Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR inline analysis

  1. Magnus Rueping,
  2. Teerawut Bootwicha and
  3. Erli Sugiono

Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany

  1. Corresponding author email

This article is part of the Thematic Series "Chemistry in flow systems II".

Guest Editor: A. Kirschning
Beilstein J. Org. Chem. 2012, 8, 300–307. https://doi.org/10.3762/bjoc.8.32
Received 03 Jan 2012, Accepted 13 Feb 2012, Published 23 Feb 2012

  • Full Research Paper

Abstract

The asymmetric organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow microreactors has been developed. Reaction monitoring was achieved by using an inline ReactIR flow cell, which allows fast and convenient optimization of reaction parameters. The reductions proceeded well, and the desired products were isolated in high yields and with excellent enantioselectivities.

Keywords: asymmetric reduction; binolphosphoric acid; Brønsted acid; Hantzsch dihydropyridine; IR spectroscopy; real-time analysis

Introduction

In recent years, a growing interest in microreactor technology has been seen in the scientific community and the development of microfabricated reaction systems is actively pursued. Microreactor technology offers numerous advantages, including precise control of reaction variables, enhanced mixing quality, improved operational safety, reduced reagent consumption and ready scale-up of chemical processes. Due to the high surface-area-to-volume ratios of microstructured reactors, a high thermal rate and high portability of substrates can be achieved, which leads to improved product formation [1-42]. Furthermore, by incorporating inline analytical devices the progress of reactions can be monitored and analyzed in real time, allowing fast reaction screening and optimization [43-55].

Continuous flow microreactors have been applied to a number of standard transformations in organic synthesis [56-80]; however, examples regarding asymmetric reactions as well as organocatalytic reactions are scarce [81-96]. Herein, we present the first example of a continuous-flow organocatalytic asymmetric transfer hydrogenation performed in a microreactor. In this work a ReactIR flow cell was coupled with the microreactor and applied as an inline monitoring device for optimizing the reactions.

Results and Discussion

The continuous-flow microreactor system for the experiment was set up according to Scheme 1. The flow device was set up either with a single reactor, or with multiple reactors when a prolonged residence time was needed. The reagents were introduced separately, by using a syringe pump, through two inlets connected to Y-shaped connectors. The internal reaction temperature was monitored with an internal thermal sensor. The ReactIR 45m microflow cell equipped with a DiComp ATR (diamond-composite attenuated total reflection) probe was attached to the microreactor at the end of the reaction stream and was used as an inline analytical tool to determine the optimum reaction conditions. The IR spectra were recorded at predefined intervals and the raw data were analysed with iC-IR analysis software.

[1860-5397-8-32-i1]

Scheme 1: Experimental setup for the asymmetric transfer hydrogenation.

The first reaction examined the asymmetric organocatalytic transfer hydrogenation [97-101] of benzoxazine 3a in the presence of Hantzsch dihydropyridine 2a as hydrogen source and a catalytic amount of chiral Brønsted acid 1a (Scheme 2) [102].

[1860-5397-8-32-i2]

Scheme 2: Asymmetric hydrogenation of benzoxazines.

Initial experiments were carried out at 0.1 mL min−1 flow rate in a commercial glass microreactor, which was attached to the ReactIR flow cell for in situ reaction monitoring. In order to control the reaction and to determine the use of educts and formation of product, reference spectra of the starting materials, solvents and reagents were recorded. Figure 1b and Figure 1c show real time IR spectra of the reaction mixtures after the subtraction of solvent in the spectral region of 1440 and 1530 cm−1. For direct inline analysis the signals at [Graphic 27] = 1479 cm−1 and [Graphic 27] = 1495 cm−1 were ideal as they could easily be assigned to benzoxazine 3a and dihydrobenzoxazine 4a. Thus, in continuous flow the substrate consumption and product formation could readily be determined.

[1860-5397-8-32-1]

Figure 1: In situ ReactIR monitoring: (a) Trend curve of product formation at different temperatures. (b) Reaction spectra showing the consumption of the substrate and the formation of product at different temperatures. (c) Three-dimensional time-resolved spectral data.

In order to find the optimal temperature for the asymmetric continuous-flow reduction, a temperature profile was recorded. The reaction temperature was initially 5 °C and was increased to 60 °C over a period of 8 h, while the conversion was monitored by inline IR-spectroscopy. Figure 1a shows the real-time plot of the peak intensity versus reaction time for the 1495 cm−1 absorption band at different temperatures. The trend-curve analysis by peak-height integration of this absorption band shows increased product formation with increasing temperature. By monitoring the signal change in this spectral region over the time of the reaction, the product formation ([Graphic 27] = 1495 cm−1) and substrate consumption ([Graphic 27] = 1479 cm−1) can be determined in real time. Analysis of the spectra provided us with an optimal temperature of 60 °C for this reaction. In general the IR-flow-cell technology is a good tool for in situ monitoring and provides a fast read out of reaction progress as the intensity of substrate and product peaks can be directly related to the conversion. Thus, as exemplified above, applying the inline analysis to different reaction parameters provides a fast and convenient method for reaction optimization.

