Continuous flow based catch and release protocol for the synthesis of α-ketoesters

  1. Alessandro Palmieri1,
  2. Steven V. Ley1,
  3. Anastasios Polyzos1,2,
  4. Mark Ladlow3 and
  5. Ian R. Baxendale1

1Innovative Technology Centre (ACS), Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom
2CSIRO Molecular and Health Technologies, Bayview Avenue, Clayton South, Melbourne, Australia, 3169
3Uniqsis, Shepreth, Cambridgeshire, SG8 6GB, United Kingdom

  1. Corresponding author email

Guest Editor: A. Kirschning
Beilstein J. Org. Chem. 2009, 5, No. 23. doi:10.3762/bjoc.5.23
Received 05 Mar 2009, Accepted 14 May 2009, Published 20 May 2009

  • Full Research Paper

Abstract

Using a combination of commercially available mesofluidic flow equipment and tubes packed with immobilised reagents and scavengers, a new synthesis of α-ketoesters is reported.

Keywords: catch and release; flow synthesis; α-ketoesters; mesoreactor; polymer supported reagents

Introduction

Organic synthesis is changing rapidly owing to the discovery of processes that challenge current dogma and lead to the invention of new chemical reactions [1,2]. Likewise, new synthesis tools are impacting on the way we assemble molecules. Of these, flow chemistry technologies are becoming especially important [3-14]. For many years, our group [15-22] has been focussed on using immobilised systems [23-29] to more effectively and cleanly bring about chemical transformations, especially in multistep mode [17,30-37]. Given the success of these concepts, it is not surprising that we would want to adapt these principles to various flow-chemical synthesis platforms to effectuate automated multistep chemical syntheses [38-54].

In this work we report the use of the Uniqsis FlowSyn™ continuous flow reactor [55] (Figure 1) to effect a flow-based preparation of α-ketoesters. The key feature of this process is the application of a catch and release protocol [56-72], under the flow reaction conditions. Our choice of α-ketoesters as products of the process was governed by their use as starting materials for various synthesis programmes [73-81] and as important products in their own right [82-88]. Common methods for the preparation of α-ketoesters include the modified Dakin-West reaction [89] and the addition of a Grignard reagent to oxalates or oxalyl chlorides [90-92] together with a few alternative syntheses [93-99]. These procedures often suffer from drastic conditions, restricted selectivity and poor yields. Our flow-based approach delivers a new and general method for the preparation of α-ketoesters, which proceeds under mild conditions, with good functional group tolerability and generates products in high purity.

[1860-5397-5-23-1]

Figure 1: The Uniqsis FlowSyn™ continuous flow reactor comprising of a column holder and heating unit (A) and the reactor coil (B). A detailed image of the reactor coil is shown on the right.

Results and Discussion

The experimental set up for these transformations involves the use of the Uniqsis FlowSyn™ device [55]. The fully integrated instrument employs a dual channel flow system, with each channel independently driven by a variable high-pressure piston pump. The starting materials and reagents are dispensed from sample loops (0.5–10 mL) and are united in a T-mixing piece and then passed into either a coil or column reactor (Figure 1). The column reactor utilises adjustable glass columns with variable internal diameter (1–1.5 cm) and range in volume from 6–83 mL (unpacked). The coil reactors are made from a selection of materials including PTFE, PEEK, stainless steel or Hastelloy® and accommodate volumes from 2–20 mL. The column reactor (Figure 1, A) can be heated up to 150 °C and the coil heater (Figure 1, B) up to 260 °C, over a range of flow rates between 0.01–20 mL/min, and can be configured for multistep or parallel operation. Exiting products can be collected as aliquots using an automated fraction collector for reaction optimisation or as a bulk sample for scale-up. In addition, product purification can be achieved as part of the overall flow process by in-line solid phase extraction (SPE) or alternatively by diverting the flow stream into an attached HPLC system [100].

