A novel synthesis of benzo[ b ]selenophenes via regioselective intramolecular transformation of 4-(3-Nitroaryl)-1,2,3-selenadiazoles

Article abstract of DOI:10.1021/ol400547n

Base-promoted transformation of 4-(3-nitroaryl)-1,2,3-selenadiazoles via intermediate formation of eneselenolates followed by 5-exo-trig cyclization is reported. The regiochemistry of the intramolecular cyclization is condition-dependent. In the presence

Full text of DOI:10.1021/ol400547n

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
A Novel Synthesis of
Benzo[b]selenophenes via Regioselective
Intramolecular Transformation of
4‑(3-Nitroaryl)-1,2,3-selenadiazoles
Anna G. Lyapunova, Mikhail L. Petrov,* and Dmitry A. Androsov*
Department of Organic Chemistry, Saint-Petersburg State Institute of Technology,
Moskovskii prospekt 26, Saint-Petersburg 190013, Russia
mlpetrov@lti-gti.ru; da_androsov@hotmail.com
Received February 27, 2013
ABSTRACT
Base-promoted transformation of 4-(3-nitroaryl)-1,2,3-selenadiazoles via intermediate formation of eneselenolates followed by 5-exo-trig
cyclization is reported. The regiochemistry of the intramolecular cyclization is condition-dependent. In the presence of an oxidant, the
oxidative nucleophilic substitution of the hydrogen (ONSH, SNArH) pathway, by oxidative aromatization of the rapidly formed σH-adduct, takes
place. In the absence of oxidant, the reaction proceeds via intermediate formation of the σCl-adduct, following nucleophilic aromatic substitution
of the halogen (SNArCl) pathway.
4-Substituted 1,2,3-selenadiazoles (I) are usually easily
decomposed with the liberation of nitrogen and formation
of alkyneselenolates (II) under the influence of strong
bases, such as organolithium reagents, potassium ethox-
ide, etc.1 The acetylenic selenolates are widely used in
organic chemistry for the synthesis of acetylenic selenides,
in 1,3-anionic cycloaddition reactions and in other cycliza-
tion reactions or, after protonation, as a source of highly
reactive alkyneselenols (III) and tautomeric selenoketenes
(IV, Scheme 1).2
W. Dehaen and our previous studies3 have demonstrated
an intramolecular 5-exo-dig cyclization reaction of the in situ
generated ortho-hydroxy- and -aminoselenoketenes to be
a facile, straightforward, and efficient approach toward
benzo[b]furans and indoles. These results prompted us
to examine the possible synthesis of benzo[b]selenophenes
by a 5-exo-trig cyclization reaction of the in situ generated
ortho-haloselenoketenes with the participation of external
nucleophiles (Scheme 2).
(1) (a) Lalezari, I.; Shafiee, A.; Yalpani, M. J. Org. Chem. 1973, 38
(2), 338–340. (b) Laishev, V. Z.; Petrov, M. L.; Petrov, A. A. Zh. Org.
Khim. 1982, 18 (3), 514–519.
It should be mentioned that the synthesis and character-
ization of benzo[b]selenophenes are of current interest
(2) (a) Petrov, M. L.; Petrov, A. A. Usp. Khim. 1987, 56 (2), 267–288.
(b) Zmitrovich, N. I.; Petrov, M. L.; Petrov, A. A. Zh. Org. Khim. 1990,
26 (1), 179–184. (c) Zmitrovich, N. I.; Petrov, M. L. Zh. Org. Khim. 1996,
32 (12), 1870–1874. (d) Terenteva, N. A.; Petrov, M. L.; Potekhin, K. A.;
Galishev, V. A.; Struchkov, Yu. T. Zh. Org. Khim. 1994, 30 (10), 1471–
1477. (e) Ishihara, H.; Yoshimi, M.; Kato, S. Angew. Chem. 1990, 102
(5), 572–573. (f) Murai, T.; Kakami, K.; Hayashi, A.; Komuro, T.;
Takuda, H.; Fujii, M.; Kanda, K.; Kato, S. J. Am. Chem. Soc. 1997, 119
(37), 8592–8597. (g) Murai, T.; Esaka, T.; Kato, S. Bull. Chem. Soc. Jpn.
