Communication
[
4] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008,
Conclusions
3
7, 320–330; b) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359–4369; c)
N. A. Meanwell, J. Med. Chem. 2011, 54, 2529–2591.
5] H. Huang, J. Cai, H. Xie, J. Tan, F. Li, G.-J. Deng, Org. Lett. 2017, 19, 3743–
The results described herein establish the first examples of
chemoselective Sonogashira cross-coupling reaction of 3 iso-
mers of unprotected bromofluoropyridinaldoxime with func-
tionalized alkynes, creating industrially and academically
relevant new scaffolds for medicinal chemistry development.
A variety of valuable functional groups, including unprotected
alcohol, unprotected amine, ester, chloro, nitrile, sulfon-
amide, N-protected amine, terminal alkene, acetonide, imide
functions and strained heterocycles were well tolerated
[
[
3
746.
6] H. Xiong, A. T. Hoye, K.-H. Fan, X. Li, J. Clemens, C. L. Horchler, N. C. Lim,
G. Attardo, Org. Lett. 2015, 17, 3726–3729.
[7] R. F. Gamache, C. Waldmann, J. M. Murphy, Org. Lett. 2016, 18, 4522–
525.
8] a) P. Brugarolas, R. Freifelder, S.-H. Cheng, O. DeJesus, Chem. Commun.
4
[
2
2
016, 52, 7150–7152; b) Z. Song, X. Huang, W. Yi, W. Zhang, Org. Lett.
016, 18, 5640–5643; c) S. J. Ryan, S. D. Schimler, D. C. Bland, M. S.
Sanford, Org. Lett. 2015, 17, 1866–1869; d) S. Chen, R. G. Bergmann, J. A.
Ellma, Org. Lett. 2015, 17, 2567–2569; e) Z. Chen, J. Zhu, H. Xie, S. Li, Y.
Wu, Y. Gong, Org. Lett. 2010, 12, 4676–4679; f) G. Duret, R. Quinlan, R. E.
Martin, P. Bisseret, M. Neuburger, V. Gandon, N. Blanchard, Org. Lett.
1
5
under the mild reaction conditions. Non-radioactive N
labelled 5-alkynyl-3-fluoro-pyridinaldoxime scaffold are also ac-
cessed in a straightforward manner for potential applications as
biomolecular probes. Chiral amino-acid and nucleoside
derivatives are fully compatible with the reaction. Owing to its
unique scope, this late stage Sonogashira cross-coupling meth-
odology proved to be an inestimable and indispensable tool
for creating molecular diversity based on fluoropyridinaldoxime
scaffold.
2016, 18, 1610–1613.
[
9] a) B. W. Stroup, P. V. Szklennik, C. J. Foster, M. H. Serrano-Wu, Org. Lett.
2007, 9, 2039–2042; b) O. Zeika, Y. Li, S. Jockusch, G. Parkin, A. Sattler,
W. Sattler, N. J. Turro, Org. Lett. 2010, 12, 3696–3699.
[
10] a) S. Roesner, S. L. Buchwald, Angew. Chem. Int. Ed. 2016, 55, 10463–
0467; Angew. Chem. 2016, 128, 10619; b) M. Schlosser, Angew. Chem.
1
Int. Ed. 2006, 45, 5432–5446; Angew. Chem. 2006, 118, 5558.
[
11] T. Katoh, Y. Tomata, T. Tsukamoto, Y. Nakada, Tetrahedron Lett. 2015, 56,
6
043–6046.
[
12] a) A. J. Roecker, M. Egbertson, K. L. G. Jones, R. Gomez, R. L. Kraus, Y. Li,
A. J. Koser, M. O. Urban, R. Klein, M. Clements, J. Panigel, C. Daley, J.
Wang, E. N. Finger, J. Majercak, V. Santarelli, I. Gregan, M. Catob, T. Filzen,
A. Jovanovska, Y.-H. Wang, D. Wang, L. A. Joyce, E. C. Sherer, X. Peng, X.
Wang, H. Sun, P. J. Coleman, A. K. Houghton, M. E. Layton, Bioorg. Med.
Chem. Lett. 2017, 27, 2087–2093; b) M. Timperley, R. E. Banks, I. M. Young,
R. N. Haszeldine, J. Fluorine Chem. 2011, 132, 541–547; c) H. C. Jeong,
N. S. Kang, N.-J. Park, E. K. Yumb, Y.-S. Jung, Bioorg. Med. Chem. Lett.
2009, 19, 1214–1217; d) H. C. Jeong, N. S. Kang, N.-J. Park, E. K. Yum, Y.-
S. Jung, Bioorg. Med. Chem. 2009, 17, 6213–6217.
Experimental Section
General Procedure for the Late Stage Sonogashira Reaction
Given for the Synthesis of 3a: To a degassed solution of oxime 2
(
249 mg, 1.144 mmol, 1.1 equiv.) in THF/Et N (8 mL/ 3 mL) were
3
added Pd[PPh ] (180 mg, 0.156 mmol, 0.15 equiv.) and CuI (60 mg,
3
4
0
5
1
.312 mmol, 0.3 equiv.). After degassing the reaction mixture for
min at room temperature, alkyne 1a (5-phenyl-1-pentyne, 150 mg,
.04 mmol, 1 equiv.) was added dropwise, and the reaction mixture
[
13] a) M. Sen, D. Kalsi, B. Sundararaju, Chem. Eur. J. 2015, 21, 15529–15533;
b) T. Rizk, E. J.-F. Bilodeau, A. M. Beauchemin, Angew. Chem. Int. Ed. 2009,
4
8, 8325–8327; Angew. Chem. 2009, 121, 8475; c) M. Toyota, C. Komori,
was stirred at the room temperature for 16 h. After completion
checked by TLC), the reaction mixture was concentrated under re-
M. Ihara, J. Org. Chem. 2000, 65, 7110–7113; d) V. M. Girijavallabhan, L.
Chen, C. Dai, R. J. Feltz, L. Firmanjah, D. Li, S. H. Kim, J. A. Kozlowski, B. J.
