Transition metals in organic synthesis. Part 101: Convergent total synthesis of 1,6-dioxygenated carbazole alkaloids

Article abstract of DOI:10.1016/j.tet.2012.05.105

Using a palladium(II)-catalysed oxidative cyclisation as key step, we describe a highly efficient total synthesis of a series of naturally occurring 1,6-dioxygenated carbazole alkaloids: clausenine, 6-methoxymurrayanine, clausenol, clausine G, clausine I, clausine Z and methyl 1,6-dihydroxy-9H- carbazole-3-carboxylate.

Full text of DOI:10.1016/j.tet.2012.05.105

Tetrahedron 68 (2012) 6727e6736
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Transition metals in organic synthesis. Part 101: Convergent total synthesis
of 1,6-dioxygenated carbazole alkaloidsq
*
€
€
Carsten Borger, Hans-Joachim Knolker
€
Department Chemie, Technische Universitat Dresden, Bergstraße 66, 01069 Dresden, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 April 2012
Received in revised form 22 May 2012
Accepted 24 May 2012
Available online 31 May 2012
Using a palladium(II)-catalysed oxidative cyclisation as key step, we describe a highly efficient total
synthesis of
a series of naturally occurring 1,6-dioxygenated carbazole alkaloids: clausenine, 6-
methoxymurrayanine, clausenol, clausine G, clausine I, clausine Z and methyl 1,6-dihydroxy-9H-carba-
zole-3-carboxylate.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Antibiotics
Catalysis
Cyclisations
Palladium
1. Introduction
the stem bark of Clausena excavata.13,14 Clausine I (4) showed an in-
hibition of rabbit platelet aggregation induced by arachidonic acid. In
The structural diversity and promising biological activities of
carbazole alkaloids has led to an intense research activity in this
area.1e9 All 1,6-dioxygenated carbazoles isolated from nature so far
have a one-carbon substituent at C-3 of the carbazole framework.
The central relay compound for the biogenesis of carbazole alka-
loids in higher plants is 3-methylcarbazole. Further oxygenation
reactions at the carbazole nucleus and oxidations at the 3-methyl
group take place afterwards.1b,3 Herein, we describe full details of
our palladium-catalysed route to the 1,6-dioxygenated carbazole
alkaloids clausenine (1), 6-methoxymurrayanine (2), clausenol (3),
clausine I (4), clausine G (5), clausine Z (6) and methyl 1,6-
dihydroxy-9H-carbazole-3-carboxylate (7) (Fig. 1).10
2005, Potterat et al. from Boehringer Ingelheim Pharma GmbH
reported the isolation of clausine Z (6) from the stems and leaves of C.
excavata.15 Clausine Z (6) showed an inhibitoryactivityagainst cyclin-
dependentkinase5 (CDK5) and a protective effectoncerebralgranule
neurons against free radical induced cell death. In 2010, Laphookhieo
et al. described the isolation of methyl 1,6-dihydroxy-9H-carbazole-
3-carboxylate (7) from the stems of C. excavata.16
Due to their biological activity, several syntheses of 1,6-
dioxygenated carbazoles have been described. In 1995, Chakraborty
et al. reported the first synthesis of clausenine (1) and clausenol (3)
MeO
R
MeO
R
In 1991, El-Feraly et al. reported the first isolation of a 1,6-
dioxygenated carbazole, 6-methoxymurrayanine (2), from the roots
of Clausena lansium.11 Four years later, Chakraborty et al. isolated
clausenine (1) and clausenol (3) from the dried stem bark of Clausena
anisata and described their antibiotic activity against Gram-positive
and Gram-negative bacteria as well as fungi.12 Clausenol (3) is much
more active than clausenine (1) and the inhibition against some
bacteria is similar to that reported for streptomycin.12 In 1996, Wu
et al. described the isolation of clausine I (4) and clausine G (5) from
N
H
N
H
OMe
OH
1 Clausenine R = Me
2 6-Methoxymurrayanine R = CHO
3 Clausenol R = Me
4 Clausine I R = CHO
5 Clausine G R = COOMe
HO
COOMe
HO
CHO
N
H
N
H
OH
OH
6 Clausine Z
7 Methyl 1,6-dihydroxy-9H-
q
For part 100, see: Ref. 6.
carbazole-3-carboxylate
* Corresponding author. Fax: þ49 351 463 37030; e-mail address: hans-joa-
€
chim.knoelker@tu-dresden.de (H.-J. Knolker).
Fig. 1. The naturally occurring 1,6-dioxygenated carbazole alkaloids 1e7.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.105

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C. Borger, H.-J. Knolker / Tetrahedron 68 (2012) 6727e6736
(three to four steps and 6% overall yield).12 In 1999, Lin and Zhang’s
optimisation of Chakraborty’s earlier synthetic route provided clau-
senol (3) in 17% overall yield.17,18 In 2007, Tamariz et al. reported
a synthesis of 6-methoxymurrayanine (2) (six steps,16% overall yield)
and clausenine (1) (six steps, 20% overall yield).19 In 2008, Fagnou
et al. described the synthesis of clausenine (1) in three steps and 69%
overall yield.9
We have developed a highly efficient palladium-catalysed syn-
thesis of the whole series of 1,6-dioxygenated carbazole alkaloids
described above (Fig. 1).10 Key steps of our route are a Buch-
waldeHartwig coupling providing diarylamines and a subsequent
palladium(II)-catalysed oxidative cyclisation.1e5 This approach has
also been successfully applied to the synthesis of 2-oxygenated,20,21
Table 1
Oxidative cyclisation of the diarylamine 10 to methyl 1,6-dimethoxy-9H-carbazole-
3-carboxylate (11)
Reagents and conditions
11, Yield [%]
10, Yield [%]
2 equiv Pd(OAc)2, HOAc,
117 ꢀC, 4 h, Ar
96
d
0.1 equiv Pd(OAc)2, 2.5
equiv Cu(OAc)2, DMF,
130 ꢀC, MW 300 W, 4 h, air
1.3 equiv Pd(OAc)2,
2.5 equiv Cu(OAc)2, HOAc,
117 ꢀC, 40 h, Ar
0.1 equiv Pd(OAc)2, 0.1
equiv K2CO3, HOPiv,
115 ꢀC, 14 h, Ar
11
76
75
75
d
d
6-oxygenated,22
7-oxygenated,23
1,7-dioxygenated,24
2,6-
dioxygenated,25 2,7-dioxygenated26 and 1,7,8-trioxygenated car-
bazoles.6 Retrosynthetic analysis of the seven 1,6-dioxygenated
carbazole alkaloids 1e7 led to identification of 4-bromoanisole
(8) and the methyl 4-aminobenzoates 9a and 9b as starting mate-
rials (Scheme 1).
presence of copper(II) acetate, 1.3 equiv of palladium(II) acetate
were sufficient to achieve satisfactory yields of carbazole 11 (Table
1, entry 3). Finally, using 10 mol % of palladium(II) acetate and
potassium carbonate in pivalic acid,9 carbazole 11 was obtained in
75% yield (Table 1, entry 4).
Reduction of carbazole 11 using lithium aluminium hydride in
diethyl ether/dichloromethane at room temperature afforded
clausenine (1) in only 48% yield along with 1,6-dimethoxy-3-
hydroxymethyl-9H-carbazole (12) in 36% yield and the previously
unknown biscarbazole 13 in up to 9% yield (Table 2). Reduction with
lithium aluminium hydride in tetrahydrofuran at elevated tem-
perature provided clausenine (1) in 74% yield (Scheme 2, Table 2).
Thus, clausenine (1) was obtained in three steps and 71% overall
yield.
Scheme 1. Retrosynthetic analysis of the 1,6-dioxygenated carbazole alkaloids 1e7.
2. Results and discussion
Table 2
Reduction of methyl 1,6-dimethoxy-9H-carbazole-3-carboxylate (11) with lithium
BuchwaldeHartwig amination of 4-bromoanisole (8) and
methyl 4-amino-3-methoxybenzoate (9a) led quantitatively to the
diarylamine 10 (Scheme 2). As described by Akermark for acceptor-
aluminium hydride
Reagents and conditions
1, Yield [%]
12, Yield [%]
13, Yield [%]
ꢀ
4 equiv LiAlH4, Et2O/
CH2Cl2 (1:1), rt, 6 h
4 equiv LiAlH4, THF, 67 ꢀC, 4 h
48
36
9
substituted diarylamines,27 oxidative cyclisation of 10 using over-
stoichiometric amounts of palladium(II) acetate afforded directly
the carbazole 11 in 96% yield (Scheme 2, Table 1). Our first
experiments with catalytic amounts of palladium(II) acetate in the
presence of copper(II) acetate for reoxidation of palladium using
either thermal induction28 or microwave heating25,29 provided
carbazole 11 only in poor yield (Table 1, entry 2). However, in the
74
d
1
Lithium aluminium hydride reductions of alkyl carbazole-3-
carboxylates to 3-methylcarbazoles have been known for a long
time.31 In 2001, Bringmann et al. obtained biscarbazoles as side
products of the reduction of carbazole-3-carboxylic acid esters and
proposed a mechanistic pathway for this transformation.30 Re-
duction of the ester group of carbazole 11 followed by elimination
of metal oxide from intermediate 14 would lead to the quinone
imine methide 15 (Scheme 3). Subsequent attack of different nu-
cleophiles at the quinone imine methide 15 would afford the
Scheme 2. Synthesis of clausenine (1). Reagents and conditions: (a) 1.1 equiv 8,
6 mol % Pd(OAc)2, 12 mol % SPhos, 1.4 equiv Cs2CO3, toluene, 110 ꢀC, 5 d, 100%; (b) see
Table 1; (c) see Table 2.
Scheme 3. Proposed mechanism for the formation of clausenine (1) and the biscar-
bazole 13.

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C. Borger, H.-J. Knolker / Tetrahedron 68 (2012) 6727e6736
6729
observed products. Addition of hydride provides clausenine (1),
whereas addition of a second carbazole moiety leads to the bis-
carbazole 13. The formation of the biscarbazole 13 is explained by
attack of carbazole 11 at intermediate 15 followed by reduction of
the ester group to a hydroxymethyl group.
Ether cleavage of 6-methoxymurrayanine (2) using boron tri-
bromide afforded clausine Z (6) and the non-natural isoclausine I
(17). This approach leads to clausine Z (6) in five steps and 20%
overall yield.
Obviously, the methoxy group at C-1 of the carbazole ring is
more stable towards ether cleavage than the methyl ether in the 6-
position. This finding led us to devise a different protecting group
strategy for the synthesis of the 1-hydroxy-6-methoxycarbazoles
clausenol (3), clausine I (4) and clausine G (5).
