O
N
N
H
8a
Scheme 1 Synthesis of b-(phenylseleno)hydrazones 3a,b, 4-(phenylseleno)pyrroles 4a–c, 2-oxohydrazones 5a,b, a-(phenylseleno)hydra-
zones 6a–c, and 4-(phenylseleno)pyrazol-3-ones 7a,b, 8a. Reagents and conditions: (i) molar ratio 1a–c/2a–c = 2:1, THF, NaH (cat.), r.t.; (ii)
molar ratio 1a–c/2a–c = 2:1, THF, NaH (1 equiv), r.t.; (iii) THF–MeOH (1:1), NaH (1 equiv), r.t.
(Michael-type) by the activated methylene group of 2a,b
to the heterodiene system of the conjugated azoalkene 1.
The subsequent intramolecular attack by the C=N nitro-
gen at the ketonic carbonyl group produces the pyrrole
ring closure (4) by loss of a water molecule.
O
R2
N
R1
N
R3
O
O
N
+
SH
R2
Se
O
1a–c
2d
i
R2
H
N
O
H
N
With the aim to synthesize new 4-selenium-substituted-
pyrazol-3-ones, we have examined the reaction between
1,2-diaza-1,3-butadienes 1a–c and phenylselenol 2c. The
reaction was carried out in tetrahydrofuran at room tem-
perature providing a-(phenylseleno)hydrazones 6a–c in
good yields by means of 1,4-addition of the phenylselenol
to the heterodiene system of 1 (Scheme 1, Table 2).16
R1
R3
R1
R3
O
N
H
O
N
N
S
O
S
O
N
Se
Se
6d–f
ii
from 6d,e
from 6f
Hydrazonic intermediates 6a–c can be easily converted
into the corresponding 4-(phenylseleno)-pyrazol-3-ones
7a,b and 8a by treatment with a stoichiometric amount of
sodium hydride in tetrahydrofuran–methanol (1:1) at
room temperature (Scheme 1, Table 2).17 The closure of
the pyrazolone ring is due to the base-promoted intramo-
lecular nucleophilic attack of the hydrazonic nitrogen at
the ester group, with loss of an alcohol molecule. The for-
mation of 2-N-unsubstituted 4-(phenylseleno)pyrazol-3-
ones 7a,b took place by the base-promoted cleavage of the
aminocarbonyl group linked to the nitrogen in the position
2 of the pyrazole ring.
N
N
R2
S
R2
S
Se
Se
N
H
N
N
H
O
O
N
H
N
O
H
7c,d
8b
Scheme 2 Synthesis of a-(1,3-benzoselenazol-2-ylthio)hydrazones
6d–f and 4-(1,3-benzoselenazol-2-ylthio)pyrazol-3-ones 7c,d, 8b.
Reagents and conditions: i, THF, r.t.; ii, THF–MeOH (1:1), NaH (1
equiv), r.t.
Based on these results, we have enlarged our studies to the
reaction between 1,2-diaza-1,3-butadienes 1a–c and 2-
mercaptobenzselenazole 2d. The reaction was carried out
in tetrahydrofuran at room temperature obtaining a-(1,3-
benzoselenazol-2-ylthio)hydrazones 6d–f, by attack of
the sulfur atom at the terminal carbon of the azo–ene sys-
tem (Scheme 2).15 Yields and reaction times are given in
Table 2.
The conversion of hydrazones 6d–f into the correspond-
ing hydrazino-forms was observed directly in the NMR
tube, using DMSO-d6 as solvent, after 168 hours. a-(1,3-
Benzoselenazol-2-ylthio)hydrazones 6d–f were convert-
ed in excellent yields into 4-(1,3-benzoselenazol-2-yl-
thio)pyrazol-3-ones 7c,d and 8b, by treatment with a
stoichiometric amount of sodium hydride, in tetrahydro-
Synlett 2009, No. 7, 1118–1122 © Thieme Stuttgart · New York