By using the optimized reaction temperature and flow rate of 0.1 mL min−1, further experiments were conducted to examine the influence of the residence time on the conversion (Table 1). By performing the reaction with a residence time of 20 min, the product was isolated in 50% yield. With residence times of 40 min and 60 min, the product was isolated in 87% and 98% yields, respectively (Table 1).

Table 1: Optimization of the Brønsted acid catalyzed reduction of benzoxazines.a

[Graphic 1]
Entry 1a
[mol %] 		Residence time
[min] 		Flow rate
[mL min−1] 		Yield
[%]b
1 2 20 0.1 50%
2 2 40 0.1 87%
3 2 60 0.1 98%

aReaction conditions: 3a, 2a (1.2 equiv), 1a in CHCl3 (0.05 M) at 60 °C. bIsolated yields after column chromatography.

Having found the optimum reaction conditions, we next investigated the scope of the Brønsted acid catalyzed reduction of 3-aryl-substituted benzoxazines 3 (Table 2). In general, 3-aryl benzoxazines 3 bearing either electron-withdrawing or electron-donating groups can be reduced in a continuous fashion and the products 4 were isolated in good yields and with excellent enantioselectivities.

Table 2: Scope of the Brønsted acid catalyzed reduction of benzoxazines.a

[Graphic 2]
Entry Product 4 Yield [%]b ee [%]c
1 [Graphic 3]
4a 		98 98
2 [Graphic 4]
4b 		96 97
3 [Graphic 5]
4c 		98 98
4 [Graphic 6]
4d 		81 97
5 [Graphic 7]
4e 		85 99

aReaction conditions: 3, 2a (1.2 equiv), 2 mol % 1a in CHCl3 (0.05 M) at 60 °C, flow rate 0.1 mL min−1, residence time = 60 min. bIsolated yields after column chromatography. cDetermined by chiral HPLC analysis.

Encouraged by the results, we next studied the transfer hydrogenation of quinolines 5 [103-106]. The optimum reaction temperature was determined according to the experiment described above. The effects of catalyst loading and residence time on the conversion and the enantioselectivity are summarized in Table 3. Performing the reaction at 60 °C with 5 mol % of Brønsted acid 1a and residence time of 20 min afforded the desired product in 88% yield and 94% enantioselectivity (Table 3, entry 1). When the catalyst loading was reduced from 5 mol % to 2 mol %, a residence time of 40 min was found to be optimal to achieve comparable results (Table 3, entry 1 versus entry 2). A slight improvement of the conversion was observed by increasing the residence time to 60 min (Table 3, entry 3 versus entry 2). The catalyst loading can be decreased to 0.5 mol % without loss of reactivity and selectivity; the desired tetrahydroquinoline was isolated in 96% yield with 94% enantiomeric excess (Table 3, entry 5). A further decrease of catalyst loading to 0.1 mol % resulted in a significant drop in chemical yield, affording the product in lower yield while enantioselectivity was maintained (Table 3, entry 6).

Table 3: Optimization of the Brønsted acid catalyzed transfer hydrogenation of quinolines.a

[Graphic 8]
Entry 1a
[mol %] 		t
[min] 		Flow rate
[mL min−1] 		Yield
[%]b 		ee
[%]c
1 5 20 0.1 88 94
2 2 40 0.1 91 92
3 2 60 0.1 97 92
4 1 60 0.1 97 92
5 0.5 60 0.1 96 94
6 0.1 60 0.1 72 94
7d 0.5 60 batch 67 94

aReaction conditions: 5a, 2a (2.4 equiv), 1a in CHCl3 (0,1 M) at 60 °C, flow rate 0.1 mL min−1. bIsolated yields after column chromatography. cDetermined by chiral HPLC analysis. dPerformed under batch conditions.

Although continuous-flow reactions provide many advantages, in certain cases it can be beneficial to conduct reactions under classical batch conditions. Therefore, we decided to carry out a direct comparison. Transferring the reaction conditions from continuous-flow to the batch showed a noticeable drop in conversion and the product was isolated only in 67% yield (Table 3, entry 5 vs entry 7). This observation is general, and typically lower reactivities were obtained. This can be explained by the better heat transfer in the microreactors as compared to the glass flask typically used in our batch reactions.