1998, 71 (5), 1193–1200. (h) Arsenyan, P.; Oberte, K.; Pudova, O.;
Lukevics, E. Chem. Heterocycle Compd. 2002, 38 (12), 1437–1447.
(3) (a) Petrov, M. L; Abramov, M. A.; Dehaen, W.; Toppet, S.
Tetrahedron Lett. 1999, 40 (20), 3903–3904. (b) Petrov, M. L.; Androsov,
D. A.; Abramov, M. A.; Dehaen, W. Russ. J. Org. Chem. 2003, 39 (2),
284–286.
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Takimiya, K.; Ikeda, M.; Kuwabara, H. Org. Lett. 2009, 11 (11),
2473–2475. (b) Rhoden, C. R. B; Zeni, G. Org. Biomol. Chem. 2011, 9
(5), 1301–1313.
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1994, 50 (31), 9315–9324. (b) Murphy, P. J. Product class 7: benzo-
[b]selenophenes. In Science of Synthesis; Thomas, E. J., Ed.; Georg Thieme
Verlag: Stuttgart, New York, 2001; Vol. 10, pp 265À299. (c) Murphy, P. J.
Product class 9: dibenzoselenophenes. In Science of Synthesis; Thomas,
E. J., Ed.; Georg Thieme Verlag: Stuttgart, NY, 2001; Vol. 10, pp 307À323.
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10.1021/ol400547n
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benzo[b]selenophenes from the readily available semicar-
bazones of nitroacetophenones. Moreover, the nature and
position of the substituents on the benzo[b]selenophene
ring make them appropriate for further use as building
blocks for assembling structurally more complex deriva-
tives. For example, the amino group at the C(2) position of
the selenophene ring may be additionaly modified. Mean-
while, the C(3) atom is very susceptible to electrophilic
attack, as it is a terminal atom of the enamine moiety and
allows smooth attachment of electrophiles. The nitro
group on the aryl ring may be reduced to amino, whereas
the halogen atom may be used in a variety of cross-
coupling reactions.
Scheme 1. Base-Promoted Generation of Selenoketens
owing to their potential applications as organic semicon-
ductors for various optoelectronic devices,4 potent biolog-
ical activity, and synthetic utility.5
In order to obtain entry to 1,2,3-selenadiazoles, and
hence selenoketenes, we prepared the novel 4-(2-
chloroaryl)-l,2,3-selenadiazoles 2a, 2b and known8 4-(3-
nitrophenyl)-l,2,3-selenadiazole 2c. To this end, the semi-
carbazones of acetophenones 1aÀ1c were treated with
selenium dioxide in acetic acid to give 2aÀ2c (Scheme 3).
