Synthesis of a new pyrido[3,2- b ]carbazole as an ellipticine-makaluvamine hybrid

Article abstract of DOI:10.1055/s-0030-1260015

The first synthesis of pyrido[3,2-b]carbazole as an ellipticine- makaluvamine hybrid in 13 steps and 2% overall yield from commercially available 2,5-dimethoxyaniline is described. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260015

1616
PAPER
Synthesis of a New Pyrido[3,2-b]carbazole as an Ellipticine–Makaluvamine
Hybrid
Synthesis of
a
é
N
ew Pyrid
b
b
]carba
a
zole stien Bouclé, Jérôme Guillard*
UMR CNRS 6239 Génétique Immunothérapie Chimie et Cancer UFR des Sciences Pharmaceutiques,
Université François Rabelais de Tours, 31 avenue Monge, 37200 Tours, France
Fax +33(2)47367229; E-mail: guillard@univ-tours.fr
Received 8 February 2011; revised 14 March 2011
N
O
Abstract: The first synthesis of pyrido[3,2-b]carbazole as an ellip-
ticine–makaluvamine hybrid in 13 steps and 2% overall yield from
commercially available 2,5-dimethoxyaniline is described.
N
N
O
N
H2N
Key words: heterocycles, Heck reaction, ring closure, homoge-
neous catalysis, polycycles
N
H
H
N
makaluvamine A
ellipticine
N
Me
Ellipticine, a member of the pyrido[4,3-b]carbazole alka-
loid family, first isolated in 1959 from the leaves of
Ochrosia elliptica plant has been shown to possess anti-
cancer activities against various tumors.1 The main reason
for the interest in ellipticine and analogues is its high effi-
ciency against several types of cancer, limited toxic side
effects, and complete lack of hematological toxicity.2 El-
lipticine is a DNA intercalating agent, and its high DNA
binding affinity is thought to be mainly responsible for its
pharmacological properties.3–7 As a consequence ellipti-
cine has proven to be a popular synthetic target, and a
wide variety of routes have been reported.8–13 Similarly,
the structurally related aryl- and heteroaryl-annulated car-
bazoles have also received considerable synthetic atten-
tion.14–18 Despite the great synthetic work developed
around ellipticine, very little attention has been focused
on its fusion with other biologically important molecules
such as makaluvamine derivatives, which could lead to
promising biological activities (Figure 1). The aim of the
work reported herein was the synthesis of a pyrido[3,2-
b]carbazole 1, which can be seen as an ellipticine-makalu-
vamine hybrid.
1
Figure 1 Structure of ellipticine, makaluvamine A, and pyrido[3,2-
b]carbazole 1
C-6, oxidation with the [bis(trifluoroacetoxy)iodo]ben-
zene (PIFA) should afford the desired quinone that should
be readily converted into carbazole 1 (Scheme 1).
The required aminotetrahydroquinoline 3 was prepared in
four steps from commercially available 2,5-dimethoxy-
aniline (4) (Scheme 2). The first step involves an N-alky-
lation of aniline 4 with 1-chloro-3-methylbut-2-ene in
anhydrous pyridine at room temperature for three days to
provide the amine 5 (70%). Cyclization of compound 5
was performed in excellent yield using concentrated sul-
furic acid leading to bicycle 6, which upon treatment with
a mixture of acetic anhydride and pyridine (1:2) furnished
the N-acetyl derivative 7.23 Nitration of 7 with extra pure
nitric acid in dichloromethane afforded the nitro deriva-
tive 8 which was reduced to aminotetrahydroquinoline 3
by classic hydrogenation.
The next N-arylation step was carried out by treatment of
6-aminotetrahydroquinoline 3 with 2-bromoiodobenzene
under Hartwig–Buchwald catalytic conditions to afford
the diarylamine 10 in satisfactory yield. Compound 10
was then efficiently cyclized to the corresponding pyri-
do[3,2-b]carbazole 2 by treatment with palladium acetate
Our approach for the synthesis of compound 1 involves a
Pd-catalyzed Hartwig–Buchwald coupling between the
aminotetrahydroquinoline 3 and 2-bromoiodobenzene
followed by a Heck reaction to provide the carbazole
ring.19–22 After introduction of the ethylazido side chain at
OMe Ac
N
OMe Ac
N
Br
I
N
N
+
N
N
H2N
Me
O
Me
OMe
OMe
2
3
1
Scheme 1 Retrosynthetic access to carbazole 1
SYNTHESIS 2011, No. 10, pp 1616–1620
x
x.
x
x
.
