A novel regioselective reaction of styrene with magnesium organoselenolates to afford unsymmetrical selenides catalyzed by CuI and l-proline

Article abstract of DOI:10.1016/j.tetlet.2012.08.046

A novel regioselective reaction of styrene with the prepared magnesium organoselenolates from magnesium, alkyl or aryl bromides, and selenium has been developed in one pot. The reaction catalyzed by CuI and l-proline proceeded in THF, water, and toluene. The scope and limitations of this reaction have been examined. The reaction afforded unsymmetrical selenides containing 12 new compounds in good to high yields.

Full text of DOI:10.1016/j.tetlet.2012.08.046

Tetrahedron Letters 53 (2012) 5688–5690
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel regioselective reaction of styrene with magnesium organoselenolates
to afford unsymmetrical selenides catalyzed by CuI and L-proline
Fei Gao a, Yu Tang a, , Zhi-hao Li a, Feng Pan a, Jun Yang a, Yuan-ming Zhang a,
⇑
⇑
a Department of Chemistry, Jinan University, Guangzhou, Guangdong 510632, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2012
Revised 21 July 2012
Accepted 10 August 2012
Available online 16 August 2012
A novel regioselective reaction of styrene with the prepared magnesium organoselenolates from magne-
sium, alkyl or aryl bromides, and selenium has been developed in one pot. The reaction catalyzed by CuI
and L-proline proceeded in THF, water, and toluene. The scope and limitations of this reaction have been
examined. The reaction afforded unsymmetrical selenides containing 12 new compounds in good to high
yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Selenides
Unsymmetrical selenides
Selenium grignard reagent
Styrene
Regioselective reaction
Organic selenides are attractive and widely prepared as key
intermediates in organic synthesis1 and as bioactive compounds
with application as antioxidants, agents to mediate apoptosis, anti-
tumor, and antiviral.2 The selenium ion formed by reducing ele-
mental selenium with reductants such as NaBH4,3 NaH,4 Na,5 or
organic lithium,6 was employed to prepare symmetrical alkyl sele-
nides. But this traditional method often requires high reaction
temperature, long reaction time, and drastic reaction conditions
in HMPA or NMP which are polar and toxic.7 Recently, an effective
way to synthesize unsymmetrical selenides through the reaction of
organic halides with diphenyl diselenide was reported.8 Catalysts
such as indium,9 copper,10 palladium,11 nickel,12 ruthenium,13 or
CuS/Fe14 are often needed. But the starting material of diphenyl
diselenide should be prepared from phenyl bromide and selenium.
It would be more efficient and economic to synthesize selenides
using organohalides and selenium directly under mild reaction
conditions. Here, we report a new regioselective reaction of styrene
with magnesium aryl or alkyl selenolates prepared from magne-
sium, aryl or alkyl bromides, and selenium to afford unsymmetrical
selenides in good to high yields via three steps as shown in Scheme
1. Although organometallic compounds, such as ethyl bromide,15
organostannanes,16 butyl magnesium chloride,17 and organozinc
reagents,18 have been employed to react with alkenes in the pres-
ence of catalysts, to the best of our knowledge, the regioselective
reaction of alkenes with organomagnesium selenoates has not
been published.
In our efforts to synthesize unsymmetrical selenides with mag-
nesium organoselenolates, the regioselective reaction of styrene
(1 equiv) with PhSeMgBr (1 equiv) was initially studied using var-
ious solvents, catalysts, and ligands (Table 1). Poor yields of
PhCH(CH3)SePh were obtained in THF + DMF or THF + DMSO (Table
1, Entries 1 and 2). The yields were improved to 26%, 30%, and 41%
in solvents of THF + benzene, THF, and THF + toluene (Table 1, En-
tries 3–5), respectively, which revealed toluene as the suitable sol-
vent. The role of toluene is to elevate the reaction temperature.
Further studies indicated that addition of water as a proton source
in the reaction could improve the yield (Table 1, Entries 6–10).
Yield of 61% revealed 5 mL of water was enough under our reaction
conditions (Table 1, Entry 8). To develop the reaction further, we
selected NiCl2 and CuI, the commonly used inexpensive catalysts,
to catalyze the reaction. CuI (Table 1, Entry 11) catalyzed to pro-
duce better yield of 65% than used no catalyst and NiCl2 (Table 1,
Entries 8 and 12). Encouraged by these exciting results, we further
explored the effects of various ligands on the reaction (Table 1, En-
tries 13–21). Phosphorous ligands impeded the reaction (Table 1,
Entries 13–16). It could be found that ligands with nitrogen atom
Se
dry THF
RSeMgBr
RBr + Mg
RMgBr
catalyst
THF + solvent
45 °C
PhCHCH3
SeR
RSeMgBr + PhCH=CH2
⇑
Corresponding authors.
E-mail addresses: tytang@jnu.edu.cn (Y. Tang), tzhangym@jnu.edu.cn (Y. Zhang).
Scheme 1. Synthesis of selenides with magnesium organoselenolate.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.046

