Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science
RESEARCH FRONT

Generation and Reactions of Pyridyllithiums via Br/Li Exchange Reactions Using Continuous Flow Microreactor Systems

Aiichiro Nagaki A , Daisuke Yamada A , Shigeyuki Yamada A , Masatomo Doi A , Daisuke Ichinari A , Yutaka Tomida A , Naofumi Takabayashi A and Jun-ichi Yoshida A B
+ Author Affiliations
- Author Affiliations

A Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.

B Corresponding author. Email: yoshida@sbchem.kyoto-u.ac.jp

Australian Journal of Chemistry 66(2) 199-207 https://doi.org/10.1071/CH12440
Submitted: 25 September 2012  Accepted: 28 November 2012   Published: 9 January 2013

Abstract

A continuous flow microreactor method for generating and carrying out reactions on pyridyllithiums has been developed based on Br/Li exchange reactions of bromopyridines and dibromopyridines. The reactions can be carried out without using cryogenic conditions by virtue of short residence times and efficient heat transfer, while very low temperatures such as –78 or –110°C are required for conventional batch macro methods. Moreover, sequential introduction of two different electrophiles has been successfully achieved using dibromopyridines in an integrated flow microreactor system composed of four micromixers and four microtube reactors.


References

[1]  R. Chinchilla, C. Nájera, M. Yus, Chem. Rev. 2004, 104, 2667. and references cited therein
         | CrossRef | 1:CAS:528:DC%2BD2cXhtVarsrY%3D&md5=175e16b37d630a2893f2e6da0bdfe0d5CAS |

[2]     (a) P. Knochel, Handbook of Functionalized Organometallics 2005 (Wiley-VCH: Weinheim).
      (b) A. Boudier, L. O. Bromm, M. Lotz, P. Knochel, Angew. Chem. Int. Ed. 2000, 39, 4414.
         | CrossRef |
      (c) P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T. Korn, I. Sapountzis, V. A. Vu, Angew. Chem. Int. Ed. 2003, 42, 4302.
         | CrossRef |

[3]  J. Clayden, Organolithiums: Selectivity for Synthesis 2002 (Pergamon: Amsterdam).

[4]  (a) G. Quéguiner, F. Marsais, V. Snieckus, J. Epsztajn, Adv. Heterocycl. Chem. 1991, 52, 187.
         | CrossRef |
      (b) A. Godard, F. Marsais, N. Plé, F. Trécourt, A. Turck, G. Quéguiner, Heterocycles 1995, 40, 1055.
         | CrossRef |
      (c) F. Trécourt, B. Gervais, M. Mallet, G. Quéguiner, J. Org. Chem. 1996, 61, 1673.
         | CrossRef |
      (d) F. Trécourt, B. Gervais, O. Mongin, C. Le Gal, F. Mongin, G. Quéguiner, J. Org. Chem. 1998, 63, 2892.
         | CrossRef |
      (e) E. Pasquinet, P. Rocca, F. Marsais, A. Godard, G. Quéguiner, Tetrahedron 1998, 54, 8771.
         | CrossRef |
      (f) P. C. Gros, Y. Fort, Eur. J. Org. Chem. 2009, 4199.
         | CrossRef |

[5]  (a) H. Gilman, S. M. Spatz, J. Org. Chem. 1951, 16, 1485.
         | CrossRef | 1:CAS:528:DyaG38XjsF2itw%3D%3D&md5=c168045f05151d7c45964cba1622b61bCAS |
      (b) H. Gilman, W. A. Gregory, S. M. Spatz, J. Org. Chem. 1951, 16, 1788.
         | CrossRef |
      (c) J. P. Wibaut, L. G. Heeringa, Recl. Trav. Chim. Pays Bas 1955, 74, 1003.
         | CrossRef |
      (d) W. E. Parham, R. M. Piccirilli, J. Org. Chem. 1977, 42, 257.
         | CrossRef |
      (e) G. R. Newkome, J. M. Roper, J. Organomet. Chem. 1980, 186, 147.
         | CrossRef |
      (f) M. Mallet, G. Quéguiner, Tetrahedron 1986, 42, 2253.
         | CrossRef |
      (g) M. Mallet, G. Branger, F. Marsais, G. Quéguiner, J. Organomet. Chem. 1990, 382, 319.
         | CrossRef |
      (h) D. Cai, D. L. Hughes, T. R. Verhoeven, Tetrahedron Lett. 1996, 37, 2537.
         | CrossRef |
      (i) R. H. Furneaux, G. Limberg, P. C. Tyler, V. L. Schramm, Tetrahedron 1997, 53, 2915.
         | CrossRef |
      (j) M. A. Peterson, J. R. Mitchell, J. Org. Chem. 1997, 62, 8237.
         | CrossRef |

