A synthesis of 6,11-disubstituted benzo[b]carbazoles

Article abstract of DOI:10.1139/v01-127

Sequential regioselective addition of organolithium reagents to indolo[1,2-b]isoquinoline-6,11-quinone (7) followed by sodium borohydride reduction of the intermediate diol 10, which is not isolated, affords 6,11-disubstituted 5H-benzo[b]carbazoles 11. The tandem combination of methyllithium and lithium triethylborohydride (Super Hydride) gives 6-methylbenzo[b]carbazole (24).

Full text of DOI:10.1139/v01-127

1515
A synthesis of 6,11-disubstituted
benzo[b]carbazoles
Heidi L. Fraser and Gordon W. Gribble
Abstract: Sequential regioselective addition of organolithium reagents to indolo[1,2-b]isoquinoline-6,11-quinone (7) fol-
lowed by sodium borohydride reduction of the intermediate diol 10, which is not isolated, affords 6,11-disubstituted
5H-benzo[b]carbazoles 11. The tandem combination of methyllithium and lithium triethylborohydride (Super Hydride)
gives 6-methylbenzo[b]carbazole (24).
Key words: benzo[b]carbazole, organolithFiuramsse,rinadnodloG[1r,ib2-bble]isoquinoline-6,11-quinone, ellipticine, indole.
Résumé : L’addition régiosélective séquentielle de réactifs organolithiens à l’indolo[1,2-b]isoquinoléine-6,11-quinone
(7), suivie d’une réduction par le borohydrure de sodium du diol intermédiaire 10 qui n’a pas été isolé, conduit à la
formation de 5H-benzo[b]carbazoles 6,11-disubstitués (11). La combinaison en tandem du méthyllithium et du triéthyl-
borohydrure de lithium (« Super Hydrure ») conduit au 6-méthylbenzo[b]carbazole (24).
Mots clés : benzo[b]carbazole, organolithiens, indolo[1,2-b]isoquinoléine-6,11-quinone, ellipticine, indole.
[Traduit par la Rédaction] 1521
The ellipticine family of alkaloids and related pyrido-
carbazoles and benzocarbazoles (1–6, Fig. 1) continue to be
intensively studied as novel DNA active compounds and po-
tential anticancer agents (for reviews see ref. 1; for recent
work, see ref. 2). For example, S16020–2 (4) is one of the
most potent such analogues yet discovered, and 9-chloro-4-
hydroxy-2,3,5,11-tetramethyl-6H-pyrido[3,2-b]carbazole (6)
has high in vivo antitumor activity against L1210 and P388
leukemia, B16 melanoma, and M5076 sarcoma (2).
As an extension of our previous work on the synthesis of
ellipticine and other pyridocarbazoles (for reviews of our
early work see ref. 3; 4, 5), we describe herein the synthesis
of 6,11-disubstituted benzo[b]carbazoles 11. Thus, sequen-
tial regioselective addition of organolithiums to indolo[1,2-
b]isoquinoline-6,11-quinone (7) followed by reduction of the
intermediate diol 10 gives 11 (Scheme 1). Our earlier experi-
ence showed that low temperatures are necessary during the
organolithium addition to preclude the ring-opening 8 J 9
prior to consumption of all of the organolithium reagents. If
this does occur, then ketone 9 can react with the organo-
lithium to give tertiary alcohol 12, useless for this approach.
affords keto acid 16 in 86% overall yield from indole.
Cleavage of the phenylsulfonyl group and cyclization with
hot acetic anhydride furnishes the desired quinone 7. Treat-
ment of 7 with methyllithium (2 equiv) followed by reduc-
tion of the crude diol mixture with sodium borohydride
gives 6,11-dimethyl-5H-benzo[b]carbazole (18) in 87%
yield (5). With this result it became of interest to examine
the sequential addition of different organolithium reagents to
quinone 7.
Based on our previous studies (5–7), we anticipated that
the ketone carbonyl in 7 would be more reactive than the
lactam carbonyl towards organolithium addition. Indeed, treat-
ment of 7 with 1 equiv of methyllithium at –100°C followed
by the addition of 1 equiv of n-butyllithium affords, after
reductive work-up, 11-n-butyl-6-methylbenzo[b]carbazole (19)
as the major product (61% yield). The regioisomeric 6-n-
butyl-11-methylbenzo[b]carbazole (20) is obtained in 12%
yield (Scheme 3). Reversing the order of addition yields 20
exclusively in 72% yield.
