10.1002/cmdc.202000066
ChemMedChem
FULL PAPER
6-amino-3,3',5-trimethoxy-4-methyl-[1,1'-biphenyl]-2-ol (8a) [2226848-
68-4]. 3,3',5-trimethoxy-4-methyl-6-nitro-(1,1'-biphenyl)-2-ol (7a) (0.08 g,
0.25 mmol) was dissolved in EtOH (4 mL) and transferred to a microwave
tube reactor (10 mL) equipped with a magnetic stirrer bar. A slurry
composed of NH4Cl (0.027 g, 0.50 mmol) in water (1.2 mL) and indium
powder (0. 086 g, 0.75 mmol, 99.99% 100 mesh, use preferably a freshly
opened bottle or stored under Ar) were then added. The reactor tube was
then sealed and stirred and heated at 120 °C for 3 h. The reaction mixture
was cooled at 20 oC, diluted with ethyl acetate (20 mL), and finally filtered
through a pad of Celite. Another portion (20 mL) of ethyl acetate was used
to wash through the filter pad. The resulting organic phase was dried over
Na2SO4, filtered, and the solvent was removed under reduced pressure
using a rotary evaporator to obtain the compound 8a as a purple oil (0.071
g, 98%).; Rf = 0.36 (ethyl acetate:hexane = 30:70); 1H-NMR (500 MHz,
CDCl3): δ= 7.40 (t, J = 8 Hz, 1H), 6.99-6.97 (m, 1H), 6.95-6.94 (m, 1H),
6.93-6.91 (m, 1H), 5.29 (s, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H),
2.27 (s, 3H),; 13C-NMR (125 MHz, CDCl3): δ= 160.1, 142.8, 138.5, 137.1,
135.3, 134.4, 130.2, 123.4, 122.7, 115.8, 113.6, 112.8, 61.0, 59.5, 55.3,
9.5; MS (EI): m/z (%): 290 (12), 289 (74, M+), 274 (100), 259 (12), 246 (26),
231 (25), 137 (14), 130 (32), 115 (15), 83 (14), 77(10);HR-MS (DART):
(M+H)+: Calcd for C16H20NO4 290.1392; Found 290.1395); IR (cm-1): 3458,
3341, 3057, 2933, 2849, 1580, 1360, 994, 727.
regulated at 120 oC for a period of 5 h. The reaction mixture was analyzed
by means of GC (94% yield). The isolated crude product was dissolved in
ethyl acetate (20 mL) and washed with water (25 mL). The water phase
was extracted with ethyl acetate (2 × 15 mL). The combined organic layer
was washed with aq. NaHCO3 (20 mL). The organic layer was dried over
Na2SO4 and filtered off. The solvent was evaporated under reduced
pressure using a rotary evaporator. The crude product was purified by
using silica gel column chromatography (ethyl acetate:hexne = 20:80) to
obtain the N-acetyl carbazole 10 (0.043 g, brown liquid) in a yield of 71%.
Rf = 0.33 (ethyl acetate:hexane = 20:80); 1H-NMR (500 MHz, CDCl3): δ =
8.26 (d, J= 8.5 Hz, 1H), 7.83 (d, J= 7.5 Hz, 1H), 7.45 (t, J= 7.5 Hz, 1H),
7.33 (t, J= 7.5 Hz, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 2.62 (s, 3H), 2.54 (s,
3H), 2.39 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ = 172.8, 168.6, 147.4,
144.0, 140.4, 134.8, 128.5, 127.7, 124.9, 123.7, 123.6, 121.1, 119.7, 115.1,
61.1, 60.0, 26.8, 20.8, 10.2; MS (EI): m/z (%): 341 (11, M+), 299 (19), 257
(46), 242 (100), 226 (11), 196 (12), 168 (22), 154 (23), 127 (22), 115 (27),
89(12), 77(12), 55(12);HR-MS (DART): (M+H)+: Calcd for C19H20NO5
342.1341; Found 342.1343); IR (cm-1): 2935, 1766, 1702, 1445, 1398,
1367, 1269, 1254, 1183, 1082, 1002, 749.
Isomer mixture of 9-acetyl-1,3,6-trimethoxy-2-methyl-9H-carbazol-4-
yl acetate (10a) and 9-acetyl-1,3,8-trimethoxy-2-methyl-9H-carbazol-
4-yl
acetate
(10b).