The scope and applicability of the method was then tested on various 2-substituted quinolines (Table 4). In general the asymmetric continuous-flow transfer hydrogenation of 2-substituted quinolines 5 proceeded well and afforded tetrahydroquinolines 6a–e with excellent yields and enantioselectivities (Table 4).

Table 4: Scope of the Brønsted acid catalyzed transfer hydrogenation of quinolines.a

[Graphic 9]
Entry Product 6 Yield
[%]b 		ee
[%]c
1 [Graphic 10]
6a 		96 94
2 [Graphic 11]
6b 		91 96
3 [Graphic 12]
6c 		94 99
4 [Graphic 13]
6d 		91 99
5 [Graphic 14]
6e 		97 96

aReaction conditions: 5, 2a (2.4 equiv), 5 mol % 1a in CHCl3 (0.1 M) at 60 °C, flow rate 0.1 mL min−1, residence time = 60 min. bIsolated yields after column chromatography. cDetermined by chiral HPLC analysis.

Having established a protocol for a general and highly enantioselective transfer hydrogenation of quinolines, we decided to extend its scope to the reduction of quinoxalines 7 (Table 5) [107]. The asymmetric reduction of quinoxalines is typically more difficult to achieve. Using the optimized conditions for the fast inline reaction, we found that the continuous-flow reduction could be performed using 10 mol % Brønsted acid 1b, a flow rate of 0.1 mL min−1 and 60 min residence time (Table 5).

Table 5: Scope of the Brønsted acid catalyzed transfer hydrogenation of quinoxalines.a

[Graphic 15]
Entry Product 8 Yield
[%]b 		ee
[%]c
1 [Graphic 16]
8a 		77 90
2 [Graphic 17]
8b 		68 84
3 [Graphic 18]
8c 		53 86
4 [Graphic 19]
8d 		86 94
5 [Graphic 20]
8e 		41 76

aReaction conditions: 7, 2a (2.4 equiv), 10 mol % 1b in CHCl3 (0.1 M) at 60 °C, flow rate 0.1 mL min−1, residence time = 60 min. bIsolated yields after column chromatography. cDetermined by chiral HPLC analysis.

To broaden the scope of the asymmetric hydrogenations in continuous flow further, the reduction of 3H-indoles 9 was studied (Table 6) [108]. Here the best reaction conditions turned out to be a temperature of 30 °C, a flow rate of 0.1 mL min−1, and a residence time of 20 min. The desired indolines 10 were isolated in good to high yields and with excellent enantioselectivities.

Table 6: Scope of the Brønsted acid catalyzed transfer hydrogenation of 3H-indoles.a

[Graphic 21]
Entry Product 10 Yield
[%]b 		ee
[%]c
1 [Graphic 22]
10a 		95d 90
2 [Graphic 23]
10b 		88d
98 		98
98
3 [Graphic 24]
10c 		60d
96 		99
99
4 [Graphic 25]
10d 		78d
95 		99
99
5 [Graphic 26]
10e 		94 97

aReaction conditions: 9, 2b (1.3 equiv), 5 mol % 1b in toluene/CHCl3 (2:1) (0.1 M) at 30 °C, flow rate 0.1 mL min−1, residence time = 20 min. bIsolated yields after column chromatography. cDetermined by chiral HPLC analysis. dRetention time: 10 min.

Conclusion

In conclusion, we have demonstrated the potential of a microreactor setup coupled with FTIR inline analysis for monitoring asymmetric continuous-flow hydrogenations of benzoxazines, quinolines, quinoxalines and 3H-indoles. Following a real-time continuous-flow optimization, the corresponding products were obtained in good yields and with excellent enantioselectivities. By applying the FTIR inline monitoring, reaction parameters can be screened rapidly in a single reaction setup, and the optimal reaction conditions can be obtained much faster as compared to the classical sequence of conducting the reaction followed by analysis. Further work will include automated integration and feedback optimization of reaction parameters.

Acknowledgements

The authors acknowledge the funding by the Excellence Initiative of the German federal and state governments and the European Research Council for a starting grant.