The isomer assignments of 19 and 20 are based on the re-
spective methyl proton chemical shifts, which in turn were
established from NOESY data obtained with 6,11-
dimethylbenzo[b]carbazole (18). Thus, the C-6 methyl pro-
tons (2.85 ppm) show a NOESY cross peak with the indole
NH (7.91 ppm) and one adjacent aromatic proton (H-7,
8.10 ppm). In contrast, the C-11 methyl protons (3.25 ppm)
interact with two aromatic protons (H-1, 8.37 ppm and H-10,
8.31 ppm). Moreover, as we have observed previously with
Results and discussion
As we have shown earlier (5), indole (13) is readily con-
verted to quinone 7 in 67% overall yield (Scheme 2). Thus, a
standard C-2 lithiation of 1-(phenylsulfonyl)indole (14) with
LDA (6) followed by reaction with phthalic anhydride (15)
Received December 4, 2000. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on October 18, 2001.
Dedicated to Victor Snieckus, a friend and colleague for nearly 40 years, in celebration of his many contributions to organic
chemistry and his outstanding service to our community.
H.L. Fraser and G.W. Gribble.1 Department of Chemistry, 6128 Burke Laboratory, Dartmouth College, Hanover, NH 03755
U.S.A.
1Corresponding author (telephone: (603) 646-3118; fax: (603) 646-3946; e-mail: grib@dartmouth.edu).
Can. J. Chem. 79: 1515–1521 (2001)
© 2001 NRC Canada
DOI: 10.1139/cjc-79-11-1515

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Can. J. Chem. Vol. 79, 2001
Fig. 1. Ellipticine alkaloids and related antitumor pyridocarbazoles.
Scheme 1.
pyridocarbazoles (5, 7), a methyl group in the C-11 position
is significantly deshielded by the indole benzene ring. The
methyl group chemical shifts observed for 19 (2.81 ppm)
and 20 (3.67 ppm) are consistent with this deshielding effect.
Similar results were obtained with reactions of phenyllithium
with quinone 7. Thus, treatment of 7 with 2 equiv of
phenyllithium affords 6,11-diphenylbenzo[b]carbazole (21),
in 70% yield after reductive work-up. Sequential treatment
of 7 with 1 equiv each of phenyllithium then methyllithium
affords 22 (37%) and 23 (22%). The reverse order of
organolithium addition is somewhat more regioselective giv-
ing 23 (47%) and 22 (18%). These two isomers were distin-
guished by their characteristic methyl group chemical shifts
(3.28 ppm for 22; 2.91 ppm for 23).
The use of hydride nucleophiles has been more problem-
atic and only one combination of reagents has been fruitful.
© 2001 NRC Canada

Fraser and Gribble
1517
Scheme 2.
Scheme 3.
Treatment of quinone 7 with methyllithium followed by Super
Hydride (LiBHEt3) affords 6-methylbenzo[b]carbazole (24)
in 56% yield, after reduction of the intermediate diol with
sodium borohydride. The reverse sequence of reagents as
well as several attempts (Super Hydride, DIBAL, LiAlH4) to
effect hydride addition to both carbonyl groups, which would
give the parent 5H-benzo[b]carbazole, were unsuccessful and
led only either to complex mixtures or partial reduction. For
example, reduction of 7 with sodium borohydride alone af-
fords the hydroxy lactam 25 (86% yield) resulting from con-
jugate reduction of the indole double bond and ketone
reduction (Scheme 4). The stereochemistry of 25 was estab-
lished by 2D NMR experiments (COSY, NOESY) and cou-
pling constants. The methine proton at C-11 is trans to the
© 2001 NRC Canada

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Can. J. Chem. Vol. 79, 2001
Scheme 4.
1-(Phenylsulfonyl)indole (14) (8)
To a stirred suspension of powdered sodium hydroxide
(67.45 g, 1.69 mol) and tetra-n-butylammonium hydrogen
sulfate (4.70 g, 0.014 mol) in methylene chloride (660 mL)
at 0°C, indole (13) (60.58 g, 0.517 mol) was added neat via
a powder funnel under N2. A solution of benzenesulfonyl
chloride (63.8 mL, 0.50 mol) in methylene chloride (40 mL)
was added to the ice-cold suspension over 20 min, not al-
lowing the temperature to surpass 20°C. The reaction mix-
ture was stirred vigorously for 3 h via mechanical stirring.
The resulting solid was filtered and the filtrate was concen-
trated in vacuo to give a light pink solid (144.7 g), which
was triturated with hexanes to yield 133.1 g (100%) of 14 as
white crystals: mp 77–79°C (lit. (8) mp 78 to 79°C).
proton at C-11a (J = 11.5 Hz), and the coupling constants
between C-11a-H and the protons at C-12 (J = 8.7 and
9.4 Hz) are consistent with this stereochemistry.
In summary, we have shown that 6,11-disubstituted
benzo[b]carbazoles are accessible via the sequential addition
several organolithium reagents to indolo[1,2-b]isoquinoline-
6,11-quinone (7). The use of Super Hydride in this strategy
allows for the synthesis of 6-methylbenzo[b]carbazole (24).
