Carbolithiation of conjugated enynes with aryllithiums in microflow system and applications to synthesis of allenylsilanes

Article abstract of DOI:10.1021/ol901352t

Image Presented Carbolithiation of conjugated enynes with aryllithiums generated by Br-Li exchange reaction followed by reaction of the allenyllithium compounds with chlorosilanes was carried out in a microflow system to obtain various allenylsilanes in g

Full text of DOI:10.1021/ol901352t

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3614-3617
Carbolithiation of Conjugated Enynes
with Aryllithiums in Microflow System
and Applications to Synthesis of
Allenylsilanes
Yutaka Tomida, Aiichiro Nagaki, and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Nishikyo-ku, Kyoto 615-8510, Japan
yoshida@sbchem.kyoto-u.ac.jp
Received June 16, 2009
ABSTRACT
Carbolithiation of conjugated enynes with aryllithiums generated by Br-Li exchange reaction followed by reaction of the allenyllithium compounds
with chlorosilanes was carried out in a microflow system to obtain various allenylsilanes in good yields.
Organolithium compounds are important intermediates in
organic synthesis.1 Various methods for generation of
organolithium intermediates have been developed so far.
Among them, carbolithiation of unsaturated compounds such
as alkenes,2 alkynes,3 and enynes4 serves as an attractive
method because carbon-carbon bond formation leads to the
formation of a second organolithium intermediate, which can
be utilized for subsequent reactions with various electro-
philes. Commercially available n-BuLi, sec-BuLi, and tert-
BuLi are often used as starting organolithium compounds.5
The use of aryllithiums as starting organolithium compounds
seems to be more attractive from a viewpoint of organic
synthesis. However, only a few examples of carbolithiation
using aryllithiums have been reported in the literature because
the additions of aryllithiums to unsaturated compounds such
as enynes are difficult.6 This is presumably because of the
following reason. At low temperatures, addition of aryllithi-
ums to a carbon-carbon unsaturated bond is rather slow.
At higher temperatures, the addition takes place at a
reasonable rate, but the resulting organolithium compound
(1) (a) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon:
Amsterdam, The Netherlands, 2002. (b) Rappoport, Z.; Marek, I. The
Chemistry of Organolithium Compounds; Wiley: Chichester, U.K., 2004.
(2) (a) Bartlett, P. D.; Tauber, S. J.; Weber, W. P. J. Am. Chem. Soc.
1969, 91, 6362. (b) Landgrebe, J. A.; Shoemarker, J. D. J. Am. Chem. Soc.
1967, 89, 4465. (c) Richey, H. G.; Heyn, A. S.; Erickson, W. F. J. Org.
Chem. 1983, 48, 3821. (d) Okamoto, Y.; Kato, M.; Yuki, H. Bull. Chem.
Soc. Jpn. 1969, 42, 760. (e) Crandall, J. K.; Clark, A. C. J. Org. Chem.
1972, 37, 4236.
(5) Recent examples of carbolithiation using alkyllithium: (a) Wei, X.;
Taylor, R. J. K. J. Chem. Soc., Chem Commun. 1996, 187. (b) Wei, X.;
Johnson, P.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 2000, 1109.
(c) Norsikian, S.; Marek, I.; Klein, S.; Poisson, J. F.; Normant, J. F.
Chem.sEur. J. 1999, 5, 2055. (d) Coleman, C. M.; O’Shea, D. F. J. Am.
Chem. Soc. 2003, 125, 4054. (e) Hogan, A.-M. L.; O’Shea, D. F. J. Am.
Chem. Soc. 2006, 128, 10360. (f) Hogan, A.-M. L.; O’Shea, D. F. Chem.
Commun. 2008, 3839.
(3) (a) Mulvaney, J. E.; Gardlund, Z. G.; Gardlund, S. L. J. Am. Chem.