6-Acetamido-3,3',5-trimethoxy-4-methyl-[1,1'-
6-acetamido-3,5-dimethoxy-4-methyl-(1,1'-biphenyl)-2-yl acetate (9)
biphenyl]-2-yl acetate 9a (0.130 g, 0.348 mmol) was transferred to a
microwave reactor tube and dissolved in glacial acetic acid (5 mL). Then,
Pd(OAc)2 (8 mg, 0.024 mmol), IMes × HCl (12 mg, 0.024 mmol). and H2O2
(35%, 0.09 mL, 1.0 mmol) were added to the reactor tube. A magnetic
stirrer bar was transferred to the reactor tube that then was sealed and
submerged into the microwave cavity at 120 oC for 5 h. The reaction
mixture was analyzed by means of GC (50% yield). The solvent (acetic
acid) was removed under reduced pressure using a rotary evaporator. The
obtained crude product was dissolved in ethyl acetate (40 mL) and washed
with water (25 mL). The water phase was extracted with ethyl acetate
(2 × 40mL). The combined organic layer was washed with aq. NaHCO3
(30 mL). The organic layer was dried over Na2SO4 and filtered off. The
solvent was evaporated under reduced pressure. The crude product was
purified by using silica gel column chromatography (ethyl acetate:hexane
= 20:80), which afforded a mixture of the two isomers 10a and 10b in a
yield of 30%. 1H-NMR (500 MHz, CDCl3): δ = 8.13 (d, J= 9 Hz, 1H), 7.64
(d, J= 7.5 Hz, 1H), 7.54-7.55 (m, 1H), 7.32 (t, J= 8 Hz, 1H), 7.25 (m, 1H),
6.96-6.98 (dd, J= 2.5, 9 Hz, 1H), 3.82 (s, 1H), 3.79 (s, 3H), 3.77 (s, 1H),
3.65 (s, 3H), 2.54 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H),; 13C-NMR (125 MHz,
CDCl3): δ = 172.5, 168.6, 159.6, 156.3, 147.4, 144.2, 135.1, 134.7, 130.5,
129.5, 129.1, 125.1, 124.6, 122.6, 120.4, 119.7, 116.2, 114.4, 114.3, 105.5,
61.1, 59.9, 55.8, 55.5, 26.6, 20.8, 10.2; MS (EI): m/z (%): 371 (7, M+), 331
(11), 287 (28), 272 (62), 207 (69), 115 (34), 96 (38), 83 (42), 77(76).
[2041574-03-0]. 6-Amino-3,5-dimethoxy-4-methyl-(1,1'-biphenyl)-2-ol
8
(0.12 g, 0.46 mmol) was transferred to round bottom flask (50 mL)
whereupon dry CH2Cl2 (10 mL) were added under agitation and inert
atmosphere. Triethylamine (0.14 mL, 0.97 mmol) was then added to the
stirred mixture, which then was cooled on an ice bath. Acetic anhydride
(0.09 mL, 1.01 mmol) was then drop-wise added to the mixture that was
stirred at 20 oC for 1 h after the completed addition. The mixture was
diluted with ethyl acetate (50 mL) and washed with water (40 mL). The
organic layer was washed further with NaHCO3 (30 mL) and finally dried
over Na2SO4. The solvent was evaporated under reduced pressure to
obtain the acetylated product 9 (0.148 g, purple liquid) in 94 % crude yield.
Rf = 0.74 (ethyl acetate:hexane = 50:50); 1H-NMR (500 MHz, CDCl3): δ =
7.34 (m, 3H), 7.20 (m, 2H), 6.50 (s, br, 1H), 3.76 (d, J=8.5Hz, 6H), 2.29 (s,
3H), 2.17 (s, 3H), 1.99 (s, 3H); MS (EI): m/z (%): 343 (11, M+), 301 (46),
270 (24), 244 (100), 201 (24), 144 (51), 128 (39), 115 (60), 89 (72), 83(94),
77(47), 55(43); HR-MS (DART): (M+H)+: Calcd for C19H22NO5 344.14980;
Found 344.14999; IR (cm-1): 2928, 2552, 1669, 1603, 1451, 1422, 1290,
1205, 707.
