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Blue Chemistry: Trifluoromethylations Going Large!
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Blue Chemistry: Trifluoromethylations Going Large! Oliver Reiser1,* Visible-light photoredox catalysis has emerged as a powerful tool for organic synthesis, but cost-effective, scalable processes are still underdeveloped. In this issue of Chem, Stephenson and coworkers demonstrate such technology in combination with continuous flow for trifluoromethylations of heteroarenes on a kilogram scale by utilizing readily available trifluoroacetic anhydride as a trifluoromethyl source. The resulting compounds and the underlying methodology are of great relevance in medicinal chemistry. Visible light, which is abundant and available anywhere in the world, can be considered the ultimate energy source for driving chemical transformations. Proposed more than 200 years ago by Ciamician, followed by groundbreaking work in the 1980s and early 1990s by Deronzier, Fukuzumi, Kellogg, Okada, Pac, Pandey, Tanaka, Tomioka, and Willner, the great potential of visible-light photocatalysis has become evident only during the last 6–8 years. Its triumphant course has become possible as a result of two important advances. On the technological side, with the development of low-cost LEDs, high-energy light sources emitting at tunable wavelengths became available and greatly simplified the experimental setup for photoreactions. On the scientific side, the dual [Ru(bpy)3]Cl2 and organocatalyzed asymmetric alkylation of aldehydes, developed in 2008 by MacMillan and coworkers, constituted not only a spectacular advancement in photochemistry but also a greatly useful transformation that was unrivaled for any type of catalysis.1 In short succession, many previously unprecedented photoredox-catalyzed transformations, most significantly novel carbon-carbon bond-forming processes,
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were developed.2 Among them, trifluoromethylation of arenes plays a prominent role given the great importance of this functional group in medicinal chemistry and the limited methodology that is available for its introduction.3 With the photoredox-catalyzed generation of trifluoromethyl radicals from appropriate precursors—such as trifluoromethanesulfonyl chloride, Langlois’s reagent, Ruppert’s reagent, Togni’s reagent, or Umemoto’s reagent—a breakthrough was made in this area, and especially chemoselective late-stage trifluoromethylations opened up exciting possibilities for drug development. Nevertheless, the corrosive nature, non-optimal atom economy, and relatively high cost involved with these trifluoromethylating agents are drawbacks for large-scale applications. Moving photoredox catalysis from the laboratory to the production scale introduces more challenges. For example, the light penetration from an external source through a glass flask into a reaction solution is only in the millimeter range, thus greatly prolonging reaction times in batch processes in larger reaction vessels. A solution to this problem was suggested more than 30 years ago with so-called falling-film photoreactors, in which the re-
Chem 1, 342–350, September 8, 2016 ª 2016 Elsevier Inc.
action solution as a thin film is passed by a photolamp very much like a waterfall rolling down a cliff. With the advent of flow chemistry, an operationally simpler solution that requires no expensive equipment and can be easily set up in any laboratory became available: in the most straightforward realization of this technique, wrapping a thin, hollow Teflon coil around a light source—again made possible by LEDs, which generate little heat—and pumping the reaction solution through this tubing allows in an operationally simple way the transfer of a photochemical batch process to flow. On the basis of this principle, photoflow systems with microreactor glass tubing are now commercially available as well.4 Another factor in scaling up photoredox reactions is the efficiency and cost of the catalyst involved. The best established catalysts are ruthenium- and iridium-based metal complexes, which have been shown to be the most capable photoreductants both in the so-called oxidative quenching cycle (involving direct electron transfer from the photoexcited catalyst to a substrate) and in the reductive quenching cycle (reducing the photoexcited catalyst by a sacrificial electron donor and subsequently transferring an electron from its ground state to the substrate). The high efficiency of such catalysts, which has been demonstrated in some processes exceeding 10,000 turnover cycles, offsets the scarcity and thus cost of these precious metals. Moreover, immobilized versions that allow flow photoprocesses with automatic catalyst refeeding have been developed.5 Metal catalysts based
1Institut
fu¨r Organische Chemie, Universita¨t Regensburg, Universita¨tsstraße 31, 93053 Regensburg, Germany *Correspondence: [email protected] http://dx.doi.org/10.1016/j.chempr.2016.08.005
[Ru(bpy)3]Cl2 (0.1 mol %) MeCN, 45°C, blue light cont. flow, 30 min residence time 48 hr run time CO2Me N Boc
F 3C
CO2Me N Boc 0.95 kg ( 50% yield, 81% purity) 2
O CF 3 N O
1.2 kg 1
CF 3CO2 in situ generation
O F 3C
O O
+ CF 3
inexpensive CF 3 source
N O
Scheme 1. Large-Scale, Continuous-Flow Trifluromethylation Employing Trifluoroacetic Anhydride as the Trifluoromethyl Source The title reaction was conducted in a continuous photoflow system, and impressive flow rates were achieved in a total run time of 48 hr, translating to a production of 0.5 kg/day.