Soc. 1963, 85, 3897. (b) Mulvaney, J. E.; North, D. J. J. Org. Chem. 1969,
24, 1936. (c) Bauer, W.; Feigel, M.; Mu¨ller, G.; Schleyer, P. v. R. J. Am.
Chem. Soc. 1988, 110, 6033. (d) Hojo, M.; Murakami, Y.; Aihara, H.;
Sakuragi, Y.; Baba, Y.; Hosomi, A. Angew. Chem., Int. Ed. 2001, 40, 621.
(e) McKinley, N. F.; O’Shea, D. F. J. Org. Chem. 2006, 71, 9552.
(4) (a) Kormer, V. A.; Petrov, A. A. Zh. Obshch. Khim. 1960, 30, 216.
(b) Miginiac, L. J. Organomet. Chem. 1982, 238, 235. (c) Lorthiois, E.;
Marek, I.; Meyer, C.; Normant, J. F. Tetrahedron Lett. 1996, 37, 6689. (d)
Lorthiois, E.; Marek, I.; Normant, J. F. Tetrahedron Lett. 1996, 37, 6693.
(6) (a) Cherkasov, L. N.; Kormer, V. A.; Bal’yan, K. V.; Petrov, A. A.
Zh. Org. Khim. 1966, 2, 1573. (b) Cherkasov, L. N.; Bal’yan, K. V.; Kormer,
V. A. Zh. Org. Khim. 1968, 4, 204.
10.1021/ol901352t CCC: $40.75
Published on Web 07/23/2009
 2009 American Chemical Society

reacts with a butyl halide, which is generated in the
halogen-lithium exchange reaction. This side reaction
competes the follow-up reaction with an electrophile.7
Therefore, it is very difficult to choose an appropriate reaction
condition.
Table 1. Carbolithiation of 4-Phenyl-but-1-en-3-yne (2) with
4-Methylphenyllithium (1′) Followed by the Reaction with
Chlorotrimethylsilane in a Macrobatch Systema
yield (%)
Microflow systems8,9 have received significant research
interest. Recently, we have reported that aryllithiums can
be generated by halogen-lithium exchange reaction of
bromoarenes at 0 and 20 °C by using a microflow system,10
whereas much lower temperatures such as -78 °C are
required for a conventional macrobatch reaction. The gener-
ated aryllithiums can be reacted with an electrophile avoiding
the side reaction with a butyl halide. Precise control of the
residence time (milliseconds to seconds) is responsible for
the success of the reaction.11 Therefore, we envisioned that
the use of a microflow system is also effective for carbo-
lithiation with aryllithiums followed by reaction with an
electrophile. The concept works. In this paper, we report
carbolithiation of enynes with aryllithiums using an integrated
microflow system and their application to the synthesis of
allenylsilanes (Scheme 1).
equiv
of 1
convn
3a + 4a
(3/4)
entry
t (°C) t′ (min) of 2(%)
5 + 6
1
2
3
4
5
6
7
8
9
1.0
3.0
1.0
1.0
3.0
1.0
1.0
3.0
1.0
1.0
-78
-78
-48
-48
-48
-28
-28
-28
0
60
60
10
60
60
10
60
10
10
10
2
17
15
66
96
74
100
95
98
100
0
0
0
0
0
2
11
4
19
10
26
40
4 (85/15)
11 (92/8)
15 (90/10)
26 (91/9)
7 (91/9)
33 (89/11)
21 (91/9)
9 (89/11)
10
25
a A solution of n-BuLi in hexane was added dropwise (1 min) to a
solution of p-bromotoluene (1) in THF in a 20 mL round-bottomed flask at
-78 °C to generate 4-methylphenyllithium (1′). After the mixture was stirred
for 60 min, a solution of 4-phenyl-but-1-en-3-yne (2) in Et2O was added
dropwise (1 min) to the reaction mixture, and the reaction temperature was
changed to t/°C. After the mixture was stirred for t′ min, a solution of
chlorotrimethylsilane in THF was added dropwise (1 min) to the reaction
solution. The mixture was stirred for 60 min at t/°C and was analyzed by
gas chromatography (GC) to determine the yield and conversion.