2
0
1
1
Advanced online publication: 19.04.2011
DOI: 10.1055/s-0030-1260015; Art ID: T18411SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of a New Pyrido[3,2-b]carbazole
1617
In conclusion, we have accomplished the synthesis of py-
rido[3,2-b]carbazole 1 using a Hartwig–Buchwald cou-
pling and Heck reaction as the key steps. The synthetic
methodology developed in this work will be extended to
access other interesting ellipticine analogues.
OMe
OMe
OMe
OMe
H
H
N
NH2
N
Cl
H2SO4
98%
Ac2O
pyridine
88%
pyridine
70%
OMe
OMe
4
5
6
All reactions requiring anhydrous conditions were conducted in
flame-dried apparatus under an argon atmosphere. THF was freshly
distilled from benzophenone-sodium. All reagents and starting ma-
terials were purchased from commercial sources and used as re-
ceived. All lithiation were carried out using Sigma-Aldrich LDA
2.0 M in THF–heptane–ethylbenzene. Analytical TLC analyses
were carried out on silica gel F254 plates. Visualization was achieved
by UV light (254 nm). Flash column chromatography was carried
using Sigma-Aldrich Versaflash silica gel (particle size 20–45 mm).
Melting points were measured on a Büchi B-540 capillary melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded in CDCl3 using a Bruker Avance 300 FT spectrometer at
r.t. (operating frequencies: 1H, 300.13 MHz; 13C, 75.47 MHz). The
chemical shifts (d) for all compounds are listed in parts per million
downfield from TMS using the NMR solvent as an internal refer-
ence. The reference values used for CDCl3 were 7.26 and 77.00 ppm
for 1H and 13C NMR spectra, respectively. Multiplicities are given
as: s (singlet), br s (broad singlet), d (doublet), t (triplet), dd (doublet
of doublets), td (triplet of doublets), or m (multiplet). Low-resolu-
tion mass (MS) were recorded on a Shimadzu GCMS-QP 2010 Gas
Chromatograph Mass Spectrometer and reported in units of mass to
charge (m/z). The mode of ionization used was electron-impact (EI,
70 eV) or chemical ionization (CI, methane reagent gas).
OMe Ac
OMe Ac
N
N
HNO3
H2, Pd/C
3
CH2Cl2
92%
Et2OH–THF
87%
O2N
OMe
OMe
7
8
Scheme 2 Synthesis of aminotetrahydroquinoline 3
Br
OMe Ac
I
Pd(OAc)2
HBF4⋅PCy3
N
Br
K2CO3, 1,4dioxane
3
2
Pd2dba3
Xant-Phos
sealed tube
74%
K2CO3, DMA
160 °C
sealed tube
80%
N
H
OMe
10
Scheme 3 Synthesis of pyrido[3,2-b]carbazole 2
as catalyst, PCy3 as optimal ligand, and potassium carbon-
ate as base in N,N-dimethylacetamide (DMA) at 160 °C
(Scheme 3).24
2,5-Dimethoxy-N-(3-methylbut-2-enyl)benzenamine (5)
To a solution of 2,5-dimethoxyaniline (4; 1.00 g, 6.50 mmol) in an-
hyd pyridine (10 mL) was added 1-chloro-3-methylbut-2-ene (0.88
mL, 7.80 mmol). The mixture was stirred and heated at reflux for 3
days. A solution of aq 1 M HCl (70 mL) was then added and the
product was extracted with EtOAc (3 × 20 mL). The combined or-
Treatment of 2 with methyl iodide in the presence of sodi-
um hydride in N,N-dimethylformamide led quantitatively
to the N-methyl derivative 11. Further chlorination
through deprotonation with LDA at –78 °C followed by
quenching of the resultant enolate with benzenesulfonyl ganic layers were washed with aq 1 M HCl (2 × 20 mL) and brine
chloride afforded chloroamide 12 (40%).25 Chlorine dis-
(30 mL), and dried (MgSO4). The solvent was removed under re-
duced pressure and the residue was purified by flash chromatogra-
phy (cyclohexane–EtOAc, 7:3) to give compound 5 as a yellow oil;
yield: 1.00 g (70%).
placement with sodium azide in N,N-dimethylformamide
afforded the desired azido derivative, the amide group of
which was reduced using BH3·THF complex to yield
compound 13 in 62% over two steps. Final oxidation with
1H NMR (300 MHz, CDCl3): d = 1.76 (s, 3 H, CH3), 1.80 (s, 3 H,
CH3), 3.72 (d, J = 6.0 Hz, 2 H, CH2), 3.80 (s, 3 H, OCH3), 3.83 (s,
PIFA led to the desired quinone, which was further re-
3 H, OCH3), 4.22 (br s, 1 H, NH), 5.40 (m, 1 H, C=CH), 6.20 (dd,
duced by catalytic hydrogenation on Pd/C to give the de-
sired imine 1 (Scheme 4).