on non-noble metals—especially copper6—or metal-free organic dyes, for which even two-photon processes for challenging bond activations have been demonstrated,7 are notable alternatives. Even more attractive are transformations for which no photoredox catalyst is needed, and indeed it has been shown for quite a number of processes that electron donor-acceptor (EDA) complexes between substrates are often being formed in situ. Such generally short-lived intermediates can be excited with visible light, upon which direct electron transfer between substrates is triggered as the key step for the reaction.8 In this context, the study reported in this issue of Chem by Stephenson and coworkers addresses in a most intriguing
way the above challenges of photoredox catalysis.9 Blue-light-mediated trifluoromethylation of methyl-N-Boc-pyrrole-2carboxylate with [Ru(bpy)3]Cl2 as a catalyst was demonstrated on a kilogram scale (Scheme 1), surpassing the scale used in pioneering studies by the process division of Merck for the synthesis of Elbasvir by a factor of 10.10 The in-situ-generated adduct of readily available pyridine N-oxide and trifluoroacetic anhydride (TFAA) was employed as the trifluoromethylating agent, ultimately allowing trifluoroacetic acid to serve as the trifluoromethyl source. Moreover, pyridine N-oxide proved to be a suitable redox trigger for other perfluorinated anhydrides as well, allowing the facile introduction of perfluoroethyl and perfluoropropyl groups into various arenes and het(arenes).
Furthermore, the study disclosed by Stephenson and coworkers provides valuable insights into the mechanism of the title process. Specifically, they showed that combining TFAA, pyridine N-oxides, and arene formed visible-light-absorbing EDA complexes that could also act as catalysts in this process, although the addition of [Ru(bpy)3]Cl2 as catalyst was generally advantageous. 200 years after Ciamician explored the potential for large-scale photochemical transformations by exposing hundreds of reaction vessels to sunlight on the roof of his institute, it appears that photoflow chemistry is ready to make his vision a reality. 1. Nicewicz, D.A., and MacMillan, D.W.C. (2008). Science 322, 77–80. 2. Ravelli, D., Protti, S., and Fagnoni, M. (2016). Chem. Rev. http://dx.doi.org/10.1021/acs. chemrev.5b00662. 3. Alonso, C., Martı´nez de Marigorta, E., Rubiales, G., and Palacios, F. (2015). Chem. Rev. 115, 1847–1935. 4. Su, Y., Straathof, N.J., Hessel, V., and Noe¨l, T. (2014). Chemistry 20, 10562–10589. 5. Rackl, D., Kreitmeier, P., and Reiser, O. (2016). Green Chem. 18, 214–219. 6. Reiser, O. (2016). Acc. Chem. Res. http://dx. doi.org/10.1021/acs.accounts.6b00296. 7. Ghosh, I., Ghosh, T., Bardagi, J.I., and Ko¨nig, B. (2014). Science 346, 725–728. 8. Kandukuri, S.R., Bahamonde, A., Chatterjee, I., Jurberg, I.D., Escudero-Ada´n, E.C., and Melchiorre, P. (2015). Angew. Chem. Int. Ed. Engl. 54, 1485–1489. 9. Beatty, J.W., Douglas, J.J., Miller, R., McAtee, R.C., Cole, K.P., and Stephenson, C.R.J. (2016). Chem 1, this issue, 456–472. 10. Yayla, H.G., Peng, F., Mangion, I.K., McLaughlin, M.M., Campeau, L.-C., Davies, I.W., DiRocco, D.A., and Knowles, R.R. (2016). Chem. Sci. 7, 2066–2073.