[6]     (a) Books on microreactor synthesis: W. Ehrfeld, V. Hessel, H. Löwe, Microreactors 2000 (Wiley-VCH: Weinheim).
         (b) V. Hessel, S. Hardt, H. Löwe, Chemical Micro Process Engineering 2004 (Wiley-VCH Verlag: Weinheim).
         (c) J. Yoshida, Flash Chemistry: Fast Organic Synthesis in Microsystems 2008 (Wiley-Blackwell: Chichester).
         (d) V. Hessel, A. Renken, J. C. Schouten, J. Yoshida, Micro Process Engineering 2009 (Wiley-Blackwell: Weinheim).

[7]  (a) Reviews on microreactor synthesis: K. Jähnisch, V. Hessel, H. Löwe, M. Baerns, Angew. Chem. Int. Ed. 2004, 43, 406.
         | CrossRef |
      (b) G. N. Doku, W. Verboom, D. N. Reinhoudt, A. van den Berg, Tetrahedron 2005, 61, 2733.
         | CrossRef |
      (c) J. Yoshida, A. Nagaki, T. Iwasaki, S. Suga, Chem. Eng. Tech. 2005, 28, 259.
         | CrossRef |
      (d) P. Watts, S. J. Haswell, Chem. Soc. Rev. 2005, 34, 235.
         | CrossRef |
      (e) K. Geyer, J. D. C. Codee, P. H. Seeberger, Chem. – Eur. J. 2006, 12, 8434.
         | CrossRef |
      (f) A. J. deMello, Nature 2006, 442, 394.
         | CrossRef |
      (g) H. Song, D. L. Chen, R. F. Ismagilov, Angew. Chem. Int. Ed. 2006, 45, 7336.
         | CrossRef |
      (h) J. Kobayashi, Y. Mori, S. Kobayashi, Chem. – Asian. J. 2006, 1, 22.
         | CrossRef |
      (i) M. Brivio, W. Verboom, D. N. Reinhoudt, Lab Chip. 2006, 6, 329.
         | CrossRef |
      (j) B. P. Mason, K. E. Price, J. L. Steinbacher, A. R. Bogdan, D. T. McQuade, Chem. Rev. 2007, 107, 2300.
         | CrossRef |
      (k) B. Ahmed-Omer, J. C. Brandtand, T. Wirth, Org. Biomol. Chem. 2007, 5, 733.
         | CrossRef |
      (l) P. Watts, C. Wiles, Chem. Commun. 2007, 443.
         | CrossRef |
      (m) T. Fukuyama, M. T. Rahman, M. Sato, I. Ryu, Synlett 2008, 151.
      (n) J. Yoshida, A. Nagaki, T. Yamada, Chem. – Eur. J. 2008, 14, 7450.
         | CrossRef |
      (o) R. L. Hartman, K. F. Jensen, Lab Chip. 2009, 9, 2495.
         | CrossRef |
      (p) W. Lin, Y. Wang, S. Wang, H. Tseng, Nano Today 2009, 4, 470.
         | CrossRef |
      (q) K. Geyer, T. Gustafsson, P. H. Seeberger, Synlett 2009, 2382.
      (r) J. P. McMullen, K. F. Jensen, Annu. Rev. Anal. Chem. 2010, 3, 19.
         | CrossRef |
      (s) S. Marre, K. F. Jensen, Chem. Soc. Rev. 2010, 39, 1183.
         | CrossRef |
      (t) D. Webb, T. F. Jamison, Chem. Sci. 2010, 1, 675.
         | CrossRef |
      (u) J. P. McMullen, K. F. Jensen, Annu. Rev. Anal. Chem. 2010, 3, 19.
         | CrossRef |
      (v) J. Yoshida, H. Kim, A. Nagaki, ChemSusChem 2011, 4, 331.
         | CrossRef |