J = 8.7, 2.7 Hz, 1 Harom), 6.28 (d, J = 2.7 Hz, 1 Harom), 6.70 (d,
J = 8.7 Hz, 1 Harom).
O
OMe Ac
N
OMe
OMe
Cl
N
MeI
PhSO2Cl
2
NaH, DMF
100%
LDA, THF
40%
N
N
OMe
Me
Me
11
12
N3
OMe
N
1) PIFA
MeOH, H2O
1
1) NaN3, DMF
2) BH3⋅THF
2) H2, Pd/C
N
THF
OMe
Me
13
35% (2 steps)
62% (2 steps)
Scheme 4 Synthesis of pyrido[3,2-b]carbazole 1
Synthesis 2011, No. 10, 1616–1620 © Thieme Stuttgart · New York

1618
S. Bouclé, J. Guillard
PAPER
13C NMR (75 MHz, CDCl3): d = 18.0 (CH3), 25.8 (CH3), 41.6
(CH2), 55.5 (OCH3), 55.9 (OCH3), 98.2 (CHarom), 98.5 (CHarom),
109.7 (CHarom), 121.7 (CHarom), 135.4 (C), 139.4 (C), 141.6 (C),
154.8 (C).
layers were successively washed with aq NaHCO3 (50 mL) and
brine (30 mL), and dried (MgSO4). The solvent was then removed
under reduced pressure. The residue was purified by flash chroma-
tography (cyclohexane–EtOAc, 8:2) to give compound 8 as a yel-
low solid; yield: 2.15 g (92%); mp 120–124 °C.
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 3 H, CH3), 1.46 (s, 3 H,
CH3), 1.77 (m, 2 H, CH2), 2.02 (s, 3 H, COCH3), 3.12 (m, 1 H,
CHaHb), 3.81 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 4.40 (m, 1 H,
CHaHb), 7.29 (s, 1 Harom).
MS (EI): m/z = 138 ([M – CH2CHC(CH3)2 – CH3]+, 100%), 221
([M]+, 58%), 206 ([M – CH3]+, 58%).
Anal. Calcd for C13H19NO2 (221.30): C, 70.59; H, 8.65; N, 6.33.
Found: C, 70.21; H, 8.71; N, 6.21.
5,8-Dimethoxy-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (6)
A solution of 96% H2SO4 (5 mL) was cooled down to 0 °C. Then,
the amine 5 (1.50 g, 6.78 mmol) was added portionwise over a 5 min
period. The mixture was stirred for 20 min under continued cooling
and basified using aq 25% NaOH until pH 9 and extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed with
brine (50 mL), dried (MgSO4), and the solvent was removed under
reduced pressure. The residue was purified by flash chromatogra-
phy (cyclohexane–EtOAc, 9:1) to give compound 6 as a brown oil;
yield: 1.45 g (97%).
1H NMR (300 MHz, CDCl3): d = 1.45 (s, 6 H, 2 × CH3), 1.82 (m, 2
H, CH2), 3.26 (m, 2 H, CH2), 3.81 (s, 3 H, OCH3), 3.83 (s, 3 H,
OCH3), 4.50 (br s, 1 H, NH), 6.20 (d, J = 8.7 Hz, 1 Harom), 6.0 (d,
J = 8.7 Hz, 1 Harom).
13C NMR (75 MHz, CDCl3): d = 22.2 (COCH3), 27.9 (CH3), 29.4
(CH3), 35.7 (C), 41.4 (CH2), 41.9 (CH2), 56.2 (CH3), 62.4 (CH3),
106.4 (CHarom), 134.2 (C), 136.2 (C), 140.7 (C), 147.7 (C), 148.4
(C), 171.3 (C=O).
MS (EI): m/z = 266 ([M – COCH3]+, 100%), 251 ([M – COCH3 –
CH3]+, 90%), 277 ([M – OCH3]+, 79%), 308 ([M]+, 50%).
Anal. Calcd for C15H20N2O2 (308.34): C, 58.43; H, 6.54; N, 9.09.
Found: C, 58.31; H, 6.48; N, 8.98.
1-(6-Amino-5,8-dimethoxy-4,4-dimethyl-3,4-dihydroquinolin-
1(2H)-yl)ethanone (3)
A solution of 8 (1.00 g, 3.20 mmol) in mixture of EtOH–THF (1:1,
20 mL) was hydrogenated (15 psi) over Pd/C (200 mg) for 18 h at
r.t. The catalyst was filtered on Celite and the filtrate concentrated
in vacuo. The residue was purified by flash chromatography (cyclo-
hexane–EtOAc, 6:4) to give compound 3 as a brown solid; yield:
780 mg (87%); mp 138–140 °C.
