J. D. Williams et al. / Bioorg. Med. Chem. 21 (2013) 7790–7806
7801
652 mg (89%) of product as a yellow powder: mp >300 °C; 1H NMR
(DMSO-d6) d 12.28 (s, 2H), 9.80 (s, 4H), 8.10 (s, 4H), 7.81 (s, 2H),
7.78 (d, 2H), 7.35 (d, 2H), 7.20 (s, 2H), 5.62 (s, 2H), 4.28 (s, 2H),
3.59 (d, 4H), 3.40 (d, 4H); m/z expected 504.2, found 253.3
(M+2H+)/2.
green solid (79% purity by analytical HPLC): mp >300 °C; 1H NMR
(DMSO-d6) d 12.54 (s, 2H), 11.64 (s, 2H), 10.87 (s, 2H), 8.23 (s,
2H), 8.15 (s, 4H), 7.77 (d, 4H), 7.25 (s, 2H), 4.65 (q, 4H), 1.54 (t,
6H); m/z expected 450.2, found 451.5 (M+H)+.
5.2.18. 1,4-Bis[6-(N0-hydroxycarbamimidoyl)indol-2-yl]benzene
(22)
5.2.14. 1,4-Bis[6-(5-methoxy-3,4,5,6-tetrahydropyrimidin-2-yl)
indol-2-yl]benzene (19d; as trifluoroacetic acid salt)
To a suspension of 1,4-bis{6-[ethoxy(imino)methyl]indol-2-
yl}benzene (21; 160 mg, 0.31 mmol) in EtOH (20 mL) was added
a solution of hydroxylamine hydrochloride (200 mg, 2.9 mmol)
and sodium hydroxide, (1.0 M aqueous; 3.5 mL, 3.5 mmol) in EtOH,
2 mL). The reaction mixture was stirred at room temperature for
3 days, then poured into cold water (100 mL). The mixture was
stirred for 30 min, then the solids were filtered, rinsed with water
(20 mL), and dried to provide 123 mg (95%) of product as a brown
powder (94% purity by analytical HPLC): mp >300 °C; 1H NMR
(DMSO-d6) d 11.67 (s, 2H), 9.50 (s, 2H), 7.98 (s, 4H), 7.71 (s, 2H),
7.50 (s, br, 2H), 7.38 (s, br, 2H), 7.00 (s, 2H), 5.77 (s, 4H); m/z ex-
pected 424.2, found 425.6 (M+H)+.
To
a suspension of 1,4-bis(6-cyanoindole-2-yl)benzene (5;
110 mg, 0.31 mmol) in 1,3-diamino-2-methoxypropane (1.0 g)
was added phosphorous pentasulfide (64 mg, 0.29 mmol). The sus-
pension was heated in a sealed vessel to 130 °C (oil bath) for 4 h,
then cooled to room temperature. Water (10 mL) was added, then
the suspension was stirred for 16 h and filtered. The solid was
rinsed with water (20 mL), then dried under vacuum to provide
164 mg (100%) of product as yellow powder: mp >300 °C; 1H
NMR (DMSO+1% TFA-d) d 12.25 (br s, 2H), 9.81 (br s, 4H), 8.08 (s,
4H), 7.79 (s, 2H), 7.76 (d, 2H), 7.33 (dd, 2H), 7.18 (s, 1H), 4.00
(m, 2H), 3.61 (m, 8H), 3.38 (s, 6H); m/z expected 532.3, found
267.7 (M+2H+)/2.
5.2.19. 1,4-Bis[6-(N0-acetoxycarbamimidoyl)indol-2-yl]benzene
(23)
5.2.15. 1,4-Bis[6-(5-fluoro-3,4,5,6-tetrahydropyrimidin-2-yl)
indol-2-yl]benzene (19e; as trifluoroacetic acid salt)
To a solution of 1,4-bis[6-(N0-hydroxycarbamimidoyl)indol-2-
yl]benzene (22; 191 mg, 0.45 mmol) in acetic acid (4.0 mL) was
To a suspension of 1,4-bis(6-cyanoindole-2-yl)benzene (5;
100 mg, 0.28 mmol) and 1,3-diamino-2-fluoropropane (240 mg)
in triethylamine (1.5 mL) was added phosphorous pentasulfide
(80 mg, 0.36 mmol). The suspension was heated in a sealed vessel
to 130 °C (oil bath) for 1 h, then cooled to room temperature.
Water (10 mL) was added, and the resulting yellow suspension
was stirred for 30 min, then filtered and evaporated. The resulting
solid was subjected to preparative HPLC purification with a gradi-
ent of 10–100% CH3CN/H2O, each containing 0.2% TFA. Product-
containing fractions were pooled, and the CH3CN removed under
vacuum. The remaining aqueous solution was lyophilized to pro-
vide 36 mg (16%) of product as yellow powder: mp >300 °C; 1H
NMR (DMSO-d6) d 12.30 (br s, 2H), 10.04 (br s, 4H), 8.10 (s,
4H), 7.83 (s, 2H), 7.79 (d, 2H), 7.37 (d, 2H), 7.21 (s, 2H), 5.48 (d,
2H), 3.83–3.67 (m, 8H); m/z expected 508.2, found 255.4
(M+2H+)/2.
added acetic anhydride (160 lL, 1.7 mmol). The mixture was stir-
red at room temperature for 20 h, then the solvent was removed
under reduced pressure to provide 282 mg (100%) of product as a
yellow solid: mp >300 °C; 1H NMR (DMSO-d6) d 11.96 (s, 2H),
11.80 (s, 2H), 8.01 (s, 4H), 7.80 (s, 2H), 7.59 (d, 2H), 7.38 (d, 2H),
7.06 (s, 2H), 6.75 (s, 4H), 2.16 (s, 6H), 1.91 (s, 6H).
