Regioselective electrophilic cyclization of o-ethynylbenzyl phenyl selenides to (Z)-1-methylidene-2-phenyl-1,3-dihydro-1H-benzo[c]selenophenium salts

Article abstract of DOI:10.1016/j.tetlet.2010.07.160

o-Ethynylbenzyl phenyl selenides regioselectively reacted with trifluoromethanesulfonic acid to afford the (Z)-1-methylidene-2-phenyl-1,3- dihydro-1H-benzo[c]selenophenium salts as the major products during the 5-exo-dig mode cyclization in good yields together with minor E isomers. The structure of the major (Z)-selenophenium salt was established by the single crystal X-ray crystallographic analysis using a tert-butyl derivative.

Full text of DOI:10.1016/j.tetlet.2010.07.160

Tetrahedron Letters 51 (2010) 5395–5398
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Tetrahedron Letters
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Regioselective electrophilic cyclization of o-ethynylbenzyl phenyl selenides
to (Z)-1-methylidene-2-phenyl-1,3-dihydro-1H-benzo[c]selenophenium salts q
Haruki Sashida a, , Shoko Nakabayashi a, Hirokazu Suzuki a, Mamoru Kaname a, Mao Minoura b
⇑
a Faculty of Pharmaceutical Sciences, Hokuriku University, Kanagawa-machi, Kanazawa 920-1181, Japan
b Department of Chemistry, School of Science, Kitasato University, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa 252-0373, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
o-Ethynylbenzyl phenyl selenides regioselectively reacted with trifluoromethanesulfonic acid to afford
the (Z)-1-methylidene-2-phenyl-1,3-dihydro-1H-benzo[c]selenophenium salts as the major products
during the 5-exo-dig mode cyclization in good yields together with minor E isomers. The structure of
the major (Z)-selenophenium salt was established by the single crystal X-ray crystallographic analysis
using a tert-butyl derivative.
Received 21 June 2010
Revised 23 July 2010
Accepted 29 July 2010
Available online 4 August 2010
Ó 2010 Published by Elsevier Ltd.
The electrophilic intramolecular cyclization of disubstituted
acetylenic compounds has been extremely effective for the synthe-
sis of a wide variety of five-membered nitrogen-,2 oxygen-3–5, or
sulfur-containing5–8 heterocycles, because of their common occur-
rence in nature and their significant biological activity including
pharmaceutical use. Benzyl o-ethynylphenyl sulfides react with io-
dine to produce 3-iodobenzo[b]thiophenes8a during the 5-endo-dig
iodocyclization by removing a benzyl moiety. Larock and Yue7 also
reported the synthesis of benzo[b]thiophenes having an electro-
philic substitution at the C-3 position by a related process involv-
ing the electrocyclization of the o-1-ethynylphenyl methyl
sulfides. Similarly, the electrophilic intramolecular cyclization of
the methyl phenyl selenides with an ethynyl group on the benzene
ring has been reported; the 2,3-disubstituted benzo[b]selenoph-
enes were obtained.9 Kitamura and co-workers5,6 have described
that the intramolecular addition of o-1-ethynylphenyl phenyl sul-
fides with electrophiles such as perchloric acid, tetrafluoroboric
acid, bromine, and benzenesulfenyl chloride produced the 1-
phenyl-1-benzo[b]thiophenium salts. A variety of 3-substituted
R
R
R
6-endo-dig
SeH
NaHSe
Se
Br
1
2
3
Scheme 1.
works12,13 in which we succeeded in preparing the various types of
the chalcogen-containing heterocycles based on the intramolecular
ring-closure reaction of the chalcogenols into an acetylene moiety,
we now report that the electrophilic cyclization using the o-ethy-
nylbenzyl phenyl selenides, in which the hydrogen atom of the
benzyl selenol is replaced by a phenyl group, and trifluorometh-
anesulfonic acid (TfOH) provides a highly regioselective 5-exo-dig
mode method for the preparation of the 1-methylidene-2-phe-
nyl-1,3-dihydro-1H-benzo[c]-selenophenium salts.
The key starting materials, the o-ethynylbenzyl methyl sele-
nides 5A, benzyl o-ethynylbenzyl selenides 5B, and o-ethynylben-
zyl phenyl selenides 5C, were readily synthesized by the coupling
reaction of the benzyl bromides 111 with the corresponding lithium
selenolate 4A–C, which were freshly generated from elemental
selenium and the alkyl or phenyllithium in dry THF in good yields,
respectively.