[8]  (a) Some recent examples: A. Nagaki, K. Kawamura, S. Suga, T. Ando, M. Sawamoto, J. Yoshida, J. Am. Chem. Soc. 2004, 126, 14702.
         | CrossRef | 1:CAS:528:DC%2BD2cXos1Wjs70%3D&md5=e5a3be5a98936b4dd69cb65e48980ef6CAS |
      (b) A. Nagaki, M. Togai, S. Suga, N. Aoki, K. Mae, J. Yoshida, J. Am. Chem. Soc. 2005, 127, 11666.
         | CrossRef |
      (c) P. He, P. Watts, F. Marken, S. J. Haswell, Angew. Chem. Int. Ed. 2006, 45, 4146.
         | CrossRef |
      (d) K. Tanaka, S. Motomatsu, K. Koyama, S. Tanaka, K. Fukase, Org. Lett. 2007, 9, 299.
         | CrossRef |
      (e) H. R. Sahoo, J. G. Kralj, K. F. Jensen, Angew. Chem. Int. Ed. 2007, 46, 5704.
         | CrossRef |
      (f) C. H. Hornung, M. R. Mackley, I. R. Baxendale, S. V. Ley, Org. Process Res. Dev. 2007, 11, 399.
         | CrossRef |
      (g) T. Fukuyama, M. Kobayashi, M. T. Rahman, N. Kamata, I. Ryu, Org. Lett. 2008, 10, 533.
         | CrossRef |
      (h) C. Wiles, P. Watts, Org. Process Res. Dev. 2008, 12, 1001.
         | CrossRef |
      (i) A. Nagaki, E. Takizawa, J. Yoshida, J. Am. Chem. Soc. 2009, 131, 1654.
         | CrossRef |
      (j) A. Nagaki, E. Takizawa, J. Yoshida, Chem. Lett. 2009, 38, 486.
         | CrossRef |
      (k) I. C. Wienhofer, A. Studer, M. T. Rahman, T. Fukuyama, I. Ryu, Org. Lett. 2009, 11, 2457.
         | CrossRef |
      (l) A. R. Bogdan, S. L. Poe, D. C. Kubis, S. J. Broadwater, D. T. McQuade, Angew. Chem. Int. Ed. 2009, 48, 8547.
         | CrossRef |
      (m) T. Tricotet, D. F. O’Shea, Chem. – Eur. J. 2010, 16, 6678.
      (n) D. L. Browne, M. Baumann, B. H. Harji, I. R. Baxendale, S. V. Ley, Org. Lett. 2011, 13, 3312.
         | CrossRef |
      (o) C. F. Carter, H. Lange, D. Sakai, I. R. Baxendale, S. V. Ley, Chem. – Eur. J. 2011, 17, 3398.
         | CrossRef |
      (p) N. Zaborenko, M. W. Bedore, T. F. Jamison, K. F. Jensen, Org. Process Res. Dev. 2011, 15, 131.
         | CrossRef |
      (q) T. Noél, S. Kuhn, A. J. Musachio, K. F. Jensen, S. L. Buchwald, Angew. Chem. Int. Ed. 2011, 50, 5943.
         | CrossRef |
      (r) A. C. Gutierrez, T. F. Jamison, Org. Lett. 2011, 13, 6414.
         | CrossRef |
      (s) W. Shu, L. Pellegatti, M. A. Oberli, S. L. Buchwald, Angew. Chem. Int. Ed. 2011, 50, 10665.
         | CrossRef |
      (t) W. Shu, S. L. Buchwald, Angew. Chem. Int. Ed. 2012, 51, 5355.
         | CrossRef |
      (u) A. Nagaki, Y. Moriwaki, J. Yoshida, Chem. Commun. 2012, 48, 11211.
         | CrossRef |

[9]  (a) Some recent examples that higher temperatures are possible in flow systems: T. Schwalbe, V. Autze, M. Hohmann, W. Stirner, Org. Process Res. Dev. 2004, 8, 440.
         | CrossRef | 1:CAS:528:DC%2BD2cXjsFGgu7k%3D&md5=14ebbd80c80f2fc35b4ce3c9431cf73dCAS |
      (b) X. Zhang, S. Stefanick, F. J. Villani, Org. Process Res. Dev. 2004, 8, 455.
         | CrossRef |
      (c) H. Pennemann, V. Hessel, H. Löwe, Chem. Eng. Sci. 2004, 59, 4789.
         | CrossRef |
      (d) D. M. Ratner, E. R. Murphy, M. Jhunjhunwala, D. A. Snyder, K. F. Jensen, P. H. Seeberger, Chem. Commun. 2005, 578.
      (e) T. Kawaguchi, H. Miyata, K. Ataka, K. Mae, J. Yoshida, Angew. Chem. Int. Ed. 2005, 44, 2413.
         | CrossRef |
      (f) O. Flogel, J. D. C. Codee, D. Seebach, P. H. Seeberger, Angew. Chem., Int. Ed. 2006, 45, 7000.
         | CrossRef |
      (g) F. R. Carrel, K. Geyer, D. C. Jeroen, J. D. C. Codee, P. H. Seeberger, Org. Lett. 2007, 9, 2285.
         | CrossRef |
      (h) Y. Ushiogi, T. Hase, Y. Iinuma, A. Takata, J. Yoshida, Chem. Commun. 2007, 2947.
         | CrossRef |
      (i) A. Nagaki, Y. Tomida, J. Yoshida, Macromolecules 2008, 41, 6322.
      (j) A. Nagaki, Y. Tomida, A. Miyazaki, J. Yoshida, Macromolecules 2009, 42, 4384.
         | CrossRef |

