Synthesis of 2-hydroxy-7-methylcarbazole, glycozolicine, mukoline, mukolidine, sansoakamine, clausine-H, and clausine-K and structural revision of clausine-TY

Article abstract of DOI:10.1002/ejoc.201402495

A Buchwald-Hartwig amination and palladium(II)-catalyzed oxidative cyclization reaction sequence provided efficient access to a series of oxygenated tricyclic carbazoles. In the present work, this approach was applied to the total syntheses of the natural

Full text of DOI:10.1002/ejoc.201402495

FULL PAPER
DOI: 10.1002/ejoc.201402495
Synthesis of 2-Hydroxy-7-methylcarbazole, Glycozolicine, Mukoline,
Mukolidine, Sansoakamine, Clausine-H, and Clausine-K and Structural
Revision of Clausine-TY[‡]
Christian Schuster,[a] Carsten Börger,[a] Konstanze K. Julich-Gruner,[a] Ronny Hesse,[a]
Anne Jäger,[a] Györley Kaufmann,[a] Arndt W. Schmidt,[a] and Hans-Joachim Knölker*[a]
Keywords: Total synthesis / Alkaloids / Nitrogen heterocycles / Amination / Cyclization / Palladium
A Buchwald–Hartwig amination and palladium(II)-catalyzed
oxidative cyclization reaction sequence provided efficient ac-
cess to a series of oxygenated tricyclic carbazoles. In the
sansoakamine, glycozolidine, clausine-H (clauszoline-C),
clausine-K (clauszoline-J), and methyl 2-hydroxy-7-meth-
oxycarbazole-3-carboxylate, which was originally proposed
present work, this approach was applied to the total synthe- as the structure of clausine-TY. The synthesis of the latter led
ses of the naturally occurring carbazole alkaloids 2-hydroxy-
7-methylcarbazole, glycozolicine, mukoline, mukolidine,
to the structural reassignment of clausine-TY.
Introduction
In 1975, Åkermark and co-workers described first the
oxidative cyclization of diarylamines to carbazoles by
double C–H bond activation using stoichiometric or over-
stoichiometric amounts of palladium(II) acetate.[1] In 1994,
we first demonstrated that the palladium(0) formed in this
reaction could be reoxidized under Wacker-like reaction
conditions, which gave rise to the development of a process
catalytic in palladium.[2] Since then, many applications of
the oxidative cyclization of diarylamines, 2-aminobiphenyls,
and analogues to the syntheses of carbazoles have been re-
ported.[3] Carbazoles are in the focus of research because of
their broad range of biological activities.[4] Naturally occur-
ring carbazole alkaloids have been isolated predominantly
from higher plants of the genera Murraya, Clausena, and
Glycosmis (Rutaceae), but they have also been isolated from
other plants and microorganisms. Herein, we describe the
application of our palladium(II)-catalyzed oxidative cycliza-
tion of diarylamines to the syntheses of 2-hydroxy-7-meth-
ylcarbazole (1), glycozolicine (2), mukoline (3), mukolidine
(4), sansoakamine (5), and 2,7-dioxygenated carbazole-3-
carboxylates 6 and 7 (see Figure 1).
Figure 1. Naturally occurring tricyclic carbazole alkaloids 1–7.
2-Hydroxy-7-methylcarbazole (1) was isolated in 1993 by
Kusano et al. from the butanol extract of the aerial parts
of Cimicifuga simplex (Ranunculaceae), which was collected
in Sendai, Japan.[5] The structural assignment was made on
the basis of the spectroscopic data of 1 and its correspond-
ing acetate. In contrast to most carbazoles that have been
isolated from higher plants, compound 1 does not have the
characteristic one-carbon substituent at C-3 of the carb-
azole skeleton. In 1992, Bhattacharyya et al. isolated glyco-
zolicine (2) from the roots of Glycosmis pentaphylla.[6] Ini-
tially, the structure of glycozolicine (2) had been incorrectly
assigned as 5-methoxy-3-methylcarbazole, but in 2001,
Chakravarty et al. reassigned its structure as 8-methoxy-3-
[‡] Transition Metals in Organic Synthesis, 119. Part 118: K. K.
Julich-Gruner, O. Kataeva, A. W. Schmidt, H.-J. Knölker,
Chem. Eur. J. 2014, DOI: 10.1002/chem.201403143.
[a] Department Chemie, Technische Universität Dresden,
Bergstrasse 66, 01069 Dresden, Germany
E-mail: hans-joachim.knoelker@tu-dresden.de
www.chm.tu-dresden.de/oc2/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402495.
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H.-J. Knölker et al.
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methylcarbazole (2) on the basis of the total syntheses of
both isomeric compounds and the comparison of spectro-
scopic data with those of the natural product.[7] Mukoline
(3) and mukolidine (4) were obtained in 1982 by Chakra-
borty and co-workers from the benzene extract of the roots
of Murraya koenigii Spreng. (Rutaceae).[8] Chakraborty et
al. confirmed the structures for 3 and 4 by their total syn-
theses, which included a Fischer–Borsche cyclization as the
key step. Tamariz et al. described the total syntheses of 3
and 4 by using a Diels–Alder cycloaddition of a 4,5-dimeth-
yleneoxazolidin-2-one and acrolein as the key step.[9] San-
soakamine (5) was isolated by Laphookhieo et al. from the
ethyl acetate extract of the stem of Clausena excavata (Rut-
aceae), which was collected in Thailand. The name of the
natural product is derived from “San Soak”, which is the
local name for C. excavata.[10]
Scheme 1. Palladium-catalyzed synthesis of 2-hydroxy-7-methyl-
carbazole (1). Reagents and conditions: (a) m-toluidine (1.3 equiv.),
Pd(OAc)2 (5 mol-%), SPhos (10 mol-%), Cs2CO3 (1.6 equiv.), tolu-
ene, 100 °C, 38 h, 100%; (b) Pd(OAc)2 (10 mol-%), Cu(OAc)2
(2.5 equiv.), microwave, 100 °C, 5 h, 86% 10, up to 5% 10a;
(c) BBr3 (2.0 equiv.), CH2Cl2, –78 °C to room temp., 4.25 h, 87%.
Clausine-TY was isolated from the ethyl acetate extract
of C. excavata Burm. f. by Taufiq-Yap and co-workers. On
1
the basis of the H and 13C NMR spectroscopic data as
well as the 1H-13C heteronuclear correlation (HETCOR)
data, the structure for clausine-TY was assigned as methyl
2-hydroxy-7-methoxycarbazole-3-carboxylate (6).[11] Thus,
clausine-TY was considered a structural isomer of clausine-
K (7), a compound that was first isolated in 1996 by Wu et
al. from the methanol extract of the stem bark of the same
plant.[12] Ito et al. obtained compound 7 from the extracts
of C. excavata and named it clauszoline-J (7).[13] Since then,
clausine-K (clauszoline-J, 7) has been identified in plant ex-
tracts by other groups as well and has been studied in vari-
ous bioactivity screenings.[4b,14] In 2005, we described the
first total synthesis of clausine-K (clauszoline-J) (7) by em-
ploying our iron-mediated approach to carbazoles.[15]
Our approach to the 8-oxygenated carbazole alkaloids
glycozolicine (2), mukoline (3), and mukolidine (4) started
with a Buchwald–Hartwig amination of o-bromoanisole
(11) (see Scheme 2). The palladium(0)-catalyzed coupling of
11 and p-toluidine provided quantitatively diarylamine 12.
The subsequent oxidative cyclization of 12 by treatment
with catalytic amounts of palladium(II) acetate in the pres-
ence of copper(II) acetate in pivalic acid in air afforded gly-
cozolicine (8-methoxy-3-methylcarbazole) (2) in 89% yield.
Compound 2 previously served as an intermediate in the
Results and Discussion
For the synthesis of 2-hydroxy-7-methylcarbazole (1),
we carried out a Buchwald–Hartwig coupling reaction
of m-bromoanisole (8) and m-toluidine using catalytic
amounts of palladium(II) acetate and 2-dicyclohexylphos-
phino-2Ј,6Ј-dimethoxybiphenyl (SPhos) as ligand (see
Scheme 1).[16] This reaction afforded quantitatively the de-
sired diarylamine 9. The subsequent oxidative cyclization
using 10 mol-% of palladium(II) acetate in the presence of
stoichiometric amounts of copper(II) acetate provided 2-
methoxy-7-methylcarbazole (10) in 86% yield. The oxidat-
ive cyclization also afforded the undesired regioisomer 10a
in up to 5% yield. Presumably, 10a results from the initial
coordination of the palladium(II) cation at the oxygen atom
and subsequent electrophilic attack ortho to the methoxy
group.[17] Finally, cleavage of the methyl ether of 10 by
treatment with boron tribromide at low temperature pro-
vided compound 1. This route represents the first synthetic
approach to 2-hydroxy-7-methylcarbazole (1), which was
obtained in three steps and 75% overall yield. The spectro-
scopic data of synthetic 1 are in full agreement with those
reported for the natural product.[5]
Scheme 2. Synthesis of glycozolicine (2), mukoline (3), and mukoli-
dine (4). Reagents and conditions: (a) p-toluidine (1.2 equiv.),
Pd(OAc)2 (6 mol-%), (Ϯ)-2,2Ј-bis(diphenylphosphino)-1,1Ј-bi-
naphthyl (rac-BINAP, 6 mol-%), Cs2CO3 (1.4 equiv.), toluene, re-
flux, 24 h, 100%; (b) Pd(OAc)2 (30 mol-%), Cu(OAc)2 (2.5 equiv.),
pivalic acid (PivOH), 130 °C, microwave, 75 min, 89%; (c)
DDQ (4.2 equiv.), MeOH/THF/H2O (15:5:1), 50 °C, 50 min, 82%;
(d) LiAlH4 (2.0 equiv.), THF, 0 °C, 10 min, 98%.
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Synthesis and Structural Revision of Clausine-TY
synthetic approaches to mukoline (3) and mukolidine (4), sansoakamine (5) has been additionally confirmed by sin-
as described by Chakraborty and Tamariz.[8,9] The oxi- gle-crystal X-ray structure analysis (see Figure 3).
dation of the methyl group at C-3 of glycozolicine (2) by
treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) provided mukolidine (4) in 82% yield. The re-
duction of 4 with lithium aluminum hydride led to muko-
line (3). Our approach provided mukoline (3) in four steps
and 72% overall yield. The spectroscopic data of the syn-
thetic carbazoles 2–4 were in full agreement with those re-
ported for the corresponding natural products.[6–8] The
structures for mukoline (3) and mukolidine (4) have been
additionally confirmed by single-crystal X-ray analysis (see
Figure 2 and Supporting Information).
Figure 2. Molecular structure of mukoline (3) in the crystal.
ORTEP plot showing thermal ellipsoids at the 50% probability
level.
Scheme 3. Synthesis of sansoakamine (5) and derivatives. Reagents
and conditions: (a) p-anisidine (1.2 equiv.), Pd(OAc)2 (6 mol-%), 2-
dicyclohexylphosphino-2Ј,4Ј,6Ј-triisopropylbiphenyl
(XPhos,
12 mol-%), Cs2CO3 (1.2 equiv.), toluene, 110 °C, 23 h, 96%;
(b) Pd(OAc)2 (15 mol-%), Cu(OAc)2 (2.5 equiv.), PivOH, 130 °C,
microwave, 1 h, 86%; (c) BBr3 (4.9 equiv.), CH2Cl2, –78 °C to 0 °C,
55 min, 83%; (d) KOH (99 equiv.), EtOH/H2O (2.7:1), reflux,
35 min, 91%; (e) BBr3 (5.7 equiv.), CH2Cl2, –78 °C to room temp.,
95 min, 81%; (f) LiAlH4 (6.0 equiv.), THF, reflux, 6 h, 43% 18 and
41% 19.