A series of preliminary experiments was carried out on the flow equipment to profile the reaction in terms of optimum reaction temperature, concentration, residence time, solvent and stoichiometry. Following rapid screening of conditions, we fixed upon a set of reaction parameters for efficient synthesis of α-ketoesters (Scheme 1). The overall reaction process proceeds in the flow apparatus via nitroolefinic esters 1 as substrates which are captured onto a benzylamine polymer 2 (QuadraPure™ QP-BZA polymer, loading 5.5 mmol/g, 4 equiv) to give 3 to effect product clean-up. In this way the immobilised species 3 can be washed and any solution phase impurities (resulting from the formation of the nitroolefinic ester – see later) are directed to waste (step 1). Next the column is treated with a flow stream of tetramethylguanidine (TMG; step 2) to cause elimination of nitrous acid and produce the corresponding enamino acid esters, which remain attached to the polymer support. Finally, after flow-washing (step 3), the solid supported species is hydrolysed, liberating α-ketoester product 4 by flowing aqueous acetic acid (step 4) through the in-line column. The overall route constitutes a new flow chemistry example of the catch-react-and-release concept that we have used successfully in other synthesis programmes [101-103].

[1860-5397-5-23-i1]

Scheme 1: General procedure for the flow synthesis of α-ketoester products 4a–j.

The nitroolefinic esters 1 were originally formed in a separate batch reaction from a Henry coupling of appropriate nitro compounds with ethyl glyoxalate over Amberlyst™ 21 (A21) resin to give the corresponding nitroalkanol 5 [104]. This was followed by treatment of 5 with methanesulfonyl chloride (MsCl) or trifluoroacetic anhydride (TFAA) to promote the base-catalysed dehydration, affording the nitroolefinic esters 1 (Scheme 2) [105]. As we have deliberately constructed this sequence for implementation in a continuous flow process, the intermediate nitroalkanols 5 were not isolated and the nitroolefinic esters were used without further purification. The average yield for the nitroolefins 1a–j prepared as described in Scheme 2 was approximately 60% by LCMS. Impurities were readily removed following immobilisation of nitroolefinic esters 1 on the QP-BZA resin.

[1860-5397-5-23-i2]

Scheme 2: General procedure for the batch synthesis of nitroolefinic esters 1a–j.

In addition, the flow synthesis of two representative compounds was undertaken to allow for the complete generation of α-ketoester products in flow from the starting nitroalkanes (Scheme 3). As shown in Table 1, we demonstrate that the synthesis of the nitroolefinic esters was achieved under flow conditions in a clean and effective fashion. Moreover, this synthesis demonstrates the first reported example of Henry reaction conducted in flow and we intend to elaborate on this important transformation in future studies.

[1860-5397-5-23-i3]

Scheme 3: General procedure for the flow synthesis of nitroolefinic esters 1a,c.

Table 1: Nitroolefinic esters 1a,c prepared under flow conditions (as described in Scheme 3).

Entry 1 Compound Yield (%)a
1 1a [Graphic 1] 63
2 1c [Graphic 2] 55

aIsolated yields are shown.

Figure 2 illustrates the examples and yields of α-ketoester products afforded by this new approach. While the list is not extensive, we have established that the process is tolerant of both aliphatic and aromatic substituted nitro-derivatives in the first step, and accommodates ester, acetate, acetal, nitrile and olefinic functionality in the final product. The process was reliable over several runs and consistently afforded very clean material (≥ 97% by NMR). The yields while only moderate for the overall process still equate to an average step conversion of 68–78% per chemical iteration, given that the sequence is a multistep process (see Supporting Information for full experimental data).

[1860-5397-5-23-2]

Figure 2: α-Ketoesters prepared and isolated yields.

Conclusion

In conclusion, we have demonstrated the versatility of the Uniqsis FlowSyn™ unit to achieve multi-step organic synthesis under continuous flow-chemistry conditions. This was accomplished by adapting the device to incorporate immobilised reagents packed in flow tubes, enabling clean transformations without recourse to conventional product work-up or purification. The overall process delivers synthetically useful α-ketoester products in high purity from various nitroalkane inputs and paves the way for more extended reaction sequences.