13C NMR (75 MHz, CDCl3): d = 29.2 (2 × CH3), 32.1 (C), 38.0
(CH2), 41.1 (CH2), 55.3 (OCH3), 55.8 (OCH3), 98.5 (CHarom), 107.0
(CHarom), 118.7 (C), 135.7 (C), 141.2 (C), 153.9 (C).
MS (EI): m/z = 206 ([M – CH3]+, 100%), 221 ([M]+, 50%), 176 ([M
1H NMR (300 MHz, CDCl3): d = 1.29 (s, 3 H, CH3), 1.42 (s, 3 H,
CH3), 1.74 (m, 2 H, CH2), 1.93 (s, 3 H, COCH3), 3.01 (m, 1 H,
CHaHb), 3.73 (s, 6 H, 2 × OCH3), 3.52 (m, 1 H, CHaHb), 6.30 (s, 1
– 3 × CH3]+, 18%).
Anal. Calcd for C13H19NO2 (221.30): C, 70.56; H, 8.65; N, 6.33.
Found: C, 70.65; H, 8.75; N, 6.21.
Harom).
13C NMR (75 MHz, CDCl3): d = 21.7 (COCH3), 27.5 (CH3), 30.0
(CH3), 35.2 (C), 40.5 (CH2), 41.3 (CH2), 55.6 (OCH3), 60.4 (OCH3),
98.4 (CH), 119.6 (C), 135.1 (C), 138.8 (C), 139.6 (C), 149.9 (C),
172.2 (C=O).
1-(5,8-Dimethoxy-4,4-dimethyl-3,4-dihydroquinolin-1(2H)-
yl)ethanone (7)
To a solution of 6 (1.00 g, 4.50 mmol) in anhyd pyridine (1.82 mL,
22.60 mmol) under argon atmosphere, was added dropwise Ac2O
(7.69 mL, 81.40 mmol). The mixture was stirred for 18 h at r.t. A
solution of aq 1 M HCl (70 mL) was then added and the product was
extracted with EtOAc (3 × 30 mL). The combined organic layers
were washed several times with aq 1 M HCl and finally with brine
(30 mL). The extract was dried (MgSO4) and the solvent was re-
moved under reduced pressure. The residue was purified by flash
chromatography (cyclohexane–EtOAc, 8:2) to give compound 7 as
a brown solid; yield: 1.04 g (88%); mp 82–85 °C.
1H NMR (300 MHz, CDCl3): d = 1.35 (s, 3 H, CH3), 1.41 (s, 3 H,
CH3), 1.76 (m, 2 H, CH2), 1.98 (s, 3 H, COCH3), 2.90 (br s, 1 H,
CHaHb), 3.76 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 4.64 (br s, 1 H,
CHaHb), 6.73 (d, J = 3.3 Hz, 2 Harom).
MS (EI): m/z = 278 ([M]+, 100%), 221 ([M – CH3 – COCH3]+,
68%), 263 ([M – CH3]+, 39%).
Anal. Calcd for C15H22N2O3 (221.30): C, 64.73; H, 7.97; N, 10.06.
Found: C, 64.81; H, 8.01; N, 10.04.
1-(6-(2-Bromophenylamino)-5,8-dimethoxy-4,4-dimethyl-3,4-
dihydroquinolin-1(2H)-yl)ethanone (10)
To a solution of 3 (300 mg, 1.08 mmol) in anhyd 1,4-dioxane (8
mL) in a resealable Schlenk tube under argon atmosphere were add-
ed successively 2-bromoiodobenzene (0.21 ml, 1.62 mmol), Xant-
PHOS (25 mg, 0.04 mmol), and K2CO3 (2.98 g, 21.58 mmol). The
flask was capped with a rubber septum and degassed with argon.
Pd2dba3 (19 mg, 0.02 mmol) was then added and the tube was sealed
and the contents were stirred at reflux for 18 h. The mixture was
then diluted with EtOAc (20 mL), filtered trough a plug of Celite,
and the solvent was evaporated under reduced pressure. The residue
was purified by flash chromatography (cyclohexane–EtOAc, 6:4) to
give compound 10 as a brown solid; yield: 340 mg (74%); mp 135–
137 °C.
13C NMR (75 MHz, CDCl3): d = 22.1 (NCH3), 28.3 (CH3), 28.6
(CH3), 34.6 (CH2), 41.4 (C), 43.0 (CH2), 55.6 (OCH3), 55.9 (OCH3),
109.1 (CH), 109.6 (CH), 129.2 (C), 130.0 (C), 147.0 (C), 152.9 (C),
172.1 (C=O).
MS (EI): m/z = 232 ([M – OCH3]+, 100%), 206 ([M – COCH3 + 1]+,
91%), 263 ([M]+, 38%).