References

  1. Ehrfeld, W.; Hessel, V.; Löwe, H. Microreactors: New Technology for Modern Chemistry; Wiley-VCH: Weinheim, Germany, 2000.
    Return to citation in text: [1]
  2. Wirth, T., Ed. Microreactors in Organic Synthesis and Catalysis;; Wiley-VCH: Weinheim, Germany, 2008.
    Return to citation in text: [1]
  3. Jas, G.; Kirschning, A. Chem.–Eur. J. 2003, 9, 5708–5723. doi:10.1002/chem.200305212
    Return to citation in text: [1]
  4. Kikutani, Y.; Kitamori, T. Macromol. Rapid Commun. 2004, 25, 158–168. doi:10.1002/marc.200300192
    Return to citation in text: [1]
  5. Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M. Angew. Chem., Int. Ed. 2004, 43, 406–446. doi:10.1002/anie.200300577
    Return to citation in text: [1]
  6. Doku, G. N.; Verboom, W.; Reinhoudt, D. N.; van den Berg, A. Tetrahedron 2005, 61, 2733–2742. doi:10.1016/j.tet.2005.01.028
    Return to citation in text: [1]
  7. Watts, P.; Haswell, S. J. Chem. Soc. Rev. 2005, 34, 235–246. doi:10.1039/b313866f
    Return to citation in text: [1]
  8. Geyer, K.; Codée, J. D. C.; Seeberger, P. H. Chem.–Eur. J. 2006, 12, 8434–8442. doi:10.1002/chem.200600596
    Return to citation in text: [1]
  9. deMello, A. J. Nature 2006, 442, 394–402. doi:10.1038/nature05062
    Return to citation in text: [1]
  10. Song, H.; Chen, D. L.; Ismagilov, R. F. Angew. Chem., Int. Ed. 2006, 45, 7336–7356. doi:10.1002/anie.200601554
    Return to citation in text: [1]
  11. Kobayashi, J.; Mori, Y.; Kobayashi, S. Chem.–Asian J. 2006, 1, 22–35. doi:10.1002/asia.200600058
    Return to citation in text: [1]
  12. Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem. Rev. 2007, 107, 2300–2318. doi:10.1021/cr050944c
    Return to citation in text: [1]
  13. Watts, P.; Wiles, C. Chem. Commun. 2007, 443–467. doi:10.1039/b609428g
    Return to citation in text: [1]
  14. Ahmed-Omer, B.; Brandt, J. C.; Wirth, T. Org. Biomol. Chem. 2007, 5, 733–740. doi:10.1039/b615072a
    Return to citation in text: [1]
  15. Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett 2008, 151–163. doi:10.1055/s-2007-1000884
    Return to citation in text: [1]
  16. Yoshida, J.-i.; Nagaki, A.; Yamada, T. Chem.–Eur. J. 2008, 14, 7450–7459. doi:10.1002/chem.200800582
    Return to citation in text: [1]
  17. Wiles, C.; Watts, P. Eur. J. Org. Chem. 2008, 1655–1671. doi:10.1002/ejoc.200701041
    Return to citation in text: [1]
  18. Kirschning, A. Beilstein J. Org. Chem. 2009, 5, No. 15. doi:10.3762/bjoc.5.15
    Return to citation in text: [1]
  19. Geyer, K.; Gustafsson, T.; Seeberger, P. H. Synlett 2009, 2382–2391. doi:10.1055/s-0029-1217828
    Return to citation in text: [1]
  20. Nagaki, A.; Takabayashi, N.; Tomida, Y.; Yoshida, J.-i. Beilstein J. Org. Chem. 2009, 5, No. 16. doi:10.3762/bjoc.5.16
    Return to citation in text: [1]
  21. Yamada, Y. M. A.; Torii, K.; Uozumi, Y. Beilstein J. Org. Chem. 2009, 5, No. 18. doi:10.3762/bjoc.5.18
    Return to citation in text: [1]
  22. Brandt, J. C.; Wirth, T. Beilstein J. Org. Chem. 2009, 5, No. 30. doi:10.3762/bjoc.5.30
    Return to citation in text: [1]
  23. Fukuyama, T.; Rahman, M. T.; Kamata, N.; Ryu, I. Beilstein J. Org. Chem. 2009, 5, No. 34. doi:10.3762/bjoc.5.34
    Return to citation in text: [1]
  24. Tanaka, K.; Fukase, K. Beilstein J. Org. Chem. 2009, 5, No. 40. doi:10.3762/bjoc.5.40
    Return to citation in text: [1]
  25. Kunz, U.; Turek, T. Beilstein J. Org. Chem. 2009, 5, No. 70. doi:10.3762/bjoc.5.70
    Return to citation in text: [1]
  26. Marre, S.; Jensen, K. F. Chem. Soc. Rev. 2010, 39, 1183–1202. doi:10.1039/b821324k
    Return to citation in text: [1]