Supporting Information

Supporting Information File 1: Supporting Information – Continuous flow based catch and release protocol for the synthesis of α-ketoesters
Format: DOC Size: 45.5 KB Download

Acknowledgements

We gratefully acknowledge financial support from the EPRSC (to I. R. Baxendale), the BP endowment (to S. V. Ley), University of Camerino and MIUR-Italy (to A. Palmieri) and CSIRO Capability Development Fund (CDF) (to A. Polyzos).

References

  1. Ley, S. V.; Baxendale, I. R. Nat. Rev. Drug Discovery 2002, 1, 573–586. doi:10.1038/nrd871
    Return to citation in text: [1]
  2. Baxendale, I. R.; Hayward, J. J.; Ley, S. V.; Tranmer, G. K. ChemMedChem 2007, 2, 768–788. doi:10.1002/cmdc.200700008
    Return to citation in text: [1]
  3. Baxendale, I. R.; Pitts, M. R. Chim. Oggi 2006, 24 (3), 41–45.
    Return to citation in text: [1]
  4. Baxendale, I. R.; Ley, S. V. Heterogeneous Reactions. In New Avenues to Efficient Chemical Synthesis, Emerging Technologies; Seeberger, P. H.; Blume, T., Eds.; Springer-Verlag: Berlin, Heidelberg, 2007; pp 151–185.
    Return to citation in text: [1]
  5. Baxendale, I. R.; Hayward, J. J.; Ley, S. V. Comb. Chem. High Throughput Screening 2007, 10, 802–836. doi:10.2174/138620707783220374
    Return to citation in text: [1]
  6. Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.; Smith, C. D. Heterogeneous Reactions. In Microreactors in Organic Synthesis and Catalysis; Wirth, T., Ed.; Wiley-VCH: Weinheim, 2008; pp 84–122.
    Chapter 4.2.
    Return to citation in text: [1]
  7. Jas, G.; Kirschning, A. Chem.–Eur. J. 2003, 9, 5708–5723. doi:10.1002/chem.200305212
    Return to citation in text: [1]
  8. Hodge, P. Curr. Opin. Chem. Biol. 2003, 7, 362–373. doi:10.1016/S1367-5931(03)00052-8
    Return to citation in text: [1]
  9. Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M. Angew. Chem. 2004, 116, 410–451. doi:10.1002/ange.200300577
    Angew. Chem., Int. Ed. 2004, 43, 406–446. doi:10.1002/anie.200300577
    Return to citation in text: [1]
  10. Kirschning, A.; Solodenko, W.; Mennecke, K. Chem.–Eur. J. 2006, 12, 5972–5990. doi:10.1002/chem.200600236
    Return to citation in text: [1]
  11. 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]
  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. Glasnov, V. T. N.; Kappe, C. O. Macromol. Rapid Commun. 2007, 28, 395–410. doi:10.1002/marc.200600665
    Return to citation in text: [1]
  14. Benito-López, F.; Egberink, R. J. M.; Reinhoudt, D. N.; Verboom, W. Tetrahedron 2008, 64, 10023–10040. doi:10.1016/j.tet.2008.07.108
    Return to citation in text: [1]
  15. Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815–4195. doi:10.1039/b006588i
    Return to citation in text: [1]
  16. Baxendale, I. R.; Lee, A.-L.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 2002, 1850–1857. doi:10.1039/b203388g
    Return to citation in text: [1]
  17. Baxendale, I. R.; Ernst, M.; Krahnert, W.-R.; Ley, S. V. Synlett 2002, 1641–1644. doi:10.1055/s-2002-34249
    Return to citation in text: [1] [2]
