Unprecedented elimination of conjugated phenylthioether groups by low-valent titanocene

Article abstract of DOI:10.1055/s-0030-1259009

The first thioether elimination reaction utilizing a low-valent titanocene has been discovered. This reaction occurs under mild conditions and affords stereospecifically a variety of dienes and styrenes. Our data suggest that this new reaction involves an

Full text of DOI:10.1055/s-0030-1259009

2928
LETTER
Unprecedented Elimination of Conjugated Phenylthioether Groups by
Low-Valent Titanocene
Elimination of
Coi
g
P
henylthio
e
ethe
r
Group
l
s
by
L
ow-V
a
R
lent
T
itanocene ibeiro,* Ludivine Fetzer, Stéphane Streiff, Laurent Désaubry
Laboratory of Therapeutic Innovation (UMR 7200), Université de Strasbourg and CNRS, 74 Route du Rhin,
BP 24, 67401 Illkirch Cedex, France
Fax +33(3)68854310; E-mail: ribeiro@chimie.u-strasbg.fr
Received 26 August 2010
This paper is amicably dedicated to Professor Carmen Nájera on the occasion of her 60th birthday
ethers in organic synthesis,3 we observed an unexpected
elimination of the phenylsulfide group of 1 to give ste-
reospecifically the alkene 2 in 77% yield (Scheme 1),
which led to the discovery of an unprecedented elimina-
Abstract: The first thioether elimination reaction utilizing a low-
valent titanocene has been discovered. This reaction occurs under
mild conditions and affords stereospecifically a variety of dienes
and styrenes. Our data suggest that this new reaction involves an in-
termediate of dimerization of titanocene as the reactant responsible tion of phenylthioethers by a low-valent titanocene spe-
for this elimination.
cies.
Key words: thioethers, titanocene, alkenes, allyl complexes, elimi-
nation
The optimal elimination conditions were obtained after
the solution of the low-valent titanocene 3 (2 equiv) was
left at room temperature for 5 minutes and chilled again at
–78 °C prior to the addition of thioether 1 (pathway A,
A major breakthrough in the field of titanium chemistry
came from Whitesides et al. who showed that a ti-
tanocene(II) species can be synthesized by addition of n-
BuLi to Cp2TiCl2.1 This convenient method opened the
door to the generation of allyltitanocenes from various al-
lylic substrates, including allylthioethers, by Takeda et
al.2 During the course of our study on the use of allylthio-
Scheme 2). Indeed, if the solution of 3 was kept at –78 °C
before the addition of the thioether 1, the protonated prod-
uct 4 was obtained as described by Takeda (pathway B,
Scheme 2).2 If the solution of 3 was left for one hour at
room temperature, there was not reaction after addition of
1 at –78 °C (pathway C, Scheme 2). This lack of reactivity
can be explained by the instability of the solution of 3 at
Cp2TiCl2 (2 equiv)
n-BuLi (4 equiv)
THF
77%
SPh
1
2
Scheme 1 Unexpected synthesis of the triene 2
H
Ti
1, –78 °C to r.t.
Ti
H
SPh
5
1
2
pathway C
1 h, r.t.
H
n-BuLi (2 equiv)
THF, –78 °C
pathway A
TiCp2
TiCp
Cp2TiCl2
[Cp2Ti] (II)
1) 5 min at r.t.
2) 1, –78 °C
3
6
pathway B 1, –78 °C to r.t.
4
Ti
SPh
Scheme 2 Proposed mechanistic pathways for the reaction of thioether 1 with species generated from Cp2Ti(II) 3 at different temperatures
SYNLETT 2010, No. 19, pp 2928–2930
x
x
.x
x
.2
0
1
0
Advanced online publication: 14.10.2010
DOI: 10.1055/s-0030-1259009; Art ID: G26110ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Elimination of Conjugated Phenylthioether Groups by Low-Valent Titanocene
2929
room temperature, which dimerized to give the inactive
fulvalene 5.4
O
H
Although we have no direct evidence for the mechanistic
pathway, two mechanisms can account for the origin of
this reactivity and stereoselectivity (Scheme 3). In 2001,
Harrod et al. had demonstrated that the species 6 was an
intermediate in the rearrangement of 3 to the unreactive
fulvalene 5.5 The involvement of 6 is suspected and may
corroborate why two equivalents of dichlorotitanocene
are required for this reaction. Indeed, 6 may coordinate to
the thiophenyl group and induce a b-elimination involv-
ing the titanocene hydride (mechanism 1, Scheme 3). An-
other pathway may invoke the oxidative addition of 6 to
the thioether moiety, followed by a b-elimination (mech-
anism 2, Scheme 3). The trans stereoselectivity may arise
from the steric hindrance between R1 and R2 groups dur-
ing the transition state of the reaction.
TiCp2
TiCp
R1
S
R2
H
6
mechanism 1
R2
+
H
Cp
R1
Ti
Ti
Cp
Cp
S
mechanism 2 oxidative addition
β-elimination
R1
Ti
R2
H
R2
β-elimination
PhS
Cp
R1
trans adduct
H
Ti
With the optimized conditions in hand, we performed the
reaction on thioethers 7, 9, 11, 13, 15, 17, and 18
(Table 1). Allylic and benzylic phenyl thioethers 7, 9, 11,
13, and 15 gave stereospecifically the corresponding
trans-alkenes in moderate to excellent yield (entries 1–5).
Cp
Cp
Scheme 3 Proposed mechanisms for the b-elimination
Table 1 Elimination of Conjugated Phenylthioethers by Low-Valent Titanocene
Entry
1
Thioether
Product
Yield (%)a
71
O
O
O
O
SPh
SPh
8
7
O
O
O
O
2
3
4
91
9
10
O
O
79
O
(95 brsm)b
O
SPh
SPh
12
11
O
O
O
27
O
(45 brsm)b
13
14
SPh
5
6
68
15
O
16
SPh
–
0c
0c
O
17
PhS(CH2)10COOMe
7
–
18
a Isolated yields.
b Yield based on recovery of the starting material.
c The starting material was recovered.
Synlett 2010, No. 19, 2928–2930 © Thieme Stuttgart · New York