Following a literature procedure, 3-hydroxy-4-nitrobenzoic acid
(18) was converted into the benzyloxy-substituted arylamine 9b via
three steps (Scheme 6).35 Benzyl ethers are cleaved selectively in
the presence of methyl ethers using hydrogen and palladium on
A selective cleavage of the methyl ether at the 1-position of the
carbazole 11 would afford clausine G (5). However, treatment of 11
with 4 equiv of boron tribromide at low temperature led to methyl
1,6-dihydroxy-9H-carbazole-3-carboxylate (7) in 67% yield along
with the non-natural isoclausine G (16) in 33% yield (Scheme 4,
Table 3). Thus, using mild reaction conditions the methyl ether at C-
6 is cleaved first. Subsequent to our original communication on this
work,10 the carbazole 7 was isolated from the stems of C. excavata
collected in southern Thailand by Laphookhieo et al.16 Therefore,
we aimed at an optimisation of the double ether cleavage of car-
bazole 11. Using 6 equiv of boron tribromide and warming to room
temperature provided exclusively methyl 1,6-dihydroxy-9H-car-
bazole-3-carboxylate (7) in 75% yield. Using this route, methyl 1,6-
dihydroxy-9H-carbazole-3-carboxylate (7) is accessible in three
steps and 72% overall yield.
COOMe
COOH
COOMe
a
b
O2N
O2N
O2N
OH
OH
OBn
18
19
20
COOMe
COOMe
MeO
c
d
H2N
N
H
OBn
9b
OBn
21
MeO
COOMe
MeO
COOMe
e
f
N
H
N
H
OH
Clausine G
OBn
22
5
Scheme 6. Synthesis of clausine G (5). Reagents and conditions: (a) MeOH, cat. H2SO4,
65 ꢀC, 17 h, 99%; (b) BnBr, K2CO3, acetone, 56 ꢀC, 17 h, 100%; (c) Fe, HOAc, rt to 40 ꢀC,
4 h, 100%; (d) 6 mol
% Pd(OAc)2, 12 mol % SPhos, 1.4 equiv Cs2CO3, 1.1 equiv 4-
Scheme 4. Synthesis of methyl 1,6-dihydroxy-9H-carbazole-3-carboxylate (7) and
isoclausine G (16). Reagents and conditions: see Table 3.
bromoanisole (8), toluene, 80 ꢀC, 64 h, 90%; (e) see Table 4; (f) 10% Pd/C, H2, CH2Cl2/
MeOH (1:1), rt, 18 h, 89%.
activated carbon. Moreover, both protecting groups can be removed
in a one pot reaction using boron tribromide. BuchwaldeHartwig
amination using similar conditions as described for the diarylamine
10 provided the diarylamine 21. The best results for the cyclisation
of 21 were achieved using 2 equiv of palladium(II) acetate, which
led to the carbazole 22 in 62% yield (Table 4). Using 1 equiv of
palladium(II) acetate in the presence of 2.5 equiv of copper(II)
acetate provided the carbazole 22 in 53% yield. Using catalytic
amounts of palladium(II) acetate and potassium carbonate in piv-
alic acid afforded the carbazole 22 in up to 54% yield. Cleavage of
the benzyl ether with palladium on activated carbon under hy-
drogen atmosphere provided clausine G (5) in six steps and 49%
overall yield based on commercially available 3-hydroxy-4-
nitrobenzoic acid (18).
Table 3
Ether cleavage of methyl 1,6-dimethoxy-9H-carbazole-3-carboxylate (11)
Reagents and conditions
7, Yield [%]
16, Yield [%]
4 equiv BBr3, CH2Cl2, ꢁ78 ꢀC to ꢁ10 ꢀC, 17.5 h
67
75
33
d
6 equiv BBr3, CH2Cl2, ꢁ78 ꢀC to rt, 16.5 h
Reduction of carbazole 11 using diisobutylaluminium hydride
(DIBAL-H)32 followed by oxidation with commercially available
manganese(IV) oxide33,34 led to 6-methoxymurrayanine (2) in 87%
yield over both steps (four steps and 84% overall yield) (Scheme 5).
Table 4
Oxidative cyclisation to methyl 1-benzyloxy-6-methoxy-9H-carbazole-3-
carboxylate (22)
Reagents and conditions
22, Yield [%]
21, Yield [%]
2 equiv Pd(OAc)2, HOAc,
100 ꢀC, 14 h, Ar
62
3
1 equiv Pd(OAc)2, 2.5 equiv
Cu(OAc)2, HOAc,
100 ꢀC, 40 h, Ar
53
29
0.1 equiv Pd(OAc)2, 0.1 equiv
K2CO3, HOPiv, 100 ꢀC, 14 h, air
0.2 equiv Pd(OAc)2, 0.1 equiv
K2CO3, HOPiv, 115 ꢀC, 40 h, air
48
54
41
17
Scheme 5. Synthesis of 6-methoxymurrayanine (2), isoclausine I (17) and clausine Z
(6). Reagents and conditions: (a) 2.6 equiv DIBAL-H, Et2O, ꢁ78 ꢀC, 3.5 h, 87%; (b)
5 equiv MnO2, CH2Cl2, rt, 24 h, 100%; (c) 3 equiv BBr3, CH2Cl2, ꢁ78 ꢀC to rt, 24 h, 73% of
17 and 24% of 6.

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Reduction of compound 22 using lithium aluminium hydride
tuberculosis (MTB) H37Rv strain using the microplate alamar blue
assay (MABA).41 Compound 23 was found to exhibit an inhibitory
activity; minimum inhibitory concentration (MTB H37Rv):
afforded the benzyl-protected clausenol 23 in 94% yield along with
the biscarbazole 24 in 3% yield (Scheme 7). Catalytic hydrogenolysis
of 23 provided clausenol (3) in seven steps and 52% overall yield.
MIC90¼31.7
mM; toxicity (vero cells): IC50 >128 mM; selectivity in-
dex (IC50/MIC90): SI >4.
3. Conclusion
We have described efficient synthetic routes to all seven 1,6-
dioxygenated carbazoles, which have been isolated so far from
natural sources. Clausenine (1), 6-methoxymurrayanine (2), clau-
senol (3), clausine I (4), clausine G (5), clausine Z (6) and methyl 1,6-
dihydroxy-9H-carbazole-3-carboxylate (7) are available in three to
eight steps and up to 83% overall yield via a sequence of Buch-
waldeHartwig amination and oxidative cyclisation as key steps for
construction of the carbazole framework. One derivative (com-
pound 23) showed a moderate activity against M. tuberculosis.
4. Experimental section
4.1. General
All reactions were carried out in oven-dried glassware using dry
solvents under an argon atmosphere unless stated otherwise.
Dichloromethane, diethyl ether, dioxane, tetrahydrofuran and tol-
uene were dried using a solvent purification system (MBraun-SPS).
Acetone was distilled from phosphorus(V) oxide and stored over
Scheme 7. Synthesis of clausenol (3). Reagents and conditions: (a) 4 equiv LiAlH4, THF,
67 ꢀC, 7 h, 94% of 23 and 3% of 24; (b) 10% Pd/C, H2, CH2Cl2/MeOH (1:1), rt, 40 h, 100%.
ꢀ
3 A molecular sieves. Palladium(II) acetate was recrystallised from
Reduction of carbazole 22 with diisobutylaluminium hydride
(DIBAL-H) led to the carbinol 25 (Scheme 8).32 Subsequent oxida-
tion using activated manganese(IV) oxide afforded the benzyl-
protected clausine I 26.33,34 Using aluminium trichloride as Lewis
acid in refluxing 1,4-dioxane resulted in selective removal of the
benzyl ether and provided quantitatively clausine I (4).36 Treatment
of compound 26 with boron tribromide led to cleavage of both
ethers and provided clausine Z (6). Thus, the present route affords
clausine I (4) in eight steps and 52% overall yield and clausine Z (6)
in eight steps and 29% overall yield both starting from commer-
cially available starting materials.
Many naturally occurring carbazoles exhibit useful antibiotic
activities.1,3 Previously, we have reported on the anti-TB activity of
carbazole derivatives.40 Therefore, a selection of the carbazoles
described in the present paper (compounds 4, 5, 6, 22, 23, 25 and
26) has been tested for their inhibitory effect on Mycobacterium
glacial acetic acid. All other chemicals were used as received from
commercial sources. Flash chromatography was performed using
silica gel from Acros Organics (0.035e0.070 mm). Thin layer chro-
matography was performed with TLC plates from Merck (60 F254
)
using UV-light for visualisation. Melting points were measured on
a Gallenkamp MPD 350 melting point apparatus. Ultraviolet spectra
were recorded on a Perkin Elmer 25 UV/VIS spectrometer. Infrared
spectra were recorded on a Thermo Nicolet Avatar 360 FT-IR
spectrometer using the ATR method (Attenuated Total Re-
flectance). NMR spectra were recorded on Bruker Avance II 300 and
DRX 500 spectrometers. Chemical shifts d are reported in parts per
million with the non-deuterated solvent as internal standard.37 The
following abbreviations have been used: s: singlet, d: doublet, dd:
doublet of doublets, t: triplet, tt: triplet of triplets, m: multiplet and
br: broad. Mass spectra were recorded on a Finnigan MAT-95
spectrometer (electron impact, 70 eV) or by GC/MS-coupling us-
ing an Agilent Technologies 6890 N GC System equipped with
a 5973 Mass Selective Detector (electron impact, 70 eV). ESI-MS
spectra were recorded on an Esquire LC with an ion trap detector
from Bruker. Positive and negative ions were detected. Elemental
analyses were measured on an EuroVector EuroEA3000 elemental
analyser.
MeO
CH2OH
MeO
COOMe
a
b
N
H
N
H
OBn
OBn
22
25
MeO
CHO
CHO
MeO
CHO
4.2. Methyl 3-methoxy-4-(4-methoxyphenylamino)benzoate(10)
c
4-Bromoanisole (8) (233 mL, 1.86 mmol) was added to a solution
N
H
N
H
OH
OBn
of methyl 4-amino-3-methoxybenzoate (9a) (306 mg, 1.69 mmol),
palladium(II) acetate (22.8 mg, 0.101 mmol), SPhos (83.2 mg,
0.203 mmol) and caesium carbonate (771 mg, 2.37 mmol) in tolu-
ene (31 mL). After stirring for 120 h at reflux, the solvent was re-
moved under reduced pressure. The residue was directly submitted
to flash chromatography on silica gel (petroleum ether/ethyl acetate
4:1) to provide methyl 3-methoxy-4-(4-methoxyphenylamino)-
benzoate (10) as colourless solid, yield: 485 mg (100%), mp
58.5e59 ꢀC.