In 2010, Sripisut and Laphookhieo described the isola-
tion of the two new naturally occurring carbazole alkaloids,
methyl 1,6-dihydroxy-9H-carbazole-3-carboxylate and san-
soakamine (5).[10] The synthesis of the former compound
was previously reported by our group in 2008, prior to its
isolation.[18] In the following year, we reported that our pal-
ladium-catalyzed approach provided broad access to 2,6-
dioxygenated carbazole alkaloids.[19] By using the palla-
dium-catalyzed method, we completed, in 2012, the first to-
tal synthesis of sansoakamine (5) in three steps and 49%
overall yield based on compound 13.[20] In 2014, Das et al.
reported an additional synthesis, which afforded sansoaka-
mine (5) in four steps and 40% overall yield by a copper-
catalyzed cross-coupling reaction of a boronic acid.[21]
Herein, we describe an improved synthesis of sansoakamine
(5) based on our original approach[20] providing the natural
product in three steps and 69% overall yield (see Scheme 3).
Buchwald–Hartwig coupling of methyl 4-bromo-2-meth-
oxybenzoate (13) and p-anisidine led to diarylamine 14. The
subsequent palladium(II)-catalyzed oxidative cyclization of
14 using microwave heating at 130 °C afforded carbazole
15. Cleavage of both methyl ether groups of 15 by careful
treatment with an excess of boron tribromide provided san-
soakamine (5) in three steps and 69% overall yield. The
spectroscopic data of synthetic 5 are in full agreement with
Figure 3. Molecular structure of sansoakamine (5) in the crystal.
ORTEP plot showing thermal ellipsoids at the 50% probability
those reported for the natural product.[10] The structure of level.
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Moreover, this approach provided access to a range of palladium(II)-catalyzed oxidative cyclization of
a di-
sansoakamine derivatives for the purpose of bioactivity arylamine with a hydroxy group. The formation of carba-
tests. Ester cleavage by treatment of carbazole 15 with po- zole 22 probably originates from the initial coordination of
tassium hydroxide led to 2,6-dimethoxycarbazole-3-carbox- palladium(II) to the hydroxy group. However, comparing
ylic acid (16). The highly polar 2,6-dihydroxycarbazole-3- the spectroscopic data of 6 with those reported by Taufiq-
carboxylic acid (17) was obtained by treatment of com- Yap et al. for natural clausine-TY revealed that the two
pound 16 with boron tribromide. The reduction of carb- compounds were not identical (see Table 1).[11]
azole 15 with lithium aluminum hydride provided glycozoli-
Table 1. Comparison of selected 1H and 13C NMR spectroscopic
data in [D6]acetone for methyl 2-hydroxy-7-methoxycarbazole-3-
carboxylate (6), methyl 7-hydroxy-2-methoxycarbazole-3-carboxyl-
ate (26), and clausine-K (clauszoline-J, 7) with those reported for
clausine-TY.[11]
dine (18) along with the 8,9Ј-bicarbazole 19. Glycozolidine
(18) was isolated from the root bark of Glycosmis penta-
phylla by Chakraborty et al. and from the roots of Gly-
cosmis arborea by Chakravarty et al.[22,23] Previously, we re-
ported a two-step palladium-catalyzed synthesis of glycozo-
lidine (18) by starting from 3-methoxy-4-methylaniline.[19]
The structure of the 8,9Ј-bicarbazole 19 was assigned on
Clausine-TY [δ,
6 [δ, ppm] 26 [δ, ppm]
7 [δ,
ppm]
ppm][11]
1
the basis of H and 13C NMR spectroscopic data and was
OCH3
OCH3
C-2/C-7
C=O
3.87
3.87
55.8
3.86
3.98
52.49
55.78
160.04
160.88
172.23
3.83
3.89
51.63
56.42
157.18
158.85
167.46
3.87
4.13
55.79
57.17
158.08
160.04
166.55
supported by COSY, HSQC, HMBC, and NOESY experi-
ments (see Supporting Information). The formation of bis-
carbazoles by treatment of carbazole-3-carboxylates with
lithium aluminum hydride has been described by
Bringmann and co-workers.[24] Bringmann et al. reported
the reduction of 1-oxygenated carbazole-3-carboxylates,[24]
and subsequently we reported the reduction of 1,6-dioxy-
genated carbazole-3-carboxylates,[18b] both generated meth-
ylene-bridged biscarbazoles. In the present case, however, a
bicarbazole with an aryl–nitrogen bond was formed.
In addition to our previously reported iron-mediated
method,[14c,15] the two-step palladium-catalyzed approach
provides broad access to a variety of substituted 2,7-dioxy-
genated carbazoles.[25] Thus, we envisaged the palladi-
um(II)-catalyzed oxidative cyclization reaction as a key step
en route to clausine-TY, for which structure 6 had been pro-
posed by Taufiq-Yap and co-workers. A Buchwald–Hartwig
coupling of methyl 4-iodosalicylate (20) and m-anisidine
provided diarylamine 21 (see Scheme 4). Subsequent oxi-
dative cyclization of 21, containing an unprotected hydroxy
group, directly afforded methyl 2-hydroxy-7-methoxycarba-
zole-3-carboxylate (6) along with the corresponding 4-hy-
droxy regioisomer 22 (combined yield of 96%, 6/22, 3.4:1).
To the best of our knowledge, this is the first example of a
57.2
158.1
160.1
166.6
For an unambiguous assignment of the correct structure
of clausine-TY, we synthesized the regioisomeric methyl
ether 26, which has the positions of the hydroxy and the
methoxy groups exchanged relative to compound 6 (see
Scheme 5). The coupling reaction of m-bromophenyl triiso-
propylsilyl ether (23) and methyl 4-amino-2-methoxybenzo-
ate (24) followed by an oxidative cyclization reaction af-
forded the silyl-protected carbazole 25 in 60% yield over
both steps. The cleavage of the silyl ether by treatment of
25 with tetra-n-butylammonium fluoride (TBAF) provided
carbazole 26, which according to its spectroscopic data was
also not identical with natural clausine-TY (see Table 1).[11]
Scheme 5. Synthesis of methyl 7-hydroxy-2-methoxycarbazole-3-
carboxylate (26). Reagents and conditions: (a) 23 (1.0 equiv., TIPS
= triisopropylsilyl) 24 (1.2 equiv.), Pd(OAc)2 (5 mol-%), SPhos
(10 mol-%), Cs2CO3 (1.4 equiv.), toluene, 100 °C, 24 h, 98%;
(b) Pd(OAc)2 (5 mol-%), K2CO3 (11 mol-%), Cu(OAc)2 (2.5 equiv.),
PivOH, 130 °C, microwave, 3 h, 61%; (c) TBAF (1.5 equiv.), N,N-
dimethylformamide (DMF), –10 °C to room temp., 10 min, 100%.
Finally, we decided to synthesize 2,7-dimethoxy-
carbazole-3-carboxylic acid (7), which is an O-methyl re-
gioisomer of 6 (see Scheme 6). Compound 7 is already
known as the natural product clausine-K (isolated by Wu
et al.)[12] and clauszoline-J (isolated by Ito et al.),[13] and
Scheme 4. Synthesis of 6, which is the proposed structure of
clausine-TY. Reagents and conditions: (a) m-anisidine (1.5 equiv.),
Pd(OAc)2 (5 mol-%), SPhos (10 mol-%), Cs2CO3 (1.5 equiv.), tolu-
ene, 100 °C, 15.25 h, 100%; (b) Pd(OAc)2 (9 mol-%), K2CO3
(5 mol-%), PivOH, 90 °C, 2 d, 74% 6 and 22% 22.
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Synthesis and Structural Revision of Clausine-TY
1
was first synthesized by us using our iron-mediated ap- the H NMR spectroscopic data with regard to the signals
proach.[14c,15] Palladium(0)-catalyzed coupling of the aryl- for the methoxy groups. The 1H NMR spectrum of our
amine 24 and m-bromoanisole (8) led to diarylamine 27, synthetic 7 has two signals at δ = 3.87 and 4.13 ppm, respec-
which by a subsequent palladium(II)-catalyzed oxidative tively, whereas that reported by Taufiq-Yap et al. had only
cyclization provided methyl 2,7-dimethoxycarbazole-3- one signal at δ = 3.87 ppm for both methoxy groups.
carboxylate (28) along with the corresponding 4-methoxy
regioisomer 29 (combined yield of 96%, 28/29, 7:1). Carb-
Conclusion
azole 28 is also a naturally occurring compound and was
first isolated in 1996 from C. excavata by Wu et al. and
designated as clausine-H.[12] In the same year, Ito et al. ob-
tained compound 28 from the same natural source and
named it clauszoline-C.[26] The first synthesis of 28 was
achieved by employing our iron-mediated approach.[14c,15]
Finally, cleavage of the methyl ester of 28 provided clausine-
K (clauszoline-J) (7). The present route afforded clausine-
K (clauszoline-J) (7) in three steps and 62% overall yield.
Thus, our new approach is superior to our previous iron-
mediated method (five steps and 20% overall yield).[14c,15]
We have applied our palladium-catalyzed approach to
the total synthesis of the eight carbazole alkaloids 2-
hydroxy-7-methylcarbazole (1), glycozolicine (2), mukoline
(3), mukolidine (4), sansoakamine (5), glycozolidine (18),
clausine-H (clauszoline-C) (28), and clausine-K (clauszo-
line-J, clausine-TY) (7). Our route also provided non-natu-
ral derivatives of sansoakamine (5) and clausine-K (claus-
zoline-J) (7), which are now available for structure–activity
relationship studies. Moreover, the present work led to a
reassignment for the structure of clausine-TY, which was
shown to be identical to that of the previously known
clausine-K (clauszoline-J) (7).
Experimental Section
General Methods: All reactions were carried out in oven-dried
glassware and employed dry solvents under argon, unless stated
otherwise. Tetrahydrofuran, toluene and dichloromethane were
dried by using a solvent purification system (MBraun-SPS). Other
chemicals were used as received from commercial sources. Flash
chromatography was performed on a Büchi Sepacore system that
was equipped with an UV monitor, and silica gel from Acros Or-
ganics (0.035–0.070 mm) was employed. Thin layer chromatog-
raphy was performed with TLC plates from Merck (60 F254), and
UV light was used for visualization. Melting points were measured
with a Gallenkamp MPD 350 melting point apparatus. Ultraviolet
spectra were recorded with a Perkin–Elmer 25 UV/Vis spectrome-
ter. Infrared spectra were recorded with a Thermo Nicolet Avatar
360 FTIR spectrometer by using the ATR (attenuated total reflec-
tance) method. The NMR spectroscopic data were recorded with
Bruker DRX 500 and Avance III 600 spectrometers. Chemical
shifts (δ) are reported in parts per million, and the nondeuterated
solvent was used as the internal standard. The abbreviations used
to report the data are s (singlet), d (doublet), t (triplet), m (mul-
tiplet), and br. (broad). Mass spectra were recorded with a Finni-
gan MAT-95 spectrometer (electron impact, 70 eV) or by using
GC–MS coupling with an Agilent Technologies 6890 N GC System
that was equipped with a 5973 Mass Selective Detector (electron
impact, 70 eV). Elemental analyses were measured with a EuroVec-
tor EuroEA3000 elemental analyzer. X-ray crystal structure analy-
ses were performed with a Bruker-Nonius Kappa CCD that was
equipped with a 700 series Cryostream low temperature device
from Oxford Cryosystems. SHELXS-97,[27] SADABS version
2.10,[28] SHELXL-97,[29] POV-Ray for Windows version
3.6.2.msvc9.win64, and ORTEP-3 for Windows[30] were used as
software.
Scheme 6. Improved synthesis of clausine-K (clauszoline-J,
clausine-TY) (7). Reagents and conditions: (a) m-bromoanisole (8)
(1.0 equiv.), 24 (1.2 equiv.), Pd(OAc)2 (5 mol-%), SPhos (10 mol-
%), Cs2CO3 (1.4 equiv.), toluene, 100 °C, 21 h, 100%; (b) Pd(OAc)
(5 mol-%), K2CO3 (10 mol-%), Cu(OAc)2 (2.5 equiv.), PivOH,
2
130 °C, microwave, 25 h, 84% 28, 12% 29; (c) KOH (21 equiv.),
EtOH/H2O (10:3), 50 °C, 2.5 h, 74%.
