Communication pubs.acs.org/OPRD
Synthesis of a Carprofen Analogue Using a Continuous Flow UVReactor Antoine Caron, Augusto C. Hernandez-Perez, and Shawn K. Collins* Department of Chemistry and Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown, Montréal, Québec, Canada H3C 3J7 S Supporting Information *
UV light photochemical flow reactor assembled from commercially available materials and demonstrate its utility in the synthesis of a carprofen9 derivative.
ABSTRACT: A continuous flow UV light reactor has been constructed using commercially available equipment, and its efficiency was demonstrated by performing a photocyclodehydrogenation reaction to prepare carbazole derivatives of the drug carprofen.
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RESULTS AND DISCUSSION At the outset of this work, no commercial combined UVreactor/continuous flow setup was available. During the preparation of this manuscript, the company Vapourtec announced a commercial UV-reactor for use with its own continuous flow apparatus.10 Consequently, a UV-reactor that was commercially available and easily assembled with existing continuous flow infrastructure was desired. Upon examination of commercial photoreactors, the Luzchem LZC-5 was selected.11 Advantages of the LZC-5 setup include its relatively small size (∼12 × 12 × 8.5 in.) whose interior can still accommodate various preassembled FEP-tubing reactors (or other tubing), which provides flexibility in controlling reaction times, accommodating both short and long residence times/ volumes. The reactor’s size allows it to fit easily in most fumehoods if more ventilation is required. The flow tubing was inserted into the photoreactor through an exhaust port located on the backside and the front door of the photochamber provided easy access to the tubing reactors (Figure 2, bottom). Both Uniqsis and Vapourtec modules were found to be compatible with the UV reactor and provided identical results. The irradiation wavelength is controlled by side lamps (four each side) (Figure 2, top). While the exchange of different lamps is convenient, the use filters to select certain wavelengths are not possible. While no effort was made to perform reactions at higher or lower temperatures, it should be noted that temperatures inside the box remained relatively constant at various wavelengths as there is sufficient air ventilation in the reactor that the temperature remained slightly above room temperature (80% 2), but the appearance of new unwanted side-products complicated the purification and accurate determination of the yield. 1572
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(3) For an example see: Pimparkar, K.; Yen, B.; Goodell, J. R.; Martin, V. I.; Lee, W.-H.; Porco, J. A., Jr.; Beeler, A. B.; Jensen, K. J. J. Flow Chem. 2011, 2, 53. (4) (a) Wiles, C.; Watts, P. Green Chem. 2014, 16, 55. (b) Hoffmann, N. Chem. Rev. 2008, 108, 1052. (c) Zeitler, K. Angew. Chem., Int. Ed. 2009, 48, 9785. (d) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527. (e) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102. (5) Tucker, J. W.; Zhang, Y.; Jamison, T. F.; Stephenson, C. R. J. Angew. Chem., Int. Ed. 2012, 51, 4144. (6) Hernandez-Perez, A. C.; Collins, S. K. Angew. Chem., Int. Ed. 2013, 52, 12696. (7) (a) Joergensen, K. B. Molecules 2010, 15, 4334. (b) Mallory, F. B.; Mallory, C. W. Org. Reactions 1984, 30, 1. (8) (a) Martin, V. I.; Goodell, J. R.; Ingham, O. J.; Porco, J. A., Jr.; Beeler, A. B. J. Org. Chem. 2014, 79, 3838. (b) Bos, P. H.; Antalek, M. T.; Porco, J. A., Jr.; Stephenson, C. R. J. J. Am. Chem. Soc. 2013, 135, 17978. (9) (a) Mellini, P.; Carafa, V.; Di Rienzo, B.; Rotili, D.; De Vita, D.; Cirilli, R.; Gallinella, B.; Provvisiero, D. P.; Di Maro, S.; Novellino, E. ChemMedChem 2012, 7, 1905. (b) Favia, A. D.; Habrant, D.; Scarpelli, R.; Migliore, M.; Albani, C.; Bertozzi, S. M.; Dionisi, M.; Tarozzo, G.; Piomelli, D.; Cavalli, A. J. Med. Chem. 2012, 55, 8807. (c) Narlawar, R.; Perez Revuelta, B. I.; Haass, C.; Steiner, H.; Schmidt, B.; Baumann, K. J. Med. Chem. 2006, 49, 7588. (d) Allegretti, M.; Bertini, R.; Cesta, M. C.; Bizzarri, C.; Di Bitondo, R.; Di Cioccio, V.; Galliera, E.; Berdini, V.; Topai, A.; Zampella, G. J. Med. Chem. 2005, 48, 4312. (10) During the preparation of this manuscript, Vapourtec reported a new commercial UV reactor, see: http://www.vapourtec.co.uk/ products/photochemicalreactor. (11) (a) Luzchem products, Side irradiation model (LZC-5). http:// www.luzchem.com/products/lzc-5.php. (b) Luzchem products, Photoreactor Lamps and Filters. http://www.luzchem.com/products/DBlamps.php. (12) For examples of additional UV reactors and methods to maintain temperatures, see: (a) Laurino, P.; Kikkeri1, R.; Seeberger, P. H. Nat. Protocols 2011, 6, 1209. (b) Lévesque, F.; Seeberger, P. H. Angew. Chem., Int. Ed. 2012, 51, 1706. (c) Lévesque, F.; Seeberger, P. H. Org. Lett. 2011, 13, 5008. (d) Knowles, J. P.; Elliott, L. D.; BookerMilburn, K. I. Beilstein J. Org. Chem. 2012, 8, 2025. (13) For a description of the light distribution in the tubing, please see the Supporting Information. (14) (a) Gribble, G. W. Alkaloids 2012, 71, 1. (b) Schmidt, A. W.; Reddy, K. R.; Knoelker, H.