26
4 Clausine I
HO
MeO
CHO
d
N
H
N
H
OH
OBn
26
6 Clausine Z
Scheme 8. Synthesis of clausine I (4) and clausine Z (6). Reagents and conditions: (a)
2.6 equiv DIBAL-H, Et2O, ꢁ78 ꢀC, 3.5 h, 95%; (b) 5 equiv MnO2, CH2Cl2, rt, 24 h, 100%;
(c) 10 equiv AlCl3, dioxane, 101 ꢀC, 3 h, 100%; (d) 4 equiv BBr3, CH2Cl2, ꢁ78 ꢀC to rt,
24 h, 55%.
UV (MeOH): lmax¼233 (sh), 325 nm. IR (ATR): ¼3400, 3000,
n
2948, 2835, 2636, 1699, 1598, 1523, 1507, 1452, 1431, 1406, 1356,
1273, 1255, 1218, 1171, 1124, 1101, 1030, 987, 898, 874, 825, 760, 724,

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660, 610 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d
¼3.82 (s, 3H), 3.87 (s,
dimethoxy-3-methyl-9H-carbazole) (1), Rf¼0.65 (petroleum
ether/ethyl acetate 1:1) as colourless crystals, yield: 57.8 mg (74%),
mp 149e150 ꢀC (lit.:12 151 ꢀC) along with 1,6-dimethoxy-3-(3-
hydroxymethyl-1,6-dimethoxy-9H-carbazol-9-yl)methyl-9H-car-
bazole (13), Rf¼0.14 (petroleum ether/ethyl acetate 1:1) as a
colourless solid, yield: 1.0 mg (1%).
3H), 3.96 (s, 3H), 6.30 (br s, 1H), 6.90 (d, J¼8.8 Hz, 2H), 6.92 (d,
J¼8.4 Hz, 1H), 7.16 (d, J¼8.8 Hz, 2H), 7.49 (d, J¼1.7 Hz, 1H), 7.55 (dd,
J¼8.4, 1.7 Hz, 1H). 13C NMR and DEPT (125 MHz, CDCl3):
¼51.84
d
(CH3), 55.64 (CH3), 55.75 (CH3), 109.85 (CH), 110.78 (CH), 114.81 (2
CH), 119.07 (C), 124.19 (CH), 124.56 (2 CH), 133.40 (C), 140.07 (C),
146.03 (C), 156.48 (C), 167.40 (C]O). MS (EI): m/z (%)¼287 (100,
Mþ), 272 (66), 256 (9), 241 (35), 228 (11), 213 (4), 198 (4), 184 (5),
170 (5), 128 (10), 121 (4). Anal. Calcd (%) for C16H17NO4: C 66.89, H
5.96, N 4.88. Found: C 67.01, H 6.10, N 4.96.
Compound 1: UV (MeOH): lmax¼226, 241, 258 (sh), 287 (sh),
299, 340, 354 nm. IR (ATR):
n
¼3385, 2955, 2918, 2852, 1619, 1581,
1505, 1486, 1459, 1451, 1437, 1394, 1304, 1268, 1207, 1145, 1129,
1035, 1025, 940, 838, 821, 800, 769 cmꢁ1 1H NMR (500 MHz,
DMSO-d6):
.
d
¼2.45 (s, 3H), 3.82 (s, 3H), 3.95 (s, 3H), 6.78 (s, 1H), 6.97
4.3. Methyl 1,6-dimethoxy-9H-carbazole-3-carboxylate (11)
(dd, J¼8.7, 2.4 Hz, 1H), 7.33 (d, J¼8.7 Hz, 1H), 7.46 (s, 1H), 7.55 (d,
J¼2.4 Hz, 1H), 10.92 (br s, 1H). 13C NMR and DEPT (125 MHz, DMSO-
Method A (2 equiv of palladium(II) acetate). A solution of methyl
3-methoxy-4-(4-methoxyphenylamino)benzoate (10) (159 mg,
0.554 mmol) and palladium(II) acetate (259 mg, 1.11 mmol) in gla-
cial acetic acid (7 mL) was heated at reflux for 4 h. The solvent was
removed under reduced pressure and the residue was purified by
flash chromatography on silica gel (petroleum ether/ethyl acetate
1:1) to afford methyl 1,6-dimethoxy-9H-carbazole-3-carboxylate
(11) as colourless crystals, yield: 152 mg (96%), mp 144.5e145.0 ꢀC.
Method B (catalytic amounts of palladium(II) acetate). A solu-
tion of methyl 3-methoxy-4-(4-methoxyphenylamino)benzoate
(10) (53.1 mg, 0.185 mmol), palladium(II) acetate (4.2 mg,
0.018 mmol) and potassium carbonate (2.6 mg, 0.018 mmol) in
pivalic acid (175 mg) was heated at 115 ꢀC for 14 h under air.
Dichloromethane was added and the solution was washed twice
with a saturated aqueous solution of potassium carbonate. The
combined aqueous layers were extracted three times with
dichloromethane. The combined organic layers were washed with
brine, dried over magnesium sulfate and the solvent was removed
under reduced pressure. Purification of the residue by flash
chromatography on silica gel (isohexane/ethyl acetate 4:1) afforded
methyl 1,6-dimethoxy-9H-carbazole-3-carboxylate (11) as colour-
less crystals, yield: 39.5 mg (75%), mp 144.5e145.0 ꢀC.
d6):
d
¼21.57 (CH3), 55.23 (CH3), 55.51 (CH3), 102.64 (CH), 107.53
(CH), 111.97 (CH), 112.31 (CH), 114.56 (CH), 122.75 (C), 123.48 (C),
127.45 (C), 128.56 (C), 134.68 (C), 145.33 (C), 152.80 (C). MS (EI): m/z
(%)¼241 (91, Mþ), 226 (100), 211 (11), 198 (20), 183 (7), 167 (9), 155
(17), 154 (14). Anal. Calcd (%) for C15H15NO2: C 74.67, H 6.27, N 5.81.
Found: C 74.88, H 6.36, N 5.50.
Compound 13: 1H NMR (300 MHz, CDCl3):
d
¼3.84 (s, 3H), 3.87 (s,
3H), 3.90 (s, 3H), 3.96 (s, 3H), 4.86 (s, 2H), 5.98 (s, 2H), 6.75 (d,
J¼1.1 Hz,1H), 6.98 (d, J¼1.3 Hz,1H), 6.99e7.05 (m, 2H), 7.28e7.35 (m,
2H), 7.38 (d, J¼2.5 Hz,1H), 7.41 (s,1H), 7.54 (d, J¼2.5 Hz,1H), 7.70 (d,
J¼1.3 Hz, 1H), 8.02 (br s, 1H). MS (ESI, ꢁ10 V): m/z¼495 (MꢁH)ꢁ.
4.5. Methyl 1,6-dihydroxy-9H-carbazole-3-carboxylate (7) and
isoclausine G (methyl 6-hydroxy-1-methoxy-9H-carbazole-3-
carboxylate) (16)
Method A. A 1 M solution of boron tribromide in dichloro-
methane (1.5 mL, 1.5 mmol) was added at ꢁ78 ꢀC to a solution of
methyl 1,6-dimethoxy-9H-carbazole-3-carboxylate (11) (108 mg,
0.378 mmol) in dichloromethane (15 mL). After stirring for 30 min
at this temperature the solution was allowed to warm to ꢁ10 ꢀC
and stirring was continued for 17 h. Methanol (4 mL) was added
and the solvents were evaporated. Purification of the residue by
flash chromatography on silica gel (petroleum ether/ethyl acetate
4:1) afforded methyl 1,6-dihydroxy-9H-carbazol-3-carboxylate (7)
as light brown crystals, yield: 66.2 mg (67%) mp 198e200 ꢀC, along
with methyl 6-hydroxy-1-methoxy-9H-carbazole-3-carboxylate
(16) as light brown crystals, yield: 34.0 mg (33%), mp 205e206 ꢀC.
Method B. A 1 M solution of boron tribromide in dichloromethane
(2.1 mL, 2.1 mmol) was added at ꢁ78 ꢀC to a solution of methyl 1,6-
dimethoxy-9H-carbazole-3-carboxylate (11) (102 mg, 0.358 mmol)
in dichloromethane (15 mL). After stirring for 30 min at this tem-
perature the solution was allowed to warm to room temperature and
stirring was continued for 16 h. Methanol (5.6 mL) was added and the
solvents were evaporated. Purification of the residue by flash chro-
matography on silica gel (isohexane/ethyl acetate 4:1) afforded
methyl 1,6-dihydroxy-9H-carbazol-3-carboxylate (7) as light brown
crystals, yield: 68.8 mg (75%), mp 198e200 ꢀC.
UV (MeOH): lmax¼224, 238, 248, 258, 268, 285, 321, 348 (sh)
nm. IR (ATR):
n
¼3355, 3013, 2998, 2921, 2851, 1761, 1686, 1629,
1609, 1585, 1506, 1482, 1462, 1435, 1404, 1357, 1310, 1261, 1202,
1174, 1132, 1102, 1036, 995, 947, 915, 880, 840, 812, 792, 767, 755,
729, 675 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d
¼3.93 (s, 3H), 3.98 (s,
3H), 4.05 (s, 3H), 7.09 (dd, J¼8.8, 2.5 Hz, 1H), 7.38 (d, J¼8.8 Hz, 1H),
7.56 (m, 2H), 8.35 (br s, 1H), 8.44 (d, J¼0.9 Hz, 1H). 13C NMR and
DEPT (125 MHz, CDCl3):
d
¼52.18 (CH3), 55.87 (CH3), 56.11 (CH3),
103.23 (CH), 106.55 (CH), 112.14 (CH) 116.02 (CH), 116.39 (CH),
121.58 (C), 123.66 (C), 124.37 (C), 133.82 (C), 134.41 (C), 145.27 (C),
154.56 (C), 168.12 (C]O). MS (EI): m/z (%)¼285 (100, Mþ), 270 (74),
254 (10), 242 (8), 224 (8), 211 (8), 183 (5), 168 (5), 142 (6), 127 (13),
120 (5), 105 (5). Anal. Calcd (%) for C16H15NO4: C 67.36, H 5.30,
N 4.91. Found: C 67.33, H 5.49, N 4.96.