The reaction of the methyl selenide 5Aa with 1.2 equiv of TfOH
in dry CH2Cl2 at 0 °C gave a complex mixture (Table 1, entry 1). No
characterized products were also obtained by the reaction of the
benzyl selenide 5Ba with TfOH (entry 2). However, the treatment
of the o-ethynylbenzyl phenyl selenides 5C with 1.2 equiv of TfOH
under the same conditions resulted in the regio- and stereoselec-
tive 5-exo-dig mode cyclization to give the (Z)-1-methylidene-2-
phenyl-1,3-dihydro-1H-benzo[c]selenophenium trifluoromethane-
sulfonates (triflates) (Z)-6C as major products, together with the E
isocoumarins and
a-pyrones, six-membered heterocycles, have
been obtained via the iodocyclization of the carboxylic acid
derivatives.10
On the other hand, we have previously succeeded in the prepa-
rations of the 1H-isoselenochromenes 3, six-membered heterocy-
cles with a bivalent selenium atom, by the successive 6-endo-dig
intramolecular cyclization of the o-ethynylbenzyl selenols 2, which
are easily prepared from the benzyl bromides 1 and NaHSe
(Scheme 1).11 The isoselenochromenes 3 were transformed into
the 2-benzoselenopyrylium salts, six-membered aromatic hetero-
cycles containing a selenium cation. As an extension of our ongoing
q
See Ref. 1.
⇑
Corresponding author. Tel.: +81 76 229 6211; fax: +81 76 229 2781.
E-mail address: h-sashida@hokuriku-u.ac.jp (H. Sashida).
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.07.160

5396
H. Sashida et al. / Tetrahedron Letters 51 (2010) 5395–5398
R2
R2
R2
R2
R1SeLi
TfOH
4
Se R1
Se R1
+
+
+
Se R1
or BF4H
Br
X-
X-
1
5
Z
E
: R1 = Me
A
a: R2 = t-Bu
6
: X = TfO
7: X = BF4 B: R1 = CH2Ph b: R2 = H
C: R1 = Ph
c: R2 = Me
d: R2 = n-Bu
e: R2 = n-Oct
f : R2 = Ph
R
g: R2 = p-MeC6H4
h: R2 = p-MeOC6H4
i: R2 = p-CF3C6H4
Te Ph
8
Scheme 2.
Table 1
the (Z)-benzoselenophenium salts (Z)-6Cg, (Z)-6Ch, and (Z)-6Ci in
73–92% yields in spite of the nature of the impressive electronic ef-
fect on the benzene ring (entries 9–12). This distinction between
an alkyl group and an aryl group at the ethynyl moiety with re-
spect to the selectivity ratio of the geometry of the olefin is not to-
tally understood. However, the significant differences of success or
failure in these electrophilic cyclizations of the o-ethynylbenzyl
selenides 5A–C with TfOH according to whether or not the Se-sub-
stituent is a phenyl group may be explained by the difference of
the Se-C bond energy dependent on the bond length. The Se–
Csp2 distance in the Se-phenyl group for 5C is clearly shorter than
that of the Se–Csp3 in the Se-methyl and -benzyl groups for 5A and
5B, respectively. Thus, the expected Se-methyl 6A and Se-benzyl
products 6B were probably decomposed because of their thermal
instability under the reaction conditions. The Te–Csp2 distance in
the Te-phenyl group for 8 is also longer than that of the corre-
sponding selenium compound.
1-Methylidene-2-phenyl-1,3-dihydro-1H-benzo[c]selenophenium salts 6, 7
Entry
R1
R2
Acid
Product
Yielda (%)
Ratio Z/Eb
1
2
3
4
5
6
7
8
Me
CH2Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
t-Bu
t-Bu
t-Bu
t-Bu
H
Me
n-Bu
n-Oct
Ph
TfOH
TfOH
TfOH
BF4H
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
6Aa
6Ba
6Ca
7Ca
6Cb
6Cc
6Cd
6Ce
6Cf
0c
—
—
0c
82
76
77
76
71
82
78
92
78
73
4:1
5:3
—
4:1
4:1
4:1
1:0
1:0
1:0
1:0
9
10
11
12
Ph
Ph
Ph
p-MeC6H4
p-MeOC6H4
p-CF3C6H4
6Cg
6Ch
6Ci
a
b
c
Isolated yield.
Determined by 1H NMR spectra.
Decomposed.