Chem 1, 342–350, September 8, 2016
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Blue Chemistry: Trifluoromethylations Going Large! Oliver Reiser1,* Visible-light photoredox catalysis has emerged as a powerful tool for organic synthesis, but cost-effective, scalable processes are still underdeveloped. In this issue of Chem, Stephenson and coworkers demonstrate such technology in combination with continuous flow for trifluoromethylations of heteroarenes on a kilogram scale by utilizing readily available trifluoroacetic anhydride as a trifluoromethyl source. The resulting compounds and the underlying methodology are of great relevance in medicinal chemistry. Visible light, which is abundant and available anywhere in the world, can be considered the ultimate energy source for driving chemical transformations. Proposed more than 200 years ago by Ciamician, followed by groundbreaking work in the 1980s and early 1990s by Deronzier, Fukuzumi, Kellogg, Okada, Pac, Pandey, Tanaka, Tomioka, and Willner, the great potential of visible-light photocatalysis has become evident only during the last 6–8 years. Its triumphant course has become possible as a result of two important advances. On the technological side, with the development of low-cost LEDs, high-energy light sources emitting at tunable wavelengths became available and greatly simplified the experimental setup for photoreactions. On the scientific side, the dual [Ru(bpy)3]Cl2 and organocatalyzed asymmetric alkylation of aldehydes, developed in 2008 by MacMillan and coworkers, constituted not only a spectacular advancement in photochemistry but also a greatly useful transformation that was unrivaled for any type of catalysis.1 In short succession, many previously unprecedented photoredox-catalyzed transformations, most significantly novel carbon-carbon bond-forming processes,
344
were developed.2 Among them, trifluoromethylation of arenes plays a prominent role given the great importance of this functional group in medicinal chemistry and the limited methodology that is available for its introduction.3 With the photoredox-catalyzed generation of trifluoromethyl radicals from appropriate precursors—such as trifluoromethanesulfonyl chloride, Langlois’s reagent, Ruppert’s reagent, Togni’s reagent, or Umemoto’s reagent—a breakthrough was made in this area, and especially chemoselective late-stage trifluoromethylations opened up exciting possibilities for drug development. Nevertheless, the corrosive nature, non-optimal atom economy, and relatively high cost involved with these trifluoromethylating agents are drawbacks for large-scale applications. Moving photoredox catalysis from the laboratory to the production scale introduces more challenges. For example, the light penetration from an external source through a glass flask into a reaction solution is only in the millimeter range, thus greatly prolonging reaction times in batch processes in larger reaction vessels. A solution to this problem was suggested more than 30 years ago with so-called falling-film photoreactors, in which the re-
Chem 1, 342–350, September 8, 2016 ª 2016 Elsevier Inc.
action solution as a thin film is passed by a photolamp very much like a waterfall rolling down a cliff. With the advent of flow chemistry, an operationally simpler solution that requires no expensive equipment and can be easily set up in any laboratory became available: in the most straightforward realization of this technique, wrapping a thin, hollow Teflon coil around a light source—again made possible by LEDs, which generate little heat—and pumping the reaction solution through this tubing allows in an operationally simple way the transfer of a photochemical batch process to flow. On the basis of this principle, photoflow systems with microreactor glass tubing are now commercially available as well.4 Another factor in scaling up photoredox reactions is the efficiency and cost of the catalyst involved. The best established catalysts are ruthenium- and iridium-based metal complexes, which have been shown to be the most capable photoreductants both in the so-called oxidative quenching cycle (involving direct electron transfer from the photoexcited catalyst to a substrate) and in the reductive quenching cycle (reducing the photoexcited catalyst by a sacrificial electron donor and subsequently transferring an electron from its ground state to the substrate). The high efficiency of such catalysts, which has been demonstrated in some processes exceeding 10,000 turnover cycles, offsets the scarcity and thus cost of these precious metals. Moreover, immobilized versions that allow flow photoprocesses with automatic catalyst refeeding have been developed.5 Metal catalysts based
1Institut
fu¨r Organische Chemie, Universita¨t Regensburg, Universita¨tsstraße 31, 93053 Regensburg, Germany *Correspondence: [email protected] http://dx.doi.org/10.1016/j.chempr.2016.08.005
[Ru(bpy)3]Cl2 (0.1 mol %) MeCN, 45°C, blue light cont. flow, 30 min residence time 48 hr run time CO2Me N Boc
F 3C
CO2Me N Boc 0.95 kg ( 50% yield, 81% purity) 2
O CF 3 N O
1.2 kg 1
CF 3CO2 in situ generation
O F 3C
O O
+ CF 3
inexpensive CF 3 source
N O
Scheme 1. Large-Scale, Continuous-Flow Trifluromethylation Employing Trifluoroacetic Anhydride as the Trifluoromethyl Source The title reaction was conducted in a continuous photoflow system, and impressive flow rates were achieved in a total run time of 48 hr, translating to a production of 0.5 kg/day.