A comparison of the spectroscopic data that were re-
ported by Taufiq-Yap et al. for clausine-TY[11] with those
of 2,7-dimethoxycarbazole-3-carboxylic acid (clausine-K,
clauszoline-J) (7) revealed that both structures are identical.
Previously, Wu et al.,[12] Ito et al.,[13] and our group[14c,15]
had reported the NMR spectroscopic data of clausine-K
(clauszoline-J) (7) using [D6]DMSO as the NMR solvent,
whereas Taufiq-Yap et al. used [D6]acetone.[11] We found a
perfect match between the 13C NMR spectroscopic data of
clausine-K (clauszoline-J) (7) with those reported for
clausine-TY when [D6]acetone was used as the NMR sol-
vent (compare 13C NMR spectroscopic data given in Exp.
Section with those reported in ref.[11], see Table 1 for a com-
3-Methoxy-N-(3-methylphenyl)aniline (9): A solution of m-bromo-
anisole (8) (498 mg, 2.66 mmol) in toluene (2 mL) was added drop-
wise over a period of 1.5 h at 100 °C to a suspension of m-toluidine
(376 mg, 3.51 mmol), palladium acetate (30.8 mg, 137 μmol),
SPhos (110 mg, 268 μmol), and cesium carbonate (1.37 g,
parison of selected signals). The only difference is found in 4.20 mmol) in toluene (20 mL), and the mixture was stirred at
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100 °C for 13.5 h (total reaction time was 15 h). After cooling to
room temperature, the solvent was evaporated. Purification of the
residue by chromatography on a silica gel column (petroleum ether/
bined aqueous layers were extracted with ethyl acetate, and the
combined organic layers were dried with sodium sulfate. The sol-
vent was evaporated to give a residue, which was purified by
diethyl ether, 2:1) provided 3-methoxy-N-(3-methylphenyl)aniline chromatography on a silica gel column (isohexane/diethyl ether,
(9) (575 mg, 100%) as a yellow oil. UV (MeOH): λ = 283 nm. IR
gradient from 4:1 to 1:2) to provide 2-hydroxy-7-methylcarbazole
(ATR): ν = 3389, 3031, 2920, 2836, 1616, 1586, 1514, 1487, 1464,
(1) (85.0 mg, 87%) as a light grey solid, m.p. 269–271 °C; ref.[5]
˜
1396, 1305, 1264, 1202, 1152, 1040, 995, 964, 840, 761, 685 cm–1. m.p. 269–271 °C. UV (MeOH): λ = 236, 261, 304 nm. Fluorescence
1H NMR (500 MHz, [D6]acetone): δ = 2.27 (s, 3 H), 3.74 (s, 3 H),
6.42 (ddd, J = 8.2, 2.4, 0.6 Hz, 1 H), 6.67–6.70 (m, 3 H), 6.94 (d,
J = 8.2 Hz, 1 H), 6.96 (s, 1 H), 7.12 (t, J = 8.0 Hz, 2 H), 7.32 (br.
s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]acetone): δ =
21.56 (CH3), 55.27 (CH3), 103.49 (CH), 106.09 (CH), 110.34 (CH),
(MeOH): λex = 261 nm, λem = 348 nm. IR (ATR): ν = 3398, 3278,
˜
3027, 2915, 2856, 1616, 1506, 1443, 1379, 1334, 1306, 1272, 1243,
1219, 1152, 1134, 1108, 1039, 955, 866, 839, 826, 796, 730,
627 cm–1. 1H NMR (500 MHz, [D6]acetone): δ = 2.44 (s, 3 H), 6.72
(dd, J = 8.4, 2.1 Hz, 1 H), 6.90 (d, J = 2.1 Hz, 1 H), 6.94 (d, J =
115.69 (CH), 119.20 (CH), 122.03 (CH), 129.83 (CH), 130.67 (CH), 7.8 Hz, 1 H), 7.20 (s, 1 H), 7.81 (d, J = 7.8 Hz, 1 H), 7.82 (d, J =
139.52 (C), 144.35 (C), 146.15 (C), 161.67 (C) ppm. MS (EI, 70 eV): 8.4 Hz, 1 H), 8.28 (s, 1 H), 9.94 (br. s, 1 H) ppm. 13C NMR and
m/z (%) = 213 (100) [M]+, 197 (10), 154 (13). C14H15NO (213.28):
calcd. C 78.84, H 7.09, N 6.57; found C 78.93, H 7.06, N 6.61.
DEPT (125 MHz, [D6]acetone): δ = 21.94 (CH3), 97.42 (CH),
109.04 (CH), 111.42 (CH), 117.25 (C), 119.49 (CH), 120.97 (CH),
121.18 (CH), 122.22 (C), 134.43 (C), 141.41 (C), 142.60 (C), 157.09
(C) ppm. MS (EI, 70 eV): m/z (%) = 197 (100) [M]+, 196 (70), 167
(12). MS (ESI, +25 V): m/z = 198 [M + H]+. HRMS: calcd. for
C13H11NO [M]+ 197.0841; found 197.0841.
2-Methoxy-7-methylcarbazole (10): A 10 mL microwave tube was
charged with diarylamine 9 (101 mg, 474 μmol), palladium acetate
(11 mg, 49 μmol), copper(II) acetate (215 mg, 1.18 mmol), and piv-
alic acid (703 mg) in air. The tube was irradiated in a microwave
reactor at 110 °C and 300 W for 5 h. The mixture was cooled to
room temperature and diluted with ethyl acetate, and the resulting
solution was washed with a saturated solution of potassium carb-
onate and brine several times. The aqueous layers were extracted
with ethyl acetate, and the combined organic layers were dried with
sodium sulfate. The solvent was evaporated to give a residue, which
was purified by chromatography on a silica gel column (petroleum
ether/diethyl ether, 4:1) to provide 2-methoxy-7-methylcarbazole
(10) (85.9 mg, 86%) as a light yellow solid and the less polar by-
2-Methoxy-N-(4-methylphenyl)aniline (12): A solution of o-bromo-
anisole (11) (140 mg, 749 μmol) in toluene (3 mL) was added drop-
wise to a suspension of p-toluidine (96.0 mg, 896 μmol), palladium
acetate (10 mg, 45 μmol), rac-BINAP (28 mg, 45 μmol), and cesium
carbonate (341 mg, 1.05 mmol) in toluene (5 mL) at reflux. The
mixture was stirred and heated at reflux for 24 h. After cooling to
room temperature, the solvent was evaporated. Purification of the
residue by chromatography on a silica gel column (petroleum ether/
ethyl acetate, 9:1) provided diarylamine 12 (159 mg, 100%) as a
product 4-methoxy-7-methylcarbazole (10a) (up to 5% yield) as a yellow oil. UV (MeOH): λ = 278, 298 nm. IR (ATR): ν = 3410,
˜
light brown solid. Data for 10: M.p. 273–274 °C. UV (MeOH): λ
= 236, 260, 303 nm. Fluorescence (MeOH): λex = 260 nm, λem
3018, 2936, 2833, 1597, 1558, 1513, 1457, 1398, 1338, 1296, 1232,
1
=
1176, 1113, 1047, 1026, 909, 882, 807, 736, 703, 648, 618 cm–1. H
352 nm. IR (ATR): ν = 3394, 3028, 2962, 2911, 2833, 1878, 1606,
NMR (500 MHz, CDCl3): δ = 2.32 (s, 3 H), 3.90 (s, 3 H), 6.82–
6.89 (m, 3 H), 7.08–7.12 (m, 4 H), 7.24 (dd, J = 7.5, 1.6 Hz, 1
˜
1572, 1542, 1501, 1443, 1374, 1311, 1288, 1229, 1196, 1160, 1105,
1031, 997, 939, 865, 796, 730, 622 cm–1. 1H NMR (500 MHz, [D6]- H) ppm. 13C NMR (125 MHz, CDCl3): δ = 20.87 (CH3), 55.74
acetone): δ = 2.45 (s, 3 H), 3.85 (s, 3 H), 6.77 (dd, J = 8.5, 2.2 Hz,
1 H), 6.96 (dd, J = 7.9, 0.6 Hz, 1 H), 6.99 (d, J = 2.2 Hz, 1 H),
7.24 (s, 1 H), 7.85 (d, J = 7.9 Hz, 1 H), 7.90 (d, J = 8.5 Hz, 1 H),
10.06 (br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]acet-
one): δ = 21.95 (CH3), 55.68 (CH3), 95.44 (CH), 108.47 (CH),
111.54 (CH), 117.86 (C), 119.73 (CH), 121.14 (CH), 121.19 (CH),
121.98 (C), 134.76 (C), 141.49 (C), 142.33 (C), 159.70 (C) ppm. MS
(EI, 70 eV): m/z (%) = 211 (100) [M]+, 196 (46), 168 (53). HRMS:
calcd. for C14H13NO [M]+ 211.0997; found: 211.0990. C14H13NO
(211.26): calcd. C 79.59, H 6.20, N 6.63; found C 79.79, H 6.45, N
6.62. Data for 10a: M.p. 125–127 °C. 1H NMR (500 MHz, [D6]-
acetone): δ = 2.47 (s, 3 H), 4.05 (s, 3 H), 6.68 (d, J = 7.9 Hz, 1 H),
6.99 (d, J = 7.9 Hz, 1 H), 7.07 (d, J = 8.1 Hz, 1 H), 7.25–7.28 (m,
2 H), 8.10 (d, J = 7.9 Hz, 1 H), 10.19 (br. s, 1 H) ppm. 13C NMR
and DEPT (125 MHz, [D6]acetone): δ = 22.03 (CH3), 55.60 (CH3),
100.61 (CH), 104.62 (CH), 111.20 (CH), 113.14 (C), 121.08 (C),
121.19 (CH), 123.23 (CH), 126.83 (CH), 135.17 (C), 140.64 (C),
142.34 (C), 156.79 (C) ppm. MS (EI, 70 eV): m/z (%) = 211 (100)
[M]+, 196 (58), 168 (74). HRMS: calcd. for C14H13NO [M]+
211.0997; found 211.0991.
(CH3), 110.57 (CH), 114.17 (CH), 119.66 (CH), 119.86 (2 CH),
120.99 (CH), 129.94 (2 CH), 131.39 (C), 133.71 (C), 139.87 (C),
148.12 (C) ppm. MS (EI, 70 eV): m/z (%) = 213 (87) [M]+, 198 (37),
183 (100), 154 (17). C14H15NO (213.28): calcd. C 78.84, H 7.09, N
6.57; found C 78.81, H 6.99, N 6.66.
Glycozolicine (8-Methoxy-3-methylcarbazole, 2): A 10 mL micro-
wave tube was charged with diarylamine 12 (100 mg, 469 μmol),
palladium acetate (15.8 mg, 70.3 μmol), copper(II) acetate (213 mg,
1.17 mmol), and pivalic acid (900 mg) in air. The tube was irradi-
ated in a microwave reactor at 130 °C and 300 W for 45 min. An
additional portion of palladium acetate (15.8 mg, 70.3 μmol) was
added, and the mixture was irradiated in the microwave reactor
under the same conditions for an additional 30 min. The mixture
was cooled to room temperature and diluted with diethyl ether,
and the resulting mixture was washed with a saturated solution of
potassium carbonate and brine several times. The combined aque-
ous layers were extracted with diethyl ether, and the combined or-
ganic layers were dried with sodium sulfate. The solvent was evapo-
rated. Purification of the residue by chromatography on a silica gel
column (isohexane/ethyl acetate, 15:1) provided glycozolicine (2)
(88.6 mg, 89%) as light brown solid, m.p. 129–130 °C; ref.[6] m.p.