4.4. Clausenine (1,6-dimethoxy-3-methyl-9H-carbazole) (1)
and 1,6-dimethoxy-3-(3-hydroxymethyl-1,6-dimethoxy-9H-
carbazol-9-yl)methyl-9H-carbazole (13)
Compound 7: UV (MeOH): lmax¼223, 242, 251, 268, 285, 326,
339 (sh), 356 (sh) nm. IR (ATR):
n
¼3339, 3237, 2955, 2921, 2850,
1672, 1614, 1589, 1504, 1460, 1435, 1342, 1315, 1283, 1244, 1205,
1182, 1088, 1002, 918, 879, 847, 806, 731, 656 cmꢁ1 1H NMR
(500 MHz, DMSO-d6):
A 1 M solution of lithium aluminium hydride in tetrahydrofuran
(1.3 mL, 1.3 mmol) was added within 5 min at room temperature to
a solution of methyl 1,6-dimethoxy-9H-carbazole-3-carboxylate
(11) (Rf¼0.53, petroleum ether/ethyl acetate 1:1) (92.3 mg,
0.325 mmol) in tetrahydrofuran (9 mL). The mixture was heated at
reflux for 4 h. Water was carefully added and the mixture was
neutralised with 1 M hydrochloric acid. The aqueous layer was
separated and extracted four times with dichloromethane. The
combined organic layers were washed with brine, dried over
magnesium sulfate and the solvent was removed in vacuum. Pu-
rification of the residue by flash chromatography on silica gel
(petroleum ether/ethyl acetate 9:1) afforded clausenine (1,6-
.
d
¼3.84 (s, 3H), 6.91 (dd, J¼8.6, 2.3 Hz, 1H),
7.31 (d, J¼8.6 Hz, 1H), 7.40 (d, J¼1.2 Hz, 1H), 7.41 (d, J¼2.3 Hz, 1H),
8.15 (d, J¼1.2 Hz, 1H), 8.31 (br s, 1H), 10.0 (br s, 1H), 11.21 (s, 1H). 13C
NMR and DEPT (125 MHz, DMSO-d6):
d¼51.70 (CH3), 104.92 (CH),
109.62 (CH), 112.18 (CH), 114.12 (CH), 115.60 (CH), 119.72 (C), 123.13
(C), 123.67 (C), 133.34 (C), 134.15 (C), 142.72 (C), 150.99 (C), 167.12
(C]O). MS (ESI, ꢁ10 V): m/z¼256 (MꢁH)ꢁ, 513 (2MꢁH)ꢁ. MS (EI):
m/z (%)¼257 (100, Mþ), 256 (9), 226 (40), 198 (16), 170 (4), 169 (4),
113 (8). HRMS: m/z calcd for C14H11NO4: 257.0688, found: 257.0697.
Compound 16: UV (MeOH): lmax¼223, 239, 248, 258, 268, 286,
324, 353 (sh) nm. IR (ATR):
n
¼3327, 3015, 2955, 2924, 2846, 2476,

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C. Borger, H.-J. Knolker / Tetrahedron 68 (2012) 6727e6736
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1698, 1681, 1608, 1583, 1500, 1460, 1432, 1329, 1294, 1273, 1234,
1212, 1108, 1033, 985, 950, 911, 890, 856, 802, 768, 754, 729,
113.50 (CH), 116.86 (CH), 120.81 (CH), 124.44 (C), 124.87 (C), 130.71
(C), 135.45 (C), 135.80 (C), 147.27 (C), 155.60 (C), 191.72 (CHO). MS
(EI): m/z (%)¼255 (100, Mþ), 240 (67), 225 (5), 224 (5), 212 (6), 184
(4). HRMS: m/z calcd for C15H13NO3: 255.0895, found: 255.0885.
672 cmꢁ1. 1H NMR (500 MHz, acetone-d6):
d
¼3.90 (s, 3H), 4.04 (s,
3H), 7.04 (dd, J¼8.7, 2.4 Hz, 1H), 7.46 (d, J¼8.7 Hz, 1H), 7.53 (d,
J¼1.1 Hz, 1H), 7.59 (d, J¼2.4 Hz, 1H), 8.14 (s, 1H), 8.37 (s, 1H), 10.51
(br s,1H). 13C NMR and DEPT (125 MHz, acetone-d6):
d¼52.01 (CH3),
4.8. Clausine Z (3-formyl-1,6-dihydroxy-9H-carbazole) (6) and
isoclausine I (3-formyl-6-hydroxy-1-methoxy-9H-carbazole) (17)
55.98 (CH3), 105.97 (CH), 106.74 (CH), 113.12 (CH), 116.60 (CH),
116.76 (CH), 121.68 (C), 124.12 (C), 125.09 (C), 134.70 (C), 135.49 (C),
146.29 (C), 152.47 (C), 168.02 (C]O). MS (EI): m/z (%)¼272 (100),
271 (91, Mþ), 270 (7), 257 (31), 256 (28), 241 (17), 240 (14), 213 (5),
212 (6), 199 (6), 198 (9), 197 (7), 170 (7), 169 (7), 121 (7), 120 (7).
HRMS: m/z calcd for C15H13NO4: 271.0845, found: 271.0856.
A 1 M solution of boron tribromide in dichloromethane (250
m
L,
0.250 mmol) was added at ꢁ78 ꢀC to
a solution of 6-
methoxymurrayanine (3-formyl-1,6-dimethoxy-9H-carbazole) (2)
(23.5 mg, 0.083 mmol) in dichloromethane (5 mL). The solution
was allowed to warm slowly to room temperature in 24 h. Meth-
anol (1.5 mL) was added and the solvents were removed in vacuum.
Purification of the residue by flash chromatography on silica gel
(petroleum ether/ethyl acetate 1:1) afforded clausine Z (3-formyl-
1,6-dihydroxy-9H-carbazole) (6) as colourless crystals, yield:
4.7 mg (24%), mp 151 ꢀC (decomp.), along with isoclausine I (3-
formyl-6-hydroxy-1-methoxy-9H-carbazole) (17) as colourless
crystals, yield: 14.7 mg (73%) mp 229e230.5 ꢀC.
4.6. 3-Hydroxymethyl-1,6-dimethoxy-9H-carbazole (12)
A 1.5 M solution of diisobutylaluminium hydride in toluene
(380
m
L, 0.570 mmol) was added in 5 min at ꢁ78 ꢀC to a solution of
methyl 1,6-dimethoxy-9H-carbazole-3-carboxylate (11) (109 mg,
0.385 mmol) in diethyl ether (10 mL). After stirring for 1.5 h at this
temperature, a further portion of a 1.5 M solution of diisobutyl-
aluminium hydride in toluene (280 mL, 0.420 mmol) was added in
Compound 6: UV (MeOH): lmax¼226, 246, 279, 298, 342,
5 min and stirring was continued for 2 h. The solution was allowed
to warm to room temperature and ice water was added. The
aqueous layer was separated and extracted with diethyl ether four
times. The combined organic layers were washed with water, dried
over magnesium sulfate and the solvents were removed under
reduced pressure. Purification of the residue by flash chromato-
graphy on silica gel (petroleum ether/ethyl acetate 3:1 to 1:3)
afforded 3-hydroxymethyl-1,6-dimethoxy-9H-carbazole (12) as
colourless crystals, yield: 85.9 mg (87%), mp 114.5e115.5 ꢀC.
UV (MeOH): lmax¼226, 246, 257, 265 (sh), 286 (sh), 298, 337,
355 nm. IR (ATR):
n
¼3219, 2922, 2853, 1657, 1579, 1457, 1327, 1196,
1136, 958, 851, 800, 711 cmꢁ1 1H NMR (500 MHz, DMSO-d6):
.
d
¼6.93 (dd, J¼8.6, 2.4 Hz, 1H), 7.24 (d, J¼1.0 Hz, 1H), 7.34 (d,
J¼8.6 Hz,1H), 7.44 (d, J¼2.4 Hz, 1H), 8.13 (d, J¼1.0 Hz, 1H), 9.12 (br s,
1H), 9.90 (s, 1H), 10.29 (br s, 1H), 11.41 (br s, 1H). 13C NMR (125 MHz,
DMSO-d6):
d
¼104.93 (CH), 106.44 (CH), 112.42 (CH), 115.73 (CH),
118.88 (CH), 123.15 (C), 123.84 (C), 128.71 (C), 134.04 (C), 134.48 (C),
143.65 (C), 151.30 (C), 191.72 (CHO). MS (EI): m/z (%)¼227 (100, Mþ),
226 (60), 198 (27), 197 (24), 170 (13), 169 (10). HRMS: m/z calcd for
C13H9NO3: 227.0582, found: 227.0573.
351 nm. IR (ATR):
n
¼3445, 3188, 2998, 2934, 2889, 2834, 1617,1582,
Compound 17: UV (MeOH): lmax¼221, 240, 253, 277, 297, 340,
1505, 1486, 1459, 1438, 1395, 1309, 1266, 1238, 1214, 1189, 1146,
352 nm. IR (ATR):
n
¼3359, 3304, 3003, 2922, 2848, 2507, 2456,
1039, 1018, 985, 941, 863, 832, 803, 774, 756, 693, 668, 617 cmꢁ1. 1H
1655, 1627, 1574,1493, 1463,1388, 1371, 1330,1297, 1257, 1207, 1132,
1035, 996, 954, 852, 807, 793, 760, 734, 712, 672 cmꢁ1 1H NMR
(500 MHz, acetone-d6):
NMR (500 MHz, CDCl3):
d
¼3.92 (s, 3H), 4.01 (s, 3H), 4.83 (s, 2H),
.
6.93 (d, J¼0.8 Hz, 1H), 7.06 (dd, J¼8.7, 2.5 Hz, 1H), 7.35 (d, J¼8.7 Hz,
d¼4.07 (s, 3H), 7.06 (dd, J¼8.6, 2.4 Hz, 1H),
1H), 7.50 (d, J¼2.5 Hz, 1H), 7.61 (s, 1H), 8.14 (br s, 1H). 13C NMR and
7.41 (d, J¼1.0 Hz, 1H), 7.49 (d, J¼8.6 Hz, 1H), 7.62 (d, J¼2.4 Hz, 1H),
DEPT (125 MHz, CDCl3):
d
¼55.67 (CH3), 56.15 (CH3), 66.65 (CH2),
8.25 (d, J¼1.0 Hz, 1H), 10.02 (s, 1H). 13C NMR (125 MHz, acetone-d6):
103.17 (CH), 105.64 (CH), 111.75 (CH), 111.91 (CH) 115.37 (CH),
124.09 (C), 124.13 (C), 130.39 (C), 132.60 (C), 134.50 (C), 145.99 (C),
154.01 (C). MS (EI): m/z (%)¼257 (100, Mþ), 255 (21), 242 (55), 240
(36), 226 (10), 214 (6), 212 (6), 198 (8), 183 (8), 170 (5), 154 (8), 140
(6), 127 (5), 115 (6). Anal. Calcd (%) for C15H15NO3: C 70.02, H 5.88, N
5.44. Found: C 70.19, H 5.82, N 5.58.
d
¼56.05 (CH3), 103.68 (CH), 105.93 (CH), 113.31 (CH), 116.69 (CH),
120.89 (CH), 124.21 (C), 125.18 (C), 130.54 (C), 135.29 (C), 135.56 (C),
147.21 (C), 152.65 (C), 191.75 (CHO). MS (EI): m/z (%)¼241 (100, Mþ),
240 (13), 227 (24), 226 (40), 171 (8), 170 (15), 121 (5). HRMS: m/z
calcd for C14H11NO3: 241.0739, found: 241.0736.