Scheme 1
.
Synthesis of Allenylsilane via Carbolithiation of
Conjugated Enynes with Aryllithium
min. At -48 °C, most of 2 was consumed after 60 min, but
the yields of desired 4-(4-methylphenyl)-1-trimethylsilyl-1-
(7) The formation of a butyl halide can be avoided by use of t-BuLi for
halogen-lithium exchange reactions. However, the use of highly reactive
t-BuLi is not suitable for large scale synthesis. It should be noted that
continuous microflow reactions can be applied to industrial production. See:
Wakami, H.; Yoshida, J. Org. Process Res. DeV. 2005, 9, 787.
(8) Reviews for microreactor: (a) Ja¨hnisch, K.; Hessel, V.; Lo¨we, H.;
Baerns, M. Angew. Chem., Int. Ed. 2004, 43, 406. (b) Doku, G. N.;
Verboom, W.; Reinhoudt, D. N.; van den Berg, A. Tetrahedron 2005, 61,
2733. (c) Watts, P.; Haswell, S. J. Chem. Soc. ReV. 2005, 34, 235. (d) Geyer,
K.; Codee, J. D. C.; Seeberger, P. H. Chem.sEur. J. 2006, 12, 8434. (e)
deMello, A. J. Nature 2006, 442, 394. (f) Song, H.; Chen, D. L.; Ismagilov,
R. F. Angew. Chem., Int. Ed. 2006, 45, 7336. (g) Kobayashi, J.; Mori, Y.;
Kobayashi, S. Chem. Asian J. 2006, 1, 22. (h) Mason, B. P.; Price, K. E.;
Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem. ReV. 2007, 107,
2301. (i) Ahmed-Omer, B.; Brandtand, J. C.; Wirth, T. Org. Biomol. Chem.
2007, 5, 733. (j) Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett
2008, 151. (k) Yoshida, J.; Nagaki, A.; Yamada, T. Chem.sEur. J. 2008,
14, 7450. (l) Yoshida, J. Flash Chemistry. Fast Organic Synthesis in
Microsystems; Wiley: Chichester, U.K., 2008.
Before using a microflow system, the reaction in a
conventional macrobatch reactor was examined (Scheme 2).
Scheme 2. Carbolithiation of 4-Phenyl-but-1-en-3-yne (2) with
4-Methylphenyllithium (1′) Generated by Br-Li Exchange
Reaction of 4-Bromotoluene (1) in a Conventional Macrobatch
Reactor
(9) Some recent examples: (a) Nagaki, A.; Togai, M.; Suga, S.; Aoki,
N.; Mae, K.; Yoshida, J. J. Am. Chem. Soc. 2005, 127, 11666. (b)
Kawaguchi, T.; Miyata, H.; Ataka, K.; Mae, K.; Yoshida, J. Angew. Chem.,
Int. Ed. 2005, 44, 2413. (c) He, P.; Watts, P.; Marken, F.; Haswell, S. J.
Angew. Chem., Int. Ed. 2006, 45, 4146. (d) Uozumi, Y.; Yamada, Y.; Beppu,
T.; Fukuyama, N.; Ueno, M.; Kitamori, T. J. Am. Chem. Soc. 2006, 128,
15994. (e) Tanaka, K.; Motomatsu, S.; Koyama, K.; Tanaka, S.; Fukase,
K. Org. Lett. 2007, 9, 299. (f) Sahoo, H. R.; Kralj, J. G.; Jensen, K. F.
Angew. Chem., Int. Ed. 2007, 46, 5704. (g) Hornung, C. H.; Mackley, M. R.;
Baxendale, I. R.; Ley, S. V. Org. Process Res. DeV. 2007, 11, 399. (h)
Fukuyama, T.; Kobayashi, M.; Rahman, M. T.; Kamata, N.; Ryu, I. Org.
Lett. 2008, 10, 533.