135 °C; ref.[7] m.p. 137–138 °C; ref.[8] m.p. 150 °C; ref.[9] m.p. 145–
146 °C. UV (MeOH): λ = 224, 242, 252, 259 (sh), 281 (sh), 291,
327, 341 nm. Fluorescence (MeOH): λex = 290 nm, λem = 352,
2-Hydroxy-7-methylcarbazole (1): Boron tribromide (1 m solution
in dichloromethane, 0.99 mL, 0.99 mmol) was added to a solution
of 2-methoxy-7-methylcarbazole (10) (105 mg, 497 μmol) in di-
chloromethane (15 mL) at –78 °C. The mixture was gradually
warmed to room temperature. After a total reaction time of 4.25 h
(complete conversion as indicated by TLC), methanol (3 mL) was
added, and the mixture was diluted with ethyl acetate. The resulting
solution was washed with water and brine several times. The com-
366 nm. IR (ATR): ν = 3854, 3745, 3411, 3016, 2930, 2828, 1630,
˜
1580, 1508, 1474, 1449, 1392, 1349, 1316, 1296, 1253, 1234, 1185,
1166, 1133, 1094, 1061, 1026, 989, 936, 885, 863, 799, 782, 746,
729, 696, 629 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.53 (s, 3 H),
4746
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4741–4752

Synthesis and Structural Revision of Clausine-TY
4.01 (s, 3 H), 6.89 (d, J = 7.9 Hz, 1 H), 7.14 (t, J = 7.9 Hz, 1 H),
7.24 (dd, J = 8.2, 1.3 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 1 H), 7.65 (d,
J = 7.9 Hz, 1 H), 7.86 (s, 1 H), 8.16 (br. s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 21.58 (CH3), 55.63 (CH3), 105.86 (CH),
110.71 (CH), 112.94 (CH), 119.62 (CH), 120.56 (CH), 123.96 (C),
IR (ATR): ν = 3504, 3286, 3000, 2934, 2835, 2030, 1903, 1630,
˜
1573, 1541, 1509, 1486, 1458, 1400, 1314, 1260, 1238, 1186, 1164,
1095, 1061, 1027, 988, 935, 895, 858, 820, 787, 753, 738, 702,
630 cm–1. 1H NMR (500 MHz, [D6]acetone): δ = 3.99 (s, 3 H), 4.10
(br. s, 1 H), 4.76 (s, 2 H), 6.95 (d, J = 7.8 Hz, 1 H), 7.10 (t, J =
124.31 (C), 127.21 (CH), 128.80 (C), 130.23 (C), 137.56 (C), 145.80 7.8 Hz, 1 H), 7.40 (dd, J = 8.3, 1.2 Hz, 1 H), 7.52 (d, J = 8.3 Hz,
(C) ppm. MS (EI, 70 eV): m/z (%) = 211 (100) [M]+, 196 (83), 168
(63), 84 (13). C14H13NO (211.26): calcd. C 79.59, H 6.20, N 6.63;
found C 79.73, H 6.28, N 6.68.
1 H), 7.68 (d, J = 7.8 Hz, 1 H), 8.05 (s, 1 H), 10.30 (br. s, 1 H) ppm.
13C NMR and DEPT (125 MHz, [D6]acetone): δ = 55.81 (CH3),
65.48 (CH2), 106.69 (CH), 111.84 (CH), 113.39 (CH), 119.45 (CH),
120.13 (CH), 124.08 (C), 125.06 (C), 125.94 (CH), 131.28 (C),
134.02 (C), 140.06 (C), 146.93 (C) ppm. MS (EI, 70 eV): m/z (%)
= 227 (100) [M]+, 212 (28), 210 (36), 198 (15), 183 (15), 167 (24),
154 (21). C14H13NO2 (227.26): calcd. C 73.99, H 5.77, N 6.16;
found C 73.94, H 5.80, N 5.86.
Mukolidine (8-Methoxycarbazole-3-carbaldehyde, 4): DDQ
(451 mg, 1.99 mmol) was added to a solution of carbazole 2
(100 mg, 473 μmol) in a mixture of methanol (15 mL), THF
(5 mL), and water (1 mL). The resulting mixture was stirred at
50 °C for 50 min. The mixture was cooled to room temperature and
diluted with diethyl ether. The mixture was washed with aqueous
sodium hydroxide (1 m) and brine several times. The aqueous layers
were extracted with diethyl ether, and the combined organic layers
were dried with sodium sulfate. The solvent was evaporated. Purifi-
cation of the residue by chromatography on a silica gel column
(isohexane/ethyl acetate, 5:1) provided mukolidine (4) (87.8 mg,
82%) as colorless crystals, m.p. 175–176 °C; ref.[8] m.p. 152–155 °C;
Crystal Data for 3: C14H13NO2, M = 227.25 gmol–1, crystal size:
0.34ϫ0.15ϫ0.15 mm3, orthorhombic, space group: P212121, a =
5.822(1) Å, b = 12.280(1) Å, c = 15.570(2) Å, V = 1113.2(3) Å3, Z
= 4, ρcalcd. = 1.356 gcm–3, μ = 0.091 mm–1, T = 198(2) K, λ =
0.71073 Å, θ range: 3.10–27.99°, 36835 reflections collected, 2685
independent reflections (Rint = 0.0469), 160 parameters. The struc-
ture was solved by direct methods and refined by full-matrix least-
ref.[9] m.p. 148–150 °C. UV (EtOH): λ = 211, 237, 271, 287, 336 nm. squares on F2, final R indices [I Ͼ 2σ(I)]: R1 = 0.0439, wR2
=
Fluorescence (EtOH): λex = 336 nm, λem = 503 nm. IR (ATR): ν =
0.0868, maximal residual electron density: 0.189 eÅ–3. CCDC-
˜
3316, 3042, 2935, 2804, 2732, 2056, 2030, 2009, 1772, 1735, 1670,
1608, 1570, 1507, 1473, 1459, 1438, 1412, 1328, 1311, 1290, 1265,
1238, 1186, 1088, 1022, 944, 885, 859, 837, 815, 776, 749, 715 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.03 (s, 3 H), 6.97 (d, J = 7.9 Hz,
1 H), 7.25 (t, J = 7.9 Hz, 1 H), 7.53 (d, J = 8.5 Hz, 1 H), 7.73 (d,
J = 7.9 Hz, 1 H), 7.98 (dd, J = 8.5, 1.6 Hz, 1 H), 8.59 (d, J =
0.6 Hz, 1 H), 8.62 (br. s, 1 H), 10.10 (s, 1 H) ppm. 13C NMR and
DEPT (125 MHz, CDCl3): δ = 55.75 (CH3), 107.07 (CH), 111.40
(CH), 113.14 (CH), 121.35 (CH), 123.97 (C), 124.37 (C), 124.70
(CH), 127.17 (CH), 129.22 (C), 130.42 (C), 142.95 (C), 145.97 (C),
192.06 (CHO) ppm. MS (EI, 70 eV): m/z (%) = 225 (100) [M]+, 210
(68), 182 (49), 153 (21), 112 (10). C14H11NO2 (225.25): calcd. C
74.65, H 4.92, N 6.22; found C 74.96, H 4.96, N 5.97.
999458 (for 3) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Methyl 2-Methoxy-4-[(4-methoxyphenyl)amino]benzoate (14):
A
solution of methyl 4-bromo-2-methoxybenzoate (13) (1.00 g,
4.08 mmol) in toluene (8 mL) was added dropwise over a period of
1 h to a suspension of p-anisidine (603 mg, 4.90 mmol), palladium
acetate (55.0 mg, 245 μmol), XPhos (233 mg, 490 μmol), and
cesium carbonate (1.6 g, 4.90 mmol) in toluene (41 mL) at reflux.
The mixture was stirred and heated at reflux for an additional 22 h.
After cooling to room temperature, the mixture was filtered
through a short pad of Celite® (ethyl acetate), and the filtrate was
concentrated. The residue was purified by chromatography on a
silica gel column (isohexane/ethyl acetate, gradient from 2:1 to 1:1)
to provide a mixture of methyl 2-methoxy-4-[(4-methoxyphenyl)
amino]benzoate (14) and p-anisidine. This mixture was dissolved
Crystal
Data
for
4:
C14H11NO2,
crystal
size:
0.42ϫ0.12ϫ0.05 mm3, M = 225.24 gmol–1, monoclinic, space
group: P21/c, a = 3.949(1) Å, b = 21.960(4) Å, c = 12.151(2) Å, β
= 93.01(3)°, V = 1052.3(4) Å3, Z = 4, ρcalcd. = 1.422 gcm–3, μ =
0.096 mm–1, T = 198(2) K, λ = 0.71073 Å, θ range: 3.25–25.40°, in dichloromethane (100 mL), and the solution was extracted with
25041 reflections collected, 1930 independent reflections (Rint
=
hydrochloric acid (2 n solution, 100 mL). The aqueous layer was
extracted with dichloromethane (50 mL). The organic layer was
dried with magnesium sulfate, and the solvent was removed to pro-
vide pure 14 (1.12 g, 96%) as a light yellow solid; m.p. 97.5–98 °C.
0.0577), 159 parameters. The structure was solved by direct meth-
ods and refined by full-matrix least-squares on F2, final R indices
[I Ͼ 2σ(I)]: R1 = 0.0533, wR2 = 0.1187, maximal residual electron
density: 0.235 eÅ–3. CCDC-999457 (for 4) contains the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
UV (MeOH): λ = 241, 318 nm. IR (ATR): ν = 3320, 3298, 3091,
˜
2993, 2964, 2941, 2907, 2835, 1690, 1597, 1512, 1460, 1432, 1396,
1344, 1321, 1236, 1207, 1177, 1148, 1110, 1086, 1028, 963, 828,
771, 698 cm–1. 1H NMR (500 MHz, CDCl3): δ = 3.80 (s, 3 H), 3.82
(s, 3 H), 3.83 (s, 3 H), 5.88 (br. s, 1 H), 6.37 (d, J = 2.2 Hz, 1 H),
6.38 (dd, J = 8.5, 2.2 Hz, 1 H), 6.90–6.92 (m, 2 H), 7.12–7.15 (m,
2 H), 7.76 (d, J = 8.5 Hz, 1 H) ppm. 13C NMR and DEPT
(125 MHz, CDCl3): δ = 51.61 (CH3), 55.66 (CH3), 55.93 (CH3),
97.16 (CH), 106.00 (CH), 109.40 (C), 114.89 (2 CH), 124.68 (2
CH), 133.41 (C), 134.22 (CH), 151.15 (C), 156.70 (C), 161.85 (C),
166.27 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 287 (100) [M]+, 272
(75), 256 (35). MS (ESI, +10 V): m/z (%) = 288 [M + H]+, 597 [2M
+ Na]+. C16H17NO4 (287.32): calcd. C 66.89, H 5.96, N 4.88; found
C 67.02, H 6.08, N 4.84.
Mukoline (3-Hydroxymethyl-8-methoxycarbazole, 3): LiAlH4 (2.4 m
in THF, 0.37 mL, 0.89 mmol) was added to a solution of mukolid-
ine (4) (100 mg, 444 μmol) in THF (12.5 mL) at 0 °C. The mixture
was stirred at 0 °C for 10 min and then quenched with ice water
and diluted with ethyl acetate. The organic layer was washed with
water and brine several times. The combined aqueous layers were
extracted with ethyl acetate. The combined organic layers were
dried with sodium sulfate, and the solvent was evaporated. Purifica-
tion of the residue by chromatography on a silica gel column
(isohexane/ethyl acetate, 2:1) provided mukoline (3) (99.3 mg, 98%)
as colorless crystals, m.p. 155–157 °C; ref.[8] m.p. 118 °C; ref.[9] m.p.
125–126 °C. UV (EtOH): λ = 225, 243, 252, 260 (sh), 282, 291, 327,
339 nm. Fluorescence (EtOH): λex = 291 nm, λem = 353, 367 nm.
Methyl 2,6-Dimethoxycarbazole-3-carboxylate (15): A 10 mL mi-
crowave tube was charged with diarylamine 14 (100 mg, 348 μmol),
palladium acetate (11.7 mg, 52.2 μmol), copper(II) acetate (158 mg,
Eur. J. Org. Chem. 2014, 4741–4752
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4747

H.-J. Knölker et al.
FULL PAPER
870 μmol), and pivalic acid (900 mg) in air. The tube was irradiated
in a microwave reactor at 130 °C and 300 W for 1 h. The mixture
was cooled to room temperature and then diluted with ethyl acet-
ate. The resulting solution was washed with a saturated solution of
potassium carbonate and brine several times. The aqueous layers
were extracted with ethyl acetate, and the combined organic layers
were dried with sodium sulfate. The solvent was evaporated. Purifi-
cation of the residue by chromatography on a silica gel column
(isohexane/ethyl acetate, 2:1) provided methyl 2,6-dimethoxycarb-
azole-3-carboxylate (15) (85.0 mg, 86%) as a light yellow solid; m.p.