4.7. 6-Methoxymurrayanine (3-formyl-1,6-dimethoxy-9H-
4.9. Methyl 3-hydroxy-4-nitrobenzoate (19)
carbazole) (2)
Concentrated sulfuric acid (0.5 mL) was added slowly to a solu-
tion of 3-hydroxy-4-nitrobenzoic acid (18) (1.88 g, 10.3 mmol) in
methanol (not dried, HPLC grade, 60 mL) and the solution was
heated under reflux for 18 h. Sodium bicarbonate was added and
the solvent was removed under reduced pressure. Water and ethyl
acetate were added to the residue and the aqueous layer was
separated. The aqueous layer was extracted five times with ethyl
acetate. The combined organic layers were washed twice with
brine, dried over magnesium sulfate and the solvent was removed
under reduced pressure to afford methyl 3-hydroxy-4-
nitrobenzoate (19) as yellow crystals, yield: 2.00 g (99%), mp
89.5e90.5 ꢀC (lit.: 86e88 ꢀC,38 91e92 ꢀC39).
Manganese(IV) oxide (77.5 mg, 0.892 mmol) was added to a so-
lution of 3-hydroxymethyl-1,6-dimethoxy-9H-carbazole (12)
(45.9 mg, 0.178 mmol) in dichloromethane (10 mL) and the sus-
pension was stirred for 24 h at room temperature. The suspension
was filtered using dichloromethane over silica gel and the solvent
was removed under reduced pressure. Purification of the residue by
flash chromatography on silica gel (petroleum ether/ethyl acetate
1:1) afforded 6-methoxymurrayanine (3-formyl-1,6-dimethoxy-
9H-carbazole) (2) as colourless crystals, yield: 45.5 mg (100%), mp
230.5e231.5 ꢀC (lit.:11 231e233 ꢀC).
UV (MeOH): lmax¼221 (sh), 240, 253, 277, 296, 337, 350 nm. IR
(ATR):
n
¼3138, 3010, 2921, 2852, 1655, 1628, 1608, 1578, 1496, 1466,
UV (MeOH): lmax¼238, 270, 351 nm. IR (ATR):
3050, 2962, 2842, 1720, 1622, 1587, 1521, 1476, 1434, 1323, 1283,
1222, 1147, 1098, 1067, 967, 891, 843, 798, 780, 743, 666 cmꢁ1 1H
n
¼3310, 3124,
1437, 1360, 1327, 1305, 1262, 1239, 1217, 1185, 1139, 1105, 1031, 1023,
944, 844, 805, 782, 749, 705, 668 cmꢁ1. 1H NMR (500 MHz, acetone-
.
d6):
d
¼3.92 (s, 3H), 4.08 (s, 3H), 7.12 (dd, J¼8.8, 2.4 Hz, 1H), 7.43 (d,
NMR (500 MHz, CDCl3):
d
¼3.96 (s, 3H), 7.61 (dd, J¼8.8, 1.7 Hz, 1H),
J¼1.0 Hz, 1H), 7.56 (d, J¼8.8 Hz, 1H), 7.79 (d, J¼2.4 Hz, 1H), 8.34 (d,
7.83 (d, J¼1.7 Hz, 1H), 8.17 (d, J¼8.8 Hz, 1H), 10.50 (s, 1H). 13C NMR
J¼1.0 Hz, 1H), 10.03 (s, 1H), 10.83 (br s, 1H). 13C NMR (125 MHz,
and DEPT (125 MHz, CDCl3):
(CH), 125.41 (CH), 135.90 (C), 138.10 (C), 154.79 (C), 164.97 (C]O).
d
¼53.08 (CH3), 120.73 (CH), 121.80
acetone-d6):
d¼56.06 (CH3), 56.08 (CH3), 103.64 (CH), 103.78 (CH),

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MS (ESI, ꢁ10 V): m/z¼196 (MꢁH)ꢁ. Anal. Calcd (%) for C8H7NO5:
0.787 mmol), palladium(II) acetate (10.6 mg, 0.047 mmol), SPhos
(38.8 mg, 0.094 mmol) and caesium carbonate (359 mg, 1.10 mmol)
in toluene (16 mL). After stirring for 64 h at 80 ꢀC, the solvent was
removed under reduced pressure. The residue was directly sub-
mitted to flash chromatography on silica gel (petroleum ether/ethyl
C 48.74, H 3.58, N 7.10. Found: C 48.58, H 3.44, N 7.25.
4.10. Methyl 3-benzyloxy-4-nitrobenzoate (20)
Potassium carbonate (771 mg, 5.75 mmol) and then benzyl
acetate
4:1)
to
provide
methyl
3-benzyloxy-4-(4-
bromide (692
m
L, 5.83 mmol) were added to a solution of methyl 3-
methoxyphenylamino)benzoate (21) as colourless solid, yield:
257 mg (90%), mp 92.5e94 ꢀC along with 16.2 mg (8%) of unreacted
methyl 4-amino-3-benzyloxybenzoate (9b).
hydroxy-4-nitrobenzoate (19) (878 mg, 4.45 mmol) in acetone
(27 mL). The suspension was heated under reflux for 17 h and then
water was added. The aqueous layer was separated and extracted
four times with ethyl acetate. The combined organic layers were
washed twice with 2 M aqueous sodium hydroxide solution, twice
with a saturated aqueous solution of ammonium chloride, and
twice with brine. The combined organic layers were dried over
magnesium sulfate and the solvents were removed in vacuum.
Purification of the residue by flash chromatography on silica gel
(petroleum ether/ethyl acetate 4:1) afforded methyl 3-benzyloxy-
4-nitrobenzoate (20) as light yellow crystals, yield: 1.28 g (100%),
mp 93e94.5 ꢀC (lit.:35 91e93 ꢀC).
UV (MeOH): lmax¼235 (sh), 325 nm. IR (ATR): ¼3402, 3035,
n
2991, 2947, 2835, 1701, 1598, 1508, 1437, 1355, 1272, 1220, 1179,
1123, 1101, 1012, 907, 872, 825, 760, 696 cmꢁ1. 1H NMR (500 MHz,
CDCl3):
d
¼3.81 (s, 3H), 3.87 (s, 3H), 5.18 (s, 2H), 6.35 (br s, 1H), 6.90
(dd, J¼8.6, 2.2 Hz, 2H), 6.93 (d, J¼8.4 Hz, 1H), 7.15 (d, J¼8.6 Hz, 2H),
7.38 (tt, J¼7.3, 1.4 Hz, 1H), 7.43 (tt, J¼6.9, 1.3 Hz, 2H), 7.49 (dd, J¼7.9,
1.6 Hz, 2H), 7.58 (dd, J¼8.4, 1.4 Hz, 1H), 7.62 (d, J¼1.4 Hz, 1H). 13C
NMR and DEPT (125 MHz, CDCl3):
d¼51.85 (CH3), 55.63 (CH3), 70.95
(CH2), 110.07 (CH), 112.27 (CH), 114.79 (2 CH), 118.99 (C), 124.49
(CH),124.89 (2 CH),128.15 (2 CH),128.48 (CH),128.82 (2 CH),133.26
(C), 136.54 (C), 140.44 (C), 145.22 (C), 156.59 (C), 167.34 (C]O). MS
(ESI, 10 V): m/z¼364 (MþH)þ, 727 (2MþH)þ. Anal. Calcd (%) for
C22H21NO4: C 72.71, H 5.82, N 3.85. Found: C 71.92, H 5.60, N 4.02.
UV (MeOH): lmax¼241 (sh), 266 (sh), 327 nm. IR (ATR): ¼3118,
n
3085, 3061, 3037, 2964, 2878, 1730, 1606, 1525, 1497, 1440, 1422,
1384, 1372, 1297, 1269, 1235, 1213, 1190, 1115, 1083, 1003, 979, 918,
883, 852, 831, 802, 743, 700 cmꢁ1 1H NMR (500 MHz, CDCl3):
.
d
¼3.96 (s, 3H), 5.29 (s, 2H), 7.35 (t, J¼7.4 Hz, 1H), 7.40 (t, J¼7.4 Hz,
4.13. Methyl 1-benzyloxy-6-methoxy-9H-carbazole-3-
carboxylate (22)
2H), 7.47 (d, J¼7.4 Hz, 2H), 7.70 (dd, J¼8.4, 1.6 Hz, 1H), 7.83 (d,
J¼1.6 Hz, 1H), 7.85 Hz (d, J¼8.4 Hz, 1H). 13C NMR and DEPT
(125 MHz, CDCl3):
d
¼53.01 (CH3), 71.49 (CH2), 116.17 (CH), 121.84
Method A (2 equiv of palladium(II) acetate). A solution of methyl
3-benzyloxy-4-(4-methoxyphenylamino)benzoate (21) (241 mg,
0.663 mmol) and palladium(II) acetate (298 mg, 1.33 mmol) in
glacial acetic acid (15 mL) was heated at 100 ꢀC for 14 h. The solvent
was removed in vacuum and the residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate 4:1) to
afford methyl 1-benzyloxy-6-methoxy-9H-carbazole-3-carboxy-
late (22) as colourless crystals, yield: 148 mg (62%), mp
174e175 ꢀC along with 7.7 mg (3%) of unreacted methyl 3-benzyl-
oxy-4-(4-methoxyphenylamino)benzoate (21).
Method B (catalytic amounts of palladium(II) acetate). A solu-
tion of methyl 3-benzyloxy-4-(4-methoxyphenylamino)benzoate
(21) (138 mg, 0.381 mmol), palladium(II) acetate (8.5 mg,
0.038 mmol) and potassium carbonate (5.2 mg, 0.038 mmol) in
pivalic acid (400 mg) was heated at 115 ꢀC for 16 h under air. A
further portion of palladium(II) acetate (8.5 mg, 0.038 mmol) was
added and stirring was continued for another 24 h. Dichloro-
methane was added and the solution was washed twice with
a saturated aqueous solution of potassium carbonate. The com-
bined aqueous layers were extracted three times with dichloro-
methane. The combined organic layers were washed with brine,
dried over magnesium sulfate and the solvent was removed in
vacuum. Purification of the residue by flash chromatography on
silica gel (isohexane/ethyl acetate 4:1) afforded methyl 1-
benzyloxy-6-methoxy-9H-carbazole-3-carboxylate (22) as colour-
less crystals, yield: 74.1 mg (54%), mp 174e175 ꢀC along with
23.8 mg (17%) of unreacted methyl 3-benzyloxy-4-(4-
methoxyphenylamino)benzoate (21).
