364
Published on the web March 2, 2011
Wittig Like Methylenation of Aldehydes in a Microflow System:
Selective Methylenation by Differential of Plural Reactions
Yoshiaki Takada and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoudai-katsura, Nishikyo-ku, Kyoto 615-8510
(Received January 14, 2011; CL-110037; E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp)
Methylenation of aldehydes with bis(iodozincio)methane
was determined by changing the residence time in R1 and the
was performed using a microflow system. Treatment of a
dialdehyde with bis(iodozincio)methane in the system can
divide two methylenation reactions and realize selective trans-
formation.
temperature of the ethylene glycol bath in the microflow system.
The residence time was adjusted by changing the flow rate in
10 m R1 (Figure 2). In M2, quenching reagent MeOH for
unreacted 1 was injected.
As shown in Figure 2, the highest yield 89% was observed
at the intersection of 3 min (residence time in R1) and 60 °C
(bath temperature). Figure 2 also shows that the methylenation
of aldehyde is fast enough to give the alkene in over 70% yield
within 1 min residence time. Under these conditions, using the
flow reactor, other aldehydes were also converted into the
corresponding alkenes as shown in Figure 3. Benzaldehyde
derivatives 2b-2d carrying various substituents were trans-
Recently, flow reactions have been intensively studied from
the viewpoint of productivity and sustainable chemistry.1 In
addition, space integration of chemical reactions has been also
realized by microflow systems.2 We have focused on the Wittig
like methylenation of aldehydes with bis(iodozincio)methane (1)
as a candidate for flow reaction (Scheme 1).3 Generally,
methylenation of aldehydes is performed with a typical Wittig
reagent, methylenetriphenylphosphorane.4 When this reaction is
attempted in a flow reactor,5 formation of insoluble phosphine
oxide may cause difficulty in the flow. As methylenation of an
aldehyde with 1 does not form any insoluble salts during the
reaction, it may not encountor any obstacle in practical
operation. In addition, a flow reaction can divide plural reactions
as well as the integration of a single reaction. Along this line, we
also expected selective methylenation in substrates carrying
plural formyl groups.
72
89
81
79
60
50
40
30
20
: >80%
:70-80%
:60-70%
:40-60%
77
46
78
66
77
68
82
73
When benzaldehyde (2a, 1.0 mmol) was treated with
bis(iodozincio)methane (1.1 mmol) in THF at 25 °C in a reaction
vessel for 0.5 h, styrene (3a) was obtained in 83% yield (in 87%
at 60 °C).3 As shown in Figure 1, we examined the reaction in a
microflow system consisting of two T-shaped micromixers, M1
and M2, and two microtube reactors, R1 and R2. The yield of 3
10
0
12
25
29
37
1
2
3
4
5
6
7
Residence Time in R1 / min
O
CH2
+ CH2(ZnI)2
+
IZnOZnI
THF
H
H
Figure 2. Effects of temperature and residence time on the
yield of styrene (3a): Contour plot with scatter overlay of the
yields (%).
R
R
2
1
3
Scheme 1. Methylenation of aldehydes with bis(iodozincio)-
methane (1).
CH2
H
CH2
H
CH2
H
CH2(ZnI)2
1
Br
MeO
O2N
R1
M1
3b (98%)
3c (84%)
3d (96%)
(3% recovery)
(2% recovery)
(15% recovery)
CHO
CH=CH2
R2
CH2
M2
H
2a
H
3a
MeOH
CH2
3f (89%)
(6% recovery)
3e (89%)
(8% recovery)
Figure 1. Microflow system for methylenation: T-shaped
micromixer: M1 (inner diameter: 250 ¯m) and M2 (inner
diameter: 250 ¯m), microtube reactor: R1 (º = 1000 ¯m,
length = 10 m), R2 (º = 1000 ¯m, length = 2 m), a solution
of 1: 0.38 M in THF, a solution of 2: 0.35 M in THF, methanol
(3.0 mL min¹1).
Figure 3. Yields of the methylenation products 3b-3f of
aldehydes 2b-2f by the flow reactor (residence time in R1:
3 min, 60 °C) in Figure 1. The reaction gave ca. 50.8-60.0 mmol
alkene per hour.
Chem. Lett. 2011, 40, 364-365
© 2011 The Chemical Society of Japan