  27. Yoshida, J-i.; Kim, H.; Nagaki, A. ChemSusChem 2011, 4, 331–340. doi:10.1002/cssc.201000271
    Return to citation in text: [1]
  28. Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011, 47, 4583–4592. doi:10.1039/c0cc05060a
    Return to citation in text: [1]
  29. Min, K.-I.; Lee, T.-H.; Park, C. P.; Wu, Z.-Y.; Girault, H. H.; Ryu, I.; Fukuyama, T.; Mukai, Y.; Kim, D.-P. Angew. Chem., Int. Ed. 2010, 49, 7063–7067. doi:10.1002/anie.201002004
    Return to citation in text: [1]
  30. McMullen, J. P.; Stone, M. T.; Buchwald, S. L.; Jensen, K. F. Angew. Chem., Int. Ed. 2010, 49, 7076–7080. doi:10.1002/anie.201002590
    Return to citation in text: [1]
  31. McMullen, J. P.; Jensen, K. F. Annu. Rev. Anal. Chem. 2010, 3, 19–42. doi:10.1146/annurev.anchem.111808.073718
    Return to citation in text: [1]
  32. Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Angew. Chem., Int. Ed. 2011, 50, 7502–7519. doi:10.1002/anie.201004637
    Return to citation in text: [1]
  33. Shvydkiv, O.; Nolan, K.; Oelgemöller, M. Beilstein J. Org. Chem. 2011, 7, 1055–1063. doi:10.3762/bjoc.7.121
    Return to citation in text: [1]
  34. Nagaki, A.; Uesugi, Y.; Tomida, Y.; Yoshida, J.-i. Beilstein J. Org. Chem. 2011, 7, 1064–1069. doi:10.3762/bjoc.7.122
    Return to citation in text: [1]
  35. Watts, K.; Gattrell, W.; Wirth, T. Beilstein J. Org. Chem. 2011, 7, 1108–1114. doi:10.3762/bjoc.7.127
    Return to citation in text: [1]
  36. Roper, K. A.; Lange, H.; Polyzos, A.; Berry, M. B.; Baxendale, I. R.; Ley, S. V. Beilstein J. Org. Chem. 2011, 7, 1648–1655. doi:10.3762/bjoc.7.194
    Return to citation in text: [1]
  37. Saito, K.; Ueoka, K.; Matsumoto, K.; Suga, S.; Nokami, T.; Yoshida, J-i. Angew. Chem., Int. Ed. 2011, 50, 5153–5156. doi:10.1002/anie.201100854
    Return to citation in text: [1]
  38. Wiles, C.; Watts, P. Chem. Commun. 2011, 47, 6512–6535. doi:10.1039/c1cc00089f
    Return to citation in text: [1]
  39. Yoshida, J-i.; Saito, K.; Nokami, T.; Nagaki, A. Synlett 2011, 1189–1194. doi:10.1055/s-0030-1259946
    Return to citation in text: [1]
  40. Bogdan, A.; McQuade, D. T. Beilstein J. Org. Chem. 2009, 5, No. 17. doi:10.3762/bjoc.5.17
    Return to citation in text: [1]
  41. Wiles, C.; Watts, P. Green Chem. 2012, 14, 38–54. doi:10.1039/c1gc16022b
    Return to citation in text: [1]
  42. Wegner, J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal. 2012, 354, 17–57. doi:10.1002/adsc.201100584
    Return to citation in text: [1]
  43. Carter, C. F.; Baxendale, I. R.; O’Brien, M.; Pavey, J. B. J.; Ley, S. V. Org. Biomol. Chem. 2009, 7, 4594–4597. doi:10.1039/b917289k
    Return to citation in text: [1]
  44. Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Wittkamp, B.; Goode, J. G.; Gaunt, N. L. Org. Process Res. Dev. 2010, 14, 393–404. doi:10.1021/op900305v
    Return to citation in text: [1]
  45. Qian, Z.; Baxendale, I. R.; Ley, S. V. Chem.–Eur. J. 2010, 16, 12342–12348. doi:10.1002/chem.201002147
    Return to citation in text: [1]
  46. Carter, C. F.; Baxendale, I. R.; Pavey, J. B. J.; Ley, S. V. Org. Biomol. Chem. 2010, 8, 1588–1595. doi:10.1039/b924309g
    Return to citation in text: [1]
  47. Leadbeater, N. E. Chem. Commun. 2010, 46, 6693–6695. doi:10.1039/c0cc01921f
    Return to citation in text: [1]
  48. Malet-Sanz, L.; Madrzak, J.; Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 5324–5332. doi:10.1039/c0ob00450b
    Return to citation in text: [1]
  49. McMullen, J. P.; Jensen, K. F. Org. Process Res. Dev. 2010, 14, 1169–1176. doi:10.1021/op100123e
    Return to citation in text: [1]