Therefore, no desired electrophilic cyclization telluronium salts
from 8 were obtained; the starting material was gradually decom-
posed. When other electrophiles such as HClO4, Br2, I2, and PhSeCl
instead of TfOH were allowed to react with the benzyl phenyl sel-
enides 5C, these cyclization reactions were unsuccessful, and the
starting material was recovered.
derivatives (E)-6C14 as shown in Scheme 2. These results are sum-
marized in Table 1. The reaction of o-(3,3-dimethylbutynyl)benzyl
phenyl selenide 5Ca with TfOH afforded the (Z)-1-(2,2-dimethyl-
propylidene)-2-phenyl-1,3-dihydro-1H-benzoselenophenium tri-
flate (Z)-6Ca and E derivative (E)-6Ca in 82% yield as a mixture of
diastereomers; the former is the major product (entry 3). When
tetrafloroboric acid (HBF4) was used instead of TfOH as the electro-
phile, the 5-exo-dig mode cyclization reaction proceeded to give
the corresponding (Z)-benzoselenophenium tetrafluoroborate
(Z)-7Ca as the major product together with the E minor product
(E)-7Ca in 76% yield (entry 4). The treatment of the unsubstituted
substrate 5Cb with TfOH furnished the 1-methylideneselenonium
salt 6Cb in 77% yield as the sole crystalline product (entry 5).
The o-ethynylbenzyl pheny selenides 5Cc–e having an alkyl group
at the sp-carbon atom of the ethynyl moiety cyclized to produce
the diastereomeric mixtures of the (Z)-1-methylidene-1H-benz-
oselenophenium salts (Z)-6Cc, (Z)-6Cd, and (Z)-6Ce and (E)-iso-
mers (E)-6Cc, (E)-6Cd, and (E)-6Ce by the reaction with TfOH
under the same conditions in 76%, 71%, and 82% yields,
respectively; the formers were also the major products in these
cases (entries 6–8). On the contrary, the phenyl o-(2-phenyleth-
ynyl)benzyl selenides 5Cf regio- and stereoselectively reacted with
TfOH to produce the single (Z)-1-benzylidene-2-phenyl-1,3-
dihydro-1H-benzo[c]selenophenium salt (Z)-6Cf in 78% yield; the
E isomer (E)-6Cf was not obtained. Similarly, the reaction of the
In this electrophilic cyclization, there are two possible types of
ring closure modes: 5-exo mode (path a) and 6-endo mode (path
b), but no 6-endo mode cyclization products 913b were actually
obtained as shown in Scheme 3. In order to explain this remark-
able result in the cyclization mode of the phenyl selenides 5C,
the HOMO coefficients of the C1 and C2 positions of the triple
bond have been calculated by the frontier orbitals theory using
the GAUSSIAN 03 (B3LYP/STO-3G) and are listed in Table 2. As can
be seen from Table 2, the HOMO electron density values of the
C2 position are higher than that of the C1 position for all substit-
uents at the triple bond. It is evident that the protonation of the
C2 position is favored than that of the C1 position generating
the cationic intermediate 10. Thus, the five-membered product
6C was formed through the attack of the lone pair on the sele-
nium atom (path a).
Furthermore, the calculated Seꢀ ꢀ ꢀC1 distance of 1.96 Å for the
intermediate 10 is much shorter than that for 11 (2.97 Å); the for-
mer indicates the approximate value of the normal Se–Csp3 bond
(2.12 Å). The results of the experiments are in good agreement
with the calculation values.
The structures of these benzoselenophenium salts 6, 7 were elu-
cidated from their 1H and 13C NMR spectra and elemental analyses
and also from single crystal X-ray studies15 in the case of the (Z)-
1-(2,2-dimethyl-propylidene)-2-phenyl-1,3-dihydro-1H-benzo[c]
selenides 5Cg–i having
a functional group, such as methyl,
methoxy, and trifluoromethyl, at the p-position of the phenyl
group, also regio- and stereoselectively proceeded to afford only

H. Sashida et al. / Tetrahedron Letters 51 (2010) 5395–5398
5397
R2
H
R2
H+
Se R1
+
R2
Se Ph
C2
C1
path a
6C
10
Se Ph
5C
H+
H
R2
R2
path b
+
Se Ph
Se Ph
11
9
Scheme 3.
Table 2
methylidene-2-phenyl-1,3-dihydro-1H-benzo[c]selenophenium
salts at room temperature. Further reactions and applications are
now in progress to extend the case of the methodology for the
preparation of more complex system structures and sulfur analogs.