(CH), 125.53 (CH), 127.40 (2 CH), 128.56 (CH), 128.90 (2 CH), 134.92
(C), 135.14 (C), 142.94 (C), 151.56 (C), 165.30 (C]O). MS (ESI, 10 V):
m/z¼305 (MþNH4)þ, 597 (2MþNa)þ. Anal. Calcd (%) for C15H13NO5:
C 62.72, H 4.56, N 4.88. Found: C 62.93, H 4.35, N 4.90.
4.11. Methyl 4-amino-3-benzyloxybenzoate (9b)
Ironpowder (2.62 g, 46.9 mmol) was added carefully to a solution
of methyl 3-benzyloxy-4-nitrobenzoate (20) (1.35 g, 4.69 mmol) in
glacial acetic acid (20 mL). The resulting mixture was stirred for 2 h
at room temperature and then for 2 h at 40 ꢀC. The suspension was
filtered with ethyl acetate over Hyflo Super CelÒ medium and the
solvents were removed under reduced pressure. Water was added
to the residue and the mixture was extracted four times with ethyl
acetate. The combined organic layers were washed with brine, dried
over magnesium sulfate and the solvents were removed under
reduced pressure. Purification of the residue by flash chromatogra-
phy on silica gel (petroleum ether/ethyl acetate 4:1) afforded methyl
4-amino-3-benzyloxybenzoate (9b) as colourless solid, yield: 1.21 g
(100%), mp 99e100 ꢀC (lit.:35 99e101 ꢀC).
UV (MeOH): lmax¼230, 278 (sh), 306 nm. IR (ATR): ¼3475,
n
3447, 3353, 3199, 3080, 3024, 2985, 2945, 1681, 1618, 1578, 1522,
1499, 1438, 1399, 1363, 1315, 1298, 1264, 1219, 1186, 1148, 1106,
1016, 994, 927, 905, 889, 841, 824, 789, 765, 736, 692, 626 cmꢁ1. 1H
NMR (500 MHz, CDCl3):
d
¼3.86 (s, 3H), 4.20 (br s, 2H), 5.12 (s, 2H),
6.69 (dd, J¼6.7, 2.0 Hz, 1H), 7.36 (tt, J¼7.2, 2.5 Hz, 1H), 7.41 (tt, J¼8.0,
2.2 Hz, 2H), 7.46 (d, J¼7.4 Hz, 2H), 7.56 (m, 1H), 7.57 (dd, J¼6.7,
1.8 Hz, 1H). 13C NMR and DEPT (125 MHz, CDCl3):
d
¼51.86 (CH3),
UV (MeOH): lmax¼225 (sh), 238, 248, 258, 268, 285, 321, 334
70.65 (CH2), 112.72 (CH), 113.41 (CH), 119.54 (C), 124.50 (CH), 127.97
(2 CH), 128.34 (CH), 128.75 (2 CH), 136.74 (C), 141.51 (C), 145.38 (C),
167.39 (C]O). MS (EI): m/z (%)¼257 (34, Mþ), 226 (6), 166 (44),
138 (9), 91 (100), 79 (6), 65 (9), 52 (5). Anal. Calcd (%) for
C15H15NO3: C 70.02, H 5.88, N 5.44. Found: C 69.86, H 5.92, N 5.35.
(sh), 350 (sh) nm. IR (ATR):
n
¼3380, 3090, 3031, 2921, 2849, 1707,
1688, 1678, 1612, 1581, 1499, 1484, 1437, 1406, 1337, 1306, 1267,
1232, 1203, 1176, 1129, 1093, 1024, 993, 956, 912, 883, 857, 839, 811,
796, 756, 729, 686, 622 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d
¼3.93 (s,
3H), 3.98 (s, 3H), 5.29 (s, 2H), 7.09 (dd, J¼8.8, 2.5 Hz, 1H), 7.36 (d,
J¼8.8 Hz, 1H), 7.40 (tt, J¼7.4, 1.4 Hz, 1H), 7.44 (tt, J¼7.2, 1.4 Hz, 2H),
7.53 (dd, J¼7.8, 1.4 Hz, 2H), 7.57 (d, J¼2.5 Hz, 1H), 7.68 (d, J¼1.0 Hz,
1H), 8.38 (br s, 1H), 8.46 (d, J¼1.0 Hz, 1H). 13C NMR and DEPT
4.12. Methyl 3-benzyloxy-4-(4-methoxyphenylamino)
benzoate (21)
(125 MHz, CDCl3):
(CH), 107.68 (CH), 112.13 (CH), 116.08 (CH), 116.62 (CH), 121.53 (C),
123.82 (C), 124.36 (C), 128.29 (2 CH), 128.56 (CH), 128.85 (2 CH),
d
¼52.20 (CH3), 56.10 (CH3), 70.78 (CH2), 103.22
4-Bromoanisole (8) (108
mL, 0.860 mmol) was added to a solu-
tion of methyl 4-amino-3-benzyloxybenzoate (9b) (202 mg,

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C. Borger, H.-J. Knolker / Tetrahedron 68 (2012) 6727e6736
6734
133.87 (C), 134.42 (C), 136.57 (C), 144.48 (C), 154.57 (C), 168.06
(C]O). MS (ESI, 25 V): m/z¼362 (MþH)þ, 379 (MþNH4)þ,
384 (MþNa)þ, 723 (2MþH)þ, 740 (2MþNH4)þ, 745 (2MþNa)þ.
Anal. Calcd (%) for C22H19NO4: C 73.12, H 5.30, N 3.88. Found:
C 72.91, H 5.41, N 3.92.
(C). MS (ESI, ꢁ10 V): m/z¼316 (MꢁH)ꢁ Anal. Calcd (%) for
C21H19NO2: C 79.47, H 6.03, N 4.41. Found: C 79.55, H 5.77, N 4.38.
Compound 24: UV (MeOH): lmax¼222, 238 (sh), 250 (sh), 272
(sh), 291, 299 (sh), 339 nm. IR (ATR):
n
¼3326, 3064, 3028, 2922,
2852, 1721, 1676, 1580, 1466, 1434, 1310, 1262, 1203, 1137, 1024, 942,
910, 836, 799, 735, 696, 621 cmꢁ1 1H NMR (500 MHz, CDCl3):
.
d
¼3.86 (s, 3H), 3.93 (s, 3H), 4.85 (s, 2H), 4.90 (s, 2H), 5.12 (s, 2H),
4.14. Clausine G (methyl 1-hydroxy-6-methoxy-9H-carbazole-3
-carboxylate) (5)
5.96 (s, 2H), 6.63 (d, J¼0.9 Hz, 1H), 7.00 (dd, J¼8.8, 2.5 Hz, 1H), 7.05
(dd, J¼8.8, 2.5 Hz, 1H), 7.03e7.06 (m, 1H), 7.18e7.21 (m, 3H),
7.25e7.27 (m, 1H), 7.29 (d, J¼8.8 Hz, 1H), 7.30e7.32 (m, 3H),
7.32e7.35 (m, 6H), 7.58 (d, J¼2.2 Hz, 1H), 7.74 (d, J¼1.3 Hz, 1H), 8.07
A suspension of methyl 1-benzyloxy-6-methoxy-9H-carbazole-
3-carboxylate (22) (76.5 mg, 0.212 mmol) and palladium on acti-
vated carbon (10% Pd) (15.3 mg) in dichloromethane (5 mL) and
methanol (5 mL) was stirred under hydrogen (1 atm) for 18 h at
room temperature. The reaction mixture was filtered with
dichloromethane over a short pad of CeliteÒ 557 and the solvents
were removed in vacuum. Purification of the residue by flash
chromatography on silica gel (petroleum ether/ethyl acetate 2:1)
afforded clausine G (methyl 1-hydroxy-6-methoxy-9H-carbazole-
3-carboxylate) (5) as beige crystals, yield: 51.0 mg (89%), mp
145e147 ꢀC (lit.:14 >280 ꢀC).
(br s, 1H). 13C NMR and DEPT (125 MHz, CDCl3):
d
¼49.42 (CH2),
56.14 (CH3), 56.24 (CH3), 66.43 (CH2), 70.25 (CH2), 70.85 (CH2),
102.93 (CH), 103.32 (CH), 105.73 (CH), 108.17 (CH), 110.51 (CH),
110.70 (CH), 111.73 (CH), 112.16 (CH), 115.35 (CH), 115.49 (CH),
123.51 (C), 123.97 (C), 124.32 (C), 124.89 (C), 127.77 (2 CH), 128.01 (2
CH), 128.26 (CH), 128.58 (2 CH), 128.67 (CH), 128.72 (2 CH), 129.81
(C), 129.83 (C), 130.64 (C), 131.94 (C), 134.29 (C), 136.03 (C), 136.56
(C), 136.63 (C), 136.68 (C), 144.81 (C), 146.31 (C), 153.69 (C). MS (ESI,
10 V): m/z¼647 (MþHeH2)þ (ESI, 75 V): m/z¼631 (MꢁOH)þ.
UV (MeOH): lmax¼224, 241, 250, 268, 284, 325 (sh), 334,
4.16. Clausenol(1-hydroxy-6-methoxy-3-methyl-9H-carbazole)
(3)
349 nm. IR (ATR):
n
¼3355, 2952, 2922, 2833, 1667, 1630, 1612, 1582,
1500, 1471, 1455, 1431, 1355, 1322, 1297, 1251, 1202, 1172, 1125, 1087,
1026, 1001, 916, 871, 828, 793, 765, 751, 723, 658 cmꢁ1 1H NMR
(500 MHz, acetone-d6):
.
A suspension of 1-benzyloxy-6-methoxy-3-methyl-9H-carba-
zole (23) (59.5 mg, 0.187 mmol) and palladium on activated carbon
(10% Pd) (11.9 mg) in dichloromethane (7 mL) and methanol (7 mL)
was stirred under a hydrogen atmosphere for 40 h at room tem-
perature. The reaction mixture was filtered using dichloromethane
over a small plug of CeliteÒ 557 fine and the solvents were removed
under reduced pressure. Purification of the residue by flash chro-
matography on silica gel (petroleum ether/ethyl acetate 2:1)
afforded clausenol (1-hydroxy-6-methoxy-3-methyl-9H-carba-
zole) (3) as beige crystals, yield: 42.5 mg (100%), mp 190.5e191 ꢀC
(lit.:12 192 ꢀC).
d
¼3.88 (s, 3H), 3.92 (s, 3H), 7.08 (dd, J¼8.8,
2.5 Hz, 1H), 7.52 (d, J¼8.8 Hz, 1H), 7.55 (d, J¼1.1 Hz, 1H), 7.77 (d,
J¼2.5 Hz, 1H), 8.37 (d, J¼1.1 Hz, 1H), 9.04 (br s, 1H), 10.45 (br s, 1H).