160–161 °C. UV (MeOH): λ = 229, 273, 289, 319 (sh) nm. Fluores-
999459 (for 5) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
2,6-Dimethoxycarbazole-3-carboxylic Acid (16):
A solution of
methyl 2,6-dimethoxycarbazole-3-carboxylate (15) (40.7 mg,
143 μmol) and potassium hydroxide (794 mg, 14.2 mmol) in eth-
anol (4 mL) and water (1.5 mL) was heated at reflux for 35 min.
The mixture was diluted with diethyl ether, and the resulting mix-
ture was acidified with hydrochloric acid (2 n solution). The or-
ganic layer was separated, and the aqueous layer was extracted with
diethyl ether. The combined organic layers were dried with magne-
sium sulfate, and the solvent was evaporated to provide 2,6-dimeth-
oxycarbazole-3-carboxylic acid (16) (38.3 mg, 91%) as a light
brown solid; m.p. 219 °C (decomp). UV (MeOH): λ = 229, 239
cence (MeOH): λex = 288 nm, λem = 468 nm. IR (ATR): ν = 3592,
˜
3517, 3328, 2992, 2953, 2836, 1703, 1634, 1589, 1492, 1458, 1434,
1395, 1349, 1297, 1235, 1196, 1154, 1078, 1022, 950, 898, 838, 811,
794, 782, 756, 726, 679 cm–1. 1H NMR (500 MHz, CDCl3): δ =
3.90 (s, 3 H), 3.91 (s, 3 H), 3.95 (s, 3 H), 6.84 (s, 1 H), 7.00 (dd, J
= 8.8, 2.5 Hz, 1 H), 7.27 (d, J = 8.8 Hz, 1 H), 7.48 (d, J = 2.5 Hz,
1 H), 8.22 (br. s, 1 H), 8.57 (s, 1 H) ppm. 13C NMR and DEPT
(125 MHz, CDCl3): δ = 52.02 (CH3), 56.12 (CH3), 56.28 (CH3),
93.65 (CH), 103.00 (CH), 111.46 (CH), 112.06 (C), 114.42 (CH),
116.58 (C), 124.11 (C), 125.09 (CH), 134.71 (C), 144.16 (C), 154.64
(C), 159.31 (C), 167.21 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 285
(100) [M]+, 270 (35), 254 (34), 242 (13), 196 (10). C16H15NO4
(285.30): calcd. C 67.36, H 5.30, N 4.91; found C 67.68, H 5.30, N
4.72.
(sh), 271, 298 nm. Fluorescence (MeOH): λex = 229 nm, λem
=
376 nm. IR (ATR): ν = 3216, 2998, 2955, 2830, 1701, 1632, 1611,
˜
1459, 1433, 1388, 1340, 1296, 1270, 1218, 1197, 1158, 1075, 1019,
1
979, 905, 834, 809, 778, 709, 646 cm–1. H NMR (500 MHz, [D6]-
acetone): δ = 3.91 (s, 3 H), 4.13 (s, 3 H), 7.01 (dd, J = 8.7, 2.5 Hz,
1 H), 7.22 (s, 1 H), 7.41 (d, J = 8.7 Hz, 1 H), 7.77 (d, J = 2.5 Hz,
1 H), 8.75 (s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]-
acetone): δ = 56.07 (CH3), 57.10 (CH3), 94.45 (CH), 103.67 (CH),
111.08 (C), 112.52 (CH), 115.52 (CH), 118.30 (C), 124.55 (C),
126.54 (CH), 136.04 (C), 145.45 (C), 155.56 (C), 158.77 (C), 166.54
(C=O) ppm. MS (EI, 70 eV): m/z (%) = 227 (100) [M – CO2]+, 212
(72), 184 (36), 169 (21), 141 (15). C15H13NO4 (271.27): calcd. C
66.41, H 4.83, N 5.16; found C 66.51, H 4.87, N 5.10.
Sansoakamine (Methyl 2,6-Dihydroxycarbazole-3-carboxylate, 5):
Boron tribromide (1 m in dichloromethane, 2.1 mL, 2.1 mmol) was
added to a solution of methyl 2,6-dimethoxycarbazole-3-carboxyl-
ate (15) (122 mg, 427 μmol) in dichloromethane (15 mL) at –78 °C.
The mixture was gradually warmed to 0 °C. After a total reaction
time of 55 min (complete conversion as indicated by TLC), meth-
anol (2.5 mL) was added at 0 °C, and the mixture was washed with
brine (3ϫ). The combined aqueous layers were extracted with di-
ethyl ether and ethyl acetate. The combined organic layers were
dried with magnesium sulfate, and the solvent was evaporated. Pu-
rification of the residue by chromatography on a silica gel column
(isohexane/diethyl ether, gradient from 4:1 to 1:2) provided san-
soakamine (5) (89.1 mg, 83%) as colorless crystals, m.p. 247.0–
247.5 °C; ref.[10] m.p. 243.8–245.6 °C. UV (MeOH): λ = 228, 241
(sh), 273, 296, 329 nm. Fluorescence (MeOH): λex = 296 nm, λem
2,6-Dihydroxycarbazole-3-carboxylic Acid (17): Boron tribromide
(1 m in dichloromethane, 1.9 mL, 1.9 mmol) was added to a solu-
tion of methyl 2,6-dimethoxycarbazole-3-carboxylic acid (16)
(90.2 mg, 333 μmol) in dichloromethane (15 mL) at –78 °C. The
mixture was gradually warmed to 0 °C over a period of 30 min,
stirred at 0 °C for 35 min, and then stirred at room temperature for
30 min. After a total reaction time of 95 min (complete conversion
as indicated by TLC), methanol (2.2 mL) was added. The mixture
was diluted with ethyl acetate, and the resulting solution was
washed with brine (3 ϫ). The combined aqueous layers were ex-
tracted with diethyl ether and ethyl acetate. The combined organic
layers were dried with magnesium sulfate, and the solvent was evap-
orated. Purification of the residue by chromatography on a silica
gel column (isohexane/diethyl ether, gradient from 1:4 to 1:6) pro-
vided 2,6-dihydroxycarbazole-3-carboxylic acid (17) (72.4 mg,
81%) as a light yellow solid; m.p. 269 °C (decomp). UV (MeOH):
= 592 nm. IR (ATR): ν = 3471, 3392, 3322, 3298, 3091, 3026, 2994,
˜
2943, 2835, 1690, 1642, 1597, 1512, 1458, 1433, 1396, 1363, 1343,
1323, 1241, 1208, 1174, 1155, 1112, 1087, 1029, 957, 906, 828, 772,
737, 697 cm–1. 1H NMR (500 MHz, [D6]acetone): δ = 3.99 (s, 3 H),
6.86 (s, 1 H), 6.93 (dd, J = 8.6, 2.4 Hz, 1 H), 7.29 (d, J = 8.6 Hz,
1 H), 7.51 (d, J = 2.4 Hz, 1 H), 8.08 (s, 1 H), 8.52 (s, 1 H), 10.27
(br. s, 1 H), 11.04 (s, 1 H) ppm. 13C NMR and DEPT (125 MHz,
[D6]acetone): δ = 52.50 (CH3), 97.38 (CH), 105.31 (C), 106.01
(CH), 112.17 (CH), 115.26 (CH), 117.83 (C), 123.43 (CH), 125.12
(C), 135.84 (C), 147.20 (C), 152.66 (C), 161.39 (C), 172.19
(C=O) ppm. MS (EI, 70 eV): m/z (%) = 257 (48), 225 (100), 169
(27), 140 (11). MS (ESI, +10 V): m/z (%) = 258 [M + H]+, 537 [2M
+ Na]+. C14H11NO4 (257.25): calcd. C 65.37, H 4.31, N 5.45; found
C 65.19, H 4.20, N 5.52.
λ = 228, 244 (sh), 274, 291, 326 nm. Fluorescence (MeOH): λex
=
291 nm, λem = 459 nm. IR (ATR): ν = 3300, 2923, 2846, 2559,
˜
2484, 1642, 1597, 1512, 1424, 1345, 1260, 1214, 1162, 1084, 1002,
1
914, 896, 854, 834, 793, 727, 689 cm–1. H NMR (500 MHz, [D6]-
DMSO): δ = 6.77 (s, 1 H), 6.82 (dd, J = 8.5, 2.4 Hz, 1 H), 7.21 (d,
J = 8.5 Hz, 1 H), 7.37 (d, J = 2.4 Hz, 1 H), 8.44 (s, 1 H), 8.99 (br.
s, 1 H), 11.08 (s, 1 H), 11.57 (br. s, 1 H), 13.50 (br. s, 1 H) ppm.
13C NMR and DEPT (125 MHz, [D6]DMSO): δ = 96.19 (CH),
104.40 (C), 105.06 (CH), 111.27 (CH), 114.25 (CH), 116.21 (C),
122.98 (CH), 123.65 (C), 134.21 (C), 145.74 (C), 151.31 (C), 160.02
(C), 172.93 (C) ppm. MS (ESI, +10 V): m/z (%) = 244 [M + H]+,
282 [M + K]+. MS (ESI, –10 V): m/z (%) = 198 [M – CO2 – H]–.
Crystal Data for 5: C14H11NO4, M = 257.24 gmol–1, crystal size:
0.24ϫ0.22ϫ0.18 mm3, orthorhombic, space group: Aba2, a =
7.755(2) Å, b = 22.026(4) Å, c = 13.725(3) Å, V = 2344.4(9) Å3, Z
= 8, ρcalcd. = 1.458 gcm–3, μ = 0.108 mm–1, T = 198(2) K, λ =
0.71073 Å, θ range: 3.16–29.99°, 15531 reflections collected, 3214
independent reflections (Rint = 0.0258), 179 parameters. The struc-
ture was solved by direct methods and refined by full-matrix least-
Glycozolidine (18) and 3Ј-Hydroxymethyl-2,2Ј,7,7Ј-tetramethoxy-3-
methyl-8,9Ј-bicarbazole (19): Lithium aluminum hydride (65.8 mg,
1.73 mmol) was added to a solution of methyl 2,6-dimethoxycarb-
azole-3-carboxylate (15) (82.3 mg, 288 μmol) in THF (15 mL) at
room temperature, and the mixture was heated at reflux for 6 h.
Water was added at 0 °C, and the mixture was extracted with di-
squares on F2, final R indices [I Ͼ 2σ(I)]: R1 = 0.0397, wR2
0.0915, maximal residual electron density: 0.247 eÅ–3. CCDC-
=
4748
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4741–4752

Synthesis and Structural Revision of Clausine-TY
ethyl ether (3ϫ). The combined organic layers were washed with
brine and dried with magnesium sulfate, and the solvent was evapo-
rated. Purification of the residue by chromatography on a silica gel
column (isohexane/ethyl acetate, gradient from 4:1 to 1:2) provided
the less polar glycozolidine (18) (30.0 mg, 43%) as light brown solid
and the more polar 3Ј-hydroxymethyl-2,2Ј,7,7Ј-tetramethoxy-3-
methyl-8,9Ј-bicarbazole (19) (29.6 mg, 41%) as a light brown solid.
Data for 18: M.p. 159.5–160 °C. UV (MeOH): λ = 217, 232, 258,
(CH), 130.95 (CH), 132.07 (CH), 143.15 (C), 152.28 (C), 161.65
(C), 164.46 (C), 171.17 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 273
(100) [M]+, 240 (56), 224 (26), 213 (18), 198 (40), 184 (10), 170 (27).
C15H15NO4 (273.29): calcd. C 65.92, H 5.53, N 5.13; found C
66.23, H 5.58, N 5.10.
