Synthesis of 1,1′- and 2,2′-Bicarbazole Alkaloids by Iron(III)-Catalyzed Oxidative Coupling of 2- and 1-Hydroxycarbazoles

Article abstract of DOI:10.1002/chem.201704554

We describe the synthesis of 1,1′- and 2,2′-bicarbazoles by oxidative homocoupling of 2- and 1-hydroxycarbazoles. The oxidative coupling using catalytic amounts of F₁₆PcFe can be applied to both groups of substrates. Although F₁₆PcFe generally provides the best yields for the synthesis of 1,1′-bicarbazoles, di-tert-butyl peroxide affords better results for the 2,2′-bicarbazoles. In our study, we have achieved the first syntheses of the biscarbalexines A–C, bisglybomine B, 2,2′-dihydroxy-7,7′-dimethoxy-3,3′-dimethyl-1,1′-bicarbazole, bispyrayafoline C, and bisisomahanine. The iron-catalyzed coupling of koenigine led to an improved synthesis of 8,8′′-biskoenigine and afforded an unprecedented decacylic product. Oxidative coupling of 1-hydroxycarbazoles led to bisclausenol, and to the first total syntheses of bismurrayafoline B and D.

Full text of DOI:10.1002/chem.201704554

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Accepted Article
Title: Synthesis of 1,1′- and 2,2′-Bicarbazole Alkaloids by Iron(III)-
Catalyzed Oxidative Coupling of 2- and 1-Hydroxycarbazoles
Authors: Christian Brütting, Raphael F. Fritsche, Sebastian K. Kutz,
Carsten Börger, Arndt W. Schmidt, Olga Kataeva, and Hans-
Joachim Knölker
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Synthesis of 1,1′- and 2,2′-Bicarbazole Alkaloids by Iron(III)-
Catalyzed Oxidative Coupling of 2- and 1-Hydroxycarbazoles**
Christian Brütting,[a] Raphael F. Fritsche,[a] Sebastian K. Kutz,[a] Carsten Börger,[a] Arndt W. Schmidt,[a]
Olga Kataeva,[b] and Hans-Joachim Knölker*[a]
Abstract: We describe the synthesis of 1,1′- and 2,2′-bicarbazoles
by oxidative homo-coupling of 2- and 1-hydroxycarbazoles. The
oxidative coupling using catalytic amounts of F16PcFe can be applied
to both groups of substrates. While it generally provides the best
yields for the synthesis of 1,1′-bicarbazoles, di-tert-butyl peroxide
affords better results for the 2,2′-bicarbazoles. In our study, we have
achieved the first syntheses of the biscarbalexines A–C,
bisglybomine B, 2,2′-dihydroxy-7,7′-dimethoxy-3,3′-dimethyl-1,1′-
bicarbazole, bispyrayafoline C, and bisisomahanine. The iron-
catalyzed coupling of koenigine led to an improved synthesis of 8,8″-
biskoenigine and afforded an unprecedented decacylic product.
Oxidative coupling of 1-hydroxycarbazoles led to bisclausenol and to
the first total syntheses of bismurrayafoline B and D.
available by our molybdenum-mediated,[25,26] iron-mediated[27–29]
and palladium-catalyzed[30–41] approaches. The present report
complements our recent syntheses of methylene-bridged
biscarbazoles based on an Ullmann-type coupling of carbazole
units as key step.[42,43]
Introduction
Biaryl compounds play a major role as chiral ligands and as
catalysts in asymmetric synthesis. They also constitute a unique
class of natural products.[1–2] A number of methods has been
developed for the synthesis of axially chiral biaryl compounds
and for the separation of their atropisomers.[3]
The synthesis of 2,2′-dihydroxy-1,1′-binaphthalenes and
ortho,ortho′-dihydroxybiphenyls by phenolic coupling of the
corresponding
hydroxyarenes
has
been
extensively
investigated.[4–8] However, the corresponding bicarbazoles have
been studied scarcely, although a range of 1,1′-, 2,2′-, and
unsymmetrical bicarbazoles has been isolated from different
natural sources, mainly plants of the genera Murraya, Glycosmis
and Clausena.[9–24] Herein, we report the synthesis of the 1,1′-
coupled bis-2-hydroxy-3-methylcarbazole (1), the methoxy-
substituted 1,1′-bicarbazole-2,2′-diols 2–5, bisglybomine B (6),
the bi(pyrano[3,2-a]carbazoles) 7–9, and the 2,2′-bicarbazoles
10–12 by oxidative coupling of the corresponding monomeric
carbazole alkaloids (Figures 1 and 2). The carbazoles are
Figure 1. Bis-2-hydroxy-3-methylcarbazole (1) and related 1,1′-bicarbazoles.
Results and Discussion
Bis-2-hydroxy-3-methylcarbazole (1) has been isolated in 1993
by Furukawa et al. from the roots of Murraya koenigii.[44] In 1996,
we described the first synthetic access to the 1,1′-bicarbazole 1
by a p-chloranil-mediated oxidative coupling of 2-hydroxy-3-
methylcarbazole (14) (Scheme 1, Table 1).[25,45] Using a similar
approach, Dash et al. obtained 1 by a copper(II) chloride-
catalyzed coupling of 14.[46] In our original paper, 2-hydroxy-3-
methylcarbazole (14) was synthesized by reaction of the
arylamine 13 with a cyclohexadienylmolybdenum salt followed
by oxidative cyclization and cleavage of the methyl ether.[25]
Since then, various synthetic approaches to 14 have been
developed.[10,18,46–49]
[a]
Dr. C. Brütting, R. F. Fritsche, Dr. S. K. Kutz, Dr. C. Börger, Dr. A.
W. Schmidt and Prof. Dr. H.-J. Knölker
Department Chemie, Technische Universität Dresden
Bergstraße 66, 01069 Dresden (Germany)
Fax: (+49) 351-463-37030
E-mail: hans-joachim.knoelker@tu-dresden.de
Dr. O. Kataeva
[b]
A. M. Butlerov Chemistry Institute, Kazan Federal University
Kremlevskaya Str. 18, Kazan 420008 (Russia)
Transition Metals in Organic Synthesis, Part 136. For Part 135, see:
F. Puls, N. Richter, O. Kataeva, H.-J. Knölker, Chem. Eur. J. 2017,
23, doi: 10.1002/chem.201703926.
[**]
Supporting information for this article is given via a link at the end of
the document.
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Figure 2. Bipyrano[3,2-a]carbazoles and 2,2′-bicarbazoles.
Our approach via Buchwald–Hartwig coupling of the aniline
13 and iodobenzene followed by palladium(II)-catalyzed
oxidative cyclization and methyl ether cleavage provided 2-
hydroxy-3-methylcarbazole (14) in three steps and 85% overall
yield on gram scale.[40,48,49] Using 14 as model compound, we
screened the performance of various reagents for the oxidative
coupling to the 1,1′-bicarbazole 1 (Table 1). Treatment of 14 with
a copper(II)–TMEDA complex under air, a method previously
used by Koga and co-workers for the oxidative coupling of β-
naphthols,[50] provided the 1,1′-bicarbazole 1 in only 12% yield.
The major product was the triscarbazole 15 containing a central
1,3-dioxepine unit. The structure of compound 15 has been
assigned by 2D NMR spectroscopy (see Supporting Information).
The X-ray analysis of a similar compound confirmed the
assignment of the heterocyclic framework (vide infra).
Analogous compounds have been described by Dryhurst et al.
on oxidation of 5-hydroxyindole derivatives.[51,52] Coupling of 14
using catalytic amounts of copper(I) iodide in the presence of
additive.[59] Under these conditions, the 1,1′-bicarbazole 1 was
obtained in 77% yield. A separation of the atropisomers of 1 was
not attempted as we did not expect a configurational stability of
the pure enantiomers of 1 at room temperature (vide infra).
Moreover, Furukawa et al. did not report any chiroptical data for
the natural product.
meso-1,2-diphenyl-1,2-diaminoethane
bicarbazole 1 in 43% yield and the triscarbazole 15 in 15% yield.
Treatment of 14 with vanadyl acetylacetonate in
provided
the
1,1′-
dichloromethane under oxygen atmosphere, as described by
Uang et al. for oxidative coupling of β-naphthols,[53] provided the
desired 1,1′-bicarbazole 1 in 52% yield and compound 15 in up
to 7% yield.
Scheme 1. Synthesis and oxidative coupling of 2-hydroxy-3-methylcarbazole
(14).
Oxidative coupling of 1 was accomplished in 80% yield without
any formation of compound 15 by treatment of 14 with
stoichiometric amounts of di-tert-butyl peroxide in chlorobenzene
at reflux.[54,55] Recently, iron-catalyzed oxidative coupling
reactions have attracted increasing attention because iron
compounds represent environmentally benign green catalysts.[56]
In this context, we recently described the oxidative C–C coupling
of diarylamines using hexadecafluorophthalocyanine–iron
(F16PcFe)[57,58] as catalyst and methanesulfonic acid as
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Table 1. Oxidative homo-coupling of 2-hydroxy-3-methylcarbazole (14).
Yield [%]
Reagents and conditions
1
15
0
2.2 equiv p-chloranil, MeOH, reflux, 8 h[25]
38
12
43
0.1 equiv [CuOH·TMEDA]2Cl2, CH2Cl2, RT, air, 1 h
18
15
0.1 equiv CuI, 0.1 equiv 1,2-diphenyl-1,2-diaminoethane,
MeCN, 40 °C, 17 h
0.1 equiv CuCl2·2 H2O, 1.5 equiv DBU, MeCN, 100 °C
51
n.r.a
(sealed tube), 26 h[46]
0.1 equiv VO(acac)2, CH2Cl2, RT, 18 h
0.1 equiv VO(acac)2, CH2Cl2–Et2O (4:1), RT, O2, 22.5 h
2.0 equiv (t-BuO)2, PhCl, reflux, 2.5 h
52
52
80
77
2
7
0
0
3.0 mol% F16PcFe, 10 mol% MsOH, CH2Cl2, RT, air, 6 h
[a] n.r.: not reported
We then investigated the synthesis of the methoxy-substituted
bicarbazoles 2–6 by oxidative coupling of the corresponding
carbazoles 16–20 (Scheme 2). In 2012, Chen et al. obtained
biscarbalexine A (2), the 5,5′-dimethoxy analog of 1, from the
stem of G. pentaphylla.[60] The corresponding precursor,
carbalexin A (16), was isolated from leaves of the same plant by
Greger et al. in 2001.[61] Recently we reported the first total
Scheme 2. Synthesis of the 1,1′-bicarbazoles 2–6, the triscarbazole 21 and
tetrahydroxy-1,1′-bicarbazole 22. Reagents and conditions: a) see Table 2; b)
4.0 equiv BBr3, CH2Cl2, −78 °C, 2h, 0 °C, 4 h, RT, 44 h (40%).
synthesis of carbalexin
A
(16) by pivaloyloxy-directed,
Table 2. Oxidative homo-coupling of the dioxygenated carbazoles 16–20.
regioselective palladium(II)-catalyzed oxidative cyclization of a
diarylamine.[62] Treatment of carbalexin A (16) with catalytic
Compd.