5.2.20. 1,4-Bis[6-(carbamimidoyl)indol-2-yl]benzene (24; as
hydrochloric acid salt)
To a suspension of 1,4-bis[6-(N0-acetoxycarbamimidoyl)indol-
2-yl]benzene (23; 78 mg, 0.15 mmol) in a 3:1 solution of EtOH/ace-
tic acid (8 mL), was added 5% palladium on carbon (10 mg). The
mixture was hydrogenated at 45 psi in a Parr apparatus for 3 days.
The resulting solution was filtered through Celite and rinsed with
EtOH (10 mL). To the filtrate was added aqueous HCl (1.0 M,
1.0 mL, 1.0 mmol). The filtrate was then evaporated under vacuum
to provide 71 mg (100%) of product as a yellow powder: mp
>300 °C; 1H NMR (DMSO-d6) d 12.37 (s, 2H), 9.27 (s, 4H), 8.85 (s,
4H), 8.12 (s, 4H), 7.94 (s, 2H), 7.77 (d, 2H), 7.45 (d, 2H), 7.21 (s,
2H); m/z expected 392.2, found 393.6 (M+H)+.
5.2.16. 1,4-Bis[6-(5,5-dimethyl-3,4,5,6-tetrahydropyrimidin-2-yl)
indol-2-yl]benzene (20; as trifluoroacetic acid salt)
To
a suspension of 1,4-bis(6-cyanoindole-2-yl)benzene (5;
360 mg, 1.0 mmol) in 2,2-dimethyl-1,3-diaminopropane (5 mL)
was added phosphorous pentasulfide (60 mg, 0.27 mmol). The sus-
pension was heated in a sealed vessel to 120 °C (oil bath) for 4 h,
then cooled to room temperature and poured into water
(100 mL). The resulting yellow suspension was stirred for 30 min,
then filtered. The solids were rinsed with water (20 mL), then dried
under vacuum to yield a yellow-brown powder. The powder was
dissolved in trifluoroacetic acid (5 mL) and MeOH (5 mL) with
heating. The yellow solution was diluted rapidly with Et2O
(100 mL). The resulting solids were filtered, rinsed with Et2O
(20 mL), and dried to provide 644 mg (85%) of product as a orange
powder: mp >300 °C; 1H NMR (DMSO-d6) d 12.26 (s, 2H), 9.94 (s,
4H), 8.10 (s, 4H), 7.82 (s, 2H), 7.78 (d, 2H), 7.37 (d, 2H), 7.20 (s,
2H), 3.25 (s, 8H), 1.08 (s, 12H); m/z expected 528.3, found 265.6
(M+2H+)/2.
5.2.21. 1,4-Bis[6-(carbamohydrazonoyl)indol-2-yl]benzene (25;
as hydrochloric acid salt)
To
yl}benzene hydrochloride (21; 160 mg, 0.31 mmol) in absolute
ethanol (20 mL) was added hydrazine (195 L, 0.61 mmol). The
a
solution of 1,4-bis{6-[ethoxy(imino)methyl]indol-2-
l
reaction mixture was allowed to stand at room temperature for
4 days, then ether (20 mL) was added to reaction mixture. The
resulting brown solid was filtered and washed with water to afford
115 mg (89%) of product as a brown solid (88% purity by analytical
HPLC): mp >300 °C; 1H NMR (DMSO-d6) d 12.38 (s, 2H), 10.90 (s,
2H), 9.38 (s, 2H), 8.73 (s, 2H), 8.12 (s, 4H), 7.84 (s, 2H), 7.75 (d,
2H), 7.35 (d, 2H), 7.181 (s, 2H), 5.28 (s, br, 4H); m/z expected
422.2, found 423.5 (M+H)+.
5.2.17. 1,4-Bis{6-[ethoxy(imino)methyl]indol-2-yl}benzene (21;
as hydrochloric acid salt)
5.2.22. 1,4-Bis[6-(carbamoyl)indol-2-yl]benzene (26)
A solution of 1,4,-bis(6-cyanoindol-2-yl)benzene (5; 169 mg,
0.47 mmol) in 4:1 TFA/H2SO4 (2.5 mL) was stirred at room temper-
ature for 17 h. The resulting mixture was then poured into cold
water (50 mL). The resulting solids were filtered, rinsed with water
(10 mL), and dried to provide 163 mg (88%) of product as a brown
powder (87% purity by analytical HPLC): mp >300 °C; 1H NMR
1,4-Bis(6-cyanoindole-2-yl)benzene (5; 210 mg, 0.5860 mmol)
was suspended in dry ethanol (200 mL) and treated with HCl gas
at 0 °C for 30 min. The resulting mixture was heated to 50 °C (oil
bath) in a sealed tube 4 days. The ethanol and HCl were then evap-
orated in vacuo to provide 306 mg (100%) of product as a dark