1120
O. A. Attanasi et al.
LETTER
Table 2 a-(Phenylseleno)hydrazones 6a–c, a-(1,3-Benzoselenazol-2-ylthio)hydrazones 6d–f, 4-(Phenylseleno)pyrazol-3-ones 7a,b, 8a, and
4-(1,3-Benzoselenazol-2-ylthio)pyrazol-3-ones 7c,d, 8b
1
R1
R2
R3
2
6
Yield (%)a
Time (h)b
18.0
24.0
24.0
0.1
7
Yield (%)c
Time (h)d
0.2
8
Yield (%)c
Time (h)d
1a
1b
1c
1a
1b
1c
Et
Me
Et
NH2
NH2
NHPh
NH2
NH2
NHPh
2c
2c
2c
2d
2d
2d
6a
6b
6c
6d
6e
6f
83
72
57
93
95
85
7a
7b
81
94
Me
Me
Et
0.3
Me
Me
Et
8a 78
8b 97
0.1
7c
99
95
0.2
0.1
Me
Me
0.2
7d
Me
0.1
0.2
a Yield of pure isolated products based on 1,2-diaza-1,3-butadienes 1.
b Time of disappearance of the starting compounds 1.
c Yield of pure isolated products based on hydrazones 6.
d Time of disappearance of the starting compounds 6.
furan–methanol (1:1; Scheme 2, Table 2),17 according to
the same base-promoted mechanism described for the
synthesis of 7a,b and 8a. Also in this case, the base-
promoted cleavage of the aminocarbonyl group linked to
the nitrogen in the position 2 of the pyrazole ring took
place, producing 2-N-unsubstituted 3-oxo-pyrazoles 7a,b.
(5) (a) Attanasi, O. A.; Caglioti, L. Org. Prep. Proced. Int. 1986,
18, 299. (b) Attanasi, O. A.; Serra-Zanetti, F. In Progress in
Heterocyclic Chemistry, Vol. 7; Suschitzky, H.; Scriven, E.
F. V., Eds.; Pergamon: Oxford, 1995. (c) Attanasi, O. A.;
Filippone, P. Synlett 1997, 1128. (d) Attanasi, O. A.; De
Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.;
Santeusanio, S. ARKIVOC 2002, (xi), 274.
(6) (a) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone,
P.; Mantellini, F.; Santeusanio, S. J. Org. Chem. 2004, 69,
2687. (b) Attanasi, O. A.; Favi, G.; Filippone, P.; Lillini, S.;
Mantellini, F.; Spinelli, D.; Stenta, M. Adv. Synth. Catal.
2007, 349, 207. (c) Schmidt, A.; Karapetyan, V.; Attanasi,
O. A.; Favi, G.; Görls, H.; Mantellini, F.; Langer, P. Synlett
2007, 2965. (d) Karapetyan, V.; Mkrtchyan, S.; Schmidt, A.;
Attanasi, O. A.; Favi, G.; Mantellini, F.; Villinger, A.;
Fischer, C.; Langer, P. Adv. Synth. Catal. 2008, 350, 1331.
(7) (a) Attanasi, O. A.; Filippone, P. In Topics in Heterocyclic
Systems, Vol. 1; Attanasi, O. A.; Spinelli, D., Eds.; Research
Signpost: Trivandrum, 1996, 157. (b) Forlani, L.; Attanasi,
O. A.; Boga, C.; De Crescentini, L.; Del Vecchio, E.; Favi,
G.; Mantellini, F.; Tozzi, S.; Zanna, N. Eur. J. Org. Chem.
2008, 4357. (c) Attanasi, O. A.; Baccolini, G.; Boga, C.;
De Crescentini, L.; Giorgi, G.; Mantellini, F.; Nicolini, S.
Eur. J. Org. Chem. 2008, 5965.
In conclusion, this work confirms once again the versatil-
ity of 1,2-diaza-1,3-butadienes in the construction of
highly functionalized heterocyclic systems.5–7 Further-
more, in consideration of the bioactive importance of or-
ganoselenium compounds,9 the presently described
reactions between the above-mentioned 1,2-diaza-1,3-
butadienes and some selenium-containing nucleophiles
offer a facile access to new Se-substituted pyrroles and
pyrazol-3-ones, not easily accessible by other methods.
Acknowledgment
This work was supported by the financial assistance from the
Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR)-
PRIN and Università degli Studi di Urbino ‘Carlo Bo’.
(8) (a) Tiecco, M.; Testaferri, L.; Bagnoli, L.; Marini, F.; Santi,
C.; Temperini, A.; Scarponi, C.; Sternativo, S.; Terlizzi, R.;
Tomassini, C. ARKIVOC 2006, (vii), 186. (b) Tiecco, M.