1-(Phenylsulfonyl)indol-2-yl 2-carboxyphenyl ketone (16) (5)
To a stirred solution of LDA in THF (10 mL) (generated
from diisopropylamine (0.60 mL, 4.25 mmol) and n-BuLi
(1.7 mL, 4.27 mmol, 2.5 M in hexane) at –78°C), was added
1-(phenylsulfonyl)indole (14) (1.11 g, 4.27 mmol) in THF
(10 mL) at –78°C under N2 over 5 min. The reaction mixture
was stirred at –78°C for 2 h and was then warmed to 14°C
over 30 min. The reaction mixture was recooled to –78°C,
followed by rapid addition of a solution of phthalic anhy-
dride (15) (0.64 g, 4.27 mmol) in THF (5 mL). The reaction
mixture was allowed to warm to room temperature over-
night. The reaction mixture was concentrated in vacuo, and
the residue was dissolved in water (20 mL). The solution
was cooled to 0°C and acidified with 20% HCl. The tan
solid which formed upon acidification was collected by vac-
uum filtration and dried in vacuo to afford 1.60 g (92%) 16
as a tan solid. The solid was recrystallized from acetone to
yield 9.12 g of 16 as a tan solid (89%): mp 212 to 213°C
(lit. (5) mp 212 to 213°C). 13C NMR (acetone-d6) d (ppm):
186.0, 167.5, 134.3, 131.7, 131.3, 130.1, 129.6, 129.4, 128.1,
128.0, 124.3, 123.6, 120.7, 115.6.
Experimental section
General experimental
Melting points were determined in open capillaries and
are uncorrected. Elemental analyses were done by Atlantic
Microlab Inc., Atlanta, Georgia. High resolution mass spec-
tra (HRMS) were carried out at the University of Illinois at
Urbana-Champaign, School of Chemical Sciences, Mass
1
Spectrometry Laboratory, Urbana, Illinois. All H NMR, 13C
NMR, HMQC, COSY, and NOESY spectra were generated
with a Varian Unity Plus NMR spectrometer (300 Hz) unless
specified otherwise. Tetramethylsilane (TMS) and deuterated
solvents were used as internal reference (CDCl3, acetone-d6,
DMSO-d6, or CD3OD). Chemical shifts are reported in parts
per million (d) downfield from TMS. The apparent multiplic-
ity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, b = broad), number of protons, and coupling con-
stants (J = xHz) are reported where appropriate. Low resolu-
tion mass spectral data were generated on a Hewlett-Packard
5890 (70 eV). Infrared spectra were taken with a PerkinElmer
1600 series FT IR spectrophotometer and are referenced to
the 1601 cm–1 band of polystyrene. Ultraviolet spectra were
taken with a Hewlett-Packard 8451A diode array spectro-
photometer in 95% ethanol. Thin layer chromatography was
done on Whatman brand 20 × 20 cm polyester backed silica
plates with fluorescent indicator. Plates were visualized by
254 nm UV light. Alternative visualization was accomplished
by treatment with a solution of ceric ammonium sulfate in
10% H2SO4. Preparative TLC was done on silica gel 60
F254 1 mm 20 × 20 plates from VWR. Flash chromatogra-
phy was carried using Fisher or SELECTO brand silica gel
60 PF254 (230–400 mesh). Alkyllithiums were standardized
prior to use by titration against dried diphenylacetic acid un-
der an atmosphere of N2 at 0°C. Tetrahydrofuran was freshly
distilled from sodium–benzophenone under N2. Anhydrous
reactions were done with glassware dried for 24 h at a tem-
perature of 120°C or greater. Apparatus was assembled hot
and cooled under an atmosphere of N2. Alternatively, glass-
ware was assembled and dried by treatment with flame of a
propane torch and cooled under an atmosphere of N2.
2-Carboxyphenyl 2-indolyl ketone (17) (5)
A solution of keto acid 16 (6.94 g, 17.14 mmol) and
K2CO3 (9.6 g, 0.068 mol) in MeOH (175 mL) and H2O
(60 mL) was refluxed for 5 h under N2. The reaction mixture
was cooled, and the MeOH was removed in vacuo. Water
(100 mL) was added, and the acidity was adjusted to pH 2
with 20% HCl. The aqueous layer was extracted with EtOAc
(3 × 200 mL), the organic layers were combined and washed
with brine (2 × 50 mL), dried (Na2SO4), and concentrated in
vacuo. The crude solid was recrystallized from acetone to
yield 4.03 g (89%) of 17 as a tan solid: mp 234–236°C (lit.
