preparation of chalcogenophene derivatives.12 The ability
of the selenium atom to stabilize both electron-deficient
and electron-rich centers is crucial for the high regioselec-
tivity observed in chalcogen cyclizations.13 It has been
recognized that an endo-cyclization is generally preferred
over an exo-ring closure in systems having the chalcogen
atom at the 5- or 6-position relative to the C(sp) or C(sp2)
center.14 For example, benzyl 3-butynyl sulfide, upon treat-
ment with an electrophilic source, exclusively gave the
thiophene derivatives via 5-endo-dig iodocyclization.15
However, despite many reports about such reactions, the
electrophilic exo-dig cyclization of organochalcogen sub-
strates bearing an alkyne partner has been scarcely reported
and the regioselectivity control has not been well-documented.
Here, as part of our study of the application of organochalco-
gens as substrates in cyclization reactions,16 we would like to
report a detailed study of the exo-dig electrophilic cycliza-
tion of the 1-butylseleno-4-alkynes 1, instead of typical endo-
dig cyclization (Scheme 1).
As can be seen, this protocol is rather general, as it is
applicable for the reactions of a variety of 1-butylseleno-4-
alkynes bearing an aryl group as well as a heteroaryl,
propargyl alcohol, an alkyl, and a heteroatom directly
bonded to the triple bond. There are some important
features of these results. For example, the reactions were
efficient with a variety of aryl bearing neutral and both
electron-rich and electron-deficient groups giving the
cyclized products in high yields (Table 1, entries 1À7).
The bulkiness of the ortho-methyl and naphthyl moieties
had no effect on the reactivity, affording products 2b and
2h in 90 and 85% yields, respectively (Table 1, entries 2 and 8).
When 1-butylseleno-4-alkynes 1b, 1d, and 1e were used
as substrates, the exo-dig products 2b, 2d, and 2e were
obtained in a ratio of 5.5:1, 4.3:1, and 3.2:1, repectively,
favoring the E-isomer.18 It is also important to point out
that 1-butylseleno-4-alkynes 1e with a methoxyl group at
the ortho position of an aryl group would give a compe-
titive cyclization when a cyclizing agent, such as I2, is used.
Therefore, we were pleased to find that the cyclization with
1e smoothly afforded the corresponding tetrahydroseleno-
phene 2e via a Se-cyclization, in the complete absence of
furan derivatives. We conclude that our result is in com-
plete agreement with the study reported by Larock, who
showed that if the substrate has selenium and oxygen
competing, the Se-cyclization is predominant.10 Further-
more, we found that the effect of changing aryl to alkyl
or propargyl alcohol substituents directly bonded to the
triple bond of 1-butylseleno-4-alkynes was not significant,
although the propargyl alcohol susbtituent gave the prod-
ucts in moderated yields (Table 2, entries 10À11). We
were delighted to observe that heteroatoms, such as sele-
nium and silicon, could be added directly to the triple bond
of 1-butylseleno-4-alkynes, giving the corresponding vinyl
selenides 2l and vinylsilane 2m in good yields (Table 1,
entries 12 and 13). Another competitive reaction, using
hydroxyl and benzyloxy groups at the homopropargyl
position of 1-butylseleno-4-alkynes, was also perfomed.
Similarly to Table 1, entry 5, the sole product isolated was
the selenophene derivative, obtained by the nucleophilic
attack of the selenium atom at the triple bond (Table 1,
entries 14 and 15). We then investigated whether terminal
1-butylseleno-4-alkyne might be used as a susbtrate to this
cyclization. Unfortunately, all attempts at the cyclization
reaction of 1p led to its decomposition even when we
changed the reaction parameters (Table 1, entry 16). Based
on the electrophilic cyclization mechanism we believe that
the molecular iodine is responsible to generate a cationic
iodonium ion a, via coordination of the carbonÀcarbon
triple bond to the electrophilic species. An intramolecular
Scheme 1
In our initial screening experiments, 1-butylseleno-5-
phenyl-pent-4-yne 1a17 and I2 (1.1 equiv) were selected as
the reactant/reagent standard to determine the optimal
reaction conditions. Usually the solvents play an impor-
tant role for a successful electrophilic cyclization. To select
the most efficient solvent, CH2Cl2, MeOH, CH3CN, THF,
and toluene were tested at room temperature. Dichloro-
methane was the best among the solvents tested, and
tetrahydroselenophene derivative 2a was isolated in 93%
yield. The solvents CH3CN and THF also showed good
behavior under the same conditions (87 and 90% yield,
respectively), whereas MeOH and toluene gave lower
yields (both 76%) of the target product. Afterwards, the
optimized conditions were established using the combina-
tion of 1 equiv of selenide 1a and 1.1 equiv of I2, in CH2Cl2
as solvent at room temperature for 4 h (Scheme 2).
Scheme 2
(15) Flynn, B. L.; Flynn, G. P.; Hamel, E.; Jung, M. K. Bioorg. Med.
Chem. Lett. 2001, 11, 2341.
(16) (a) Roehrs, J. A.; Pistoia, R. P.; Back, D. F.; Zeni, G. Adv. Synth.
Catal. 2012, 354, 1791. (b) Stein, A. L.; Bilheri, F. N.; da Rocha, J. T.;
Back, D. F.; Zeni, G. Chem.;Eur. J. 2012, 18, 10602.
(17) For preparation of compounds 1aÀp, see the Supporting
Information.
(12) (a) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem.
ꢀ
2006, 71, 2307. (b) Schumacher, R. F.; Rosario, A. R.; Souza, A. C. G.;
Menezes, P. H.; Zeni, G. Org. Lett. 2010, 12, 1952.
~
(13) Perin, G.; Lenardao, E. J.; Jacob, R. G.; Panatieri, R. B. Chem.
Rev. 2009, 109, 1277.
(14) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513.
(18) The E/Z stereochemistry of 2b was determined by conversion to
the hydrogen derivative through I/Li exchange reactions via reaction
with n-BuLi in hexane. The stereochemistry was assigned via analysis of
the J-coupling constant.
B
Org. Lett., Vol. XX, No. XX, XXXX
Gai, Rafaela M.
