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

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 http://dx.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.

Graphical Abstract Image


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 | open url image1

[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 | open url image1
      (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 | open url image1

[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 | open url image1
      (b) A. Godard, F. Marsais, N. Plé, F. Trécourt, A. Turck, G. Quéguiner, Heterocycles 1995, 40, 1055.
         | CrossRef | open url image1
      (c) F. Trécourt, B. Gervais, M. Mallet, G. Quéguiner, J. Org. Chem. 1996, 61, 1673.
         | CrossRef | open url image1
      (d) F. Trécourt, B. Gervais, O. Mongin, C. Le Gal, F. Mongin, G. Quéguiner, J. Org. Chem. 1998, 63, 2892.
         | CrossRef | open url image1
      (e) E. Pasquinet, P. Rocca, F. Marsais, A. Godard, G. Quéguiner, Tetrahedron 1998, 54, 8771.
         | CrossRef | open url image1
      (f) P. C. Gros, Y. Fort, Eur. J. Org. Chem. 2009, 4199.
         | CrossRef | open url image1

[5]  (a) H. Gilman, S. M. Spatz, J. Org. Chem. 1951, 16, 1485.
         | CrossRef | 1:CAS:528:DyaG38XjsF2itw%3D%3D&md5=c168045f05151d7c45964cba1622b61bCAS | open url image1
      (b) H. Gilman, W. A. Gregory, S. M. Spatz, J. Org. Chem. 1951, 16, 1788.
         | CrossRef | open url image1
      (c) J. P. Wibaut, L. G. Heeringa, Recl. Trav. Chim. Pays Bas 1955, 74, 1003.
         | CrossRef | open url image1
      (d) W. E. Parham, R. M. Piccirilli, J. Org. Chem. 1977, 42, 257.
         | CrossRef | open url image1
      (e) G. R. Newkome, J. M. Roper, J. Organomet. Chem. 1980, 186, 147.
         | CrossRef | open url image1
      (f) M. Mallet, G. Quéguiner, Tetrahedron 1986, 42, 2253.
         | CrossRef | open url image1
      (g) M. Mallet, G. Branger, F. Marsais, G. Quéguiner, J. Organomet. Chem. 1990, 382, 319.
         | CrossRef | open url image1
      (h) D. Cai, D. L. Hughes, T. R. Verhoeven, Tetrahedron Lett. 1996, 37, 2537.
         | CrossRef | open url image1
      (i) R. H. Furneaux, G. Limberg, P. C. Tyler, V. L. Schramm, Tetrahedron 1997, 53, 2915.
         | CrossRef | open url image1
      (j) M. A. Peterson, J. R. Mitchell, J. Org. Chem. 1997, 62, 8237.
         | CrossRef | open url image1

