Dithioacetal as a 1,1-zwitterion synthon. Synthesis of functionalized alkenes by the coupling of benzylic dithioacetals with another 1,1-zwitterion synthon

Article abstract of DOI:10.1016/j.tetlet.2004.12.016

Reaction of a dithioacetal sequentially with BuLi and alkyl bromide having an electron withdrawing substituent at the α-position followed by treatment with neutral alumina gives the corresponding olefination product in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2004.12.016

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 771–773
Dithioacetal as a 1,1-zwitterion synthon. Synthesis of
functionalized alkenes by the coupling of benzylic dithioacetals
with another 1,1-zwitterion synthon
Hai-Yang Tu, Yi-Hung Liu, Yu Wang and Tien-Yau Luh*
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, Province of China
Received 17 November 2004; revised 3December 2004; accepted 6 December 2004
Available online 18 December 2004
Dedicated to Professor Iwao Ojima on the occasion of his 60th birthday
Abstract—Reaction of a dithioacetal sequentially with BuLi and alkyl bromide having an electron withdrawing substituent at the a-
position followed by treatment with neutral alumina gives the corresponding olefination product in moderate to good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Direct coupling of a 1,1-zwitterion synthon with an-
other kind of 1,1-zwitterion synthon appears to be an
attractive route for the synthesis of carbon–carbon dou-
ble bond. It is well documented that the dithioacetal
ment of 1 with BuLi followed by alkyl halides gives regio-
selectively the corresponding alkylated alkynes 3 via
an allenyl lithium or propargyllithium intermediate
3
,4
2. The remaining carbon–sulfur bond in 3 can be re-
placed by a nucleophile (e.g., a Grignard reagent) in
1
functionality can serve as a dication synthon. In the
presence of a catalytic amount of NiCl (PPh ) , benzylic
3
the presence of a nickel catalyst (Eq. 2) to give 4. a-Bro-
moacetate and related compounds are known to serve as
2
3 2
or allylic dithioacetals react with Grignard reagents to
1
give the corresponding olefination products (Eq. 1).
The reaction can also proceed with aliphatic substrates
1,1-zwitterion equivalent in, for example, Darzens reac-
5
tion to form epoxide with a carbonyl compound. It is
2
when trialkylphosphine ligands are employed. The
envisaged that the thioether moiety in 3 may serve as a
leaving group such that functionalized olefins can be ob-
tained when such functionalized alkyl halides is used in
the reaction shown in Eq. 2. As part of our continuing
interests in the synthetic applications of propargylic
major limitation of this olefination reaction is the use
of Grignard reagents. Substrates containing functional
groups such as carbonyl, cyano groups, terminal alky-
nes, etc., cannot be employed under the reaction
conditions.
3
,4
dithioacetals, we report herewith the first examples
of olefination of benzylic and propargylic dithiaocetals
having a range of functional groups.
R2
Ar
2
R CH MgX
2
S
Ar
S
ð1Þ
R1
NiCl (PPh )
R1
2
3 2
In the beginning of this study, a THF solution of benzo-
phenone dithioacetal 5 was treated with 1.1 equiv of
BuLi at ꢀ78 °C for 1 h. To this mixture was added a
THF solution of 1 equiv of phanacyl bromide at
We have recently shown that propargylic dithioacetal 1
behaves like an allene-1,3-zwitterion equivalent. Treat-
ꢀ
78 °C and the mixture was gradually warmed to rt
and stirred for an additional 10 h. Neutral Al O was
6
2
3
Keywords: Dithioacetals; Olefination; Grignard active functional
groups; Butyllithium; Dimerization.
added and the slurry was stirred for 0.5 h at rt. After
filtration and usual workup, the corresponding olefin-
ation product 6a was obtained in 75% yield. In a similar
manner, the nitro-substituted olefin 6b was isolated in
54% yield.
*
Corresponding author. Tel.: +886 2 2363 6288; fax: +886 2 2364
971; e-mail addresses: tyluh@ntu.edu.tw; tyluh@ccms.ntu.edu.tw
7
4
On leave from Department of Chemistry, China Central Normal
University, Wuhan, Hubei Province.
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.016