  18. Ley, S. V.; Baxendale, I. R. Chem. Rec. 2002, 2, 377–388. doi:10.1002/tcr.10033
    Return to citation in text: [1]
  19. Baxendale, I. R.; Ley, S. V.; Nesi, M.; Piutti, C. Tetrahedron 2002, 58, 6285–6304. doi:10.1016/S0040-4020(02)00628-2
    Return to citation in text: [1]
  20. Storer, R. I.; Takemoto, T.; Jackson, P. S.; Ley, S. V. Angew. Chem. 2003, 115, 2625–2629. doi:10.1002/ange.200351413
    Angew. Chem., Int. Ed. 2003, 42, 2521–2525. doi:10.1002/anie.200351413
    Return to citation in text: [1]
  21. Storer, R. I.; Takemoto, T.; Jackson, P. S.; Brown, D. S.; Baxendale, I. R.; Ley, S. V. Chem.–Eur. J. 2004, 10, 2529–2547. doi:10.1002/chem.200305669
    Return to citation in text: [1]
  22. Baxendale, I. R.; Ley, S. V. Ind. Eng. Chem. Res. 2005, 44, 8588–8592. doi:10.1021/ie048822i
    Return to citation in text: [1]
  23. Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324–337. doi:10.1016/S1367-5931(00)00096-X
    Return to citation in text: [1]
  24. Kobayashi, S. Curr. Opin. Chem. Biol. 2000, 4, 338–345. doi:10.1016/S1367-5931(00)00097-1
    Return to citation in text: [1]
  25. Kirschning, A.; Monenschein, H.; Wittenberg, R. Chem.–Eur. J. 2000, 6, 4445–4450. doi:10.1002/1521-3765(20001215)6:24<4445::AID-CHEM4445>3.0.CO;2-W
    Return to citation in text: [1]
  26. Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew. Chem. 2001, 113, 670–701. doi:10.1002/1521-3757(20010216)113:4<670::AID-ANGE6700>3.0.CO;2-G
    Angew. Chem., Int. Ed. 2001, 40, 650–679. doi:10.1002/1521-3773(20010216)40:4<650::AID-ANIE6500>3.0.CO;2-C
    Return to citation in text: [1]
  27. Sherrington, D. C. J. Polym. Sci., Part A: Polym. Chem. 2001, 39, 2364–2377. doi:10.1002/pola.1213
    Return to citation in text: [1]
  28. Hodge, P. Ind. Eng. Chem. Res. 2005, 44, 8542–8553. doi:10.1021/ie040285e
    Return to citation in text: [1]
  29. Solinas, A.; Taddei, M. Synthesis 2007, 2409–2453. doi:10.1055/s-2007-983806
    Return to citation in text: [1]
  30. Baxendale, I. R.; Ley, S. V. Bioorg. Med. Chem. Lett. 2000, 10, 1983–1986. doi:10.1016/S0960-894X(00)00383-8
    Return to citation in text: [1]
  31. Ley, S. V.; Baxendale, I. R.; Brusotti, G.; Caldarelli, M.; Massi, A.; Nesi, M. Farmaco 2002, 57, 321–330. doi:10.1016/S0014-827X(02)01210-7
    Return to citation in text: [1]
  32. Baxendale, I. R.; Brusotti, G.; Matsuoka, M.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 2002, 143–154. doi:10.1039/b109482n
    Return to citation in text: [1]
  33. Baxendale, I. R.; Lee, A.-L.; Ley, S. V. Synlett 2002, 516–518. doi:10.1055/s-2002-20483
    Return to citation in text: [1]
  34. Baxendale, I. R.; Ley, S. V.; Lumeras, W.; Nesi, M. Comb. Chem. High Throughput Screening 2002, 5, 197–199.
    Return to citation in text: [1]
  35. Baxendale, I. R.; Ley, S. V.; Sneddon, H. F. Synlett 2002, 775–777. doi:10.1055/s-2002-25333
    Return to citation in text: [1]
  36. Baxendale, I. R.; Storer, R. I.; Ley, S. V. Supported Reagents and Scavengers in Multi-Step Organic Synthesis. In Polymeric Materials in Organic Synthesis and Catalysis; Buchmeiser, M. R., Ed.; Wiley-VCH: Weinheim, 2003; pp 53–136. doi:10.1002/3527601856.ch2
