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down to ꢀ15 °C. Within 15 min, a solution of t-butyllithium in n-
2.7.4. 2-Hydroxy-5-methyl-8,9-methylenedioxy-
phenanthridinium chloride (19b)
pentane (50 mL, 1.7 M, 85 mmol) was added. After stirring the
mixture for 3 h at ꢀ10 to ꢀ14 °C, trimethyl borate (11.6 mL,
102 mmol) was added within 10 min. The mixture solidified to be-
come a glassy mass that on shaking by hand was resolubilized,
warmed up to room temperature and stirred overnight. The mix-
ture was quenched with saturated ammonium chloride (90 mL)
and water (60 mL) and extracted with ethyl acetate (3 ꢁ 150 mL).
The combined organic layers were dried over sodium sulfate and
purified by flash chromatography on silica gel (EtOAc, MeOH) to af-
ford pure 5c (9.10 g, 23.1 mmol, 68%). 1H NMR (400 MHz; CDCl3):
1.07 (d, 18H, 3J 7.2 Hz, CH(CH3)2), 1.20–1.25 (m, 3H, CH(CH3)2),
1.39 (s, 9H, C(CH3)3), 3.47 (s, 2H B(OH)2), 6.75 (dd, 1H, 3J 8.5 Hz,
4J 2.7 Hz, C4-H), 7.00 (d, 1H, 4J 2.6 Hz, C6-H), 7.13 (d, 1H, 3J
8.4 Hz, C3-H), 9.90 (br, 1H, NH); 13C {1H} NMR (100 MHz; CDCl3):
12.6, 17.9, 27.0, 38.8, 117.7, 119.4, 121.8, 122.4, 131.6, 154.6,
177.4. Anal. Calcd for C20H36BNO4Si: C, 61.06; H, 9.22; N, 3.56.
Found: C, 61.16; H, 9.38; N, 3.62.
Dimethyl sulfate (4.0 mL, 5.33 g, 42.3 mmol) was added to a
suspension of 15 (2.22 g, 5.6 mmol) in nitrobenzene (40 mL) and
xylene (20 mL). Within 30 min, the mixture was heated to 175 °C
and stirring was continued for another 30 min. The chilled mixture
was poured into Et2O (250 mL), the precipitate was allowed to set-
tle down and filtered off, washed with Et2O (2 ꢁ 50 mL) and dried
in vacuo to afford 2-hydroxy-5-methyl-8,9-methylenedioxy-phe-
nanthridinium methyl sulfate (1.87 g, 91%) as a whitish solid. It
was dissolved in boiling water (300 mL), a solution of sodium chlo-
ride (8%, 100 mL) was added, and the mixture was chilled. The pre-
cipitate was filtered off, washed with ice-cold water, and dried in
vacuo to yield pale yellow crystals of 19b (948 mg, 64%, 3.3 mmol).