(5) mp 234 to 235°C).
Indolo[1,2-b]isoquinoline-6,11-quinone (7) (5)
Keto acid 17 (3.01 g, 11.4 mmol) was suspended in acetic
anhydride (560 mL) and heated to 90–109°C for 24 h under
N2. The reaction mixture was cooled to room temperature
and kept at 0°C for 12 h. The gold needles that formed were
collected by vacuum filtration (1.84 g, 65%). The Ac2O present
in the filtrate was removed by vacuum distillation (10–20 torr
(1 torr = 133.322 Pa)) and the residue was recrystallized
from acetone to yield 0.49 g of 7 as gold needles (overall
1
yield 83%): mp 217 to 218°C (lit. (5) mp 217 to 218°C). H
NMR (acetone-d6) d (ppm): 8.41 (d, 1H), 8.24 (dd, 1H), 8.15
© 2001 NRC Canada

Fraser and Gribble
1519
(dd, 1H), 7.93–7.79 (m, 3H), 7.65 (s, 1H), 7.57 (t, 1H), 7.36
(t, 1H).
(15.5 mg) of the minor isomer also as a film. Attempts to pu-
rify these compounds for elemental analysis were unsuccessful.
Major isomer 19: MS m/z: 287 (M+), 273, 244 (100%), 230,
202, 143, 120. HRMS calcd. m/z: 287.1674; found m/z:
287.1666. UV (95% EtOH) ꢀmax (nm): 296 (5.70), 320 (5.17),
334 (4.23), 380 (5.05), 398 (5.09). IR (film) (cm–1): 3733,
2922, 2355, 1211, 1151, 638, 502. 1H NMR (CDCl3) d (ppm):
8.41 (d, J = 8.7 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.19 (d,
J = 8.1 Hz), 7.94 (bs, 1H), 7.67 (m, 4H), 7.36 (t, J = 7.2,
1H), 3.75 (t, 2H), 2.81 (s, 3H), 1.95 (m, 2H), 1.78 (m, 2H),
1.52 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3) d (ppm): 127.3,
126.8, 124.8, 123.9, 123.6, 122.4, 119.7, 111.6, 110.5, 32.5,
31.2, 29.2, 23.8, 14.5.
6,11-Dimethyl-5H-benzo[b]carbazole (18) (5)
To a stirred solution of quinone 7 (130 mg, 0.530 mmol)
in THF (25 mL) at –100°C under N2 was added MeLi (0.8 mL,
1.13 mmol, 1.4 M in ether) dropwise via syringe. The result-
ing dark green solution was stirred at –90°C for 2 h and was
warmed to room temperature overnight. The solvent was re-
moved in vacuo and the residue was dissolved in absolute
EtOH (50 mL). The solution was then heated to reflux and
NaBH4 (1 pellet, 1.0 g, 27.0 mmol) was added; another pel-
let of NaBH4 was then added after every 24 h of reflux. The
reaction was refluxed for a total of 78 h. The reaction was
cooled to room temperature, the EtOH was removed in vacuo,
and the residue was partitioned between H2O (300 mL) and
CH2Cl2 (200 mL) with stirring for 48 h. The layers were
separated, the aqueous layer was acidified with concd HCl
to pH 2 and extracted with CH2Cl2 (1 × 100 mL); the aque-
ous layer was basified with KOH pellets to pH 12 and ex-
tracted with CH2Cl2 (1 × 100 mL); the aqueous layer was
then neutralized with concentrated HCl and extracted with
CH2Cl2 (1 × 100). This process was repeated twice. The or-
ganic layers were combined, dried over (Na2SO4), and con-
centrated in vacuo to yield 0.24 g of a yellow residue, which
was chromatographed (2:1, hexanes:CH2Cl2) to yield
90.3 mg (69%) of 18 as a light yellow solid: mp 211 to
212°C (lit. (5) mp 211–213°C). 1H NMR (DMSO-d6) d
(ppm): 8.39 (t, 2H), 8.16 (d, 1H), 7.91 (br s, 1H), 7.62–7.45,
(m, 4H), 3.25 (s, 3H), 2.85 (s, 3H). 13C NMR (acetone-d6) d
(ppm): 126.7, 124.7, 124.5, 123.9, 123.4, 121.9, 118.9,
110.5, 15.6, 12.9.