    Return to citation in text: [1]
  37. Baxendale, I. R.; Ley, S. V. Curr. Org. Chem. 2005, 9, 1521–1534. doi:10.2174/138527205774370513
    Return to citation in text: [1]
  38. Baxendale, I. R.; Deeley, J.; Griffiths-Jones, C. M.; Ley, S. V.; Saaby, S.; Tranmer, G. K. Chem. Commun. 2006, 2566–2568. doi:10.1039/b600382f
    Return to citation in text: [1]
  39. Baumann, M.; Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tranmer, G. K. Org. Lett. 2006, 8, 5231–5234. doi:10.1021/ol061975c
    Return to citation in text: [1]
  40. Smith, C. J.; Iglesias-Sigüenza, F. J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 2758–2761. doi:10.1039/b709043a
    Return to citation in text: [1]
  41. Smith, C. D.; Baxendale, I. R.; Lanners, S.; Hayward, J. J.; Smith, S. C.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 1559–1561. doi:10.1039/b702995k
    Return to citation in text: [1]
  42. Hornung, C. H.; Mackley, M. R.; Baxendale, I. R.; Ley, S. V. Org. Process Res. Dev. 2007, 11, 399–405. doi:10.1021/op700015f
    Return to citation in text: [1]
  43. Baumann, M.; Baxendale, I. R.; Ley, S. V. Synlett 2008, 2111–2114. doi:10.1055/s-2008-1078026
    Return to citation in text: [1]
  44. Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D. Org. Biomol. Chem. 2008, 6, 1587–1593. doi:10.1039/b801634h
    Return to citation in text: [1]
  45. Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D.; Tierney, J. P. Org. Biomol. Chem. 2008, 6, 1577–1586. doi:10.1039/b801631n
    Return to citation in text: [1]
  46. Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tamborini, L.; Voica, A.-F. J. Comb. Chem. 2008, 10, 851–857. doi:10.1021/cc800070a
    Return to citation in text: [1]
  47. Jas, G.; Kirschning, A. Chem.–Eur. J. 2003, 9, 5708–5723. doi:10.1002/chem.200305212
    Return to citation in text: [1]
  48. Bernstein, D.; France, S.; Wolfer, J.; Lectka, T. Tetrahedron: Asymmetry 2005, 16, 3481–3483. doi:10.1016/j.tetasy.2005.09.014
    Return to citation in text: [1]
  49. Bonfils, F.; Cazaux, I.; Hodge, P.; Caze, C. Org. Biomol. Chem. 2006, 4, 493–497. doi:10.1039/b515241k
    Return to citation in text: [1]
  50. Wiles, C.; Watts, P.; Haswell, S. J. Tetrahedron Lett. 2006, 47, 5261–5264. doi:10.1016/j.tetlet.2006.05.157
    Return to citation in text: [1]
  51. Dräger, G.; Kiss, C.; Kunz, U.; Kirschning, A. Org. Biomol. Chem. 2007, 5, 3657–3664. doi:10.1039/b712804e
    Return to citation in text: [1]
  52. Burguete, M. I.; Cornejo, A.; García-Verdugo, E.; Gil, M. J.; Luis, S. V.; Mayoral, J. A.; Martínez-Merino, V.; Sokolova, M. J. Org. Chem. 2007, 72, 4344–4350. doi:10.1021/jo070119r
    Return to citation in text: [1]
  53. Solodenko, W.; Jas, G.; Kunz, U.; Kirschning, A. Synthesis 2007, 583–589. doi:10.1055/s-2007-965877
    Return to citation in text: [1]
  54. Odedra, A.; Geyer, K.; Gustafsson, T.; Gilmour, R.; Seeberger, P. H. Chem. Commun. 2008, 3025–3027. doi:10.1039/b803715a
    Return to citation in text: [1]
  55. Uniqsis web site. http://www.uniqsis.com (accessed April 6, 2009).
