Organic Process Research & Development
Technology Report
hot zone. The prefill and the reaction mixture as well as the
washing with methanol are captured in a collection flask. The
impurity profile of this larger-scale reaction corresponds to the
previous small-scale reaction. From the collected reaction
mixture, methanol and DMC were distilled off. From the
distillation of anisole (4) we obtained 207 g corresponding to
an isolated yield of 96%.
REFERENCES
■
(1) See: (a) Johnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35,
2169. (b) Ahmad, A. R.; Mehta, L. K.; Parrick, J. Tetrahedron 1995, 51,
12899.
(2) See: (a) Basak, A.; Nayak, M. K.; Chakraborti, A. K. Tetrahedron
Lett. 1998, 39, 4883. (b) Voskresensky, S.; Makosza, M. Synth.
Commun. 2000, 30, 3523. (c) Luo, Y.-L.; Chou, T.- C.; Cheng, C. C. J.
Heterocycl. Chem. 1996, 33, 113−117.
(3) Shieh, W.-C.; Dell, S.; Repic,
references cited.
(4) Rajabi, F.; Saidi, M., R. Synth. Commun. 2004, 34, 4179.
(5) (a) Shimizu, I.; Lee, Y. Synlett 1998, 1063. (b) Barcelo, G.;
Grenouillat, D.; Senet, J.-P.; Sennyey, G. Tetrahedron 1990, 46, 1839.
(6) Perosa, A.; Selva, M.; Tundo, P.; Zordan, F. Synlett 2000, 272.
(7) Gooden, P. N.; Bourne, R. A.; Parrot, A. J.; Bevinakatti, H. S.;
Irvine, D. J.; Poliakoff, M. Org. Process Res. Dev. 2010, 14, 411.
(8) (a) Henk, L.; Aalten, H. L.; Koten, G.; Grove, D.; Kuilman, M.
T.; Piekstra, O. G.; Lumbertus, A.; Hulshof, L. A.; Roger, A.; Sheldon,
R. A. Tetrahedron 1989, 45, 5565. (b) Grinev, A. N.; Ryabova, S.Y.
Chem. Heterocycl. Compd., Engl. Transl. 1982, 18, 153. (c) Kotake, Y.;
Okauchi, T.; Jijima, A.; Yoshimatsu, K.; Nomura, H. Chem. Pharm.
Bull. 1995, 43, 829.
(9) Dorothea, G. Phenol Derivatives. In Ullmann’s Encyclopedia of
Industrial Chemistry; Barbara, E., Stephen, H., Gail, S., Eds.; VCH
Verlagsgesellschaft: Weinheim, Germany, 1991; Vol. A19.
(10) Nie, J.-Q.; Chen, H.-W.; Song, Q.-H.; Liao, B.; Guo, Q.-X.
Energy Fuels 2010, 24, 5722.
̂
O. Org. Lett. 2001, 3, 4279 and
SUMMARY
■
We have found that the use of a conventional, heated, standard
316 stainless steel or steel-braided PTFE tube reactor is a good
and easily scalable alternative to the use of continuous
microwave-heated reactors. The heat-up is almost as fast as
with microwave heating, and the reactors can easily be scaled
towards large-scale production. The transfer of the reported3
microwave procedure to the continuous flow method went
smoothly, and we found that we could further optimize the
reaction to a catalytic procedure with 10 mol % of DBU and 3
equiv of DMC. The reaction can be run neat in cases where the
starting material is soluble in DMC as phenol (3) is, or with a
small amount of DMF (2−3 vol). The reaction is efficient for
different types of phenols giving a clean reaction in high yields.
EXPERIMENTAL SECTION
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(11) Bomben, A.; Selva, M.; Tundo, P. Ind. Eng. Chem. Res. 1999, 38,
2075. See also ref 6.
(12) Tundo, P.; Rosomilia, A. E.; Arico,
1233.
All solvents were purchased as anhydrous and used as received.
All reagents were used as received. All manipulations were
performed under nitrogen atmosphere. Reactions were
monitored with reversed phase HPLC on a Waters instrument
with a photodiode array detector using a Waters Sunfire (4.8
mm × 50 mm C8 3.5 μm). The mobile phase (water/
acetonitrile/phosphoric acid (0.1%), 85:5:10 in 0 min to
0:90:10 in 3.3 min; 3.3 min to 0:90:10 in 5.0 min; 0:90:10 in 5
min to 85:5:10 in 5.1 min with a flow rate of 3.0 mL/min.
The reactor setup (see Figure 1): Connect the pump with
the coiled tube reactor at the front end. Connect the back end
of the coiled steel-braided PTFE reactor (internal volume 15.8
mL) to a T-joint. To the T-joint is a pressure gauge connected
at one end and to the other a back-pressure regulator prior to
the outlet into the collection flask. Insert the coiled reactor part
into the GC-oven. Fill the reactor with DMC and heat the oven
for the hot zone to 220 °C
̀
J. Chem. Educ. 2010, 87,
A typical experimental procedure is here described for phenol
without solvent. Dissolve phenol (188 g, 2 mol) in DMC (540
g, 6 mol). Add DBU (30.4 g, 0.2 mol). Fill the mixture into the
syringe pump. Start the pump with a flow rate of 1.6 mL/min.
As the pump empties, refill with 60 mL of DMC and continue
to pump. At the end collect a sample to verify that the complete
reaction mixture has left the reactor. Stop the pump and refill
the collection flask into a round-bottom flask. Distill off the
methanol and the DMC at reduced pressure. Thereafter, distill
the anisole at 11 mbar into a collection flask. After distillation is
finished, the obtained yield of anisole is 207 g (96%). After the
distillation, no analysis of the small amount of residue was
performed.
AUTHOR INFORMATION
■
Corresponding Author
Notes
The author declares no competing financial interest.
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dx.doi.org/10.1021/op200379j | Org. Process Res. Dev. 2012, 16, 1150−1153