Inhibitors of Bacterial Enoyl-ACP Reductases
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 9 1633
(E)-3-(6-Am in o-5-m et h ylp yr id in -3-yl)-N-m et h yl-N-(1-
m eth yl-1H-in d ol-2-ylm eth yl)a cr yla m id e (5). According to
the procedure of compound 21, except substituting 2-amino-
5-bromo-3-methylpyridine (1.72 g, 10.0 mmol) for 6-bromo-3,4-
dihydro-1H-1,8-naphthyridin-2-one (18), the title compound
(1.65 g, 49% for three steps) was prepared as a light yellow
solid. 1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, 1H), 7.75 (d,
1H), 7.49 (d, J ) 15.2 Hz, 1H), 7.45 (m, 2H), 7.15 (t, J ) 7.5
Hz, 1H), 7.02 (m, 2 H), 6.42 (s, 1H), 6.28(m, 2H), 4.84 (s, 2H),
3.68 (s, 3H), 3.09 (s, 3H), 2.06 (s, 3H). LCMS (ES) m/e 335 (M
+ H)+. Anal. (C20H22N4O1‚0.25 H2O) C, H, N.
(E)-3-[6-Acetylam in o)pyr idin -3-yl]-N-m eth yl-N-(1-m eth -
yl-1H-in d ol-2-ylm eth yl)a cr yla m id e (12). To a solution of
4 (0.50 g, 1.56 mmol) and acetic anhydride (0.19 g, 1.87 mmol)
in THF (75 mL) was added NaHCO3 (0.17 g, 2.03 mmol). After
36 h at 60 °C with vigorous stirring, the reaction contents were
concentrated under vacuum and partitioned between EtOAc
and H2O. The organic layer was separated, washed with brine,
dried over Na2SO4, and concentrated. Trituration with diethyl
ether and drying under high vacuum afforded 12 (0.55 g, 98%)
as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.69 (s,
1H), 8.63 (s, 1H), 8.19 (m, 2H), 7.58 (d, J ) 11.5 Hz, 1H), 7.51-
7.26 (m, 3H), 7.12 (m, 1H), 7.01 (m, 1H), 6.43 (s, 1H), 4.86 (s,
2H), 3.72 (s, 3H), 3.12 (s, 3H), 2.12 (s, 3H). LCMS (ES) m/e
363 (M + H)+. Anal. (C21H22N4O2) C, H, N.
(E)-3-[6-Acetyla m in o-5-m eth ylp yr id in -3-yl)-N-m eth yl-
N-(1-m et h yl-1H -in d ol-2-ylm et h yl)a cr yla m id e (13). To a
solution of 5 (0.47 g, 1.41 mmol) and acetic anhydride (0.29 g,
2.82 mmol) in THF (75 mL) was added NaHCO3 (0.35 g, 4.22
mmol). After 50 h at 60 °C with vigorous stirring, the reaction
contents were concentrated under vacuum and partitioned
between EtOAc and H2O. The organic layer was separated,
washed with brine, dried over Na2SO4, and concentrated.
Trituration with diethyl ether and drying under high vacuum
afforded 13 (0.49 g, 93%) as a white solid. 1H NMR (400 MHz,
CDCl3) δ 8.36 (s, 1H), 7.70 (m, 1H), 7.58 (d, J ) 7.7 Hz, 1H),
7.25 (m, 2H), 7.11 (t, J ) 7.5 Hz, 1H), 6.92 (d, J ) 15.5 Hz,
1H), 6.50 (s, 1H), 4.86 (s, 2H), 3.72 (s, 3H), 3.12 (s, 3H), 2.29
(s, 3H), 2.10 (s, 3H). LCMS (ES) m/e 377 (M + H)+. Anal.
(C22H24N4O2‚1.25 H2O) C, H, N.
NaBH4 (2.84 g, 75.0 mmol) was added. After 6 h the reaction
was concentrated to a slurry and dissolved in 1 N NaOH (75
mL). The aqueous solution was extracted with Et2O (2 × 200
mL), and the combined organic fractions were dried over Na2-
SO4 and concentrated. Flash chromatography on silica gel (9:1
CHCl3/MeOH containing 5% NH4OH) and drying in high
vacuum afforded the title compound (7.33 g, 52%) as a faintly
yellow oil. H NMR (400 MHz, CDCl3) δ 7.60 (d, J ) 7.7 Hz, 1
H), 7.29 (d, J ) 8.0 Hz, 1 H), 7.19 (t, 1 H), 7.12 (t, 1 H), 3.93
(s, 2 H), 3.69 (s, 3 H), 2.49 (s, 3 H), 2.45 (s, 3 H).