13C NMR (125 MHz, acetone-d6):
d¼51.91 (CH3), 56.07 (CH3), 103.59
(CH), 111.10 (CH), 113.23 (CH), 115.71 (CH), 116.67 (CH), 121.96 (C),
124.94 (C), 124.98 (C), 134.35 (C), 136.09 (C), 143.46 (C), 155.26 (C),
168.01 (C]O). MS (ESI, 10 V): m/z¼272 (MþH)þ, 543 (2MþH)þ,
560 (2MþNH4)þ, 565 (2MþNa)þ. Anal. Calcd (%) for C15H13NO4:
C 66.41, H 4.83, N 5.16. Found: C 66.43, H 4.95, N 4.76.
4.15. 1-Benzyloxy-6-methoxy-3-methyl-9H-carbazole (23) and
1-benzyloxy-3-(1-benzyloxy-3-hydroxymethyl-6-methoxy-9H-
carbazol-9-yl)methyl-6-methoxy-9H-carbazole (24)
UV (MeOH): lmax¼227, 242, 292 (sh), 299, 343, 357 nm. IR
(ATR):
n
¼3367, 3228, 2921, 2851, 1652, 1621, 1590, 1578, 1520, 1481,
1457, 1434, 1388, 1318, 1298, 1269, 1210, 1178, 1142, 1095, 1024,
1005, 988, 943, 871, 833, 796, 748, 662, 623 cmꢁ1 1H NMR
(500 MHz, DMSO-d6):
.
A 1 M solution of lithium aluminium hydride in tetrahydrofuran
(1.2 mL, 1.2 mmol) was added within 5 min at room temperature to
d
¼2.37 (s, 3H), 3.81 (s, 3H), 6.61 (s, 1H), 6.95
(dd, J¼8.7, 2.5 Hz, 1H), 7.31 (s, 1H), 7.32 (d, J¼8.7 Hz, 1H), 7.51 (d,
a
solution of methyl 1-benzyloxy-6-methoxy-9H-carbazole-3-
J¼2.5 Hz, 1H), 9.59 (s, 1H), 10.64 (br s, 1H). 13C NMR (125 MHz,
carboxylate (22) (108 mg, 0.298 mmol) in tetrahydrofuran
(14 mL). The mixture was heated under reflux for 7 h and then,
water was added slowly. The aqueous layer was separated and
extracted four times with diethyl ether. The combined organic
layers were washed with brine, dried over magnesium sulfate and
the solvents were removed under reduced pressure. Purification of
the residue by flash chromatography on silica gel (petroleum ether/
ethyl acetate 6:1 to 1:1) afforded 1-benzyloxy-6-methoxy-3-
methyl-9H-carbazole (23) as colourless crystals, yield: 89.4 mg
(94%), mp 119.5e120 ꢀC along with 1-benzyloxy-3-(1-benzyloxy-3-
hydroxymethyl-6-methoxy-9H-carbazol-9-yl)methyl-6-methoxy-
9H-carbazole (24) as a colourless solid, yield 5.7 mg (3%).
DMSO-d6):
d
¼21.36 (CH3), 55.53 (CH3), 102.65 (CH), 110.90 (CH),
111.36 (CH), 111.89 (CH), 114.37 (CH), 122.98 (C), 123.98 (C), 127.43
(C), 128.45 (C), 134.72 (C), 142.86 (C), 152.66 (C). MS (ESI, ꢁ10 V):
m/z¼226 (MꢁH)ꢁ, 453 (2MꢁH)ꢁ.
4.17. 1-Benzyloxy-3-hydroxymethyl-6-methoxy-9H-carbazole
(25)
A 1.5 M solution of diisobutylaluminium hydride in toluene
(220
tion
m
L, 0.330 mmol) was added within 5 min at ꢁ78 ꢀC to a solu-
of
methyl
1-benzyloxy-6-methoxy-9H-carbazole-3-
carboxylate (22) (77.9 mg, 0.216 mmol) in diethyl ether (15 mL).
Compound 23: UV (MeOH): lmax¼223, 226, 242, 259 (sh), 287
After stirring for 1.5 h at this temperature, an additional portion of
a 1.5 M solution of diisobutylaluminium hydride in toluene (160 mL,
(sh), 299, 341, 355 nm. IR (ATR):
n
¼3437, 3033, 2998, 2917, 2828,
1618, 1578, 1504, 1480, 1459, 1432, 1393, 1379, 1315, 1305, 1264,
1210, 1180, 1145, 1125, 1038, 1027, 969, 948, 905, 841, 826, 802, 769,
0.240 mmol) was added within 5 min and stirring was continued
for 2 h. Water (2 mL) was added and the solution was allowed to
warm to room temperature. Additional water was added, the
aqueous layer was separated and extracted with diethyl ether four
times. The combined organic layers were washed with brine, dried
over magnesium sulfate and the solvents were removed under
reduced pressure. Purification of the residue by flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate 1:1) afforded
1-benzyloxy-3-hydroxymethyl-6-methoxy-9H-carbazole (25) as
colourless crystals, yield: 67.9 mg (95%), mp 120e120.5 ꢀC.
737, 697, 621 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d¼2.53 (s, 3H), 3.92
(s, 3H), 5.23 (s, 2H), 6.81 (s, 1H), 7.04 (dd, J¼8.7, 2.5 Hz, 1H), 7.31 (d,
J¼8.7 Hz, 1H), 7.39 (t, J¼7.3 Hz, 1H), 7.44 (t, J¼7.3 Hz, 2H) 7.47 (s,
1H), 7.50 (d, J¼2.5 Hz, 1H), 7.52 (d, J¼6.9 Hz, 2H), 8.04 (br s, 1H). 13C
NMR and DEPT (125 MHz, CDCl3):
d
¼22.06 (CH3), 56.15 (CH3), 70.49
(CH2), 103.19 (CH), 108.89 (CH), 111.73 (CH), 112.83 (CH), 115.06
(CH), 124.00 (C), 124.54 (C), 128.03 (2 CH), 128.31 (CH), 128.77 (2
CH), 129.10 (C), 129.14 (C), 134.55 (C), 137.13 (C), 144.80 (C), 153.79

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C. Borger, H.-J. Knolker / Tetrahedron 68 (2012) 6727e6736
6735
UV (MeOH): lmax¼226, 247, 258, 287 (sh), 298, 324 (sh), 338,
352 nm. IR (ATR):
¼3488, 3278, 3030, 2990, 2929, 2828, 1618,
1581, 1505, 1485, 1463, 1434, 1383, 1318, 1299, 1265, 1214, 1144,
1029, 1009, 961, 947, 827, 799, 776, 738, 698, 673 cmꢁ1 1H NMR
(500 MHz, CDCl3):
J¼0.9 Hz, 1H), 7.06 (dd, J¼8.8, 2.4 Hz, 1H), 7.34 (d, J¼8.8 Hz, 1H),
7.35e7.39 (m, 1H), 7.44 (tt, J¼7.3, 1.6 Hz, 2H), 7.49e7.52 (m, 3H),
7.64 (d, J¼0.9 Hz, 1H), 8.17 (br s, 1H). 13C NMR and DEPT (125 MHz,
116.76 (CH), 119.60 (CH), 125.04 (C), 125.08 (C), 130.79 (C), 135.43
(C), 136.03 (C), 144.40 (C), 155.47 (C), 191.76 (CHO). MS (EI): m/z
(%)¼241 (100, Mþ), 240 (10), 226 (78),198 (15). HRMS: m/z calcd for
C14H11NO3: 241.0739, found: 241.0735.
n
.
d
¼3.92 (s, 3H), 4.83 (s, 2H), 5.26 (s, 2H), 7.03 (d,
4.20. Clausine Z (3-formyl-1,6-dihydroxy-9H-carbazole) (6)
A 1 M solution of boron tribromide in dichloromethane (510 mL
0.510 mmol) was added at ꢁ78 ꢀC to a solution of 1-benzyloxy-3-
formyl-6-methoxy-9H-carbazole (26) (41.9 mg, 0.126 mmol) in
dichloromethane (10 mL). The solution was allowed to warm
slowly to room temperature over 18 h. Methanol (4 mL) was added
and the solvents were removed in vacuum. Purification of the
residue by flash chromatography on silica gel (petroleum ether/
ethyl acetate 1:1) afforded clausine Z (3-formyl-1,6-dihydroxy-9H-
carbazole) (6) as colourless crystals, yield: 15.8 mg (55%), mp 151 ꢀC
(decomp.).
CDCl3):
d
¼56.15 (CH3), 66.63 (CH2), 70.59 (CH2), 103.17 (CH), 106.84
(CH), 111.90 (CH), 112.05 (CH), 115.45 (CH), 124.08 (C), 124.31 (C),
128.11 (2 CH), 128.44 (CH), 128.83 (2 CH), 130.57 (C), 132.55 (C),
134.51 (C), 136.88 (C), 145.22 (C), 154.03 (C). MS (ESI, 100 V):
m/z¼316 (MꢁOH)þ, 356 (MþNa)þ 631 (2MꢁH2OeOH)þ, 689
(2MþNa)þ. Anal. Calcd (%) for C21H19NO3: C 75.66, H 5.74, N 4.20.
Found: C 75.81, H 5.88, N 4.24.
4.18. 1-Benzyloxy-3-formyl-6-methoxy-9H-carbazole (26)
Spectroscopic data, see above.
Manganese(IV) oxide (63.9 mg, 0.736 mmol) was added to
a solution of 1-benzyloxy-3-hydroxymethyl-6-methoxy-9H-carba-
zole (25) (49.1 mg, 0.147 mmol) in dichloromethane (10 mL) and
the suspension was stirred for 24 h at room temperature. The
suspension was filtered using dichloromethane over silica gel and
the solvent was removed under reduced pressure. Purification of
the residue by flash chromatography on silica gel (petroleum ether/
ethyl acetate 1:1) afforded 1-benzyloxy-3-formyl-6-methoxy-9H-
carbazole (26) as colourless crystals, yield: 48.8 mg (100%), mp
209.5e210 ꢀC.
Acknowledgements
We are grateful to Professor Scott G. Franzblau (Institute for
Tuberculosis Research, University of Illinois at Chicago, USA) for
investigating the anti-TB activity of the carbazoles. We thank Dr.
Margit Gruner (TU Dresden) for the 2D-NMR experiments.