Reagents and conditions
Product
(yield)
amounts
of
[CuOH·TMEDA]2Cl2
under
air
provided
biscarbalexine A (2) in 53% yield (Table 2). In agreement with
the oxidative coupling of 2-hydroxy-3-methylcarbazole (14),
these conditions led to the formation of the triscarbazole 21 as
by-product (29% yield). The structure of 21 was assigned based
on 2D NMR spectroscopy (see Supporting Information) and
unequivocally confirmed by an X-ray analysis of single crystals
(Figure 3). Oxidative coupling of 16 using catalytic amounts of
vanadyl acetylacetonate under oxygen atmosphere provided
exclusively biscarbalexine A (2) in 74% yield. The iron(III)-
catalyzed oxidative coupling of carbalexin A (16) using 1 mol%
of F16PcFe in acetic acid afforded biscarbalexine A (2) in 70%
yield. Although the chirality of biscarbalexine A (2) has not been
discussed on its isolation,[60] we have separated the
atropisomers by chiral HPLC (Figure 4). It was found that the
individual enantiomers racemize slowly at room temperature
(solvent: MeCN–H2O, 70:30 + 0.1% TFA). This finding strongly
suggests that naturally occurring biscarbalexine A (2) is a
racemic mixture.
16
0.1 equiv [CuOH·TMEDA]2Cl2, CH2Cl2, RT, air, 45
min
2 (53%) [a]
16
16
17
17
0.1 equiv VO(acac)2, CH2Cl2, RT, O2, 2.5 h
1.0 mol% F16PcFe, HOAc, RT, air, 20 min
2.0 equiv (t-BuO)2, PhCl, reflux, 2.25 h
2 (74%)
2 (70%)
3 (91%)
3 (92%)
3.0 mol% F16PcFe, 10 mol% MsOH, CH2Cl2, RT, air,
80 min
18
18
19
19
20
20
3.0 equiv (t-BuO)2, PhCl, reflux, 1.5 h
2.0 mol% F16PcFe, HOAc, RT, air, 10 min
0.1 equiv VO(acac)2, CH2Cl2, RT, O2, 24 h
3.0 mol% F16PcFe, HOAc, RT, air, 30 min
4.0 equiv (t-BuO)2, PhCl, reflux, 2 h
6 (56%)
6 (63%)
4 (50%)
4 (61%)
5 (23%)
5 (54%)
2.0 mol% F16PcFe, HOAc, RT, air, 30 min
[a] The triscarbazole 21 was obtained as by-product in 29% yield.
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The 2,2′,7,7′-tetraoxygenated 1,1′-bicarbazole 4 has not been
obtained from natural sources yet. The same is true for the
corresponding 2-hydroxy-7-methoxy-3-methylcarbazole (19).
However, compound 19 has been mentioned as synthetic
intermediate by Anwer in 1972,[65] and also served as precursor
for our approach to the pyrano[3,2-a]carbazoles O-
methylmurrayamine
A
and O-methylmahanine.[32] Oxidative
homo-coupling of 19 using catalytic amounts of vanadyl
acetoacetonate under oxygen atmosphere afforded the 1,1′-
bicarbazole 4 in 50% yield. Oxidative homo-coupling of 19 using
catalytic amounts of F16PcFe in the presence of air led to the
1,1′-bicarbazole 4 in 61% yield. Treatment of compound 4 with
boron tribromide provided 2,2′,7,7′-tetrahydroxy-3,3′-dimethyl-
1,1′-bicarbazole (22). Finally, we also prepared the non-natural
biscarbalexine B (5). The corresponding carbalexin B (20) was
first mentioned as synthetic compound by Reisch in 1980,[66]
later isolated by Greger from Glycosmis pentaphylla in 2001,[61]
and obtained by our total synthesis in 2014.[35,36] Treatment of 20
with di-tert-butyl peroxide in chlorobenzene at reflux led to the
8,8′-dimethoxy-1,1′-bicarbazole in only 23% yield accompanied
by extensive decomposition. The iron(III)-catalyzed oxidative
homo-coupling of 20 afforded biscarbalexine B (5) in 54% yield.
The successful oxidative homo-coupling of simple 2-
hydroxycarbazoles to the corresponding 1,1′-bicarbazoles 1–6
encouraged us to apply the approach to the coupling of the
pyrano[3,2-a]carbazoles 23–25 (Scheme 3). Pyrayafoline C (23)
and D (24) were isolated in 1991 by Furukawa from the stem
bark of Murraya euchrestifolia.[67] In 2014, we described a
synthetic route to both compounds.[32] Bispyrayafoline C (7) has
not been obtained from natural sources yet. Bisisomahanine (8),
a homo-coupling product of pyrayafoline D, was isolated in 2004
by Cuong et al. from the roots of Glycosmis stenocarpa and
Figure 3. Molecular structure of 21 in the crystal (monoclinic, C2c); ORTEP
plot showing thermal ellipsoids at the 50% probability level.
The 6,6′-dimethoxy analog biscarbalexine C (3) has not been
obtained from natural sources so far. However, in 2012 Chen
and co-workers reported the isolation of bisglybomine B (6), a
closely related 6,6′-dimethoxybicarbazole featuring an additional
prenyl substituent at C-5 of the carbazole moieties.[60] In 2009
we described the first total synthesis of carbalexin C (17),[41,63]
the precursor for 3, which was isolated in 2001 from Glycosmis
pentaphylla.[61] We also achieved the first total synthesis of the
prenylated analog glybomine B (18),[62] which had been isolated
from Glycosmis arborea.[64] Both 6,6′-dimethoxy substituted 1,1′-
bicarbazoles 3 and 6 were synthesized by treatment of 17 and
18 with di-tert-butyl peroxide in chlorobenzene at reflux (Table 2).
Oxidative homo-coupling of carbalexin C (17) provided the
corresponding dimer biscarbalexine C (3) in 91% yield, whereas
the coupling of glybomine B (18) required a higher load of the
oxidant to provide the natural product 6 in 56% yield. Using our
iron(III)-catalyzed oxidative coupling, 3 and 6 were obtained in
slightly better yields and considerably shorter reaction times.
20
reported to be optically active ([α]D = −13.1, c = 0.25,
CHCl3).[68] However, the authors did not assign the absolute
configuration. Treatment of pyrayafoline C (23) and D (24) with
di-tert-butyl peroxide afforded the corresponding dimers 7 and 8
in 85% and 64% yield, respectively (Table 3). The prenyl-
substituted compounds 24 and 8 seem to be more sensitive
towards decomposition under these reaction conditions. The
iron(III)-catalyzed oxidative coupling with 1 mol% of F16PcFe in
acetic acid proved to be superior and provided bispyrayafoline C
(7) and bisisomahanine (8) in 93% yield. For compound 8 only
one set of signals was observed in the 1H and 13C NMR spectra,
although most likely it was obtained as
a mixture of
diastereoisomers. Since the relative configuration of the natural
product is unknown, we did not attempt to separate the
atropisomers.
Figure 4. Separation of the atropisomers of biscarbalexine A (2) by chiral
HPLC (Nucleocel delta RP, isocratic elution, MeCN–H2O, 70:30 + 0.1% TFA).
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Figure 5. Molecular structure of the decacyclic coupling product 26 in the
crystal (triclinic, P-1).
Scheme 3. Synthesis of bispyrayafoline C (7), bisisomahanine (8), 8,8″-
biskoenigine (9), compound 26 and O,O″-diacetyl(8,8″-biskoenigine) (27).
Reagents and conditions: a) see: Table 3; b) 3.0 equiv Ac2O, 4.0 equiv Et3N,
cat. DMAP, THF, RT, 2 h (93%); c) 8.0 equiv K2CO3, MeOH–CH2Cl2 (1:1), RT
18 h (100%).
Table 3. Oxidative homo-coupling of the pyrano[3,2-a]carbazoles 23–25.
Compd.
Reagents and conditions
Product (yield)
23
23
24
24
25
2.9 equiv. (t-BuO)2, PhCl, reflux, 2.5 h
1.0 mol% F16PcFe, HOAc, RT, air, 10 min
2.0 equiv. (t-BuO)2, PhCl, reflux, 1.5 h
1.0 mol% F16PcFe, HOAc, RT, air, 20 min
7 (85%)
7 (93%)
8 (64%)
8 (93%)
9 (70%)
Scheme 4. Proposed mechanism for the formation of compound 26.
The dioxygenated pyrano[3,2-a]carbazole koenigine (25) was
isolated in 1970 by Narasimhan from leaves of Murraya
koenigii.[69,70] 8,8″-Biskoenigine (9) was obtained by Hao more
0.1 equiv [CuOH·TMEDA]2Cl2, CH2Cl2, RT, air,
20 min
25
25
25
0.1 equiv. VO(acac)2, CH2Cl2, RT, O2, 1.75 h
1.0 mol% F16PcFe, HOAc, RT, air, 3 h
1.0 mol% F16PcFe, CH2Cl2, RT, air, 20 min
9 (72%)
26 (51%)
9 (90%)
than 30 years later from the dried leaves of the same plant.[71,72]
24
8,8″-Biskoenigine (9) was reported to be optically active: [α]D
=
+139.6 (c = 1.00, CHCl3).[72] Hao and co-workers also described
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the iron(III) chloride-mediated oxidative coupling of natural
koenigine (25) to racemic 8,8″-biskoenigine (9) in 30% yield.[72]
Recently, we described the first total synthesis of koenigine (25)
by using our palladium-catalyzed approach.[41] Oxidation of
synthetic koenigine (25) with catalytic amounts of
[CuOH·TMEDA]2Cl2 under air led to 8,8″-biskoenigine (9) in 70%
yield (Table 3). Treatment of 25 with catalytic amounts of
vanadyl acetylacetonate under oxygen atmosphere provided
8,8″-biskoenigine (9) in 72% yield. The iron(III)-catalyzed
oxidative coupling of 25 with 1 mol% of F16PcFe in acetic acid in
the presence of air afforded, after an unusually long reaction
time of 3 hours, the decacyclic coupling product 26 in 51% yield.
The relative configuration of 26 has been assigned by 2D NMR
spectroscopy (see Supporting Information) and unambiguously
confirmed by an X-ray crystal structure determination (Figure 5).
