Berberine–INF55 (5-Nitro-2-phenylindole) Antibacterials
1479
8.59 (s, 1H), 10.40 (s, 1H). dC (125 MHz, [D7]DMF) 28.3, 32.2,
36.2, 57.4, 58.0, 62.6, 103.1, 104.4, 109.1, 109.2, 111.2, 117.3,
117.6, 121.1, 122.5, 122.5, 126.8, 127.6, 129.4, 130.6, 130.9,
133.9, 135.2, 138.5, 140.9, 141.9, 142.2, 145.1, 145.6, 146.8,
147.6, 150.4, 151.3. m/z (ESI-MS) 600.2122. Anal. calc. for
C36H30N3Oþ6 600.2129.
mixture was stirred for 1–2 h. The mixture was concentrated
under vacuum and the residue redissolved in EtOAc (100mL).
The EtOAc layer was washed with water and brine, and dried
over anhydrous Na2SO4 before concentrating under vacuum. The
residue was purified by flash column chromatography (EtOAc/
hexane, 1 : 2) to afford 13 as an off-white crystalline solid (1.3g,
79%); mp 204–2058C. dH (500MHz, CD3COCD3) 3.90 (s, 3H),
7.029–7.059 (m, 2H), 7.14 (appt, J 7.0, 1H), 7.45 (d, J 8.5, 1H),
7.59 (d, J 8.0, 1H), 7.96 (d, J 8.5, 2H), 8.05 (d, J 8.5, 2H), 11.01
(bs, 1H). dC (125MHz, CD3COCD3) 52.2, 101.8, 112.2, 120.6,
121.4, 123.3, 125.6, 129.3, 129.9, 130.8, 137.3, 137.8, 138. 8,
166.9. m/z (ESI-MS) 252.1014. Anal. calc. for C16H14NO2
[M þ Hþ] requires 252.1025.
9,10-Dimethoxy-13-(4-(1-methyl-1H-indol-2-yl)benzyl)-
5,6-dihydro-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]
isoquinolin-7-ium chloride 9
To a solution of the crude chloride 21 (128 mg, 0.5 mmol) in
anhydrous CH3CN (10 mL) was added sodium iodide (12.7 mg,
0.53 mmol) and the reaction was stirred for 1 h at 708C.
8-Acetonyldihydroberberine (17) (196.8 mg, 0.501 mmol) was
then added and stirring continued for another 3–4 h at 708C.
The reaction was monitored by TLC (EtOAc/hexane, 1 : 4) to
observe consumption of the chloride, and also by ESI-MS. On
completion, the reaction mixture was purified by silica-gel
column chromatography using EtOAC/CH3CN/hexane
(1 : 1 : 2) followed by EtOAc/CH3CN/MeOH (1 : 1 : 0.1).
The semi-pure material was further purified by preparative
RP-HPLC using a gradient from 0 % A to 100 % B over 30 min
(Rt 21.5 min). The fractions containing pure product were
pooled and concentrated by freeze-drying to yield 9 as a yellow
solid (118 mg, 40 %); mp 186–1898C. dH (500 MHz, [D7]DMF)
3.37 (s, 2H), 3.83 (s, 3H), 4.15 (s, 3H), 4.23 (s, 3H), 5.01 (s, 2H),
5.22 (bs, 2H), 6.20 (s, 2H), 6.63 (s, 1H), 7.10 (appt, J 7.5, 1H),
7.20–7.25 (m, 3H), 7.48 (d, J 7.5, 2H), 7.53 (d, J 8.5, 1H), 7.62
(d, J 7.5, 1H), 7.69 (d, J 8.0, 2H), 8.04 (d, J 7.5, 1H), 8.22 (d,
J 7.5, 1H) 9.42 (s, 1H). dC (125 MHz, [D7]DMF) 28.3, 31.5,
36.2, 57.4, 58.2, 62.6, 102.1, 103.1, 109.1, 109.2, 110.6, 120.2,
120.8, 121.1, 122.2, 122.4, 122.5, 126.8, 128.6, 129.2, 130.4,
131.1, 131.9, 134.0, 135.1, 138.5, 139.3, 139.9, 141.4, 145.5,
146.5, 147.6, 150.4, 151.2. m/z (ESI-MS) 555.2289. Anal. calc.
for C36H31N2Oþ4 555.2278.
Methyl 4-(1-methyl-1H-indol-2-yl)benzoate 19
A stirring solution of (N-methylindol-2-yl)tributylstannane 18
(5.0 g, 11.9 mmol) in anhydrous THF was charged with
methyl-4-iodobenzoate (2.18 g, 8.3 mmol) and PdCl2 (97.6 mg,
0.832 mmol). The reaction mixture was purged with nitrogen for
30 min and then heated at reflux for 3–4 h with monitoring by
TLC (EtOAc/hexane, 1 : 5). The crude reaction mixture was
adsorbed onto silica gel and purified by flash column chroma-
tography with petroleum spirit/EtOAc (9.5 : 0.5 to 8 : 2) to yield
19 as an off-white solid (2.36 g, 75 %); mp 1058C. dH (500 MHz,
CDCl3) 3.75 (s, 3H), 3.94 (s, 3H), 6.63 (s, 1H), 7.15 (appt, J 7.5,
1H), 7.26 (appt, J 7.5, 1H), 7.36 (d, J 8.0, 1H), 7.58 (d, J 8.5, 2H),
7.64 (d, J 7.5, 1H), 8.12 (d, J 9.8, 2H). dC (125 MHz, (CDCl3)
31.3, 52.1, 102.8, 109.7, 120.1, 120.7, 122.2, 127.8, 128.9,
129.2, 129.7, 137.2, 138.6, 140.1, 166.7. m/z (ESI-MS)
