C. B. Kelly et al. / Tetrahedron Letters 52 (2011) 263–265
265
equipped with a top that allows tube access. Ethyl acetate was placed in
another glass bottle. The aluminium block was heated from room temperature
to 110 °C, passing ethanol/water (1:1 mixture) through the coil reactor, from
bottom to top, at a rate of 1 mL/min. The flow was then changed from solvent
to reaction mixture by means of a switch on the control unit. The reaction
mixture was then passed through the coil reactor at a rate of 1 mL/min. As the
mixture neared the end of the coil reactor, an empty, clean collection vessel
was put in place and a flow of ethyl acetate (1 mL/min) started into the T-piece
mixer. After all the reaction mixture had entered the coil reactor, the flow was
changed back to solvent and this flowed through the reactor at a rate of 1 mL/
min to push the remaining reaction mixture through and out into the collection
vessel. As soon as this was achieved, the flow was stopped. The contents of the
collection vessel were transferred to a separatory funnel, the aqueous layer
removed, the organics washed with water, then 50% calcium chloride and
finally brine. The organic solvent was removed on a rotary evaporator and the
product conversion determined by means of NMR spectroscopy.
of biaryl occurred when intercepting the product stream with ethyl
acetate (2 mL/min). Again, a quantitative conversion was obtained
and, upon isolation, a 97% yield recorded.13
In summary, we have shown that a very simple adaptation al-
lows batch protocols developed using microwave heating that in-
volve formation of solid organic products to be scaled up using
conventionally-heated flow chemistry without need for re-optimi-
zation or modification of the reaction conditions. Upon exiting the
heated zone, the product stream is intercepted with a flow of or-
ganic solvent solubilizing the product and allowing it to pass to
the collection vessel without aggregation of particulate material.
Acknowledgements
10. An approach for Hantzch synthesis of the same 1,4-dihydropyridine has
previously been developed using flow chemistry but in a more ethanol-rich
solvent mixture, probably keeping the product in solution throughout. A 42%
yield was reported: Bagley, M. C.; Fusillo, V.; Lubinu, M. C., Uniqsis Application
11. (a) Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.; Williams, V. A.; Granados, P.;
Singer, R. D. J. Org. Chem. 2005, 70, 161–168; (b) Leadbeater, N. E.; Williams, V.
A.; Barnard, T. M.; Collins, M. J. Org. Process Res. Dev. 2006, 10, 833–837; (c)
Arvela, R. K.; Leadbeater, N. E.; Collins, M. J. Tetrahedron 2005, 61, 9349–9355.
12. Preparation of 4-methoxybiphenyl: 4-Bromoanisole (18.7 g, 100 mmol),
phenylboronic acid (14.6 g, 120 mmol), NaOH (8 g, 200 mmol), ethanol
(100 mL), water (100 mL) and an aliquot of palladium ICP standard solution
Funding from the National Science Foundation (CAREER award
CHE-0847262) and the University of Connecticut is acknowledged.
Uniqsis Inc. is thanked for access to a FlowSyn continuous-flow
unit.
References and notes
1. For an overview see: Chemical Reactions and Processes under Flow Conditions,
Royal Society of Chemistry; Luis, S. V., Garcia-Verdugo, E., Eds.; Cambridge: UK,
2010.
2. For recent reviews see: (a) Razzaq, T.; Kappe, C. O. Chem. Asian J. 2010, 5, 1274–
1289; (b) Mark, D.; Haeberle, S.; Roth, G.; von Stetten, F.; Zengerle, R. Chem. Soc.
Rev. 2010, 39, 1153–1182; (c) Kockmann, N.; Roberge, D. M. Chem. Eng. Technol.
2009, 32, 1682–1694; (d) Wiles, C.; Watts, P. Eur. J. Org. Chem. 2008, 1655–
1671.
(800 lL of a 1000 ppm PdCl2 stock solution) were combined in a glass bottle
equipped with a top that allows tube access. Ethyl acetate was placed in
another glass bottle. The aluminium block was heated from room temperature
to 150 °C, passing ethanol through the coil reactor, from bottom to top, at a rate
of 2 mL/min. The flow was then changed from solvent to reaction mixture by
means of a switch on the control unit. The reaction mixture was then passed
through the coil reactor at a rate of 2 mL/min. As the mixture neared the end of
the coil reactor, an empty, clean collection vessel was put in place and a flow of
ethyl acetate (2 mL/min) started into the T-piece mixer. After all the reaction
mixture had entered the coil reactor, the flow was changed back to solvent and
this flowed through the reactor at a rate of 2 mL/min to push the remaining
reaction mixture through and out into the collection vessel. As soon as this was
achieved, the flow was stopped. The contents of the collection vessel were
transferred to a separatory funnel, the aqueous layer removed, the organics
washed with water, then 50% calcium chloride and finally brine. The organic
solvent was removed on a rotary evaporator and the product conversion
determined by means of NMR spectroscopy.