The formation of compound 26 can be rationalized by an
iron(III)-catalyzed oxidative homo-coupling of koenigine (25)
followed by an intramolecular hetero-Diels-Alder cycloaddition
(Scheme 4). When the iron(III)-catalyzed homo-coupling of 25
was performed in dichloromethane as solvent, 8,8″-biskoenigine
(9) was obtained in 90% yield. Synthetic 9 was subjected to
chiral HPLC (Figure 6A). Although the two enantiomers were
distinguishable, we were unable to establish conditions suitable
for the separation of (+)- and (−)-9 by preparative HPLC. The
atropisomers eventually were separated after double O-
acetylation to O,O′′-diacetyl(8,8″-biskoenigine) (27). Preparative
HPLC provided (+)-27 and (−)-27 in >98% ee (Figure 6A). The
individual enantiomers proved to be stable towards racemization
at room temperature and even after heating a solution of (+)- or
(−)-27 (Figure 6B). However, cleavage of the acetyl groups by
exposure to potassium carbonate in methanol at room
temperature led to racemic 8,8″-biskoenigine (9). Base-
facilitated racemization of hydroxybiaryls was observed
previously by other groups.[73,74]
Figure 6. Chiral HPLC separation (Nucleocel delta RP) of the atropisomers of
8,8″-biskoenigine (9) (68% eluent B, isocratic) and O,O″-diacetyl(8,8″-
biskoenigine) (27) (72% eluent B, isocratic; for details, see exp. section), and
thermal stability of the atropisomers of 27 against racemization (Nucleocel
delta RP, MeCN–H2O, 70:30 + 0.1% TFA, rt, 24h and 45 °C, 2 h).
The 2,2′-bicarbazoles 10–12 were synthesized by oxidative
coupling of the corresponding 1-hydroxycarbazoles 28, 29 and
31 (Scheme 5) Clausenol (28) has been isolated by Chakraborty
et al. from Clausena excavata.[75] Different synthetic approaches
to 28 have been reported[75–78] including our palladium-catalyzed
route.[79,80] The oxidative homo-coupling of clausenol (28) using
di-tert-butyl peroxide to the non-natural 2,2′-bicarbazole 10 has
already been reported by Lin and Zhang, who also described the
separation of the atropisomers.[76,77] We have achieved a yield of
93% for the transformation of clausenol (28) to bisclausenol (10)
with di-tert-butyl peroxide. The bismurrayafolines B (11) and D
(12) were isolated by Furukawa from Murraya euchrestifolia in
1983 and 1991, respectively.[81,82] Murrayafoline B (29), the
monomer of 11, was isolated in 1985 by Furukawa from the
same plant.[83] Synthetic approaches to 29 have been reported
by Kapil[84] and by our group.[85] Oxidation of synthetic
murrayafoline B (29)[85] with di-tert-butyl peroxide provided
bismurrayafoline B (11) in 76% yield. The spectroscopic data
were in agreement with those reported for the natural compound.
The 7-geranyl-substituted carbazole (E)-31 has not yet been
isolated from nature. The corresponding O-tosyl derivative 30
(E:Z=1.3:1) was an intermediate of our synthetic approach to
murrayaquinone C.[85] Cleavage of the tosyl group afforded the
1-hydroxycarbazole 31 which has been fully characterized as it
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represents the presumed natural product murrayafoline D.
Oxidation of compound 31 with an excess of di-tert-butyl
peroxide provided the corresponding dimer 12 as a mixture of
diastereoisomers in 99% yield. The iron(III)-catalyzed homo-
coupling reaction of the 1-hydroxycarbazoles 28, 29, and 31
afforded the corresponding 2,2′-bicarbazoles 10, 11, and 12 in
63%, 45% and 38% yield, respectively (see Supporting
Information).
amounts of vanadyl acetylacetonate) was generally less efficient,
but still provided the desired coupling products in reasonable
yields. With chiral ligands, the two latter methods offer a
possibility to obtain enantiomerically pure bicarbazoles.[4,86]
Using the iron(III)-catalyzed homo-coupling as key step, we
achieved the first total syntheses of the naturally occurring 1,1′-
bicarbazole alkaloids biscarbalexine A (2), bisglybomine B (6)
and bisisomahanine (8). Moreover, the iron(III)-catalyzed
coupling provided efficient routes to the non-natural 1,1′-
bicarbazoles 3–5 and the bipyrano[3,2-a]carbazole 7. When
using dichloromethane as solvent, the iron(III)-catalyzed
coupling could also be applied to an efficient total synthesis of
8,8′′-biskoenigine (9). Double O-acetylation of 9 enabled the
separation of the atropisomers by chiral HPLC of compound 27.
In acetic acid as solvent, the homo-coupling of koenigine (25) in
the presence of air and catalytic amounts of F16PcFe affords the
unprecedented decacylic coupling product 26. Finally, the
oxidative homo-coupling of the 1-hydroxycarbazoles 28, 29 and
31 afforded the 1,1′-dihydroxy-2,2′-bicarbazoles 10–12 and thus
led to the first total syntheses of bismurrayafoline B (11) and
bismurrayafoline D (12). In this case, di-tert-butyl peroxide as
oxidant was superior to the iron(III)-catalyzed coupling reaction.
Experimental Section
General. All reactions were carried out in oven-dried glassware using
anhydrous solvents under an argon atmosphere, unless stated otherwise.
CH2Cl2, THF, and toluene were dried using a solvent purification system
(MBraun-SPS). Pd(OAc)2 was recrystallized from glacial AcOH. All other
chemicals were used as received from commercial sources. The iron(III)-
catalyzed reactions were carried out in non-dried solvents and open to air.
Activated carbon on silica gel was prepared by mixing activated carbon
powder (50 mg) with silica gel (1.0 g). Hexadecafluorophthalocyanine–
iron was prepared following the procedure reported previously.[57a,59]
Petroleum ether (PE) refers to the hydrocarbon mixture with a boiling
range of 40–65 °C. Flash chromatography was performed using silica gel
from Acros Organics (0.035–0.070 mm). TLC was performed with TLC
plates from Merck (60 F254) using UV light for visualization. Melting
points were measured on
a Gallenkamp MPD 350 melting point
apparatus. Ultraviolet spectra were recorded on a PerkinElmer 25 UV/Vis
spectrometer. IR spectra were recorded on a Thermo Nicolet Avatar 360
FT-IR spectrometer using the ATR method (Attenuated Total
Reflectance). NMR spectra were recorded on Bruker DRX 500 and
Avance III 600 spectrometers. Chemical shifts δ are reported in parts per
million with the solvent signal as internal standard. Standard
abbreviations were used to denote the multiplicities of the signals. EI-MS
and EI-HRMS were recorded on a Finnigan MAT-95 spectrometer (70
eV) or by GC/MS-coupling using an Agilent Technologies 6890 N GC
System equipped with a 5973 Mass Selective Detector (70 eV). ESI-MS
spectra were recorded on an Esquire LC with an ion trap detector from
Bruker. Positive and negative ions were detected. ESI-HRMS were
recorded using an Q-TOF 6538 (Agilent) or LTQ ORBITRAP XL
instrument (Thermo Scientific). Elemental analyses were measured on an
EuroVector EuroEA3000 elemental analyzer. X-ray crystal structure
analyses were performed with a Bruker-Nonius Kappa CCD (for 21) and
a with Bruker AXS Smart APEX diffractometer (for 26) equipped with a
700 series Cryostream low temperature device from Oxford Cryosystems.
SHELXS-97,[87] SADABS version 2.10,[88] SHELXL-97,[89] POV-Ray for
Windows version 3.7.0.msvc10.win64, and ORTEP-3 for Windows[90]
were used as software. Analytical HPLC was carried out on an Agilent
Scheme 5. Synthesis of the 2,2′-bicarbazoles 10, 11 and 12. Reagents and
conditions: a) 1.3 equiv (t-BuO)2, PhCl, reflux, 2 h (93%); b) 1.5 equiv (t-BuO)2,
PhCl, reflux, 2 h (76%); c) 8.6 equiv LiAlH4, THF, reflux, 16 h; d) 2.9 equiv (t-
BuO)2, PhCl, reflux, 3.25 h (99%, 2 steps).
Conclusions
The efficiency of several reagents and catalysts for the oxidative
homo-coupling of 2-hydroxy-3-methylcarbazole (14) has been
investigated. The iron(III)-catalyzed homo-coupling of 2-
hydroxycarbazoles by oxidation with catalytic amounts of
hexadecafluorophthalocyanine–iron in the presence of air
provides overall the best results for the synthesis of 1,1′-
bicarbazoles with yields up to 93%. Oxidative coupling with
alternative reagents (di-tert-butyl peroxide, air in the presence of
catalytic amounts of copper(II) chloride, or oxygen and catalytic
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10.1002/chem.201704554
Chemistry - A European Journal
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Model 1100 with G1315B UV-DAD (detection at 215, 260 and 560 nm),
G1321A fluorescence and an evaporative light scattering detector (ELS
1000, Polymer Laboratories); column: Macherey-Nagel Nucleocel delta
RP (4.6 × 250 mm); flow rate: 0.5 mL min−1; eluent A: H2O + 0.1% TFA;
eluent B: MeCN + 0.1% TFA. Preparative HPLC was carried out using a
Varian PrepStar system with a Varian ProStar Model 320 UV and an
evaporative light scattering detector (ELS 1000, Polymer Laboratories)
connected via a Sunchrom Quick-Split splitter; column: Macherey-Nagel
Nucleocel delta RP (21 × 250 mm); flow rate: 8.5 mL min−1; eluent A:
H2O + 0.1% TFA; eluent B: MeCN + 0.1% TFA.
(ESI, +10 V): m/z
C39H27N3O3: 585.2052; found: 585.2047.
=
586.3 [M+H]+; HRMS (ESI): m/z calcd for
Biscarbalexine
bicarbazole) (2): Hexadecafluorophthalocyanine–iron (2.11 mg, 2.46
µmol) was added to solution of 2-hydroxy-5-methoxy-3-
A (2,2′-dihydroxy-5,5′-dimethoxy-3,3′-dimethyl-1,1′-
a
methylcarbazole (carbalexin A) (16) (56.8 mg, 250 µmol) in acetic acid (5
mL) and the solution was stirred at room temperature for 20 min under air.
Then argon was bubbled through the reaction mixture and the solvent
was removed in vacuo. Then toluene (3 mL) was added to remove the
residual acetic acid as an azeotrope in vacuo. The residue was dissolved
in dichloromethane (1 mL), filtered through a short pad of activated
carbon on silica gel with dichloromethane (20 mL) and the solvent was
removed in vacuo. Purification of the residue by column chromatography
(silica gel, isohexane/ethyl acetate, 20%–35%) provided the 1,1′-
bicarbazole 2 (39.5 mg, 87.3 µmol, 70%) as light yellow solid. The
atropisomers were separated by HPLC (70% eluent B, isocratic). M.p.