772
H.-Y. Tu et al. / Tetrahedron Letters 46 (2005) 771–773
Li
S
S
BuLi
S
Li
R
R2
SBu
R2
C
SBu
S
2
R1
R1
R1
1
2a
2b
3
R X
ð2Þ
R3
R1
R3
4
4
2
R MgX
R
R
S
R2
C
SBu
NiCl (PPh )
R1
2
3 2
4
3
1
0
processes. Accordingly the fluorenyl anion thus gener-
ated may undergo rapid electron transfer to give the cor-
responding sulfur-substituted fluorenyl radical, which
may dimerize leading to 9.
R
S
S
1
. BuLi
2
. Br CH R
2
3
. Al O
2 3
R
5
6
6
a COPh 75%
1
. BuLi
b NO2 54%
7
BuS
2
3
. Br CH NO
. Al O
S
S
2
2
SBu
2
3
The reactions with fluorenone derivative 7 behaved simil-
arly. Thus, treatment of 7 with BuLi followed by phan-
acyl bromide or by a-bromoacetonitrile afforded the
corresponding olefination product 8a or 8b in 73% or
9
When propargylic dithioacetal 10 was allowed to react
with BuLi followed by treatment with ethyl a-bromoace-
tate, the corresponding enyne 11 was obtained in 71%
yield. It is noteworthy that an ester group is stable under
the reaction conditions. Accordingly, reaction of 12
under the same conditions afforded an E and Z (1:1) mix-
ture of stereoisomeric 13 in 63% yield. Presumably, the
replacement of the phenyl group in 10 by a butyl group
in 12 may result in non-selective elimination giving a
mixture of stereoisomers 13.
6
4% yield, respectively.
R
S
S
1
. BuLi
2
3
. Br CH R
2
. Al O
2
3
R
7
8a COPh 73%
8
b CN
64%
To our surprise, when a-bromonitromethane was used
as the electrophile, no olefination product was detected.
Instead, the corresponding dimeric product 9 was iso-
lated in 73% yield. The structure of 9 was unambigu-
ously proved by spectroscopic methods and X-ray
In summary, we have described the coupling of benzylic
dithioacetals with methyl bromide having electron with-
drawing substituent at the a-position leading to the cor-
responding olefins in moderate yields. The reaction can
be considered as a direct combination of two different
zwitterion equivalents for the preparation of functional-
ized olefins. This reaction can thus compliment with our
previous works on nickel-catalyzed olefination of the
8
diffraction. It is well documented that fluorene deriva-
tive can readily undergo radical dimerization to form
9
bifluorenyls and the nitroalkanes under strong basic
conditions are known to facilitate electron transfer
1
dithioacetals with Grignard reagents. As can be seen
EtO C
2
S
1
. BuLi
Ph
S
Ph
Ph
2
3
. Br CH CO Et
. Al O
2
2
Ph
2
3
1
0
11
13
EtO C
2
S
1
. BuLi
MeO C
S
Bu
MeO C
2
2
2
3
. Br CH CO Et
. Al O
2
2
Bu
2
3
1
2