[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 | open url image1
      (b) G. N. Doku, W. Verboom, D. N. Reinhoudt, A. van den Berg, Tetrahedron 2005, 61, 2733.
         | CrossRef | open url image1
      (c) J. Yoshida, A. Nagaki, T. Iwasaki, S. Suga, Chem. Eng. Tech. 2005, 28, 259.
         | CrossRef | open url image1
      (d) P. Watts, S. J. Haswell, Chem. Soc. Rev. 2005, 34, 235.
         | CrossRef | open url image1
      (e) K. Geyer, J. D. C. Codee, P. H. Seeberger, Chem. – Eur. J. 2006, 12, 8434.
         | CrossRef | open url image1
      (f) A. J. deMello, Nature 2006, 442, 394.
         | CrossRef | open url image1
      (g) H. Song, D. L. Chen, R. F. Ismagilov, Angew. Chem. Int. Ed. 2006, 45, 7336.
         | CrossRef | open url image1
      (h) J. Kobayashi, Y. Mori, S. Kobayashi, Chem. – Asian. J. 2006, 1, 22.
         | CrossRef | open url image1
      (i) M. Brivio, W. Verboom, D. N. Reinhoudt, Lab Chip. 2006, 6, 329.
         | CrossRef | open url image1
      (j) B. P. Mason, K. E. Price, J. L. Steinbacher, A. R. Bogdan, D. T. McQuade, Chem. Rev. 2007, 107, 2300.
         | CrossRef | open url image1
      (k) B. Ahmed-Omer, J. C. Brandtand, T. Wirth, Org. Biomol. Chem. 2007, 5, 733.
         | CrossRef | open url image1
      (l) P. Watts, C. Wiles, Chem. Commun. 2007, 443.
         | CrossRef | open url image1
      (m) T. Fukuyama, M. T. Rahman, M. Sato, I. Ryu, Synlett 2008, 151. open url image1
      (n) J. Yoshida, A. Nagaki, T. Yamada, Chem. – Eur. J. 2008, 14, 7450.
         | CrossRef | open url image1
      (o) R. L. Hartman, K. F. Jensen, Lab Chip. 2009, 9, 2495.
         | CrossRef | open url image1
      (p) W. Lin, Y. Wang, S. Wang, H. Tseng, Nano Today 2009, 4, 470.
         | CrossRef | open url image1
      (q) K. Geyer, T. Gustafsson, P. H. Seeberger, Synlett 2009, 2382. open url image1
      (r) J. P. McMullen, K. F. Jensen, Annu. Rev. Anal. Chem. 2010, 3, 19.
         | CrossRef | open url image1
      (s) S. Marre, K. F. Jensen, Chem. Soc. Rev. 2010, 39, 1183.
         | CrossRef | open url image1
      (t) D. Webb, T. F. Jamison, Chem. Sci. 2010, 1, 675.
         | CrossRef | open url image1
      (u) J. P. McMullen, K. F. Jensen, Annu. Rev. Anal. Chem. 2010, 3, 19.
         | CrossRef | open url image1
      (v) J. Yoshida, H. Kim, A. Nagaki, ChemSusChem 2011, 4, 331.
         | CrossRef | open url image1

[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 | open url image1
      (b) A. Nagaki, M. Togai, S. Suga, N. Aoki, K. Mae, J. Yoshida, J. Am. Chem. Soc. 2005, 127, 11666.
         | CrossRef | open url image1
      (c) P. He, P. Watts, F. Marken, S. J. Haswell, Angew. Chem. Int. Ed. 2006, 45, 4146.
         | CrossRef | open url image1
      (d) K. Tanaka, S. Motomatsu, K. Koyama, S. Tanaka, K. Fukase, Org. Lett. 2007, 9, 299.
         | CrossRef | open url image1
      (e) H. R. Sahoo, J. G. Kralj, K. F. Jensen, Angew. Chem. Int. Ed. 2007, 46, 5704.
         | CrossRef | open url image1
      (f) C. H. Hornung, M. R. Mackley, I. R. Baxendale, S. V. Ley, Org. Process Res. Dev. 2007, 11, 399.
         | CrossRef | open url image1
      (g) T. Fukuyama, M. Kobayashi, M. T. Rahman, N. Kamata, I. Ryu, Org. Lett. 2008, 10, 533.
         | CrossRef | open url image1
      (h) C. Wiles, P. Watts, Org. Process Res. Dev. 2008, 12, 1001.
         | CrossRef | open url image1
      (i) A. Nagaki, E. Takizawa, J. Yoshida, J. Am. Chem. Soc. 2009, 131, 1654.
         | CrossRef | open url image1
      (j) A. Nagaki, E. Takizawa, J. Yoshida, Chem. Lett. 2009, 38, 486.
         | CrossRef | open url image1
      (k) I. C. Wienhofer, A. Studer, M. T. Rahman, T. Fukuyama, I. Ryu, Org. Lett. 2009, 11, 2457.
         | CrossRef | open url image1
      (l) A. R. Bogdan, S. L. Poe, D. C. Kubis, S. J. Broadwater, D. T. McQuade, Angew. Chem. Int. Ed. 2009, 48, 8547.
         | CrossRef | open url image1
      (m) T. Tricotet, D. F. O’Shea, Chem. – Eur. J. 2010, 16, 6678. open url image1
      (n) D. L. Browne, M. Baumann, B. H. Harji, I. R. Baxendale, S. V. Ley, Org. Lett. 2011, 13, 3312.
         | CrossRef | open url image1
      (o) C. F. Carter, H. Lange, D. Sakai, I. R. Baxendale, S. V. Ley, Chem. – Eur. J. 2011, 17, 3398.
         | CrossRef | open url image1
      (p) N. Zaborenko, M. W. Bedore, T. F. Jamison, K. F. Jensen, Org. Process Res. Dev. 2011, 15, 131.
         | CrossRef | open url image1
      (q) T. Noél, S. Kuhn, A. J. Musachio, K. F. Jensen, S. L. Buchwald, Angew. Chem. Int. Ed. 2011, 50, 5943.
         | CrossRef | open url image1
      (r) A. C. Gutierrez, T. F. Jamison, Org. Lett. 2011, 13, 6414.
         | CrossRef | open url image1
      (s) W. Shu, L. Pellegatti, M. A. Oberli, S. L. Buchwald, Angew. Chem. Int. Ed. 2011, 50, 10665.
         | CrossRef | open url image1
      (t) W. Shu, S. L. Buchwald, Angew. Chem. Int. Ed. 2012, 51, 5355.
         | CrossRef | open url image1
      (u) A. Nagaki, Y. Moriwaki, J. Yoshida, Chem. Commun. 2012, 48, 11211.
         | CrossRef | open url image1

