Lithiation of 1,2-dichloroethene in flow microreactors: Versatile synthesis of alkenes and alkynes by precise residence-time control

Article abstract of DOI:10.1002/anie.201108932

It′s all about the timing: Precise control of the residence time (t^Rx; see picture) of reactive intermediates in flow microreactors enables the reaction pathway of lithiated 1,2-dichloroethene to be switched to produce either alkenes or alkynes. This method also allows versatile syntheses of asymmetric disubstituted dichloroalkenes and alkynes. Copyright

Full text of DOI:10.1002/anie.201108932

Angewandte
Chemie
DOI: 10.1002/anie.201108932
Microreactors
Lithiation of 1,2-Dichloroethene in Flow Microreactors: Versatile
Synthesis of Alkenes and Alkynes by Precise Residence-Time
Control**
Aiichiro Nagaki, Chika Matsuo, Songhee Kim, Kodai Saito, Atsuo Miyazaki, and
Jun-ichi Yoshida*
Although a variety of methods for the synthesis of alkenes
and alkynes have been developed, the pursuit of new and
versatile methods remains topical. Reactions that involve 2-
halovinyl metals serve as powerful methods in this context.[1]
For example, the b-elimination of 2-halovinyl metals is one of
the most straightforward methods for making a carbon–
carbon triple bond.[2] In contrast, the direct use of 2-halovinyl
metals without b-elimination serves as a method for synthe-
sizing substituted alkenes that contain a halogen atom,[3]
which can be used for further reactions.[4] 2-Halovinyllithium
compounds are especially attractive intermediates because of
their high reactivity relative to other 2-halovinyl metals.
However, the use of 2-halovinyllithium is often problematic
as a result of competing b-elimination.
Figure 1. A flow microreactor system for the lithiation of trans-1,2-
dichloroethene with nBuLi and subsequent reaction with electrophiles.
T-shaped micromixers: M1 and M2; microtube reactors: R1 and R2.
The reaction was carried out over various residence times
(tR1) in R1, and at various temperatures (T1). The results are
summarized in Figure 2, in which the yield of 1a is plotted
In flash chemistry[5] in a flow microreactor system,[6–8]
a highly reactive and unstable intermediate can be generated
and used in a subsequent reaction before it decomposes by
virtue of precise control of the reaction time.[9] Herein, we
report that flash chemistry enables the versatile synthesis of
alkenes and alkynes from trans-1,2-dichloroethene.
The first step in the synthesis is the generation of 1,2-
dichlorovinyllithium[10] by deprotonation of trans-1,2-dichlor-
oethene. It is well known that the reaction should be
conducted at À788C or below in a batch macroreactor. To
confirm this, the reaction of trans-1,2-dichloroethene with
nBuLi (1.05 equiv) and subsequent treatment with benzalde-
hyde was examined at 08C in a conventional batch macro-
reactor. The desired product, (E)-2,3-dichloro-1-phenylprop-
2-en-1-ol (1a, Table 1, below) was not obtained at all because
a significant amount of 3-chloro-1-phenyl-prop-2-yn-1-ol (2a)
was produced. In contrast the reaction at À788C gave 1a in
81% yield (See the Supporting Information for details).
We examined the reaction in a flow microreactor system
that consists of two T-shaped micromixers (M1 and M2) and
two microtube reactors (R1 and R2), as shown in Figure 1.
Figure 2. A contour map with scatter overlay of the effects of temper-
ature (T1) and residence time (tR1) on the yield [%] of (E)-2,3-dichloro-
1-phenylprop-2-en-1-ol (1a) from the lithiation of trans-1,2-dichloroe-
thene with nBuLi (1.05 equiv) and subsequent reaction with benzalde-
hyde in the flow microreactor system.
against T1 and tR1 as a contour map with scattered overlay.
[*] Dr. A. Nagaki, C. Matsuo, S. Kim, Dr. K. Saito, A. Miyazaki,
Prof. J.-i. Yoshida
High yields (greater than 80%) were obtained with a short tR1
,
such as 0.055 s at 08C. An increase in tR1 caused a decrease in
the yield, presumably because of b-elimination of trans-1,2-
dichlorovinyllithium. At low temperatures, the yield was low
after a short tR1 because of incomplete deprotonation. It is
important to note that trans-1,2-dichlorovinyllithium could be
used for the subsequent reaction at 08C. In fact, under the
optimized conditions (T1 = 08C, tR1 = 0.055 s), reactions with
various electrophiles were successfully carried out to obtain
the corresponding alkenes, which contain two chlorine atoms,
Department of Synthetic and Biological Chemistry
Graduate School of Engineering, Kyoto University
Nishikyo-ku, Kyoto, 615-8510 (Japan)
E-mail: yoshida@sbchem.kyoto-u.ac.jp
Homepage: http://www.sbchem.kyoto-u.ac.jp/yoshida-lab/index_