(10) (a) Usutani, H.; Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami,
T.; Yoshida, J. J. Am. Chem. Soc. 2007, 129, 3047. (b) Nagaki, A.; Tomida,
Y.; Usutani, H.; Kim, H.; Takabayashi, N.; Nokami, T.; Okamoto, H.;
Yoshida, J. Chem. Asian J. 2007, 2, 1513. (c) Nagaki, A.; Takabayashi,
N.; Tomida, Y.; Yoshida, J. Org. Lett. 2008, 10, 3937. (d) Nagaki, A.;
Kim, H.; Yoshida, J. Angew. Chem., Int. Ed. 2008, 47, 7833. (e) Nagaki,
A.; Takabayashi, N.; Tomida, Y.; Yoshida, J. Beilstein J. Org. Chem. 2009,
5, No16.
(11) (a) Nagaki, A.; Takizawa, E.; Yoshida, J. J. Am. Chem. Soc. 2009,
131, 1654. (b) Nagaki, A.; Takizawa, E.; Yoshida, J. Chem. Lett. 2009, 38,
486.
The carbolithiation of 4-phenyl-but-1-en-3-yne (2) using
4-methylphenyllithium (1′) generated by Br-Li exchange
reaction of 4-bromotoluene (1) followed by the reaction with
chlorotrimethylsilane was carried out with varying temper-
atures (t) and reaction times (t′). The results are summarized
in Table 1.
At -78 °C, the carbolithiation reaction was slow, and a
significant amount of 2 remained unchanged even after 60
Org. Lett., Vol. 11, No. 16, 2009
3615

Table 2. Carbolithiation of 4-Aryl-but-1-en-3-yne and
4-Heteroaryl-but-1-en-3-yne using Various Aryllithiums
Followed by the Reaction with Chlorotrimethylsilane in the
Integrated Microflow Systema
Figure 1. Integrated microflow system for carbolithiation of a
conjugated enyne with an aryllithium followed by the reaction with
a chlorosilane. T-shaped micromixer: M1 (φ ) 250 µm), M2 (φ
) 500 µm), M3 (φ ) 500 µm). Microtube reactor: R1 (φ ) 1000
µm, L ) 50 cm (residence time in R1: 7.9 s)), R2 (φ ) 1000 µm),
R3 (φ ) 1000 µm, L ) 50 cm (residence time in R3: 2.0 s)). Flow
rate of a solution of bromoarene (1.2 M in THF (3.0 equiv)):12
1.50 mL/min. Flow rate of a solution of n-BuLi (1.2 M in hexane):
1.50 mL/min. Flow rate of a solution of 4-aryl-but-1-en-3-yne (0.10
M in Et2O): 6.00 mL/min. Flow rate of a solution of chlorosilane
(0.80 M in THF): 3.00 mL/min.
phenyl-but-1,2-diene (3a) and 4-(4-methylphenyl)-3-trim-
ethylsilyl-1-phenyl-but-1-yne (4a) were low. The major side
products were 1-butyl-4-(4-methylphenyl)-1-phenyl-but-1,2-
diene (5) and 3-butyl-4-(4-methylphenyl)-1-phenyl-but-1-yne
(6), which seem to be produced by the reaction of the lithium
intermediate with butyl bromide produced in the Br-Li
a Bromoarene (3.0 equiv) in THF (1.2 M), n-BuLi (3.0 equiv) in hexane
(1.2 M), 4-aryl-but-1-en-3-yne or 4-heteroaryl-but-1-en-3-yne in Et2O (0.10
M), and chlorotrimethylsilane (4.0 equiv) in THF (0.80 M) were allowed
to react using the integrated microflow system at 25 °C. b Determined by
GC. c Residence time in R2, 21 s. d Residence time in R2, 42 s.
exchange reaction. At higher temperatures such as -28, 0,
and 25 °C, the yields of 3a and 4a were still low, and
significant amounts of 5 and 6 were obtained.