  50. Foley, D. A.; Doecke, C. W.; Buser, J. Y.; Merritt, J. M.; Murphy, L.; Kissane, M.; Collins, S. G.; Maguire, A. R.; Kaerner, A. J. Org. Chem. 2011, 76, 9630–9640. doi:10.1021/jo201212p
    Return to citation in text: [1]
  51. Smith, C. J.; Nikbin, N.; Ley, S. V.; Lange, H.; Baxendale, I. R. Org. Biomol. Chem. 2011, 9, 1938–1947. doi:10.1039/c0ob00815j
    Return to citation in text: [1]
  52. Lange, H.; Carter, C. F.; Hopkin, M. D.; Burke, A.; Goode, J. G.; Baxendale, I. R.; Ley, S. V. Chem. Sci. 2011, 2, 765–769. doi:10.1039/c0sc00603c
    Return to citation in text: [1]
  53. Koos, P.; Gross, U.; Polyzos, A.; O’Brien, M.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2011, 9, 6903–6908. doi:10.1039/c1ob06017a
    Return to citation in text: [1]
  54. Keybl, J.; Jensen, K. F. Ind. Eng. Chem. Res. 2011, 50, 11013–11022. doi:10.1021/ie200936b
    Return to citation in text: [1]
  55. Brodmann, T.; Koos, P.; Metzger, A.; Knochel, P.; Ley, S. V. Org. Process Res. Dev. 2011. doi:10.1021/op200275d
    Return to citation in text: [1]
  56. Hook, B. D. A.; Dohle, W.; Hirst, P. R.; Pickworth, M.; Berry, M. B.; Booker-Milburn, K. I. J. Org. Chem. 2005, 70, 7558–7564. doi:10.1021/jo050705p
    Return to citation in text: [1]
  57. Wiles, C.; Watts, P.; Haswell, S. J. Tetrahedron Lett. 2007, 48, 7362–7365. doi:10.1016/j.tetlet.2007.08.027
    Return to citation in text: [1]
  58. Griffiths-Jones, C. M.; Hopkin, M. D.; Jönsson, D.; Ley, S. V.; Tapolczay, D. J.; Vickerstaffe, E.; Ladlow, M. J. Comb. Chem. 2007, 9, 422–430. doi:10.1021/cc060152b
    Return to citation in text: [1]
  59. Mennecke, K.; Solodenko, W.; Kirschning, A. Synthesis 2008, 1589–1599. doi:10.1055/s-2008-1072579
    Return to citation in text: [1]
  60. Mennecke, K.; Kirschning, A. Synthesis 2008, 3267–3272. doi:10.1055/s-2008-1067274
    Return to citation in text: [1]
  61. Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D. Angew. Chem., Int. Ed. 2009, 48, 4017–4021. doi:10.1002/anie.200900970
    Return to citation in text: [1]
  62. Wang, N.; Matsumoto, T.; Ueno, M.; Miyamura, H.; Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 4744–4746. doi:10.1002/anie.200900565
    Return to citation in text: [1]
  63. Brasholz, M.; Macdonald, J. M.; Saubern, S.; Ryan, J. H.; Holmes, A. B. Chem.–Eur. J. 2010, 16, 11471–11480. doi:10.1002/chem.201001435
    Return to citation in text: [1]
  64. Costantini, F.; Benetti, E. M.; Tiggelaar, R. M.; Gardeniers, H. J. G. E.; Reinhoudt, D. N.; Huskens, J.; Vancso, G. J.; Verboom, W. Chem.–Eur. J. 2010, 16, 12406–12411. doi:10.1002/chem.201000948
    Return to citation in text: [1]
  65. Gutmann, B.; Roduit, J.-P.; Roberge, D.; Kappe, C. O. Angew. Chem., Int. Ed. 2010, 49, 7101–7105. doi:10.1002/anie.201003733
    Return to citation in text: [1]
  66. Wahab, B.; Ellames, G.; Passey, S.; Watts, P. Tetrahedron 2010, 66, 3861–3865. doi:10.1016/j.tet.2010.03.005
    Return to citation in text: [1]
  67. Fuse, S.; Tanabe, N.; Yoshida, M.; Yoshida, H.; Doi, T.; Takahashi, T. Chem. Commun. 2010, 46, 8722–8724. doi:10.1039/c0cc02239j
    Return to citation in text: [1]
  68. Venturoni, F.; Nikbin, N.; Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 1798–1806. doi:10.1039/b925327k
    Return to citation in text: [1]
  69. Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675–680. doi:10.1039/c0sc00381f
    Return to citation in text: [1]
  70. Gutmann, B.; Roduit, J.-P.; Roberge, D.; Kappe, C. O. Chem.–Eur. J. 2011, 17, 13146–13150. doi:10.1002/chem.201102772
    Return to citation in text: [1]
  71. Maurya, R. A.; Park, C. P.; Lee, J. H.; Kim, D.-P. Angew. Chem., Int. Ed. 2011, 50, 5952–5955. doi:10.1002/anie.201101977