on non-noble metals—especially copper6—or metal-free organic dyes, for which even two-photon processes for challenging bond activations have been demonstrated,7 are notable alternatives. Even more attractive are transformations for which no photoredox catalyst is needed, and indeed it has been shown for quite a number of processes that electron donor-acceptor (EDA) complexes between substrates are often being formed in situ. Such generally short-lived intermediates can be excited with visible light, upon which direct electron transfer between substrates is triggered as the key step for the reaction.8 In this context, the study reported in this issue of Chem by Stephenson and coworkers addresses in a most intriguing
way the above challenges of photoredox catalysis.9 Blue-light-mediated trifluoromethylation of methyl-N-Boc-pyrrole-2carboxylate with [Ru(bpy)3]Cl2 as a catalyst was demonstrated on a kilogram scale (Scheme 1), surpassing the scale used in pioneering studies by the process division of Merck for the synthesis of Elbasvir by a factor of 10.10 The in-situ-generated adduct of readily available pyridine N-oxide and trifluoroacetic anhydride (TFAA) was employed as the trifluoromethylating agent, ultimately allowing trifluoroacetic acid to serve as the trifluoromethyl source. Moreover, pyridine N-oxide proved to be a suitable redox trigger for other perfluorinated anhydrides as well, allowing the facile introduction of perfluoroethyl and perfluoropropyl groups into various arenes and het(arenes).
Furthermore, the study disclosed by Stephenson and coworkers provides valuable insights into the mechanism of the title process. Specifically, they showed that combining TFAA, pyridine N-oxides, and arene formed visible-light-absorbing EDA complexes that could also act as catalysts in this process, although the addition of [Ru(bpy)3]Cl2 as catalyst was generally advantageous. 200 years after Ciamician explored the potential for large-scale photochemical transformations by exposing hundreds of reaction vessels to sunlight on the roof of his institute, it appears that photoflow chemistry is ready to make his vision a reality. 1. Nicewicz, D.A., and MacMillan, D.W.C. (2008). Science 322, 77–80. 2. Ravelli, D., Protti, S., and Fagnoni, M. (2016). Chem. Rev. http://dx.doi.org/10.1021/acs. chemrev.5b00662. 3. Alonso, C., Martı´nez de Marigorta, E., Rubiales, G., and Palacios, F. (2015). Chem. Rev. 115, 1847–1935. 4. Su, Y., Straathof, N.J., Hessel, V., and Noe¨l, T. (2014). Chemistry 20, 10562–10589. 5. Rackl, D., Kreitmeier, P., and Reiser, O. (2016). Green Chem. 18, 214–219. 6. Reiser, O. (2016). Acc. Chem. Res. http://dx. doi.org/10.1021/acs.accounts.6b00296. 7. Ghosh, I., Ghosh, T., Bardagi, J.I., and Ko¨nig, B. (2014). Science 346, 725–728. 8. Kandukuri, S.R., Bahamonde, A., Chatterjee, I., Jurberg, I.D., Escudero-Ada´n, E.C., and Melchiorre, P. (2015). Angew. Chem. Int. Ed. Engl. 54, 1485–1489. 9. Beatty, J.W., Douglas, J.J., Miller, R., McAtee, R.C., Cole, K.P., and Stephenson, C.R.J. (2016). Chem 1, this issue, 456–472. 10. Yayla, H.G., Peng, F., Mangion, I.K., McLaughlin, M.M., Campeau, L.-C., Davies, I.W., DiRocco, D.A., and Knowles, R.R. (2016). Chem. Sci. 7, 2066–2073.
Chem 1, 342–350, September 8, 2016
345