Y. Riadi et al. / C. R. Chimie xxx (xxxx) xxx
5
[11] M.R. Mahmoud, E.A.A. El-Bordany, N.F. Hassan, F.S.M. Abu El-Azm,
Phosphorus, Sulfur Silicon Relat. Elem. 182 (2007) 2507e2521.
[12] (a) J. Bulicz, C.G. Daniela, D.C.G. Bertarelli, D. Baumert, F. Fülle,
E.M. Christa, D. Heber, Bioorg. Med. Chem. 14 (2006) 2837e2849.
until its solidification. After cooling, the solid obtained was dis-
solved in 500 mL of solution of sodium hydroxide (2 N) and filtered.
Then, the filtrate was neutralized with hydrochloric acid solution (6
N) to pH 8 until total precipitation of product. The resultant solid
was filtered and then washed with cold water to obtain compound
4 as yellow solid in 64% yield.
(b) A. Monge, V. Martinez-Merino, C. Sanmartin, F.J. Fernandez,
M.C. Ochoa, C. Berllver, P. Artigas, E. Fernandez-Alvarez, Eur. J. Med.
[25] Procedure for the synthesis of 6 and 7. 2,4,6-Trichloro-pyrido[2,3-d]
pyrimidine (6) (C7H2Cl3N3): A mixture of 50 mL of POCl3, two
drops of DMF, and 5 g of 6-chloro-1H-pyrido[2,3-d]pyrimidine-2,4-
dione 4 were heated to reflux. After 6 h, the reaction was evapo-
rated under reduced pressure; 400 mL of CH2Cl2 and 20 mL of
water were added to the residue at 0ꢀC. The aqueous phase was
extracted, the organic layers were combined and then dried over
magnesium sulfate. After filtration the filtrate was evaporated
under reduced pressure, and then washed with Et2O to obtain
compound 6 as a yellow solid in 64% yield.
[13] (a) E.C. Taylor, D.C. Palmer, T.J. George, S.R. Fletcher, C.P. Tseng,
P.J. Harrington, G.P. Beardsley, J. Org. Chem. 48 (1983) 4852e4860,
(b) J.I. Degraw, P.H. Christie, W.T. Colwell, F.M. Sirotnak, J. Med.
[14] T. Saurat, F. Buron, N. Rodrigues, M.L. de Tauzia, L. Colliandre,
S. Bourg, P. Bonnet, G. Guillaumet, M. Akssira, A. Corlu, C. Guillouzo,
ꢀ
ꢀ
P. Berthier, P. Rio, M.L. Jourdan, H. Benedetti, S. Routier, J. Med.
[27] Procedure for the synthesis of 8e12 via Suzuki cross-coupling re-
action: To an argon degassed solution of 6-halogeno-2,4-
dichloropyrido[2,3-d]pyrimidine 6 or 7 (0.5 mmol) in toluene (6
mL) the desired (Het)aryl boronic acid was added then (1.5 equiv)
potassium carbonate and (0.05 equiv) Pd(PPh3)4 were also added.
The reaction was stirred at 110ꢀC for the desired time. After
completion of the reaction, 10 mL of water was added, and then
extracted with dichloromethane (3 Â 10 mL), the organic layers
were combined and dried using magnesium sulfate, and the solvent
was evaporated under reduced pressure. The obtained material was
purified on silica gel by column chromatography (CH2Cl2/PE: 90/10)
to afford compounds 8e12. 2,4-Dichloro-6-(4-methoxyphenyl)
pyrido[2,3-d]pyrimidine (8) (C14H9Cl2N3O): Compound 8 was ob-
ꢀ
ꢀ
[16] M. Font, A. Gonzalez, J.A. Palop, C. Sanmartín, Eur. J. Med. Chem. 46
[18] (a) Y. Riadi, S. Massip, J.M. Leger, C. Jarry, S. Lazar, G. Guillaumet,
(b) Y. Riadi, M. Geesi, O. Dehbi, M.A. Bakht, M. Alshammari, M.-
C. Viaud-Massuarde, Green Chem. Lett. Rev. 10 (2017) 101e106.
(c) Y. Riadi, M. Geesi, Chem. Pap. 72 (2018) 697e701. http://doi.
tained from 2,4,6-trichloropyrido[2,3-d]pyrimidine
6 using 4-
[19] A. Tikad, M. Akssira, S. Massip, J.M. Leger, C. Jarry, G. Guillaumet,
[20] R.A. Smits, M. Adami, E.P. Istyastono, O.P. Zuiderveld, C.M.E. Van
Dam, F.J.J. de Kanter, A. Jongejan, G. Coruzzi, R. Leurs, I.J.P. de Esch, J.