163–167 °C; UV (MeOH): λ = 242, 256 (sh), 295, 321 (sh), 334 nm;
fluorescence (MeOH): λex = 295 nm, λem = 355 nm; IR (ATR): ν = 3527,
3455, 3397, 2917, 2837, 1702, 1607, 1578, 1504, 1417, 1356, 1316,
1262, 1196, 1129, 1093, 1064, 1043, 1019, 971, 888, 782, 758, 728, 697,
653, 622 cm−1; 1H NMR (500 MHz, acetone-d6): δ = 2.45 (s, 6 H), 4.10 (s,
6 H), 6.68 (d, J = 7.9 Hz, 2 H), 6.90 (d, J = 7.9 Hz, 2 H), 7.14 (t, J = 7.9
Hz, 2 H), 7.28 (s, 2 H), 8.03 (s, 2 H), 9.61 (br s, 2 H); 13C NMR (125 MHz,
acetone-d6): δ = 17.39 (2 CH3), 55.65 (2 CH3), 100.42 (2 CH), 102.32 (2
C), 104.82 (2 CH), 113.63 (2 C), 116.43 (2 C), 117.91 (2 C), 125.08 (2
CH), 125.41 (2 CH), 139.27 (2 C), 142.31 (2 C), 152.38 (2 C), 156.23 (2
C); MS (ESI, +10 V): m/z = 453.2 [M+H]+, 905.5 [2 M+H]+; MS (EI): m/z =
492 (100) [M]+, 437 (5), 226 (26); HRMS (EI): m/z calcd for C28H24N2O4:
452.1736; found: 452.1739.
Bis-2-hydroxy-3-methylcarbazole (2,2′-dihydroxy-3,3′-dimethyl-1,1′-
bicarbazole) (1): Dichloromethane (5 mL) was added to a mixture of
hexadecafluorophthalocyanine–iron
(6.44
mg,
7.52
µmol),
methanesulfonic acid (2.41 mg, 25.0 µmol) and 2-hydroxy-3-
methylcarbazole (14) (49.3 mg, 250 µmol). The resulting suspension was
stirred at room temperature for 6 h under air. The mixture was filtered
through a short pad of silica gel with dichloromethane (20 mL). Removal
of the solvent in vacuo provided the 1,1′-bicarbazole 1 (37.8 mg, 96.3
µmol, 77%) as colorless solid. M.p. 259 °C (dec.); UV (MeOH): λ = 213,
236, 257 (sh), 303, 335 nm; IR (KBr): ν = 3529, 3401, 1610, 1460, 1419,
1307, 1216, 1193, 1168, 1132, 887, 749, 739 cm−1 1H NMR (500 MHz,
;
CDCl3): δ = 2.53 (s, 6 H), 5.28 (s, 2 H), 7.22–7.26 (m, 4 H), 7.30–7.33 (m,
2 H), 7.65 (s, 2 H), 7.99 (s, 2 H), 8.03 (d, J = 7.8 Hz, 2 H); 13C NMR and
DEPT (125 MHz, CDCl3): δ = 16.73 (2 CH3), 99.03 (2 C), 110.71 (2 CH),
117.10 (2 C), 117.94 (2 C), 119.47 (2 CH), 119.79 (2 CH), 123.12 (2 CH),
123.62 (2 C), 124.79 (2 CH), 137.69 (2 C), 139.26 (2 C), 151.17 (2 C);
1H NMR (400 MHz, acetone-d6): δ = 2.45 (s, 6 H), 7.10 (m, 2 H), 7.19 (m,
2 H), 7.27 (d, J = 8.0 Hz, 2 H), 7.42 (s, 2 H), 7.89 (s, 2 H), 7.99 (d, J = 7.7
Hz, 2 H), 9.62 (br s, 2 H); 13C NMR (100 MHz, acetone-d6): δ = 18.10 (2
CH3), 103.29 (2 C), 112.24 (2 CH), 117.62 (2 C), 118.95 (2 C), 120.03 (2
CH), 120.25 (2 CH), 123.11 (2 CH), 125.16 (2 CH), 125.37 (2 C), 140.88
(2 C), 141.65 (2 C), 154.12 (2 C); MS (EI): m/z (%) = 392 (100) [M]+, 196
(19); HRMS (EI): m/z calcd for C26H20N2O2: 392.1525; found: 392.1537;
elemental analysis (%) calcd for C26H20N2O2: C 79.57, H 5.14, N 7.14;
found: C 79.43, H 5.31, N 7.30.
Triscarbazole 21: (CuOH·TMEDA)2Cl2 (12.3 mg, 26.4 µmol) was added
to a solution of 2-hydroxy-5-methoxy-3-methylcarbazole (carbalexin A)
(16) (60 mg, 0.26 mmol) in dichloromethane (2.7 mL) and the solution
was stirred at room temperature under air for 45 min. The mixture was
diluted with dichloromethane and washed with water. The aqueous layer
was extracted with dichloromethane. The combined organic layers were
dried (magnesium sulfate) and the solvent was evaporated. Purification
of the residue by column chromatography (silica gel; pentane/ethyl
acetate, 6:1) provided the less polar 1,1′-bicarbazole 2 (31.4 mg, 69.4
µmol, 53%; spectroscopic data: see above) and the more polar
compound 21 (17.1 mg, 25.3 µmol, 29%) as orange solid. M.p. >170 °C
Triscarbazole 15: Method A: [CuOH·TMEDA]2Cl2 (18.8 mg, 40.6 μmol)
was added to a solution of 2-hydroxy-3-methylcarbazole (14) (80.0 mg,
406 μmol) in dichloromethane (4 mL) and the solution was stirred at room
temperature under air for 1 h. The mixture was diluted with
dichloromethane and washed with water. The aqueous layer was
extracted with dichloromethane, the combined organic layers were dried
(sodium sulfate) and the solvent was evaporated. Purification of the
residue by column chromatography (silica gel; isohexane/ethyl acetate,
10:1) provided the less polar compound 15 (ochreous solid; 14.7 mg,
25.1 µmol, 18%) and the more polar 1,1′-bicarbazole 1 (colorless solid;
9.4 mg, 24 µmol, 12%). 15: M.p. 182 °C (dec.); UV (MeOH): λ = 228, 288
nm; fluorescence (MeOH): λex = 288 nm, λem = 362 nm; IR (ATR) ν =
3367, 3055, 2920, 2851, 1663, 1607, 1560, 1492, 1457, 1409, 1370,
1315, 1253, 1206, 1191, 1165, 1127, 1059, 999, 953, 917, 872, 811, 771,
742, 702 cm−1; 1H NMR (600 MHz, acetone-d6): δ = 1.77 (s, 3 H), 2.00 (d,
J = 1.4 Hz, 3 H), 2.36 (s, 3 H), 7.16–7.28 (m, 5 H), 7.35 (ddd, J = 8.2, 7.0,
1.1 Hz, 1 H), 7.40 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H), 7.48 (dd, J = 7.9, 0.6
Hz, 1 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.84–7.86 (m, 1 H), 7.89 (d, J = 1.4
Hz, 1 H), 7.96 (s, 1 H), 8.08 (s, 1 H), 8.16 (d, J = 7.9 Hz, 2 H), 10.07 (br s,
1 H), 10.13 (br s, 1 H), 10.76 (br s, 1 H); 13C NMR and DEPT (150 MHz,
acetone-d6): δ = 16.65 (CH3), 15.97 (CH3), 17.54 (CH3), 105.61 (C),
110.27 (C), 111.79 (C), 112.32 (2 CH), 113.39 (CH), 113.95 (C), 119.45
(CH), 119.78 (CH), 119.88 (CH), 120.41 (CH), 120.69 (CH), 121.51 (C),
121.59 (CH), 121.75 (CH), 121.87 (CH), 122.58 (C), 123.53 (C), 123.90
(C), 123.98 (CH), 124.02 (2 C), 124.84 (C), 125.63 (C), 125.73 (CH),
126.16 (CH), 136.23 (C), 136.29 (CH), 136.77 (C), 136.89 (C), 137.85
(C), 141.81 (C), 141.93 (C), 146.64 (C), 149.43 (C), 193.20 (C=O); MS
(dec.); UV (MeOH): λ = 237, 276, 339 nm; fluorescence (MeOH) λex
=
339 nm, λem = 361 nm; IR (ATR): ν = 3390, 2920, 2837, 1666, 1605,
1582, 1555, 1505, 1458, 1435, 1406, 1334, 1263, 1200, 1168, 1096,
1064, 998, 951, 910, 881, 765, 725 cm−1; 1H NMR (500 MHz, CDCl3): δ =
1.94 (s, 3 H), 2.04 (d, J = 1.3 Hz, 3 H), 2.32 (s, 3 H), 4.01 (s, 3 H), 4.12 (s,
3 H), 4.14 (s, 3 H), 6.59 (d, J = 7.8 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H),
6.75 (d, J = 8.0 Hz, 1 H), 6.79 (d, J = 8.2 Hz, 1 H), 6.95 (d, J = 8.0 Hz, 1
H), 7.01 (d, J = 8.0 Hz, 1 H), 7.10 (t, J = 8.0 Hz, 1 H), 7.30 (t, J = 8.0 Hz,
1 H), 7.36 (t, J = 8.0 Hz, 1 H), 7.81 (s, 1 H), 7.94 (s, 1 H), 7.98 (d, J = 1.3
Hz, 1 H), 8.08 (s, 1 H), 8.22 (s, 1 H), 8.27 (s, 1 H); 13C NMR (125 MHz,
CDCl3): δ = 15.65 (CH3), 16.11 (CH3), 16.91 (CH3), 55.23 (CH3), 55.47
(CH3), 55.52 (CH3), 100.91 (2 CH), 101.31 (CH), 103.63 (C), 103.92 (CH),
104.06 (CH), 105.14 (CH), 110.02 (C), 110.26 (C), 112.28 (C), 112.67
(C), 112.99 (C), 113.92 (C), 121.00 (C), 121.25 (C), 123.90 (CH), 124.18
(C), 124.33 (C), 124.47 (CH), 124.52 (CH), 125.66 (C), 126.34 (CH),
127.01 (CH), 133.49 (C), 134.28 (C), 134.46 (C), 137.52 (C), 138.00
(CH), 141.40 (C), 141.50 (C), 145.29 (C), 146.69 (C), 154.93 (C), 156.00
(C), 156.04 (C), 191.34 (C); MS (ESI, +10 V): m/z = 676.4 [M+H]+; MS
(ESI, −50 V): m/z = 674.1 [M−H]−; HRMS (EI): m/z calcd for C42H33N3O6:
675.2369; found: 675.2362.
