586
C. Klein et al. / Tetrahedron Letters 52 (2011) 584–587
Compound 6a–7a: the resulting brown solid was dissolved in
R
R
N
the minimum volume of CH2Cl2 and hexane (100 ml) was added.
The insoluble brown impurities were filtered off and the clear
filtrate was evaporated to afford 1.4 g of a mixture composed of
disubstituted 6a and monosubstituted 7a compound in a 1:6 ratio
according to the 1H NMR.
N
N
N
a
R
R
6a-7a or 7b
N
N
Compound 6b–7b: the resulting brown solid was dissolved in
the minimum volume of CH2Cl2 and purified by column chroma-
tography (SiO2, CH2Cl2) to afford 1.5 g (54%) of pure 7b as a white
solid (first band). 1H NMR (200 MHz, 25 °C, CDCl3) d 1.43 (t,
J = 7 Hz, 3H), 2.31 (s, 3H), 2.67 (s, 3H), 4.44 (q, J = 7 Hz, 2H), 6.02
(s, 1H), 7.68 (s, 1H), 8.35 (s, 1H).
EtO2C
CO2Et
8a : R = H
8b : R = Me
Scheme 3. Synthesis of compounds 8a and 8b by nickel-catalysed homocoupling
reaction. Reagents and conditions: (a) (i) NiCl2ꢃ6H2O, PPh3, Zn, DMF, 60 °C (ii) 6a–7a
or 7b.
2.3. General procedure for the synthesis of 8a and 8b
Compound 2: Citrazinic acid 1 (20.0 g, 129 mmol) and benzyltri-
ethylammonium chloride (32.3 g, 142 mmol) in 40 ml of POCl3
were heated to 140 °C for 24 h under a CaCl2 drying tube. After
being cooled to room temperature, the brown mixture was poured
on ice (400 g) and stirred for 2 h. The resulting brown solid was fil-
tered off, washed with water and dissolved in EtOAc (400 ml). The
organic phase was then washed with saturated NH4Cl, dried over
Na2SO4 and evaporated to dryness to afford 20 g (81%) of the de-
sired compound as a brown solid. 1H and 13C NMR were in accor-
dance with those already reported.18
Zn powder (1.5 equiv) was added to a stirred solution of
NiCl2ꢃ6H2O (1 equiv) and PPh3 (4 equiv) in anhydrous DMF
(50 ml) at 60 °C. The resulting solution was stirred at 60 °C under
argon for 2 h during which time the colour changed from blue to
dark red. A solution of 6a–7a (1.4 g) or 7b (1.43 g, 5.11 mmol) in
anhydrous DMF (10 ml) was added via syringe and the resulting
mixture allowed to be stirred at 60 °C for 20 h. DMF was evapo-
rated and CHCl3 (150 ml) was added followed by a 10% NH4OH
solution (100 ml). The organic phase was separated, washed with
a 10% NH4OH solution (100 ml), dried over MgSO4 and evaporated.
Et2O was added and the slurry sonicated for 2 min. The resulting
precipitate was filtered off and purified by column chromatogra-
phy (SiO2, CH2Cl2/MeOH; 95:5) to afford the desired compounds
8a or 8b.
2.1. General procedure for the synthesis of 4a and 4b
To a suspension ofNaH (55–65%in mineral oil, 1.31 g, ꢁ30 mmol)
in anhydrous DMF (30 ml) was dropwise added a solution of 3a or 3b
(30 mmol) in anhydrous DMF (10 ml) at room temperature and un-
der argon. The resulting slurry was heated to 100 °C for 45 min and
compound 2 (1 g, 5.21 mmol) was added in one portion. The brown
mixture was then heated to 130 °C under argon for three days. DMF
was evaporated and water (100 ml) was added. The mixture was
acidified with concd HCl and the formed precipitate was filtered
and washed with water. The solid was dissolved in the minimum
volume of hot acetone and let to stand overnight in the freezer. Com-
pounds 4a and 4b were, respectively, obtained after filtration and
washing with cold portions of acetone (3 ꢂ 5 ml).
Compound 8a: 400 mg, ꢁ30%, white solid. 1H NMR (200 MHz,
25 °C, CDCl3) d 1.49 (t, J = 7 Hz, 6H), 4.51 (q, J = 7 Hz, 4H), 6.57
(dd, J = 1.5 and 2.5 Hz, 2H), 7.83 (s, 2H), 8.59 (s, 2H), 8.78 (d,
J = 2.5 Hz, 2H), 8.84 (s, 2H). 13C NMR (50 MHz, 25 °C, CDCl3) d
14.3, 62.2, 108.3, 112.7, 118.0, 127.4, 141.9, 142.7, 151.9, 154.1,
164.5. Anal. Calcd for C22H20N6O4ꢃH2O: C, 58.66; H, 4.92; N,
18.66. Found: C, 58.72; H, 4.97; N, 18.64. HRMS-ESI (m/z):
433.1629 (calcd 433.1624 for MH+); melting point 210–212 °C.