6-n-Butyl-11-methyl-5H-benzo[b]carbazole (20)
To a stirred solution of quinone 7 (145.2 mg, 0.550 mmol)
at –60°C under N2 was added 1 equiv of n-BuLi (0.3 mL,
0.55 mmol, 2.1 M in hexanes). This was stirred for 15 min
while cooling the reaction to –100°C, at which time 1 equiv
of MeLi (0.4 mL, 0.55 mmol, 1.4 M in diethyl ether) was
added. The solution was then warmed to room temperature
overnight. The solvent was removed in vacuo, the residue
was dissolved in EtOH (60 mL) and treated with a NaBH4
pellet (1 pellet = 1.0 g, 27 mmol, crushed), and the solution
was refluxed. After refluxing for 15 h, another NaBH4 pellet
(1 pellet = 1.0 g, 27 mmol, crushed) was added to the refluxing
solution. The reaction mixture was refluxed for a total of
80 h. The reaction was cooled and the solvent was removed
by vacuum. The residue was partitioned between CH2Cl2
(200 mL) and H2O (100 mL) and the two phases were stirred
over 12 h. The layers were separated. The basic aqueous
layer was acidified to pH 2 with concd HCl and extracted
with CH2Cl2 (1 × 50 mL). The aqueous layer was neutral-
ized with NaOH pellets and extracted with CH2Cl2 (1 ×
50 mL). The aqueous layer was rebasified with NaOH pel-
lets to pH 12 and extracted with CH2Cl2 (1 × 50 mL). The
extraction process was repeated. The organic layers were
combined, washed with brine (2 × 25 mL), dried (Na2SO4),
and concentrated in vacuo to yield an orange oil. The oil was
chromatographed (3:1, hexanes:CH2Cl2) to give 113.7 mg
(72%) of 20 as a light yellow film. This compound could not
be crystallized. MS m/z: 287 (M+), 244 (100%), 229, 202,
120. HRMS calcd. m/z: 287.1674; found: m/z 287.1666. UV
(95% EtOH) ꢀmax (nm): 298 (5.80), 322 (5.31), 336 (5.21),
386 (5.12), 404 (5.17). IR (film) (cm–1): 3411, 2922, 2856,
1617, 1467, 1400, 1372, 1322, 1228, 1078, 878, 778, 739.
1H NMR d (ppm): 8.39 (s, 1H), 8.14 (d, 1H, J = 7.7 Hz),
8.08 (d, 1H, J = 8.4 Hz), 8.01 (d, 1H, J = 8.7 Hz), 7.80 (s,
1H), 7.51–7.32 (m, 3H), 7.20 (t, 1H), 3.67 (s, 3H), 3.25 (t,
2H, J = 7.8 Hz), 1.83–1.70 (m, 2H), 1.58–1.44 (m, 2H), 0.95
(t, 3H, J = 7.3 Hz). 13C NMR (CDCl3) d (ppm): 146.9,
142.2, 129.6, 127.5, 125.2, 123.0, 122.6, 121.4, 119.7, 117.2,
111.4, 110.6, 54.2, 32.4, 27.7, 23.6, 14.4.
11-n-Butyl-6-methyl-5H-benzo[b]carbazole (19)
To a stirred yellow solution of quinone 7 (119.6 mg,
0.450 mmol) in THF (20 mL) at –100°C under N2 was
added 1 equiv of MeLi (0.3 mL, 0.450 mmol, 1.4 M in
ether). The solution was stirred for 15 min at –100°C, then
1 equiv of n-BuLi (0.2 mL, 0.450 mmol, 2.0 M in hexanes)
was added, increasing the temperature to –95°C which was
recooled to –100°C immediately. The reaction mixture was
warmed to room temperature gradually overnight. The sol-
vent was removed by vacuum, the residue was dissolved in
95% EtOH (50 mL) to which a NaBH4 pellet (1 pellet =
1.0 g, 27 mmol, crushed) was added, and the solution was
heated to reflux. Another NaBH4 pellet was added after 24 h
of refluxing. The reaction mixture was refluxed for a total of
67 h, cooled to room temperature, and concentrated in vacuo.
The residue was partitioned between CH2Cl2 (200 mL) and
H2O (100 mL) and the two layers were stirred for 12 h. The
layers were separated. The originally basic aqueous layer
was acidified to pH 2 with concd HCl and extracted with
CH2Cl2 (1 × 50 mL). The aqueous acid layer was neutralized
with NaOH pellets and extracted with CH2Cl2 (1 × 50 mL).