1H NMR (300 MHz, CDCl3): d = 1.40 (s, 3 H, CH3), 1.49 (s, 3 H,
CH3), 1.74 (m, 1 H, CHaHb), 1.82 (m, 1 H, CHaHb), 2.04 (s, 3 H,
NCOCH3), 3.02 (br s, 1 H, CHcHd), 3.74 (s, 3 H, OCH3), 3.75 (s, 3
H, OCH3), 4.60 (br s, 1 H, CHcHd), 6.31 (s, 1 Harom), 6.79 (m, 1
Anal. Calcd for C15H21NO3 (263.34): C, 68.42; H, 8.04; N, 5.32.
Found: C, 69.05; H, 8.31; N, 5.21.
1-(5,8-Dimethoxy-4,4-dimethyl-6-nitro-3,4-dihydroquinolin-
1(2H)-yl)ethanone (8)
Harom), 6.83 (s, 1 Harom), 7.26 (m, 2 Harom), 7.57 (d, J = 9 Hz, 1 H,
NH).
A solution of 7 (2.00 g, 9.00 mmol) in anhyd CH2Cl2 (20 mL) was
cooled down to 0 °C under argon atmosphere. Extra pure HNO3
(0.48 mL, 10.80 mmol) was added carefully and the mixture was al-
lowed to stir at 0 °C for 2 h before hydrolysis over ice. The product
was extracted with EtOAc (3 × 20 mL) and the combined organic
13C NMR (75 MHz, CDCl3): d = 21.9 (COCH3), 28.0 (CH3), 29.9
(CH3), 35.0, (C), 40.8 (CH2), 41.7 (CH2), 55.9 (OCH3), 61.1
(OCH3), 102.6 (C), 112.4 (C), 115.5 (CH), 121.1 (CH), 123.5 (C),
Synthesis 2011, No. 10, 1616–1620 © Thieme Stuttgart · New York

PAPER
Synthesis of a New Pyrido[3,2-b]carbazole
1619
128.3 (CH), 133.1 (CH), 133.3 (C), 135.1 (C), 140.8 (CH), 144.2
(C), 149.5 (C), 171.8 (C=O).
2-Chloro-1-(5,11-dimethoxy-4,4,6-trimethyl-3,4-dihydro-2H-
pyrido[3,2-b]carbazol-1(6H)-yl)ethanone (12)
To a stirred solution of 11 (100 mg, 0.27 mmol) in THF (5 mL)
cooled at –10 °C under an argon atmosphere was added LDA (0.15
mL, 1.1 equiv, 0.3 mmol, 2.0 M in THF–heptane–ethylbenzene).
After completion of the addition, the mixture was stirred for 30 min
at –10 °C, and then PhSO2Cl (42 mL, 0.636 mmol) was added. The
reaction mixture was stirred at –10 °C for 2 h and allowed to warm
slowly to r.t. before adding dropwise to a sat. aq NH4Cl (50 mL) and
extracted with EtOAc (3 × 40 mL). The combined organic layers
were dried (MgSO4) and concentrated in vacuo to afford the crude
product, which were purified by column chromatography (cyclo-
hexane–EtOAc, 8:2) to give compound 12 as a brown solid; yield:
210 mg (99%); mp 186–188 °C.
1H NMR (300 MHz, CDCl3): d = 1.46 (s, 3 H, CH3), 1.65 (s, 3 H,
CH3), 1.80 (m, 1 H, CHaHb), 1.96 (m, 1 H, CHaHb), 3.30 (m, 1 H,
CHcHd), 3.83 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 4.14 (s, 3 H,
NCH3), 4.15 (d, J = 15 Hz, 1 H, CHeHf), 1.96 (d, J = 15 Hz, 1 H,
CHeHf), 3.30 (m, 1 H, CHcHd), 7.28 (m, 1 Harom), 7.43 (m, 1 Harom),
7.53 (m, 1 Harom), 8.22 (m, 1 Harom).
MS (EI): m/z = 434 ([M, Br81]+, 100%), 432 ([M, Br79]+, 100%), 419
([M – CH3, Br81]+, 62%), 417 ([M – CH3, Br79]+, 60%), 377 ([M –
COCH3 – CH3 + H, Br81]+, 60%), 375 ([M – COCH3 – CH3 + H,
Br79]+, 60%).
Anal. Calcd for C21H25BrN2O3 (433.35): C, 58.21; H, 5.82; N, 6.46.
Found: C, 58.36; H, 5.79; N, 6.47.