Next, we examined the reactions using an integrated
microflow system consisting of three T-shaped micromixers
(M1, M2, and M3) and three microtube reactors (R1, R2,
and R3) (Figure 1). The reactions were carried out with
varying temperatures (t) and residence times (tR2) in R2. The
results are summarized in Figure 2.
Figure 2. Effects of temperature and residence time in R2 in the
integrated microflow system.
3616
Org. Lett., Vol. 11, No. 16, 2009

As profiled in Figure 2, the conversion and the yields
significantly depend on both temperature and residence time.
At 0 °C, the carbolithiation did not complete within the
residence time of 60 s. At higher temperatures, the enyne
(2) was consumed within 60 s, but the reaction with butyl
bromide also took place in some extent to give 5 and 6 before
adding chlorotrimethylsilane. The desired 3a and 4a were
obtained in high yields at 25 °C by choosing an appropriate
residence time in R2 (21 s).13 It is important to note that
the Br-Li exchange reaction could be also carried out at
the same temperature using the microflow system. The use
of a macrobatch reactor requires much lower temperatures
such as -78 °C for this purpose. Therefore, the use of the
intergrated microflow system is the key to the success of
the present transformation.
Table 3. Carbolithiation of 4-Phenyl-but-1-en-3-yne (2)
followed by the Reaction with Various Chlorosilanesa
Next, reactions of 2 with various aryllithium compounds
generated by Br-Li exchange reaction were examined by
using the integrated microflow systems. As shown in Table
2, reactions with phenyllithium having an electron-donating
and an electron-withdrawing group were successfully achieved
to obtain the corresponding allenylsilanes in good yields.
Various 4-aryl-but-1-en-3-ynes and 4-heteroaryl-but-1-en-
3-yne can be also used for the present reaction, and the
corresponding allenylsilanes were obtained in good yields
without being influenced by the nature of substituents on
the benzene ring.
a Bromotoluene (1) (3.0 equiv) in THF (1.2 M), n-BuLi (3.0 equiv) in
hexane (1.2 M), 4-phenyl-but-1-en-3-yne (2) in Et2O (0.10 M), and a
chlorolsilane (4.0 equiv) in THF (0.80 M) were allowed to react using the
integrated microflow system at 25 °C and residence time in R2 (21 s).
b Determined by GC. c Isolated yield. d Determined by NMR.
Next, reactions with other chlorosilanes such as chlo-
rodimethylsilane, chlorodimethyl(vinyl)silane, and allylchlo-
rodimethylsilane were examined, and the corresponding
allenylsilanes were obtained in high yields (Table 3).
In conclusion, we have developed carbolithiation of
conjugated enynes with aryllithiums generated by Br-Li
exchange reactions followed by reactions with chlorosilanes
using an integrated microflow system. Precise residence time
control is responsible for the success of the transformation.
The method adds a new possibility in carbolithiation
chemistry, and further studies on its applications are currently
in progress.
Allenylsilanes have attracted a great deal of attention as
intermediates in synthetic chemistry.14,15 Although allenyl-
silanes are often prepared by organocuprate substitution of
γ-acetoxyalkynylsilanes, the present transformation serves
as a straightforward and powerful method for this purpose.
(12) The use of 3 equiv of bromoarene gave the best results. The yields
of the desired products decreased with a decrease in the amount of
bromoarene. For example, when 1 equiv of 4-bromotoluene was used (tR2
:
21 s), the desired 3a and 4a were obtained in 65% yield (3/4 ) 91/9), and
the conversion of 4-phenyl-but-1-en-3-yne (2) was 83%.
(13) In all cases, the ratio of 3a and 4a was ca 90:10. See the Supporting
Information for details.
Acknowledgment. This work was partially supported by
the Grant-in-Aid for Scientific Research and a NEDO project.
(14) Review for reactions of allenylsilanes: Masse, C. E.; Panek, J. S.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Chem. ReV. 1995, 95, 1293
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