Electronic effect on the regioselectivity in the ring opening of para-substituted phenyloxiranes by acetylides

Article abstract of DOI:10.1016/j.tetlet.2004.10.049

The electronic effect on the regioselectivity in the alkynylation of phenyloxiranes was investigated using three kinds of metal acetylides. BF ₃ mediated lithium acetylide provided either the α- or β-alkynylated products by controlling the effe

Full text of DOI:10.1016/j.tetlet.2004.10.049

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9265–9268
Electronic effect on the regioselectivity in the ring opening of
para-substituted phenyloxiranes by acetylides
Mitsuru Shindo,* Tomoyuki Sugioka and Kozo Shishido
Institute of Health Biosciences, The University of Tokushima Graduate School, Sho-machi 1, Tokushima 770-8505, Japan
Received 13 September 2004; revised 5 October 2004; accepted 12 October 2004
Available online 22 October 2004
Abstract—The electronic effect on the regioselectivity in the alkynylation of phenyloxiranes was investigated using three kinds of
metal acetylides. BF3 mediated lithium acetylide provided either the a- or b-alkynylated products by controlling the effect of the
para-substituents of the phenyloxiranes. LiClO4 mediated lithium acetylide and titanium acetylide, on the other hand, afforded pre-
dominantly the b- and a-products, respectively.
Ó 2004 Elsevier Ltd. All rights reserved.
The alkynylation of oxiranes via ring opening with me-
tal acetylides is an important carbon–carbon forming
reaction.1 However, this useful reaction suffers from
some intrinsic limitations, including low yields and reg-
ioselectivity. Recently, several new methods have been
suggested in order to solve these issues. Lithium acety-
lides in the presence of BF3ÆOEt2 by Yamaguchi and
Hirao,2 titanium acetylides by Krause and Seebach,3 tri-
methylgallium catalyzed lithium acetylides by Matsub-
ara and co-workers,4 and lithium acetylides in the
presence of LiClO4 by Crotti and co-workers5 all afford
better yields than the classical methods. While simple
alkyloxiranes are usually attacked at the less hindered
position, the regioselectivity of aryloxiranes depends
on a balance between the steric and resonance effects
at the benzylic carbon. The procedures described above
differ in their regiochemical control: whereas the ring
opening of phenyloxirane by BF3 or Me3Ga mediated
lithium acetylides provides mixtures of the a- and b-
alkynylated products, the use of titanium acetylides
leads only to the a-alkynylated products, and LiClO4 as-
sisted ring opening by lithium acetylides predominantly
affords b-alkynylated products. The regioselectivity also
seems to depend on a balance between the nucleophilic-
ity of the acetylides and the Lewis acidity of the metal.
Although the metal effect of acetylides has been exten-
sively studied, systematic studies on the sensitivity of
the regioselectivity to the influence of the substituents
on the aromatic ring of the aryloxiranes have not been
reported as far as we know.6 We report herein the elec-
tronic effect on the regioselectivity in the alkynylation of
para-substituted phenyloxiranes.
The above mentioned lithium acetylide with BF3ÆOEt2
(2a), lithium acetylide with LiClO4 (2b) and titanium
acetylides (2c) were used as metal acetylides (Scheme
1). Table 1 shows the results of the alkynylation of
para-substituted phenyloxiranes with 2a.7 The ratios of
Scheme 1.
Keywords: Oxirane; Alkynylation; Regioselectivity; Electronic effect; Lewis acid.
*
Corresponding author. Tel./fax: +81 88 633 7294; e-mail: shindo@ph.tokushima-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.049