Electrophilic Selenium, Selenocyclizations, In Topics in
Current Chemistry. Organoselenium Chemistry: Modern
Developments in Organic Synthesis ; Wirth, T., Ed.;
Springer: Heidelberg, 2000, Chap. 2, 7. (c) Tiecco, M.;
Carlone, A.; Sternativo, S.; Marini, F.; Bartoli, G.;
References and Notes
(1) (a) Sundberg, R. J. In Comprehensive Heterocyclic
Chemistry, Vol. 4; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984, 314. (b) Gribble, G. W.
In Comprehensive Heterocyclic Chemistry II, Vol. 2;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon-Elsevier Science: Amsterdam, 1996, Chap. 4.
(2) Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
(3) Progress in Heterocyclic Chemistry, Vol. 15-20; Gribble,
G. W.; Joule, J. A., Eds.; Elsevier: Oxford, 2003–2008.
(4) Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S.
In Targets in Heterocyclic Systems – Chemistry and
Properties, Vol. 6; Attanasi, O. A.; Spinelli, D., Eds.;
Società Chimica Italiana: Rome, 2002, 52.
Melchiorre, P. Angew. Chem. Int. Ed. 2007, 42, 6882.
(d) Tiecco, M.; Testaferri, L.; Temperini, A.; Terlizzi, R.;
Bagnoli, L.; Marini, F.; Santi, C. Org. Biomol. Chem. 2007,
5, 3510. (e) Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini,
C.; Marini, F.; Bagnoli, L.; Temperini, A. Angew. Chem. Int.
Ed. 2003, 42, 3131. (f) Organoselenium Chemistry - A
Practical Approach; Back, T. G., Ed.; Oxford University
Press: New York, 2000. (g) Wirth, T. Angew. Chem. Int. Ed.
2000, 39, 3742. (h) Petragnani, N.; Stefani, H. A.; Valduga,
C. J. Tetrahedron 2001, 57, 1411. (i) Special issue: Curr.
Org. Chem. 2006, 10, 1891.
Synlett 2009, No. 7, 1118–1122 © Thieme Stuttgart · New York

LETTER
Synthesis of Selenium-Substituted Pyrroles
1121
(9) (a) Mugesh, G.; du Mont, W.-W.; Sies, H. Chem. Rev. 2001,
101, 2125. (b) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T.
Chem. Rev. 2004, 104, 6255. (c) Soriano-Garcia, M. Curr.
Med. Chem. 2004, 11, 1657. (d) Narajji, C.; Karvekar,
M. D.; Das, A. K. Indian. J. Pharm. Sci. 2007, 8, 344.
(e) Naithani, R. Mini-Rev. Med. Chem. 2008, 69, 344.
(10) (a) Hartke, K.; Wendebourg, H. H. Heterocycles 1988, 27,
639. (b) Hartke, K.; Wendebourg, H. H. Liebigs Ann. Chem.
1989, 415. (c) Bella, M.; Piancatelli, G.; Squarcia, A.; Trolli,
C. Tetrahedron Lett. 2001, 41, 3669.
2-(phenylseleno)ethanone12 (2b, 1.0 mmol) in THF (5 mL)
at r.t., a stoichiometric amount (1.0 mmol) of NaH was
added. The reaction mixture was magnetically stirred for
6.0–8.0 h until the disappearance of the starting 1. 4-(Phenyl-
seleno)pyrroles 4a–c and 2-oxohydrazones14 5a,b were
separated by chromatography on SiO2 column (elution
mixtures: cyclohexane–EtOAc), and they were crystallized
from Et2O-light PE (40–60) or EtOAc–light PE (40–60),
respectively.
Ethyl 1-[(Aminocarbonyl)amino]-2,5-dimethyl-4-
(phenylseleno)-1H-pyrrole-3-carboxylate (4a)
(11) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.;
Kel’in, A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130,
1440.