Methyl 2-Hydroxy-7-methoxycarbazole-3-carboxylate (6) and
Methyl 4-Hydroxy-7-methoxycarbazole-3-carboxylate (22): A mix-
ture of diarylamine 21 (215 mg, 787 μmol), potassium carbonate
(5.9 mg, 43 μmol), and pivalic acid (566 mg) was heated at 90 °C
in air. Palladium acetate (5.3 mg, 24 μmol) was added, and the mix-
ture was vigorously stirred at 90 °C in air. Additional portions of
palladium acetate (3.3, 3.3, and 3.6 mg; Σ 47 μmol) were added
after 15, 24, and 39 h, respectively. After a total reaction time of
47 h, the mixture was cooled to room temperature and diluted with
ethyl acetate. The resulting mixture was washed with a saturated
solution of potassium carbonate and brine several times. The aque-
ous layers were extracted with ethyl acetate, and the combined or-
ganic layers were dried with sodium sulfate. The solvent was evapo-
rated. Purification of the residue by chromatography on a silica
gel column (pentane/dichloromethane/ethyl acetate, gradient from
20:5:1 to 13:5:1) provided the less polar methyl 4-hydroxy-7-meth-
oxycarbazole-3-carboxylate (22) (46.4 mg, 22%) and the more
polar methyl 2-hydroxy-7-methoxycarbazole-3-carboxylate (6)
(141 mg, 74%) as a colorless solid. Data for 22: M.p. 252 °C, UV
310, 330 (sh) nm. Fluorescence (MeOH): λex = 232 nm, λem
=
377 nm. IR (ATR): ν = 3398, 3365, 2997, 2935, 2833, 1630, 1582,
˜
1469, 1457, 1323, 1298, 1276, 1217, 1197, 1170, 1132, 1109, 1026,
1
1000, 891, 843, 813, 777, 614 cm–1. H NMR (500 MHz, CDCl3):
δ = 2.36 (s, 3 H), 3.90 (s, 3 H), 3.91 (s, 3 H), 6.82 (s, 1 H), 6.96
(dd, J = 8.5, 2.4 Hz, 1 H), 7.26 (d, 1 H, coupling constant could
not be calculated because of signal overlap with CHCl3), 7.44 (d,
J = 2.4 Hz, 1 H), 7.74 (br. s, 1 H), 7.75 (s, 1 H) ppm. 13C NMR
and DEPT (125 MHz, CDCl3): δ = 16.86 (CH3), 55.65 (CH3), 56.19
(CH3), 92.57 (CH), 102.69 (CH), 111.02 (CH), 113.10 (CH), 116.40
(C), 119.12 (C), 121.55 (CH), 124.17 (C), 134.29 (C), 140.16 (C),
154.01 (C), 157.59 (C) ppm. MS (EI, 70 eV): m/z (%) = 241 (100)
[M]+, 226 (74), 198 (21), 183 (20), 154 (12). Data for 19: M.p.
168.5–169 °C. UV (MeOH): λ = 218, 238, 261 (sh), 300 (sh), 311,
332 (sh), 347 (sh) nm. Fluorescence (MeOH): λex = 311 nm, λem
=
375 nm. IR (ATR): ν = 3415, 3274, 2927, 2826, 1631, 1591, 1486,
˜
1457, 1422, 1294, 1269, 1197, 1165, 1120, 1076, 1032, 921, 866,
815 cm–1. 1H NMR (600 MHz, [D6]acetone): δ = 2.33 (s, 3 H), 3.71
(s, 3 H), 3.82 (s, 3 H), 3.92 (s, 3 H), 3.96 (s, 3 H), 4.00 (br. t, J =
6.0 Hz, 1 H), 4.78 (d, J = 6.0 Hz, 2 H), 6.70 (s, 1 H), 6.91 (s, 1 H),
6.92 (dd, J = 8.8, 2.4 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 1 H), 7.10 (d,
J = 2.3 Hz, 1 H), 7.72 (d, J = 2.4 Hz, 1 H), 7.76 (d, J = 2.3 Hz, 1
H), 7.91 (s, 1 H), 8.18 (s, 1 H), 9.69 (br. s, 1 H) ppm. 13C NMR
and DEPT (150 MHz, [D6]acetone): δ = 16.91 (CH3), 55.69 (CH3),
55.85 (CH3), 56.19 (CH3), 56.41 (CH3), 60.82 (CH2), 92.77 (CH),
93.71 (CH), 103.50 (CH), 103.78 (CH), 111.33 (CH), 111.76 (CH),
113.91 (CH), 116.98 (C), 117.07 (C), 119.40 (C), 120.31 (CH),
121.76 (C), 122.30 (CH), 124.55 (C), 125.28 (C), 127.01 (C), 131.82
(C), 136.54 (C), 141.86 (C), 142.62 (C), 154.97 (C), 155.64 (C),
157.80 (C), 158.84 (C) ppm. MS (EI, 70 eV): m/z (%) = 496 (100)
[M]+, 494 (27), 480 (31), 248 (9). MS (ESI, +10 V): m/z = 479 [M –
OH]+.
(MeOH): λ = 235, 253, 269, 336 nm. Fluorescence (MeOH): λex
=
269 nm, λem = 416 nm. IR (ATR): ν = 3421, 3324, 3071, 2999,
˜
2945, 2920, 2850, 1612, 1583, 1541, 1507, 1490, 1474, 1435, 1360,
1341, 1243, 1196, 1155, 1100, 1041, 974, 947, 849, 811, 776, 747,
722, 694, 648, 626 cm–1. 1H NMR (500 MHz, [D6]acetone): δ =
3.87 (s, 3 H), 3.96 (s, 3 H), 6.90 (dd, J = 8.6, 2.2 Hz, 1 H), 7.03 (d,
J = 8.6 Hz, 1 H), 7.07 (d, J = 2.2 Hz, 1 H), 7.77 (dd, J = 8.6,
0.6 Hz, 1 H), 8.14 (d, J = 8.6 Hz, 1 H), 10.66 (br. s, 1 H), 11.80 (s,
1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]acetone): δ = 52.37
(CH3), 55.77 (CH3), 95.67 (CH), 103.43 (C), 103.91 (CH), 109.96
(CH), 111.80 (C), 117.07 (C), 124.05 (CH), 126.80 (CH), 141.54
(C), 145.98 (C), 159.49 (C), 159.78 (C), 172.29 (C=O) ppm. MS
(ESI, +25 V): m/z = 272 [M + H]+. MS (ESI, –10 V): m/z = 270
[M – H]–. MS (EI, 70 eV): m/z (%) = 271 (21) [M]+, 239 (100), 224
(50), 196 (22). HRMS: calcd. for C15H13NO4 [M]+ 271.0845; found
271.0837. C15H13NO4 (271.27): calcd. C 66.41, H 4.83, N 5.16;
found C 65.84, H 4.63, N 5.05. Data for 6: M.p. 189–190 °C. UV
Methyl 2-Hydroxy-4-(3-methoxyphenylamino)benzoate (21): A solu-
tion of methyl 4-iodosalicylate (20) (1.00 g, 3.60 mmol) in toluene
(10 mL) was added dropwise over a period of 11 h to a mixture
of m-anisidine (664 mg, 5.39 mmol), palladium acetate (40.6 mg,
181 μmol), SPhos (148 mg, 360 μmol), and cesium carbonate
(1.75 g, 5.38 mmol) in toluene (10 mL) at 100 °C. The mixture was
stirred at 100 °C for 4.25 h (total reaction time of 15.25 h). The
mixture was filtered through a short pad of Celite® (ethyl acetate),
and the solvent was evaporated. Purification of the residue by
chromatography on a silica gel column (pentane/dichloromethane/
ethyl acetate, gradient from 35:5:1 to 22:5:1) provided methyl 2-
hydroxy-4-(3-methoxyphenylamino)benzoate (21) (993 mg, 100%)
as a colorless solid; m.p. 80 °C. UV (MeOH): λ = 328 nm. IR
(MeOH): λ = 224, 246, 288, 338 nm. Fluorescence (MeOH): λex
=
288 nm, λem = 465 nm. IR (ATR): ν = 3314, 3068, 2921, 2851,
˜
1665, 1623, 1597, 1506, 1435, 1397, 1375, 1327, 1272, 1242, 1216,
1192, 1159, 1126, 1085, 1025, 987, 942, 897, 842, 815, 803, 784,
714, 689, 645, 601 cm–1. 1H NMR (500 MHz, [D6]acetone): δ =
3.86 (s, 3 H), 3.98 (s, 3 H), 6.82 (dd, J = 8.5, 2.2 Hz, 1 H), 6.88 (s,
1 H), 7.01 (d, J = 2.2 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 8.48 (s,
1H), 10.39(br. s,1 H),11.01 (s,1 H) ppm. 13C NMRand DEPT(125 -
MHz, [D6]acetone): δ = 52.49 (CH3), 55.78 (CH3), 96.13 (CH),
97.64 (CH), 105.64 (C), 109.18 (CH), 117.72 (C), 118.03 (C), 121.25
(CH), 122.05 (CH), 143.29 (C), 146.73 (C), 160.04 (C), 160.88 (C),
172.23 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 271 (62) [M]+, 239
(100), 211 (16), 196 (9), 183 (16). HRMS: calcd. for C15H13NO4
[M]+ 271.0845; found 271.0854. C15H13NO4 (271.27): calcd. C
66.41, H 4.83, N 5.16; found C 65.92, H 4.78, N 5.06.
(ATR): ν = 3374, 3162, 2949, 2843, 1643, 1599, 1578, 1527, 1492,
˜
1436, 1384, 1340, 1278, 1264, 1247, 1206, 1189, 1148, 1102, 1046,
981, 958, 884, 841, 768, 752, 725, 691, 664, 638, 623 cm–1. 1H NMR
(500 MHz, [D6]acetone): δ = 3.79 (s, 3 H), 3.88 (s, 3 H), 6.56 (d, J
= 2.3 Hz, 1 H), 6.60 (dd, J = 8.8, 2.0 Hz, 1 H), 6.64 (ddd, J = 8.3,
Methyl
2-Methoxy-4-{[3-(triisopropylsilyloxy)phenyl]amino}-
benzoate: A solution of m-bromophenyl triisopropylsilyl ether (23)
2.3, 0.6 Hz, 1 H), 6.78 (t, J = 2.2 Hz, 1 H), 6.83 (dd, J = 8.1, (1.52 g, 4.61 mmol) in toluene (10 mL) was added dropwise over a
1.5 Hz, 1 H), 7.25 (t, J = 8.1 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 1 H),
8.04 (br. s, 1 H), 10.92 (s, 1 H) ppm. 13C NMR and DEPT
(125 MHz, [D6]acetone): δ = 52.20 (CH3), 55.50 (CH3), 101.36
(CH), 104.05 (C), 107.26 (CH), 108.35 (CH), 109.17 (CH), 113.75
period of 8 h to a mixture of methyl 4-amino-2-methoxybenzoate
(24) (1.00 g, 5.53 mmol), palladium acetate (51.5 mg, 229 μmol),
SPhos (189 mg, 461 μmol), and cesium carbonate (2.13 g,
6.55 mmol) in toluene (14 mL) at 100 °C. The mixture was stirred
Eur. J. Org. Chem. 2014, 4741–4752
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4749

H.-J. Knölker et al.
FULL PAPER
at 100 °C for 16 h (total reaction time of 24 h). The mixture was
filtered through a short pad of Celite® (ethyl acetate), and the sol-
vent was evaporated. Purification of the residue by chromatography
on a silica gel column (pentane/ethyl acetate, gradient from 20:1 to
8:1) provided methyl 2-methoxy-4-{[3-(triisopropylsilyloxy)phenyl]-
amino}benzoate (1.95 g, 98%) as a colorless solid; m.p. 121–
ent from 6:1 to 3.5:1) provided hydroxycarbazole 26 (55.4 mg,
100%) as a pale grey solid; m.p. 245–246 °C. UV (MeOH): λ =
221, 245, 280, 310, 320, 336 nm. Fluorescence (MeOH): λex
=
280 nm, λem = 428 nm. IR (ATR): ν = 3403, 3337, 3008, 2949,
˜
2836, 1689, 1618, 1565, 1431, 1362, 1322, 1279, 1226, 1202, 1149,
1
1123, 1080, 1025, 958, 906, 829, 785, 727, 681, 633, 604 cm–1. H
122 °C. UV (MeOH): λ = 241, 290 (sh), 324 nm. IR (ATR): ν =
NMR (500 MHz, [D6]acetone): δ = 3.83 (s, 3 H), 3.89 (s, 3 H), 6.76
(dd, J = 8.4, 2.1 Hz, 1 H), 6.93 (d, J = 2.1 Hz, 1 H), 7.08 (s, 1 H),
7.87 (d, J = 8.4 Hz, 1 H), 8.37 (s, 1 H), 8.38 (s, 1 H), 10.26 (br. s,
1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]acetone): δ = 51.63
(CH3), 56.42 (CH3), 94.89 (CH), 97.87 (CH), 109.87 (CH), 113.27
(C), 117.08 (C), 117.49 (C), 121.14 (CH), 123.63 (CH), 143.09 (C),
144.64 (C), 157.18 (C), 158.85 (C), 167.46 (C=O) ppm. MS (EI,
70 eV): m/z (%) = 271 (100) [M]+, 256 (25), 240 (46), 226 (17).