266.1173. Anal. calc. for C17H16NO2 [M þ Hþ] 266.1181.
(4-(1-Methyl-1H-indol-2yl)phenyl)methanol 20
To a stirred solution of 19 (250 mg, 0.94 mmol) in anhydrous
THF was added LiAlH4 (34 mg, 0.94 mmol) and the temperature
gently raised to 408C. Another 3–4 equiv. of LiAlH4 was added
in portions over 20–30 min and the reaction mixture was stirred
at 408C for a further 3–4 h. The reaction was monitored by TLC
(EtOAc/petroleum spirit, 2 : 3) and on completion was slowly
quenched by dropwise addition of saturated aqueous NH4Cl.
After cessation of bubbling, the mixture was diluted with water
and extracted with EtOAc (3 ꢂ 10 mL). The organic layer was
dried over anhydrous MgSO4 and concentrated under vacuum to
yield 20 as an off-white solid (190 mg, 85 %); mp 97–998C. dH
(500 MHz, CDCl3) 3.71 (s, 3H), 4.72 (s, 2H), 6.54 (s, 1H), 7.13
(appt, J 7.5, 1H), 7.24 (appt, J 15.5, 1H), 7.34 (d, J 8.5, 1H), 7.43
(d, J 8.0, 2H), 7.49 (d, J 8.5, 2H), 7.62 (d, J 8.0, 1H). dC
(125 MHz, CDCl3) 31.1, 64.9, 101.6, 109.5, 119.8, 120.4, 121.6,
127.0, 127.9, 129.4, 132.1, 138.3, 140.4, 141.2. m/z (ESI-MS)
238.1224. Anal. calc. for C16H16NO [M þ Hþ] 238.1232.
tert-Butyl-2-(4-(methoxycarbonyl)phenyl)-1H-indole-1-
carboxylate 12
To a stirred solution of 11 (5 g, 9.9 mmol) in anhydrous 1,4-
dioxan (50 mL) were added 4-iodomethylbenzoate (2.04 g,
7.78 mmol) and palladium(II) chloride (43 mg, 0.24 mmol) and
the reaction mixture was purged with nitrogen for 15 min. The
reaction mixture was then heated to 1008C and stirred for 1 h
while monitoring by TLC (EtOAc/hexane, 1 : 9). The mixture
was cooled, diluted with EtOAc (100 mL), and stirred with 15 %
aqueous potassium fluoride (300 mL) for 15 min. The precipi-
tate was removed by filtration and washed well with EtOAc
(200 mL). The organic layer was separated, washed with water
and brine, dried over anhydrous Na2SO4, and concentrated
under vacuum. The crude residue was purified by silica-gel
column chromatography (EtOAc/hexane, 1.5 : 8.5) to afford 12
as a white semi-solid (2.3 g, 84 %); mp 79–838C. dH (500 MHz,
CDCl3) 1.32 (s, 9H), 3.94 (s, 3H), 6.6 (s, 3H), 7.2 (appt, J 7.5,
1H), 7.35 (appt, J 7.5, 1H), 7.50 (d, J 7.5, 2H), 7.56 (d, J 7.5, 1H),
8.07 (d, J 7.5, 2H), 8.21 (d, J 8.5, 1H). dC (125 MHz, CDCl3)
27.6, 52.1, 83.8, 110.7, 115.2, 123.4, 125.1, 128.3, 128.8, 129.0,
129.2, 137.9, 139.4, 149.9, 166.86. m/z (ESI-MS) 374.1368.
Anal. calc. for C21H21NNaO4 [M þ Naþ] 374.1368.
2-(4-Chloromethyl)phenyl)-1-methyl-1H-indole 21
A solution of alcohol 20 (300 mg, 1.26 mmol) in CCl4/CH2Cl2
(1 : 2, 7 mL) was stirred for 10 min at rt. PPh3 (991 mg,
3.78 mmol) was then added and stirring continued for 1 h. TLC
analysis (EtOAc/hexane, 1 : 4) indicated complete consumption
of the alcohol. The product was filtered over a neutral alumina
bed and washed with dichloromethane (3 ꢂ 5 mL). The com-
bined filtrates were concentrated under vacuum (water bath
temperature kept below 408C). The residue obtained was tritu-
rated with pentane (3 ꢂ 4 mL) to afford crude 21 (210 mg, 65 %),
which was used immediately. Owing to its instability, 21 was
unable to be characterised.
Methyl 4-(1H-indol-2-yl)benzoate 13
To a stirred solution of 12 (2.3 g, 6.6 mmol) in anhydrous CH2Cl2
(7mL) was added trifluoroacetic acid (7mL) and the reaction