[10]  (a) J. Yoshida, Chem. Commun. 2005, 4509.
         | CrossRef | 1:CAS:528:DC%2BD2MXpvV2qtbw%3D&md5=c8e69caa10af8534f9c83f375b189e42CAS |
      (b) J. Yoshida, A. Nagaki, T. Yamada, Chem. – Eur. J. 2008, 14, 7450.
         | CrossRef |
      (c) J. Yoshida, Chem. Rec. 2010, 10, 332.
         | CrossRef |
      (d) A. Nagaki, N. Takabayashi, Y. Moriwaki, J. Yoshida, Chem. – Eur. J. 2012, 18, 11871.
         | CrossRef |

[11]  (a) H. Usutani, Y. Tomida, A. Nagaki, H. Okamoto, T. Nokami, J. Yoshida, J. Am. Chem. Soc. 2007, 129, 3046.
         | CrossRef | 1:CAS:528:DC%2BD2sXitVyiuro%3D&md5=a6c61e5f0b095dd559d74daaead4dd64CAS |
      (b) A. Nagaki, Y. Tomida, H. Usutani, H. Kim, N. Takabayashi, T. Nokami, H. Okamoto, J. Yoshida, Chem. – Asian J. 2007, 2, 1513.
         | CrossRef |
      (c) A. Nagaki, N. Takabayashi, Y. Tomida, J. Yoshida, Org. Lett. 2008, 10, 3937.
         | CrossRef |
      (d) A. Nagaki, N. Takabayashi, Y. Tomida, J. Yoshida, Beilstein J. Org. Chem. 2009, 5, 1.
         | CrossRef |
      (e) Y. Tomida, A. Nagaki, J. Yoshida, Org. Lett. 2009, 11, 3614.
         | CrossRef |
      (f) A. Nagaki, C. Matsuo, S. Kim, K. Saito, A. Miyazaki, J. Yoshida, Angew. Chem. Int. Ed. 2012, 51, 3245.
         | CrossRef |

[12]  (a) A. Nagaki, H. Kim, J. Yoshida, Angew. Chem. Int. Ed. 2008, 47, 7833.
         | CrossRef | 1:CAS:528:DC%2BD1cXht1OhsrnJ&md5=177476e8e83f7c800ac43b50a222cc66CAS |
      (b) A. Nagaki, H. Kim, J. Yoshida, Angew. Chem. Int. Ed. 2009, 48, 8063.
         | CrossRef |
      (c) A. Nagaki, H. Kim, Y. Moriwaki, C. Matsuo, J. Yoshida, Chem. – Eur. J. 2010, 16, 11167.
         | CrossRef |
      (d) A. Nagaki, H. Kim, C. Matuo, J. Yoshida, Org. Biomol. Chem. 2010, 8, 1212.
         | CrossRef |
      (e) H. Kim, A. Nagaki, J. Yoshida, Nature Commun. 2011, 2, 264.
         | CrossRef |

[13]  (a) A. Nagaki, E. Takizawa, J. Yoshida, J. Am. Chem. Soc. 2009, 131, 1654.
         | CrossRef | 1:CAS:528:DC%2BD1MXntlOiug%3D%3D&md5=1dce7c7ef96077a8e490e17008753be6CAS |
      (b) A. Nagaki, E. Takizawa, J. Yoshida, Chem. – Eur. J. 2010, 16, 14149.
         | CrossRef |

[14]  A. Nagaki, E. Takizawa, J. Yoshida, Chem. Lett. 2009, 38, 1060.
         | CrossRef | 1:CAS:528:DC%2BD1MXhsVChsbvJ&md5=ef3091461388719784c077739e14c7afCAS |