Compd
R2
HOMO electron density
C1
C2
5Ca
5Cb
5Cc
5Cd
5Ce
5Cf
5Cg
5Ch
5Ci
t-Bu
H
Me
n-Bu
n-Oct
Ph
p-MeC6H4
p-MeOC6H4
p-CF3C6H4
0.0271
0.0169
0.0248
0.0257
0.0231
0.0265
0.0280
0.0506
0.0229
0.0405
0.0192
0.0357
0.0427
0.0422
0.0413
0.0422
0.0574
0.0387
Acknowledgments
A part of this work was supported by a Grant-in-Aid for Scien-
tific Research from The Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan (No. 19590022). The authors wish to
thank Miss Yohko Atoh (Hokuriku University) for her technical
assistance.
References and notes
1. This Letter constitutes Part. 32 in the ‘Studies on Tellurium-Containing
Heterocycles’, Part. 31: Sashida, H.; Chao, P.; Kaname, M.; Minoura, M.
Synthesis, in press, doi:10.1055/s-0030-1258171. Art ID F07110SS.
2. Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2003,
42, 2406–2409.
3. Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett 1999, 1432–1434.
4. Arcadi, A.; Cacchi, S.; Giuseppe, S. D.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4,
2409–2412.
5. Kitamura, T.; Takeuchi, T.; Kawasato, H.; Kobayashi, S.; Taniguchi, H.
Tetrahedron Lett. 1989, 30, 7445–7446.
6. Kitamura, T.; Takeuchi, T.; Miyaji, M.; Kawasato, H.; Taniguchi, H. J. Chem. Soc.,
Perkin Trans. 1 1994, 1907–1911.
7. (a) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011–6013; (b) Yue, D.;
Larock, R. C. J. Org. Chem. 2002, 67, 1905–1909.
8. (a) Flynn, B.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651–654; (b)
Matsnev, A.; Noritake, S.; Nomura, Y.; Tokunaga, E.; Nakamura, S.; Shibata, N.
Angew. Chem., Int. Ed. 2010, 49, 572–576.
9. Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006, 71, 2307–2312.
10. Yao, T.; Larock, R. C. Tetrahedron Lett. 2002, 43, 7401–7404.
11. (a) Sashida, H.; Ohyanagi, K. J. Chem. Soc., Perkin Trans. 1 1998, 2123–2124; (b)
Sashida, H.; Ohyanagi Heterocycles 1999, 51, 17–20; (c) Sashida, H.; Ohyanagi,
K.; Minoura, M.; Akiba, K.-y. J. Chem. Soc., Perkin Trans. 1 2002, 606–612.
12. Reviews: (a) Sashida, H. Rev. Heteroatom Chem. 2000, 22, 59–78; (b) Sashida, H.
J. Synth. Org. Chem. Jpn. 2001, 59, 355–362; (c) Sashida, H. Mini-Rev. Org. Chem.
2007, 4, 105–114; (d) Sashida, H.; Minoura, M. J. Synth. Org. Chem. Jpn. 2009, 67,
714–723.
13. Recent works: (a) Sashida, H.; Nakayama, A.; Kaname, M. Synthesis 2008,
3229–3236; (b) Sashida, H.; Nakabayashi, S.; Kaname, M.; Minoura, M.
Heterocycles 2010, 80, 1339–1352; (c) Sashida, H.; Satoh, H.; Ohyanagi, K.;
Kaname, M. Molecules 2010, 15, 1466–1472; (d) Sashida, H.; Kaname, M.;
Ohyanagi, K. Heterocycles, in press, doi:10.3987/COM-10-S(E)15.; (e)
Sashida, H.; Kaname, M.; Nakayama, A.; Suzuki, H.; Minoura, M.
Tetrahedron 2010, 66, 5149–5157.
Figure 1. An ORTEP drawing of (Z)-6Ca with thermal ellipsoid plot (50% probabil-
ity). Selected bond lengths (Å) and angles (°); Se1–C1 1.941(2), Se1–C9 1.953(2),
Se1–C8 1.957(2), C1–Se1–C9 98.68(9), C1–Se1–C8 89.64(8), C9–Se1–C8 97.14(9).