[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 | open url image1
      (b) X. Zhang, S. Stefanick, F. J. Villani, Org. Process Res. Dev. 2004, 8, 455.
         | CrossRef | open url image1
      (c) H. Pennemann, V. Hessel, H. Löwe, Chem. Eng. Sci. 2004, 59, 4789.
         | CrossRef | open url image1
      (d) D. M. Ratner, E. R. Murphy, M. Jhunjhunwala, D. A. Snyder, K. F. Jensen, P. H. Seeberger, Chem. Commun. 2005, 578. open url image1
      (e) T. Kawaguchi, H. Miyata, K. Ataka, K. Mae, J. Yoshida, Angew. Chem. Int. Ed. 2005, 44, 2413.
         | CrossRef | open url image1
      (f) O. Flogel, J. D. C. Codee, D. Seebach, P. H. Seeberger, Angew. Chem., Int. Ed. 2006, 45, 7000.
         | CrossRef | open url image1
      (g) F. R. Carrel, K. Geyer, D. C. Jeroen, J. D. C. Codee, P. H. Seeberger, Org. Lett. 2007, 9, 2285.
         | CrossRef | open url image1
      (h) Y. Ushiogi, T. Hase, Y. Iinuma, A. Takata, J. Yoshida, Chem. Commun. 2007, 2947.
         | CrossRef | open url image1
      (i) A. Nagaki, Y. Tomida, J. Yoshida, Macromolecules 2008, 41, 6322. open url image1
      (j) A. Nagaki, Y. Tomida, A. Miyazaki, J. Yoshida, Macromolecules 2009, 42, 4384.
         | CrossRef | open url image1

[10]  (a) J. Yoshida, Chem. Commun. 2005, 4509.
         | CrossRef | 1:CAS:528:DC%2BD2MXpvV2qtbw%3D&md5=c8e69caa10af8534f9c83f375b189e42CAS | open url image1
      (b) J. Yoshida, A. Nagaki, T. Yamada, Chem. – Eur. J. 2008, 14, 7450.
         | CrossRef | open url image1
      (c) J. Yoshida, Chem. Rec. 2010, 10, 332.
         | CrossRef | open url image1
      (d) A. Nagaki, N. Takabayashi, Y. Moriwaki, J. Yoshida, Chem. – Eur. J. 2012, 18, 11871.
         | CrossRef | open url image1