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10.1002/chem.201704554
Chemistry - A European Journal
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Crystallographic data for compound 21: C42H33N3O6, M = 675.71 g mol−1
crystal size 0.43 × 0.23 × 0.11 mm3, monoclinic, space group C2/c, a =
33.995(7), b = 11.140(2), c = 28.591(6) Å, β = 116.83(3) °, V = 9662(3)
Å3, Z = 8, ρcalcd = 0.929 g cm−3, μ = 0.063 mm−1, λ = 0.71073 Å, T =
,
with dichloromethane. The combined organic layers were washed with
brine, dried (MgSO4) and the solvent was removed. Purification of the
residue by column chromatography (silica gel; pentane/ethyl acetate,
gradient from 2:1 to 1:1) provided the tetrahydroxy-1,1′-bicarbazole 22
(4.4 mg, 10 µmol, 40%) as ochreous solid. M.p. 254.5–256 °C. UV
(MeOH): λ = 219 (sh), 236, 267, 284 (sh), 313, 321 nm; fluorescence
(MeOH): λex = 313 nm, λem = 387 nm; IR (ATR): ν = 3336, 2920, 2851,
2056, 1701, 1609, 1488, 1362, 1257, 1157, 1048, 1019, 955, 876, 803,
639 cm−1; 1H NMR (500 MHz, acetone-d6): δ = 2.42 (s, 6 H), 6.68 (dd, J =
8.4, 2.2 Hz, 2 H), 6.76 (s, 2 H), 7.17 (s, 2 H), 7.74 (s, 2 H), 7.78 (d, J =
8.4 Hz, 2 H), 8.07 (s, 2 H), 9.94 (s, 2 H); 13C NMR (125 MHz, acetone-
d6): δ = 17.35 (2 CH3), 97.62 (2 CH), 102.74 (2 C), 108.61 (2 CH), 117.44
(2 C), 117.63 (2 C), 117.86 (2 C), 120.06 (2 CH), 121.42 (2 CH), 139.76
(2 C), 142.39 (2 C), 151.90 (2 C), 156.00 (2 C); MS (ESI, +25 V): m/z =
425.4 [M+H]+.
198(2) K,
θ range = 3.08–25.40°, reflections collected 88289,
independent reflections 8877 (Rint = 0.0507), 475 parameters. The
structure was solved by direct methods and refined by full-matrix least-
squares on F2; final R indices [I > 2σ(I)] R1 = 0.0621 and wR2 = 0.1718;
maximal residual electron density 0.477 e Å−3. CCDC 1570474.
Biscarbalexine
bicarbazole) (3): Dichloromethane (5 mL) was added to a mixture of
hexadecafluorophthalocyanine–iron (6.39 mg, 7.46 µmol),
C (2,2′-dihydroxy-6,6′-dimethoxy-3,3′-dimethyl-1,1′-
methanesulfonic acid (2.44 mg, 25.3 µmol) and 2-hydroxy-6-methoxy-3-
methylcarbazole (carbalexine C) (17) (56.8 mg, 250 µmol) and the
suspension was stirred at room temperature for 80 min under air. The
mixture was filtered through
a
short pad of silica gel with
Biscarbalexine
bicarbazole) (5): Hexadecafluorophthalocyanine–iron (2.15 mg, 2.51
µmol) was added to solution of 2-hydroxy-8-methoxy-3-
B (2,2′-dihydroxy-8,8′-dimethoxy-3,3′-dimethyl-1,1′-
dichloromethane (40 mL). Removal of the solvent in vacuo provided the
1,1′-bicarbazole 3 (51.8 mg, 115 µmol, 92%) as light yellow solid. M.p
>180 °C (dec.); UV (MeOH): λ = 229, 260, 312 nm; fluorescence
(MeOH): λex = 312 nm, λem = 383 nm; IR (ATR): ν = 3517, 3494, 3402,
3312, 2965, 2937, 2909, 2830, 2050, 2030, 2007, 1970, 1632, 1483,
1461, 1433, 1329, 1293, 1205, 1177, 1113, 1053, 1023, 995, 954, 917,
a
methylcarbazole (carbalexin B) (20) (28.4 mg, 125 µmol) in acetic acid (5
mL) and the solution was stirred at room temperature for 30 min under air.
Then, argon was bubbled through the reaction mixture and most of the
acetic acid was removed in vacuo. Toluene (3 mL) was added to remove
the residual acetic acid as an azeotrope in vacuo. The residue was
dissolved in dichloromethane (10 mL), filtered through a short pad of
silica gel with dichloromethane (50 mL) and the solvent was removed in
vacuo. Purification of the residue by column chromatography (silica gel,
isohexane/ethyl acetate, 20%–50%) provided the 1,1′-bicarbazole 5 (15.2
mg, 33.6 µmol, 54%) as light yellow solid. M.p. >260 °C; UV (MeOH): λ =
873, 846, 792, 767, 730, 628 cm−1 1H NMR (500 MHz, DMSO-d6): δ =
;
2.42 (s, 6 H), 3.82 (s, 6 H), 6.80 (dd, J = 8.7, 2.5 Hz, 2 H), 7.18 (d, J =
8.7 Hz, 2 H), 7.54 (d, J = 2.5 Hz, 2 H), 7.87 (s, 2 H), 7.91 (s, 2 H), 9.75 (s,
2 H); 13C NMR (125 MHz, DMSO-d6): δ = 17.59 (2 CH3), 55.50 (2 CH3),
101.99 (2 CH), 103.75 (2 C), 111.32 (2 CH), 111.91 (2 CH), 115.41 (2 C),
116.49 (2 C), 120.86 (2 CH), 123.63 (2 C), 134.70 (2 C), 139.81 (2 C),
152.15 (2 C), 152.69 (2 C); MS (ESI, +10 V): m/z = 453.2 [M+H]+; MS
238 (sh), 254 (sh), 289 nm; fluorescence (MeOH): λex = 289 nm, λem
=
(ESI, −10 V): m/z
=
450.9 [M−H]−; HRMS (ESI): m/z calcd for
368 nm; IR (ATR): ν = 3386, 3064, 2998, 2969, 2939, 2916, 2846, 1728,
C28H24N2O4: 452.1736; found: 452.1733.
1627, 1611, 1575, 1502, 1450, 1384, 1339, 1296, 1256, 1207, 1144,
1085, 997, 922, 869, 807, 781, 728, 695, 653, 618 cm−1 1H NMR (500
;
MHz, DMSO-d6): δ = 2.43 (s, 6 H), 3.81 (s, 6 H), 6.82 (d, J = 7.8 Hz, 2 H),
7.03 (t, J = 7.8 Hz, 2 H), 7.60 (d, J = 7.8 Hz, 2 H), 7.86 (s, 2 H), 7.95 (s, 2
H), 9.31 (s, 2 H); 13C NMR (125 MHz, DMSO-d6): δ = 17.64 (2 CH3),
55.07 (2 CH3), 104.43 (2 C), 104.71 (2 CH), 111.62 (2 CH), 115.94 (2 C),
117.56 (2 C), 118.93 (2 CH), 120.82 (2 CH), 124.78 (2 C), 129.13 (2 C),
139.03 (2 C), 145.33 (2 C), 152.22 (2 C); MS (ESI, +10 V): m/z = 453.2
[M+H]+; MS (ESI, −50 V): m/z = 450.9 [M−H]−; HRMS (ESI): m/z calcd for
C28H24N2O4: 452.1736; found: 452.1727.
2,2′-Dihydroxy-7,7′-dimethoxy-3,3′-dimethyl-1,1′-bicarbazole
(4):
Hexadecafluorophthalocyanine–iron (3.21 mg, 3.75 µmol) was added to
a solution of 2-hydroxy-7-methoxy-3-methylcarbazole (19) (28.4 mg, 125
µmol) in acetic acid (4 mL) and the solution was stirred at room
temperature for 30 min under air. Subsequently, argon was bubbled
through the reaction mixture and the solvent was removed in vacuo.
Toluene (3 mL) was added to remove the residual acetic acid as an
azeotrope in vacuo. The residue was dissolved in dichloromethane (1
mL), filtered through a short pad of activated carbon on silica gel with
dichloromethane (20 mL) and the solvent was removed in vacuo.
Purification of the residue by column chromatography (silica gel,
isohexane/ethyl acetate, 30%–40%) provided the 1,1′-bicarbazole 4 (17.3
mg, 38.2 µmol, 61%) as colorless solid. M.p. 294.5–296 °C; UV (MeOH):
λ = 216 (sh), 237, 266, 312, 322 nm; fluorescence (MeOH): λex = 236 nm,
λem = 365 nm; IR (ATR): ν = 3414, 2922, 2853, 1610, 1501, 1472, 1446,
1403, 1376, 1321, 1252, 1193, 1156, 1127, 1031, 1018, 946, 883, 817,
Bisglybomine
B
(2,2′-dihydroxy-6,6′-dimethoxy-3,3′-dimethyl-5,5′-
bis(3-methylbut-2-enyl)-1,1′-bicarbazole) (6): Hexadecafluorophthalo-
cyanine–iron (2.11 mg, 2.46 µmol) was added to a solution of glybomine
B (18) (36.9 mg, 125 µmol) in acetic acid (2.5 mL) and the solution was
stirred at room temperature for 10 min under air. Subsequently, argon
was bubbled through the reaction mixture and most of the acetic acid
removed in vacuo. Toluene (3 mL) was added to remove the residual
acetic acid as an azeotrope in vacuo. The residue was dissolved in
dichloromethane (1 mL) and filtered through a short pad of silica gel with
dichloromethane (25 mL). Removal of the solvent in vacuo provided the
1,1′-bicarbazole 6 (23.1 mg, 39.2 µmol, 63%) as colorless solid. M.p.
740, 657, 631 cm−1 1H NMR (500 MHz, acetone-d6): δ = 2.43 (s, 6 H),
;
3.76 (s, 6 H), 6.75 (dd, J = 8.6, 2.3 Hz, 2 H), 6.85 (d, J = 2.2 Hz, 2 H),
7.26 (s, 2 H), 7.78 (s, 2 H), 7.86 (d, J = 8.5 Hz, 2 H), 9.47 (s, 2 H);
13C NMR and DEPT (125 MHz, acetone-d6): δ = 17.38 (2 CH3), 55.59 (2
CH3), 95.75 (2 CH), 102.87 (2 C), 108.10 (2 CH), 117.21 (2 C), 118.01 (2
C), 118.58 (2 C), 120.21 (2 CH), 121.66 (2 CH), 140.01 (2 C), 142.25 (2
C), 152.30 (2 C), 158.79 (2 C); MS (ESI, +25 V): m/z = 453.2 [M+H]+;
HRMS (ESI): m/z calcd for C28H24N2O4: 452.1736; found: 452.1726.
