1678
B. Brodbeck et al. / Tetrahedron Letters 44 (2003) 1675–1678
the combined organic layers with MgSO4, and removal of
Acknowledgements
the volatile components. The residue was purified by
column chromatography on silica eluting with a gradient
of dichloromethane:ethylacetate to afford the title com-
pound.
The authors are grateful to Drs. A. Alanine, C. Riemer,
R. Norcross, R. Jakob-Roetne, and A. Flohr for help-
ful discussions and support. They would like to thank
C. Kuratli for technical assistance. They would also like
to thank Drs. A. Thomas and R. Norcross for careful
proofreading and revision of this manuscript.
1
Compound 2e: H NMR (400 MHz, DMSO-d6): l 7.38
(s, 3H, 8-H, NH2), 7.08 (s, 1H, furanyl (3-H)), 6.73 (s,
1H, 6-H)), 6.34 (s, 1H, furanyl (4-H)), 3.89 (s, 3H,
OCH3), 2.40 (s, 3H, furanyl (CH3)). MS m/e (%): 272.2
(MH+, 100). Anal. calcd for C13H12N4O3: C, 57.35; H,
4.44; N, 20.58. Found: C, 57.46; H, 4.61; N, 20.08%.
Compound 2l: 1H NMR (400 MHz, DMSO-d6): l 8.09
(d, J=2.8 Hz, 1H, thiazolyl (5-H)), 8.01 (d, J=2.8 Hz,
1H, thiazolyl (4-H)), 7.51 (s, br, 2H, NH2), 7.50 (s, 1H,
8-H), 6.81 (s, 1H, 6-H), 3.91 (s, 3H, OCH3). MS m/e (%):
275.3 (MH+, 100). Anal. calcd for C11H9N5O2S: C, 47.99;
H, 3.30; N, 25.44; S, 11.65. Found: C, 48.27; H, 3.51; N,
24.49; S, 10.69%.
References
1. (a) Furka, A. Drug Discov. Today 2002, 7, 1–4; (b)
Beck-Sickinger, A.; Weber, P. Combinatorial Strategies in
Biology and Chemistry; Wiley-VCH: Chinchester, 2002.
2. Adang, A. E. P.; Hermkens, P. H. H. Curr. Med. Chem.
2001, 8, 985–998.
3. (a) Everett, J.; Gardner, M.; Pullen, F.; Smith, G. F.;
Snarey, M.; Terrett, N. Drug Discov. Today 2001, 6,
779–785; (b) Macdonald, S. J. F.; Smith, P. W. Drug
Discov. Today 2001, 5, 947–953.
4. Nettekoven, M.; Thomas, A. W. Curr. Med. Chem. 2002,
9, 2179–2190.
5. Nettekoven, M. Synlett 2001, 12, 1917–1920.
6. v. Beck, E. R.; Meyer, H. Monatsh. Chem. verw. Teile
and. Wiss. 1915, 36, 731–749.
10. For a more detailed description of the procedure that led
to the amine starting material selection for the respective
iterative cycle, see: Schneider, G.; Nettekoven, M. J.
Comb. Chem. 2003, in press.
11. (a) Akakura, M.; Yamamoto, M. Synlett 1997, 3, 277–
278; (b) Williams, J. M.; Jobson, R. B.; Yasuda, N.;
Marchesini, G.; Dolling, U.-H.; Grabowski, E. J. J. Tet-
rahedron Lett. 1995, 36, 5461–5464; (c) Patterson, J. W. J.
Org. Chem. 1995, 60, 4542–4548.
7. 2,6-Diaminoisonicotinic acid methyl ester 4: A mixture of
20 g (0.1 mol) 2,6-dichloroisonicotinic acid and 2 g (30
mmol) copper powder in 300 ml aqueous ammonia
(ꢀ30%) was heated for 12 h to 180°C in an autoclave (20
bar). After cooling to room temperature the copper was
filtered of and the filtrate was treated with 1N HCl to pH
5. The precipitate was filtered and purified by repeated
dissolving in aqueous ammonia (25%) and subsequent
precipitation with 1N HCl. Filtration and drying in HV
yielded 13.2 g (83%) 2,6-diaminoisonicotinic acid as a
12. General procedure for the synthesis of 1: To a solution of
0.44 mmol amine in 0.5 ml dioxane was added 0.5 ml
methylaluminoxane (10% in toluene) (use of trimethylalu-
minium instead of methylauminoxane gave comparable
results) and the mixture was stirred for 1 h at room
temperature. 0.11 mmol [1,2,4]triazolo[1,5-a]pyridine-7-
carboxylic acid methyl ester in 1 ml dioxane was added
and the mixture was heated to 90°C for 72 h. After
addition of 0.4 ml 1N HCl the mixture was evaporated to
dryness and the residue was taken up in 1.5 ml DMSO,
filtered, and the title compound was isolated by reversed-
phase HPLC eluting with a water/acetonitrile gradient.