Yield 266.5 mg (70%) obtained as light yellow solid; mp
182–184 °C. IR (Nujol): nmax = 3518, 3374, 3193, 1727,
1704 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 1.04 (t, 3 H,
J = 7.2 Hz), 2.10 (s, 3 H), 2.28 (s, 3 H), 4.03 (q, 2 H, J = 7.2
Hz), 6.38 (s, 2 H), 7.15–7.19 (m, 2 H), 7.49–7.53 (m, 2 H),
7.73–7.75 (m, 1 H), 9.29 (s, 1 H). 13C NMR (100 MHz,
DMSO-d6): d = 10.8 (q), 13.9 (q), 14.2 (q), 58.8 (t), 98.5 (s),
110.3 (s), 118.7 (s), 125.3 (s), 128.2 (d), 128.8 (d), 134.2 (s),
145.9 (d), 156.9 (s), 164.3 (s). MS: m/z (%) = 383 (23)
[M+ + 3], 381 (100) [M+ + 1], 379 (57) [M+ – 1], 378 (21)
[M+ – 2], 377 (22) [M+ – 3], 375 (2) [M+ – 5]. Anal. Calcd
for C16H19N3O3Se: C, 50.53; H, 5.04; N, 11.05. Found: C,
50.48; H, 5.21; N, 10.96.
(12) (a) Synthesis of the a-Seleno Ketones 2a,b
Compound 2a
Phenyl selenyl chloride (5.0 mmol) was added at r.t. to
acetone (4 mL), and the solution was stirred for 30 min. The
reaction mixture was poured into H2O and extracted with
CH2Cl2. The organic layer was dried over Na2SO4, filtered,
and evaporated under vacuum. The crude product 2a (89%
yield) was used without further purification.
Compound 2b
The phenylselenyl sulfate was generated from (PhSe)2 (1.7
mmol) and (NH4)2S2O8 (2.3 mmol) in MeCN (20 mL) at
80 °C. After 30 min the 1-phenylethanone (1.7 mmol) was
added. The mixture was stirred overnight at the same
temperature, then was poured into an aq solution of NaHCO3
and extracted with CH2Cl2. The organic layer was dried over
Na2SO4, filtered, and evaporated under vacuum. The residue
was purified by flash chromatography (elution mixture: PE–
CH2Cl2 = 85:15) to yield 2b in 40% yield. (b) Spectral data
of 2a and 2b are identical to those already described in the
literature: Houllemare, D.; Ponthieux, S.; Outurquin, F.;
Paulmier, C. Synthesis 1997, 101.
(15) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Foresti, E.;
Mantellini, F. J. Org. Chem. 2000, 65, 2820.
(16) General Procedure for the Synthesis of a-(Phenylseleno)-
hydrazones 6a–c and a-(1,3-Benzoselenazol-2-ylthio)-
hydrazones 6d–f
A solution of 1,2-diaza-1,3-butadienes 1a–c as a mixture
of E/Z isomers18 (1.0 mmol) and phenylselenol(2c) or 2-
mercaptobenzselenazole (2d, 1.0 mmol) in THF (5 mL) was
magnetically stirred at r.t., for 0.1–24.0 h until the
disappearance of the starting 1. Hydrazones 6a–c were
obtained by chromatography on SiO2 column (elution
mixtures: cyclohexane–EtOAc) and by subsequent
crystallization from Et2O–light PE (40–60), while
hydrazones 6d–f were crystallized from Et2O–light PE
(40–60), after the evaporation of the reaction solvent. The
conversion of a-(1,3-benzoselenazol-2-ylthio)hydrazones
6d–f into the corresponding hydrazino forms occurred in one
week, directly in the NMR tube, using DMSO-d6 as solvent.
Methyl 3-[(Aminocarbonyl)hydrazono]-2-(phenylseleno)-
pentanoate (6b)
Yield 247.5 mg (72%) obtained as white solid; mp 124–
126 °C. IR (Nujol): nmax = 3454, 3299, 3191, 1793, 1697
cm–1. 1H NMR (400 MHz, DMSO-d6): d = 0.93 (t, 3 H,
J = 7.6 Hz), 2.33–2.38 (m, 2 H), 3.60 (s, 3 H), 4.94 (s, 1 H),
6.18 (br s, 2 H), 7.30–7.32 (m, 3 H), 7.54–7.56 (m, 2 H), 9.44
(s, 1 H). 13C NMR (100 MHz, DMSO-d6) : d = 9.6 (q), 21.0
(t), 50.1 (d), 52.5 (q), 128.1 (s), 128.2 (d), 129.1 (d), 134.1
(d), 145.8 (s), 156.8 (s), 169.8 (s). MS: m/z (%) = 345 (8)[M+
+ 3], 343 (35) [M+ + 1], 341 (17) [M+ – 1], 340 (6) [M+ – 2],
339 (6) [M+ – 3], 337 (1) [M+ – 5], 317 (3), 315 (15), 313 (9),
312 (4), 311 (4), 270 (6), 268 (30), 266 (15), 265 (6), 264 (6),
262 (2), 186 (100). Anal. Calcd for C13H17N3O3Se: C, 45.62;
H, 5.01; N, 12.28. Found: C, 45.48; H, 5.17; N, 12.41.