C15H13NO4 (271.27): calcd. C 66.41, H 4.83, N 5.16; found C
66.62, H 4.87, N 5.17.
˜
3319, 2943, 2866, 1696, 1653, 1614, 1582, 1532, 1509, 1488, 1459,
1432, 1345, 1307, 1255, 1214, 1180, 1150, 1089, 1029, 1000, 967,
1
944, 883, 865, 829, 767, 716, 666, 610 cm–1. H NMR (500 MHz,
[D6]acetone): δ = 1.12 (d, J = 7.4 Hz, 18 H), 1.25–1.33 (m, 3 H),
3.75 (s, 3 H), 3.79 (s, 3 H), 6.58 (dd, J = 8.1, 2.2 Hz, 1 H), 6.69
(dt, J = 8.6, 1.8 Hz, 1 H), 6.72 (t, J = 1.8 Hz, 1 H), 6.81 (t, J =
2.2 Hz, 1 H), 6.85–6.87 (m, 1 H), 7.20 (t, J = 8.1 Hz, 1 H), 7.71 (d,
J = 8.6 Hz, 1 H), 7.92 (br. s, 1 H) ppm. 13C NMR and DEPT
(125 MHz, [D6]acetone): δ = 13.38 (3 CH), 18.27 (6 CH3), 51.36
(CH3), 55.88 (CH3), 99.75 (CH), 107.64 (CH), 111.26 (C), 111.79
(CH), 113.42 (CH), 114.57 (CH), 130.99 (CH), 134.34 (CH), 143.90
(C), 150.32 (C), 157.82 (C), 162.21 (C), 166.28 (C=O) ppm. MS
(EI, 70 eV): m/z (%) = 429 (52) [M]+, 398 (9), 386 (100), 358 (36),
344 (10), 330 (11), 149 (16). C24H35NO4Si (429.63): calcd. C 67.10,
H 8.21, N 3.26; found C 67.45, H 8.42, N 3.31.
Methyl 2-Methoxy-4-[(3-methoxyphenyl)amino]benzoate (27):
A
solution of m-bromoanisole (8) (863 mg, 4.61 mmol) in toluene
(10 mL) was added dropwise over a period of 11 h to a mixture of
methyl 4-amino-2-methoxybenzoate (24) (1.00 g, 5.53 mmol), pal-
ladium acetate (52.1 mg, 232 μmol), SPhos (189 mg, 461 μmol),
and cesium carbonate (2.13 g, 6.55 mmol) in toluene (14 mL) at
Methyl 2-Methoxy-7-(triisopropylsilyloxy)carbazole-3-carboxylate 100 °C. The mixture was stirred at 100 °C for 10 h (total reaction
(25): A 10 mL microwave tube was charged with methyl 2-methoxy-
4-{[3-(triisopropylsilyloxy)phenyl]amino}benzoate (204 mg,
474 μmol), palladium acetate (5.2 mg, 23 μmol), potassium carb-
time of 21 h). The mixture was filtered through a short pad of
Celite® (ethyl acetate), and the solvent was evaporated. Purification
of the residue by chromatography on a silica gel column (pentane/
onate (7.1 mg, 51 μmol), copper(II) acetate (216 mg, 1.19 mmol), ethyl acetate, gradient from 5:1 to 3.5:1) provided diarylamine 27
and pivalic acid (509 mg) in air. The tube was irradiated in a micro-
wave reactor at 130 °C and 300 W for 3 h. The mixture was cooled
to room temperature and diluted with ethyl acetate, and the re-
sulting mixture was washed with a saturated solution of potassium
carbonate and brine several times. The aqueous layers were ex-
tracted with ethyl acetate, and the combined organic layers were
dried with sodium sulfate. The solvent was evaporated. Purification
of the residue by chromatography on a silica gel column (pentane/
ethyl acetate, gradient from 5:1 to 3:1) provided carbazole 25
(123 mg, 61%) as a colorless solid; m.p. 142 °C. UV (MeOH): λ =
223, 238 (sh), 246, 278, 285 (sh), 310, 320, 335 nm. Fluorescence
(1.33 g, 100%) as a colorless solid; m.p. 68–69 °C. UV (MeOH): λ
= 213, 241, 324 nm. IR (ATR): ν = 3347, 3187, 3058, 3006, 2937,
˜
2838, 1691, 1653, 1593, 1508, 1492, 1458, 1434, 1395, 1339, 1307,
1276, 1212, 1176, 1159, 1141, 1097, 1050, 1034, 971, 949, 868, 818,
1
782, 751, 689, 664, 639 cm–1. H NMR (500 MHz, [D6]acetone): δ
= 3.75 (s, 3 H), 3.79 (s, 3 H), 3.80 (s, 3 H), 6.58 (dd, J = 8.3, 2.4 Hz,
1 H), 6.70 (dt, J = 8.6, 2.0 Hz, 1 H), 6.76 (t, J = 1.7 Hz, 1 H), 6.80
(t, J = 2.2 Hz, 1 H), 6.83 (dd, J = 8.0, 2.0 Hz, 1 H), 7.23 (t, J =
8.0 Hz, 1 H), 7.71 (d, J = 8.6 Hz, 1 H), 7.92 (br. s, 1 H) ppm. 13C
NMR and DEPT (125 MHz, [D6]acetone): δ = 51.36 (CH3), 55.47
(CH3), 55.89 (CH3), 99.65 (CH), 105.97 (CH), 107.71 (CH), 108.61
(MeOH): λex = 278 nm, λem = 413 nm. IR (ATR): ν = 3333, 2942, (CH), 111.18 (C), 112.74 (CH), 130.94 (CH), 134.38 (CH), 143.86
˜
2865, 2056, 2030, 1703, 1652, 1612, 1582, 1499, 1475, 1459, 1432,
1389, 1340, 1313, 1276, 1234, 1198, 1162, 1117, 1085, 1037, 1015,
990, 970, 919, 880, 864, 833, 800, 775, 751, 726, 707, 681, 640 cm–1.
1H NMR (500 MHz, [D6]acetone): δ = 1.14 (d, J = 7.5 Hz, 18 H),
1.33 (m, 3 H), 3.83 (s, 3 H), 3.90 (s, 3 H), 6.82 (dd, J = 8.4, 2.2 Hz,
1 H), 7.03 (d, J = 2.2 Hz, 1 H), 7.11 (s, 1 H), 7.94 (d, J = 8.4 Hz,
1 H), 8.42 (s, 1 H), 10.30 (br. s, 1 H) ppm. 13C NMR and DEPT
(125 MHz, [D6]acetone): δ = 13.44 (3 CH), 18.33 (6 CH3), 51.67
(CH3), 56.43 (CH3), 94.93 (CH), 102.59 (CH), 113.54 (C), 113.95
(CH), 117.14 (C), 118.45 (C), 121.02 (CH), 124.04 (CH), 142.78
(C), 144.83 (C), 155.41 (C), 159.11 (C), 167.41 (C=O) ppm. MS
(EI, 70 eV): m/z (%) = 427 (100) [M]+, 396 (9), 384 (18), 352 (35),
325 (20), 310 (13), 282 (15), 148 (22). C24H33NO4Si (427.62): calcd.
C 67.41, H 7.78, N 3.28; found C 67.70, H 7.87, N 3.30.
(C), 150.35 (C), 161.69 (C), 162.19 (C), 166.31 (C=O) ppm. MS
(EI, 70 eV): m/z (%) = 287 (95) [M]+, 256 (100). C16H17NO4
(287.32): calcd. C 66.89, H 5.96, N 4.88; found C 67.15, H 5.90, N
4.89.
Methyl 2,7-Dimethoxycarbazole-3-carboxylate (Clausine-H, Claus-
zoline-C, 28) and Methyl 2,5-Dimethoxycarbazole-6-carboxylate
(29): A 10 mL microwave tube was charged with diarylamine (27)
(301 mg, 1.05 mmol), palladium acetate (12 mg, 52 μmol), potas-
sium carbonate (14.3 mg, 103 μmol), copper(II) acetate (474 mg,
2.61 mmol), and pivalic acid (799 mg) in air. The tube was irradi-
ated in a microwave reactor at 110 °C and 300 W for 3 h. The mix-
ture was cooled to room temperature and diluted with ethyl acetate,
and the resulting mixture was washed with a saturated solution of
potassium carbonate and brine several times. The aqueous layers
were extracted with ethyl acetate, and the combined organic layers
were dried with sodium sulfate. The solvent was evaporated. Purifi-
cation of the residue by chromatography on a silica gel column
(dichloromethane/ethyl acetate, gradient from 50:1 to 20:1) pro-
Methyl 7-Hydroxy-2-methoxycarbazole-3-carboxylate (26): TBAF
(1 m in THF, 305 μL, 305 μmol) was added to a solution of carb-
azole 25 (86.9 mg, 203 μmol) in DMF (10 mL) at –10 °C. The cool-
ing bath was removed, and the mixture was stirred for 10 min.
Water and diethyl ether were added, and the organic layer was sep- vided the less polar carbazole 29 (36 mg, 12%) as a colorless solid
arated. The organic layer was washed with water and brine, and
the combined aqueous layers were extracted with ethyl acetate. The
combined organic layers were dried with sodium sulfate, and the
solvent was evaporated. Purification of the residue by chromatog-
raphy on a silica gel column (dichloromethane/ethyl acetate, gradi-
and the more polar clausine-H (clauszoline-C) (28) (249 mg, 84%)
as a colorless solid. Data for 29: M.p. 203–204 °C. 1H NMR
(500 MHz, [D6]acetone): δ = 3.84 (s, 3 H), 3.91 (s, 3 H), 4.07 (s, 3
H), 6.76 (d, J = 8.0 Hz, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 7.12 (s, 1
H), 7.29 (t, J = 8.0 Hz, 1 H), 8.65 (s, 1 H), 10.49 (br. s, 1 H) ppm.
4750
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4741–4752

Synthesis and Structural Revision of Clausine-TY
13C NMR and DEPT (125 MHz, [D6]acetone): δ = 51.69 (CH3),
55.75 (CH3), 56.33 (CH3), 94.44 (CH), 101.72 (CH), 104.83 (CH),
113.01 (C), 113.75 (C), 116.28 (C), 127.07 (CH), 127.22 (CH),
142.79 (C), 143.87 (C), 156.43 (C), 159.09 (C), 167.56 (C=O) ppm.
MS (EI, 70 eV): m/z (%) = 285 (100) [M]+, 270 (22), 254 (53), 242
(14). Data for 28: M.p. 193–194 °C; ref.[12] m.p. 191–192 °C. UV
(MeOH): λ = 224, 246, 281, 309, 319, 334 nm. Fluorescence
[2]
[3]
a) H.-J. Knölker, N. O’Sullivan, Tetrahedron 1994, 50, 10893;
for reviews, see: b) H.-J. Knölker, Curr. Org. Synth. 2004, 1,
309; c) H.-J. Knölker, Chem. Lett. 2009, 38, 8.
a) B. Åkermark, J. D. Oslob, U. Heuschert, Tetrahedron Lett.
1995, 36, 1325; b) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett 2008,
949; c) B. Liégault, D. Lee, M. P. Huestis, D. R. Stuart, K.