The aqueous layer was rebasified with NaOH pellets to pH 12
and extracted with CH2Cl2 (1 × 50 mL). The entire extrac-
tion process was repeated. The organic layers were com-
bined, washed with brine (2 × 25 mL), dried (Na2SO4) and
concentrated in vacuo to give 156.7 mg of a brown oil. The
oil was then chromatographed (1:1, hexanes:CH2Cl2) to ob-
tain 61% (78.5 mg) of the major isomer as a film and 12%
6,11-Diphenyl-5H-benzo[b]carbazole (21)
To a stirred solution of quinone 7 (136.9 mg, 0.52 mmol)
in THF (25 mL) at –100°C was added 2 equiv of PhLi
(1.8 mL, 1.0 mmol, 1.8 M in hexanes). The reaction mixture
immediately turned dark and it was warmed to room temper-
ature overnight. In the morning the solution was golden yel-
low, the solvent was removed by rotary evaporation, and the
© 2001 NRC Canada

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Can. J. Chem. Vol. 79, 2001
residue was dissolved in EtOH (30 mL) and a NaBH4 pellet
was added (1 pellet = 1 g, 27 mmol, crushed). The reaction
was refluxed for a total of 80.5 h. The EtOH was then re-
moved by vacuum, the residue was partitioned between
CH2Cl2 (200 mL) and H2O (100 mL), and the two phases
were stirred for 12 h. The layers were separated and the ba-
sic aqueous layer was acidified to pH 2 with concd HCl and
extracted with CH2Cl2 (1 × 50 mL). The aqueous layer was
neutralized with NaOH pellets and extraction with CH2Cl2
(1 × 50 mL). The aqueous layer was rebasified with NaOH
pellets to pH 12 and extracted with CH2Cl2 (1 × 50 mL). The
extraction process was repeated. The organic layers were com-
bined, washed with brine (2 × 25 mL), dried (Na2SO4),
and concentrated in vacuo to give a brown oil which was
chromatographed (1:1, hexanes:CH2Cl2) to give 255 mg of a
yellow oil. The oil was then triturated with hexanes to give
132.7 mg (70%) of 21 as a tan film. MS m/z: 369 (100%,
M+), 316, 291, 183, 146, 105. HRMS calcd. m/z: 369.1518;
found m/z: 369.1516. UV (95% EtOH) ꢀmax (nm): 298 (3.80),
324 (3.26), 338 (3.25), 360 (2.94), 366 (3.02), 404 (3.27). IR
7.37 (td, 1H, J = 7.6 Hz, J = 1.6 Hz), 7.31–7.20 (m, 2H),
6.85 (s, 1H), 3.28 (s, 3H). 13C NMR (CDCl3) d (ppm): 153.3,
140.2, 131.9, 131.6, 131.3, 130.4, 130.1, 128.9, 128.1, 127.7,
126.1, 125.5, 124.2, 123.0, 122.3, 118.4, 111.0, 109.5, 14.5.
6-Methyl-11-phenyl-5H-benzo[b]carbazole (23)
To a stirred solution of quinone 7 (141.8 mg, 0.540 mmol)
at –78°C under N2 was added 1 equiv of MeLi (0.4 mL,
0.540 mmol, 1.4 M in ether). This was stirred for 20 min
while the solution was cooled to –100°C. Then 1 equiv of
PhLi (0.3 mL, 0.540 mmol, 1.8 M hexane) was added, and
the solution was warmed gradually to room temperature
overnight. The solvent was removed by rotary evaporation,
and the residue was dissolved in EtOH (50 mL). The
ethanolic solution was treated with one NaBH4 pellet (1 pel-
let = 1 g, 27 mmol, crushed) and refluxed, another NaBH4
pellet was added after 48 h of reflux. The reaction was
refluxed for a total of 72 h. The reaction was cooled to room
temperature, and the solvent was removed in vacuo. The res-
idue was partitioned between CH2Cl2 (200 mL) and H2O
(100 mL) and the two phases were stirred for 12 h. The lay-
ers were separated. The basic aqueous layer was acidified to
pH 2 with concd HCl and extracted with CH2Cl2 (1 × 50 mL).
The aqueous layer was neutralized with NaOH pellets and
extracted with CH2Cl2 (1 × 50 mL). The aqueous layer was
rebasified with NaOH pellets to pH 12 and extracted with
CH2Cl2 (1 × 50 mL). The extraction process was repeated.