14. A typical procedure for electrophilic cyclization of o-ethynylbenzyl phenyl
selenide 5Ca with TfOH is as follows:
A
mixture of o-
selenophenium salt (Z)-6Ca (Fig. 1). In the crystal, the cationic
selenium center of (Z)-6Ca is weakly coordinated by oxygen atoms
of triflate anions, the distances from Se to O atoms are 2.967 and
3.047 Å, respectively.
In conclusion, we have shown that the employment of the o-
ethynylbenzyl phenyl selenides in the 5-exo-dig electrophilic cycli-
zation reaction can provide the regioselective production of 1-
ethynylbenzylphenylselenide (328 mg, 1 mmol) and TfOH (180 mg,
1
1.2 mmol) in dry CH2Cl2 (5 mL) was stirred at room temperature for 12–15 h
under argon atmosphere. Ether (50 mL) was added to the mixture, and then the
resulting residual solid was triturated, collected by filtration, and washed with
ether. The crude solid was recrystallized from chloroform–ether to give a
mixture of diastereomers in 82% yield. The Z and E salts could be separated by
recrystallization from CHCl3–hexane and are stable under air at ambient
temperature.

5398
Major
H. Sashida et al. / Tetrahedron Letters 51 (2010) 5395–5398
product:
(Z)-1-Methylidene-2-phenyl-1,3-dihydro-1H-benzo[c]
Diffraction data were collected on
equipped with graphite monochromated MoKa radiation source
(l = 0.71073 Å). The structures were solved by direct methods (SHELXS-97),16
and refined by full-matrix least-square methods on F2 for all reflections (SHELXL
a Bruker Apex-II CCD diffractometer
selenophenium triflate (Z)-6Ca, colorless prisms, mp 155–156 °C. 1H NMR
(CDCl3) d: 1.26 (9H, s, t-Bu), 4.74 and 5.54 (each 1H, d, J = 16.0 Hz, 3-H2), 7.09
(1H, s, 10-H), 7.39–7.72 (9H, m, Ph-H). 13C NMR (CDCl3) d: 29.8 (q), 36.1 (s), 51.8 (t),
120.7 (qF), 122.9 (d), 127.3 (d), 128.9 (s), 129.2 (s), 129.2 (d), 129.4 (d), 130.9 (d),
131.3(d),133.1 (d), 134.2(s), 137.7(s),148.4(d).IR(KBr)(cmꢁ1):1259, 1222, 1169
(SO3). Anal. Calcd for C20H21O3F3SSe: C, 50.32; H, 4.43. Found: C, 50.29; H, 4.42.
a
-
97)17 with all non-hydrogen atoms anisotropic and all hydrogen atoms
isotropic. For (Z)-6Ca, the structure analysis is based on 4628 observed
reflections with I > 2.00 s(I) and 260 variable parameters; colorless prisms,
196 K, monoclinic, space group P21/n, a = 12.386(12) Å, b = 8.570(5) Å,
c = 19.326(13) Å, b = 98.560(3)°, V = 2029(3) Å3, Z = 4, R = 0.0292, Rw = 0.0698,
GOF = 1.040. CCDC-(Z)-6Ca for (Z)-6Ca contains the supplementary
crystallographic data for this Letter. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/products/csd/request/.
Minor
product:
(E)-1-Methylidene-2-phenyl-1,3-dihydro-1H-benzo[c]-
selenophenium triflate (E)-6Ca, colorless prisms, mp 142–143 °C. 1H NMR
(CDCl3) d: 1.41 (9H, s, t-Bu), 4.68 and 5.53 (each 1H, d, J = 15.8 Hz, 3-H2), 6.84
(1H, s, 10-H), 7.34–7.89 (9H, m, Ph-H). 13C NMR (CDCl3) d: 29.7 (q), 36.1 (s), 49.1 (t),
120.7 (qF), 128.1 (s), 128.2 (d), 128.6 (d), 128.8 (d), 129.0 (d), 130.7 (d), 130.9 (d),
132.7 (d), 134.36 (s), 134.43 (s), 139.2 (s), 155.7 (d).
IR (KBr) (cmꢁ1):1281, 1275, 1155(SO3). Anal. Calcd for C20H21O3F3SSe:C, 50.32;H,
4.43. Found: C, 50.26; H, 4.46.
16. Sheldrick, G. M. SHELXS-97, Program for Crystal Structure Solution, Universität
Göttingen, 1997.
15. Single crystals of (Z)-6Ca were obtained from solutions of n-hexane/
dichloromethane after slow evaporation of the solvent at room temperature.
17. Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Refinement,
Universität Göttingen, 1997.