    Return to citation in text: [1] [2]
  56. Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc. 1977, 99, 4165–4167. doi:10.1021/ja00454a050
    Return to citation in text: [1]
  57. Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc. 1981, 103, 7620–7629. doi:10.1021/ja00415a034
    Return to citation in text: [1]
  58. Patchornik, A. In Proc. IUPAC, I. U. P. A. C., Macromol. Symp., 28th, 1982, University of Massachusetts, Amherst, July 12–16, 1982; IUPAC: Oxford, 1982; p 85.
    Return to citation in text: [1]
  59. Brown, S. D.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 6331–6332. doi:10.1021/ja961203j
    Return to citation in text: [1]
  60. Hu, Y.; Baudart, S.; Porco, J. A., Jr. J. Org. Chem. 1999, 64, 1049–1051. doi:10.1021/jo981874v
    Return to citation in text: [1]
  61. Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science 1997, 275, 823–826. doi:10.1126/science.275.5301.823
    Return to citation in text: [1]
  62. Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.; South, M. S.; Woodard, S. J. Am. Chem. Soc. 1997, 119, 4874–4881. doi:10.1021/ja963462e
    Return to citation in text: [1]
  63. Curran, D. P. Angew. Chem. 1998, 110, 1230–1255. doi:10.1002/(SICI)1521-3757(19980504)110:9<1230::AID-ANGE1230>3.0.CO;2-Y
    Angew. Chem., Int. Ed. 1998, 37, 1174–1196. doi:10.1002/(SICI)1521-3773(19980518)37:9<1174::AID-ANIE1174>3.0.CO;2-P
    Return to citation in text: [1]
  64. Bosanac, T.; Yang, J.; Wilcox, C. S. Angew. Chem. 2001, 113, 1927–1931. doi:10.1002/1521-3757(20010518)113:10<1927::AID-ANGE1927>3.0.CO;2-#
    Angew. Chem., Int. Ed. 2001, 40, 1875–1879. doi:10.1002/1521-3773(20010518)40:10<1875::AID-ANIE1875>3.0.CO;2-5
    Return to citation in text: [1]
  65. Ley, S. V.; Massi, A.; Rodríguez, F.; Horwell, D. C.; Lewthwaite, R. A.; Pritchard, M. C.; Reid, A. M. Angew. Chem. 2001, 113, 1088–1090. doi:10.1002/1521-3757(20010316)113:6<1088::AID-ANGE10880>3.0.CO;2-#
    Angew. Chem., Int. Ed. 2001, 40, 1053–1055. doi:10.1002/1521-3773(20010316)40:6<1053::AID-ANIE10530>3.0.CO;2-D
    Return to citation in text: [1]
  66. Galante, A.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 2001, 42, 5425–5427. doi:10.1016/S0040-4039(01)01055-3
    Return to citation in text: [1]
  67. Yoshida, J.-i.; Itami, K. Chem. Rev. 2002, 102, 3693–3716. doi:10.1021/cr0103524
    Return to citation in text: [1]
  68. Dobbs, A. P.; McGregor-Johnson, C. Tetrahedron Lett. 2002, 43, 2807–2810. doi:10.1016/S0040-4039(02)00322-2
    Return to citation in text: [1]
  69. Lan, P.; Porco, J. A., Jr.; South, M. S.; Parlow, J. J. J. Comb. Chem. 2003, 5, 660–669. doi:10.1021/cc030028h
    Return to citation in text: [1]
  70. Siu, J.; Baxendale, I. R.; Lewthwaite, R. A.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 3140–3160. doi:10.1039/b503778f
    Return to citation in text: [1]
  71. Curran, D. P.; Wang, X.; Zhang, Q. J. Org. Chem. 2005, 70, 3716–3719. doi:10.1021/jo050116j
    Return to citation in text: [1]
  72. Mothana, S.; Chahal, N.; Vanneste, S.; Hall, D. G. J. Comb. Chem. 2007, 9, 193–196. doi:10.1021/cc060149s
