Flash generation of α-(trifluoromethyl)vinyllithium and application to continuous flow three-component synthesis of α-trifluoromethylamides

Article abstract of DOI:10.1039/c4cc06709f

α-(Trifluoromethyl)vinyllithium was generated and used for the reaction with electrophiles at -78 °C in a flow microreactor although the batch reaction should be carried out at ca. -100°C, and the method was applied to continuous flow three-component synt

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Flash generation of a-(trifluoromethyl)vinyllithium
and application to continuous flow three-
Cite this:DOI: 10.1039/c4cc06709f
component synthesis of a-trifluoromethylamides†
Received 26th August 2014,
Accepted 6th October 2014
Aiichiro Nagaki, Shinya Tokuoka and Jun-ichi Yoshida*
DOI: 10.1039/c4cc06709f
www.rsc.org/chemcomm
a-(Trifluoromethyl)vinyllithium was generated and used for the
reaction with electrophiles at À78 8C in a flow microreactor
although the batch reaction should be carried out at ca. À100 8C,
and the method was applied to continuous flow three-component
synthesis of a-trifluoromethylamides.
Trifluoromethyl-substituted vinylmetals1 such as a-(trifluoro-
methyl)vinyllithium serve as powerful building blocks2 for
constructing CF3-containing molecules.3 However, because
a-(trifluoromethyl)vinyllithium is very unstable,4 it should be
generated and reacted at extremely low temperatures if we use
batch macro reactors. In fact, Tarrant4a and Ichikawa2c reported
independently that the generation of a-(trifluoromethyl)-
Fig. 1 A flow microreactor system for generation of a-(trifluoromethyl)-
vinyllithium followed by reactions with electrophiles and the subsequent
quenching with methanol or acetic acid. T-shaped micromixers: M1, M2
and M3, microtube reactors: R1, R2 and R3.
vinyllithium followed by the reaction with an electrophile should yield (79%) based on 2-bromo-3,3,3-trifluoropropene at À78 1C
be carried out at ca. À100 1C because of rapid elimination of LiF to (Table 1). The reactions with other aldehydes also gave the
give 1,1-difluoroallene. Notably, batch reactions are often carried corresponding products in good yields as shown in Table 1.
out using an excess amount of a-(trifluoromethyl)vinyllithium, Thus, the flash method enables efficient generation and use of
and the yields are usually reported based on the amounts of a-(trifluoromethyl)vinyllithium under easily accessible conditions.
electrophiles. Here, we show that flash chemistry5,6 using flow
The reactions with isocyanates are interesting. Quenching
microreactor systems7–9 enables the generation and reactions with methanol gave the compounds having a methoxy group,
of a-(trifluoromethyl)vinyllithium at more easily accessible although the use of acetic acid as a quenching agent gave the
temperatures to give the desired products in good yields without desired alkenes having CF3 and amide groups in good yields
using an excess amount of the lithium reagent. We also report (Table 1).
here that the method enables continuous flow three-component
synthesis10–12 of a-trifluoromethylamides,13 which serve as can be explained by deprotonation of methanol by the initially
fascinating motifs in peptidomimetics. formed lithium amide followed by the addition of the methoxide
The formation of the compounds having a methoxy group
A flow microreactor system consisting of three T-shaped ion to the carbon–carbon double bond activated by the electron
micromixers (M1, M2, and M3) and three microtube reactors withdrawing CF3 and amide groups. This explanation leads to the
(R1, R2, and R3) shown in Fig. 1 was used for Br/Li exchange of idea of using carbon nucleophiles having an acidic proton instead of
2-bromo-3,3,3-trifluoropropene with s-BuLi to generate a-(tri- methanol (Fig. 2). The lithium amide deprotonates a subsequently
fluoromethyl)vinyllithium followed by reactions with electrophiles. added carbon nucleophile (Nu–H), and the resulting carbanion
First, we examined the reaction using benzaldehyde as an (NuÀÁLi+) adds to the electron-deficient carbon–carbon double
electrophile, and the desired product was obtained in good bond. Protonation gives the corresponding three-component
coupling products.
We chose to use malonate esters as carbon nucleophiles.
Thus, the Br/Li exchange of 2-bromo-3,3,3-trifluoropropene, the
Kyoto University, Department of Synthetic Chemistry and Biological Chemistry,
Graduate School of Engineering, Nishikyo-ku, Kyoto, Japan.
reaction of the resulting a-(trifluoromethyl)vinyllithium with an
E-mail: yoshida@sbchem.kyoto-u.ac.jp
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc06709f isocynate, and the subsequent reaction with a malonate ester
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Table 1 Reactions of a-(trifluoromethyl)vinyllithium with various electrophiles
Quenching
agent
Yield
(%)
Electrophile
PhCHO
Product
MeOH
MeOH
MeOH
MeOH
AcOH
MeOH
AcOH
79
72
90
80
62
65
63
(p-CF3)PhCHO
OQCQN–Bn
OQCQN–Ph
OQCQN–Bu
Fig. 3 An integrated flow microreactor system for generation of a-(trifluoro-
methyl)vinyllithium followed by the reactions with isocyanates and sub-
sequently added malonate esters. T-shaped micromixers: M1, M2, M3 and M4,
microtube reactors: R1, R2, R3 and R4.
Table 2 Three-component coupling of a-(trifluoromethyl)vinyllithium,
isocyanates, and malonate esters
Yield
(%)
Malonate ester
Isocyanate
Product
OQCQN–Bn
80
OQCQN–Ph
OQCQN–Bu
65
73
MeOH
AcOH
83
72
OQCQN–Bn
OQCQN–Bn
51
66
Fig. 2 The reaction of a-(trifluoromethyl)vinyllithium with an isocyanate
followed by the reaction with a subsequently added nucleophile.
were integrated14 using a flow microreactor system consisting
of four T-shaped micromixers (M1, M2, M3, and M4) and four reactions of a-(trifluoromethyl)vinyllithium with isocyanates and
microtube reactors (R1, R2, R3, and R4) shown in Fig. 3. malonate esters. The key to the success of the three-component
As shown in Table 2, the integration of the reactions was coupling is deprotonation of malonate esters by the lithium
successfully achieved with diethyl malonate, dibenzyl malonate, amide intermediates followed by the nucleophilic attack of
and di-tert-butyl malonate to obtain the corresponding addition the resulting carbanions on the carbon–carbon double bond
products in good yields, although the use of 1,3-diketones such activated by the CF3 and the amide groups. This mode of
as 2,4-pentanedione did not give the desired products.
reaction integration adds a new dimension to continuous
In conclusion, flash chemistry enables efficient generation of flow multicomponent coupling.15 Further applications of the
a-(trifluoromethyl)vinyllithium and its reactions with electro- present method to the continuous-flow synthesis of fluorine-
philes at À78 1C. Space integration of reactions enabled three- containing organic compounds16 are currently in progress in
component synthesis of a-trifluoromethylamides by successive our laboratory.
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This work was partially supported by the Grant-in-Aid for
Scientific Research (S) (no. 26220804) and Scientific Research (B)
(no. 26288049). We also thank Taiyo Nippon Sanso for providing
a low temperature cooling device and partial financial support.
Communication
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