2930
N. Ribeiro et al.
LETTER
Hz, 1 H), 6.97 (s, 1 H), 7.14 (t, J = 7.2 Hz, 1 H), 7.25 (t, J = 7 Hz, 2
H), 7.38 (d, J = 8 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d = 101.3
(CH2), 105.7 (CH), 108.6 (CH), 121.6 (CH), 126.5 (CH), 127.2
(CH), 127.5 (CH), 128.5 (CH), 128.8 (CH), 132.1 (C), 137.6 (C),
147.5 (C), 148.3 (C).
However, nonconjugated thioethers 17 and 18 were unre-
active, and the starting materials were recovered (Table 1,
entries 6 and 7). The temperature plays an important role
in order to achieve high yield and trans stereoselectivity.
After the addition of the thioether, the reaction should be
warmed slowly from –78 °C to room temperature over 2
or 3 hours. On the contrary, if the temperature increases
suddenly to room temperature, the substrate 9 gives 10
with only 48% yield and an equimolar ratio of E/Z.
Product 2
1H NMR (300 MHz, CDCl3): d = 1.61 (s, 3 H), 1.68 (s, 3 H), 1.80
(s, 3 H), 1.89 (s, 3 H), 2.12 (s, 4 H), 4.93 (d, J = 6.0 Hz), 5.11 (m, 1
H), 5.90 (d, J = 10.8 Hz, 1H), 6.24 (d, J = 15.3 Hz, 1 H), 6.42 (dd,
J = 15.3, 10.8 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 16.8
(CH3), 17.7 (CH3), 18.6 (CH3), 25.7 (CH3), 26.6 (CH2), 40.1 (CH2),
115.5 (CH2), 123.9 (CH), 125.0 (CH), 125.6 (CH), 131.7 (C), 133.1
(CH), 139.7 (C), 142.5 (C).
In conclusion, we reported an unprecedented elimination
of conjugated phenyl thioether groups by a low-valent ti-
tanocene species. The study of this new reactivity and
mechanism are now under investigation, and the results
will be reported in due course.
Acknowledgment
N.R. and S.S. have been funded by a doctoral fellowship from the
Ministry of Research and Technology (MRT, France).
Typical Procedure
Dichlorotitanocene (298 mg, 1.2 mmol) was diluted in 3 mL of an-
hydrous THF and cooled to –78 °C, and then n-BuLi (1.6 M in hex-
ane, 2.4 mmol) was added dropwise. After 30 min at –78 °C, the
solution was left at r.t. for 5 min, and then chilled again to –78 °C.
A solution of the thioether 9 in anhydrous THF (2 mL) was added
dropwise. The reaction was then slowly warmed to r.t. and stirred
overnight. The reaction was stopped by addition of distilled H2O
(10 mL) and extracted twice with Et2O. The cumulated organic
phase were dried over MgSO4, and the crude was purified on silica
gel column with pentane–Et2O (95:5) as eluant to yield 123 mg of
the expected product 10.
References
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1974, 96, 947.
(2) Takeda, T.; Miura, I.; Horikawa, Y.; Fujiwara, T.
Tetrahedron Lett. 1995, 36, 1495.
(3) Streiff, S.; Ribeiro, N.; Désaubry, L. J. Org. Chem. 2004, 69,
7592.
(4) Brintzinger, H.; Bercaw, J. E. J. Am. Chem. Soc. 1970, 92,
6182.
(5) Shu, R.; Harrod, J. F.; Lebuis, A. M. Can. J. Chem. 2002, 80,
1H NMR (400 MHz, CDCl3): d = 5.86 (s, 2 H), 6.70 (d, J = 8 Hz, 1
H), 6.84 (d, J = 16 Hz, 1 H), 6.85 (d, J = 9 Hz, 1 H), 6.93 (d, J = 16
489.
Synlett 2010, No. 19, 2928–2930 © Thieme Stuttgart · New York