1-(5,11-Dimethoxy-4,4-dimethyl-3,4-dihydro-2H-pyrido[3,2-
b]carbazol-1(6H)-yl)ethanone (2)
Crushed K2CO3 (96 mg, 0.69 mmol), compound 10 (100 mg, 0.23
mmol), Pd(OAc)2 (15 mg, 0.07 mmol), and PCy3/HBF4 (52 mg,
0.14 mmol) were placed in a 10 mL screw-cap vial equipped with a
magnetic stir bar. The vial was purged with argon and anhyd de-
gassed DMA (8 mL) was added. The reaction mixture was then
heated at 130 °C for 24 h. The mixture was then diluted with EtOAc
(15 mL) and filtered trough a plug of Celite. The organic layer was
washed with brine (2 × 10 mL), dried (MgSO4), and the solvent was
removed under reduced pressure. The crude product was purified by
flash chromatography (cyclohexane–EtOAc, 7:3) to give com-
pound 2 as a brown solid; yield: 57 mg (70%); mp 280–283 °C.
1H NMR (300 MHz, CDCl3): d = 1.42 (s, 3 H, CH3), 1.59 (s, 3 H,
CH3), 1.79 (m, 1 H, CHaHb), 1.90 (m, 1 H, CHaHb), 2.10 (s, 3 H,
NCOCH3), 3.14 (m, 1 H, CHcHd), 3.86 (s, 3 H, OCH3), 4.03 (s, 3 H,
OCH3), 4.74 (m, 1 H, CHcHd), 7.25 (m, 1 Harom), 7.44 (m, 2 Harom),
8.25 (m, 1 Harom), 8.47 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 26.9 (CH3), 30.4 (CH3), 31.5 (C),
35.8 (COCH3), 40.8 (CH2), 41.5 (CH2), 42.5 (CH2), 60.9 (OCH3),
63.6 (OCH3), 105.8 (C), 108.9 (CH), 116.5 (C), 119.9 (CH), 121.4
(C), 122.3 (C), 122.5 (CH), 126.1 (CH), 133.7 (C), 141.6 (C), 142.1
(C), 145.0 (C), 167.9 (C=O).
MS (CI): m/z = 402 ([M + 1]+, 100%).
Anal. Calcd for C22H25ClN2O3 (400.91): C, 65.91; H, 6.29; N, 6.99.
Found: C, 66.05; H, 6.33; N, 6.89.
13C NMR (75 MHz, CDCl3): d = 21.9 (COCH3), 27.7 (CH3), 30.2
(CH3), 35.4 (C), 40.8 (CH2), 41.1 (CH2), 60.6 (OCH3), 61.4 (OCH3),
110.7 (CH), 116.2 (C), 120.1 (CH), 122.4 (C), 122.7 (CH), 124.0
(C), 125.9 (CH), 131.7 (C), 133.0 (C), 139.4 (C), 139.9 (C), 145.8
(C), 172.6 (C=O).
1-(2-Azidoethyl)-5,11-dimethoxy-4,4,6-trimethyl-2,3,4,6-tet-
rahydro-1H-pyrido[3,2-b]carbazole (13)
Under an inert atmosphere, NaN3 (105 mg, 1.8 mmol) was added to
a solution of 12 (40 mg, 0.10 mmol) in anhyd DMF (3 mL). After
completion of the addition, the mixture was heated to reflux for 2 h.
After hydrolysis with sat. aq NaHCO3 (30 mL), the product was ex-
tracted with EtOAc (3 × 20 mL), and the combined organic layers
were washed with brine (30 mL), dried (MgSO4), and the solvent
was removed under reduced pressure to afford the desired azido
compound, which was used without further purification.
MS (EI): m/z = 321 ([M – OCH3]+, 100%), 352 ([M]+, 44%).
Anal. Calcd for C21H24N2O3 (352.44): C, 71.57; H, 6.86; N, 7.95.
Found: C, 71.32; H, 6.91; N, 7.90.
1-(5,11-Dimethoxy-4,4,6-trimethyl-3,4-dihydro-2H-pyrido[3,2-
b]carbazol-1(6H)-yl)ethanone (11)
Under an inert atmosphere, a solution of 2 (200 mg, 0.57 mmol) in
anhyd DMF (10 mL) was cooled to 0 °C in an ice bath. NaH (30 mg,
0.79 mmol) was then added portionwise and the mixture was stirred
for 30 min and then MeI (0.05 mL, 0.85 mmol) was added. The re-
sulting mixture was warmed to r.t. over 2 h. The mixture was poured
onto ice and the product was extracted with EtOAc (3 × 30 mL).
The combined organic layers were washed successively with brine
(30 mL) and H2O (30 mL), dried (MgSO4), and the solvent was re-
moved under reduced pressure. The residue was purified by flash
chromatography (cyclohexane–EtOAc, 8:2) to give compound 11
as a brown solid; yield: 210 mg (~100%); mp 186–188 °C.