    Return to citation in text: [1]
  73. Audrain, H.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2000, 65, 4487–4497. doi:10.1021/jo9918596
    Return to citation in text: [1]
  74. Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2002, 4, 2945–2948. doi:10.1021/ol026343e
    Return to citation in text: [1]
  75. Yu, S.; Saenz, J.; Srirangam, J. K. J. Org. Chem. 2002, 67, 1699–1702. doi:10.1021/jo016131f
    Return to citation in text: [1]
  76. Griesbeck, A. G.; Bondock, S.; Lex, J. Org. Biomol. Chem. 2004, 2, 1113–1115. doi:10.1039/b401990c
    Return to citation in text: [1]
  77. Sun, Y.; Wan, X.; Wang, J.; Meng, Q.; Zhang, H.; Jiang, L.; Zhang, Z. Org. Lett. 2005, 7, 5425–5427. doi:10.1021/ol052212c
    Return to citation in text: [1]
  78. Zhang, W.; Shi, M. Chem. Commun. 2006, 1218–1220. doi:10.1039/b516467b
    Return to citation in text: [1]
  79. Howard, B. E.; Woerpel, K. A. Org. Lett. 2007, 9, 4651–4653. doi:10.1021/ol702148x
    Return to citation in text: [1]
  80. Kratzer, R.; Nidetzky, B. Chem. Commun. 2007, 1047–1049. doi:10.1039/b616475g
    Return to citation in text: [1]
  81. Ntaganda, R.; Milovic, T.; Tiburcio, J.; Thadani, A. N. Chem. Commun. 2008, 4052–4054. doi:10.1039/b808302a
    Return to citation in text: [1]
  82. Peet, N. P.; Burkhart, J. P.; Angelastro, M. R.; Giroux, E. L.; Mehdi, S.; Bey, P.; Kolb, M.; Neises, B.; Schirlin, D. J. Med. Chem. 1990, 33, 394–407. doi:10.1021/jm00163a063
    Return to citation in text: [1]
  83. Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Free, C. A.; Smith, S. A.; Petrillo, E. W., Jr. J. Med. Chem. 1993, 36, 2431–2447. doi:10.1021/jm00069a001
    Return to citation in text: [1]
  84. Li, Z.; Patil, G. S.; Golubski, Z. E.; Hori, H.; Tehrani, K.; Foreman, J. E.; Eveleth, D. D.; Bartus, R. T.; Powers, J. C. J. Med. Chem. 1993, 36, 3472–3480. doi:10.1021/jm00074a031
    Return to citation in text: [1]
  85. Koutek, B.; Prestwich, G. D.; Howlett, A. C.; Chin, S. A.; Salehani, D.; Akhavan, N.; Deutsch, D. G. J. Biol. Chem. 1994, 269, 22937–22940.
    Return to citation in text: [1]
  86. Conde-Frieboes, K.; Reynolds, L. J.; Lio, Y.-C.; Hale, M. R.; Wasserman, H. H.; Dennis, E. A. J. Am. Chem. Soc. 1996, 118, 5519–5525. doi:10.1021/ja953553w
    Return to citation in text: [1]
  87. Otto, H.-H.; Schirmeister, T. Chem. Rev. 1997, 97, 133–172. doi:10.1021/cr950025u
    Return to citation in text: [1]
  88. Choe, Y.; Brinen, L. S.; Price, M. S.; Engel, J. C.; Lange, M.; Grisostomi, C.; Weston, S. G.; Pallai, P. V.; Cheng, H.; Hardy, L. W.; Hartsough, D. S.; McMakin, M.; Tilton, R. F.; Baldino, C. M.; Craik, C. S. Bioorg. Med. Chem. 2005, 13, 2141–2156. doi:10.1016/j.bmc.2004.12.053
    Return to citation in text: [1]
  89. Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91–109. doi:10.1039/cs9881700091
    Return to citation in text: [1]
  90. Nimitz, J. S.; Mosher, H. S. J. Org. Chem. 1981, 46, 211–213. doi:10.1021/jo00314a057
    Return to citation in text: [1]
  91. Creary, X.; Mehrsheikh-Mohammadi, M. E. J. Org. Chem. 1986, 51, 2664–2668. doi:10.1021/jo00364a009
