d
Reagents and conditions: 7b or 8a (0.15 mmol, 1.0 equiv.), amine (50.0 equiv.), 165 °C, microwave irradiation.
Bach, S.; Baratte, B.; Sauvain, M.; Castillo Pareja, D.; Vaisberg,
A.; Le Pape, P. Eur. J. Med. Chem. 2015, 103, 381–395; (b)
On the basis of these optimised reaction conditions,
functionalization of the C-7 position through C‒C and C‒N
linkages was investigated (Table 3). As the chlorine atom in this
position is difficult to displace, microwave-promoted heating was
required for between one to five hours. Suzuki-Miyaura cross-
coupling reactions using 4-chlorophenylboronic acid (Entries 1
and 7) and 4-pyridylboronic acid (Entry 4) proceeded to give the
desired 7-arylated compounds. This transformation was
compatible with C-3 substituents such as aryl, carboxamide and
amine moieties. Next, compounds 7a and 8a underwent
Buchwald-Hartwig reactions to provide 9b and 9e in moderate
yields (Entries 2 and 5). However, extended heating was required
Bazin, M.-A.; Marhadour, S.; Tonnerre, A.; Marchand, P.
Tetrahedron Lett. 2013, 54, 5378–5382; (c) Marhadour, S.;
Marchand, P.; Pagniez, F.; Bazin, M.-A.; Picot, C.; Lozach, O.;
Ruchaud, S.; Antoine, M.; Meijer, L.; Rachidi, N.; Le Pape, P.
Eur. J. Med. Chem. 2012, 58, 543–556; (d) Marhadour, S.; Bazin,
M.-A.; Marchand, P. Tetrahedron Lett. 2012, 53, 297–300.
(a) Montoir, D.; Tonnerre, A.; Duflos, M.; Bazin, M.-A.
Tetrahedron 2015, 71, 3303–3313; (b) Montoir, D.; Tonnerre, A.;
Duflos, M.; Bazin, M.-A. Eur. J. Org. Chem. 2014, 7, 1487–1495.
Montoir, D.; Barillé-Nion, S.; Tonnerre, A.; Juin, P.; Duflos, M.;
Bazin, M.-A. Eur. J. Med. Chem. 2016, 119, 17–33.
5
6
.
.
7. (a) Sabatini, S.; Cecchetti, V.; Tabarrini, O.; Fravolini, A. J.
Heterocyclic Chem. 1999, 36, 953–957; (b) Sanchez, J. P.;
Gogliotti, R. D. J. Heterocyclic Chem. 1993, 30, 855–859.
(
3‒5 h), compared to the Suzuki and S Ar reactions. Therefore,
N
higher amounts of the catalyst system (Pd(OAc) and XantPhos)
2
8
.
(a) Massari, S.; Mercorelli, B.; Sancineto, L.; Sabatini, S.;
were required. Finally, we carried out nucleophilic aromatic
Cecchetti, V.; Gribaudo, G.; Palu, G.; Pannecouque, C.; Loregian,
A.; Tabarrini, O. ChemMedChem 2013, 8, 1403–1414; (b) Platts,
M. Y.; Barber, C. G.; Chiva, J.-Y.; Eastwood, R. L.; Fenwick, D.
R.; Paradowski, K. A.; Blakemore, D. C. Tetrahedron Lett. 2011,
substitutions (S Ar) with two aliphatic amines following our
N
5
a
previously reported protocol. The desired products were
obtained within one hour (Entries 3 and 6).
5
2, 512–514; (c) Tabarrini, O.; Massari, S.; Sancineto, L.;
In conclusion, we have developed an efficient route to 3,7-
disubstituted 1,6-naphthyridin-4(1H)-ones. Our synthesis features
the construction of 3,7-dihalogenated compounds that enables
access to a range of C‒C and C‒N linkages using cross-coupling
Daelemans, D.; Sabatini, S.; Manfroni, G.; Cecchetti, V.;
Pannecouque, C. ChemMedChem 2011, 6, 1249–1257.
Harrington, P. E.; Croghan, M. D.; Fotsch, C.; Frohn, M.;
Lanman, B. A.; Pennington, L. D.; Pickrell, A. J.; Reed, A. B.;
Sham, K. K. C.; Tasker, A.; Arnett, H. A.; Fiorino, M.; Lee, M.
R.; McElvain, M.; Morrison, H. G.; Xu, H.; Xu, Y.; Zhang, X.;
Wong, M.; Cee, V. J. ACS Med. Chem. Lett. 2012, 3, 74–78.
9
1
.
and S Ar reactions with good functional-group tolerance and
N
substrate scope.
0. Ehara,T.; Irie, O.; Kosaka, T.; Kanazawa, T.; Breitenstein, W.;
Grosche, P.; Ostermann, N.; Suzuki, M.; Kawakami, S.; Konishi,
K.; Hitomi, Y.; Toyao, A.; Gunji, H.; Cumin, F.; Schiering, N.;
Wagner, T.; Rigel, D. F.; Webb, R. L.; Maibaum, J.; Yokokawa,
F. ACS Med. Chem. Lett. 2014, 5, 787–792.
11. Sato, M.; Motomura, T.; Aramaki, H.; Matsuda, T.; Yamashita,
M.; Ito, Y.; Kawakami, H.; Matsuzaki, Y.; Watanabe, W.;
Yamataka, K.; Ikeda, S.; Kodama, E.; Matsuoka, M.; Shinkai, H.
J. Med. Chem. 2006, 49, 1506–1508.
Acknowledgments
The authors gratefully acknowledge support of this project
by the Ligue Contre le Cancer (Comité du Maine-et-Loire et de
Loire-Atlantique).This work was supported by the network
“
Produits de la mer en cancérologie” from the Cancéropôle
Grand Ouest.
1
2. (a) Maignan, J. R.; Lichorowic, C. L.; Giarrusso, J.; Blake, L. D.;
Casandra, D.; Mutka, T. S.; LaCrue, A. N.; Burrows, J. N.; Willis,
References and notes
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(a) Marchand, P.; Bazin, M.-A.; Pagniez, F.; Rivière, G.; Bodero,
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