Supplementary data
UV (MeOH): lmax¼240, 255 (sh), 278, 296, 338, 350 nm. IR
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.05.105. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
(ATR):
n
¼3147, 3009, 2924, 2853, 1655, 1632, 1607, 1575, 1497, 1477,
1434,1396,1359,1325,1308,1263,1236,1217,1180,1140, 1031,1021,
952, 924, 874, 839, 812, 786, 752, 709, 699, 682, 632 cmꢁ1. 1H NMR
(500 MHz, CDCl3):
d
¼3.94 (s, 3H), 5.31 (s, 2H), 7.12 (dd, J¼8.8,
2.5 Hz, 1H), 7.40 (d, J¼8.8 Hz, 1H), 7.40 (m, 1H), 7.45 (m, 2H), 7.53 (d,
J¼7.7 Hz, 2H), 7.54 (d, J¼1.0 Hz, 1H), 7.58 (d, J¼2.5 Hz, 1H), 8.19 (d,
J¼1.0 Hz, 1H), 8.50 (br s, 1H), 10.05 (s, 1H). 13C NMR and DEPT
References and notes
€
1. For comprehensive reviews, see: (a) Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002,
€
(125 MHz, CDCl3):
d¼56.12 (CH3), 70.83 (CH2), 103.23 (CH), 104.50
102, 4303e4427; (b) Schmidt, A. W.; Reddy, K. R.; Knolker, H.-J. Chem. Rev. 2012,
112, 3193e3328.
(CH), 112.39 (CH), 116.29 (CH), 120.79 (CH), 123.86 (C), 124.32 (C),
128.32 (2 CH), 128.68 (CH), 128.90 (2 CH), 129.89 (C), 134.29 (C),
134.96 (C), 136.29 (C), 145.46 (C), 154.88 (C), 191.88 (CHO). MS (ESI,
75 V): m/z¼332 (MþH)þ, 354 (MþNa)þ. Anal. Calcd (%) for
C21H17NO3: C 76.12, H 5.17, N 4.23. Found: C 76.12, H 5.16, N 4.10.
€
€
2. (a) Knolker, H.-J. Curr. Org. Synth. 2004, 1, 309e331; (b) Frohner, W.; Krahl, M. P.;
€
Reddy, K. R.; Knolker, H.-J. Heterocycles 2004, 63, 2393e2407.
€
3. Knolker, H.-J.; Reddy, K. R. In The Alkaloids; Cordell, G. A., Ed.; Academic:
Amsterdam, 2008; Vol. 65, pp 1e430.
€
4. Knolker, H.-J. Chem. Lett. 2009, 38, 8e13.
5. (a) Knolker, H.-J. Top. Curr. Chem. 2005, 244, 115e148; (b) Bauer, I.; Knolker, H.-J.
€
€
Top. Curr. Chem. 2012, 309, 203e253.
€
6. Huet, L.; Forke, R.; Knolker, H.-J. Synlett 2012, 1230e1234.
4.19. Clausine I (3-formyl-1-hydroxy-6-methoxy-9H-carbazole)
(4)
€
€
7. Gensch, T.; Ronnefahrt, M.; Czerwonka, R.; Jager, A.; Kataeva, O.; Bauer, I.;
Knolker, H.-J. Chem.dEur. J. 2012, 18, 770e776.
€
8. Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
581e590.
9. Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008, 73,
Aluminium trichloride (176 mg, 1.32 mmol) was added to a so-
lution of 1-benzyloxy-3-formyl-6-methoxy-9H-carbazole (26)
(43.8 mg, 0.132 mmol) in 1,4-dioxane (8 mL) at room temperature.
The reaction mixture was heated under reflux for 3 h, then water
was added. The aqueous layer was separated and extracted with
diethyl ether four times. The combined organic layers were washed
with brine, dried over magnesium sulfate and the solvents were
removed in vacuum. Purification of the residue by flash chroma-
tography on silica gel (petroleum ether/ethyl acetate 1:1) afforded
clausine I (3-formyl-1-hydroxy-6-methoxy-9H-carbazole) (4) as
colourless crystals, yield: 31.8 mg (100%), mp 221.5e223 ꢀC (lit.:13
222e224 ꢀC).
ꢁ
5022e5028.
€
€
10. For a preliminary communication, see: Borger, C.; Knolker, H.-J. Synlett 2008,
1698e1702.
11. Li, W.-S.; McChesney, J. D.; El-Feraly, F. S. Phytochemistry 1991, 30, 343e346.
12. Chakraborty, A.; Chowdhury, B. K.; Bhattacharyya, P. Phytochemistry 1995, 40,
295e298.
13. Wu, T.-S.; Huang, S.-C.; Wu, P.-L.; Teng, C.-M. Phytochemistry 1996, 43, 133e140.
14. Wu, T.-S.; Huang, S.-C.; Wu, P.-L. Phytochemistry 1996, 43, 1427e1429.
15. Potterat, O.; Puder, C.; Bolek, W.; Wagner, K.; Ke, C.; Ye, Y.; Gillardon, F. Phar-
mazie 2005, 60, 637e639.
16. Sripisut, T.; Laphookhieo, S. J. Asian Nat. Prod. Res. 2010, 12, 614e617.
17. Lin, G.; Zhang, A. Tetrahedron Lett. 1999, 40, 341e344.
18. Lin, G.; Zhang, A. Tetrahedron 2000, 56, 7163e7171.
19. Bernal, P.; Benavides, A.; Bautista, R.; Tamariz, J. Synthesis 2007, 1943e1948.
UV (MeOH): lmax¼225 (sh), 242, 255, 278, 296, 340 (sh),
€
20. Gruner, K. K.; Knolker, H.-J. Org. Biomol. Chem. 2008, 6, 3902e3904.
€
€
21. Forke, R.; Jager, A.; Knolker, H.-J. Org. Biomol. Chem. 2008, 6, 2481e2483.
354 nm. IR (ATR):
n
¼3385, 2955, 2919, 2852, 1619, 1581, 1486, 1460,
€
22. Forke, R.; Krahl, M.; Krause, T.; Schlechtingen, G.; Knolker, H.-J. Synlett 2007,
1437, 1393, 1304, 1268, 1207, 1184, 1145, 1130, 1111, 1035, 1025, 940,
268e272.
838, 821, 800, 769, 733, 712, 674 cmꢁ1. 1H NMR (500 MHz, acetone-
€
€
23. Krahl, M. P.; Jager, A.; Krause, T.; Knolker, H.-J. Org. Biomol. Chem. 2006, 4,
3215e3219.
24. Fuchsenberger, M.; Forke, R.; Knolker, H.-J. Synlett 2011, 2056e2058.
25. Schmidt, M.; Knolker, H.-J. Synlett 2009, 2421e2424.
26. Forke, R.; Krahl, M. P.; Dabritz, F.; Jager, A.; Knolker, H.-J. Synlett 2008,
1870e1876.
d6):
d
¼3.92 (s, 3H), 7.11 (dd, J¼8.8, 2.4 Hz,1H), 7.40 (d, J¼0.6 Hz,1H),
€
7.55 (d, J¼8.8 Hz, 1H), 7.77 (d, J¼2.4 Hz, 1H), 8.25 (d, J¼0.6 Hz, 1H),
€
9.27 (s, 1H), 9.99 (s, 1H), 10.64 (br s, 1H). 13C NMR (125 MHz, ace-
€
€
€
tone-d6):
d¼56.05 (CH3), 103.66 (CH), 107.95 (CH), 113.46 (CH),

€ €
C. Borger, H.-J. Knolker / Tetrahedron 68 (2012) 6727e6736
6736
ꢀ
27. Akermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E. J. Org. Chem. 1975, 40,
1365e1367.
38. Walker, D. P.; Wishka, D. G.; Piotrowski, D. W.; Jia, S.; Reitz, S. C.; Yates, K. M.;
Myers, J. K.; Vetman, T. N.; Margolis, B. J.; Jacobsen, E. J.; Acker, B. A.; Groppi, V. E.;
Wolfe, M. L.; Thornburgh, B. A.; Tinholt, P. M.; Cortes-Burgos, L. A.; Walters, R. R.;
Hester, M. R.; Seest, E. P.; Dolak, L. A.; Han, F.; Olson, B. A.; Fitzgerald, L.; Staton, B.
A.; Raub, T. J.; Hajos, M.; Hoffmann, W. E.; Li, K. S.; Higdon, N. R.; Wall, T. M.; Hurst,
R. S.; Wong, E. H. F.; Rogers, B. N. Bioorg. Med. Chem. 2006, 14, 8219e8248.
39. Sathunuru, R.; Rao, U. N.; Biehl, E. Arkivoc 2003, xv, 124e133.
€
28. Knolker, H.-J.; O’Sullivan, N. Tetrahedron 1994, 50, 10893e10908.
29. Sridharan, V.; Martín, M. A.; Menendez, J. C. Synlett 2006, 2375e2378.
30. Bringmann, G.; Tasler, S. Tetrahedron 2001, 57, 2337e2343.
31. Chakraborty, D. P.; Roy, S.; Dutta, A. K. J. Indian Chem. Soc. 1987, 64, 215e217.
32. Winterfeldt, E. Synthesis 1975, 617e630.
ꢁ
€
33. Manganese dioxide (precipitated, active) from Merck (art. 805958).
34. (a) Fatiadi, A. J. Synthesis 1976, 65e104; (b) Knolker, H.-J. J. Prakt. Chem. 1995,
40. (a) Choi, T. A.; Czerwonka, R.; Frohner, W.; Krahl, M. P.; Reddy, K. R.; Franzblau,
€
€
S. G.; Knolker, H.-J. ChemMedChem 2006, 1, 812e815; (b) Choi, T. A.; Czerwonka,
€ €
R.; Forke, R.; Jager, A.; Knoll, J.; Krahl, M. P.; Krause, T.; Reddy, K. R.; Franzblau,
337, 75e77.
€
€
35. Charrier, N.; Demont, E.; Dunsdon, R.; Maile, G.; Naylor, A.; O’Brien, A.; Red-
shaw, S.; Theobald, P.; Vesey, D.; Walter, D. Synthesis 2006, 3467e3477.
36. Rajakumar, P.; Murali, V. Synth. Commun. 2003, 33, 3891e3896.
37. Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.;
Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. Organometallics 2010, 29, 2176e2179.
S. G.; Knolker, H.-J. Med. Chem. Res. 2008, 17, 374e385; (c) Knolker, H.-J. Sit-
€
zungsber. d. Sachs. Akad. d. Wiss. 2008, 131, 1e24.
41. (a) Collins, L. A.; Franzblau, S. G. Antimicrob. Agents Chemother. 1997, 41,
1004e1009; (b) Pauli, G. F.; Case, R. J.; Inui, T.; Wang, Y.; Cho, S.; Fischer, N. H.;
Franzblau, S. G. Life Sci. 2005, 78, 485e494.