20% palladium over charcoal to give indoline derivative 18.
Deprotection of the Boc group in 18, followed by thiocyan-
ation6,11,12 yielded the corresponding thiocyanate 19. The
indoline nitrogen in 19 was protected as a Boc derivative
20 and the thiocyanate was converted to thiotosylate 21 via
thiol as described above (Scheme 4).
compound 25 was hydrogenated using Raney nickel as
catalyst to give diamine 26. Boc protection of amino groups
gave 27, which was reduced with DTT to give thiol 28.
Compound 28 on sulfonylation was converted to thiosul-
fonate 29, followed by cleavage of the Boc groups using 4
N HCl in dioxane gave the diamine 30. Imidazole ring
formation was accomplished by treating 30 with formic acid
to give 31 in excellent yields.14 Compound 30 on treatment
with triphosgene afforded imidazol-2-one-containing thio-
sulfonates 32 in excellent yields.
A synthesis of benzoimidazole containing thiosulfonates
is shown in Scheme 5. Nitration of 3-tert-butylaniline or
Scheme 5a
The synthesis of quinoxalinedione-containing thiosul-
fonates began with thiocyanate 25 (Scheme 6). Compound
Scheme 6a
e
a Reagents: (1) ClCOCOOMe, pyridine, 0 °C, rt for 16 h; (2)
H2 (50 psi), Raney nickel, THF, 16 h; NaSH (3 equiv), NaBH4 (6
equiv), MeOH/H2O in 2:1 ratio, addition at 0 °C, rt for 16 h; (4)
tosyl bromide, pyridine.
25 was acylated with methyl chlorooxoacetate in the presence
of pyridine to furnish 33 in quantitative yield.15 The nitro
group in compound 33 was hydrogenated using Raney nickel
(5) Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Repke,
D. B.; Souchet, M. Synthesis 1991, 871.
a Reagents: (1) Trifluoroacetic anhydride, KNO3, 0 °C for 1 h;
rt for 1 h; (2) 7% aqueous K2CO3, MeOH, rt, 16 h; (3) NaSCN(6
equiv), NaBr (1.2 equiv) Br2 (1.2 equiv), 0 °C, 4 h, followed by
warming to rt, 1 h; (4) H2 (50 psi), Raney nickel, THF, 16 h; (5)
Boc anhydride, EtOAc/hexanes in 1:3 ratio, reflux, 16 h; (6) NaSH
(3 equiv), NaBH4 (6 equiv), MeOH/H2O in 2:1 ratio, addition at 0
°C, rt for 16 h; (7) tosyl bromide, pyridine; (8) 4 N HCl in dioxane,
followed by neuatralizing with a buffer of pH 7.5; (9) 95% HCOOH
reflux, 3 h; (10) triphosgene, Et3N, THF, 90 °C, 1.5 h.
(6) Vara Prasad, J. V. N.; Boyer, F. E.; Domagala, J. M.; Ellsworth, E.
L.; Gajda, C.; Hagen, S. E.; Markoski, L. J.; Tait, B. D.; Lunney, E. A.;
Tummino, P. J.; Ferguson, P. J.; Holler, T.; Hupe, D.; Nouhan, C.; Gracheck,
S. J.; VanderRoest, S.; Saunders: J.; Iyer, K.; Sinz, M.; Brodfuehrer, J.
Bioorg. Med. Chem. Lett. 1999, 9, 1481.
(7) All the compounds were characterized by 1H NMR and mass
spectra.
(8) Ranasinghe, M. G.; Fuchs, P. L. Synth. Commun. 1988, 18, 227.
(9) Hagen, S.; Vara Prasad, J. V. N.; Boyer, F. E.; Domagala, J. M.;
Ellsworth, E. L.; Gajda, C.; Hamilton, H. W.; Markoski, L. J.; Steinbaugh,
B. A.; Tait, B. D.; Lunney, E. A.; Tummino, P. J.; Ferguson, D.; Hupe, D.;
Nouhan, C.; Gracheck, S. J.; Saunders: J. M.; VanderRoest, S. J. Med.
Chem. 1997, 40, 3707.
(10) Gagliardi, S.; Nadler, G.; Consolandi, E.; Parini, C.; Morvan, M.;
Legave, M.-N.; Belfiore, P.; Zocchetti, A.; Clarke, G. D.; James, I.; Nambi,
P.; Gowen, M.; Farina, C. J. Med. Chem. 1998, 41, 1568.
(11) Wardell, J. L. In The Chemistry of Thiol Group; Patai, S., Ed.; John
Wiley & Sons: New York, 1974; 230p.
3-isopropylaniline 22 was performed using trifluoroacetic
anhydride and potassium nitrate in excellent yields to obtain
23.13 The trifluoroacetyl group in compound 23 was removed
on treatment with aqueous K2CO3 to give 24.12 Compound
24 on subjecting to thiocyanation conditions afforded the
corresponding thiocyanate 25 as the only regioisomer. The
(12) Greene, T. W.; Wuts, P. G. ProtectiVe Groups in Organic Synthesis;
John Wiley & Sons: New York, 1999.
Org. Lett., Vol. 2, No. 8, 2000
1071