6-acetamido-3,3',5-trimethoxy-4-methyl-(1,1'-biphenyl)-2-yl acetate
(9a) [2226848-72-0]. 6-Amino-3,3',5-trimethoxy-4-methyl-(1,1'-biphenyl)-
2-ol 8a (0.13 g, 0.45 mmol) was transferred to a round bottom flask (50 mL)
and dissolved in dry CH2Cl2 (10 mL) under inert atmosphere. Triethylamine
(0.13 mL, 0.97 mmol) was then added to the stirred mixture. The mixture
was cooled on an ice bath, whereupon acetic anhydride (0.09 mL, 1.01
mmol) was drop-wise added to the mixture. The reaction mixture was
stirred at room temperature for 1 h. The mixture was then was diluted with
ethyl acetate (50 mL) and then washed with water (40 mL). The organic
layer was further washed with NaHCO3 (30 mL) and finally dried over
Na2SO4. The solvent was evaporated under reduced pressure to obtain
the acetylated product 9a (0.131 g, purple liquid) in 92% crude yield. Rf =
0.67 (ethyl acetate:hexane = 50:50); MS (EI): m/z (%): 373 (16, M+), 332
(12), 331 (68), 316(7), 300 (26), 274 (100), 256 (11), 242 (13), 231 (11),
174 (12), 115 (9), 83 (15). The acetylated product 9a was used in the next
step without further purification.
1,3-dimethoxy-2-methyl-9H-carbazol-4-ol (11) [2226848-80-0]. 9-
Acetyl-1,3-dimethoxy-2-methyl-9H-carbazol-4-yl acetate 10 (0.023 g, 0.07
mmol) was transferred to a round bottom flask and then added methanol
(10 mL) at 0 oC. To this mixture, a solution of conc. HCl (2 mL) in methanol
(5 mL) was added dropwise, and continuously stirred for 1 h at 70 oC. The
reaction mixture was then cooled at room temperature, diluted with water
(40 mL), and extracted with ethyl acetate (2 ´ 20 mL). The combined
organic layer was dried over Na2SO4 and then filtered. The solvent was
evaporated to obtain compound 11 as a brown solid (0.017 g, 94%). Rf =
0.42 (ethyl acetate:hexane = 20:80); 1H-NMR (500 MHz, CDCl3): δ = 8.24
(d, J= 8 Hz, 1H), 8.10 (s, br, 1H), 7.41 (m, 1H), 7.39-7.35 (td, J= 1.0 Hz,
6.5 Hz, 1H), 7.24-7.20 (m, 1H), 6.03 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H),
2.42 (s, 3H),; 13C-NMR (125 MHz, CDCl3): δ = 140.7, 139.1, 137.6, 135.8,
130.7, 125.0, 123.2, 122.6, 121.0, 119.5, 110.6, 110.2, 61.3, 60.8, 9.8; HR-
MS (DART): (M+H)+: Calcd for C15H16NO3 258.1130; Found 258.1133); IR
(cm-1): 3309, 3244, 2973, 2924, 2896, 1624, 1321, 1087, 1046, 879.
9-acetyl-1,3-dimethoxy-2-methyl-9H-carbazol-4-yl
acetate
(10)
[2041574-04-1]. 6-Acetamido-3,5-dimethoxy-4-methyl-(1,1'-biphenyl)-2-yl
acetate 9 (0.063 g, 0.183 mmol) was placed in a microwave reactor tube
and dissolved in glacial acetic acid (5 mL). Pd(OAc)2 (2.1 mg, 0.009 mmol),
IMes × HCl (3.2 mg, 0.009 mmol), and H2O2 (35%, 0.05 mL, 0.53 mmol)
were then added to the mixture. The reactor tube was sealed whereupon
a magnetic stirrer bar was transferred to the tube. The tube was
submerged into the microwave cavity and the temperature was raised and
3-methoxy-2-methyl-1-carbazole-1,4 (9H)-dione (12) [192188-88-8].
1,3-Dimethoxy-2-methyl-9H-carbazol-4-ol (11) (40 mg, 0.155 mmol) in
glacial acetic acid (3 mL) was placed in round bottom flask. HNO3 (90%,
0.01 mL, 0.186 mmol) was then added dropwise in order to maintain a
7
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