Scheme 2. Possible Cyclization Pathways for ortho-Substituted
Arylselenoketenes
Scheme 3. Synthesis of 4-Aryl-1,2,3-selenadiazoles
The examples of benzo[b]selenophene ring construc-
tion are numerous. One of the most versatile and well-
developed approaches to the benzo[b]selenophenes provided
by electrophilic cyclization of various 1-(1-alkynyl)-
2-(methylseleno)arenes under the action of Br2, NBS, I2,
ICl, PhSeCl, PhSeBr, and Hg(OAc)2 was reported by
Larock.6
However, the syntheses of benzo[b]selenophenes having
other than alkyl and aryl substituents at the C(2) position
of the selenophene ring are few and nonsystematic.7
In particular, the only reported method for the synthe-
sis of 2-aminobenzo[b]selenophene was the reduction of
2-nitrobenzo[b]selenophene. 2-Aminobenzo[b]selenophene
was used for the preparation of selenium-containing
polymethine dyes.7a Beckmann rearrangement of 2-acetyl-3-
phenylbenzo[b]selenophene oxime promoted by polypho-
sphoric acid gave 2-acetylamino-3-phenylbenzo[b]seleno-
phene.7b Another 2-aminobenzo[b]selenophene derivative,
2-benzoyl-amino-3-phenylbenzo[b]selenophene, was synthe-
sized by a reaction of diphenyldiazomethane with benzoyl
isoselenocyanate.7c
We next conducted a base-catalyzed anionic ring open-
ing of selenadiazoles 2aÀ2c to generate alkyneselenolates
3. The intermediacy of 3 was confirmed by trapping its
methyl derivatives 4a and 4b upon addition of iodo-
methane. In turn, the addition of such a weakly nucleo-
philic proton donor as H2O resulted in the immediate
formation of alkyneselenol-selenoketene tautomeric spe-
cies 5 and 6 dimerized to diselenafulvene 7. Whereas the
introduction of more powerful nucleophiles, such as ali-
phatic amines, led to the competitive addition of the
nucleophile to the selenoketene moiety affording enesele-
nolates 8 which, intheabsenceofanactivating nitrogroup,
underwent no subsequent transformation and formed
stable selenoamides 9aÀ9c upon addition of an acid
(Scheme 4).
In the case of eneselenolates 8 having an electron-with-
drawing nitro group on the aromatic ring, the reaction
progressed further. In addition, when the reaction was
carried out under an oxygen-free atmosphere (argon) the
exclusive isolated products were the expected benzo-
[b]selenophenes 12aÀ12d. We noticed that the presence of
oxygen dramatically changed the course of the reaction.
Thus, decomposition of 2b in the medium N,N-diethylamine
under an air atmosphere gave the mixture of products 12a
Herein, we would like to report a convenient two-step
regioselective synthesis of a variety of multifunctional
(6) (a) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem.
2006, 71, 2307–2312. (b) Mehta, S.; Waldo, J. P.; Larock, R. C. J. Org.
Chem. 2009, 74, 1141–1147.
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1977, 11, 1495–1498. (b) Deprets, S.; Kirsch, G. Eur. J. Org. Chem. 2000,
7, 1353–1357. (c) L’abbe, G.; Dekerk, J.-P.; Martens, C.; Toppet, S.
J. Org. Chem. 1980, 45 (22), 4366–4371.
(8) Caplin, A. J. Chem. Soc., Perkin Trans. 1 1974, 30–31.
Org. Lett., Vol. XX, No. XX, XXXX
B

Table 1. Synthesis of Benzo[b]selenophenes
product (yield, %)
Scheme 4. Transformations of Alkyneselenolates in the
Presence of Electrophiles, Good Nucleophiles, and Poor
Nucleophiles
entry
NuH (solvent)
X
SNArCl
SNArH
cond.a
1
2
(CH3CH2)2NH
(CH2)4NH
Cl 12a (54)
Cl 12b (79)
Cl 12c (47)
A
A
A
A
B
C
C
C
C
C
3
(CH2)5NH
4
[(CH2)O(CH2)2]NH Cl 12d (71)
5
(CH3CH2)2NH
(CH3CH2)2NH
(CH(CH3)2NH
(CH2)5NH
Cl 12a (8)
14a (30)
14a (83)
14b (74)
14c (60)
14d (57)
14e (63)
6
Cl
Cl
Cl
7
8
9
[(CH2)O(CH2)2]NH Cl
(CH3CH2)2NH
10
H
a A: argon atmosphere. B: air atmosphere. C: air atmosphere,
KMnO4.
hydrogen toproduceσH-adduct13. Itmay indicatethe rate
of 13formation is higher thanthat of the σCl-adduct 10and
that oxidation of the former with oxygen is also a relatively
fast process.9 The exclusive oxidative nucleophilic substi-
tution of hydrogen (ONSH) took place in the presence of
the stronger oxidant KMnO4. Inthe absenceof the oxidant
the σH-adduct 13 rearranged to the σCl-adduct 10, which
irreversibly transformed to the final substitution product
12 after the departure of chlorine.