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M. Shindo et al. / Tetrahedron Letters 45 (2004) 9265–9268
Table 1. Alkynylation of p-X-phenyloxiranes 1 by lithium acetylide in
the presence of BF3ÆOEt2 (2a)a
It is noteworthy that the reaction of the optically active
p-methoxyphenyloxirane 1 (X = OMe, 93% ee)9 with
lithium trimethylsilylacetylide/BF3ÆOEt2 gave the almost
racemic a-alkynylated product 6 (6% ee), while the reac-
tion of the unsubstituted phenyloxirane 1 (X = H, 90%
ee)9 furnished the a-alkynylated product 710 without
any loss of optical purity, along with the b-alkynylated
one 8 (Scheme 2).
Entry
X
Time
3:4
Yieldb (%)
1
2
3
4
5
6
NO2
CO2Me
Cl
5h
3h
1:>99
28:72
58:42
68:32
93:7
85
79
90
81
85
49
1h
H
Me
10min
10min
10min
OMe
>99:1
a All reactions were carried out with 1:lithium acetylide:BF3ÆOEt2
(1:3:3) at ꢀ78°C in THF.
In contrast, the LiClO4 mediated lithium acetylide 2b,
which is much less reactive than 2a, furnished mainly
the b-alkynylated products 4 (Table 2, entries 1–3),11
even in the reaction of p-methoxyphenyloxirane (1,
X = OMe), along with 27% of the side product 11, which
would be formed by the Meinwald rearrangement,12
followed by addition of the acetylide to the resulting
aldehyde 10. However p-nitrophenyloxirane provided
exclusively 4 in moderate yield along with 12% of 11
(Scheme 3). The titanium acetylide 2c afforded only
the a-alkynylated products 3 (entries 5 and 6),13
although p-nitrophenyloxirane did not give the alkynyl-
ated products, but rather 2-chloro-1-(4-nitrophenyl)eth-
anol (9) was obtained in 30% yield (entry 4).
b Isolated yields.
the a- and b-alkynylated products 4/3 in the reactions of
the phenyloxiranes with electron withdrawing groups
are higher than that of the unsubstituted one (entries
1–4). When a nitro group was the substituent, the b-
alkynylated product 4 was produced exclusively in 5h
(entry 1). On the other hand, substrates with an electron
donating group afforded mainly the a-alkynylated prod-
ucts 3 within 10min (entries 5 and 6), clearly demon-
strating that the electron withdrawing z substituents
retard the reaction. Plots of DDGꢀ (DGb ꢀ DGaz (kJ/
mol)) versus the r+ values from the Hammett equation8
gave a straight line, indicating the dramatic electronic ef-
fect (Fig. 1).
From these results, among the acetylide species, the BF3
mediated lithium acetylide 2a was found to be the most
sensitive to the influence of the electronic effect of the
para-substituents in terms of the a/b selectivity. This
species can afford either the a- or b-alkynylated prod-
ucts by simply changing the para-substituent of phenyl-
oxirane, while the LiClO4–lithium acetylides and
titanium acetylides provide the b- and a-alkynylated
products, respectively.
The mechanism of the regioselectivity depends on a bal-
ance between the nucleophilicity and the Lewis acidity.
Since the lithium acetylide would not be converted into
the boron acetylide at ꢀ78°C,14 BF3, it would function
as a relatively strong Lewis acid, and, thus, efficiently
activate both the Ca–O and the Cb–O bonds of the oxir-
anes (Fig. 2, 14). Since electron donating para-substitu-
ents stabilize the a-carbocation via resonance, the Ca–O
Figure 1. Plots of r+ value versus DDGꢀ for alkynylation of para-
substituted phenyloxiranes with 2a.
Table 2. Alkynylation of p-X-phenyloxiranes 1 by lithium acetylide in the presence of LiClO4 (2b) and by titanium acetylide (2c)
X
2ba
2cb
Entry
Time (h)
3:4
Yieldc (%)
Entry
Time (h)
3:4
Yieldc (%)
NO2
H
1
2
3
10
36
20
1:>99
3:97
25:75
44d
85
35e
4
5
6
48
10
1
—
>99:1
>99:1
0f
78
82
OMe
a Reactions were carried out with 1:lithium acetylide:LiClO4 = 1:3:2 at room temperature in THF.
b Reactions were carried out with 1:titanium acetylide = 1:2 at ꢀ50°C then warmed to room temperature over 2h and stirred for indicated hours.
c Isolated yield.
d The byproduct 11 was isolated in 12% yield.
e The byproduct 11 was isolated in 27% yield.
f The chlorinated product 9 was formed in ca. 30% yield.

M. Shindo et al. / Tetrahedron Letters 45 (2004) 9265–9268
9267
Scheme 2.
temperature, the Meinwald rearrangement competed
with the a-alkynylation.
In contrast, the triisopropoxy titanium acetylide would
have moderate Lewis acidity and very poor nucleophilic-
ity. The generation of the benzylic carbocation by coor-
dination of the oxirane to titanium is crucial for the
reaction of titanium acetylide, and thus p-nitrophenyl-
oxirane did not provide alkynylated products, but gave
the chlorinated product (9) instead.16
Scheme 3.
bond would be more activated and elongated than the
Cb–O bond, and the nucleophile would selectively attack
the a-site (15) via the SN1 like mechanism. However,
since electron withdrawing substituents deactivate the
a-site, b-attack via SN2 is relatively favored, although
the reaction is retarded (13). The linear relationship be-
tween r+ and the regioselectivity indicates that increas-
ing carbocation character of the a-site tends to
increase a-attack. LiClO4 is a much weaker Lewis acid
than BF3, and thus, the oxiranes are only slightly acti-
vated (12).15 However, since this species still has nucleo-
philicity as high as lithium acetylide, only the b-
alkynylated products were obtained due to the steric ef-
fect, and the resonance effect does not contribute to the
selectivity. Since the reaction was carried out at room
In conclusion, we have demonstrated the electronic ef-
fect on the alkynylation of aryloxiranes by metal acety-
lides. The BF3 mediated lithium acetylide is very
sensitive to the effect, and the selectivity is controlled
by the para-substituents. LiClO4 mediated lithium acety-
lide and titanium acetylides are much less sensitive to the
effect in terms of the regioselectivity, and afford the b-
and a-alkynylated products, respectively. This is the first
systematic study on the electronic effect in alkynylation,
which should be useful for organic chemists, since the
products are synthetically very important.
Acknowledgements
This work was partly supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Sci-
ence, Sports, and Culture of Japan.
References and notes
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Figure 2. Activation of oxiranes by Lewis acids.