[23] Procedure for the synthesis of 2 and 3. 2-Amino-5-chloronicotinic
acid (2) (C6H5ClN2O2): Acetic acid (200 mL) and water (5 mL)
were poured into the solution of 2-aminonicotinic acid 1 (5 g, 36.20
mmol). Chlorine generated by the action of 24 mL of hydrochloric
acid and 30 g of KMnO4 was bubbled into the acid suspension. The
mixture was reacted for 8 h at room temperature, and then filtered
and the solvent evaporated under reduced pressure. The obtained
crude material was washed with Et2O and methanol to give com-
pound 2 as a white solid in 81% yield. 2-Amino-5-bromonicotinic
acid (3) (C6H5BrN2O2): Acetic acid (250 mL) and water (10 mL)
were poured into the solution of 2-aminonicotinic acid 1 (10 g, 72.4
mmol). The suspension was placed at 0ꢀC and Br2 (4 mL, 79 mmol,
1.1 equiv) was added dropwise. After 8 h of stirring at room tem-
perature, the mixture was filtered and then concentrated under
reduced pressure. The crude material obtained was washed with
Et2O to afford compound 3 as a white solid in 89% yield.
[24] Procedure for the synthesis of 4 and 5. 6-Chloro-1H-pyrido[2,3-d]
methoxyphenyl boronic acid (1.05 equiv), as a white solid in 83%
yield.
[28] Procedure for the synthesis of 13e15 and 17 via Suzuki cross-
coupling reaction: Compounds 13e15 and 17 were obtained via a
Suzuki reaction by reacting compounds 8e12 (0.5 mmol) with (het)
arylboronic acid (1.05 equiv) in the presence of Na2CO3 (2 equiv),
Pd(PPh3)4 (0.05 equiv), and a mixture of toluene/ethanol (3/1) at
110ꢀC. After total completion of the reaction, 10 mL of water and 10
mL CH2Cl2 were added. The water layer was extracted with
dichloromethane (3 Â 10 mL), the organic layers were combined
and dried using magnesium sulfate, and then the solvent was
evaporated under reduced pressure. The crude material was puri-
fied on column chromatography using silica gel (CH2Cl2/PE: 90/10)
to afford compounds 13e15 and 17.
[29] Procedure for the synthesis of 16 via Suzuki cross-coupling reaction:
Compound 16 was obtained via a Suzuki reaction from compound 8
(0.5 mmol) and (het)arylboronic acid (1.2 equiv), in the presence of
Na2CO3 (1.5 equiv) and Pd(PPh3)4 (0.05 equiv) in refluxing toluene
at 110ꢀC. After complete reaction of compound 8, 10 mL of water
and 10 mL of CH2Cl2 were added. Then, the water layer was
extracted with dichloromethane (3 Â 10 mL), organic layers were
combined, dried over magnesium sulfate, and the solvent was
removed under reduced pressure. The crude material was obtained
by evaporation of solvent under reduced pressure, and then purified
by flash chromatography using silica gel (CH2Cl2/PE: 90/10) to
afford compound 16.
[30] I. Ali, Z. Hassan, M. Hein, A. Falodun, T. Patonay, A. Villinger,
pyrimidine-2,4-dione
(4)
(C7H4ClN3O2):
The
2-amino-5-
chloronicotinic acid 2 (5.96 g, 28.51 mol) was finely ground with
urea (13.7 g, 228.1 mmol, 8 equiv). The mixture was heated to the
point of evaporation of the urea (280ꢀC) by means of a sand bath
[31] S.T. Handy, Y. Zhang, Chem. Commun. (2006) 299e301. https://doi.
Please cite this article as: Y. Riadi et al., Regioselective palladium-catalyzed SuzukieMiyaura coupling reaction of 2,4,6-triha-