-J. Chem. Rev. 2012, 112, 3193. (15) Maneerat, W.; Ritthiwigrom, T.; Cheenpracha, S.; Promgool, T.; Yossathera, K.; Deachathai, S.; Phakhodee, W.; Laphookhieo, S. J. Nat. Prod. 2012, 75, 741. (16) For recent advances in the synthesis of carbazoles see: (a) Tsang, P. W. C.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (b) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184. (c) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133, 5996. (d) Stokes, B. J.; Jovanović, B.; Dong, H.; Richert, K. J.; Riell, R. D.; Driver, T. G. J. Org. Chem. 2009, 74, 3225. (e) Stokes, B. J.; Richert, K. J.; Driver, T. G. J. Org. Chem. 2009, 74, 6442. (17) (a) Clark, V. M.; Cox, A.; Herbert, E. J. J. Chem. Soc. C 1968, 831. (b) Carruthers, W. Chem. Commun. 1966, 272. (c) Grellmann, K. H.; Sherman, G. M.; Linschitz, H. J. Am. Chem. Soc. 1963, 85, 1881. (18) For more mechanistic and photochemical information of the UV-mediated cyclization of carbazoles see: (a) Neckers, D. C. Mechanistic Organic Photochemistry; Reinhold Publishing Corporation: New York, 1967; pp 239−241. (b) Huigsen, R. Angew. Chem., Int. Ed. 1980, 19, 947. (c) Chapman, O. L.; Elan, G. L.; Clardy, J. J. Am. Chem. Soc. 1971, 93, 2918. (d) Föster, E. W.; Grellmann, K. H.; Linschitz, H. J. Am. Chem. Soc. 1973, 95, 3108. (e) Fischer, G.; Fischer, E.; Grellman, K. H.; Linschitz, H.; Temizer, A. J. Am. Chem. Soc. 1974, 96, 6267. (f) Grellman, K.-H.; Kühnle, W.; Weller, H.; Wolff, T. J. Am. Chem. Soc. 1981, 103, 6889. (g) Görner, H. J. Phys. Chem. A 2008, 112,
Scheme 3. Synthesis of additional carprofen derivatives
In summary, a UV reactor/continuous flow setup has been assembled using both commercially available flow modules (Vapourtec/Uniqsis) and photoreactors (Luzchem LZC-5). The infrastructure afforded a modular setup that allowed for use of large reactor volumes and modular control of the UV wavelength of irradiation. As a demonstration of the efficiency, the synthesis of carbazoles was demonstrated in good yield. In addition, the synthesis of carprofen derivatives was possible and allowed for the synthesis of different regioisomers of potentially interesting carbazole skeletons. Considering the widespread interest in continuous flow methods and the synthesis of heterocycles, the reactor setup described herein should find wide application in process applications.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures and characterization data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors acknowledge the Natural Sciences and Engineering Research Council of Canada (NSERC), Université de Montreal, and the Centre for Green Chemistry and Catalysis (CGCC) for generous funding. The Canadian Foundation for Innovation (CFI) is acknowledged for generous funding of the flow chemistry infrastructure.
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REFERENCES
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1245. (h) Shizuka, H.; Takayama, Y.; Morita, T.; Matsumoto, S.; Tanaka, I. J. Am. Chem. Soc. 1971, 93, 5987. (19) (a) Ibrahim-Ouali, M.; Missoum, A.; Sinibaldi, M.-E.; Troin, Y.; Gramain, J.-C. Synth. Commun. 1996, 26, 657. (b) Lemster, T.; Pindur, U.; Lenglet, G.; Depauw, S.; Dassi, C.; David-Cordonnier, M.-H. Eur. J. Med. Chem. 2009, 44, 3235. (c) Protti, S.; Palmieri, A.; Petrini, M.; Fagnoni, M.; Ballini, R.; Albini, A. Adv. Synth. Catal. 2013, 355, 643. (20) Traditionally, molecular oxygen has been used as the oxidant to promote aromatization fo the carbazole following electrocyclization; see ref 17. The photocyclizations described herein employed an I2/ propylene oxide oxidant system that has been used for the same purpose for the UV-mediated synthesis of helicenes, see (a) Blackburn, E. V.; Loader, C. E.; Timmons, C. J. J. Chem. Soc. C 1968, 1576. (b) Liu, L.; Katz, T. J. Tetrahedron Lett. 1991, 32, 6831. (21) Yamakawa, N.; Suemasu, S.; Matoyama, M.; Tanaka, K.; Katsu, T.; Miyata, K.; Okamoto, Y.; Otsuka, M.; Mizushima, T. Bioorg. Med. Chem. 2011, 19, 3299.
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