>250 °C (dec.); UV (MeOH):
λ = 218, 235, 261, 307, 340 nm;
fluorescence: λex = 307 nm, λem = 385 nm; IR (ATR): ν = 3267, 2985,
2962, 2909, 2850, 2826, 1725, 1607, 1491, 1449, 1391, 1304, 1285,
1252, 1220, 1179, 1133, 1101, 1083, 1026, 1012, 938, 872, 844, 800,
1
784, 725, 641 cm−1; H NMR (500 MHz, CDCl3): δ = 1.76 (d, J = 0.7 Hz,
6 H), 1.99 (s, 6 H), 2.51 (s, 6 H), 3.88 (s, 6 H), 3.98 (d, J = 6.1 Hz, 4 H),
5.25 (s, 2 H), 5.35–5.40 (m, 2 H), 6.97 (d, J = 8.7 Hz, 2 H), 7.03 (d, J =
8.6 Hz, 2 H), 7.49 (br s, 2 H), 8.02 (s, 2 H); 13C NMR (125 MHz, CDCl3):
δ = 16.90 (2 CH3), 18.30 (2 CH3), 25.62 (2 CH2), 25.83 (2 CH3), 57.84 (2
CH3), 98.59 (2 C), 108.12 (2 CH), 111.12 (2 CH), 117.21 (2 C), 117.28 (2
C), 122.34 (2 CH), 123.04 (2 C), 124.34 (2 C), 125.79 (2 CH), 132.54 (2
2,2′,7,7′-Tetrahydroxy-3,3′-dimethyl-1,1′-bicarbazole
(22):
Boron
tribromide (1 M in CH2Cl2, 104 µL, 104 µmol) was added at −78 °C to a
solution of 1,1′-bicarbazole 4 (11.7 mg, 25.9 µmol) in dichloromethane (4
mL) and the solution was stirred at −78 °C for 2 h, at 0 °C for 4 h and at
room temperature for 44 h. Methanol (2 mL) and water were added, the
layers were separated and the aqueous layer was extracted four times
This article is protected by copyright. All rights reserved.

10.1002/chem.201704554
Chemistry - A European Journal
FULL PAPER
C), 134.82 (2 C), 138.90 (2 C), 150.89 (2 C), 151.15 (2 C); MS (ESI, +10
V): m/z = 589.6 [M+H]+, 1177.0 [2M+H]+; MS (ESI, −50 V): m/z = 587.4
[M−H]−; HRMS (ESI): m/z calcd for C38H40N2O4: 588.299; found: 588.295.
short pad of activated carbon on silica gel with isohexane/ethyl acetate
(2:1, 15 mL). Removal of the solvent in vacuo provided 8,8″-biskoenigine
(9) (34.8 mg, 56.4 µmol, 90%) as brown solid. M.p. 240–242 °C; UV
(MeOH): λ = 225, 301, 344 nm; fluorescence (MeOH): λex = 301 nm, λem
= 382 nm; IR (ATR): ν = 3357, 2971, 2931, 1723, 1641, 1610, 1492,
1455, 1419, 1373, 1358, 1282, 1251, 1199, 1126, 1053, 1023, 979, 943,
Bispyrayafoline
C
(9,9'-Dihydroxy-3,3,3′,3′,8,8′-hexamethyl-
(7):
3,3′,11,11′-tetrahydro-10,10′-bipyrano[3,2-a]carbazole)
1
888, 835, 774, 728, 663, 623 cm−1; H NMR (500 MHz, acetone-d6): δ =
Hexadecafluorophthalocyanine–iron (1.06 mg, 1.24 µmol) was added to
a solution of pyrayafoline C (23) (34.9 mg, 125 µmol) in acetic acid (2.5
mL) and the solution was stirred at room temperature for 10 min under air.
Then, argon was bubbled through the reaction mixture and most of the
acetic acid was removed in vacuo. Toluene (3 mL) was added to remove
the residual acetic acid as an azeotrope in vacuo. The residue was
dissolved in dichloromethane (1 mL) and filtered through a short pad of
activated carbon on silica gel with dichloromethane (50 mL). Removal of
the solvent in vacuo provided the bipyrano[3,2-a]carbazole 7 (32.4 mg,
58.2 µmol, 93%) as colorless solid. M.p. >205 °C (dec.); UV (MeOH): λ =
221, 239, 283 (sh), 294, 333 nm; fluorescence (MeOH): λex = 294 nm,
λem = 368 nm; IR (ATR): ν = 3426, 2973, 2920, 2853, 1723, 1699, 1622,
1587, 1446, 1419, 1372, 1321, 1257, 1188, 1168, 1153, 1131, 1116,
1.390 (s, 6 H), 1.393 (s, 6 H), 2.29 (s, 6 H), 4.01 (s, 6 H), 5.54 (d, J = 9.9
Hz, 2 H), 6.72 (d, J = 9.8 Hz, 2 H), 7.23 (s, 2 H), 7.60 (s, 2 H), 7.64 (s, 2
H), 9.55 (br s, 2 H); 13C NMR (125 MHz, acetone-d6): δ = 16.29 (2 CH3),
27.59 (2 CH3), 27.87 (2 CH3), 57.06 (2 CH3), 75.97 (2 C), 102.28 (2 CH),
104.92 (2 C), 105.66 (2 C), 115.38 (2 C), 117.45 (2 C), 118.79 (2 C),
119.21 (2 CH), 120.46 (2 CH), 129.18 (2 CH), 135.89 (2 C), 136.06 (2 C),
143.56 (2 C), 144.44 (2 C), 148.97 (2 C); MS (ESI, +25 V): m/z = 617.4
[M+H]+; MS (ESI, −50 V): m/z = 615.2 [M−H]−; MS (EI): m/z = 616 (100)
[M]+, 601 (66), 293 (18); HRMS (EI): m/z calcd for C38H36N2O6: 616.2573;
found: 616.2563.
Decacyclic coupling product (26): Hexadecafluorophthalocyanine–iron
(1.09 mg, 1.25 µmol) was added to a solution of koenigine (25) (38.7 mg,
125 µmol) in acetic acid (5 mL) and the solution was stirred at room
temperature for 3 h under air. Subsequently, argon was bubbled through
the reaction mixture and most of the acetic acid was removed in vacuo.
Toluene (3 mL) was added to remove the residual acetic acid as an
azeotrope in vacuo. The residue was dissolved in ethyl acetate (1 mL),
filtered through a short pad of activated carbon on silica gel with ethyl
acetate (10 mL) and the solvent was removed in vacuo. Purification of
the residue by column chromatography (silica gel, isohexane/ethyl
acetate, 20–45%) provided the decacyclic coupling product 26 (19.6 mg,
31.8 µmol, 51%) as light brown solid. M.p. 154 °C; UV (MeOH): λ = 237,
313 nm; fluorescence (MeOH): λex = 237 nm, λem = 363 nm; IR (ATR): ν
= 3349, 2965, 2924, 2850, 2056, 1757, 1691, 1640, 1451, 1433, 1322,
1
1039, 1000, 944, 897, 849, 804, 778, 719, 693, 633 cm−1; H NMR (500
MHz, DMSO-d6): δ = 1.35 (s, 12 H), 2.39 (s, 6 H), 5.58 (d, J = 9.9 Hz, 2
H), 6.54 (d, J = 8.3 Hz, 2 H), 7.07 (d, J = 9.9 Hz, 2 H), 7.62 (s, 2 H), 7.69
(d, J = 8.3 Hz, 2 H), 7.74 (s, 2 H), 9.97 (s, 2 H); 13C NMR (125 MHz,
DMSO-d6): δ = 17.62 (2 CH3), 27.10 (2 CH3), 27.30 (2 CH3), 75.01 (2 C),
104.28 (2 C), 104.72 (2 C), 107.78 (2 CH), 115.80 (2 C), 116.77 (2 C),
118.15 (2 C), 118.60 (2 CH), 118.94 (2 CH), 119.85 (2 CH), 128.04 (2
CH), 136.29 (2 C), 139.66 (2 C), 149.31 (2 C), 151.48 (2 C); MS (ESI,
+10 V): m/z = 557.4 [M+H]+; MS (ESI, −10 V): 555.1 [M−H]−; elemental
analysis (%) calcd for C36H32N2O4: C 77.68, H 5.79, N 5.03; found: C
77.48, H 5.63, N 5.02.
Bisisomahanine (8): Hexadecafluorophthalocyanine–iron (1.08 mg, 1.26
µmol) was added to a solution of pyrayafoline D (24) (43.4 mg, 125 µmol)
in acetic acid (4 mL) and the solution was stirred at room temperature for
20 min under air. Then, argon was bubbled through the reaction mixture
and most of the acetic acid was removed in vacuo. Toluene (3 mL) was
added to remove the residual acetic acid as an azeotrope in vacuo. The
residue was dissolved in dichloromethane (1 mL) and filtered through a
short pad of activated carbon on silica gel with dichloromethane (40 mL).
Removal of the solvent in vacuo provided bisisomahanine (8) (40.4 mg,
58.3 µmol, 93%) as yellow solid. M.p. 130–140 °C. UV (MeOH): λ = 224,
239, 287 (sh), 296, 332, 354 (sh) nm; fluorescence (MeOH): λex = 296
nm, λem = 421 nm; UV (CHCl3): λ = 239, 288 (sh), 298, 332 nm;
fluorescence (CHCl3): λex = 298 nm, λem = 427 nm; IR (ATR): ν = 3532,
3465, 3339, 3031, 2967, 2917, 2850, 1741, 1636, 1612, 1588, 1473,
1446, 1417, 1374, 1319, 1298, 1257, 1179, 1131, 1083, 1041, 907, 875,
846, 804, 780, 724, 636 cm−1; 1H NMR (500 MHz, CDCl3): δ = 1.39 (s, 6
H), 1.54 (s, 3 H), 1.55 (s, 3 H), 1.63 (s, 3 H), 1.64 (s, 3 H), 1.65–1.77 (m,
4 H), 2.06–2.15 (m, 4 H), 2.49 (s, 6 H), 5.03–5.09 (m, 2 H), 5.10 (s, 2 H),
5.55 (d, J = 9.9 Hz, 2 H), 6.44 (d, J = 9.8 Hz, 2 H), 6.74 (d, J = 8.4 Hz, 2
H), 7.46 (s, 2 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.85 (s, 2 H); 13C NMR (125
MHz, CDCl3): δ = 16.69 (2 CH3), 17.61 (2 CH3), 22.69 (2 CH2), 25.64 (2
CH3), 25.87 (2 CH3), 40.74 (2 CH2), 78.24 (2 C), 98.94 (2 C), 104.94 (2
C), 109.91 (2 CH), 117.36 (2 CH), 117.74 (4 C), 117.91 (2 C), 119.45 (2
CH), 122.32 (2 CH), 124.07 (2 CH), 128.81 (2 CH), 131.70 (2 C), 135.97
(2 C), 137.74 (2 C), 150.27 (2 C), 151.09 (2 C); MS (ESI, +25 V): m/z =
693.7 [M+H]+; MS (ESI, −75 V): m/z = 691.6 [M–H]–; elemental analysis
(%) calcd for C46H48N2O4: C 79.74, H 6.98, N: 4.04; found: C 79.46, H:
7.29, N: 3.69.