Lavey, A. Kosinski, J. J. Piwinski, J. Popovici-Muller, R. Rizvi, K. E. Rosner,
B. B. Shankar, N.-Y. Shih, M. A. Siddiqui, L. Tong, M. K. C. Wong, D.-Y.
Yanhg, L. Yang, W. Yu, G. Zhou, Z. Guo, P. Orth, V. Madison, H. Bian, D.
Lundell, X. Niu, H. Shah, J. Sun, S. Umland, Bioorg. Med. Chem. Lett. 2010,
(
duced pressure, and the residue was purified by column chroma-
tography (EtOAc/PE, 1:9) to afford the desired coupled fluoro oxime
3
a as a white solid in 92 % isolated yield.
2
0, 7283–7287.
[
14] a) J. Renou, J. Dias, G. Mercey, T. Verdelet, C. Rousseau, A.-J. Gastellier, M.
Arboleas, M. Touvrey-Loiodice, R. Baati, L. Jean, F. Nachon, P.-Y. Renard,
RSC Adv. 2016, 6, 17929–17940; b) M. Kliachyna, V. Nussbaum, J. Renou,
G. Santoni, B. Sanson, J.-P. Colletier, M. Arboléas, M. Loiodice, M. Weik, L.
Jean, P.-Y. Renard, F. Nachon, R. Baati, Eur. J. Med. Chem. 2014, 78, 455–
Acknowledgments
We gratefully acknowledge the financial support to J. Y. from
the Agence National de la Recherche, the Centre National de la
Recherche Scientifique (CNRS), and the Délégation Générale de
l'Armement (DGA).
4
67.
[
15] a) J. Renou, M. Loiodice, M. Arboléas, R. Baati, L. Jean, F. Nachon, P.-Y.
Renard, Chem. Commun. 2014, 50, 3947–3950; b) J. Renou, G. Mercey,
T. Verdelet, E. Păunescu, E. Gillon, M. Arboléas, M. Touvrey-Loiodice, M.
Kliachyna, R. Baati, F. Nachon, L. Jean, P.-Y. Renard, Chem.-Biol. Interactions
2
013, 203, 81–84.
Keywords: Fluoropyridines · Homogeneous catalysis ·
Cross-coupling · Reactivation · Oximes
[
16] a) G. Mercey, T. Verdelet, G. Saint-André, E. Gillon, A. Wagner, R. Baati, L.
Jean, F. Nachon, P.-Y. Renard, Chem. Commun. 2011, 47, 5295–5297; b)
G. Mercey, T. Verdelet, J. Renou, M. Klyachina, R. Baati, E. Gillon, M. Loio-
dice, F. Nachon, L. Jean, P.-Y. Renard, J. Med. Chem. 2012, 55, 10791–
10795.
[17] a) P. Masson, F. Nachon, J. Neurochem. 2017, 140-143, 1–15; b) G. Mercey,
T. Verdelet, J. Renou, M. Kliachyna, R. Baati, F. Nachon, L. Jean, P.-Y. Ren-
ard, Acc. Chem. Res. 2012, 45, 756–766; c) M. C. de Koning, M. J. A.
Joosen, F. Worek, F. Nachon, M. van Grol, S. D. Klaasen, D. P. W. Alkema,
T. Wille, H. M. de Bruijn, J. Med. Chem. 2017, 60, 9376–9392; d) T. Zorbaz,
A. Braïki, N. Maraković, J. Renou, E. de la Mora, N. M. Hrvat, M. Katalinić,
I. Silman, J. L. Sussman, G. Mercey, C. Gomez, R. Mougeot, B. Pérez, R.
Baati, F. Nachon, M. Weik, L. Jean, Z. Kovarik, P.-Y. Renard, Chem. Eur. J.
2018, 24, 9675–9691.
[
[
[
1] a) R. A. Shenvi, D. P. O'Malley, P. S. Baran, Acc. Chem. Res. 2009, 42, 530–
541; b) J. Mahatthananchai, A. M. Dumas, J. W. Bode, Angew. Chem. Int.
Ed. 2012, 51, 10954–0990; Angew. Chem. 2012, 124, 11114.
2] a) K. Muller, C. Faeh, F. Diederich, Science 2007, 317, 1881–1886; b) P.
Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications,
2nd ed., Wiley-VCH, Weiheim, 2013.
3] a) J. Wang, M. Sanchez-Rosello, J. Acenặ, C. Del Pozo, A. E. Sorochinsky,
S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432–2506; b)
E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med.
Chem. 2015, 58, 8315–8359.
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