Compound 8b: 650 mg, 52%, white solid. 1H NMR (200 MHz,
25 °C, CDCl3) d 1.47 (t, J = 7 Hz, 6H), 2.36 (s, 6H), 2.89 (s, 6H),
4.47 (q, J = 7 Hz, 4H), 6.10 (s, 2H), 8.54 (s, 2H), 8.75 (s, 2H). 13C NMR
(50 MHz, 25 °C, CDCl3) d 13.7, 14.2, 15.4, 61.9, 109.9, 115.4, 117.0,
141.4, 141.8, 150.5, 153.9, 154.0, 164.7. Anal. Calcd for C26H28N6O4:
C, 63.92; H, 5.78; N, 17.20. Found: C, 63.96; H, 5.58; N, 16.86.
HRMS-ESI (m/z): 489.2238 (calcd 489.2250 for MH+); melting point
248–250 °C.
Compound 4a: 1.06 g, yield = 80%, white solid. 1H and 13C NMR
were in accordance with those already reported.18
Compound 4b: 1.16 g, yield = 71%, white solid. 1H NMR
(200 MHz, 25 °C, DMSO-d6) d 2.22 (s, 6H), 2.57 (s, 6H), 6.16 (s,
2H), 8.05 (s, 2H). 13C NMR (50 MHz, 25 °C, DMSO-d6) d 13.7, 14.2,
109.9, 112.5, 141.2, 143.4, 150.3, 152.2, 165.5.
Acknowledgement
2.2. General procedure for the synthesis of 6a–7a and 7b
This work was supported by the Swiss Science Foundation,
Swiss Federal Office for Energy and the European Office of U.S.
Air Force under contract no. F61775-00-C0003. M.K.N. thanks the
World Class University (WCU) programme funded by the Ministry
of Education, Science and Technology (Grant No. R31-2009-000-
10035-0).
To a suspension of NaH (55–65% in mineral oil, 1.1 g, ꢁ25 mmol)
in anhydrous DMF (40 ml) was dropwise added a solution of 3a or 3b
(21 mmol) in anhydrous DMF (10 ml) at room temperature and un-
der argon. The resulting slurry was heated to 60 °C for 45 min and
compound 2 (2 g, 10 mmol) was added in one portion. The brown
mixture was then heated to 60 °C under argon for 24 h. DMF was
evaporated and water (100 ml) was added. The mixture was acidi-
fied with concd HCl and the formed precipitate was filtered and
washed with water. The solid was dissolved in EtOAc, dried over
MgSO4 and evaporated to afford crude mixtures of compounds 4a–
5a (1.4 g) or 4b–5b (1.65 g) as slightly brown solids. Crude mixture
of 4a–5a or 4b–5b was refluxed overnight in 75 ml of EtOH and
2 ml of concd H2SO4. After being cooled to room temperature, EtOH
was evaporated and the resulting residue was dissolved in CH2Cl2
(150 ml), successively washed with saturated NaHCO3 solution
(2 ꢂ 100 ml), water (100 ml), dried over MgSO4 and finally evapo-
rated to dryness. Purifications were performed as follows:
References and notes
1. Constable, E. C. Chem. Soc. Rev. 2007, 36, 246–253.
2. Heller, M.; Schubert, U. S. Eur. J. Org. Chem. 2003, 947–961.
3. Baranoff, E.; Collin, J.-P.; Flamigni, L.; Sauvage, J.-P. Chem. Soc. Rev. 2004, 33,
147–155.
4. Halcrow, M. A. Coord. Chem. Rev. 2005, 249, 2880–2908.
5. Willison, S. A.; Jude, H.; Antonelli, R. M.; Rennekamp, J. M.; Eckert, N. A.; Krause
Bauer, J. A.; Conninck, W. B. Inorg. Chem. 2004, 43.
6. Catalano, V. J.; Kurtaran, R.; Heck, R. A.; Öhman, A.; Hill, M. G. Inorg. Chim. Acta
1999, 286, 181–188.
7. Zhu, X. J.; Holliday, B. J. Macromol. Rapid Commun. 2010, 31, 904–909.