1
1276, 1202, 1178, 1129, 1084, 1033, 868, 845, 777, 725 cm−1; H NMR
(600 MHz, acetone-d6): 0.86 (s, 3 H), 1.25 (s, 3 H), 1.33 (s, 3 H), 1.72 (s,
3 H), 1.86 (d, J = 0.6 Hz, 3 H), 2.19 (s, 3 H), 3.38 (dd, J = 11.0, 5.0 Hz, 1
H), 3.62 (d, J = 11.0 Hz, 1 H), 3.69 (dd, J = 4.9, 1.3 Hz, 1 H), 3.79 (s, 3
H), 3.97 (s, 3 H), 5.57 (d, J = 9.8 Hz, 1 H), 6.17 (s, 1 H), 6.49 (s, 1 H),
6.53 (d, J = 9.8 Hz, 1 H), 7.31 (s, 1 H), 7.50 (s, 1 H), 7.67 (s, 1 H), 7.83 (s,
1 H), 10.04 (br s, 1 H); 13C NMR (150 MHz, acetone-d6): 15.40 (CH3),
16.22 (CH3), 26.60 (CH3), 27.67 (CH3), 27.81 (CH3), 32.75 (CH3), 32.82
(CH), 50.08 (CH), 50.12 (CH), 53.48 (CH3), 57.25 (CH3), 59.47 (CH),
76.05 (C), 82.79 (C), 88.05 (C), 101.12 (CH), 104.78 (C), 105.14 (CH),
109.58 (C), 110.78 (C), 117.92 (CH), 118.71 (C), 119.08 (CH), 119.85
(C), 120.33 (C), 120.39 (C), 120.80 (C), 122.93 (CH), 129.59 (CH),
132.43 (C), 133.01 (C), 139.90 (C), 141.51 (C), 144.30 (C), 146.71 (C),
147.50 (C), 151.37 (C), 200.90 (C=O); MS (ESI, −10 V): m/z = 614.9
[M−H]−; HRMS (ESI): m/z calcd for C38H36N2O6: 616.2573; found:
616.2558.
Crystallographic data for compound 26: The crystals were obtained from
acetone-d6 as thin weakly diffracting needles. C38H36N2O6, M = 616.69
g mol−1, crystal size 0.68 × 0.06 × 0.04 mm3, triclinic, space group P-1, a
= 11.052(4), b = 26.160(10), c = 29.125(12) Å, α = 101.418(12)°, β =
98.247(6)°, γ = 94.891(7)°, V = 8113(5) Å3, Z = 8, ρcalcd = 1.010 g cm−3
(solvent molecules not taken into account) μ = 0.068 mm−1, λ = 0.71073
Å, T = 120(2) K, θ range = 1.60–23.53°, reflections collected 59288,
independent reflections 23818 (Rint = 0.1971), 774 parameters. The
structure was solved by direct methods and refined by full-matrix least-
squares on F2; final R indices [I > 2σ(I)] R1 = 0.1123 and wR2 = 0.2475.
CCDC 1570475.
8,8″-Biskoenigine (9): Hexadecafluorophthalocyanine–iron (1.07 mg,
1.25 µmol) was added to a solution of koenigine (25) (38.7 mg, 125
µmol) in dichloromethane (1 mL) and the solution was stirred at room
temperature for 20 min under air. The mixture was filtered through a
O,O′-Diacetyl-8,8″-biskoenigine
3,3,3′,3′,5,5′-hexamethyl-3,3′,11,11′-tetrahydro-10,10′-bipyrano[3,2-
a]carbazole) (27): Triethylamine (0.31 mL, 2.2 mmol), acetic anhydride
(9,9′-diacetoxy-8,8′-dimethoxy-
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10.1002/chem.201704554
Chemistry - A European Journal
FULL PAPER
(0.16 mL, 1.7 mmol) and catalytic amounts of DMAP were added
sequentially to a solution of 8,8″-biskoenigine (9) (343 mg, 0.556 mmol)
in THF (38 mL) and the mixture was stirred at room temperature for 2 h.
The mixture was diluted with diethyl ether and extracted with a saturated
aqueous solution of ammonium chloride. The aqueous layer was
extracted with diethyl ether, the combined organic layers were dried
(magnesium sulfate) and the solvent was evaporated. Purification of the
residue by column chromatography (silica gel; isohexane/ethyl acetate,
3:1) provided the diacetate 27 (363 mg, 0.518 mmol, 93%) as light brown
solid. M.p. 173–174 °C; UV (MeOH): λ = 234, 287 (sh), 298, 338, 355
(sh) nm; fluorescence (MeOH): λex = 298 nm, λem = 392 nm; IR (ATR): ν
= 3409, 2971, 1754, 1642, 1475, 1418, 1366, 1289, 1216, 1165, 1129,
1028, 981, 894, 776, 728 cm−1; 1H NMR (500 MHz, CDCl3): δ = 1.38 (s, 6
H), 1.47 (s, 6 H), 1.97 (s, 6 H), 2.33 (s, 6 H), 4.01 (s, 6 H), 5.57 (d, J =
9.8 Hz, 2 H), 6.51 (d, J = 9.8 Hz, 2 H), 7.60 (s, 2 H), 7.64 (s, 2 H), 7.99
(br s, 2 H); 13C NMR (125 MHz, CDCl3): δ = 16.12 (2 CH3), 20.55 (2 CH3),
27.25 (2 CH3), 27.90 (2 CH3), 56.73 (2 CH3), 75.93 (2 C), 102.80 (2 CH),
104.89 (2 C), 109.93 (2 C), 116.42 (2 C), 117.37 (2 CH), 118.66 (2 C),
120.54 (2 CH), 121.02 (2 C), 129.09 (2 CH), 132.96 (2 C), 135.42 (2 C),
sodium thiosulfate was added and the mixture was extracted twice with
ethyl acetate. The combined organic layers were dried (magnesium
sulfate) and the solvent was evaporated. Purification of the residue by
column chromatography (silica gel; isohexane/ethyl acetate, gradient
15:1 to 10:1) provided bismurrayafoline B (11) (37.6 mg, 63.9 µmol, 76%)
as as brown solid. M.p. 123 °C; UV (MeOH): λ = 233, 251 (sh), 259, 303,
322 (sh), 335 (sh) nm; fluorescence (MeOH): λex = 303 nm, λem = 369
nm; IR (ATR): ν = 3511, 3448, 3408, 2952, 2914, 2853, 2826, 1725,
1696, 1619, 1565, 1474, 1444, 1372, 1326, 1219, 1171, 1081, 1041, 968,
1
847, 792 cm−1; H NMR (500 MHz, CDCl3): δ = 1.74 (s, 6 H), 1.90 (s, 6
H), 2.16 (s, 6 H), 3.66 (d, J = 6.7 Hz, 4 H), 3.95 (s, 6 H), 4.97 (br s, 2 H),
5.34 (m, 2 H), 6.91 (d, J = 8.6 Hz, 2 H), 7.59 (s, 2 H), 7.85 (d, J = 8.5 Hz,
2 H), 8.06 (br s, 2 H); 13C NMR and DEPT (125 MHz, CDCl3): δ = 18.14
(2 CH3), 20.12 (2 CH3), 24.09 (2 CH2), 25.87 (2 CH3), 56.79 (2 CH3),
105.12 (2 CH), 111.64 (2 C), 113.33 (2 CH), 114.74 (2 C), 117.92 (2 C),
118.55 (2 CH), 122.39 (2 CH), 126.00 (2 C), 127.14 (2 C), 129.34 (2 C),
133.12 (2 C), 139.52 (2 C), 140.75 (2 C), 155.94 (2 C); MS (ESI, +25 V):
m/z = 589.9 [M+H]+; MS (ESI, −75 V): 587.5 [M−H]−; HRMS (ESI): m/z
calcd for C38H40N2O4: 588.2988; found: 588.2977.
1
136.33 (2 C), 145.77 (2 C), 149.77 (2 C) 171.16 (2 C=O); H NMR (500
MHz, DMSO-d6): δ = 1.36 (s, 6 H), 1.37 (s, 6 H), 1.85 (s, 6 H), 2.26 (s, 6
H), 3.89 (s, 6 H), 5.58 (d, J = 9.9 Hz, 2 H), 6.95 (d, J = 10.0 Hz, 2 H),
7.78 (s, 2 H), 7.80 (s, 2 H), 10.10 (s, 2 H); 13C NMR (125 MHz, DMSO-
d6): δ = 16.00 (2 CH3), 20.22 (2 CH3), 27.34 (4 CH3), 56.25 (2 CH3),
75.30 (2 C), 102.61 (2 CH), 104.63 (2 C), 110.25 (2 C), 116.56 (2 C),
116.63 (2 C), 118.78 (2 CH), 119.99 (2 C), 120.56 (2 CH), 127.95 (2 CH),
133.54 (2 C), 135.70 (2 C), 136.29 (2 C), 145.24 (2 C), 148.62 (2 C),
167.97 (2 C=O); MS (ESI, +25 V): m/z = 701.6 [M+H]+; MS (ESI, −25 V):
m/z = 699.3 [M−H]−; MS (EI): m/z = 700 (77) [M]+, 658 (100), 643 (24),
616 (62), 601 (55), 293 (40); HRMS (EI): m/z calcd for C42H40N2O8:
700.2785; found: 700.2771.
1-Hydroxy-7-methoxy-3-methyl-8-(3,7-dimethylocta-2,6-dien-1-yl)-
carbazole (murrayafoline D) (31): Lithium aluminum hydride (138.2 mg,
3.64 mmol) was added at room temperature to a solution of carbazolyl
tosylate 30 (ratio of E/Z = 1.4:1; 268.8 mg, 519 µmol)85 in THF (30 mL)
and the mixture was heated at reflux for 23 h. After cooling to 0 °C, a
saturated aqueous solution of potassium sodium tartrate was added and
the mixture was extracted twice with ethyl acetate. The combined organic
layers were dried (MgSO4) and the solvent was evaporated. Purification
of the residue by column chromatography (silica gel, isohexane/ethyl
acetate, 10:1) provided the 1-hydroxycarbazole 31 (84.4 mg, 232 µmol,
45%; light brown, highly viscous oil) as a mixture of diastereoisomers
(ratio of E/Z = 1.4:1). UV (MeOH): λ = 231, 246, 256, 301 nm;
fluorescence (MeOH): λex = 231 nm, λem = 368 nm; IR (ATR): ν = 3366,
2959, 2915, 2853, 1620, 1590, 1512, 1491, 1448, 1417, 1374, 1350,
The atropisomers of compound 27 were separated by chiral HPLC (72%
20
eluent B, isocratic). Isomer 1: [α]D −301 (c = 0.073, CHCl3); m.p. 170–
171 °C. Isomer 2: [α]D20 +304 (c = 0.070, CHCl3); m.p. 174–175 °C.