[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 | open url image1
      (b) A. Nagaki, Y. Tomida, H. Usutani, H. Kim, N. Takabayashi, T. Nokami, H. Okamoto, J. Yoshida, Chem. – Asian J. 2007, 2, 1513.
         | CrossRef | open url image1
      (c) A. Nagaki, N. Takabayashi, Y. Tomida, J. Yoshida, Org. Lett. 2008, 10, 3937.
         | CrossRef | open url image1
      (d) A. Nagaki, N. Takabayashi, Y. Tomida, J. Yoshida, Beilstein J. Org. Chem. 2009, 5, 1.
         | CrossRef | open url image1
      (e) Y. Tomida, A. Nagaki, J. Yoshida, Org. Lett. 2009, 11, 3614.
         | CrossRef | open url image1
      (f) A. Nagaki, C. Matsuo, S. Kim, K. Saito, A. Miyazaki, J. Yoshida, Angew. Chem. Int. Ed. 2012, 51, 3245.
         | CrossRef | open url image1

[12]  (a) A. Nagaki, H. Kim, J. Yoshida, Angew. Chem. Int. Ed. 2008, 47, 7833.
         | CrossRef | 1:CAS:528:DC%2BD1cXht1OhsrnJ&md5=177476e8e83f7c800ac43b50a222cc66CAS | open url image1
      (b) A. Nagaki, H. Kim, J. Yoshida, Angew. Chem. Int. Ed. 2009, 48, 8063.
         | CrossRef | open url image1
      (c) A. Nagaki, H. Kim, Y. Moriwaki, C. Matsuo, J. Yoshida, Chem. – Eur. J. 2010, 16, 11167.
         | CrossRef | open url image1
      (d) A. Nagaki, H. Kim, C. Matuo, J. Yoshida, Org. Biomol. Chem. 2010, 8, 1212.
         | CrossRef | open url image1
      (e) H. Kim, A. Nagaki, J. Yoshida, Nature Commun. 2011, 2, 264.
         | CrossRef | open url image1

[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 | open url image1
      (b) A. Nagaki, E. Takizawa, J. Yoshida, Chem. – Eur. J. 2010, 16, 14149.
         | CrossRef | open url image1

[14]  A. Nagaki, E. Takizawa, J. Yoshida, Chem. Lett. 2009, 38, 1060.
         | CrossRef | 1:CAS:528:DC%2BD1MXhsVChsbvJ&md5=ef3091461388719784c077739e14c7afCAS | open url image1

[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 | open url image1

[16]  Y. Tomida, A. Nagaki, J. Yoshida, J. Am. Chem. Soc. 2011, 133, 3744.
         | CrossRef | 1:CAS:528:DC%2BC3MXisFWlsLw%3D&md5=0f9ee9649b164643f4858faedc433a96CAS | open url image1

[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. open url image1
      (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 | open url image1

[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 | open url image1

[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 | open url image1
      (b) A. Nagaki, A. Kenmoku, Y. Moriwaki, A. Hayashi, J. Yoshida, Angew. Chem. Int. Ed. 2010, 49, 7543.
         | CrossRef | open url image1
      (c) J. Yoshida, K. Saito, T. Nokami, A. Nagaki, Synlett 2011, 2011, 1189.
         | CrossRef | open url image1

[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 | open url image1
      (b) M. Mallet, G. Quéguiner, Tetrahedron 1985, 41, 3433.
         | CrossRef | open url image1
      (c) G. J. Quallich, D. E. Fox, R. C. Friedmann, C. W. Murtiashaw, J. Org. Chem. 1992, 57, 761.
         | CrossRef | open url image1

[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 | open url image1
      (b) X. Wang, P. Rabbat, P. O’Shea, R. Tillyer, E. J. J. Grabowski, P. J. Reider, Tetrahedron Lett. 2000, 41, 4335.
         | CrossRef | open url image1
      (c) P. C. Gros, A. Doudouh, C. Woltermann, Chem. Commun. 2006, 2673.
         | CrossRef | open url image1
      (d) A. Doudouh, C. Woltermann, P. C. Gros, J. Org. Chem. 2007, 72, 4978.
         | CrossRef | open url image1

[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 | open url image1
      (b) Y. Uchida, N. Echikawa, S. Oae, Heteroat. Chem. 1994, 5, 409.
         | CrossRef | open url image1
      (c) D. Cai, D. L. Hughes, T. R. Verhoeven, Tetrahedron Lett. 1996, 37, 2537.
         | CrossRef | open url image1



Supplementary MaterialSupplementary Material 1.13 MB Export Citation