An approach for continuous-flow processing of reactions that involve the in situ formation of organic products

Tetrahedron Letters

Volumn 52, Issue 2, 2011, Pages 263-265

  Kelly, Christopher B ^a   Lee, Christopher ^a   Leadbeater, Nicholas E ^a  

^a UNIVERSITY OF CONNECTICUT   (United States)

Author keywords

Coumarins; Dihydropyridines; Flow chemistry; Microwave heating; Suzuki coupling

Indexed keywords

ORGANIC SOLVENT;

ARTICLE; CHEMICAL REACTION; FLOW RATE; MICROWAVE COOKING;

EID: 78650017489     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2010.11.027     Document Type: Article

References (19)

1. For an overview see: S.V. Luis, E. Garcia-Verdugo, Chemical Reactions and Processes under Flow Conditions, Royal Society of Chemistry 2010 Cambridge UK
2. For recent reviews see: T. Razzaq, and C.O. Kappe Chem. Asian J. 5 2010 1274 1289
3. D. Mark, S. Haeberle, G. Roth, F. von Stetten, and R. Zengerle Chem. Soc. Rev. 39 2010 1153 1182
4. N. Kockmann, and D.M. Roberge Chem. Eng. Technol. 32 2009 1682 1694
5. C. Wiles, and P. Watts Eur. J. Org. Chem. 2008 1655 1671
6. S. Sedelmeier, S.V. Ley, I.R. Baxendale, and M. Baumann Org. Lett. 12 2010 3618 3621
7. Uniqsis FlowSyn (www.uniqsis.com ).
8. J.R. Schmink, C.M. Kormos, W.G. Devine, and N.E. Leadbeater Org. Process Res. Dev. 14 2010 205 214
9. M.D. Bowman, J.R. Schmink, C.M. McGowan, C.M. Kormos, and N.E. Leadbeater Org. Process Res. Dev. 12 2008 1078 1088
10. 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.
11. From a synthetic chemistry perspective, there is the potential for a Knoevenagel condensation between the acetone solvent and the ethyl acetoacetate reagent.
12. M.D. Bowman, J.L. Holcomb, C.M. Kormos, N.E. Leadbeater, and V.A. Williams Org. Process Res. Dev. 12 2008 41 57
13. 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 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.
14. 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 Note 10 (www.uniqsis.com ).
15. R.K. Arvela, N.E. Leadbeater, M.S. Sangi, V.A. Williams, P. Granados, and R.D. Singer J. Org. Chem. 70 2005 161 168
16. N.E. Leadbeater, V.A. Williams, T.M. Barnard, and M.J. Collins Org. Process Res. Dev. 10 2006 833 837
17. R.K. Arvela, N.E. Leadbeater, and M.J. Collins Tetrahedron 61 2005 9349 9355
18. 2 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.
19. 4, the solvent was removed on a rotary evaporator and the isolated product yield obtained.