The superior regioselectivity of the reaction toward the
SNArH product in the presence of oxidant may be ratio-
nalized considering the possible method of σH-adduct 13
formation depicted in Scheme 6. As it was shown above
(Scheme 4) the base-promoted decomposition of selena-
diazole 2b led to the alkyneselenolate 3 which, on proto-
nation, formed the higly reactive selenoketene species 5.
The intermediate 5 may assumedly exist in two rotational
conformations 5-I and 5-II. In either event, the sequential
nucleophilic attack takes place on the side opposite to the
position of the bulky aryl ring affording conformeric
eneselenolates 8-I and 8-II. Despite the relatively higher
positive charge on the C-atom para to the NO2 group
compared to that of the C-atom ortho to the NO2 group10
the formation of σH-adducts 13 occurs exclucively in the
precence of an oxidant. It may be explained considering
that the selenolate anion is a “soft” and polarizable
(8%) and 14a, (30%). Thereafter, we investigated the influ-
ence of a classical oxidant (KMnO4) on the course of the
reaction. Benzo[b]selenophenes 14aÀ14e were formed selec-
tively under the oxidative conditions (Scheme 5, Table 1).
Scheme 5. Pathways of Eneselenolates Transformation. Synth-
esis of Benzo[b]selenophenes from 4-(3-Nitroaryl)-1,2,3-selena-
diazoles
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Obviously, the reaction proceeded through the fast and
reversible intramolecular addition of highly nucleophilic
eneselenolate species 8 in a position ortho occupied with
Org. Lett., Vol. XX, No. XX, XXXX
C

mation of 13 is the lower steric repulsion between the large
Se-atom and small H-atom in the transition state on the
way from 8-II to 13 compared to that between the Se-atom
and Cl-atom in the transition state on the way from 8-I to
10. Additional stabilization of the σH-adduct 13 may be
achieved through the formation of hydrogen bonding
between the O-atom of the NO2 group and the H-atom
at the sp3 carbon of the σH-adduct 13, which is not the case
for the σCl-adduct 10. Rapid accumulation along with the
high concentration and stability of the σH-adduct 13 due to
the previously discussed factors resulted in a substantial
predominance of 14a (30%, SNArH) over 12a (8%,
SNArCl) product even in the presence of such a moderate
oxidant as atmospheric oxygen. In the presence of a
powerful oxidant such as KMnO4, the formation of 14a
occurs exclusively despite the low solubility of the oxidiz-
ing agent in the reaction medium.
Scheme 6. Formation of σH- and σCl-Adducts upon Addition of
Nucleophile to Selenoketene Moiety
It should be noted that numerous examples of the
nucleophilic substitution of hydrogen (ONHS) in the
reactionsofaromaticandheteroaromaticcompoundswith
carbon,11 nitrogen,12 phosphorus,13 and oxygen14 nucleo-
philes have been well documented and thoroughly inves-
tigated. To our knowledge, we reported the first evidence
of the ONHS process with the participation of a selenium
nucleophile.
In summary, we have developed a new, convenient, and
straightforward approach to benzo[b]selenophenes from
the readily available 4-(nitroaryl)-l,2,3-selenadiazole.
The regioselectivity of the reaction may be easily varied
depending on the presence or absence of the oxidating
agent in the reaction mixture.
nucleophile enabling an orbitally controlled mode of
cyclization. Under the orbital control, the C-atom (ortho
to NO2) accommodating the relatively higher electron
density, compared to the C-atom para to NO2, provides
a better overlap between the HOMO of the nucleophile
and the LUMO of the electrophile favoring the formation
of the σH-adduct 13. Another factor facilitating the for-
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1
with copies of H, 13C NMR and mass spectra. This
material is available free of charge via the Internet at
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The authors declare no competing financial interest.
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