e.html
[**] This work was partially supported by a Grant-in-Aid for Scientific
Researchfrom JSPS.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108932.
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Table 2: Synthesis of disubstituted 1,2-dichloroethenes.[a]
in high yields (Table 1). The two chlorine atoms could be used
for further transformations to obtain a variety of substituted
alkenes.[11]
Electrophile
Product
Yield [%]
71
E1: PhCHO
E2: PhCHO
Table 1: Reactions of lithiated trans-1,2-dichloroethene with various
electrophiles.[a]
3aa
3ab
3ac
3ad
Electrophile
Product
Yield [%]
88
E1: PhCHO
72
E2: Me3SiOTf
PhCHO
1a
1b
1c
E1: PhCHO
E2: Bu3SnCl
73[b]
Me3SiCl
Me3SiOTf
91
92
E1: PhCHO
62[b]
85[b]
E2: Me2SiHCl
Bu3SnCl
PhNCO
[a] T1 =08C, tR1 =0.055 s, T2 =À788C, tR3 =4.6 s. Determined by GC
analysis with an internal standard. [b] Yield of isolated product.
93
1d
electrophiles were performed under the optimized conditions
to obtain the corresponding alkenes, which bear two chlorine
atoms, in high yields (Table 2).
[a] T1 =08C, tR1 =0.055 s. Determined by GC analysis with an internal
standard. [b] Yield of isolated product.
We examined the synthesis of asymmetric disubstituted
alkynes from trans-1,2-dichloroethene (Figure 4). 1,2-
Dichlorovinyllithium undergoes b-elimination with a longer
We examined sequential reactions in an integrated flow
microreactor system that consists of four micromixers (M1,
M2, M3, and M4) and four microtube reactors (R1, R2, R3,
and R4), as shown in Figure 3. Trans-1,2-dichlorovinyllithium
Figure 4. An integrated flow microreactor system for the synthesis of
asymmetric disubstituted alkynes.
Figure 3. An integrated flow microreactor system for the synthesis of
disubstituted dichloroalkenes by sequential introduction of two electro-
philes. T-shaped micromixers: M1, M2, M3, and M4, microtube
reactors: R1, R2, R3, and R4.
residence time at 08C to give chloroacetylene. The use of
2.10 equiv of nBuLi gave rise to deprotonation, and the
subsequent reaction with benzaldehyde gave 3-chloro-1-
phenylprop-2-yn-1-ol (2a) in 90% yield (tR1 = 50 s, see the
Supporting Information for details). This result demonstrates
that precise control of the residence-time is quite effective for
the selective synthesis of either an alkene or an alkyne at will.
Furthermore, asymmetric disubstituted alkynes 4 could be
synthesized based on the Cl–Li exchange reaction of sub-
stituted chloroacetylenes shown in Figure 5. The results are
summarized in Table 3. Furthermore, asymmetric disubsti-
tuted alkynes could also be synthesized by another route. As
shown in Figure 5a, lithiation of 1,2-dichloroethene and
was generated in M1 and R1 at 08C (tR1 = 0.055 s). The
reaction with the electrophile was carried out in M2 and R2 at
the same temperature (tR2 = 8.2 s). The desired product 2,3-
dichloro-3-trimethylsilyl-1-phenyl-prop-(2E)-en-1-ol
(3ab,
Table 2) was obtained in a high yield (greater than 70%)
from the reaction with Me3SiOTf (Tf = trifluoromethanesul-
fonate) only at low temperatures and by adjusting the
residence time (tR3 = 4.6 s, T2 = À788C), presumably because
b-elimination of the monosubstituted trans-1,2-dichlorovinyl-
lithium intermediate is very fast. Reactions with various
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subsequent reaction with an electrophile gave 1. Further
lithiation, b-elimination, Cl–Li exchange, and reaction with
an electrophile gave the corresponding asymmetric disubsti-
tuted alkynes 4. Some examples are shown in Figure 5b.
Figure 5. a) An integrated flow microreactor system for an alternative
synthesis of asymmetric disubstituted alkynes. b) The structures and
the yields of the disubstituted alkynes obtained.
Scheme 1. Versatile synthesis of alkenes and alkynes from trans-1,2-
dichloroethene.
Table 3: Synthesis of asymmetric disubstituted alkynes.
Electrophile
Product
Yield [%][a]
78
E1: PhCHO
E2: PhCHO
In conclusion, we have demonstrated that precise control
of the residence time enables the reaction pathway of a 1,2-
dichlorovinyllithium intermediate to be switched. Based on
this switch, versatile syntheses of alkenes and alkynes from
trans-1,2-dichloroethene were developed by space integra-
tion[12] (Scheme 1).
4aa
4ab
4ac
4ad
E1: PhCHO
66(78)[b]
28(48)[c]
73(77)[b]
E2: Me3SiOTf
E1: PhCHO
E2: Bu3SnCl
Received: December 19, 2011
Revised: January 30, 2012
Published online: February 15, 2012
E1: PhCHO
E2: Me2SiHCl
Keywords: alkenes · alkynes · lithiation · microreactors ·
.
synthetic methods
E1: PhCHO
74
79
E2: (CH3)2CO
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