1H NMR (400 MHz, DMSO-d6); dH 4.51 (s, 3H, NCH3), 6.45 (s, 2H,
OCH2O), 7.62 (dd, 1H, 3J 9.5 Hz, 4J 2.5 Hz, C3-H), 7.81 (s, 1H, C7-
H), 8.16 (d, 1H, 4J 2.5 Hz, C1-H), 8.28 (d, 1H, 3J 9.5 Hz, C4-H), 8.37
(s, 1H, C10-H), 9.66 (s, 1H, C6-H), 11.03 (s 1H, OH). 13C {1H} NMR
(100 MHz, DMSO-d6/D2O 1/1, 350 K) dc 46.0, 101.6, 105.2, 107.9,
108.0, 121.4, 121.9, 123.1, 127.9, 128.8, 134.3, 148.8, 151.2,
157.7, 158.5. Anal. Calcd for C15H12ClNO3: C, 62.19; H, 4.17; N,
4.83. Found: C, 61.82; H, 4.17; N, 4.65.
2.7.2. 8,9-Methylenedioxy-2-triisopropylsilyloxy-
phenanthridine (15)
To a degassed solution of 2-bromo-4,5-methylenedioxybenzal-
dehyde 3d (2.06 g, 9 mmol) in dry 1,2-dimethoxyethane (25 mL)
was added tetrakis(triphenylphosphine)palladium (0.468 g,
0.41 mmol, 4.5 mol%) and 3.89 g (9.9 mmol) of 5c. The mixture
was stirred at room temperature for 5 min, an aqueous solution
of sodium carbonate decahydrate (7.73 g, 27 mmol, 25 mL) was
added, and the resulting mixture was refluxed for 2 h. Then 4 N
HCl. (15 mL) was added slowly to the chilled solution, and the
resulting mixture was refluxed for 30 min. An aqueous solution
of 10 M NaOH was added to justify pH 10. Water (50 mL) and
CH2Cl2 (250 mL) were added and the mixture was transferred to
a separation funnel, shaken thoroughly and allowed to stand over-
night. The solvent was removed in vacuo, the residue extracted
with diethyl ether (2 ꢁ 150 mL), and filtered. The etheric solution
was concentrated and subjected to column chromatography (silica
gel). Eluting with EtOAc/n-hexane 1:1, followed by EtOAc, and
EtOAc/MeOH (1:1) afforded protected phenanthridine 15 (3.00 g,
77%, Rf 0.7, EtOAc, whitish solid) and unprotected phenanthridine
19a (0.29 g, 12%, Rf 0.4, EtOAc, slightly yellow solid, mp >250 °C
decomposition). 1H NMR data of 15 (400 MHz, CDCl3); dH 1.16 (d,
18H, 3J 7.3 Hz, CH(CH3)2), 1.30–1.40 (m, 3H, –CH(CH3)2), 6.14 (s,
2H, OCH2O), 7.27 (dd, 1H, 3J 8.9 Hz, 4J 2.6 Hz, C3-H), 7.29 (s, 1H,
C7-H), 7.74 (d, 1H, 4J 2.1 Hz, C-1H), 7.75 (s, 1H, C10-H), 8.00 (d,
1H, 3J 8.9 Hz, C4-H), 8.94 (s, 1H, C6-H), 13C {1H} NMR (100 MHz;
CDCl3): 12.8, 18.0, 99.9, 101.8, 105.4, 110.2, 122.5, 123.1, 125.4,
129.5, 131.3, 139.6, 148.2, 149.5, 151.0, 154.8. Anal. Calcd for
3. Chemistry
We started the phenanthridine syntheses applying a cyclization
with potassium in liquid ammonia as crucial step, a method re-
ported by Kessar et al.,31,32 since intermediates for this cyclization
could easily be prepared. For example, 2-methoxyphenanthridine
11a was synthesized by cyclization of N-(4-methoxyphenyl)-2-
bromobenzylamine (20) that was prepared via sodium borohy-
dride reduction of the Schiff base formed by reaction of p-anisidine
(4d) and 2-bromobenzaldehyde (3e) (Scheme 1).
However, yields of cyclization products decreased markedly
when additional methoxy substituents were placed in 8- and/or
9-position. These phenanthridines (6a–10a) were found to be more
efficiently synthesized via Suzuki cross-coupling reaction of appro-
priately substituted 2-bromobenzaldehydes and BOC protected
ortho-aminophenylboronic acids25 as depicted in Scheme 2.
2-Hydroxyphenanthridines (16a–19a) were prepared analo-
gously, the phenolic hydroxy group being TIPS protected during
cyclization procedure and deprotected with tetrabutylammonium
fluoride in THF (Scheme 2a). Furthermore, the more stable pivaloyl
(PIV) protection of the aminogroup was found to be more effective
for the syntheses of the 2-hydroxyphenanthridines.
Intermediates for the cross-coupling reactions were readily pre-
pared referring to methods reported in the literature. The ortho-
bromo benzaldehydes 3a,c,d were prepared by direct bromination
of the aldehydes 2a,c,d33–35 or were commercially available (3e).
2-Bromo-4-methoxybenzaldehyde 3b was prepared via ortho-lith-
iation of anisaldehyde dimethylacetal and subsequent bromination
with carbon tetrabromide as reported previously.25 Phenyl car-
bamic acid tert-butylester and 4-methoxyphenyl carbamic acid
tert-butylester 4a,b were prepared by reacting aniline or p-anisi-
dine and di-tert-butyl dicarbonate in THF.36 N-(4-(triisopropylsilyl-
oxy)phenyl)pivalamide 4c was obtained by sequential reactions of
p-aminophenol with triisopropylsilyl chloride and imidazole in
dichloromethane followed by pivaloyl chloride and triethylamine
in THF/Et2O 1/1 with high yield. ortho-Lithiation of the protected
aniline derivatives with tert-butyllithium,37 reaction with tri-
methyl borate38 and cautious hydrolysis afforded the TIPS/PIV- or
BOC-protected boronic acids 5a–c.
C23H29NO3Si: C, 69.84; H, 7.39; N, 3.54. Found: C, 69.53; H, 7.48;
N, 3.52.
2.7.3. 2-Hydroxy-8,9-methylenedioxy-phenanthridine (19a)
To 936 mg (2.4 mmol) of 15 in THF (25 mL) a solution of
Bu4NF in THF (1 M, 3 mL) was added. The mixture was stirred
for 2 h, poured into water (140 mL), extracted with EtOAc three
times (200 mL each). The combined organic layers were dried
over Na2SO4, the solvent was removed under reduced pressure
to afford slightly yellow crystals of 19a (483 mg, 84%). 1H NMR
(400 MHz, DMSO-d6); dH 6.24 (s, 2H, OCH2O), 7.22 (dd, 1H, 3J
8.8 Hz, 4J 2.1 Hz, C3-H), 7.57 (s, 1H, C7-H), 7.79 (d, 1H, 4J
2.1 Hz, C-1H), 7.85 (d, 1H, 3J 8.8 Hz, C-4H), 8.02 (s, 1H, C10-H),
8.92 (s, 1H, C6-H), 9.94 (s,1H, OH). 13C {1H} NMR (100 MHz;
DMSO-d6, 363 K): dc 99.7, 101.7, 104.8, 105.2, 118.5, 122.6,
125.0, 128.4, 130.6, 138.1, 147.7, 148.1, 150.6, 155.9. Anal. Calcd
for C14H9NO3: C, 70.29; H, 3.79; N, 5.85. Found: C, 70.04; H,
3.72; N, 5.85.
Suzuki cross coupling reactions of the bromobenzaldehydes
3a–c with the boronic acids 5a–c were performed in 1,2-dime-
thoxyethane in presence of tetrakis(triphenylphosphine)palladium