Ethyl 3-[(Aminocarbonyl)hydrazono]-2-(1,3-benzo-
selenazol-2-ylthio)butanoate (Hydrazono Form of 6d)
Yield 372.5 mg (93%) obtained as white solid; mp 144–
146 °C. IR (Nujol): nmax = 3463, 3313, 3200, 1790, 1692
cm–1. 1H NMR (400 MHz, DMSO-d6): d = 1.20 (t, 3 H,
J = 7.2 Hz), 1.98 (s, 3 H), 4.16–4.24 (m, 2 H), 5.51 (s, 1 H),
6.28 (br s, 2 H), 7.29 (t, 1 H, J = 8.0 Hz), 7.44 (t, 1 H, J = 8.0
Hz), 7.78 (d, 1 H, J = 7.2 Hz), 8.04 (d, 1 H, J = 6.8 Hz), 9.55
(s, 1 H). 13C NMR (100 MHz, DMSO-d6) : d = 13.9 (q), 14.5
(q), 57.4 (t), 61.9 (d), 122.5 (d), 124.6 (d), 125.3 (d), 126.4
(13) General Procedure for the Synthesis of b-(Phenylseleno)-
hydrazones 3a,b
To a magnetically stirred solution of 1,2-diaza-1,3-butadiene
1a as a mixture of E/Z isomers18 (1.0 mmol) and 1-(phenyl-
seleno)acetone12(2a) or 1-phenyl-2-(phenylseleno)-ethanone12
(2b, 1.0 mmol) in THF (5 mL) at r.t., a catalytic amount (0.1
mmol) of NaH was added. The reaction mixture was
magnetically stirred for 1.0–1.5 h until the disappearance of
the starting 1. b-(Phenylseleno)hydrazones 3a,b were
obtained by chromatography on SiO2 column (elution
mixtures: cyclohexane–EtOAc) and by subsequent
crystallization from Et2O-light PE (40–60). The reaction
between 1b,c and 2a,b gave complicated mixtures.
Data for Ethyl 2-[N-(Aminocarbonyl)ethanehydra-
zonoyl]-2,5-dideoxy-3-Se-phenyl-3-selenopent-4-
ulosonate (3a)
Yield 294.5 mg (74%) obtained as yellow solid; mp 148–
152 °C. IR (Nujol): nmax = 3420, 3291, 3195, 1765, 1720,
1690 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 1.08 (t, 3 H,
J = 6.8 Hz), 1.85 (s, 3 H), 2.32 (s, 3 H), 3.44 (d, 1 H, J = 11.6
Hz), 3.97–4.02 (m, 2 H), 4.70 (d, 1 H, J = 11.6 Hz), 6.38 (s,
2 H), 7.38–7.47 (m, 5 H), 9.30 (s, 1 H). 13C NMR (100 MHz,
DMSO-d6): d = 13.8 (q), 15.2 (q), 27.7 (q), 49.3 (d), 53.8 (d),
60.8 (t), 125.5 (s), 128.8 (d), 129.1 (d), 136.2 (d), 142.4 (s),
156.9 (s), 169.3 (s), 202.0 (s); during the MS analysis, we
have observed only the signals of pyrrole 4a. Anal. Calcd for
C16H21N3O4Se: C, 48.25; H, 5.31; N, 10.55. Found: C, 48.19;
H, 5.39; N, 10.63.