1H NMR (300 MHz, CDCl3): d = 1.40 (s, 3 H, CH3), 1.66 (s, 3 H,
CH3), 1.75 (m, 1 H, CHaHb), 1.86 (m, 1 H, CHaHb), 2.06 (s, 3 H,
COCH3), 3.21 (m, 2 H, CH2), 3.85 (s, 3 H, OCH3), 3.89 (s, 3 H,
OCH3), 4.12 (s, 3 H, NCH3), 4.63 (m, 2 H, CH2), 7.27 (t, J = 9 Hz,
1 Harom), 7.42 (d, J = 9 Hz, 1 Harom), 7.50 (t, J = 9 Hz, 1 Harom), 7.27
(t, J = 9 Hz, 1 Harom).
1H NMR (300 MHz, CDCl3): d = 1.42 (s, 3 H, CH3), 1.65 (s, 3 H,
CH3), 1.79 (m, 1 H, CHaHb), 1.90 (m, 1 H, CHaHb), 3.30 (m, 1 H,
CHcHd), 3.55 (d, J = 18Hz, 1 H, CHeHf), 3.84 (s, 3 H, OCH3), 3.89
(s, 3 H, OCH3), 4.13 (s, 3 H, NCH3), 4.35 (d, J = 18Hz, 1H, CHeHf),
4.64 (m, 1 H, CHcHd), 7.27 (m, 1 Harom), 7.45 (m, 1 Harom), 7.53 (m,
1 Harom), 8.25 (m, 1 Harom).
Under an inert atmosphere, a solution of BH3·THF complex (0.22
mL, 1 M solution in THF, 0.22 mmol) was added dropwise to a so-
lution of the above azide (30 mg, 0.073 mmol) in anhyd THF at
0 °C. After completion of the addition, the reaction mixture was
then heated to reflux for 2 h. After pouring the mixture onto ice, the
product was extracted with EtOAc (3 × 30 mL). The combined or-
ganic layers were successively washed with H2O (20 mL), sat. aq
NaHCO3 (20 mL), and brine (20 mL). The organics were dried
(MgSO4) and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography (cyclohexane–
EtOAc, 7:3) to give compound 13 as a brown oil; yield: 13 mg
(45%).
13C NMR (75 MHz, CDCl3): d = 21.8 (COCH3), 26.6 (CH3), 30.4
(CH3), 31.4 (C), 35.8 (NCH3), 40.4 (CH2), 40.9 (CH2), 60.7 (OCH3),
63.6 (OCH3), 108.8 (CH), 116.5 (C), 119.8 (CH), 121.8 (C), 122.6
(CH), 123.5 (C), 125.9 (CH), 133.0 (C), 133.4 (C), 141.1 (C), 142.0
(C), 146.1 (C), 172.3 (C=O).
1H NMR (300 MHz, CDCl3): d = 1.51 (s, 6 H, 2 × CH3), 1.70 (m, 2
H, CH2), 3.15 (m, 2 H, CH2), 3.31 (m, 2 H, CH2), 3.63 (m, 2 H,
CH2), 3.83 (s, 3 H, NCH3), 3.90 (s, 3 H, OCH3), 3.99 (s, 3 H, OCH3),
7.20 (m, 1 Harom), 7.34 (m, 1 Harom), 7.44 (m, 1 Harom), 8.21 (m, 1
MS (EI): m/z = 335 ([M – OCH3]+, 100%), 366 ([M]+, 65%).
Harom).
13C NMR (75 MHz, CDCl3): d = 26.9 (2 × CH3), 30.27 (NCH3),
30.7 (C), 31.9 (C), 33.4 (CH2), 38.5 (CH2), 41.5 (CH2), 43.4 (CH2),
Anal. Calcd for C22H26N2O3 (366.46): C, 72.11; H, 7.15; N, 7.64.
Found: C, 70.21; H, 6.99; N, 7.55.
Synthesis 2011, No. 10, 1616–1620 © Thieme Stuttgart · New York

1620
S. Bouclé, J. Guillard
PAPER
59.0 (OCH3), 61.9 (OCH3), 108.8 (CH), 118.9 (CH), 121.8 (C),
122.5 (CH), 123.8 (C), 125.4 (CH), 127.8 (C), 131.9 (C), 136.7 (C),
142.7 (C), 143.3 (C).
MS (CI): m/z = 394, ([M + 1]+, 100%).
(2) Le-Pecq, J. B.; Dat-Xuong, N.; Gosse, C.; Paoletti, C. Proc.
Natl. Acad. Sci. U.S.A. 1974, 71, 5078.
(3) Kohn, K. W.; Waring, M. J.; Glaubiger, D.; Friedman, C. A.
Cancer Res. 1975, 35, 71.