9268
M. Shindo et al. / Tetrahedron Letters 45 (2004) 9265–9268
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7. A typical procedure: to a solution of phenylacetylene
(306mg, 3.0mmol) in THF (3mL) was added a solution of
butyllithium (3.0mmol, 1.58M in hexane) at ꢀ78°C under
argon, and the mixture was stirred for 1h. BF3ÆOEt2
(0.43mmol, 3mmol) was added, and after 10min, a
solution of 4-nitrophenyloxirane (165mmol, 1.0mmol) in
THF (1mL) was added. After the reaction was stirred for
5h at ꢀ78°C, it was quenched with satd aq NaHCO3. The
mixture was extracted with ethyl acetate, and the organic
layer was dried over MgSO4 and concentrated in vacuo to
give a crude mixture, which was purified by preparative
HPLC (LiChrosorbÒ Si, ethyl acetate/hexane) to afford
227mg (85%) of 4 (X = NO2).
11. A typical procedure: to a solution of phenylacetylene
(306mg, 3.0mmol) in THF (5mL) was added a solution of
butyllithium (3.0mmol, 1.58M in hexane) at 0°C under
argon, and the mixture was stirred for 10min. A solution
of phenyloxirane (120mg, 1.0mmol) and LiClO4 (212mg,
2.0mmol) in THF (1mL) was added. The reaction was
stirred for 36h at room temperature, then diluted with
H2O. The mixture was extracted with ether, and the
organic layer was dried over MgSO4 and concentrated in
vacuo to give a crude mixture, which was purified by
preparative HPLC (LiChrosorbÒ Si, ethyl acetate/hexane)
to afford 188mg (85%) of 4 (X = H).
12. Meinwald, J.; Labana, S. S.; Chadha, M. S. J. Am. Chem.
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13. A typical procedure: to a solution of phenylacetylene
(204mg, 2.0mmol) in THF (3.5mL) was added a solution
of butyllithium (2.0mmol, 1.58M in hexane) at 0°C under
argon, and the mixture was stirred for 10min. The solvents
were removed in vacuo, and 4.5mL of THF was added. A
solution of triisopropyloxytitanium chloride (2.0mmol,
1M in hexane) was added at ꢀ50°C. After 10min, a
solution of p-methoxyphenyloxirane (150mg, 1.0mmol) in
THF (1.5mL) was added to the solution at ꢀ50°C,
and the mixture was allowed to stand at room tempera-
ture over 2h. The reaction was stirred for 1h, and 1M
HCl was added. The mixture was extracted with ether,
and the organic layer was dried over MgSO4 and
concentrated in vacuo to give a crude mixture, which
was purified with preparative HPLC (LiChrosorbÒ Si,
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`
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9010. The enantiomeric excess was determined by HPLC
analysis on a Daicel CHIRAL PAK AD-H column.
10. The enantiomeric excess was determined by HPLC anal-
ysis on a Daicel CHIRAL PAK AD-H column. The
absolute configuration was confirmed by comparison of
the sign of the specific rotation with the literature value of
17 derived from 3. (R)-17: Nagao, Y.; Kumagai, T.;
Yamada, S.; Fujita, E.; Inoue, Y.; Nagase, Y.; Aoyagi, S.;
Abe, T. J. Chem. Soc., Perkin Trans. 1 1985, 2361–2367.
ethyl acetate/hexane) to afford 206mg (82%) of
(X = OMe).
3
14. Yamaguchi, M.; Nobayashi, Y.; Hirao, I. Tetrahedron
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15. Without Lewis acids, the alkynylation does not proceed.
See Ref. 5.
16. According to Ref. 3, when optically pure phenyloxirane is
used, the product is partially racemized. This supports
the SN1 like reaction involving a carbocation inter-
mediate.