    Return to citation in text: [1]
  72. Sniady, A.; Bedore, M. W.; Jamison, T. F. Angew. Chem., Int. Ed. 2011, 50, 2155–2158. doi:10.1002/anie.201006440
    Return to citation in text: [1]
  73. Li, P.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 6396–6400. doi:10.1002/anie.201102401
    Return to citation in text: [1]
  74. Noël, T.; Maimone, T. J.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 8900–8903. doi:10.1002/anie.201104652
    Return to citation in text: [1]
  75. Shu, W.; Pellegatti, L.; Oberli, M. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 10665–10669. doi:10.1002/anie.201105223
    Return to citation in text: [1]
  76. O’Brien, A. G.; Lévesque, F.; Seeberger, P. H. Chem. Commun. 2011, 47, 2688–2690. doi:10.1039/c0cc04481d
    Return to citation in text: [1]
  77. Noël, T.; Buchwald, S. L. Chem. Soc. Rev. 2011, 40, 5010–5029. doi:10.1039/c1cs15075h
    Return to citation in text: [1]
  78. Kim, H.; Nagaki, A.; Yoshida, J.-i. Nat. Commun. 2011, 264. doi:10.1038/ncomms1264
    Return to citation in text: [1]
  79. Browne, D. L.; Baumann, M.; Harji, B. H.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2011, 13, 3312–3315. doi:10.1021/ol2010006
    Return to citation in text: [1]
  80. Allian, A. D.; Richter, S. M.; Kallemeyn, J. M.; Robbins, T. A.; Kishore, V. Org. Process Res. Dev. 2011, 15, 91–97. doi:10.1021/op100249z
    Return to citation in text: [1]
  81. Wiles, C.; Wattts, P.; Haswell, S. J.; Pombo-Villar, E. Lab Chip 2004, 4, 171–173. doi:10.1039/b400280f
    Return to citation in text: [1]
  82. Jönsson, C.; Lundgren, S.; Haswell, S. J.; Moberg, C. Tetrahedron 2004, 60, 10515–10520. doi:10.1016/j.tet.2004.08.080
    Return to citation in text: [1]
  83. de Bellefon, C.; Lamouille, T.; Pestre, N.; Bornette, F.; Pennemann, H.; Neumann, F.; Hessel, V. Catal. Today 2005, 110, 179–187. doi:10.1016/j.cattod.2005.09.002
    Return to citation in text: [1]
  84. Hamberg, A.; Lundgren, S.; Wingstrand, E.; Moberg, C.; Hult, K. Chem.–Eur. J. 2007, 13, 4334–4341. doi:10.1002/chem.200601638
    Return to citation in text: [1]
  85. Sakeda, K.; Wakabayashi, K.; Matsushita, Y.; Ichimura, T.; Suzuki, T.; Wada, T.; Inoue, Y. J. Photochem. Photobiol., A 2007, 192, 166–171. doi:10.1016/j.jphotochem.2007.05.019
    Return to citation in text: [1]
  86. Mak, X. Y.; Laurino, P.; Seeberger, P. H. Beilstein J. Org. Chem. 2009, 5, No. 19. doi:10.3762/bjoc.5.19
    Return to citation in text: [1]
  87. Shi, L.; Wang, X.; Sandoval, C. A.; Wang, Z.; Li, H.; Wu, J.; Yu, L.; Ding, K. Chem.–Eur. J. 2009, 15, 9855–9867. doi:10.1002/chem.200900899
    Return to citation in text: [1]
  88. Rolland, J.; Cambeiro, X. C.; Rodríguez-Escrich, C.; Pericàs, M. A. Beilstein J. Org. Chem. 2009, 5, No. 56. doi:10.3762/bjoc.5.56
    Return to citation in text: [1]
  89. Alza, E.; Rodríguez-Escrich, C.; Sayalero, S.; Bastero, A.; Pericàs, M. A. Chem.–Eur. J. 2009, 15, 10167–10172. doi:10.1002/chem.200901310
    Return to citation in text: [1]
  90. Tomida, Y.; Nagaki, A.; Yoshida, J.-i. J. Am. Chem. Soc. 2011, 133, 3744–3747. doi:10.1021/ja110898s
    Return to citation in text: [1]
  91. Carter, C. F.; Lange, H.; Sakai, D.; Baxendale, I. R.; Ley, S. V. Chem.–Eur. J. 2011, 17, 3398–3405. doi:10.1002/chem.201003148
    Return to citation in text: [1]
  92. Massi, A.; Cavazzzini, A.; Del Zoppo, L.; Pandoli, O.; Costa, V.; Pasti, L.; Giovannini, P. P. Tetrahedron Lett. 2011, 52, 619–622. doi:10.1016/j.tetlet.2010.11.157
    Return to citation in text: [1]
  93. Takeda, K.; Oohara, T.; Shimada, N.; Nambu, H.; Hashimoto, S. Chem.–Eur. J. 2011, 17, 13992–13998. doi:10.1002/chem.201102733