13. The NMR samples were processed with a stop-flow
method and the Bruker-efficient sample transfer (BEST)
procedure.
1
brown solid. H NMR (400 MHz, DMSO-d6): l 7.23 (s,
br, 1H, COOH), 6.10 (s, 2H, Ar-H), 5.64 (s, br, 4H,
NH2). MS m/e (%): 153 (MH+, 100). A suspension of 11
g (70 mmol) 2,6-diaminoisonicotinic acid in 270 ml
methanol was treated at 0°C for 2 h with gaseous HCl.
The mixture was concentrated, the residue was dissolved
in water and saturated NaHCO3 was added to pH 8.
Exhaustive extraction with ethylacetate, drying of the
combined organic phases with MgSO4 and removal of the
volatiles yielded 9.3 g (77%) 2,6-diaminoisonicotinic acid
methyl ester 4 as yellow solid. 1H NMR (400 MHz,
DMSO-d6): l 6.11 (s, 2H, Ar-H), 5.69 (s, 4H, NH2), 3.77
(s, 3H, CH3). MS m/e (%): 167 (MH+, 100). Anal. calcd
for C7H9N3O2: C, 50.30; H, 5.43; N, 25.14. Found: C,
50.27; H, 5.26; N, 24.11.
1
Compound 3j: H NMR (500 MHz, DMSO): l 7.24 (s,
2H, NH2), 7.03 (d, J=3 Hz, 1H, furanyl (3-H)), 6.79 (s,
1H, 8-H), 6.32 (d, J=3 Hz, 1H, furanyl (4-H)), 6.09 (s,
1H, 6-H), 2.39 (s, 3H, CH3), 1.15 (m, 3H, NCH2CH3),
1.08 (m, 3H, NCH2CH3), signal for NCH2 under DMSO
signal.
1
Compound 3s: H NMR (500 MHz, DMSO): l 8.60 (t,
J=5.6 Hz, 1H, NH), 7.63 (d, J=3.6 Hz, 1H, thiophenyl
3-H), 7.32 (s, 1H, 8-H), 7.15 (s, br, 2H, NH2), 6.93 (d,
J=3.6 Hz, 1H, thiophenyl 4-H), 6.63 (s, 1H, 6-H), 3.27
8. Tamura, Y.; Minamikawa, J.; Miki, Y.; Matsugashita, S.;
(m, 2H, NCH2), 1.54 (m, 2H, CH6 2CH2CH3), 1.35 (m, 2H,
Ikeda, M. Tetrahedron Lett. 1972, 13, 4133–4135.
CH2CH3), 0.96 (t, J=7.7 Hz, 2H, CH3).
1
9. General procedure for the synthesis of 2: To a solution of
1 g (5.98 mmol) 2,6-diaminoisonicotinic acid methyl ester
4 in 50 ml dioxane at room temperature was added 1.41
g (6.58 mmol, 1.1 equiv.) O-mesitylenesulfonylhydroxyl-
amine and, after 2 h, 1.3 equiv. of the respective aldehyde
was added and the mixture was stirred for 3 h at 100°C.
After the addition of 6 ml 1N KOH in MeOH the
mixture was stirred at room temperature for 12 h and
concentrated. The residue was taken up in 50 ml water
followed by extraction with dichloromethane, drying of
Compound 3w: H NMR (500 MHz, DMSO): l 8.07 (d,
J=2.8 Hz, 1H, thiazolyl 5-H), 7.98 (d, J=2.8 Hz, 1H,
thiazolyl 4-H), 7.34 (s, br, 2H, NH2), 7.10 (s, 1H, 8-H),
6.33 (s, 1H, 6-H), 3.49 (t, J=7.2 Hz, 2H, NCH2), 3.43 (t,
J=7.2 Hz, 2H, NCH2), 1.89 (m, 2H, CH2), 1.84 (m, 2H,
CH2).
14. For a more detailed description of workflow procedures
and automation technology utilised for this synthetic
array, see: Nettekoven, M.; Thomas, A. W. Curr. Med.
Chem. 2002, 9, 2179–2190.