The organic layers were combined, washed with brine (2 ×
25 mL), dried (Na2SO4), and concentrated in vacuo to give a
brown oil (>100%). The oil was chromatographed to give
78.4 mg (47%) of 23 and 30.5 mg (18%) of 22 both as films
for an overall yield of 65%. 23: MS m/z: 307 (M+), 231
(100%), 202, 146, 116. HRMS calcd. m/z: 307.1361; found
m/z: 307.1357. UV (95% EtOH) ꢀmax (nm): 298 (5.87), 320
(5.51), 334 (5.51), 380 (5.32), 400 (5.38). IR (film) (cm–1):
3733, 2356, 1215, 1152, 638, 503. 1H NMR d (ppm): 8.40 (s,
1H), 8.14, (d, 1H, J = 7.7 Hz), 8.04 (d, 1H, J = 8.7 Hz), 8.01
(d, 1H, J = 8.4 Hz), 7.70 (d, 1H, J = 8.7 Hz), 7.62–7.22 (m,
8H), 7.20 (td, 1H, J = 1.7 Hz, J = 6.3 Hz), 2.91 (s, 3H). 13C
NMR (CDCl3) d (ppm): 147.8, 131.1, 129.9, 129.6, 128.4,
127.9, 127.6, 125.6, 125.5, 124.7, 123.5, 123.1, 121.8, 120.2,
119.9, 111.0, 13.5.
1
(film) (cm–1): 3756, 2992, 2356, 1206, 1150, 639, 500. H
NMR (CDCl3) d (ppm): 8.22 (d, 1H, J = 6.8 Hz), 7.95 (s,
1H), 7.93 (d, 1H, J = 8.4 Hz), 7.80–7.62 (m, 6H), 7.58–7.26
(m, 6H), 7.02 (dd, 3H, J> = 1.2 Hz, J>> = 6.3 Hz). 13C NMR
(CDCl3) d (ppm): 139.4, 131.2, 130.5, 129.6, 129.2, 128.4,
126.9, 126.1, 124.7, 122.8, 119.4.
11-Methyl-6-phenyl-5H-benzo[b]carbazole (22)
To a stirred solution of quinone 7 (120.7 mg, 0.460 mmol)
at –78°C under N2 in THF (15 mL) was added 1 equiv of
PhLi (0.3 mL, 0.460 mmol, 1.8 M hexane). This was stirred
for 20 min while the solution was cooled to –100°C. At this
time 1 equiv of MeLi (0.3 mL, 0.460 mmol, 1.4 M in ether)
was added, and the solution was warmed gradually to room
temperature overnight. The solvent was then removed by rotary
evaporation and the residue was dissolved in EtOH (30 mL).
The ethanolic solution was treated with NaBH4, 1 pellet was
added (1 pellet = 1 g, 27 mmol, crushed) and refluxed, an-
other NaBH4 pellet was added after 24 h of reflux. The reac-
tion was refluxed for a total of 82 h and was cooled to room
temperature and the solvent was removed in vacuo. The resi-
due was partitioned between CH2Cl2 (200 mL) and H2O
(100 mL) and stirred over 12 h. The layers were separated.
The basic aqueous layer was acidified to pH 2 with concd
HCl and extracted with CH2Cl2 (1 × 50 mL). The aqueous
layer was neutralized with NaOH pellets and extracted with
CH2Cl2 (1 × 50 mL). The aqueous layer was rebasified with
NaOH pellets to pH 12 and extracted with CH2Cl2 (1 ×
50 mL). The extraction process was repeated. The organic
layers were combined, washed with brine (2 × 25 mL), dried
(Na2SO4) and concentrated in vacuo to give a brown oil
(>100%). The oil was chromatographed to give 51.8 mg
(37%) of 22 and 31.2 mg (22%) of 23, both as films for an
overall yield of 59%. The major isomer was crystallized
from pentane–CHCl3; (major 22) mp 231–233°C. MS m/z:
307 (100%, M+), 293, 230, 146. HRMS calcd. m/z: 307.1361;
found m/z: 307.1358. UV (95% EtOH) ꢀmax (nm): 298 (4.24),
324 (3.72), 338 (3.72), 404 (3.78). IR (film) (cm–1): 3451,
3057, 2360, 1609, 1484, 1488, 1391, 1344, 1315, 1251, 1258,
6-Methyl-5H-benzo[b]carbazole (24)
To a stirred solution of quinone 7 (538.8 mg, 2.18 mmol)
in THF (150 mL) under N2 at –100°C was added MeLi
(2.2 mL, 2.18 mmol, 1.0 M in ether). The solution immediately
turned deep purple. After stirring at –100°C for 15 min,
1 equiv of Super Hydride (LiBHEt3) (2.2 mL, 2.18 mmol,
1.0 M in THF) was added and the solution was warmed to
room temperature overnight. The solvent was removed by
vacuum; the residue was dissolved in EtOH (275 mL) to
which was added a NaBH4 pellet (1 pellet = 1.0 g, 27 mmol),
and the solution was heated to reflux. After refluxing for 6 h
another NaBH4 pellet was added; additional NaBH4 pellets
were added every 24 h. The reaction mixture was refluxed
for a total of 72 h, at which time the solvent was removed by
vacuum to give an orange oil. The orange oil was treated
with CHCl3 and the fine insoluble solid was removed by fil-
tration to give 0.56 g of an orange oil, which was chromato-
graphed (1:1, hexanes:CH2Cl2) to yield 285 mg (56%) of 24
1
1144, 1028, 907, 746, 700, 667. H NMR (CDCl3) d (ppm):
7.81 (m, 1H), 7.74 (d, 1H, J = 8.4 Hz), 7.63–7.50 (m, 7H),
© 2001 NRC Canada

Fraser and Gribble
1521
as a light yellow solid: mp 209–212°C (lit. (9) mp 210 to
211°C). GC–MS m/z: 231 (M+, 100%), 216, 202, 115, 88,
44. UV (95% EtOH) ꢀmax (nm) 331, 320, 298, 285, 272, 234,
ddd, J = 11.5 Hz, J = 9.6 Hz, J = 8.7 Hz), 3.51 (1H, dd, J =
8.7 Hz, J = 16.1 Hz), 3.29 (1H, dd, J = 9.9 Hz, J = 16.2 Hz),
2.85 (1H, s). 13C NMR (CDCl3) d (ppm): 171.8, 132.9, 130.2,
128.7, 128.6, 128.2, 125.1, 124.5, 123.6, 117.0, 30.0, 29.9,
23.0.