1325, 1253, 1220, 1173, 1083, 975, 874, 830, 791 cm−1 1H NMR (600
;
MHz, CDCl3): 1.55 (E, s) and 1.65 (Z, s, 3 H), 1.60 (E, d, J = 0.9 Hz) and
1.70 (Z, d, J = 0.8 Hz, 3 H), 1.74 (Z, d, J = 1.2 Hz) and 1.89 (E, d, J = 0.5
Hz, 3 H), 2.01–2.07 (E, m) and 2.31–2.36 (Z, m, 2 H), 2.07–2.13 (E, m)
and 2.17–2.24 (Z, m, 2 H), 2.44 (s, 3 H), 3.64 (d, J = 6.8 Hz, 2 H), 3.906
(Z, s) and 3.912 (E, s, 3 H), 4.86 (br. s, 1 H), 5.04–5.09 (E, m) and 5.21–
5.25 (Z, m, 1 H), 5.30–5.36 (m, 1 H), 6.57 (s, 1 H), 6.84 (Z, d, J = 8.5 Hz)
and 6.85 (E, d, J = 8.5 Hz, 1 H), 7.36 (s, 1 H), 7.768 (Z, d, J = 8.5 Hz)
and 7.771 (E, d, J = 8.5 Hz, 1 H), 7.96 (Z, s) and 7.97 (E, s, 1 H); 13C
NMR (150 MHz, CDCl3): 16.34 (E) and 23.34 (Z, CH3), 17.65 (E) and
17.71 (Z, CH3), 21.45 (CH3), 23.62 and 23.86 (CH2), 25.60 (E) and 25.72
(Z, CH3), 26.49 (E) and 26.68 (Z, CH2), 32.18 (Z) and 39.71 (E, CH2),
56.61 (Z) and 56.70 (E, CH3), 104.69 (Z) and 104.78 (E, CH), 111.32 and
111.35 (CH), 111.40 and 111.43 (C), 112.49 (CH), 118.03 (C), 118.33
(E) and 118.35 (Z, CH), 122.22 (E) and 122.91 (Z, CH), 124.12 (E) and
124.17 (Z, CH), 125.87 and 125.90 (C), 127.25 (C), 129.42 and 129.43
(C), 131.58 and 132.0 (C), 136.56 and 136.77 (C), 140.40 and 140.41
(C), 140.52 and 140.60 (C), 155.51 and 155.56 (C); MS (ESI, +10 V): m/z
= 364.2 [M+H]+, 727.5 [2M+H]+; MS (ESI, −50 V): m/z = 361.9 [M−H]-,
725.1 [2M−H]−; HRMS (ESI): m/z calcd for C24H29NO2: 363.2198; found:
363.2192.
1,1′-Dihydroxy-6,6′-dimethoxy-3,3′-dimethyl-2,2′-bicarbazole
(bisclausenol) (10): Di-tert-butyl peroxide (0.06 mL, 0.05 g, 0.3 mmol)
was added to
a solution of clausenol (1-hydroxy-6-methoxy-3-
methylcarbazole) (28) (51.6 mg, 0.227 mmol) in chlorobenzene (5 mL)
and the mixture was heated at reflux for 2 h. After cooling to room
temperature, the solvent was evaporated and the residue was purified by
column chromatography (silica gel; hexane/ethyl acetate, 2:1) to provide
bisclausenol (10) (47.9 mg, 0.106 mmol, 93%) as light yellow crystals.
M.p. >250 °C (dec.); UV (EtOH): λ = 228, 254, 293 (sh), 303, 342, 357
nm; fluorescence (EtOH): λex = 303 nm; λem = 388 nm; IR (ATR): ν =
3403, 3349, 2920, 2830, 2508, 1686, 1621, 1562, 1542, 1522, 1492,
1474, 1459, 1436, 1384, 1338, 1297, 1260, 1206, 1150, 1089, 1057,
1014, 987, 953, 866, 835, 806, 778, 765 cm−1 1H NMR (500 MHz,
;
acetone-d6): δ = 2.09 (s, 6 H), 3.91 (s, 6 H), 7.04 (dd, J = 8.7, 2.5 Hz, 2
H), 7.45 (s, 2 H), 7.48 (d, J = 8.7 Hz, 2 H), 7.56 (s, 2 H), 7.63 (d, J = 2.4
Hz, 2 H), 9.94 (s, 2 H); 13C NMR and DEPT (125 MHz, acetone-d6): δ =
20.56 (2 CH3), 56.05 (2 CH3), 103.34 (2 CH), 112.72 (2 CH), 113.33 (2
CH), 115.50 (2 CH), 118.69 (2 C), 124.69 (2 C), 125.03 (2 C), 129.16 (2
C), 130.20 (2 C), 135.96 (2 C), 141.92 (2 C), 154.57 (2 C); MS (ESI, +25
V): m/z = 453.2 [M+H]+; 927.4 [2M+Na]+; MS (ESI, −50 V): m/z = 451.0
[M−H]−; 903.1 [2M−H]−; HRMS (ESI): m/z calcd for C28H24N2O4:
452.1736; found: 452.1732.
1,1′-Dihydroxy-7,7′-dimethoxy-3,3′-dimethyl-8,8′-bis(3,7-
dimethylocta-2,6-dien-1-yl)-2,2′-bicarbazole (bismurrayafoline D)
(12): Lithium aluminum hydride (2.4 M in THF, 0.6 mL, 1.4 mmol) was
added at room temperature to a solution of carbazolyl tosylate 30 (ratio of
E/Z = 1.3:1; 83.9 mg, 0.162 mmol)85 in THF (10 mL) and the mixture was
heated at reflux for 16 h. After cooling to 0 °C, a saturated aqueous
solution of potassium sodium tartrate was added and the mixture was
extracted with twice ethyl acetate. The combined organic layers were
Bismurrayafoline
8,8′-bis(3-methylbut-2-en-1-yl)-2,2′-bicarbazole) (11):
B
(1,1′-dihydroxy-7,7′-dimethoxy-3,3′-dimethyl-
mixture of
A
murrayafoline-B (29) (50.0 mg, 0.170 mmol), di-tert-butyl peroxide (37.0
mg, 0.253 mmol) and chlorobenzene (15 mL) was heated at reflux for 2 h.
After cooling to room temperature, a saturated aqueous solution of
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10.1002/chem.201704554
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dried (MgSO4) and the solvent was evaporated. Highly polar compounds
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,
were removed by filtration through
a short plug of silica gel
(isohexane/ethyl acetate, 15:1) to provide the 1-hydroxycarbazole 31
(58.8 mg, 0.162 mmol). A mixture of the 1-hydroxycarbazole 31 (36.0 mg,
99.2 µmol), di-tert-butyl peroxide (22.0 mg, 0.151 mmol) and
chlorobenzene (7 mL) was heated at reflux for 90 min. A further portion
of di-tert-butyl peroxide (20.0 mg, 0.137 mmol) was added and the
mixture was heated at reflux for further 105 min. After cooling to room
temperature, a saturated aqueous solution of sodium thiosulfate was
added and the mixture was extracted with twice ethyl acetate. The
combined organic layers were dried (magnesium sulfate) and the solvent
was evaporated. Purification of the residue by column chromatography
(silica gel, isohexane/ethyl acetate, gradient 15:1 to 10:1) provided the
2,2′-bicarbazole 12 (35.8 mg, 49.4 µmol, 99%; light yellow, highly viscous
oil) as a mixture of diastereoisomers. UV (MeOH): λ = 232, 251 (sh), 259,
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305, 321 (sh), 335 (sh) nm; fluorescence (MeOH): λex = 305 nm, λem
=
369 nm; IR (ATR): ν = 3511, 3435, 3411, 2959, 2916, 2846, 1726, 1641,
1620, 1566, 1484, 1473, 1444, 1373, 1328, 1236, 1175, 1084, 968, 848,
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1.59 (E, s) and 1.68 (Z, s, 6 H), 1.74 (Z, d, J = 1.1 Hz) and 1.89 (E, s, 6
H), 2.01–2.12 (E, m, 8 H) and 2.17–2.24 (Z, m, 4 H) and 2.31–2.36 (Z, m,
4 H), 2.14 (E, s) and 2.15 (Z, s, 6 H), 3.67 (d, J = 6.8 Hz, 4 H), 3.938 (Z,
s) and 3.942 (E, s, 6 H), 5.06 (E, m) and 5.22 (Z, m, 2 H), 5.36 (t, J = 6.8
Hz, 2 H), 6.89 (Z, d, J = 8.6 Hz) and 6.90 (E, d, J = 8.5 Hz, 2 H), 7.58 (s,
2 H), 7.842 (Z, d, J = 8.4 Hz) and 7.844 (E, d, J = 8.5 Hz, 2 H) 8.08 (br s,
2 H); 13C NMR (150 MHz, CDCl3): 16.32 (E) and 23.35 (Z, 2 CH3), 17.63
and 17.69 (2 CH3), 19.92 and 19.94 (2 CH3), 23.64 and 23.88 (2 CH2),
25.58 and 25.70 (2 CH3), 26.47 and 26.64 (2 CH2), 32.18 (Z) and 39.72
(E, 2 CH2), 56.58 and 56.66 (2 CH3), 104.91 and 105.00 (2 CH), 111.48
and 111.52 (2 C), 113.13 (2 CH), 114.59 (2 C), 117.79 (2 C), 118.38 (2
CH), 122.15 and 122.85 (2 CH), 124.08 and 124.11 (2 CH), 125.79 and
125.81 (2 C), 127.01 (2 C), 129.17 (2 C), 131.52 and 132.00 (2 C),
136.69 and 136.91 (2 C), 139.40 (2 C), 140.61 and 140.69 (2 C), 155.76
and 155.81 (2 C); MS (ESI, +25 V): 725.7 [M+H]+; MS (ESI, −10 V):
723.3 [M−H]−, 1447.3 [2M−H]−; HRMS (ESI): m/z calcd for C48H56N2O4:
724.4240; found: 724.4228.
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We would like to thank the International Union of Pure and
Applied Chemistry (IUPAC) for the financial support of our
project “Green and Sustainable Catalysts for Synthesis of
Organic Building Blocks” (DFG grant KN 240/19-1). We are
grateful to Anne Jäger, Gabriele Theumer and Adrian Kishonti
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Entry for the Table of Contents
FULL PAPER
Christian Brütting, Raphael F. Fritsche,
Sebastian K. Kutz, Carsten Börger,
Arndt W. Schmidt, Olga Kataeva and
Hans-Joachim Knölker*
Page No. – Page No.
Synthesis of 1,1′- and 2,2′-
The iron-catalysed oxidative homo-coupling of hydroxycarbazoles to bicarbazoles
using hexadecafluorophthalocyanine–iron in the presence of air has been
investigated and compared to other methods for biaryl coupling.
Bicarbazole Alkaloids by Iron(III)-
Catalyzed Oxidative Coupling of 2-
and 1-Hydroxycarbazoles
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