Cross-Coupling Chemistry in Continuous Flow - New Trends in Cross-Coupling: Theory and Applications - page 625

and liquid phases flow in two different compartments and are separated by a
gas-permeable membrane. A membrane microreactor was used for the
preparation of styrenes via the Mizoroki-Heck coupling between aryl iodides
and ethylene (Figure 13.13). 40 The ethylene gas was brought into contact
with the liquid reagents in a so-called tube-in-tube reactor, which consists of
two concentric capillaries in which the central capillary is gas permeable.
Next, the reaction was sent to a capillary microreactor heated to 120 1Cto
achieve full conversion. A back-pressure regulator was utilized to prevent
out-gassing of the reaction mixture. The optimal catalyst system consisted of
Pd(OAc) 2 with JohnPhos as a ligand and allowed a wide variety of styrenes to
be prepared.
A multistep continuous flow system was developed to prepare enol ethers
starting from p-tert-butylphenol (Figure 13.14). 41 The first reaction step in-
volved triflate formation by reaction of the starting compound with triflic
anhydride in dichloromethane. Impurities were removed via a liquid-liquid
microextraction step and, subsequently, a solvent switch from dichloro-
methane to DMF was effected in a microfluidic distillation device. DMF was
the optimal solvent to carry out the Mizoroki-Heck coupling step. Overall,
0.135 mmol product h 1 (79% yield) could be obtained with this system.

Pd(OAc) 2 (5 mol%)
JohnPhos (12 m ol%)

I

R R

+

Et 3 N, TBAI, DMF/toluene (1:4)

O

N

Me

N

O

HO CN

H

H

78% 81% 40% 95% 95%

P( t -Bu) 2

JohnPhos

Figure 13.13 Gas-liquid Mizoroki-Heck vinylation in a tube-in-tube microreactor. 40
Copyright Wiley-VCH Verlag GmbH & Co. KGaA 2013.
Reproduced with permission.