    Return to citation in text: [1]
  92. Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A. Tetrahedron 1996, 52, 13513–13520. doi:10.1016/0040-4020(96)00805-8
    Return to citation in text: [1]
  93. Wasserman, H. H.; Ives, J. L. J. Org. Chem. 1985, 50, 3573–3580. doi:10.1021/jo00219a025
    Return to citation in text: [1]
  94. Bulman Page, P. C.; Rosenthal, S. Tetrahedron Lett. 1986, 27, 1947–1950. doi:10.1016/S0040-4039(00)84419-6
    Return to citation in text: [1]
  95. Sakakura, T.; Yamashita, H.; Kobayashi, T.-a.; Hayashi, T.; Tanaka, M. J. Org. Chem. 1987, 52, 5733–5740. doi:10.1021/jo00235a017
    Return to citation in text: [1]
  96. Wong, M.-K.; Yu, C.-W.; Yuen, W.-H.; Yang, D. J. Org. Chem. 2001, 66, 3606–3609. doi:10.1021/jo0015974
    Return to citation in text: [1]
  97. Li, L.-S.; Wu, Y.-L. Tetrahedron Lett. 2002, 43, 2427–2430. doi:10.1016/S0040-4039(02)00290-3
    Return to citation in text: [1]
  98. Ma, M.; Li, C.; Peng, L.; Xie, F.; Zhang, X.; Wang, J. Tetrahedron Lett. 2005, 46, 3927–3929. doi:10.1016/j.tetlet.2005.03.199
    Return to citation in text: [1]
  99. Shimizu, H.; Murakami, M. Chem. Commun. 2007, 2855–2857. doi:10.1039/b704105e
    Return to citation in text: [1]
  100. Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. K. Synlett 2006, 427–430. doi:10.1055/s-2006-926244
    Return to citation in text: [1]
  101. Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tranmer, G. K. Chem. Commun. 2006, 4835–4837. doi:10.1039/b612197g
    Return to citation in text: [1]
  102. Smith, C. D.; Baxendale, I. R.; Tranmer, G. K.; Baumann, M.; Smith, S. C.; Lewthwaite, R. A.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 1562–1568. doi:10.1039/b703033a
    Return to citation in text: [1]
  103. 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]
  104. Ballini, R.; Bosica, G.; Forconi, P. Tetrahedron 1996, 52, 1677–1684. doi:10.1016/0040-4020(95)00996-5
    Return to citation in text: [1]
  105. Ballini, R.; Fiorini, D.; Palmieri, A. Tetrahedron Lett. 2004, 45, 7027–7029. doi:10.1016/j.tetlet.2004.07.141
    Return to citation in text: [1]

Article is part of the issue

Chemistry in flow systems

Andreas Kirschning

Interesting articles

3D printed fluidics with embedded analytic functionality for automated reaction optimisation

Andrew J. Capel , Andrew Wright , Matthew J. Harding , George W. Weaver , Yuqi Li , Russell A. Harris , Steve Edmondson , Ruth D. Goodridge and Steven D. R. Christie

Mild and selective reduction of aldehydes utilising sodium dithionite under flow conditions

Nicole C. Neyt and Darren L. Riley

Photocatalytic formation of carbon–sulfur bonds

Alexander Wimmer and Burkhard König

News

Coming Spring 2019: Beilstein Archives – the preprint server for the Beilstein Journals
Logo OA

The updated journal statistics include the 2017 impact factor and alternative journal metrics.
Logo OA

Registration is open for this Beilstein Symposium, 9 - 11 April, 2019
Logo OA

© 2009 Palmieri 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