    Return to citation in text: [1]
  94. Fritzsche, S.; Ohla, S.; Glaser, P.; Giera, D. S.; Sickert, M.; Schneider, C.; Belder, D. Angew. Chem., Int. Ed. 2011, 50, 9467–9470. doi:10.1002/anie.201102331
    Return to citation in text: [1]
  95. Cambeiro, X. C.; Martín-Rapún, R.; Miranda, P. O.; Sayalero, S.; Alza, E.; Llanes, P.; Pericàs, M. A. Beilstein J. Org. Chem. 2011, 7, 1486–1493. doi:10.3762/bjoc.7.172
    Return to citation in text: [1]
  96. Ayats, C.; Henseler, A. H.; Pericàs, M. A. ChemSusChem 2012, 5, 320–325. doi:10.1002/cssc.201100570
    Return to citation in text: [1]
  97. Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett. 2005, 7, 3781–3783. doi:10.1021/ol0515964
    Return to citation in text: [1]
  98. Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2007, 46, 4562–4565. doi:10.1002/anie.200701158
    Return to citation in text: [1]
  99. Rueping, M.; Sugiono, E.; Schoepke, F. R. Synlett 2010, 852–865. doi:10.1055/s-0029-1219528
    Return to citation in text: [1]
  100. Rueping, M.; Merino, E.; Koenigs, R. M. Adv. Synth. Catal. 2010, 352, 2629–2634. doi:10.1002/adsc.201000547
    Return to citation in text: [1]
  101. Rueping, M.; Dufour, J.; Schoepke, F. R. Green Chem. 2011, 13, 1084–1105. doi:10.1039/c1gc15027h
    Return to citation in text: [1]
  102. Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 6751–6755. doi:10.1002/anie.200601832
    Return to citation in text: [1]
  103. Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683–3686. doi:10.1002/anie.200600191
    Return to citation in text: [1]
  104. Rueping, M.; Theissmann, T.; Raja, S.; Bats, J. W. Adv. Synth. Catal. 2008, 350, 1001–1006. doi:10.1002/adsc.200800020
    Return to citation in text: [1]
  105. Rueping, M.; Stoeckel, M.; Sugiono, E.; Theissmann, T. Tetrahedron 2010, 66, 6565–6568. doi:10.1016/j.tet.2010.04.091
    Return to citation in text: [1]
  106. Rueping, M.; Theissmann, T.; Stoeckel, M.; Antonchick, A. P. Org. Biomol. Chem. 2011, 9, 6844–6850. doi:10.1039/c1ob05870c
    Return to citation in text: [1]
  107. Rueping, M.; Tato, F.; Schoepke, F. R. Chem.–Eur. J. 2010, 16, 2688–2691. doi:10.1002/chem.200902907
    Return to citation in text: [1]
  108. Rueping, M.; Brinkmann, C.; Antonchick, A. P.; Atodiresei, I. Org. Lett. 2010, 12, 4604–4607. doi:10.1021/ol1019234
    Return to citation in text: [1]

Article is part of the thematic issue

Chemistry in flow systems II

Andreas Kirschning

Interesting articles

A combined continuous microflow photochemistry and asymmetric organocatalysis approach for the enantioselective synthesis of tetrahydroquinolines

Erli Sugiono and Magnus Rueping

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

Chinmay A. Shukla and Amol A. Kulkarni

Ammonium-tagged ruthenium-based catalysts for olefin metathesis in aqueous media under ultrasound and microwave irradiation

Łukasz Gułajski, Andrzej Tracz, Katarzyna Urbaniak, Stefan J. Czarnocki, Michał Bieniek and Tomasz K. Olszewski

News

Beilstein Talk by Radovan Šebesta on March 11 – Free registration is open!
Logo OA

Call for papers is open for this thematic issue. Submit your original research!
Logo OA

2.622 is the 2019 Journal Impact Factor.
Logo OA

© 2012 Rueping et al; licensee Beilstein-Institut.
This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc)

 
Back to Article List

Other Beilstein-Institut Open Science Activities

Logo
Logo
Logo
Logo

Keep Informed

RSS Feed

Subscribe to our Latest Articles RSS Feed.

Subscribe

Follow the Beilstein-Institut

LinkedIn

Twitter: @BeilsteinInst