(14) General Procedure for the Synthesis of 4-(Phenylseleno)-
pyrroles 4a–c and 2-Oxohydrazones 5a,b
To a magnetically stirred solution of 1,2-diaza-1,3-
butadienes 1a–c as a mixture of E/Z isomers18 (2.0 mmol)
and 1-(phenylseleno)acetone12 (2a, 1.0 mmol) or 1-phenyl-
Synlett 2009, No. 7, 1118–1122 © Thieme Stuttgart · New York

1122
O. A. Attanasi et al.
LETTER
(d), 138.3 (s), 140.5 (s), 153.6 (s), 156.6 (s), 166.1 (s), 167.5
(s); MS: m/z (%) = 400 (1) [M+ + 3], 398 (5) [M+ + 1], 396
(2) [M+ – 1], 397 (1) [M+ – 2], 396 (1) [M+ – 3], 328 (9), 326
(45), 324 (19), 323 (8), 322 (8), 320 (1), 313 (31), 311 (100),
309 (60), 308 (24), 307 (23), 305 (3); Anal. Calcd for
C14H16N4O3SSe: C, 42.11; H, 4.04; N, 14.03. Found: C,
42.31; H, 4.11; N, 14.20.
Ethyl 3-[2-(Aminocarbonyl)hydrazino]-2-(1,3-benzo-
selenazol-2-ylthio)but-2-enoate (Hydrazino Form of 6d)
1H NMR (400 MHz, DMSO-d6): d = 1.11 (t, 3 H, J = 7.2
Hz), 2.30 (s, 3 H), 4.09 (q, 2 H, J = 7.2 Hz), 6.28 (s, 2 H),
7.21 (t, 1 H, J = 8.0 Hz), 7.39 (t, 1 H, J = 8.0 Hz), 7.75 (d, 1
H, J = 6.8 Hz), 7.96 (d, 1 H, J = 8.0 Hz), 8.60 (s, 1 H), 11.08
(s, 1 H). 13C NMR (100 MHz, DMSO-d6): d = 14.3 (q), 16.4
(q), 59.9 (t), 82.3 (s), 122.4 (d), 123.7 (d), 125.0 (d), 126.1
(d), 137.8 (s), 156.8 (s), 157.8 (s), 168.7 (s), 172.4 (s), 180.3
(s).
4-(1,3-Benzoselenazol-2-ylthio)-5-methyl-1,2-dihydro-
3H-pyrazol-3-one (7c)
Yield 309.1 mg (99%) obtained as white solid; mp 192–
194 °C. IR (Nujol): nmax = 3398, 3328, 1739, 1697, 1673,
1655 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 2.02 (s, 3
H), 7.01 (s, 1 H), 7.15 (t, 1 H, J = 7.6 Hz), 7.35 (t, 1 H,
J = 8.0 Hz), 7.69 (d, 1 H, J = 8.0 Hz), 7.86 (d, 1 H, J = 8.0
Hz), 8.39 (s, 1 H). 13C NMR (100 MHz, DMSO-d6): d = 13.4
(q), 80.7 (s), 122.1 (d), 123.2 (d), 124.9 (d), 125.8 (d), 138.0
(s), 153.1 (s), 157.3 (s), 165.8 (s), 184.2 (s). MS: m/z (%) =
313 (28) [M+ + 3], 311 (100) [M+ + 1], 309 (52) [M+ – 1],
308(18) [M+ – 2], 307(18) [M+ – 3], 305 (1) [M+ – 5]. Anal.
Calcd for C11H9N3OSSe: C, 42.59; H, 2.92; N, 13.54. Found:
C, 42.39; H, 3.01; N, 13.28.
3-Methyl-5-oxo-N-phenyl-4-(phenylseleno)-2,5-dihydro-
1H-pyrazole-1-carboxamide (8a)
Yield 292.1 mg (78%) obtained as white solid; mp 144–
147 °C. IR (Nujol): nmax = 3342, 3191, 1721, 1687 cm–1. 1H
NMR (400 MHz, DMSO-d6): d = 2.12 (s, 3 H), 6.98 (t, 1 H,
J = 7.2 Hz), 7.24–7.28 (m, 5 H), 7.45 (br s, 1 H), 7.51–7.68
(m, 4 H), 11.98 (br s, 1 H). 13C NMR (100 MHz, DMSO-d6):
d = 13.0 (q), 110.4 (s), 119.1 (d), 122.1 (d), 127.7 (d), 127.8
(d), 129.0 (d), 129.5 (d), 130.8 (s), 139.1 (s), 147.3 (s), 154.2
(s), 164.8 (s). MS: m/z (%) = 375 (20) [M+ + 3], 373 (100)
[M+ + 1], 371 (41) [M+ – 1], 370 (19) [M+ – 2], 369 (21)
[M+ – 3], 367 (3) [M+ – 5]. Anal. Calcd for C17H15N3O2Se:
C, 54.85; H, 4.06; N, 11.29. Found: C, 54.96; H, 4.17; N,
11.36.