1
1-Meth yl-3-(m eth yla m in om eth yl)-1H-in d ole (26). Ac-
cording to the procedure for compound 25, except substituting
1-methylindole-3-carboxaldehyde (10.0 g, 62.8 mmol) for 1,2-
dimethylindole-3-carboxaldehyde (24), the title compound (10.1
g, 92%) was prepared as a faintly yellow oil. 1H NMR (400
MHz, CDCl3) δ 7.63 (d, J ) 6.8 Hz, 1H), 7.29 (m, 1), 7.21 (t, J
) 6.4 Hz, 1H), 7.12 (t, J ) 6.5 Hz, 1H), 6.95 (s, 1H), 3.90 (s,
2H), 3.71 (s, 3H), 2.48 (s, 3H). LCMS (ES) m/e 175 (M + H)+.
2-Meth yl-3-(m eth yla m in om eth yl)in d ole (27). According
to the procedure for compound 25, except substituting 2-me-
thylindole-3-carboxaldehyde (10.0 g, 62.8 mmol) for 1,2-di-
methylindole-3-carboxaldehyde (24), the title compound (6.88
g, 63%) was prepared as a faintly yellow low-melting solid.
1H NMR (400 MHz, CDCl3) δ 7.96 (br s, 1H), 7.56 (d, J ) 6.7
Hz, 1 H), 7.27 (d, J ) 6.4 Hz, 1 H), 7.10 (m, 2 H), 3.88 (s, 2 H),
2.46 (s, 3 H), 2.41 (s, 3H). LCMS (ES) m/e 175 (M + H)+.
3-(Meth yla m in om eth yl)-1,2,7-tr im eth ylin d ole (28). Ac-
cording to the procedure for compound 25, except substituting
2,7-dimethylindole (1.14 g, 7.84 mmol) for the 2-methyl-1H-
indole (22), the title compound (570 mg, 36% for three steps)
was obtained as a light yellow oil which solidified upon
1
standing. H NMR (400 MHz, CDCl3) δ 7.42 (d, J ) 7.6 Hz, 1
H), 6.96 (t, 1 H), 6.87 (m, 1 H), 3.97 (s, 3 H), 3.88 (s, 2 H), 2.80
(s, 3 H), 2.49 (s, 3 H), 2.41 (s, 3 H). LC-MS (ES) m/e 405 (2M
+ H)+.
(E)-N-Met h yl-N-(1-m et h yl-1H -in d ol-3-ylm et h yl)-3-(7-
oxo-5,6,7,8-t et r a h yd r o-1,8-n a p h t h yr id in -3-yl)a cr yla m -
id e (29). According to the procedure of compound 21, except
substituting 1-methyl-3-(methylaminomethyl)indole (26) (0.75
g, 3.3 mmol) for 1-methyl-2-(methylaminomethyl)indole, the
title compound (0.59 g, 72%) was prepared as a light yellow
1,2-Dim eth yl-1H-in d ole (23). To a stirred solution of
2-methylindole (22) (15.0 g, 114.3 mmol) in dry DMF (200 mL)
was added NaH (60% dispersion in oil, 5.0 g, 125.0 mmol) in
portions. The mixture was stirred for 30 min, then iodo-
methane (8.0 mL, 129.0 mmol) was added in one portion. The
reaction became exothermic and was cooled in an ice bath.
After 16 h at RT, the reaction was concentrated under vacuum
and the residue was taken up in ethyl acetate. The solution
was washed with H2O then with brine, dried (MgSO4), and
concentrated to dryness. Purification on silica gel (hexanes/
EtOAc, 1:1) gave the title compound (16.10 g, 97%) as a off-
1
solid. H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.58 (s,
1H), 8.37 (s, 1H), 8.06 (m, 2H), 7.64-6.93 (m, 5H), 4.73 (s, 2H),
3.76 (s, 3H), 3.37 (s, 3H), 2.90 (m, 2H), 2.51 (m, 2H). MS (ES)
m/e 375 (M + H)+. Anal. (C22H22N4O2‚0.9H2O) C, H, N.