3. Sedelmeier, S.; Ley, S. V.; Baxendale, I. R.; Baumann, M. Org. Lett. 2010, 12,
3618–3621.
5. (a) Schmink, J. R.; Kormos, C. M.; Devine, W. G.; Leadbeater, N. E. Org. Process
Res. Dev. 2010, 14, 205–214; (b) Bowman, M. D.; Schmink, J. R.; McGowan, C.
M.; Kormos, C. M.; Leadbeater, N. E. Org. Process Res. Dev. 2008, 12, 1078–1088.
6. Preparation of 3-acetylcoumarin: Salicylaldehyde (5.3 mL, 50 mol), ethyl
acetoacetate (6.4 mL, 50 mol) and piperidine (0.4 mL, 8 mol %) and ethyl
acetate (50 mL) were combined in a glass bottle equipped with a top that
allows tube access. Acetone was placed in another glass bottle. The aluminium
block was heated from room temperature to 140 °C, passing ethyl acetate
through the coil reactor, from bottom to top, at a rate of 1.5 mL/min. The flow
was then changed from solvent to reaction mixture by means of a switch on the
control unit. The reaction mixture was then passed through the coil reactor at a
rate of 1.5 mL/min. As the mixture neared the end of the coil reactor, an empty,
clean collection vessel was put in place and a flow of acetone (1.5 mL/min)
started into the T-piece mixer. After all the reaction mixture had entered the
coil reactor, the flow was changed back to solvent and this flowed through the
reactor at a rate of 1.5 mL/min to push the remaining reaction mixture through
and out into the collection vessel. As soon as this was achieved, the flow was
stopped. The organic solvent was removed on a rotary evaporator and the
product conversion determined by means of NMR spectroscopy. The product
was then purified by washing with cold ethanol and dried under vacuum.
13. Preparation of 4-acetylbiphenyl: 4-Bromoacetophenone (5.06 g, 25 mmol),
phenylboronic acid (3.65 g, 30 mmol), NaOH (2 g, 50 mmol), ethanol (80 mL),
water (60 mL) and an aliquot of palladium ICP standard solution (200 lL of a
1000 ppm PdCl2 stock solution) were combined in a glass bottle equipped with
a top that allows tube access. Ethyl acetate was placed in another glass bottle.
The aluminium block was heated from room temperature to 150 °C, passing
ethanol through the coil reactor, from bottom to top, at a rate of 2 ml/min. The
flow was then changed from solvent to reaction mixture by means of a switch
on the control unit. The reaction mixture was then passed through the coil
reactor at a rate of 2 mL/min. As the mixture neared the end of the coil reactor,
an empty, clean collection vessel was put in place and a flow of ethyl acetate
(2 mL/min) started into the T-piece mixer. After all the reaction mixture had
entered the coil reactor, the flow was changed back to solvent and this flowed
through the reactor at a rate of 2 mL/min to push the remaining reaction
mixture through and out into the collection vessel. As soon as this was
achieved, the flow was stopped. The contents of the collection vessel were
transferred to a separatory funnel, the aqueous layer removed, the organics
washed with water, then 50% calcium chloride and finally brine. The organic
7. From
a synthetic chemistry perspective, there is the potential for a
Knoevenagel condensation between the acetone solvent and the ethyl
acetoacetate reagent.
8. Bowman, M. D.; Holcomb, J. L.; Kormos, C. M.; Leadbeater, N. E.; Williams, V. A.
Org. Process Res. Dev. 2008, 12, 41–57.
9. Hantzch synthesis of a 1,4-dihydropyridine: Benzaldehyde (5.3 g, 50 mmol), ethyl
acetoacetate (21.5 mL, 160 mmol), concentrated ammonium hydroxide (28 mL,
800 mmol), ethanol (50 mL) and water (50 mL) were combined in a glass bottle
washings were dried over MgSO4, the solvent was removed on
evaporator and the isolated product yield obtained.
a rotary