(4) Paoletti, C.; Le-Pecq, J. B.; Dat-Xuong, N.; Juret, P.;
Garnier, H.; Amiel, J. L.; Rouesse, J. Recent Results Cancer
Res. 1980, 74, 107.
Anal. Calcd for C22H27N5O2 (393.49): C, 67.15; H, 6.92; N, 17.80.
Found: C, 67.31; H, 7.00; N, 17.25.
(5) Wang, J. C. Annu. Rev. Biochem. 1996, 65, 635.
(6) Monks, N. R.; Blankey, D. C.; East, S. J.; Dowell, R. I.;
Caluete, J. A.; Curtin, N. J.; Arris, C. E.; Newell, D. R. Eur.
J. Cancer 2002, 11, 1543.
(7) Auclair, C. Arch. Biochem. Biophys. 1987, 259, 1.
(8) Sainsbury, M. Synthesis 1977, 437.
(9) Hewlins, M. J. E.; Oliviera-Campos, A.-M.; Shannon, P. V.
R. Synthesis 1984, 289.
(10) Kansal, V. K.; Potier, P. Tetrahedron 1986, 42, 2389.
(11) Knölker, H. J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(12) Ishikura, M.; Hino, A.; Yaginuma, T.; Agata, I.; Katagiri, N.
Tetrahedron 2000, 56, 193.
6,6,8-Trimethyl-2,5,6,8-tetrahydro-1,3a,8-triazaindeno[1,2-
a]phenalen-7(1H,8H)-one (1)
To a suspension of 13 (40 mg, 0.10 mmol) in mixture of H2O–
MeOH (9:1, 5 mL) at r.t. was added PIFA (130 mg, 0.30 mmol) and
the mixture was stirred for 2 h at r.t.. Then, H2O (10 mL) was added
and the product was extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic layers were washed with brine (20 mL), dried
(MgSO4), and the solvent was removed under reduced pressure to
afford the desired quinone used, which was used without further pu-
rification. A solution of the above quinone in a mixture of EtOH–
THF (1:1, 20 mL) was hydrogenated (15 psi) over Pd/C (8 mg) for
5 h at r.t. The catalyst was filtered on a pad of Celite and the filtrate
concentrated in vacuo. The residue was purified by flash chroma-
tography (cyclohexane–EtOAc, 6:4) to give compound 1 as a red
oil; yield: 11 mg (35% for 2 steps).
(13) Mal, D.; Senapati, B. K.; Pahari, P. Synlett 2005, 994.
(14) Ferlin, M. G.; Chiarelotto, G.; Basadonna, O.; Gias, O.;
Mobilio, S.; Carlassare, F.; Baccichetti, F. Farmaco 1989,
44, 1141.
1H NMR (300 MHz, CDCl3): d = 1.48 (s, 6 H, 2 × CH3), 1.83 (m, 2
H, CH2), 3.28 (m, 4 H, 2 × CH2), 4.15 (m, 2 H, CH2), 4.19 (s, 3 H,
NCH3), 7.37 (m, 3 H, 3 Harom), 8.48 (m, 1 Harom).
(15) Tsuchimoto, T.; Matsubayashi, H.; Kaneko, M.; Shirakawa,
E.; Kawakami, Y. Angew. Chem. Int. Ed. 2005, 44, 1336.
(16) Martinez-Esperon, M. F.; Rodriguez, D.; Castedo, L.; Saà,
C. Org. Lett. 2005, 7, 2213.
(17) Gaddam, V.; Nagarajan, R. Org. Lett. 2008, 10, 1975.
(18) The Alkaloids, Vol. 65; Cordell, G. A., Ed.; Academic Press:
Amsterdam, 2008, 1–430.
MS (EI): m/z = 304 ([M – CH3]+, 100%), 319 ([M]+, 41%).
Anal. Calcd for C20H21N3O (319.41): C, 75.21; H, 6.63; N, 13.16.
Found: C, 75.36; H, 6.68; N, 12.99.
(19) Hartwig, J. F.; Louie, J. Tetrahedron Lett. 1995, 36, 3609.
(20) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(21) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1348.
(22) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320.
(23) Bouclé, S. Ph.D. Thesis; University of François Rabelais
Tours: France, 2010.
Acknowledgment
We thank the Comité du Cher de la Ligue National Contre le cancer
for financial support and the Deptarment of Analytic Chemistry of
University of Tours François Rabelais for technical support. We
also thank Prof. Y. Bleriot for his helpful suggestions regarding this
manuscript.
(24) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 581.
(25) Bouclé, S.; Guillard, J.; Viaud-Massuard, M.-C. Molecules
2010, 15, 7742.
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Synthesis 2011, No. 10, 1616–1620 © Thieme Stuttgart · New York