1
203. H NMR (CDCl3) d (ppm): 8.46 (1H, s), 8.21 (1H, d,
J = 7.5 Hz), 8.14 (1H, d, J = 8.7 Hz), 8.08 (1H, d, J =
8.1 Hz), 7.85 (1H, s), 7.69–7.41 (4H, m), 7.28 (1H, td, J =
7.6 Hz, J = 1.6 Hz), 2.85 (3H, s). 13C NMR (CDCl3) d
(ppm): 142.3, 138.6, 131.3, 129.5, 129.0, 127.5, 125.3, 125.2,
124.0, 123.1, 122.7, 121.4, 119.8, 117.0, 111.6, 110.6, 13.0.
Acknowledgements
This work was supported in part by the Donors of the Pe-
troleum Research Fund (PRF), administered by the Ameri-
can Chemical Society. We also thank Wyeth–Ayerst for their
support. H.L.F. acknowledges receipt of an Arthur Dunhan
Holmes 1906 Graduate Fellowship in Nutritional Chemistry.
11,11a-Dihydroindolo[1,2-b]isoquinoline-6,11-
hydroquinone (25)
An ethanol solution of quinone 7 under N2 (108.6 mg,
0.410 mmol) was treated with NaBH4 (1 pellet = 1 g,
27 mmol, crushed) and refluxed for 24 h, then stirred at
room temperature for 24 h. The EtOH was removed by vacuum
and the residue was partitioned between CH2Cl2 (200 mL)
and H2O (100 mL) and the two phases were stirred for 12 h.
The layers were separated. The basic aqueous layer was
acidified to pH 2 with concd HCl and extracted with CH2Cl2
(1 × 50 mL). The aqueous layer was neutralized with NaOH
pellets and extracted with CH2Cl2 (1 × 50 mL). The aqueous
layer was rebasified with NaOH pellets to pH 12 and ex-
tracted with CH2Cl2 (1 × 50 mL). The extraction process
was repeated. The organic layers were combined, washed
with brine (2 × 25 mL), dried (Na2SO4), and concentrated in
vacuo. The resulting residue was chromatographed to give
94.9 mg (86%) of the indoline alcohol 25 (89% yield with
recovered starting material): mp 244–247°C. MS m/z: 251
(M+), 234, 204, 134, 118 (100%), 105, 91, 77. HRMS calcd.
m/z: 251.0946; found m/z: 251.0953. UV (95% EtOH) ꢀmax
(nm): 258, 274, 284, 304, 364. UV (95% EtOH + HCl) ꢀmax
(nm): 254, 304, 364. IR (film) (cm–1): 2918, 2357, 1480,
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1
1211, 1150, 633, 501. H NMR (acetone-d6) d (ppm): 8.31
(1H, d, J = 8.0 Hz), 8.08 (1H, d, J = 7.5 Hz), 7.79 (1H, d,
J = 7.8 Hz), 7.66 (1H, t, J = 7.6 Hz), 7.50 (1H, t, J =
7.6 Hz), 7.34 (1H, d, J = 6.8 Hz), 7.26 (1H, t, J = 7.8 Hz),
7.08 (1H, t, J = 7.5 Hz), 5.05 (1H, d, J = 11.5 Hz), 4.34 (1H,
© 2001 NRC Canada

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