[15]  A. Nagaki, S. Tokuoka, S. Yamada, Y. Tomida, K. Oshiro, H. Amii, J. Yoshida, Org. Biomol. Chem. 2011, 9, 7559.
         | CrossRef | 1:CAS:528:DC%2BC3MXhtlSgsrvF&md5=bb981dc52b2fdf0925e6993543ec975cCAS |

[16]  Y. Tomida, A. Nagaki, J. Yoshida, J. Am. Chem. Soc. 2011, 133, 3744.
         | CrossRef | 1:CAS:528:DC%2BC3MXisFWlsLw%3D&md5=0f9ee9649b164643f4858faedc433a96CAS |

[17]  (a) Br/Li exchange reaction of bromopyridines with ketones under in-situ-quench conditions in microreactor: S. Goto, J. Velder, S. E. Sheikh, Y. Sakamoto, M. Mitani, S. Elmas, A. Adler, A. Becker, J.-M. Neudörfl, J. Lex, H.-G. Schmalz, Synlett 2008, 9, 1361.
      (b) LiCl-mediated Br/Mg exchange reaction of bromopyridines in flow: T. Brodmann, P. Koos, A. Metzger, P. Knochel, S. V. Ley, Org. Process Res. Dev. 2012, 16, 1102.
         | CrossRef |

[18]  A. Nagaki, S. Yamada, M. Doi, Y. Tomida, N. Takabayashi, J. Yoshida, Green Chem. 2011, 13, 1110.
         | CrossRef | 1:CAS:528:DC%2BC3MXlsF2ns7w%3D&md5=4866818f53a15a9006bfc7ad8eb1303bCAS |

[19]  (a) Integration of a sequence of reactions in flow by adding reaction components at different places: S. Suga, D. Yamada, J. Yoshida, Chem. Lett. 2010, 39, 404.
         | CrossRef | 1:CAS:528:DC%2BC3cXltFWmu70%3D&md5=acb4769eb310984bf5dab1bca77d039eCAS |
      (b) A. Nagaki, A. Kenmoku, Y. Moriwaki, A. Hayashi, J. Yoshida, Angew. Chem. Int. Ed. 2010, 49, 7543.
         | CrossRef |
      (c) J. Yoshida, K. Saito, T. Nokami, A. Nagaki, Synlett 2011, 2011, 1189.
         | CrossRef |

[20]  (a) For an example on the lithiation of 2,3-dibromopyridine: M. Mallet, G. Quéguiner, Tetrahedron 1979, 35,
         | CrossRef | 1:CAS:528:DyaL3cXhvFyhsLw%3D&md5=a9e087db7e70178944fddc9b6fa17e40CAS |
      (b) M. Mallet, G. Quéguiner, Tetrahedron 1985, 41, 3433.
         | CrossRef |
      (c) G. J. Quallich, D. E. Fox, R. C. Friedmann, C. W. Murtiashaw, J. Org. Chem. 1992, 57, 761.
         | CrossRef |

[21]  (a) For an example on the lithiation of 2,5-dibromopyridine: W. E. Parham, R. M. Piccirilli, J. Org. Chem. 1977, 42, 257.
         | CrossRef | 1:CAS:528:DyaE2sXnt1eksA%3D%3D&md5=39451f42939608574c4959b7e77dbfcbCAS |
      (b) X. Wang, P. Rabbat, P. O’Shea, R. Tillyer, E. J. J. Grabowski, P. J. Reider, Tetrahedron Lett. 2000, 41, 4335.
         | CrossRef |
      (c) P. C. Gros, A. Doudouh, C. Woltermann, Chem. Commun. 2006, 2673.
         | CrossRef |
      (d) A. Doudouh, C. Woltermann, P. C. Gros, J. Org. Chem. 2007, 72, 4978.
         | CrossRef |

[22]  (a) For an example on the lithiation of 2,6-dibromopyridine: E. De Vos, E. L. Esmans, F. C. Alderweireldt, J. Heterocycl. Chem. 1993, 30, 1245.
         | CrossRef | 1:CAS:528:DyaK2cXislWjtro%3D&md5=c2ee88381623032eece459ea4e5e0e4cCAS |
      (b) Y. Uchida, N. Echikawa, S. Oae, Heteroat. Chem. 1994, 5, 409.
         | CrossRef |
      (c) D. Cai, D. L. Hughes, T. R. Verhoeven, Tetrahedron Lett. 1996, 37, 2537.
         | CrossRef |



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