H.-Y. Tu et al. / Tetrahedron Letters 46 (2005) 771–773
773
from the examples, a range of Grignard active func-
tional groups can be introduced under the reaction con-
ditions. Further investigation on the use propargylic
dithioacetals in organic synthesis is in progress in our
laboratory.
7. Typical procedure: To a THF solution (60 mL) of
dithioacetal (1 mmol) was added under N atmosphere
BuLi (1.1 equiv) at ꢀ78 °C and the mixture was stirred at
78 °C for 1 h. A THF solution (5 mL) of alkyl bromide
1 equiv) was introduced. The mixture was gradually
warmed to rt and stirred for an 10 h. Neutral alumina
15 g) was then added and the slurry was stirred at rt for
.5 h. After filtration, the solvent was evaporated in vacuo
2
ꢀ
(
(
0
Acknowledgements
and the residue was chromatographed on alumina to give
the desired product.
1
8
. Physical properties of 9: mp 100–103 °C, H NMR
This work is supported by the National Science Council
and the Ministry of Education of the Republic of China.
(
3
400 mHz, CDCl ) d 0.78 (t, J = 7.0 Hz, 6H), 1.15–1.19
(
m, 8H), 1.80–1.90 (m, 4H), 1.95 (t, J = 7.0 Hz, 4H), 2.00–
2
7
.10 (m, 4H), 7.05 (t, J = 7.2 Hz, 4H), 7.17–7.26 (m, 8H),
.31 (d, J = 7.6 Hz, 4H); C NMR d 13.5, 21.8, 30.1, 31.3,
1
3
References and notes
31.4, 31.5, 67.2, 118.8, 126.5, 126.9, 128.3, 140.7, 145.5;
HRMS calcd for C38 : 627.2248, Found 627.2261; X-
ray data: triclinic (P-1), a = 9.3193(2), b = 12.5142(2),
43 4
H S
1
2
3
. For reviews, see: (a) Luh, T.-Y. Acc. Chem. Res. 1991, 24,
57; (b) Luh, T.-Y. Synlett 1996, 201.
. Huang, L.-F.; Huang, C.-H.; Stulgies, B.; de Meijere, A.;
Luh, T.-Y. Org. Lett. 2003, 5, 4489.
. (a) Tseng, H.-R.; Luh, T.-Y. J. Org. Chem. 1996, 61, 8685;
b) Tseng, H.-R.; Lee, C.-F.; Yang, L.-M.; Luh, T.-Y. J.
Org. Chem. 1999, 64, 8582.
. (a) Lee, C.-F.; Yang, L.-M.; Hwu, T.-Y.; Feng, A.-H.;
Tseng, J.-C.; Luh, T.-Y. J. Am. Chem. Soc. 2000, 122,
˚
2
c = 18.5513(4) A, a = 101.7280 (11)°, b = 102.1700(11)°,
˚
3
c = 108.0060(12)°, volume = 1718.04(6) A , z = 2, and
density = 1.212 g/cm .
3
9. (a) Bordwell, F. G.; Bausch, M. J.; Wilson, C. A. J. Am.
Chem. Soc. 1987, 109, 5465; (b) Guthrie, R. D.; Wesley, D.
P.; Perndygraft, G. W.; Young, A. T. J. Am. Chem.
Soc. 1976, 98, 5870; (c) Guthrie, R. D.; Hartmann, C.;
Neill, R.; Nutter, D. E. J. Org. Chem. 1987, 52, 736;
(d) Bellos, K.; Stamm, H.; Speth, D. J. Org. Chem. 1991,
56, 6846; (e) Knjazhanski, S. Y.; Moreno, G.; Cadenas,
G.; Belsky, V. K.; Bulychev, B. M. Tetrahedron 1999, 55,
1639.
10. (a) Al-Khalil, S. I.; Bowman, W. R.; Gaitonde, K.;
Marley, M. A.; Richardson, G. D. J. Chem. Soc., Perkin
Trans. 2 2001, 1557, and references therein; (b) Kornblum,
N.; Michel, R. E.; Kerber, R. C. J. Am. Chem. Soc. 1966,
88, 5662; (c) Russell, G. A.; Danen, W. C. J. Am. Chem.
Soc. 1966, 88, 5663.
(
4
4
992; (b) Zhang, L.-Z.; Chen, C.-W.; Lee, C.-F.; Wu, C.-
C.; Luh, T.-Y. Chem. Commun. 2002, 2336; (c) Lee, C.-F.;
Liu, C.-Y.; Song, H.-C.; Luo, S.-J.; Tseng, J.-C.; Tso, H.-
H.; Luh, T.-Y. Chem. Commun. 2002, 2824; (d) Liu, C.-Y.;
Luh, T.-Y. Org. Lett. 2002, 4, 4305.
5
6
. For a review, see: Berti, G. Top. Stereochem. 1973, 7, 93 .
. Neutral alumina was employed to facilitate the elimina-
tion process. For example, in the absence of alumina, a
significant amount of propargyl thioether precursor 3
1
2
3
(
e.g., R , R = Ph, R = CH CO Me) was obtained.
2 2