(17) General Procedure for the Synthesis of 4-(Phenylseleno)-
pyrazol-3-ones 7a,b, 8a and 4-(1,3-benzoselenazol-2-
ylthio)pyrazol-3-ones 7c,d, 8b
a-(Phenylseleno)- or a-(1,3-benzoselenazol-2-ylthio)hydra-
zones (6a–c and 6d–f, 1.0 mmol) were dissolved in a
mixture of THF (5 mL)–MeOH (5 mL), and a stoichiometric
amount of NaH (1.0 mmol) was added. The reaction mixture
was magnetically stirred for 0.1–0.3 h until the disappear-
ance of the starting 6. Pyrazol-3-ones 7a–d were obtained
from 6a,b,d,e, respectively, while pyrazol-3-ones 8a,b were
obtained from 6c,f, respectively. Products 7a–d and 8a,b
were purified by chromatography on SiO2 column (elution
mixtures: EtOAc–MeOH) and by subsequent crystallization
from Et2O–light PE (40–60).
4-(1,3-Benzoselenazol-2-ylthio)-3-methyl-5-oxo-N-
phenyl-2,5-dihydro-1H-pyrazol-1-carboxamide (8b)
Yield 417.1 mg (97%) obtained as white solid; mp 246–
248 °C. IR (Nujol): nmax = 3351, 3186, 1706, 1683 cm–1. 1H
NMR (400 MHz, DMSO-d6): d = 2.10 (s, 3 H), 7.05 (t, 1 H,
J = 7.6 Hz), 7.17 (t, 1 H, J = 7.6 Hz), 7.32–7.51 (m, 4 H),
7.54 (d, 2 H, J = 8.0 Hz), 7.72 (d, 1 H, J = 8.0 Hz), 7.88 (d,
1 H, J = 8.0 Hz), 12.21 (s, 1 H). 13C NMR (100 MHz,
DMSO-d6): d = 13.4 (q), 81.2 (s), 119.0 (d), 122.2 (d), 122.7
(d), 123.4 (d), 124.9 (d), 125.8 (d), 129.0 (d), 138.0 (s), 138.7
(s), 149.6 (s), 152.8 (s), 157.2 (s), 165.8 (s), 183.3 (s). MS:
m/z (%) = 430 (14) [M+ + 3], 428 (45) [M+ + 1], 426 (35)
[M+ – 1], 425 (12) [M+ – 2], 424 (13) [M+ – 3], 422 (2)
[M+ – 5], 313 (15), 311 (55), 309 (26), 308 (10), 307 (10),
305 (2), 215 (100). Anal. Calcd for C18H14N4O2SSe: C,
50.35; H, 3.29; N, 13.05. Found: C, 50.39; H, 3.31; N, 13.23.
(18) (a) Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S.
Synthesis 1984, 671. (b) Attanasi, O. A.; Filippone, P.; Mei,
A.; Santeusanio, S. Synthesis 1984, 873.
5-Ethyl-4-(phenylseleno)-1,2-dihydro-3H-pyrazol-3-one
(7b)
Yield 252.1 mg (94%) obtained as white solid; mp 120–
122 °C. IR (Nujol): nmax = 3369, 3116, 1735, 1702, 1636 cm–
1. 1H NMR (400 MHz, DMSO-d6): d = 1.03 (t, 3 H, J = 7.6
Hz), 2.35–2.41 (m, 2 H), 7.18–7.32 (m, 4 H), 7.46 (br s, 1 H),
7.57–7.59 (m, 1 H), 8.65 (br s, 1 H). 13C NMR (100 MHz,
DMSO-d6): d = 13.1 (q), 20.8 (d), 125.2 (s), 127.7 (d), 128.9
(d), 129.5 (d), 130.8 (s), 158.6 (s), 164.4 (s). MS: m/z (%) =
270 (20)[M+ + 3], 268 (100) [M+ + 1], 266 (39) [M+ – 1], 265
(19) [M+ – 2], 264 (21) [M+ – 3], 262 (2) [M+ – 5]. Anal.
Calcd for C11H12N2OSe: C, 49.45; H, 4.53; N, 10.48. Found:
C, 49.49; H, 4.47; N, 10.41.
Synlett 2009, No. 7, 1118–1122 © Thieme Stuttgart · New York

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