F. Gao et al. / Tetrahedron Letters 53 (2012) 5688–5690
5689
Table 1
Table 2
Effects of solvents, water amount, catalysts, and ligands on the yield of
PhCH(CH3)SePh
Synthesis of unsymmetrical selenides
dry THF
45 °C
Se
PhCH=CH2
PhCH(CH3)SeR
RBr+Mg
Entry
1
RSeMgBr
PhCH=CH2
Se
RMgBr
dry THF
CuI; L-proline
H2O; toluene
PhCH(CH3)SePh
PhBr+Mg
PhSeMgBr
PhMgBr
catalyst, solvent
45 °C
RX
Products
Se
Yielda (%)
82
Entry
Solvent
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21a
DMF
Non
Non
Non
Non
Non
Non
Non
Non
Non
Non
CuI
NiCl2
NiCl2 + PPh3
NiCl2 + dppe
CuI + PPh3
CuI + dppe
CuI + bipy
CuI + PMDETA
CuI + TMEDA
9
8
Br
DMSO
benzene
THF
20
30
41
46
57
61
54
48
65
25
0
Toluene
F
Br
F
Se
Toluene + H2O (1 mL)
Toluene + H2O (3 mL)
Toluene + H2O (5 mL)
Toluene + H2O (8 mL)
Toluene + H2O (10 mL)
toluene + H2O (5 mL)
Toluene + H2O (5 mL)
Toluene + H2O (5 mL)
Toluene + H2O (5 mL)
Toluene + H2O (5 mL)
Toluene + H2O (5 mL)
Toluene + H2O (5 mL)
Toluene + H2O (5 mL)
Toluene + H2O (5 mL)
Toluene + H2O (5 mL)
Toluene + H2O (5 mL)
2
3
80
72
Se
Br
10
0
15
37
46
73
65
82
Br
Se
4
65
CuI +
CuI + 2
L
-proline
L-proline
Se
a
PhBr (5 mmol) reacted with magnesium (1.5 equiv) in dry THF (15 mL) for 1 h
at 45 °C. Selenium powder (5 mmol) was added to the reacting mixture in batches.
After reacting for 0.5 h, CuI (15 mol %), -proline (30 mol %), toluene (20 mL), H2O
Br
5
6
7
56
68
57
L
(5 mL), and styrene (5 mmol) were added and kept for 8 h at 85 °C.
b
Isolated yield.
Se
O
O
Br
O
O
had a good effect on the reaction (Table 1, Entries 17–21). Notably,
PhCH(CH3)SePh19 was obtained in high isolated yield of 82% by
employing CuI and L-proline (2 equiv of CuI amount).
Under the optimized conditions (see footnote of Table 1), other
aryl and alkyl halides were examined to explore the scope and lim-
itations of this methodology. Different unsymmetrical selenides
were obtained in good to high yields (Table 2).
Br
Br
Se
Upon analysis of Table 2, it could be verified that 1-bromo-3-
fluorobenzene could produce the corresponding selenide in high
yield of 80% (Table 2, Entry 2). However, in the case of o-bromotol-
uene, p-bromotoluene, 6-bromo-m-xylene, o-bromoanisole, and p-
bromoanisole, the selenides were obtained in fair to good yields of
56–72% (Table 2, Entries 3–7). Compared with bromobenzene (Ta-
ble 2, entry 1), this result indicates that the electron-donating
groups of Me and MeO impede the reaction. Due to steric hin-
drance, o-bromotoluene and o-bromoanisole provided little lower
yields than their para isomers (Table 2, Entries 4 and 7). Selenide
corresponding to 6-bromo-m-xylene was also given in lower yield
than that corresponding to o-bromotoluene due to a stronger elec-
tron donating effect caused by two methyl groups. The other aryl
bromides, 1-bromonaphthalene and 2-bromothiophene afforded
selenides in yields of 67% and 72% respectively (Table 2, Entries 8
and 9), which were close to those of p-bromotoluene and p-bromo-
anisole. As primary bromoalkane, benzyl bromide and n-butyl bro-
mide gave high yields of 77% and 71%, respectively (Table 2, Entries
10 and 11). Another primary bromide, 3-methoxypropyl bromide,
afforded selenide in 61% yield due to the effect of methoxy group
(Table 2, Entry 12). It is noteworthy that sterically hindered 2-bro-
mopropane and bromocyclohexane also provided selenides in good
yields of 68% (Table 2, Entries 13 and 14), which were close to that
of butyl bromide. The more steric hindered 1-phenylethyl bromide
and t-butyl bromide could still result in fair yields of 55% and 51%
(Table 2, Entries 15 and 16), respectively. We tried to determine
ee% values of the prepared selenides with 1H NMR using chiral shift
Se
8
9
67
72
Br
Se
S
S
Br
10
11
12
13
7720a
7120b
62
Se
Br
Se
O
Br
O
Se
Br
Se
68
Se
Br
14
68
(continued on next page)

5690
F. Gao et al. / Tetrahedron Letters 53 (2012) 5688–5690
Table 2 (continued)
Supplementary data
Entry
RX
Products
Yielda (%)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
046.
15
Br
5520c
Se
References and notes
Br
Se
16
51
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could be improved by elevating the reaction temperature with
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Acknowledgments
We are grateful to the Natural Science Foundation of China
Guangdong Province (Grant Nos.039213) and National University
Student Innovation Program (Grant No.101055920 and cx10067)
for supporting this work.