Fagnou, J. Org. Chem. 2008, 73, 5022; d) J. A. Jordan-Hore,
C. C. C. Johansson, M. Gulias, E. M. Beck, M. J. Gaunt, J.
Am. Chem. Soc. 2008, 130, 16184; e) M. Zhang, Adv. Synth.
Catal. 2009, 351, 2243; f) H.-J. Knölker, Chem. Lett. 2009, 38,
8; g) L. Ackermann, A. Althammer, P. Mayer, Synthesis 2009,
3493; h) J. J. Song, J. T. Reeves, D. R. Fandrick, Z. Tan, N. K.
Yee, C. H. Senanayake, ARKIVOC 2010, i, 390; i) B. J. Stokes,
T. G. Driver, Eur. J. Org. Chem. 2011, 4071; j) I. Bauer, H.-J.
Knölker, Top. Curr. Chem. 2012, 309, 203; k) D. Tsvelikhovsky,
S. L. Buchwald, J. Am. Chem. Soc. 2012, 134, 16917; l) N.
Yoshikai, Y. Wei, Asian J. Org. Chem. 2013, 2, 466; m) C.
Thomas, H.-J. Knölker, Tetrahedron Lett. 2013, 54, 591; n) R.
Hesse, K. K. Gruner, O. Kataeva, A. W. Schmidt, H.-J.
Knölker, Chem. Eur. J. 2013, 19, 14098; o) R. B. Bedford, J. G.
Bowen, A. L. Weeks, Tetrahedron 2013, 69, 4389; p) V. P. Ku-
mar, K. K. Gruner, O. Kataeva, H.-J. Knölker, Angew. Chem.
Int. Ed. 2013, 52, 11073.
a) H.-J. Knölker, K. R. Reddy, Chem. Rev. 2002, 102, 4303; b)
D. P. Chakraborty, S. Roy, in: Progress in the Chemistry of Or-
ganic Natural Products (Eds.: W. Herz, H. Grisebach, G. W.
Kirby, W. Steglich, C. Tamm), Springer, Wien, 2003, vol. 85, p.
125; c) H.-J. Knölker, K. R. Reddy, in: The Alkaloids (Ed.:
G. A. Cordell), Academic Press, Amsterdam, 2008, vol. 65, p.
1; d) T. Nagappan, P. Ramasamy, M. E. A. Wahid, T. C. Se-
garan, C. S. Vairappan, Molecules 2011, 16, 9651; e) A. W.
Schmidt, K. R. Reddy, H.-J. Knölker, Chem. Rev. 2012, 112,
3193; f) M. Ishikura, T. Abe, T. Choshi, S. Hibino, Nat. Prod.
Rep. 2013, 30, 694.
(MeOH): λex = 281 nm, λem = 418 nm. IR (ATR): ν = 3286, 3002,
˜
2942, 2837, 2056, 2030, 2009, 1694, 1635, 1612, 1581, 1523, 1506,
1475, 1434, 1381, 1345, 1321, 1274, 1226, 1186, 1152, 1112, 1085,
1038, 1025, 960, 940, 912, 819, 799, 779, 726, 679, 642, 618 cm–1.
1H NMR (500 MHz, [D6]acetone): δ = 3.83 (s, 3 H), 3.86 (s, 3 H),
3.90 (s, 3 H), 6.83 (dd, J = 8.5, 2.2 Hz, 1 H), 7.03 (d, J = 2.2 Hz,
1 H), 7.11 (s, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 8.41 (s, 1 H), 10.36
(br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]acetone): δ
= 51.66 (CH3), 55.76 (CH3), 56.41 (CH3), 94.93 (CH), 95.97 (CH),
109.22 (CH), 113.51 (C), 117.21 (C), 117.75 (C), 121.14 (CH),
123.89 (CH), 142.82 (C), 144.68 (C), 158.97 (C), 159.72 (C), 167.44
(C=O) ppm. MS (EI, 70 eV): m/z (%) = 285 (100) [M]+, 270 (45),
254 (26), 240 (11). C16H15NO4 (285.30): calcd. C 67.36, H 5.30, N
4.91; found C 66.91, H 5.41, N 4.93.
[4]
2,7-Dimethoxycarbazole-3-carboxylic Acid (Clausine-K, Clauszo-
line-J, Clausine-TY) (7): A degassed solution of clausine-H (claus-
zoline-C) (28) (166 mg, 582 μmol) and potassium hydroxide
(676 mg, 12.0 mmol) in ethanol (10 mL) and water (3 mL) was
stirred at 50 °C for 2.5 h. The mixture was diluted with ethyl acet-
ate, and the resulting mixture was washed with dilute hydrochloric
acid, water, and brine several times. The combined aqueous layers
were extracted with ethyl acetate, and the combined organic layers
were dried with sodium sulfate. The solvent was evaporated. Purifi-
cation of the residue by chromatography on a silica gel column
(dichloromethane/ethyl acetate, gradient from 20:1 to 13:1) pro-
vided 2,7-dimethoxycarbazole-3-carboxylic acid (7) (117 mg, 74%)
as a pale grey solid, m.p. 257 °C; ref.[12] m.p. 250–256 °C; ref.[13]
m.p. 252–256 °C; ref.[11] m.p. 220–222 °C. UV (MeOH): λ = 223
[5]
[6]
G. Kusano, M. Shibano, M. Idoji, K. Minoura, Heterocycles
1993, 36, 2367.
S. S. Jash, G. K. Biswas, S. K. Bhattacharyya, P. Bhattach-
aryya, A. Chakraborty, B. K. Chowdhury, Phytochemistry
1992, 31, 2503.
A. K. Chakravarty, T. Sarkar, K. Masuda, T. Takey, H. Doi,
E. Kotani, K. Shiojima, Indian J. Chem. B 2001, 40, 484.
S. Roy, L. Bhattacharyya, D. P. Chakraborty, J. Indian Chem.
Soc. 1982, 59, 1369.
R. Bautista, P. Bernal, L. E. Montiel, F. Delgado, J. Tamariz,
Synthesis 2011, 929.
[7]
(sh), 245, 282, 309, 320, 335 (sh) nm. Fluorescence (MeOH): λex
=
282 nm, λem = 414 nm. IR (ATR): ν = 3308, 3064, 3002, 2962,
˜
[8]
2924, 2834, 1734, 1716, 1699, 1661, 1611, 1571, 1472, 1460, 1443,
1409, 1342, 1285, 1232, 1198, 1160, 1113, 1080, 1036, 1021, 945,
[9]
1
898, 817, 801, 782, 747, 725, 678, 624 cm–1. H NMR (500 MHz,
[D6]acetone): δ = 3.87 (s, 3 H), 4.13 (s, 3 H), 6.86 (dd, J = 8.5,
2.2 Hz, 1 H), 7.05 (d, J = 2.2 Hz, 1 H), 7.24 (s, 1 H), 8.03 (d, J =
8.5 Hz, 1 H), 8.64 (s, 1 H), 10.49 (br. s, 1 H), 10.85 (br. s, 1 H) ppm.
13C NMR and DEPT (125 MHz, [D6]acetone): δ = 55.79 (CH3),
57.17 (CH3), 94.66 (CH), 96.06 (CH), 109.56 (CH), 111.40 (C),
117.57 (C), 118.52 (C), 121.52 (CH), 125.16 (CH), 143.04 (C),
145.15 (C), 158.08 (C), 160.04 (C), 166.55 (C=O) ppm. MS (ESI,
+10 V): m/z = 272 [M + H]+, 543 [2M + H]+.
[10]
[11]
[12]
[13]
[14]
T. Sripisut, S. Laphookhieo, J. Asian Nat. Prod. Res. 2010, 12,
614.
Y. H. Taufiq-Yap, T. H. Peh, G. C. L. Ee, M. Rahmani, M. A.
Sukari, A. M. Ali, R. Muse, Nat. Prod. Res. 2007, 21, 810.
T.-S. Wu, S.-C. Huang, P.-L. Wu, C.-M. Teng, Phytochemistry
1996, 43, 133.
C. Ito, S. Katsuno, H. Ohta, M. Omura, I. Kajiura, H. Furu-
kawa, Chem. Pharm. Bull. 1997, 45, 48.
a) N. Kongkathip, B. Kongkathip, Heterocycles 2009, 79, 121;
b) K. Thevissen, A. Marchand, P. Chaltin, E. M. K. Meert,
B. P. A. Cammue, Curr. Med. Chem. 2009, 16, 2205; c) M. P.
Krahl, O. Kataeva, A. W. Schmidt, H.-J. Knölker, Eur. J. Org.
Chem. 2013, 59.
O. Kataeva, M. P. Krahl, H.-J. Knölker, Org. Biomol. Chem.
2005, 3, 3099.
a) J. F. Hartwig, Angew. Chem. Int. Ed. 1998, 37, 2046; Angew.
Chem. 1998, 110, 2154; b) A. R. Muci, S. L. Buchwald, Top.
Curr. Chem. 2002, 219, 131; c) M. D. Charles, P. Schultz, S. L.
Buchwald, Org. Lett. 2005, 7, 3965; d) D. S. Surry, S. L. Buch-
wald, Angew. Chem. Int. Ed. 2008, 47, 6338; Angew. Chem.
2008, 120, 6438.
T. Gensch, M. Rönnefahrt, R. Czerwonka, A. Jäger, O. Kata-
eva, I. Bauer, H.-J. Knölker, Chem. Eur. J. 2012, 18, 770.
a) C. Börger, H.-J. Knölker, Synlett 2008, 1698; b) C. Börger,
H.-J. Knölker, Tetrahedron 2012, 68, 6727.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of all compounds,
2D NMR spectra (COSY, HSQC, HMBC, and NOESY) of 8,9Ј-
bicarbazole 19, and data for the X-ray crystal structure analysis of
mukolidine (4).
[15]
[16]
Acknowledgments
The authors are grateful to M. Sc. Arlett Großmann and Dr.
Philipp Linning for experimental support.
[17]
[18]
[1] B. Åkermark, L. Eberson, E. Jonsson, E. Pettersson, J. Org.
Chem. 1975, 40, 1365.
Eur. J. Org. Chem. 2014, 4741–4752
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4751

H.-J. Knölker et al.
FULL PAPER
[19] M. Schmidt, H.-J. Knölker, Synlett 2009, 2421.
[20] G. Kaufmann, B. Sc. Thesis, TU Dresden, Germany, 2012.
[21] S. Rasheed, D. N. Rao, K. R. Reddy, S. Aravinda, R. A. Vish-
wakarma, P. Das, RSC Adv. 2014, 4, 4960.
[22] a) D. P. Chakraborty, B. P. Das, Sci. Cult. 1966, 32, 181; b)
D. P. Chakraborty, B. P. Das, S. P. Basak, Plant Biochem. J.
1974, 1, 73.
[23] A. K. Chakravarty, T. Sarkar, K. Masuda, K. Shiojima, Phyto-
chemistry 1999, 50, 1263.
[24] G. Bringmann, S. Tasler, Tetrahedron 2001, 57, 2337.
[25] a) R. Forke, M. P. Krahl, F. Däbritz, A. Jäger, H.-J. Knölker,
Synlett 2008, 1870; b) R. Hesse, A. Jäger, A. W. Schmidt, H.-
J. Knölker, Org. Biomol. Chem. 2014, 12, 3866.
[26]
[27]
[28]
C. Ito, H. Ohta, H. T.-W. Tan, H. Furukawa, Chem. Pharm.
Bull. 1996, 44, 2231.
G. M. Sheldrick, SHELXS-97, Programs for Crystal Structure
Solution, University of Göttingen, Germany, 1997.
G. M. Sheldrick, SADABS, v. 2.10, Bruker/Siemens Area De-
tector Absorption Correction Program, Bruker AXS Inc., Madi-
son, WI, USA, 2002.
[29] G. M. Sheldrick, SHELXL-97, Programs for Crystal Structure
Refinement, University of Göttingen, Germany, 1997.
[30] L. Farrugia, J. Appl. Crystallogr. 1997, 30, 565.
Received: April 27, 2014
Published Online: June 17, 2014
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Eur. J. Org. Chem. 2014, 4741–4752