6-ANILINO-SUBSTITUTED PURINES
3249
cross-coupling reactions.[9] To the best of our knowledge, substitution on a 2-chloro-
N-heterocycle as reported here has not been described elsewhere.
Finally, in a further modification, the 2-position of the intermediates is substi-
tuted with 4-cyanoaniline in a classical Buchwald–Hartwig coupling Pd2(dba)3,
BINAP, Cs2CO3, toluene 80 ꢀC, 12 h and the PMB group is removed in TFA at
60 ꢀC to obtain structures A (see Fig. 1).
General Procedure for Coupling TFA-Activated Anilines 6 to Purine
2a Resulting in Products B
The TFA aniline 6 (1.0 mmol, 1.0 eq.) and the protected dichloropurine 2a (1.0 eq.)
were dissolved in dimethoxyethane (DME; 20 mL), and K2CO3 (3.0 eq) was added.
The reaction mixture was stirred vigorously at 60–80 ꢀC and checked by thin-layer
chromatography (TLC) and liquid chromatography–mass spectrometry (LCMS).
After observing an acceptable conversion, the reaction was worked up.
The solvent was evaporated, and the residue was dissolved in EtOAc and
washed with aqueous NaHCO3 (sat.). The layers were separated, and the water layer
was re-extracted with EtOAc. The combined EtOAc layer was dried (brine and
Na2SO4) and concentrated.
The residue was purified by trituration with ethanol or by preparative TLC
using n-heptane=DME 2:3 as the eluent.
1H NMR of 5 (Scheme 2) (300 MHz, [d6]DMSO, 25 ꢀC, TMS): d ¼ 9.88 (s, 1H;
NH), 8.37 (s, 1H; purine-H), 7.59 [d, 3J(H,H) ¼ 16.6 Hz, 1H; ¼ CH-], 7.43 (s,
3
3
2H; ArH2), 7.32 (d, J(H,H) ¼ 8.8 Hz, 2H; ArH2), 6.92 [d, J(H,H) ¼ 8.8 Hz, 2H;
3
ArH2], 6.42 [d, J(H,H) ¼ 16.6 Hz, 1H; ¼ CH-], 5.28 (s, 2H; ArCH2), 3.72 (s, 3H;
OCH3), 2.13 ppm (s, 6H; 2 CH3).
REFERENCES
1. Leenders, R.; Heeres, J.; Guillemont, J.; Lewi, P. A. Novel route to 2,4-dianilino-
substituted pyrimidines. Tetrahedron Lett. 2010, 51, 543–544, and the literature cited there
in as Refs. 1 and 2.
2. (a) Lewi, P.; Janssen, P.; de Jonge, M.; Koymans, L.; Vinkers, H.; Daeyaert, F.; Heeres, J.;
Leenders, R.; Hoornaert, G..; Kilonda, A.; Ludovici, D. HIV-inhibiting 1,2,4-triazines.
WO Patent 2004=074266, 2004; (b) Hoornaert, G.; Kilonda, A.; Heeres, J.; Lewi, P.; de
Jonge, M.; Daeyaert, F.; Vinkers, H.; Koymans, L.; Janssen, P. HIV-inhibiting 1,2,4-
triazin-6-one derivatives. WO Patent 2006=015985, 2006; (c) Leenders, R.; Heeres, J.;
Vandenput, D.; Zijlmans, R.; Guilemont, J.; Lewi, P. 3-(Arylamino)-1,2,4-triazin-5-one:
A novel synthesis and its use. Eur. J. Org. Chem. 2010, 15, 2852–2854.
3. Janssen, P.; Lewi, P.; de Jonge, M.; Koymans, L.; Daeyaert, F.; Heeres, J.; Vinkers, H.;
Leenders, R.; Vandenput, D. HIV replication inhibiting purine derivatives. WO Patent
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4. Kelley, J.; Linn, J.; Krochmal, M.; Selway, J. 9-Benzyl-6-(dimethylamino)-9H-purines with
antirhinovirus activity. J. Med. Chem. 1988, 31, 2001–2004. Here 2 is prepared in 59% yield.
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purines. J. Med. Chem. 1990, 33, 1360–1363; (b) Mott, B.; Ferreira, R.; Simeonov, A.;
Jadhav, A.; Kean-Hooi Ang, K.; Leister, W.; Shen, M.; Silveira, J.; Doyle, P.; Arkin,
M.; McKerrow, J.; Inglese, J.; Austin, C.; Thomas, C.; Shoichet, B.; Maloney, D.