(E)-N-Met h yl-N-(2-m et h yl-1H -in d ol-3-ylm et h yl)-3-(7-
oxo-5,6,7,8-t et r a h yd r o-1,8-n a p h t h yr id in -3-yl)a cr yla m -
id e (30). According to the procedure of compound 21, except
substituting 2-methyl-3-(methylaminomethyl)indole (27) (1.40
g, 8.0 mmol) for 1-methyl-2-(methylaminomethyl)indole, the
title compound (1.30 g, 65%) was prepared as a light yellow
1
solid. H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.64 (s,
1
white solid. H NMR (400 MHz, CDCl3) δ 7.49 (d, J ) 8.0 Hz,
1H), 8.36 (s, 1H), 8.06 (m, 1H), 7.53 (d, J ) 15.4 Hz, 1H), 7.49
(m, 1H), 7.33-7.23 (m, 2H), 7.16 (d, J ) 15.4 Hz, 1H), 6.97 (t,
J ) 7.5 Hz, 1H), 6.90 (t, J ) 7.5 Hz, 1H), 4.74 (s, 2H), 2.96 (s,
3H), 2.89 (m, 2H), 2.52 (m, 2H), 2.42 (s, 3H). LCMS (ES) m/e
375 (M + H)+. Anal. (C22H22N4O2‚0.9H2O) C, H, N.
1H), 7.03-7.19 (m, 3H), 6.21 (s, 1H), 3.56 (s, 3H), 2.34 (s, 3H).
1,2-Dim eth yl-1H-in d ole-3-ca r boxa ld eh yd e (24). To a
stirred solution of phosphorus oxychloride (7.0 mL, 75.0 mmol)
in DMF (25 mL) was added dropwise a solution of 1,2-
dimethyl-1H-indole (23) (12.0 g, 82.6 mmol) in dry DMF (6.0
mL). The reaction was stirred at RT for 2 h and then poured
onto ice. The mixture was made basic with a solution of NaOH
(13.2 g, 330 mmol) in H2O (44 mL), then was extracted with
Et2O (2 × 50 mL). The combined organic layers were washed
with brine, dried (MgSO4), and concentrated under vacuum.
Flash chromatography on silica gel (10% ethyl acetate/hex-
anes) gave the title compound (13.03 g, 91%) as an off-white
(E)-N-(1,2-Dim et h yl-1H -in d ol-3-ylm et h yl)-N-m et h yl-
3-(7-oxo-5,6,7,8-tetr ah ydr o-1,8-n aph th yr idin -3-yl)acr ylam -
id e (31). According to the procedure of compound 21, except
substituting 1,2-dimethyl-3-(methylaminomethyl)indole (26)
(0.50 g, 2.66 mmol) for 1-methyl-2-(methylaminomethyl)indole,
the title compound (0.74 g, 79%) was prepared as a light yellow
1
solid. H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.36 (s,
1H), 8.05 (m, 1H), 7.56 (m, 2H), 7.37 (m, 1H), 7.17 (d, J )
15.4 Hz, 1H), 7.07 (t, J ) 7.5 Hz, 1H), 6.96 (t, J ) 7.5 Hz, 1H),
4.78 (s, 2H), 3.67 (s, 3H), 2.96 (s, 3H), 2.89 (m, 2H), 2.51 (m,
2H), 2.45 (s, 3H). LCMS (ES) m/e 389 (M + H)+. Anal.
(C23H24N4O2‚1.0H2O) C, H, N.
1
solid. H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.16 (d,
J ) 7.9 Hz, 1H), 7.54 (d, J ) 7.6 Hz, 1H), 7.22 (m, 2H), 3.73
(s, 3H), 2.69 (s, 3H). LCMS (ES) m/e 174 (M + H)+.
1,2-Dim et h yl-3-(m et h yla m in om et h yl)-1H-in d ole (25).
To a solution of 1,2-dimethyl-1H-indole-3-carboxaldehyde (24)
(13.0 g, 75.0 mmol) in MeOH (200 mL) was added a solution
of 2.0 M CH3NH2 in MeOH (113 mL, 225.0 mmol). The reaction
was stirred at RT for 3 h, then was concentrated to a light
yellow oil. This oil was dissolved in EtOH (300 mL), and
(E)-N-Meth yl-3-(7-oxo-5,6,7,8-tetr a h yd r o-1,8-n a p h th y-
r id in -3-yl)-N-(1,2,7-tr im eth yl-1H-in d ol-3-ylm eth yl)a cr yl-
a m id e (32). According to the procedure of compound 21,
except substituting 3-(methylaminomethyl)-1,2,7-dimethylin-
dole (28) (0.57 g, 2.8 mmol) for 1-methyl-2-(methylamino-