Organic Process Research & Development
Communication
higher purity would be possible by carefully monitoring the
distillation fractions.13
ASSOCIATED CONTENT
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S
* Supporting Information
1H NMR, 13C NMR, and 19F NMR spectra of compound 1.
The Supporting Information is available free of charge on the
We were very pleased to report that the use of silicone oil as
a solvent for this reaction not only improved the reaction yield
dramatically but also obviated the tedious workup and massive
waste production. Just for an estimate, producing 1 kg of the
compound 1 using the original method would generate ∼300
kg of solid and liquid waste, whereas the new method required
only 1 kg of silica gel for filtration. The silicone oil could still be
recycled for further use. To our best knowledge, this is the first
report of conducting an organic reaction using silicone oil as an
organic solvent, and it sets a great example for green chemistry.
The method should be applicable to the synthesis of many
other chromenes10 and chromans via such an intramolecular
reaction which generates no other product(s). It can also be
potentially used for intermolecular reactions such as the Diels−
Alder reaction as long as the reagents and products have
reasonable solubility in silicone oil and do not have a negative
impact on it. Such a reaction would have wide application in
pharmaceutical as well as chemical industry with tremendously
positive impact on the environment.
AUTHOR INFORMATION
Corresponding Author
Present Address
J.K.: Wuxi AppTec Co., 168 Nanhai Road, TEDA, Tianjin,
China 300457.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank Mr. Jianping Pan, Peter Dormer, and Dr. Alexei
Buevich for the final purification and characterization of
compound 1. We also thank Dr. Brian McKittrick for providing
valuable suggestions to the manuscript.
In summary, we have reported for the first time the use of
silicone oil as an organic solvent for an organic reaction as well
as a novel method to produce chromene 1 in a significantly
improved yield with minimum waste production. This novel
synthetic procedure would serve as a general method to
produce simple chromenes in large quantities. We certainly
hope that our example will lead to the discovery of many more
green chemistry examples in the future.
REFERENCES
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(1) Thomas, N.; Zhachariah, S. M. Asian J. Pharma. Clin. Res. 2013, 6,
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(4) Zsindely, J.; Schmidt, H. Helv. Chim. Acta 1968, 51, 1510.
(5) Bigi, F.; Carloni, S.; Maggi, R.; Muchetti, C.; Sartori, G. J. Org.
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(6) Majumdar, N.; Paul, N. D.; Mandal, S.; de Bruin, B.; Wulff, W. D.
ACS Catal. 2015, 5, 2329.
EXPERIMENTAL SECTION
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(7) Majumdar, N.; Korthals, K. A.; Wulff, W. D. J. Am. Chem. Soc.
2012, 134, 1357.
(8) Paul, N. D.; Mandal, S.; Otte, M.; Cui, X.; Zhang, P. X.; de Bruin,
B. J. Am. Chem. Soc. 2014, 136, 1090.
(9) Xu, R.; Cole, D.; Asberom, T.; Bara, T.; Bennett, C.; Burnett, D.
A.; Clader, J.; Domalski, M.; Greenlee, W. J.; Hyde, L.; Josien, H.; Li,
H.; McBriar, M.; McKittrick, B. A.; McPhail, A. T.; Pissarnitski, D.;
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710 g of compound 6 (prepared according to refs 2 and 10,
4.22 mol) was dissolved in 7.5 L of silicon oil (recycled from
the previous 690 g scale reaction) in a 12 L three-neck flask
equipped with a mechanic stirrer under nitrogen atmosphere.
The solution was heated to 195 °C (internal temperature)
using a heating mantle for 18 h. The crude was cooled down,
1
and a sample was taken directly for H NMR. The NMR
spectrum indicated the presence of 8% of starting material.
Distillation of the crude through a 15 cm Vigreux column at 3−
4 mmHg into a room temperature-cooled receiver was initiated.
The first fraction was collected at 75 °C (internal temperature,
external temperature 115 °C, 4 mmHg) to afford 61 g of
compound 1 (91% pure, with 9% starting material based on 1H
NMR).14 A major fraction of 1 was obtained at the same
temperature (444 g, 94% pure with 6% starting material). The
third and last fraction (40 g of 1, 97% pure with 3% starting
material) was collected and combined with the major fraction.
Excluding the first fraction (which was recycled for the next
round reaction), this process provide 484 g of the desired
product 1 as colorless oil in 68% yield with 94% purity. The
silicone oil was filtered through a 1 kg silica gel pad.
1H NMR (500 MHz, CDCl3): δ 4.92 (dd, 2 H, J = 3.4, 1.9
Hz, C2 CH2) 5.89 (dt, 1 H, J = 10.1, 3.4 Hz, C3 CH), 6.55
(ddd, 1H, J = 9.2, 8.6, 3.8 Hz, C6 CH), 6.67 (ddt, 1 H, J = 10.1,
3.8, 1.9 Hz, C4 CH), 6.89 (ddd, 1 H, J = 10.1, 9.2, 5.1 Hz, C7
CH).
(10) Sund, C.; Roue, N.; Linstrom, S.; Antonov, D.; Sahlberg, C.;
̈
Jansson, K. PCT Int. Appl. WO2005066131.
(11) At the time we initiated this scale up investigation (early 2007),
there was no report of optimization of the Claisen reaction on large
scale. We thank Dr. Hans-Jurgen Federsel who kindly reminded us of
̈
their elegant work on this reaction. (a) Federsel, H.-J.; Sveno, A.
Process Chemistry in the Pharmaceutical Industry, Volume II: Challenges
in an Ever Changing Climate; Gadamasetti, K., Braish, T., Eds; Taylor &
Francis: Boca Raton, 2008; Ch 7, pp 111−135. (b) Federsel, H.-J.
Bioorg. Med. Chem. 2010, 18, 5775.
(12) It was reported in 2010 that dowtherm A could be used as a
solvent for the Claisen rearrangement. Walker, A. J.; Adolph, S.;
Connell, R. B.; Laue, K.; Roeder, M.; Rueggeberg, C. J.; Hahn, D. U.;
Voegtli, K.; Watson, J. Org. Proc. Res. Dev. 2010, 14, 85.
(13) The difficulty of completely separating the starting material
from the desired product by fractional distillation under our conditions
was likely due to the high saturation pressure requirement for
distillation vs the large volume of the reaction flask. It is therefore
conceivable to gain better separation by using smaller reaction flask
and longer Vigreux column for distillation.
13C NMR (126 MHz, CDCl3): δ 154.10 (dd, J = 245.0, 2.4
Hz), 147.46 (dd, J = 240.6, 3.1 Hz), 141.99 (dd, J = 12.6, 7.3
Hz), 122.80 (d, J = 2.6 Hz), 117.59−117.42 (m), 115.83 (dd, J
= 20.8, 10.0 Hz), 112.81 (dd, J = 20.7, 2.4 Hz), 107.06 (dd, J =
23.8, 7.1 Hz), 65.85.
(14) We observed internal boiling point variation ranging from 75 to
120 °C in different runs. This was due to the challenge of keeping the
three-neck system tightly sealed while operating.
19F NMR (500 MHz, CDCl3): δ −142.8, −127.8.
C
Org. Process Res. Dev. XXXX, XXX, XXX−XXX